Exploring nickel- and iron- catalyzed cycloaddition routes to N- heterocycles

Transition metal catalyzed [2+2+2] cycloaddition reactions are an important class of reactions that provide the means for the rapid construction of various carbocyclic and heterocyclic compounds. Over the past several years, our efforts have been focused on exploring metal catalyzed cycloaddition reactions to find new methods and improve existing methods to access heterocyclic core structures such as pyridines, pyridones and pyrimidones. Enynes and isocyanates in the presence of a nickel-based catalyst system undergoes cycloaddition affording E- and the Z-dienamides in moderate to good yields with the Edienamide being the major product. The substrate scope with respect to isocyanate and enyne structures was also determined. It was observed that aryl as well as alkyl isocyanates undergo this cycloaddition reaction. Internal enynes afforded the dienamide products while terminal enynes afforded lactams. A new catalytic system involving iron acetate and a sterically hindered bis(aldimino)pyridyl ligand was also developed. This Fe-complex catalyzed the cycloaddition reaction of alkynenitriles and alkynes to afford pyridines in moderate to good yields. Symmetrical and unsymmetrical exogenous alkynes can be used in this cycloaddition reaction. Alkyl, aryl, and terminal alkynenitrile afford good yields of the pyridine products. Five- and six-membered fused pyridines can be synthesized in good yields by this methodology. The synthesis of 2-aminopyridines by the cycloaddition reaction of diynes and cyanamides in the presence of an iron catalyst system has also been studied. The Fecatalytic system is a combination of iron chloride and a bis(aldimino)pyridyl ligand and it leads to good to excellent yields of desired product. Five- and six-membered fused 2-aminopyridines were prepared in good yields by utilizing this methodology. Various Nalkyl- alkyl, N-aryl-aryl, and N-alkyl-aryl cyanamides undergo this cycloaddition reaction with diynes to afford 2-aminopyridines in good yields.

EXPLORING NICKEL- AND IRON- CATALYZED CYCLOADDITION ROUTES TO N- HETEROCYCLES by Brendan Roberto D'Souza A dissertation submitted to the faculty of The University of Utah in partial fulfillment of the requirement for the degree of Doctor of Philosophy Department of Chemistry The University of Utah May 2012 Copy right © Brendan Roberto D'Souza 2012 All Rights Reserved Th e Un i v e r s i t y o f Ut a h Gr a d u a t e S c h o o l STATEMENT OF DISSERTATION APPROVAL The dissertation of Brendan Roberto D'Souza has been approved by the following supervisory committee members: Janis Louie , Chair 07-08-2011 Date Approved Gary Keck , Member 07-08-2011 Date Approved Joel S. Miller , Member 07-08-2011 Date Approved Matthew S. Sigman , Member 07-08-2011 Date Approved Kuberan Balagurunathan , Member 07-08-2011 Date Approved and by Henry S. White , Chair of the Department of Chemistry and by Charles A. Wight, Dean of The Graduate School. ABSTRACT Transition metal catalyzed [2+2+2] cycloaddition reactions are an important class of reactions that provide the means for the rapid construction of various carbocyclic and heterocyclic compounds. Over the past several years, our efforts have been focused on exploring metal catalyzed cycloaddition reactions to find new methods and improve existing methods to access heterocyclic core structures such as pyridines, pyridones and pyrimidones. Enynes and isocyanates in the presence of a nickel-based catalyst system undergoes cycloaddition affording E- and the Z-dienamides in moderate to good yields with the E-dienamide being the major product. The substrate scope with respect to isocyanate and enyne structures was also determined. It was observed that aryl as well as alkyl isocyanates undergo this cycloaddition reaction. Internal enynes afforded the dienamide products while terminal enynes afforded lactams. A new catalytic system involving iron acetate and a sterically hindered bis(aldimino)pyridyl ligand was also developed. This Fe-complex catalyzed the cycloaddition reaction of alkynenitriles and alkynes to afford pyridines in moderate to good yields. Symmetrical and unsymmetrical exogenous alkynes can be used in this cycloaddition reaction. Alkyl, aryl, and terminal alkynenitrile afford good yields of the iv pyridine products. Five- and six-membered fused pyridines can be synthesized in good yields by this methodology. The synthesis of 2-aminopyridines by the cycloaddition reaction of diynes and cyanamides in the presence of an iron catalyst system has also been studied. The Fe-catalytic system is a combination of iron chloride and a bis(aldimino)pyridyl ligand and it leads to good to excellent yields of desired product. Five- and six-membered fused 2- aminopyridines were prepared in good yields by utilizing this methodology. Various N-alkyl- alkyl, N-aryl-aryl, and N-alkyl-aryl cyanamides undergo this cycloaddition reaction with diynes to afford 2-aminopyridines in good yields. TABLE OF CONTENTS ABSTRACT……………………………………………………………………………iii LIST OF ABBREVIATIONS…………………………………………………………vii CHAPTER I. METAL CATALYZED CYCLOADDITION REACTIONS - AN INTRODUCTION………………………………………………………………..1 References.………………………………………………………………………25 II. NICKEL-CATALYZED CYCLOADDITIVE COUPLING OF ENYNES AND ISOCYANATES………………………………………………………………...27 Introduction….…………………………………………………………………..27 Results and Discussion...………………………………………………………...29 Conclusions...…………………………………………………………………….33 Experimental....…….…………………………………………………………….33 References.……………………………………………………………………….70 III. Fe-CATALYZED CYCLOADDITION OF ALKYNENITRILES AND ALKYNES……………………………………………………………………….72 Introduction………………………………………………………………………72 Results and Discussion...………………………………………………………...74 Conclusions...…………………………………………………………………….78 Experimental....………..…………………………………………………………79 References………………………………………………………………………128 IV. Fe-CATALYZED CYCLOADDITION OF DIYNES AND CYANAMIDES..132 Introduction…………………………………………………………………….132 Results and Discussion...……………………………………………………….134 vi Conclusions……………………………………………………………………134 Experimental....………………………………………………………………..137 References……………………………………………………………………..152 LIST OF ABBREVIATIONS Ac- acetyl acac - acetylacetone BINAP - 2,2' - bis(diphenylphoshino)-1,1'-binaphtyl Bn - benzyl Boc - tert-butyl carbamate COD - cyclooctadiene Cy - cyclohexyl d - doublet dba - trans, trans - dibenzylideneacetone DIAD - diisopropylazodicarboxylate DMF - N, N - dimethylformamide DMA - N, N - dimethylacetamide dppe - 1,2- Bis(diphenylphosphino)ethane dppf - diphenylphosphinoethane Et - ethyl ItBu - 1,3-di-tert-butylimidazol-2-ylidene IMes - 1,3-bis-(2,4,6-trimethylphenyl)-imidazol-2-ylidene IPr - 1,3-bis-(2,6-diisopropylphenyl)-imidazol-2-ylidene iPr - iso-propyl M- metal m - multiplet vii MeCN - acetonitrile NBS - N-bromosuccinimide n-Bu - normal-butyl NHC - N-heterocyclic carbene Ni(COD)2 - Bis(1,5-cyclooctadiene)nickel NMR - nuclear magnetic resonance PnBu3 - tri(n-butyl)phosphine PCy3 - tricyclohexylphosphine Ph - phenyl PPh3 - triphenylphosphine q - quartet s - singlet SIPr - 1,3-bis(2,6-diisopropylphenyl)-imidazolin-2-ylidene t - triplet THF- tetrahydrofuran TMS- trimethylsilyl X - halogen CHAPTER 1 METAL CATALYZED CYCLOADDITION REACTIONS- AN INTRODUCTION Heterocycles are prevalent in various natural products and pharmaceutically active compounds.1 Among various methodologies, transition metal-catalyzed methodologies have played an important role in the synthesis of carbo- and heterocyclic compounds.2 Of the many transition metal-catalyzed synthetic methods used for the preparation of cyclic compounds, the [2+2+2] cycloaddition reactions are of significant importance. Examples of [2+2+2] cycloaddition reactions involve the reaction of three alkyne moieties to form benzene derivatives, or the reaction of a diyne with an alkene group to form a cyclohexadiene core. It is noteworthy that unsaturated systems used in cycloaddition reactions could be heteroatomic (e.g., isocyanates, nitriles, carbon dioxide etc.). These reactions involving the use of heteroatomic unsaturated moieties lead to the formation of heterocyclic compounds such as pyridine, pyrimidone, cyanamide, and pyrans. The [2+2+2] cycloaddition reactions2a could be classified into three types based on the location of the unsaturated used in the substrate: 2 a) Intermolecular: three unsaturated systems present in three different molecules undergo cycloaddition (Figure 1.1, Equation 1.1). b) Partially intermolecular: two unsaturated functionalities of the same molecule undergo cycloaddition with another unsatuared molecule (Figure 1.1, Equation 1.2). c) Intramolecular: all three unsaturated functionalities are present in the same molecule (Figure 1.1, Equation 1.3). Typically, cycloaddition reactions involve the formation and cleavage of multiple bonds in a concerted manner to form cyclic compounds. In these reactions, all the atoms of the starting materials are retained in the product. Thus, the [2+2+2] cycloaddition methodology is an elegant and atom efficient synthetic approach to cyclic compounds. Utilization of this unique methodology affords heterocycles from relatively simple starting materials. Before we go into the details of the cycloaddition reactions, it is important to understand the possible mechanistic pathways2b of product formation. A simple representation of the [2+2+2] cycloaddition reactions is shown in Figure 1.2. For simplicity, the reaction of an internal diyne and a generic isocyanate as the heteroatomic unsaturated system coupling partner is discussed. Initial oxidative coupling of an alkyne moiety and an isocyanate (Figure 1.2, pathway A) in the presence of a transition metal is followed by the insertion of the second alkyne moiety between the metal-carbon bond results in the formation of a seven membered metallacycle. An alternative mechanism involves the oxidative coupling of the alkyne moieties that is followed by the insertion of the isocyanate moiety (Figure 1.2, pathway B). This would result in the formation of the same seven membered metallacycle. Reductive elimination of the metal from the seven membered metallacycle would afford the corresponding cycloaddition product. The 3 reaction mechanism may vary depending on the metal and substrates used in the cycloaddition reaction. This chapter will provide a background on the [2+2+2] cycloaddition reaction of alkynes and various Ni-based heterocumulenes for the synthesis of pyridones and pyridines. It has been divided into the following sections based on the product formed and further subdivided based on the type of metal catalyst used in the reaction: I) [2+2+2] Cycloaddition of alkynes and isocyanates to synthesize pyridones using cobalt, nickel, ruthenium, and rhodium II) [2+2+2] Cycloaddition of alkynes and nitriles to synthesize pyridines using cobalt, rhodium, ruthenium, nickel/zirconium, titanium, tantalum, and iron. [2+2+2] Cycloaddition reactions of alkynes and isocyanates to synthesize pyridones Pyridones can be constructed by the reaction of alkynes and isocyanates in the presence of a suitable transition metal catalyst. Isocyanates are easily accessible via the Curtius rearrangement.3 Similarly, diversely substituted alkynes2 are easily accessible and hence useful coupling partners in cycloaddition reactions. Application of cobalt based catalysts Yamazaki4a reported the first synthesis of pyridones using cycloaddition chemistry by reacting alkynes and isocyanates in the presence of catalytic amounts of a cobalt based catalyst (Equation 1.4). To access differently substituted pyridones, Vollhardt4b tethered 4 an alkyne and an isocyanate functionality and reacted the alkynyl-isocyanates with various alkyne substrates in the presence of a cobalt-catalyst to yield pyridones at elevated temperatures (130 °C) (Equation 1.5). Bicyclic pyridones containing a macrocycle can be prepared in good yields by reacting diynes and isocyanates (Equation 1.6) as demonstrated by Marynoff.4c However, a large excess of the isocyanate is required for the cycloaddition reaction. Application of nickel/zirconium based catalysts Hoberg5a-c was the first to demonstrate the use of nickel in the synthesis of pyridones. Selective pyridone formation in the reaction of an alkyne 1 with an isocyanate in the presence of a stoichiometric amount of nickel (Scheme 1.1) was reported. Nickelacyclopentenone 2 was isolated by the oxidative coupling of alkyne 1 and phenyl isocyanate and was then coupled with one more equivalent of an alkyne functionality to afford the pyridone in moderate yields via nickelacycle 3. Although this was the first successful protocol to prepare pyridones using nickel, the process to prepare the nickelacycle required low temperatures (-50 °C) and long reaction time (3 days). The synthesis of pyridones has been reported by Louie5d,e by using metal complexes as catalysts. Using a Ni/SIPr (1,3-bis(2,6-diisopropylphenyl)-imidazolin-2-ylidene) catalytic system, pyridones can be prepared in high yields at ambient temperature by the reaction of diynes and isocyanates (Equations 1.7 and 1.8). Using the same Ni/NHC catalytic system, the synthesis of pyrimidines was also achieved in moderate to good yields by the reaction of two equivalents of isocyanate and one equivalent of alkyne 5 (Equation 1.9). It was observed that both activated and unactivated isocyanates provided the desired cycloaddition products. Application of ruthenium based catalysts Using a ruthenium-based catalyst, Itoh6 reported the synthesis of pyridones by the reaction of 1,6-diynes and isocyanates (Equation 1.10). The reaction afforded pyridones in good yields in the presence of activated isocyanates. Application of rhodium based catalysts Tanaka7 synthesized pyridones and axially chiral pyridones by reacting diynes and isocyanates in good yields using a cationic rhodium catalyst (Equations 1.11 and 1.12). In all these cycloadditon reactions discussed so far, pyridones were synthesized by the cycloaddition of alkynes or diynes and isocyanates. If one of the alkyne moieties were to be substituted for an alkene, the product thus formed would be a lactam. Lactams are structurally important and present in highly significant biologically active compounds.8 Rovis demonstrated that in the presence of a rhodium catalyst,9a cyclization of an alkenyl-isocyanate and an alkyne afforded a vinylogous amide and lactam products (Equation 1.13). High selectivity of >20:1 was observed favoring the vinylogous amide product. This methodology was also extended to access structural cores of lasubine alkaloids. Matsubara9c used a combination of nickel cyclooctadiene and IPr [1,3-bis- (2,6-diisopropylphenyl)-imidazol-2-ylidene] catalyzed cycloaddition reaction of alkynes, 6 acrylates, and isocyanates affording two regioisomers of γ-butyrolactams in moderate regioselectivity and yields (Equation 1.14). [2+2+2] Cycloaddition of Alkynes and Nitriles for the Synthesis of Pyridines Pyridine rings are omnipresent in various natural products and bioactive compounds.1a Transition metal catalysts have been used extensively to construct pyridine rings via the [2+2+2] cycloaddition reaction. Application of cobalt based catalysts Cobalt based catalysts has by far dominated the field of cycloaddition chemistry. Bönnenman10a was among the first to demonstrate the use of cobalt in cycloaddition reactions of alkynes and activated nitriles (Equation 1.15). Pyridines can be also be synthesized by the cycloaddition reaction of alkynenitriles and exogenous alkynes in the presence of CoCp(CO)2 as demonstrated by Vollhardt10b (Equation 1.16). However, the catalytic system required high temperatures and photolytic conditions for catalyst activation. Eaton10c developed a water-soluble cobalt catalyst system which afforded pyridines in good yields (Equation 1.17). 7 Application of rhodium based catalysts The earliest example of the use of rhodium in the preparation of pyridines by cycloaddition reactions was demonstrated by Ingrossio11a wherein RhCp(C2H4)2 used in the cycloaddition of 1-hexyne and propionitrile. By this method, pyridine products were obtained albeit in moderate yields in an almost equal mixture of regioisomers. By switching to RhCp*(C2H4)2 the yield of the pyridine11b products increased to 67 %. However, high reaction temperatures were necessary for the cycloaddition reaction. Tanaka11c demonstrated pyridines can be prepared with only 3 mol % rhodium based catalyst by reacting diynes with nitriles. The yields of the pyridine product were quantitative when activated nitriles were used. However, the yields dropped significantly when unactivated nitriles were used in the cycloadddition reaction. In another example, reacting activated aryl ethynyl ethers with nitriles catalyzed by rhodium11d to yield the pyridine product as a single regioisomer. Application of ruthenium based catalysts Itoh12a was the first to synthesize pyridines using a ruthenium based catalyst (Equation 1.22). Diynes and dicyanides reacted to afford only one regioisomer of the pyridine product in good yields. Modification of the ruthenium catalyst to Cp*RuCl12b (Equation 1.23) synthesized pyridines in excellent yields with low catalyst loading. However, slight excess of nitriles is required for the cycloaddition reaction. Saa12c used a cationic Ru based catayst (Equation 1.23) in the presence of NEt4Cl to obtain good yields of the pyridine product from the reaction of diynes and dicyanides. 8 Application of nickel/zirconium based catalysts Takahashi13a synthesized pyridines by an intermolecular cycloaddition between two different alkynes and a nitrile (Equation 1.25). The alkyne and the isocyanate were coupled with zirconium (Zr) to form an azazirconacyclopentenone. Then Ni(PPh3)2Cl2 reacted with the azazirconacyclopentenone to form the nickelcyclopentenone. Insertion of the second alkyne affords the pyridine. This marked the first report of the use of nickel in the synthesis of pyridines. Unfortunately in this method stoichiometric amounts of both Ni and Zr were needed for this reaction. Louie13b successfully demonstrated that stoichiometric amounts of nickel were not needed to synthesize pyridines (Equation 1.26). Employing a combination of nickel and an N-heterocyclic carbene, IPr, pyridines were prepared in excellent yields with both unactivated nitriles at room temperature. This reaction can be carried out in an intermolecular fashion by combining alkynes and nitriles (Equation 1.27).13c Applications of titanium based catalysts Cycloaddition reactions are not entirely dependent on late transition metals for catalysis. Early transition metals such as titanium14 have also been used in the synthesis of pyridines (Equation 1.28). Although, the reaction for some alkynes are high yielding, stoichiometric amounts of titanium are required for the cycloaddition reaction. 9 Application of tantalum based catalysts Tantalum15 has been used in the cycloaddition reaction of alkynenitriles and alkynes (Equation 1.29). However, this cycloaddition reaction has been applied to only one substrate and the reaction is stoichiometric in tantalum hexachloride. Applications of iron based catalysts Iron has also been used in the past for the preparation of pyridine. The very first example was reported by Sir William Ramsay16a,b in 1876. He synthesized pyridine in traces by passing hydrocyanic acid and acetylene through a red hot iron tube. Knoch16c prepared pyridine derivatives from the cycloaddition of alkynes and nitriles using an iron-phosphoranecyclooctadiene complex (Equation 1.30). Although the cycloaddition reaction required low catalyst loading, the desired pyridine product and alkyne cyclotrimerization products were obtained. By designing an iron-pentamethyl( cyclopentadienyl)acetonitrile sandwich complex, Ferré16d successfully afforded pyridine product in 73 % yield (Equation 1.31). However, this cycloaddition reaction required stoichiometric amounts of the iron-complex and was limited to one activated alkyne. The above examples demonstrate the importance of the use of transition metal catalysts in the [2+2+2] cycloaddition reactions. It is clear that a variety of reactions with diverse substrates and catalysts have been developed and reported. However, certain deficiencies exist in our understanding and application of cycloaddition reactions. One example is the lack of a reaction protocol that combines readily accessible substrates 10 such as enynes and isocyanates. Therefore, developing such a cycloaddition reaction that could utilize the reactivity of an enyne and an isocyanate would be an interesting study. This study was undertaken in the Louie lab and the results obtained in the investigation using a nickel catalyst are discussed in Chapter 2. The pyridine ring is an important structural motif. Although various metals catalyst have been developed to synthesize pyridine rings, very little work has been done in the application of iron based catalysis in these cycloaddition reactions. Iron is an interesting candidate for cycloaddition catalysts because it is less-toxic, relatively inexpensive, and readily available. Therefore, a study involving the use of Fe-catalysts in cycloaddition reactions was undertaken and the results have been discussed in Chapters 3 and 4. Chapter 3 provides the details of Fe-catalyzed synthesis of pyridine derivatives, whereas chapter 4 provides the details of Fe-catalyzed synthesis of 2-aminopyridine derivatives. 11 Figure 1.1 [2+2+2] Types of cycloaddition reactions (equations1.1-1.3) 12 Figure 1.2 A [2+2+2] cycloaddition reaction between a diyne and an isocyanate 13 14 Scheme 1.1 Hoberg's synthesis of pyridones using nickel 15 16 17 III 0, 'c + ;J Ar Ar =-3,4-0Me-CsH3 o Me,--,,~-Ph + ~OMe + Ph C",O "'N~ 5 mol % [Rh(C2H.hCI21 10 mol % (-)-L toluene, 110°C 72 %, 95 % ee (1 :20) Ph Ph ><:r}-{J Ph Ph (-)-L 10 mol % Ni(CODh 10 mol % IPr 1,4- dioxane, 100°C, 5 h 56 % (2:1) 0 ArLo H • lactam (1.13) + Ar oW H vinylogous amide o • Me:>t_ Ph ~ OMe PH (1.14) + 0 o PhfQ_Ph ~ OMe Me o 18 c + N III Ph + II HOl N III + Me OH 20 mol % CpCo(COh m-xylene, hv, 145 'c 20 mol % CpCo(COh m-xylene, hv, 145 'c 0 • • ~OH 2.5 mol % Co(COD) 70 % H2O/MeOH 85C, 24 h 76% Yield ~Ph 'J".J N (1.15) 50 % Yield ~SiMe3 'J" .. .l N SiMe3 (1.16) 77%Yeild OH Me • OH (1.17) HO OH 19 + N III El = nBu + + N III Et 1 mol % RhCp(C:!H4n 150 ·C 70 % (56:44) • RhCp·(C2H4 )2, 130 ·C • 67 % Yield 2 mol % Rh(COD)2BF4i BINAP, rt, CH2CI2 R :=N • 63-99 % EtyYBU Ny nBu + ElY') N0nBU nBu ElyYBU Ny nBu + ElY') N0nBU nBu EvhR E~N (1.18) (1.19) (1.20) 20 OEI ~ + E=C02Me R1 = Ph, R2 = H R1= TMS, R2 = H EC E = E=C02Me + 10 mol % Rh(COD),BF 41 H8-BINAP, rI, CH2CI2 64-32 % R=C02EI, Me R = C02EI, COPh 10 mol % Cp*Ru(COD)CI 60 cC, 24 h, CICH2CH2CI 78-92 % 2 mol % Cp*RuCI 60 cC, 0.5 h, CICH2CH2CI 84% • E~~ E~R (1.23) 21 EC E = + Et Et + N III Me 10 mol % Cp*[Ru(CH3CN)]PFe 10 mol % NE4CI, 0.5 h, DMF 84% 1. CpZrEt2 2. NiPPh3CI2 Pr Pr • 86 % Yield (1.24) Me Et* (1.25) Et::"" Pr Pr 22 Scheme 1.2 Pyridine synthesis using stoichiometric amounts of zirconium and nickel 23 N Et Et + 'I' Ph 3 mol % Ni(CODl:! 6 mol % IPr, rt 82% 1) Ti(OJpr).v2 iprMgCl, 50°C, THF 0.8 equiv 1. TaCls, Zn, DME, PhH 2. THF, pyridine 3. n 50°C,4h I I W 4. NaOH, H20 73% • Ph Et* Et ::". I Et (1.27) Et 62 % Yield • (1.29) 24 + 3 mol % A, toluene 20 'C, 96 h 41 % ---b-SiM9 3 I A Fe 61 • + • (1.30) + benzene derivatives (1.31) 25 References 1. a) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell:Oxford, 2000. b) Romeo, G.; Chiacchigo, U.; Merino, P. Chem. Rev. 2010, 110, 3337-3370. c) Kollár, L.; Keglevish, G.; Chem. Rev. 2010, 110, 4257-4302. 2. Reviews of cycloaddition; a) S. Kotha, S.; Brahmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741. b) Varela, J. A.; Saá, C. Chem. Rev. 2003, 103, 3787. c) Chopade, P.; Louie, J. Adv. Synth. Catal. 2006, 348, 2307. d) Schore, N. Chem. Rev. 1988, 88, 1081. e) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127. f) Varela, J. A.; Saá, C. Synlett. 2008, 2571 3. Synthesis of isocyanates and their reactions: a) Braunstein, P.; Nobel, D. Chem. Rev. 1989, 89, 1927. b) Ozaki, S. Chem. Rev. 1972, 72, 457. 4. Cobalt catalyzed: a) Hong, P.; Yamazaki, H. Tetrahedron Lett. 1977, 1333. b) Earl, R. A.; Vollhardt, K. P. C.; J. Org. Chem. 1984, 49, 4786. c) Boñaga, L. V. R.; Zhang, H-C.; Moretto, A. F.; Ye, H.; Gauthier, D. A.; Li, J.; Leo, G. C.; Maryanoff, B. E. J. Am. Chem. Soc. 2005, 127, 3473. 5. Nickel catalyzed: a) Hoberg, H.; Oster, B. W. J. Organomet. Chem. 1982, 234- 235. b) Hoberg, H.; Oster, B. W. Synthesis 1982, 324. c) Hoberg, H.; Oster, B. W. J. Organomet. Chem. 1983, 252, 359. d) Duong, H. A.; Cross, M. J. Louie, J. Am. Chem. Soc. 2004, 126, 11438-11439. e) Duong, H. A.; Louie, J. Tetrahedron 2006, 62, 7552. 6. Ru catalyzed: a) Yamamoto, Y.; Takagishi, H.; Itoh, K. Org. Lett. 2001, 3, 2117. 7. Rh catalyzed: a) Tanaka, K.; Wada, A.; Noguchi, K. Org. Lett. 2006, 8, 907. b) Kondo, T.; Nomura, M.; Ura, Y.; Wada, K.; Mitsudo, T. Tetrahedron Lett. 2006, 47, 7107. 8. a) Williams, R.; Manka, J. T.; Rodriguez, A. L.; Vinson, P. N.; Niswender, C. M.; Weaver, D. C.; Jones, C. K.; Conn, P. J.; Lindsley, C. W.; Stauffer, S. R. Bioorg. Med. Chem. Lett. 2011, 21, 1350. b) Dow, R. L.; Carpino, P. A.; Hadcock, J. R.; Black, S. C.; Iredale, P. A.; DaSilva-Jardine, P.; Schneider, S. R.; Paight, E. S.; Griffith, D. A.; Scott, D. O.; O'Connor, R. E.; Chudy, I. ; Nduaka, C. I. J. Med. Chem. 2009, 52, 2652. 9. Yu, T. R.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 2782-2783. (b) Yu, T. R.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 12370-12371. (c) Lee, E. E.; Rovis, T. Org. Lett. 2008, 10, 1231-1234. (d) Ozawa, T.; Horie, H.; Kurahashi, T.; Matsubara, S. Chem. Commun., 2010, 46, 8055-8057. 26 10. Cobalt catalyzed pyridine synthesis: a) Bonnemann, H.; Brinkman, R.; Schenklum, H. Synthesis 1974, 8, 575. b) Brien, J. D.; Naiman, A.; Vollhardt, P. K. C. J. Chem. Soc. Chem. Commun. 1982, 133-134. c) Fatland, A. W.; Eaton, B. E. Org. Lett. 2000, 2, 3131. 11. Rhodium pyridine catalysts: a) Cioni, P.; Diversi, P.; Ingrosso, G.; Lucherini, A.; Ronca, P. J. Mol. Catal. 1987, 40, 337-357. b) Cioni, P.; Diversi, P.;Ingrosso, G.; Lucherini, A.; Ronca, P. J. Organometal. Chem. 1993, 447, 291. c) Tanaka, K.; N. Suzuki, N.; G. Nishida, G. Eur. J. Org. Chem. 2006, 3917. d) Komine, Y.; Tanaka, K. Org. Lett. 2010, 12, 1312 12. Ru pyridine catalysts: a) Yamamoto, Y.; Ogawa, R.; Itoh, K. J. Am. Chem. Soc. 2001,123, 6189. b) Yamamoto, Y.; Kinpara, K.; Saigoku, T.; Takagishi, H.; Okuda, S.; Nishiyama, H.; K. Itoh, K. J. Am. Chem. Soc. 2005, 127, 605. c) Varela, J. A.; Castedo, L.; Saá, C. J. Org. Chem. 2003, 68, 8595. 13. Nickel pyridine catalysts: a) Takahashi, T.; Tsai, F.-Y.; Li, Y.; Wang, H.; Kondo, Y.; Yamanaka, M.; Nakajima, K.; Kotora, M. J. Am. Chem. Soc. 2002, 124,5059. b) McCormick, M. M.; Duong, H. A; Zuo, G.; Louie, J. J. Am. Chem. Soc. 2005, 127, 5030; c) Tekavec, T. N.; Zuo, G.; Simon, K.; Louie, J. J. Org. Chem. 2006, 71, 5834 14. Titanium pyridine catalysts: Tanaka, R.; Yuza, A.; Watai, Y.; Suzuki, D.; Takayama, Y.; Sato, F.; Urabe, H. J. Am. Chem. Soc. 2005, 127, 7774 15. Tantalum pyridine catalysts: Takai, K.; Yamada, M.; Utimoto, K. Chem. Lett. 1995, 851. 16. Iron pyridine synthesis: a) Ramsay, W. Philos. Mag. 1876, 2, 269. (b) Ramsay, W. Philos. Mag. 1877, 4, 241. c) Ferré, K.; Toupet, L.; Guerchais, V. Organometallics 2002, 21, 2578. d) Schmidt, U.; Zenneck, U. J. Organomet. Chem. 1992, 440, 187. e) Knoch, F.; Kremer, F.; Schmidt, U.; Zenneck, U.; Floch, P. L.; Mathey, F. Organometallics 1996, 15, 2713. CHAPTER 2 NICKEL-CATALYZED CYCLOADDITION OF ENYNES AND ISOCYANATES Introduction Our group is interested in utilizing the transition metal catalyzed [2+2+2] cycloaddition reactions1,2 to construct such structurally useful and biologically relevant cores. In 2004, we reported the use of a Ni and IPr (an N-heterocyclic carbene ligand) catalyst system for the coupling of diynes and nitriles to prepare pyridine rings3 in high yields at room temperature (Equation 2.1). The potential of the Ni/NHC catalytic system was later extended to synthesis of substituted pyridones4 which can be accessed by the coupling of diynes and isocyanates (Equation 2.2). A year later, our group demonstrated that enynes5 and aldehydes couple under Ni/NHC conditions to afford a mixture of enones and ketones with excellent regioselectivity for the enone product (>95:5) (Equation 2.3). The lactam core is prevalent in various natural products and biologically relevant compounds.6 We envisioned that lactams could be constructed by the cycloaddition of enynes and isocyanates under Ni catalyzed conditions (Equation 2.4). The cycloaddition 28 of enynes and isocyanates had previously not been studied. This prompted us to investigate this reaction. Currently, only two examples are reported in literature for the cycloaddition of an alkene, alkyne, and isocyanates. The first one is the cycloaddition utilizing an alkenyl-isocyanate (Equation 2.5) and an alkyne using a rhodium7a catalyst to obtain a vinylogous amide and a lactam product. A high selectivity of >20:1 was observed favoring the vinylogous amide product. This methodology was also extended to access structural cores of lasubine alkaloids. Matsubara7b has demonstrated a Ni/IPr catalyzed cycloaddition of alkynes, acrylates, and isocyanates affording two regioisomers of γ-butyrolactams with moderate regioselectivity and yields (Equation 2.6). In order to predict the reactivity of enynes with isocyanates, we need to first know whether enynes and isocyanates react under cycloaddition reaction conditions. Earlier reports indicate that enynes are reactive substrates under Ni/NHC catalytic conditions. They readily undergo cycloisomerization8a to form conjugated dienes (Equation 2.7). A previous report has shown that isocyanates can undergo trimerization8b in the presence of catalytic NHCs to isocyanurates (Equation 2.8). With these two competing side reactions it was unclear if the reaction of enynes and isocyanates would cyclize in a productive manner. However, we were encouraged by a report by Jamison9 demonstrating that 1,1- and 1,2-disubstituted acrylamides (Equation 2.9) can be prepared by reacting alkenes and alkyl isocyanates with a Ni/IPr catalyst system. This was the first example of an oxidative coupling of an alkene and an isocyanate using a Ni/NHC catalyst system. This suggested that enynes and isocyanates together in a cycloaddition reaction could be reactive under nickel catalyzed conditions. 29 Results and Discussion Our initial efforts where to develop optimum reaction conditions that would yield the desired lactam product in good to excellent yields. As shown in Table 2.1, a variety of phosphines and NHCs were evaluated as prospective ligands to determine the potential reactivity between enyne 1a and cyclohexyl isocyanate 2a (Table 2.1, Equation 2.10). No enyne and isocyanate coupling product was observed when Ni(COD)2 was used in the absence of a donor ligand (Table 2.1, entry 1). Low conversions of enyne 1a were observed with monodendate phosphines (entries 2-4) with no detectable product by gas chromatography. Poor conversions and no detectable product was also observed when bidentate phosphines were employed (Table 2.1, entries 5-7). A slight increase in the conversion of starting material was observed when the reaction was run with bulky NHCs such as ItBu and IMes (Table 2.1, entries 8-9). However, in all cases (Table 2.1, entries 2-9), no detectable coupling product was observed. In contrast, when bulkier NHC ligands such as SIPr and IPr were employed, a distinct coupling product were isolated in good yields (Table 2.1, entries 10-11). Isolation of the major product revealed that cyclization did indeed occur. Dienamides 3a, rather than a lactam product were isolated in 70 % yield. Interestingly the two dienamide products isolated were namely E-and Z- products. The structures of these products were unambigiously assigned by 1H and 13C NMR, and finally by nOe (Nuclear Overhauser effect) correlations. We propose the following mechanisms for the formation of the dienamide products as shown in Scheme 2.1. In mechanism A (Scheme 2.1, Equation 2.11), initial oxidiative coupling and subsequent insertion leads to 7-membered intermediate 5. Rather than undergoing C-N bond-forming reductive elimination,10 β-hydride elimination occurs 30 resulting in nickelacycle 6. Facile reductive elimination from nickelacycle 6 would afford the Z-dienamide product 3. Alternatively, mechanism B (Scheme 2.2, Equation 2.12) could involve the oxidative coupling between the isocyanate and the alkyne of the enyne followed by the insertion of the pendant olefin to afford nickelacycle 5 which may undergo β-hydride elimination. Again, facile reductive elimination from nickelacycle would afford the Z-dienamide. The proposed mechanism explains only the formation of the Z-dienamide product. In order to better understand the E- and Z-dienamide product formation, we subjected the E and Z isomers of dienamide 3b to the reaction conditions. Thus when the E-isomer of 3b was resubjected to the reaction conditions, no isomerization to the Z-dienamide was observed (Scheme 2.1, Equation 2.13). However, when the Z-isomer of 3b was resubjected to the reaction conditions, a mixture of E- and Z- products were obtained (Scheme 2.1, Equation 2.14). Also, no isomerization was observed when the E- and the Z- isomers were resubjected to the IPr ligand in the absence of nickel catalyst. Thus, the Z-dienamide could most likely be the initial coupling product and undergo a Ni(0)- mediated interconversion to the more stable E-isomer over the course of the reaction. The combination of Ni and IPr catalyzed the coupling of enyne 1a with a variety of isocyanates (Table 2.2). Alkyl isocyanates reacted smoothly at room temperature within 1-2 h. Furthermore, these reactions afforded dienamides in excellent overall yields with good E:Z ratios (Table 2.2, entries 1-3). In contrast, aryl isocyanates reacted more sluggishly and required slightly more forcing conditions.9 For example, the Ni-catalyzed coupling of enyne 1a and phenyl isocyanate 2d proceeded at 60 °C while no reaction occurred at room temperature (entry 4). Nevertheless, dienamide 3d was isolated in 89 31 % yield. Both aryl isocyanates possessing electron-donating groups as well as electron-withdrawing groups were converted to their respective dienamides in 71 % and 80 % yield (Table 2.2, entries 5 and 6 respectively). Aryl isocyanates possessing electron-withdrawing groups reacted slower than those possessing electron-donating groups (Table 2.2, entries 5-7). Sterically-hindered aryl isocyanates such as 2h and 2i were also converted to their respective dieneamides, although under higher reaction temperatures, in good yields, 71 % and 80 %, respectively (Table 2.2, entries 8-9). No desired dienamide product was observed when TMS-NCO was employed. Only the cycloisomerization of enyne 1a was observed. A variety of enynes were successfully converted to their respective dienamide products (Table 2.3). A significant increase in dienamide yield (3j and 3k) was observed when ethyl-substituted enyne 1b was used as a coupling partner in lieu of methyl-substituted enyne 1a despite the similarity in the backbones of these two substrates (Table 2.3, entries 1-2 versus Table 1.2, entries 1 and 4, respectively). A five carbon linker enyne 1c afforded a five membered cyclic dienamide in good yield (Table 2.3, entries 3-4). Dienamides having a bicyclic ring system with a nitrogen atom on the bridgehead were also prepared in good yields (Table 2.3, entries 5-6). Although enyne which possesses a bulky trimethylsilyl group on the alkyne, has been used as a substrate in other Ni-catalyzed cycloddition reactions,5b this enyne undergoes cycloisomerization8a exclusively and does not afford a dienamide product. Enynes with internal alkynes afforded good to excellent yields for the dienamide products. We turned our attention to enynes with terminal alkynes. Interestingly, when terminal enyne 1f was subjected to the coupling conditions with either 32 cyclohexylisocyanate 2a or phenyl isocyanate 2d, dienamide formation did not occur. Instead, lactam 10 or 11 was formed as the sole product, albeit in low yields (Equation 2.15). Lactams 10 and 11 likely arise from C-N bond-forming reductive elimination from a seven membered nickelacycle such as 7b (Scheme 2.3). Insertion of the isocyanate into the Ni-sp3 bond rather than the Ni-sp2 bond in nickelacycle 4, would lead to the formation of 5b (Scheme 2.3, Pathway B). Alternatively, nickelacycle 5b may arise from the initial oxidative coupling between the enyne and the isocyanate followed by insertion of the pendant alkyne (Scheme 2.3, Pathway B). Formation of nickelacycle 5b may be favored over 5a when the steric interaction of the alkyne substitutent and the ligand (i.e. IPr) is small. In fact, we have observed this type of sterically-driven selectivity in other Ni-catalyzed8 cycloaddition chemistry. Iminoethers are useful building blocks which could be hydrolyzed furthur under mild reaction conditions. Dienamides can be conveniently converted to iminoethers.11 For example, the reaction of 3b with N-bromosuccinimide (NBS) afforded the bromosubstituted iminoether 12 in 53 % isolated yield (Equation 2.16). Furthermore, when 3b was subjected to I2 in lieu of NBS, higher yields were obtained of the halo substituted iminoether. That is, the iodo-substituted iminoether 13 was obtained in 90 % isolated yield (Equation 2.16). 33 Conclusions Enynes can be prepared from readily available starting materials and undergoes the cycloaddition reaction with isocyanates using Ni(COD)2 and IPr ligand system to afford dienamides in good to excellent yields. Both alkyl and aryl isocyanates undergo coupling with enynes. In previous Ni-catalyzed reactions arylisocyanates reacted very sluggishly in low yields. However, under Ni/IPr catalytic conditions arylisocyantes react very smoothly affording dienamides in good yields. This catalyst system can be used to prepare dienamides containing five- or six- membered rings. In our substrate scope we have tested enynes with terminal alkenes. Experimental All reactions were carried out in the dry glove box until otherwise specified. Toluene was dried over neutral alumina under N2 using a Grubbs type solvent purification system. Tetrahydrofuran (THF) was freshly distilled from Na/benzophenone. Ni(COD)2 was purchased from Strem Chemicals and used without further purification. Sodium hydride used was previously washed with hexanes, dried under reduced pressure prior to use. Enyne 1a-1g were prepared analogously to known literature procedures.5a IPr, SIPr, IMes, and ItBu ligands were prepared as previously reported.12 The compounds 1- bromo-2-methylbutyne was prepared from the corresponding alcohol.13 Allyl bromide, 3-bromoprop-1-yne, (3-bromoprop-1-ynyl)trimethylsilane, tetraethyl-1,1,2,2-ethanete tracarboxylate, and isocyanates 2a-2j were purchased from Sigma Aldrich Chemicals. 34 All isocyanates were dried over calcium hydride and distilled under freeze-pump-thaw technique. 1H, 13C, nOe, and HMBC nuclear magnetic resonance spectra of pure compounds were acquired at 300, 400, and 500 MHz instruments. All spectras were carried out using CDCl3 and C6D6 as the solvent purchased from Cambridge Isotope Labs. Inc. All spectra are referenced to a singlet of chloroform at 7.27 ppm for 1H and to the center line of a triplet at 77.26 ppm for 13C or 7.16 ppm for 1H and 126.80 ppm for 13C unless specified otherwise. The abbreviations s, d, dd, t, q, quint, sept, and m stand for singlet, doublet, doublet of doublets, triplet, quartet, quintet, septet, and multiplet in that order. All 13C NMR spectra were proton decoupled. (E-), (Z-) geometry of the dienamides was confirmed by nOe experiments (nuclear Overhauser effect). IR spectra were recorded on a Bruker Tensor 27 FT-IR spectrometer using a NaCl crystal. Gas chromatography were performed on an Agilent 6890 instrument with a 30 meter HP-5 column using the following conditions: initial oven temperature: 100 ºC; temperature ramp rate 25 °C/min.; final temperature: 300 ºC held for 7 min; detector temperature: 250 ºC. Preparation of tetraethylpent-4-ene-1,1,2,2-tetracarboxylate (14): To a stirring suspension of NaH (415 mg, 17.3 mmol) in 150 ml THF (Equation 2.17) was added tetraethyl-1,1,2,2-ethanetetracarboxylate (5.0 g, 15.7 mmol) under N2 counter-flow in two portions (Equation 2.17). The resulting solution was stirred at room temperature for 1 h after which time allyl bromide (2.1 g, 17.3 mmol) was added. A reflux condenser was attached and the mixture was stirred at reflux for 8 h at which time GC analysis showed no starting ester remained. The solution was cooled to room temperature and quenched with 100 ml of a saturated NH4Cl 35 solution. The layers were separated and aqueous layer was extracted with Et2O (3 x 100 ml). The combined organics were washed with brine (100 ml), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The resulting crude yellow oil was purified by flash column chromatography (10 % EtOAc/hexanes then 12 % EtOAc/hexanes) to yield 14 (5.3 g, 94 %) as a pale yellow oil. Spectral data were compared with literature values1. Preparation of tetraethyl 8-(trimethylsilyl)oct-1-en-7-yne-4,4,5,5- tetracarboxylate (1e): To a stirring solution of NaH (147 mg, 6.14 mmol) in 20 ml THF, tetraethyl-pent-4-ene-1,1,2,2- tetracarboxylate (14) in 8 ml THF was added. The resulting mixture was stirred at room temperature for 1 h. To this reaction mixture was added (3-bromoprop-1- ynyl)trimethylsilane (1.17 g, 6.14 mmol) in a single portion (Equation 2.18). The resulting solution was refluxed for 48 h. After checking the completion of the reaction by gas chromatography, the reaction mixture was quenched by the addition of saturated NH4Cl (10 ml) and H2O (10 ml). To the reaction mixture Et2O (20 ml) was added. The layers were separated and the aqueous layer was extracted with Et2O (3 x 20 ml). All organic layers were combined and washed with brine (10 ml), dried over Na2SO4, and concentrated under reduced pressure. The resulting crude oil was purified by flash column chromatography eluting with 10 % EtOAc/hexanes to yield enyne 1e as a yellow oil (862 mg, 66 %). 1H NMR (300 MHz, CDCl3): δ (ppm) 5.82-6.13 (m, 1H), 5.05-5.12 (m, 2H), 4.15- 4.32 (m, 8H), 3.20 (s, 2H), 2.80 (d, J = 6.9 Hz, 2H), 1.25-1.30 (m, 12H), 0.20 (s, 9H). 13C {1H} NMR (75 MHz, CDCl3): δ (ppm) 169.3, 168.8, 134.0, 119.1, 102.9, 87.1, 62.6, 62.3, 62.1, 61.8, 36.5, 23.7, 14.0, 14.1, 0.1. IR (neat): 3080, 2983, 36 2906, 2182, 1737, 1639, 1445, 1390, 1367, 1207, 1033, 920, 847 cm-1. HRMS calculated m/z for C23H36O8NaSi (M+Na) 491.2077, found 491.2071. Preparation of tetraethyl-oct-1-en-7-yne-4,4,5,5-tetracarboxylate (1f): To a stirring solution of NaH (294 mg, 12.3 mmol) in 50 ml THF was added compound 14 (2.0 gms, 5.58 mmol). The reaction mixture was stirred for 1 h after which 3-bromoprop-1-yne (1.46 g, 12.3 mmol) as an 80% w/v solution in toluene in a single portion (Equation 2.19). The reaction mixture was stirred for 1 h and then the resulting mixture was refluxed for 24 h. After checking the completion of the reaction by gas chromatography, the reaction mixture was quenched by the addition of saturated NH4Cl (20 ml) and H2O (20 ml). To the reaction mixture Et2O (20 ml) was added. The layers were separated and the aqueous layer was extracted with Et2O (3 x 20 ml). All organic layers were combined and washed with brine (20 ml), dried over Na2SO4, and concentrated under reduced pressure. The resulting crude oil was purified by flash column chromatography eluting with 30 % ethyl acetate/hexanes to yield enyne 1f as a colorless solid (1.79 g, 81 %). 1H NMR (300 MHz, CDCl3): δ (ppm) 5.81-6.11 (m, 1H), 5.05-5.20 (m, 2H), 4.15-4.30 (m, 8H), 3.15 (d, J = 2.4 Hz, 2H), 2.81 (d, J = 7.2 Hz, 2H), 2.07 (t, J = 2.7 Hz, 1H), 1.20-1.40 (m, 12H). 13C {1H} NMR (75 MHz, CDCl3): δ (ppm) 169.1, 168.8, 133.8, 119.4, 80.2, 70.8, 62.1, 62.0, 61.9, 36.4, 22.4, 14.0. IR (neat): 3277, 3080, 2984, 2906, 1736, 1639, 1445, 1390, 1367, 1209, 1035, 864 cm-1. HRMS calculated m/z for C20H28O8Na (M+Na) 419.1682, found 419.1684. 37 General Cycloaddition Procedure In a dry glove box, the enyne and isocyanate was added to an oven dried scintillation vial equipped with a magnetic stir bar and dissolved in toluene. To this reaction mixture, a solution of Ni(COD)2 and IPr which was previously equilibrated for atleast 4 h was added using a calibrated microsyringe. The reaction mixture was stirred at room temperature or heated in an oil-bath at the desired temperature until the reaction was complete. The consumption of starting material was monitored by GC. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography. Compounds (Z) and (E)-tetraethyl-4-(1-(cycloamino)-1 -oxopropan-2-ylidene)-5-methylenecyclohexane-1,1,2,2 -tetracarboxylate (Z/E-3a): General cycloaddition procedure was used with enyne 1a (100 mg, 0.24 mmol), cyclohexyl isocyanate (30.5 mg, 0.24 mmol) 2a, Ni(COD)2 (6.77 mg, 0.024 mmol), IPr (18.9 mg, 0.048 mmol) and 2.4 ml toluene and stirred for 1 h at room temperature. The crude compound was purified by flash chromatography eluting with 30 % EtOAc/hexanes to yield compounds E-3a as a colorless solid (m.p. 130-132 °C) and Z-3a as an oil (90.3 mg, 70 %). E-3a: 1H NMR (400 MHz, CDCl3): δ (ppm) 5.82 (d, J= 8.8 Hz, 1H), 5.35 (s, 1H), 4.90 (s, 1H), 4.2 (m, 8H), 3.80-3.85 (m, 1H), 3.05 (d, J = 6 Hz, 4H), 1.98 (s, 3H), 1.9-1.1 (brm, 10H), 1.2-1.3 (q, J = 5.2 Hz, 12H). 13C {1H} NMR (100 MHz, CDCl3): δ (ppm) 170.8, 169.7, 169.2, 139.7, 131.6, 130.5, 116.8, 61.9, 61.8, 60.7, 58.8, 47.8, 39.7, 35.4, 33.2, 25.7, 24.9, 17.7, 14.1, 13.9. IR (neat): 3608, 3583, 2983, 2933, 2260, 1740, 1262, 1207 cm-1. nOe correlation was seen with a proton on C-7 and 38 the methyl protons on C-9. HRMS calculated m/z for C28H41NO9Na (M+Na) 558.2679, found 558.2670. Z-3a: 1H NMR (400 MHz, CDCl3): δ (ppm) 5.6 (m, 2H), 4.1-4.2 (m, 8H), 3.6-3.8 (s, 1H), 3.20 (s, 2H), 2.90 (s, 2H), 1.90 (s, 3H), 1.5-1.75 (m, 6H), 1.05-1.20 (m, 16H). 13C {1H} NMR (100 MHz, CDCl3): δ (ppm) 171.6, 169.5, 169.4, 141.0, 133.6, 131.5, 116.6, 62.1, 61.9, 60.9, 58.8, 47.7, 39.0, 33.4, 32.5, 30.5, 29.9, 25.8, 24.9, 16.0, 14.1, 14.0. IR (neat): 3583, 3392, 2984, 2933, 2855, 2253, 1730, 1656, 1267, 912 cm-1. nOe correlation was seen with vinylic proton on C-7 and methylene protons on C-6. HRMS calculated m/z for C28H41NO9Na (M+Na) 558.2679, found 558.2673. Compounds (Z) and (E)-tetraethyl 4-(1-(benzylamino) 1-oxopropan-2-ylidene)-5-methylenecyclohexane-1, 1, 2,2-tetracarboxylate (E/Z-3b): General procedure was used with enyne 1a (100 mg, 0.24 mmol), benzyl isocyanate (32.4 mg, 0.24 mmol) 2b, Ni(COD)2 (6.77 mg, 0.024 mmol), IPr (18.9 mg, 0.048 mmol) and 2.4 ml toluene and stirred for 2 h at room temperature. The crude compound was purified by flash chromatography eluting with 30 % EtOAc to yield compound E-3b as a colorless solid (m.p. 95-98 °C) and compound Z-3b as an oil (90 mg, 68 %). E-3b: 1H NMR (300 MHz, CDCl3): δ (ppm)7.20-7.40 (m, 5H), 5.92 (t, J = 6.3 Hz, 1H), 5.0 (s, 1H), 4.71 (d, J = 1.2 Hz, 1H), 4.34 (d, J = 5.7 Hz, 2H), 4.25-4.13 (m, 8H), 3.05 39 (s, 2H), 2.84 (s, 2H), 1.94 (s, 3H), 1.15-1.25 (m, 12H). 13C {1H} NMR (75 MHz, CDCl3): δ (ppm) 172.4, 169.4, 169.3, 140.9, 138.2, 134.2, 130.8, 128.7, 128.1, 127.5, 116.6, 62.1, 61.9, 60.8, 58.7, 43.9, 38.9, 33.5, 16.1, 14.1, 14.0. IR (neat): 3396, 2983, 1735, 1659, 1266, 1204, 864 cm-1. nOe correlation was seen with a proton on C-7 and the protons on C-9. HRMS calculated for m/z C29H37NO9Na (M+Na) 566.2366, found 566.2360. Z-3b: 1H NMR (300 MHz, CDCl3): δ (ppm) 7.29-7.25 (m, 5H), 6.26 (t, J = 5.4 Hz, 1H), 5.12 (m, H), 4.94 (d, J = 1.8 Hz, 1H), 4.54 (d, J = 6.3 Hz, 2H), 3.8 - 4.2 (m, 8H), 2.98 (d, J = 15.9 Hz, 4H), 1.98 (s, 3H), 1.25 -1.05 (m, 12 H). 13C {1H} NMR (75 MHz, CDCl3): δ (ppm) 171.6, 169.7, 169.2, 139.8, 138.4, 132.3, 129.6, 128.8, 128.1, 127.6, 116.9, 61.9, 61.9, 60.8, 58.8, 43.6, 39.6, 35.7, 14.0, 13.8. IR (neat): 3396, 2983, 1735, 1659, 1266, 1204, 1041, 912 cm-1. nOe correlation was seen with vinylic proton on C-7 and methylene protons on C-6. HRMS calculated for m/z C29H37NO9Na (M+Na) 566.2366, found 566.2369. Compounds (Z) and (E)-tetraethyl 4-(1-(ethylamino)-1-oxo propan-2-ylidene)-5-methylenecyclohexane-1,1,2,2-tetracarb-oxylate (Z/E-3c): General cycloaddition procedure was used with enyne 1a (100 mg, 0.24 mmol), ethyl isocyanate (17.3 mg, 0.24 mmol) 2c, Ni(COD)2 (6.77 mg, 0.024 mmol), IPr (18.9 mg, 0.048 mmol) and 2.4 ml toluene and stirred for 2 h at 80 °C. The crude compound was purified by flash chromatography eluting with 30 % EtOAc/hexanes to yield compound E-3c as a colorless solid (m.p. 98- 100 °C) and compound Z-3c as an oil (94 mg, 80 %). 40 E-3c: 1H NMR (300 MHz, CDCl3): δ (ppm) 5.59 (brs, 1H), 5.10 (s, 1H), 4.90 (s, 1H), 4.18-4.28 (m, 8H), 3.21 (q, J = 6.4 Hz, 2H), 2.89 (s, 4H), 1.60 (d, J = 6.4 Hz, 3H), 1.15-1.25 (m, 12H). 13C {1H} NMR (75 MHz, CDCl3): δ (ppm) 171.7, 169.8, 169.3, 139.6, 131.8, 130.4, 117.0, 62.0, 60.7, 58.9, 39.6, 35.5, 34.2, 17.8, 14.9, 14.1, 13.9. IR (neat): 3609, 3584, 2982, 1738, 1647, 1367, 1263, 1209, 1042, 864 cm-1. nOe correlation was seen with a proton on C-7 and the methyl protons on C-9. HRMS m/z calculated for C24H35NO9Na (M+Na) 504.2210, found 504.2209. Z-3c: 1H NMR (400 MHz, CDCl3): δ (ppm) 5.59 (t, J = 5.6 Hz, 2H), 5.10 (s, 1H), 4.90 (s, 1H), 4.15 -4.24 (m, 8H), 3.21 (q, J= 6.6 Hz, 2H) 3.14 (s, 2H), 2.84 (s, 2H), 1.84 (s, 3H), 1.26 (m, 12H), 1.06 (t, J = 7.2 Hz, 3H). 13C {1H} NMR (75 MHz, CDCl3): δ (ppm) 172.5, 169.5, 169.4, 141.0. 133.8, 131.2, 116.4, 61.8, 61.7, 58.5, 55.9, 31.4, 14.0, 12.9, 3.8. IR (neat): 3584, 3402, 2982, 1735, 1519, 1266, 913 cm-1. nOe correlation was seen with vinylic proton on C-7 and methylene protons on C-6. HRMS m/z calculated for C28H41NO9Na (M+Na) 504.2210, found 504.2207. Compounds (Z)- and (E)-tetraethyl- 4-methylene-5-(1- oxo1-(phenylamino)propan-2-ylidene)cyclohexane-1,1,2,2- tetracarboxylate (Z/E-3d): General cycloaddition procedure was used with enyne 1a (100 mg, 0.24 mmol), phenyl isocyanate (29.1 mg, 0.24 mmol) 2d, Ni(COD)2 (6.77 mg, 0.024 mmol), IPr (18.9 mg, 0.048 mmol) and 2.4 ml toluene and stirred for 2 h at 60 °C. The crude compound was 41 purified by flash chromatography eluting with 30 % EtOAc/hexanes to yield compound E-3d and compound Z-3d as oils (105 mg, 79 %). E-3d: 1H NMR (400 MHz, CDCl3): δ (ppm). 8.10 (s, 1H), 7.5 (d, J = 7.6 Hz, 2H), 7.33 (t, J = 6Hz, 2H), 7.13 (t, J = 5.4 Hz, 1H), 5.20 (s, 1H), 4.99 (s, 1H), 4.15-4.26 (m, 8H), 3.16 (s, 2H), 2.99 (m, 2H), 2.07 (s, 3H), 1.15-1.4 (m, 12H). 13C {1H} NMR (100 MHz, CDCl3): δ (ppm) 169.9, 169.2, 139.5, 138.3, 132.2, 130.5, 129.2, 124.3, 119.8, 117.3, 62.2, 62.1, 60.4, 59.3, 39.8, 35.6, 18.1, 14.1, 13.9. IR (neat): 3348, 2984, 1738, 1673, 1532, 1441, 1266, 1041, 915, 732 cm-1. nOe correlation was seen with a proton on C-7 and the methyl protons on C-9. HRMS calculated m/z for C28H35NO9Na (M+Na) 552.2210, found 552.2205. Z-3d: 1H NMR (400 MHz, CDCl3): δ (ppm) 7.55 (s, 1H), 7.48 (d, J = 8 Hz, 2H), 7.31 (t, J = 7.6 Hz, 2H), 7.09 (t, J = 4.1 Hz, 1H), 5.20 (s, 1H), 4.99 (s, 1H), 4.25 (m, 8H), 3.23 (s, 2H), 2.89 (s, 2H), 1.95 (s, 3H), 1.42-1.28 (m, 12H). 13C {1H} NMR (100 MHz, CDCl3): δ (ppm) 170.6, 169.5, 169.4, 141.2, 138.7, 135.3, 131.4, 129.1, 124.2, 119.8, 117.1, 62.2, 62.1, 60.9, 58.6, 38.7, 33.5, 15.9, 14.1, 14.0. IR (neat): 3365, 2984, 1739, 1681, 1598, 1440, 1267, 1043, 915 cm-1. nOe correlation was seen with vinylic proton on C-7 and methylene protons on C-6. HRMS calculated for m/z C28H35NO9Na (M+Na) 552.2210, found 558.2208. Compounds (Z) and (E)-tetraethyl 4-(1-(4-methox-yphenylamino)- 1-oxopropan-2-ylidene)-5-methyl- 42 enecyclohexane-1,1,2,2-tetracarboxylate (Z/E-3e): General cycloaddition procedure was used with enyne 1a (100 mg, 0.24 mmol), p-methoxyphenyl isocyanate (36.3 mg, 0.24 mmol) 2e, Ni(COD)2 (6.7 mg, 0.024 mmol), IPr (18.9 mg, 0.048 mmol) and 2.4 ml toluene and stirred for 2 h at 60° C. The crude compound was purified by flash chromatography eluting with 30 % EtOAc/hexanes to yield compound E-3e as a colorless solid (m.p. 119-120 °C) and compound Z-3e as an oil (102 mg, 74 %). E-3e: 1H NMR (400 MHz, CDCl3): δ (ppm) 7.96 (s, 1H), 7.48 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 5.19 (s, 1H), 5.0 (s, 1H), 4.05 -4.20 (m, 8H), 3.80 (s, 3H), 3.15 (s, 2H), 2.99 (s, 2H), 2.07(s, 3H), 1.05-1.25 (m, 12H). 13C {1H} NMR (100 MHz, CDCl3): δ (ppm) 169.9, 169.7, 169.2, 156.6, 139.7, 132.3, 131.4, 130.6, 121.7, 117.2, 114.4, 62.2, 62.0, 60.5, 59.4, 55.7, 39.9, 35.7, 18.0, 14.1, 13.9. IR (neat): 3351, 2984, 2253, 1739, 1513, 1248, 1038 cm-1. nOe correlation was seen with a proton on C- 7 and the methyl protons on C-8. HRMS calculated for m/z C29H37NO10Na (M+Na) 582.2315, found 582.2314. Z-3e: 1H NMR (400 MHz, CDCl3): δ (ppm) 7.42 (s, 1H), 7.38 (d, J = 9.2 Hz, 2H), 6.85 (d, J = 9.2 Hz, 2H), 5.16 (s, 1H), 4.94 (s, 1H), 4.05-4.24 (m, 8H), 3.79 (s, 3H), 3.23 (s, 2H), 2.88 (s, 2H), 1.94 (s, 3H), 1.20-1.28 (m, 12H) . 13C {1H} NMR (100 MHz, CDCl3): δ (ppm) 170.5, 169.5, 169.4, 156.7, 141.3, 135.1, 131.9, 131.5, 121.7, 116.9, 114.4, 62.2, 62.1, 61.1, 58.7, 55.7, 38.8, 33.6, 29.9, 16.0, 14.1, 14.0. IR (neat): 3372, 2985, 2937, 2253, 1729, 1513, 1268, 911 cm-1. nOe correlation was seen 43 with vinylic proton on C-7 and methylene protons on C-6. HRMS calculated for m/z C29H37NO10Na (M+Na) 582.2315, found 582.2313. Compounds (Z) and (E)-tetraethyl- 4-methylene-5-(1 -oxo-1-(4-(trifluoromethyl)phenylamino)propan-2- ylidene)cyclohexane-1,1,2,2-tetracarboxylate (Z/E- 3f): General cycloaddition procedure was used with enyne 1a (100 mg, 0.24 mmol), 4- trifluoromethylphenyl isocyanate (36.3 mg, 0.24 mmol) 2f, Ni(COD)2 (6.8 mg, 0.024 mmol), IPr (18.9 mg, 0.048 mmol) and 2.4 ml toluene and stirred for 7 h at 100° C. The crude compound was purified by flash chromatography eluting with 30 % EtOAc/hexanes to yield compound E-3f and compound Z-3f as oils (83.2 mg, 57 %). E-3f: 1H NMR (400 MHz, CDCl3): δ (ppm) 8.52 (s, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 8.8 Hz, 2H), 5.22 (s, 1H), 5.01 (s, 1H), 4.15-4.21 (m, 8H), 3.16 (s, 2H), 2.95 (s, 2H), 2.08 (s, 3H), 1.15-1.40 (m, 12H). 13C {1H} NMR (100 MHz, CDCl3): δ (ppm) 170.2, 169.9, 169.1, 141.5, 139.4, 132.8, 130.2, 126.5 (q, J= 18.4 Hz), 119.4, 117.6, 62.4, 62.1, 60.3, 59.6, 39.9, 35.7, 18.1, 14.1, 13.9. IR (neat): 3339, 2985, 2940, 2257, 1737, 1684, 1368, 1262 cm-1. HRMS calculated for m/z C28H41NO9Na (M+Na) 620.2083, found 620.2079. Z-3f: 1H NMR (400 MHz, CDCl3): δ (ppm). 7.79 (s, 1H), 7.59 (m, 4H), 5.14 (s, 1H), 4.93 (s, 1H), 4.15- 4.25 (m, 8H), 3.24 (s, 2H), 2.88 (s, 2H), 1.94 (s, 3H), 1.29 (m, 12H). 13C {1H} NMR (100 MHz, CDCl3): δ (ppm) 170.9, 169.5, 169.3, 141.9, 141.4, 136.3, 125.7, 126.4 (q, J = 15.2 Hz), 119.4, 119.3, 117.4, 62.3, 62.2, 61.1, 58.6, 44 38.6, 33.6, 15.9, 14.1, 14.0. IR (neat): 3356, 2986, 1739, 1692, 1324, 1266, 1117, 919 cm-1. nOe correlation was seen with vinylic proton on C-7 and methylene protons on C- 6. HRMS calculated for m/z C28H41NO9Na (M+Na) 620.2083, found 620.2079. Preparation of compounds (Z)- and (E)-tetraethyl-4 methylene-5-(1-oxo-1-(4(trifluoromethoxy)phenyl amino)propan-2-ylidene)cyclohexane-1,1,2,2-tetra carboxylate (Z/E-3g): General cycloaddition procedure was used with enyne 1a (100 mg, 0.24 mmol), 4-(trifluoromethoxy)phenyl isocyanate (49.5 mg, 0.24 mmol) 2g, Ni(COD)2 (6.80 mg, 0.024 mmol), IPr (18.9 mg, 0.048 mmol) and 2.4 ml toluene and stirred for 5 h at 80° C. The crude compound was purified by flash chromatography eluting with 30 % EtOAc/hexanes to yield compound E-3g and compound Z-3g as oils (99.8 mg, 66.7 %). E-3g: 1H NMR (400 MHz, CDCl3): δ (ppm) 8.36 (s, 1H), 7.61 (d, J = 12.4 Hz, 2H), 7.17 (d, J = 10.8 Hz, 2H), 5.19 (s, 1H), 4.98 (s, 1H), 4.18 (m, 8H), 3.14 (s, 2H), 2.96 (s, 2H), 2.05 (s, 3H), 1.24 (m, 12H). 13C {1H} NMR (100 MHz, CDCl3): δ (ppm) 169.9, 169.1, 145.4, 139.5, 137.1, 132.7, 130.3, 126.49, 121.9, 121.0, 117.4, 62.3, 62.1, 60.3, 59.6, 39.9, 35.7, 18.0, 14.1, 13.9. IR (neat): 3339, 2985, 2874, 1738, 1265, 1203, 1058, 918 cm-1. HRMS calculated for m/z C28H41NO9Na (M+Na) 636.2033, found 636.2027. Z-3g: 1H NMR (400 MHz, CDCl3): δ (ppm) 7.67(s, 1H), 7.51 (d, J = 9.2 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 5.14 (s, 1H), 4.94 (s, 1H), 4.05-4.25 (m, 8H), 3.24 (s, 2H), 2.88 (s, 2H), 1.93 (s, 3H) 1.05- 1.29 (m, 12H). 13C {1H} NMR (100 MHz, 45 CDCl3): δ (ppm) 170.8, 169.5, 169.3, 145.3, 141.4, 137.4, 135.9, 131.2, 121.9, 120.9, 117.2, 62.3, 62.1, 61.1, 58.6, 38.7, 33.5, 15.9, 14.1, 14.0. IR (neat): 3358, 2985, 2940, 2255, 1738, 1682, 1512, 1265, 1200, 1107, 1043, 919, 861 cm-1. nOe correlation was seen between the two vinylic proton on C-7. HRMS calculated for m/z C28H41NO9Na (M+Na) 636.2033, found 636.2031. Compounds (Z)- and (E)-tetraethyl 4-methylene-5-[1-oxo -1-(o-tolylamino) propan-2-ylidene]cyclohexane-1,1,2,2- tetracarboxylate (Z/E-3h): The general cycloaddition procedure was used with enyne 1a (100 mg, 0.24 mmol), 2-methylphenyl isocyanate (32.4 mg, 0.24 mmol) 2h, Ni(COD)2 (6.77 mg, 0.024 mmol), IPr (18.9 mg, 0.048 mmol) and 2.4 ml toluene and stirred for 1 h at 80° C. The crude compound was purified by flash chromatography eluting with 30 % EtOAc/ hexanes to yield compounds E-3h and Z-3h as an inseparable mixture of isomers as an oil (94 mg, 71 %). E-3h and Z-3h: 1H NMR (400 MHz, CDCl3): δ (ppm 7.94 (d, J = 7.2 Hz, 2H), 7.76 (d, J = 7.8 Hz, 2H), 7.60 (s, 1H), 7.44 (s, 2H), 7.23-7.08 (m, 6H), 7.03 (q, J = 4.8 Hz, 2H), 5.22-5.19 (m, 3H), 4.99 (d, J = 2.1 Hz, 1H), 4.94 (d, J = 1.5 Hz, 2H), 4.28 - 4.09 (m, 16H), 3.21 (d, 6H), 3.02 (s, 2H), 2.88 (s, 4H), 2.27 (d, J = 11.4 Hz, 8H), 2.10 (s, 3H), 1.95 (s, 6H), 1.31- 1.71 (m, 24H). 13C {1H} NMR (100 MHz, CDCl3): δ (ppm) 170.6, 170.1, 169.7, 169.3, 169.3, 169.2, 141.1, 139.5, 136.4, 135.6, 134.7, 132.4, 131.4, 130.7, 130.5, 130.3, 130.2, 128.2, 126.8, 125.6, 124.6, 123.8, 121.1, 117.3, 62.2, 62.0, 61.9, 60.9, 60.5, 59.0, 58.5, 46 39.7, 38.9, 35.7, 33.4, 18.1, 17.7, 16.1, 14.0, 13.9, 13.8. IR (neat): 3386, 2983, 2939, 2906, 2248, 1726, 1682, 1517, 1268, 1200, 1096, 1057, 1044, 919, 863, 702 cm-1. HRMS m/z calculated for C28H41NO9Na (M+Na) 566.2366, found 566.2368. Compounds (Z)- and (E)-tetraethyl 4-[1-(2,6)-dimethyl phenylamino]-1-(oxopropan-2-ylidene)-5-methylenecyclo hexane-1,1,2,2-tetracarboxylate (Z/E-3i): General cycload dition procedure was used with enyne 1a (100 mg, 0.24 mmol), 2,6-dimethylphenyl isocyanate (35.8 mg, 0.24 mmol) 2i, Ni(COD)2 (6.77 mg, 0.024 mmol), IPr (18.9 mg, 0.048 mmol) and 2.4 ml toluene and stirred for 1.5 h at 80 ° C. The crude compound was purified by flash chromatography eluting with 30 % EtOAc/hexanes to yield compound E-3i as a colorless solid (m.p. 138-140 °C) and compound Z-3i as oil (109 mg, 80 %). E-3i:1H NMR (400 MHz, CDCl3): δ (ppm) 7.33 (s, 1H), 7.09 (s, 3H), 5.20 (s, 1H), 4.99 (d, J = 1.2 Hz, 1H), 4.18- 4.25 (m, 8H), 3.28 (s, 2H), 3.06 (s, 2H), 2.28 (s, 6H), 2.14 (s, 3H), 1.20-1.24 (m, 12H). 13C {1H} NMR (100 MHz, CDCl3): δ (ppm) 170.4, 169.8, 169.3, 139.6, 135.8, 133.7, 132.2, 130.1, 128.5, 127.5, 117.2, 62.1, 60.8, 59.1, 39.8, 36.1, 19.0, 18.3, 14.1, 13.9. IR (neat): 3354, 2983, 2240, 1739, 1270, 1041 cm-1. HRMS calculated for m/z C30H39NO9Na (M+Na) 580.2523, found 580.2515. Z-3i: 1H NMR (400 MHz, CDCl3): δ (ppm) 7.22 (s, 1H), 7.06 (s, 3H), 5.32 (s, 1H), 5.029 (s, 1H), 4.15- 4.23 (m, 8H), 3.29 (s, 2H), 2.90 (s, 2H), 2.23 (s, 6H), 1.98 (s, 3H), 1.15-1.30 (m, 12H). 13C {1H} NMR (100 MHz, CDCl3): δ (ppm) 170.8, 169.5, 169.4, 141.5, 135.8, 133.9, 133.6, 130.9, 128.6, 127.6, 117.9, 62.24, 62.0, 61.2, 58.7, 39.0, 33.6, 47 18.7, 16.5, 14.1, 14.0. IR (neat): 3368, 2982, 2360, 1738, 1266, 1041 cm-1. nOe correlation was seen between the two vinylic protons on C-7. HRMS m/z calculated for C28H41NO9Na (M+Na) 580.2523, found 580.2515. Compounds (Z)- and (E)-tetraethyl-4-[1(cyclohexylam ino)-1-oxobutan-2-ylidene)-5-methylenecyclohexane-1,1 2,2-tetracarboxylate (Z/E-3j): General cycloaddition procedure was used with enyne 1b (100 mg, 0.23 mmol), cyclohexylisocyanate (29.5 mg, 0.23 mmol) 2a, Ni(COD)2 (6.80 mg, 0.023 mmol), IPr (18.9 mg, 0.046 mmol) and 2.3 ml toluene and stirred for 4 h at room temperature. The crude compound was purified by flash chromatography eluting with 30 % EtOAc/hexanes to yield compounds E-3j as a colorless solid (m.p. 88- 90 °C) and Z-3j as an oil (116 mg, 89 %). E-3j: 1H NMR (300 MHz, CDCl3): δ (ppm) 5.81 (d, J= 8.7 Hz, 1H), 5.06 (s, 1H), 4.93 (d, J = 1.8 Hz, 1H), 4.20 (m, 8H), 3.80-3.91 (m, 1H), 3.0 (d, J = 7.2 Hz, 4H), 2.43 (q, J= 7.5 Hz, 2H), 1.90-1.95 (m, 2H), 1.6-1.8 (m, 4H), 1.58-1.05 (m, 12H), 0.99 (t, J= 7.2, 3H). 13C {1H} NMR (75 MHz, CDCl3): δ (ppm) 169.8, 169.8, 169.3, 139.9, 136.8, 131.2, 116.1, 62.0, 61.9, 61.0, 58.8, 47.9, 39.8, 35.7, 33.3, 30.5, 29.8, 25.8, 25.0, 24.1, 14.1, 13.9, 13.5. IR (neat): 3385, 3068, 2982, 2253, 1727, 1641, 1268, 1206, 912 cm-1. nOe correlation was seen between a vinylic proton on C-7 and the protons of the ethyl group on C-8. HRMS m/z calculated for C29H43NO9Na (M+Na) 572.2836, found 572.2831. Z-3j: 1H NMR (300 MHz, CDCl3): δ (ppm) 5.61 (d, J= 8.7 Hz, 1H), 5.16 (s, 1H), 4.89 (s, 1H), 4.12- 4.30 (m, 48 8H), 3.71-3.80 (m, 1H), 3.19 (s, 2H), 2.80 (s, 2H), 2.27 (q, J= 5.7 Hz, 2H), 1.7-1.85 (m, 2H), 1.5-1.72 (m, 4H), 1.20-1.0 (m, 16H), 0.94 (t, J= 7.5 Hz, 3H). 13C {1H} NMR (75 MHz, CDCl3): δ (ppm) 170.9, 169.5, 141.2, 137.8, 133.1, 116.6, 62.2, 61.9, 61.2, 58.6, 47.6, 38.8, 33.1, 32.6, 25.8, 24.9, 23.0, 14.1, 12.8. IR (neat): 3394, 3087, 2981, 2856, 2253, 1730, 1640, 1267, 913 cm-1. nOe correlation was seen between the two vinylic protons on C-7. HRMS m/z calculated for C29H43NO9Na (M+Na) 572.2836, found 572.2834. Compounds (Z) and (E)-tetraethyl 4-methylene-5-(1oxo- 1-(phenylamino)butan-2-ylidene)cyclohexane-1,1-2,2- tetracarboxylate (Z/E-10k): General cycloaddition procedure was used with enyne 1b (100 mg, 0.23 mmol), phenylisocyanate (28.1 mg, 0.23 mmol) 2b, Ni(COD)2 (6.80 mg, 0.023 mmol), IPr (18.9 mg, 0.046 mmol) and 2.3 ml toluene and stirred for 6 h at room temperature. The crude compound was purified by flash chromatography eluting with 30 % EtOAc/hexanes to yield compound E-3k and compound Z-3k as oils (115 mg, 89 %). E-3k: 1H NMR (400 MHz, CDCl3): δ (ppm) 7.98 (s, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 7.6 Hz, 2H), 7.12 (t, J = 7.6 Hz, 1H), 5.13 (s, 1H), 5.01 (s, 1H), 4.15-4.24 (m, 8H), 3.13 (s, 2H), 3.02 (s, 2H), 2.54 (q, J = 7.6 Hz, 2H), 1.09 (s, 3H), 1.19-1.30 (m, 8H), 1.09 (t, J = 7.6 Hz, 3H). 13C {1H} NMR (100 MHz, CDCl3): δ (ppm) 169.9, 169.2, 139.9, 138.2, 136.9, 132.0, 129.2, 124.4, 120.0, 116.4, 62.2, 62.1, 60.8, 59.4, 40.0, 36.1, 30.5, 29.9, 24.6, 14.1, 13.9, 13.7. IR (neat): 3370, 2983, 2937, 2253, 1727, 1656, 1270, 1200, 912, 733 cm-1. nOe correlation was seen between a vinylic proton on C-7 and the 49 protons of the ethyl group on C-8. HRMS m/z calculated for C29H37NO9Na (M+Na) 566.2366, found 566.2353. Z-3k: 1H NMR (300 MHz, CDCl3): δ (ppm) 7.63 (s, 1H), 7.50 (d, J = 5.4 Hz, 2H), 7.31 (t, J = 5.7 Hz, 2H), 7.09 (t, J = 5.4 Hz, 1H), 5.17 (s, 1H), 4.92 (s, 1H), 4.29-4.17 (m, 8H), 3.26 (s, 2H), 2.86 (s, 2H), 2.37 (q, J = 5.7 Hz, 2H), 1.25-1.32 (m, 12H), 1.01 (t, J = 5.7 Hz, 3H). 13C {1H} NMR (75 MHz, CDCl3): δ (ppm) 170.3, 169.5, 169.4, 141.5, 138.8, 137.8, 134.9, 129.1, 124.2, 119.8, 117.2, 62.3, 62.1, 61.3, 58.6, 38.6, 33.2, 23.2, 14.1, 12.9. IR (neat): 3372, 2981, 2935, 1727, 1683, 1269, 1039 cm-1. nOe correlation was seen between the two vinylic protons on C-7. HRMS m/z calculated for C29H37NO9Na (M+Na) 566.2366, found 566.2361. Compounds (Z)- and (E)-diethyl-3-(1-cyclohexylamino) 1-oxopropan-2-ylidene)-4-methylenecyclopentane-1,1- dicarboxylate (Z/E-3l): General cycloaddition procedure was used with enyne 1c (50 mg, 0.2 mmol), cyclohexylisocyanate (24.8 mg, 0.2 mmol) 2a, Ni(COD)2 (5.5 mg, 0.02 mmol), IPr (15.5 mg, 0.04 mmol), 2 ml toluene and stirred for 4 h at 80 °C. The crude compound was purified by flash chromatography eluting with 30 % EtOAc/hexanes to yield compounds E-3l and Z-3l as oils (48.7 mg, 65 %). E-3l: 1H NMR (300 MHz, CDCl3): δ (ppm) 5.86 (d, J = 8.1 Hz, 1H), 5.25 (d, J = 9.3 Hz, 2H), 4.18 (q, J = 7.2 Hz, 4H), 3.76-3.92 (m, 1H), 3.11 (s, 2H), 3.04 (s, 2H), 2.05 (s, 3H), 1.90-2.02 (m, 2H), 1.56-1.8 (m, 6H), 1.1-1.4 (m, 8H). 13C {1H} NMR (75 MHz, CDCl3): δ (ppm) 171.4, 170.6, 144.7, 135.9, 129.4, 113.7, 61.9, 57.5, 48.3, 42.2, 40.3, 33.2, 30.5, 50 29.9, 25.7, 25.1, 17.9, 14.2. IR (neat): 3372, 2982, 2933, 2856, 2244, 1730, 1632, 1524, 1242, 971, 733 cm-1. nOe correlation was seen between a vinylic proton on C-6 and the protons of the methyl group on C-8. HRMS m/z calculated for C21H31NO5Na (M+Na) 400.2100, found 400.2099. Z-3l: 1H NMR (400 MHz, CDCl3): δ (ppm) 5.44 (d, J = 8.4 Hz, 1H), 5.32 (s, 1H), 5.06 (s, 1H), 4.19 (q, J = 7.5 Hz, 4H), 3.70-3.88 (brm,1H), 2.97-3.02 (s, 3H), 1.92 (s, 3H), 1.8-1.9 (m, 2H), 1.57-1.77 (m, 6H), 1.32-1.10 (m, 8H). 13C {1H} NMR (75 MHz, CDCl3): δ (ppm) 171.4, 170.7, 142.5, 134.3, 128.5, 111.0, 61.9, 57.0, 48.0, 42.4, 39.0, 32.7, 25.7, 25.0, 19.1, 14.2. IR (neat): 3375, 3285, 2981, 2931, 2855, 2361, 1733, 1625, 1247, 1190, 1159, 891, 862 cm-1. HRMS m/z calculated for C21H31NO5Na (M+Na) 400.2100, found 400.2102 Compounds (Z)- and (E)-diethyl-3-methylene-4-(1-oxo-1- phenylamino)propan-2-ylidene)cyclopentane-1,1-dicarbox ylate (Z/E-3m): General cycloaddition procedure was used with enyne 1c (50 mg, 0.2 mmol), phenyl isocyanate (23.7 mg, 0.2 mmol) 2b, Ni(COD)2 (5.5 mg, 0.02 mmol), IPr (15.5 mg, 0.04 mmol) and 2 ml toluene and stirred for 3 h at 80 °C. The crude compound was purified by flash chromatography eluting with 30 % EtOAc/hexanes to yield compounds E-3m and Z-3m both as oils (72 mg, 72 %). E-3m: 1H NMR (300MHz, CDCl3): δ (ppm) 8.24 (s, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.35 (t, J = 7.5 Hz, 2H), 7.15 (s, 1H), 5.34 (s, 2H), 4.21 (q, J = 7.2 Hz, 4H), 3.14 (s, 4H), 2.16 (s, 3H), 1.25 (t, J = 6.9 Hz, 6H). 13C {1H} NMR (75 MHz, CDCl3): δ (ppm) 171.5, 169.6, 51 144.2, 138.4, 136.8, 129.4, 129.2, 124.4, 119.9, 114.3, 62.1, 57.4, 41.7, 40.5, 17.8, 14.2. IR (neat): 3299, 2982, 1733, 1654, 1533, 1239, 1074, 904, 861, 757 cm-1. nOe correlation between the vinylic proton on C-6 and the methyl protons on C-7. HRMS m/z calculated for C21H25NO5Na (M+Na) 394.1630, found 394.1642. Z-3m: 1H NMR (300 MHz, CDCl3): δ (ppm) 7.52 (d, J = 8 Hz, 2H), 7.34 (t, J = 7.6 Hz, 3H), 7.13 (t, J = 7.2 Hz, 1H), 5.30 (s, 1H), 5.12 (s, 1H), 4.23 (q, J = 7.2 Hz, 4H), 3.06 (s, 4H), 2.31 (s, 3H), 1.27 (t, J = 7.2 Hz, 6H). 13C {1H} NMR (75 MHz, CDCl3): δ (ppm) 171.3, 169.4, 142.7, 138.2, 136.1, 129.3, 128.3, 124.6, 119.8, 111.9, 62.02, 56.9, 42.3, 39.2, 18.8, 14.2. IR (neat): 3306, 2980, 1731, 1665, 1255, 1194, 1096, 756 cm-1. nOe correlation between the two vinylic protons on C-6. HRMS m/z calculated for C21H25NO5Na (M+Na) 394.1630, found 394.1639. Compounds (Z)- and (E)-N-cyclohexyl-2-(2-methylene- 1H-quinolizin-3(2H,4H,6H,7H,8H,9H,9aH)ylidene)butana mide (Z/E-3n): General cycloaddition procedure was used with enyne 1d (100 mg, 0.52 mmol), cyclohexylisocyanate (65.5 mg, 0.52 mmol) 2b, Ni(COD)2 (14.30 mg, 0.052 mmol), IPr (40.4 mg, 0.104 mmol) and 5.2 ml toluene and stirred for 3 h at 80 °C. The crude compound was purified by flash chromatography eluting with 30 % EtOAc/hexanes to yield compounds E-3n as a colorless solid (m.p.172-175 °C) and Z-3n as an oil (131 mg, 79 %). E-3n: 1H NMR (400 MHz, CDCl3): δ (ppm) 5.76 (m, 1H), 4.98 (s, 1H), 4.79 (s, 1H), 3.85-3.92 (m, 1H), 3.40-3.52 (m, 52 1H), 2.80-2.85 (m, 1H), 2.57-2.60 (m, 1H), 2.30-2.50 (m, 2H), 2.20-2.25 (m, 1H), 1.93- 2.10 (m, 6H), 1.52-1.740 (m, 8H), 1.15-1.43 (m, 6H), 1.01 (t, J = 7.6 Hz, 3H). 13C {1H} NMR (75 MHz, CDCl3): δ (ppm) 169.8, 143.8, 134.6, 134.3, 111.9, 63.9, 60.6, 56.1, 48.3, 43.6, 33.4, 32.9, 25.8, 25.7, 25.2, 24.1, 23.9, 13.5. IR (neat): 3372, 2981, 2935, 1727, 1683, 1269, 1039 cm-1. nOe correlation between a vinylic proton on C-7 and the ethyl protons on C-8. HRMS m/z calculated for C20H33N2ONa (M+Na) 317.2593, found 317.2588. Z-3n: 1H NMR (300 MHz, CDCl3): δ (ppm) 5.41-5.39 (m, 1H), 5.05 (s, 1H), 4.80 (s, 1H), 3.60-3.80 (m, 1H), 3.57-3.60 (m, 1H), 3.53 (s, 1H), 2.80-2.92 (m, 1H), 1.8-2.4 (m, 6H), 1.4-1.8 (m, 6H) 0.8-1.4 (m, 8H),. 13C {1H} NMR (75 MHz, CDCl3): δ (ppm) 170.2,143.6, 135.7, 133.7, 113.1, 63.4, 57.6, 56.4, 47.6, 42.9, 33.3, 33.1, 25.7, 25.6, 24.8, 24.1, 23.4, 13.2. IR (neat): 3372, 2981, 2935, 1727, 1683, 1269, 1039 cm-1. nOe correlation between the two vinylic protons on C-7. HRMS m/z calculated for C20H33N2ONa (M+Na) 317.2593, found 317.2593. Compounds (Z)- and (E)-2-(2-methylene)-1H-quinolizin- 3(2H,4H,6H,7H,8H,9H,9aH)-ylidene)-N-phenylbutanamide (Z/E-3o): General cycloaddition procedure was used with enyne 1d (100 mg, 0.52 mmol), phenyl isocyanate (62.5 mg, 0.52 mmol) 2b, Ni(COD)2 (14.30 mg, 0.052 mmol), IPr (40.4 mg, 0.104 mmol) and 5.2 ml toluene and stirred for 3 h at 80 °C. The crude compound was purified by flash chromatography eluting with 30 % EtOAc/hexanes to yield compound E-3o as a colorless solid (m.p. 98 -100 °C) and compound Z-3o as oil (115 mg, 71 %). 53 E-3o: 1H NMR (300 MHz, CDCl3): δ (ppm) 8.08 (m, 1H), 7.62 (d, J = 5.7 MHz, 2H), 7.20-7.35 (m, 2H), 7.12 (t, J = 7.2 Hz, 2H), 5.04 (s, 1H), 4.85 (s, 1H), 3.65-3.70 (m, 1H), 2.9-3.1 (s, 1H), 2.81 (d, J= 11.2 Hz, 1H), 2.66 (d, J= 12 Hz, 1H), 2.49-2.58 (m, 2H), 2.31 (m, 1H), 2.01-2.15 (m, 3H), 1.59-1.76 (m, 4H), 1.24 -1.56 (m, 2H), 1.09 (t, J = 7.6 Hz, 3H). 13C {1H} NMR (75 MHz, CDCl3): δ (ppm) 169.6, 144.0, 138.5, 129.6, 124.8, 120.4, 112.3, 64.4, 61.0, 56.4, 44.0, 33.3, 26.0, 24.4, 24.4, 14.0. IR (neat): 3275, 2930, 2798, 1672, 1590, 1539, 1250, 735, 690 cm-1. nOe correlation between a vinylic proton on C-7 and the ethyl protons on C-8. HRMS m/z calculated for C20H27N2O (M+Na) 311.2123, found 311.2124. Z-3o: 1H NMR (300 MHz, CDCl3): δ (ppm) 7.43-7.55 (m, 3H), 7.29 (d, J = 7.2 Hz, 2H), 7.05-7.09 (m, 1H), 5.06 (t, J = 2 Hz, 1H), 4.85 (m, 1H), 3.61 (d, J = 12.4 Hz, 1H), 2.95-3.0 (m, 1H), 2.55-2.61 (m, 1H), 1.90-2.46 (m, 4H), 1.45-1.80 (m, 4H ), 1.05-1.20 (m, 6H ). 13C {1H} NMR (75 MHz, CDCl3): 169.9, 143.8, 138.6, 135.4, 135.4, 129.1, 124.3, 119.8, 113.4, 63.3, 57.6, 56.4, 42.7, 33.1, 25.7, 24.1, 23.5, 13.4. IR (neat): 3285, 2935, 2798, 1662, 1598, 1539, 1247, 907, 732, 693 cm-1. nOe corelation between the two vinylic protons on C-7. HRMS m/z calculated for C20H27N2O (M+Na) 311.2123, found 311.2122. Synthesis of (E)-tetraethyl-2-butyryl-4-methylene-5[(trimethyl silyl)methylene)]cyclohexane-1,1,2-tricarboxylate (3p): General cycloaddition procedure was used with enyne 1e (50 mg, 0.11 mmol) and cyclohexylisocyanate 2a (13.35 mg, 0.11 mmol), Ni(COD)2 (3.0 mg, 0.011 54 mmol), IPr (8.54 mg, 0.022 mmol) and stirred for 24 h at 100 C. The crude compound was purified by column chromatography eluting with 30 % EtOAc/hexanes to yield compound 3p as an oil (13.8 mg, 31 %). 1H NMR (300 MHz, CDCl3) δ (ppm) 8.24 (s, 1H), 5.94 (s, 1H), 5.12 (s, 1H), 5.03 (s, 1H), 4.18 (m, 8H), 2.16 (s, 3H), 1.73 (s, 2H), 1.21-1.29 (m, 12H), 0.03 (s, 9H). 13C {1H} NMR (75 MHz, CDCl3): δ (ppm). 169.3, 139.0, 136.8, 120.7, 113.6, 62.0, 61.9, 60.3, 36.3, 29.9, 22.5, 14.0, -0.9 ppm. HRMS m/z calculated for C23H36O8NaSi (M+Na) 491.2077, found 491.2071. Synthesis of tetraethyl-2-cyclohexyl-3-oxo-3,4,4a,5-tetra hydroisoquinoline-6,6,7,7(2H,8H)-tetracarboxylate (10): General cycloaddition procedure was used with enyne 1f and cyclohexylisocyanate (31.6 mg, 0.25 mmol) 2a, Ni(COD)2, IPr, and toluene stirring for 4 h at 80 C. The crude compound was purified by flash chromatography eluting with 30 % EtOAc/hexanes to yield compound 10 as an oil (9.5 mg, 15 %). 1H NMR (300 MHz, CDCl3) δ (ppm) 5.89 (s, 1H), 4.0-4.3 (m, 8H), 3.4-3.6 (m, 1H), 2.8-3.0 (m, 2H), 2.5-2.6 (m, 4H), 1.8-2.0 (m, 2H), 1.5-1.8, 1.0-1.2 (m, 6H), 1.2-1.4 (m, 14H). 13C {1H} NMR (75 MHz, CDCl3): δ (ppm) 170.6, 170.4, 168.9, 168.9, 167.6, 120.4, 114.6, 62.3, 62.1, 61.9, 61.7, 59.3, 51.5, 49.3, 38.8, 36.2, 34.2, 33.8, 31.7, 30.8, 29.9, 28.8, 25.9, 25.8, 14.2, 14.1 14.0 ppm. nOe correlation between the vinylic protons on C-10 with a) protons on the cyclohexyl ring, and b) protons on C-10. HRMS calculated for C27H33NO9Na (M+Na) 538.2053, found 538.2061. Synthesis of tetraethyl-3-oxo-2-phenyl-3,4,4a,5- tetrahydroisoquinoline-6,6,7,7(2H,8H)-tetracarboxylate 11: 55 General cycloaddition procedure was used with enyne 1f (100 mg, 0.25 mmol), phenyl isocyanate (30.1 mg, 0.25 mmol), NiCOD2 (6.87 mg, 0.025 mmol), IPr (19.4 mg, 0.050 mmol) and toluene 2.5 ml were stirred for 4 h at 80 C. The crude compound was purified by flash chromatography eluting with 30 % EtOAc/hexanes to yield compound 11 as an oil (25.4 mg, 19 %). 1H NMR (300 MHz, CDCl3) δ (ppm) 7.39 (t, J = 7.2 Hz , 2H), 7.23-7.29 (m, 3H), 6.09 (s, 1H), 4.17-4.32 (m, 8H), 2.76-2.93 (m, 4H), 2.61-2.50 (m, 2H), 2.26-2.30 (m, 1H), 1.18-1.38 (m, 12H). 13C {1H} NMR (75 MHz, CDCl3): δ (ppm) 171.6, 169.7, 144.2, 138.4, 136.8, 129.5, 129.2, 124.4, 119.9, 114.3, 62.1, 57.5, 41.8, 40.6, 17.9, 14.2. nOe correlation between the vinylic proton on C-10 and a) phenyl protons and b) protons on C-6. HMBC correlation between the vinylic proton on C-10 and a) C-8, b) C-6, and c) C-1'. HRMS m/z calculated for C28H41NO9Na (M+Na) 544.2523, found 544.2514 (E)-tetraethyl-2-(benzylimino)-7a-(bromomethyl)-3-methyl- 7,7'-dihydrobenzofuran-5,5,6,6(2H,4H)-tetracarboxylate (12): Compound 12 were prepared as described by Wang and co-workers. 8 Under nitrogen atmosphere, dienamide Z-3b (83 mg, 0.15 mmol), N-bromosuccinimide (27.2 mg, 0.15 mmol) and 1.5 ml THF were stirred at room temperature for 3 h. The reaction mixture was quenched with deionized water and extracted twice with dichloromethane (10 ml x 2 times). After drying the organic layer with MgSO4, the crude product was isolated and purified by flash chromatography (30 % ethyl acetate/ hexanes) to obtain compound 12 (50 mg, 53 %) as an oil. 1H NMR (400 MHz, C6D6) δ (ppm). 7.58-7.59 (s, 2H), 7.21 (t, J = 8.0 Hz, 2H), 7.11 (d, J = 7.2 Hz, 1H), 4.82 (dd, J = 15.0, 2.5 Hz, 2H), 3.80-4.11 (m, 8H), 3.1-3.6 (m, 6H), 1.79 (s, 3H), 0.86- 56 1.1 (m, 12H) 13C {1H} NMR (75 MHz, C6D6): δ (ppm) 170.3, 169.4, 162.2, 145.9, 142.2, 131.1, 128.9, 128.8, 127.9, 127.0, 85.6, 26.8, 62.6, 62.4, 61.5, 60.1, 52.0, 39.2, 30.6, 29.9, 29.2, 29.2, 14.1, 9.9. HRMS m/z calculated for C29H37NO9Br (M+H) 622.50, found 622.1652. (E)-tetraethyl-2-(benzylimino)-7a-(iodomethyl)-3-methyl -7,7'-dihydrobenzofuran-5,5,6,6(2H,4H)-tetracarboxylate (13): Compound 13 was prepared as described by Wang and co-workers.8 Under nitrogen atmosphere, compound Z-3b (30 mg, 0.06 mmol), iodine (16.8 mg, 0.07 mmol), and dichloromethane (0.6 ml) were stirred at room temperature for 8 h. The reaction was quenched with 1 ml deionozed water and extracted with dichloromethane (5 ml x 2). The organic layers were dried over MgSO4. The crude product was isolated and purified using silica gel flash chromatography with 30 % ethyl acetate/ hexanes to yield compound 13 (33.6 mg, 90 %) as an oil. 1H NMR (400 MHz, C6D6) δ (ppm) 7.58-7.59 (s, 2H), 7.21 (t, J = 8.0 Hz, 2H), 7.11 (d, J = 7.2 Hz, 1H), 4.82 (dd, J = 15.0, 2.5 Hz, 2H), 3.80-4.11 (m, 8H), 3.1-3.6 (m, 6H), 1.79 (s, 3H), 0.86-1.1 (m, 12H). 13C {13H} NMR (75 MHz, CDCl3): 170.3, 169.4, 162.2, 145.9, 142.2, 131.1, 128.9, 128.8, 127.9, 127.0, 85.6, 62.8, 62.6, 62.3, 61.5, 60.1, 52.0, 39.2, 30.6, 30.3, 30.3, 29.9. 29.2, 14.1, 9.9. HRMS calculated for C29H37NO9I (M+H) 670.14, found 670.1497. 57 :>(\..-=~- + :>< + E=C02Me + E' E' "r: Et E' = C02Et Ph'N C" 0" 3 mol % Ni(CODJ:, 6 mol % IPr, rt 86% 3 mol % Ni(COD), 3 mol % SIPr, rt 86% 5 mol % Ni(COD)2 10 mol % SIPr toluene, rt 87 % (>95:5) • Ev-h Ph E~N (2.1 ) • ,«X0 E "'" N'Ph (2.2) E' E' E,WPh Et • (2.3) enone + E' E'WPh E' "" 0 E' Et ketone 58 :~R'+ III + Ar Ar =-3,4-0Me-CsH3 R N=C=O 0, 'c ;> [M] • 5 mol % [Rh(C2H4hClii 10 mol % (-)-L toluene, 110°C 72 %, 95 % ee (1 :20) Ph Ph ><:r}-{J Ph Ph (-)-L R' " E,~O" E~~'R (2.4) 0 Arm H • lactam (2.5) Ar+ olp H vinylogous amide 59 o 10 mol % Ni(COO)2 10 mol % IPr Me--==--Ph + ~OMe 1,4- dioxane, 100 °C, 5 h 56 %, (2:1) + L' /; E' E' - E' - E' = C02Et 5 mol % Ni(COO)2 10 mol % IOTB, 60 °C, toluene 90% • o • Me:tq_Ph ~ OMe Pti + 0 o Phf-Q_Ph ~ OMe Me o E'M E ' E' E' "'" (2.6) (2.7) 60 Ph-N=C=O nhex~ + 0 C" ()~ 0.1 % SIPr, rt, THF 99% 10 mol % Ni(CODn 10 mol % IPr toluene 60°C 93 % (79:14) • (2.8) • nheXYll~D (2.9) 1,1-<lisubstituted + nhex~ND H 1,2-<lisubstiuted 61 Table 2.10 Nickel catalyzed cycloaddition of enyne 1a and cyclohexylisocyanate 2a EV E~ CyNCO E - 1a E = C02Et 2a entry ligand none 2 P(n-Buh 3 PPh3 4 P(p-Tolh 5 DPPF 6 BINAP 10 mol % Ni(COD)2 20 mol % IPr, toluene • % conversion of 1 ab 10 31 17 31 7 5 7 biphenp(t-Buk 17 8 ItBu 14 9 IMes 33 10 SIPr 90 11 IPr 100 3a % yield of 3ab nd nde nd nd nd nd nd nd nd 78 80 • Reaction conditions: 10 mol % Ni(COD)2, 20 mol % ligand, 0.1 M 1,0.11 M 2a, toluene, room temperature, 17h. b Determined by GC using naphthalene as an internal standard. e nd = not detectable by GC. (2.10) 62 Scheme 2.1 Possible mechanisms for dienamide formation 63 . H H tl'" 10 mol% Ni(COD)2 tl-& E ~ 20mol% IPr E ~ (2.13) • E E rt, 2h, dB-toluene E E no interconversion observed mtajolr is-om&er (HE-3b ) E ~ t(rH E E E ,r N'Bn 10 mol% Ni(COD12 (2.14) E 0 20 mol% IPr major isomer (E-3b) E rt, 2h, dB-toluene + 6:1 Interconverslon t(rH observed E ,r N'Bn E 0 E minor isomer (Z-3b) 64 E E E H 'rt 10 mol % Ni(COD)2 Eb:x + R-N=C=O 20 mol % IPr • R (2.15) II :::,.. 80°C,4h EE 0 0.1 M toluene H 1f R=Cy,2a 15 % Yield, 10 R= Ph, 2d 19 % Yield, 11 65 Table 2.2 Dienamide formation from enyne 1a and isocyanate 2a-2i entry isocyanate EIZ products reaction E:Z ratio· % yieldb time 1 Cy2NaC O X~ :xl'0 C, E/Z-3a rt, 1 h 5:1 70 2 BnNCO 2b ~xl'" X 0 E/Z-3b rt,2h 2:1 68 3 EtNCO ~:Xir~'" 2c X 0 E/Z-3c 80'C,lh 2:1 80 4 PhNCO ~=tr~'Ph 2d X 0 E/Z-3d 60'C,2h 2:1 79 5 Meo-Q-NCO ~:Xir~u E/Z-3a 60'C,2h 2:1 74 - X 0 -& 28 OMe :Xr-ir"N "'" 6 F3C-Q-NCO ~ 0 UC~Z-3f 100'C,7h 1.8:1 57 2f 3 :Xr-ir"N "'" 7 F3CO-Q--NCO X~ 0 U -& E/Z-3g 80'C,5h 2:1 66 2g OCF3 8 < }-NCO ~:Xir~D X 0 -& E/Z-3h 80'C,lh 2:1 71 2h 9 <~ ~:Xir:o E/Z-3i 80 'c, 1.5 h 2:1 80 X 0 -& Reaction condns: 1 equiv. 1, 1 equiv. 2 • Determined by 1 H-NMR, b isolated yields, average of 2 runs X = [C(C02Et)12 66 Table 2.3 Substrate scope using enynes 1b-1d and isocyanates 2a and 2b entry enyne isocyanate E, Z products reaction time E:Z ratio· %yieldb ,J Et H X ~:(rN'Cy 1 I CyNCO rt,4 h 4:1 89 X , X 0 Et X = [C(COhEt12 1b 28 EIZ-3j Et H PhNCO ~:(rN'Ph rt, 6 h 4:1 89 2 1b 2d X 0 EIZ-3k :L E~~'CY 3 E 0 80 DC, 4 h 4:1 65 E=C02Me 1c 28 ElZ-31 4 1c 2d Ex:(r~'Ph E 0 80 DC, 3 h 4:1 72 EIZ-3m Et H cc: Et cc:(rN,CY 5 28 80 DC, 3h 1.4:1 72 1d '\:::: EIZ-3n Et H 6 1d 2d cc:(rN'Ph 80 DC, 3 h 1.4:1 72 ,J EIZ-3o X I X 7 , SiMe3 no dienamide 1e 2aJ2d product isolated Reaction condns: 0.1 M enyne, 0.11 M isocyanate, 0.1 M toluene • determined by 1 H NMR b isolated yields, average of 2 runs 67 Scheme 2.3 Possible mechanism for lactam formation 68 Z-3b 1 equiv. NBS rt, THF, 3 h NaH,THF • ~Br • E1:*Bn ~ , -N E 0 E X X = Br, 12, 53 % Yield X = I, 13,90 % Yield 14 (2.16) (2.17) 69 70 References 1. Reviews of cycloaddition : (a) Varela, J. A.; Saá, C. Chem. Rev. 2003, 103, 3787. b) Chopade, P.; Louie, J. Adv. Synth. Catal. 2006, 348, 2307. c) Schore, N. Chem. Rev. 1988, 88, 1081. d) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127. e) Varela, J. A.; Saá, C. Synlett. 2008, 2571. 2. Trost, B. M. Science, 1991, 254, 1471. 3. a) McCormick, M. M.; Duong, H. A.; Zuo, G.; Louie, J. J. Am. Chem. Soc. 2005, 127, 5030; b) Tekavec, T. N.; Zuo, G.; Simon, K.; Louie, J. J. Org. Chem. 2006, 71, 5834. 4. a) Duong, H. A.; Cross, M. J.; Louie, J. J. Am. Chem. Soc. 2004, 126, 11438. (b) Duong, H. A.; Louie, J. J. Organomet. Chem. 2005, 690, 5098. (c) Duong, H. A.; Louie, J. Tetrahedron 2006, 62, 7547. 5. a) Tekavec, T. N.; Louie, J. Org. Lett. 2005, 7, 4037. (b) Tekavec, T. N.; Louie, J. J. Org. Chem. 2008, 73, 2641. 6. a) Williams, R.; Manka, J. T.; Rodriguez, A. L.; Vinson, P. N.; Niswender, C. M.; Weaver, D. C.; Jones, C. K.; Conn, P. J.; Lindsley, C. W.; Stauffer, S. R. Bioorg. Med. Chem. Lett. 2011, 21, 1350. b) Dow, R. L.; Carpino, P. A.; Hadcock, J. R.; Black, S. C.; Iredale, P. A.; DaSilva-Jardine, P.; Schneider, S. R.; Paight, E. S.; Griffith, D. A.; Scott, D. O.; O'Connor, R. E.; Nduaka, C. I. J. Med. Chem. 2009, 52, 2652. 7. Yu, T. R.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 2782-2783. (b) Yu, T. R.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 12370-12371. (c) Lee, E. E.; Rovis, T. Org. Lett. 2008, 10, 1231-1234. (d) Ozawa, T.; Horie, H.; Kurahashi, T.; Matsubara, S. Chem. Commun., 2010, 46, 8055-8057. 8. a) Tekavec,T. N.; Louie, J. Tetrahedron 2006, 64, 6870. b) Duong, H. A.; Cross, M. J.; Louie, J. Org. Lett. 2004, 6, 4679. 9. Scleicher, K. D.; Jamison, T. Org. Lett. 2007, 9, 875-878. 10. Koo, K.; Hillhouse, G. Organometallics 1995, 14, 4421-4423. 11. Wang, C.; Lu, J.; Mao, G.; Xi, Z. J. Org. Chem. 2005, 70, 5150. 71 12. (a) Böhm, V. P. W.; Gstüttmayr, C. W. K., Weskamp, T.; Herrmann, W. A. Angew. Chem. Int. Ed. 2001, 40, 3387. (b) Arduengo, A. J. III; Krafczyk, R.; Schmutzler, R.; Craig, H. A.; Goerlich, J. R.; Marshall, W. J. Unverzagt, M. Tetrahedron 1999, 55, 14523. (c) Böhm, V. P. W.; Weskammp, T.; Gstottmayr, W. K.; Herrmann, W. A. Angew. Chem. Int. Ed. 2000, 39, 1602. (d) Jensen, D. R.; Sigman, M. S. Org. Lett. 2003, 5, 63. 13. Marson, C. M.; Grabowska, U.; Walsgrove, T.; Eggleston, D. S.; Baures, P. W. J. Org. Chem. 1994, 59, 284. CHAPTER 3 IRON-CATALYZED CYCLOADDITION OF ALKYNENITRILES AND ALKYNES Introduction Pyridine1 rings are common in various natural products and bioactive compounds.2,3 Synthetic methods that provide a rapid and efficient pathway for the synthesis of such rings would be useful. A reported methodology for the synthesis of pyridine rings involves the [2+2+2] cycloaddition reaction of alkynes and nitriles.3 Various metals such as Co,4 Rh,5 Ru,6 and Ni7 have been utilized as catalysts to synthesize diversely substituted pyridine rings in these methods. Another approach to construction of pyridine rings with different substitution patterns is by the cycloaddition of alkynenitriles and alkynes. Seminal work in this field was demonstrated by Vollhardt4b (Figure 3.1, Equation 3.1-3.3). The reaction of a tethered alkyne and the nitrile with an alkyne afforded pyridines in moderate to good yields with CpCo(CO)2. The pyridine product was obtained in good yields when symmetrical alkynes are used in the cycloaddition (Equation 3.1). Poor regioselectivity were observed for the pyridine product when unsymmetrical alkynes were used in the cycloaddition (Equations 3.2-3.3). The reaction 72 also requires the slow addition of the alkynenitrile and alkyne over a 4-5 h time period using a syringe pump. The other drawback of this method is that the cobalt-catalyst requires ultra-violet light for activation. Saá4f extended the substrate scope with the same CpCo(CO)2 catalyst system as that used by Vollhardt to synthesize annelated bipyridines (Equation 3.4), and terpyridines (Equation 3.4) albeit in low yields. Spiro-pyridines4e can also be prepared (Equation 3.5) using catalytic CpCo(CO)2 albeit in low yields and low selectivity. Microwaves can also be used to prepare tetrahydronaphthyridines4d by reacting dialkynenitriles in the presence of CpCo(CO)2 catalyst (Equation 3.6). Interestingly, tantalum8 has been utilized in the cycloaddition reaction of alkynenitriles and alkynes to form pyridines. However, this cycloaddition reaction has been applied to only one substrate and the reaction required stoichiometric amounts of tantalum hexachloride. With all these transition metals been used in the cycloaddition reactions, there is a need to use cost-effective, environmentally less-toxic, and easily available metal salts. Therefore, a mild and effective catalyst system for the cycloaddition of alkynenitriles and alkynes is highly desired. Replacing the use of precious metals in catalysis with more abundant and potentially less-toxic metal complexes is highly desrired. Iron salts are easily available, cost effective, and less-toxic that other transition metal complexes thus making it an attractive alternative as a catalyst. The majority of the use of iron in catalysis has been in cross coupling,9 oxidation,10 and polymerization.9 Only in the last decade Fe-catalyst systems have been demonstrated in [2+2+2] cycloaddition chemistry. The cyclotrimerization of alkynes represents the majority of the [2+2+2] cycloaddition reaction examples. Okamoto12a used a combination of iron chloride and IPr as the catalyst to synthesize a 73 tricyclic benzene derivative in moderate to good yields (Equation 3.7). Breshi12b and co-workers developed a Fe-cyclohexatriene-cyclooctadiene [Fe(CHT)(COD)] complex. This complex was used in the intermolecular cycloaddition of alkynes affording benzene products (Equation 3.8). The major drawback to this method is the tedious preparation of the Fe-complex. Fürstner12c developed a very effective iron catalyst for the cyclotrimerization of alkynes (Equation 3.9). Cyclized products were obtained in good yields. However, the reactivity of this iron catalyst was demonstrated with only alkenes and alkynes. There are very few examples that are reported for synthesizing pyridines using iron by cycloaddition reactions. The very first example of the use of iron in pyridine synthesis was reported by Sir William Ramsay13 in 1872 (Figure 3.1). He synthesized pyridine in traces by passing hydrocyanic acid and acetylene through a red hot iron tube. It was not until 1996 that Knoch14a isolated a phosphorane-cyclooctadiene-iron complex and used it in the synthesis of pyridine derivatives from alkynes and nitriles (Equation 3.10). Although the cycloaddition reaction required low catalyst loading, along with the desired pyridine products, significant cyclotrimerization of the alkyne was also observed. Ferré14b designed an ironpentamethyl(cyclopentadienyl)acetonitrile sandwich complex that successfully afforded pyridine product in 73 % yield (Equation 3.11). However, this cycloaddition reaction required stoichiometric amounts of the iron-complex and was limited to one activated alkyne. Wan14c has reported an iron-catalyzed cycloaddition of diynes and unactivated nitriles (Equation 3.12). Excellent yields were obtained for the pyridine product. However, the reaction requires a large excess of nitrile for the cycloaddition reaction. To the best of our knowledge, these examples represent the only 74 examples of Fe being used as a catalyst in the preparation of pyridine rings. We were interested in developing an iron catalyst system to synthesize pyridines and expanding on the existing substrate scope in the cycloaddition of alkynenitriles and alkynes. Results and Discussion The efficiency of previous iron-catalyzed cycloaddition reactions to generate benzannulated compounds prompted us to investigate the cycloaddition of alkynenitriles and alkynes to synthesize pyridines. We inferred that the difficulty in preparation of pyridines from diynes may be due to the limited reactivity of the nitrile to undergo cycloaddition reactions. Therefore, we strategically chose to tether the alkyne and the nitrile to promote the initial cycloaddition of the alkyne, nitrile, and Fe-catalyst moities. The first step in our study involved the evaluation of various ligands in their ability to bind to Fe and generate an efficient catalyst. Alkynenitrile 1a and decyne 2a were subjected to 30 mol % iron acetate and 40 mol % ligand, and zinc dust in DMA at 80 °C. Various ligands such as amines, phosphines, and NHCs were used based on their successful application as ligands in other cycloaddition reactions involving iron.12 However, the use of phosphines or NHCs as ligands did not result in the formation of the desired cycloaddition pyridine product. Only the unreacted alkynenitrile 1a was observed by gas chromatography (GC). We then turned our attention to imino-based ligands such as 1,2-diimine and di(imino)pyridine15,16 ligands. Low or no pyridine product was detected by GC with diimine ligands L1-L5 (Table 3.1, entries 1-5). The 1,2-diimine ligand L6 afforded the pyridine product (Table 3.1, entry 6) with 47 % yield 75 by gas chromatography and 30 % isolated yield. Chirik and other research groups have demonstrated that iron-bis(imino)pyridyl15, 16 complexes are effective in polymerization reactions. Hence, we evaluated the use of various bis(imino)pyridyl ligands in this cycloaddition reaction in order to obtain higher yields for the desired pyridine product. In our study, low conversions of starting material with no formation of pyridine product was observed in the presence of ketimine-based bis(imino)pyridine ligands (Table 3.1, entries 7-8). On the other hand, reactions involving the use of pyridyl bis(aldimino)pyridine derivatives as ligands gave promising results. The complete conversion of alkynenitrile 1a was observed by GC in the presence of ligand L9, with a yield of 84 % of the desired pyridine product. Increasing the steric bulk of the ligand by using L10 (Table 3.1, entry 9) had a deleterious effect on the reaction with low conversions of starting material and formation of trace amounts of pyridine product. Interestingly the insertion of an electron-donating group (i.e. -OBn) on to the para position of the aryl ring of the ligand (L11) had a profound effect on the reaction outcome. In the presence of L11 as ligand, the pyridine product was obtained in 62 % yield with lower catalyst loading (entry 11). Gratifyingly, reactions run with L12 as ligand provided 95 % pyridine product with 20 mol % catalyst loading. In contrast to the trend observed for neutral ligands, an increase in steric hindrance led to an increase in yield (entries 9-10 v/s entries 11-12, respectively). Control reactions were also performed in the absence of Fe(OAc)2, ligand, or Zn successively. These control reactions resulted in no pyridine product formation. Lowering the catalyst loading and switching solvents from DMA to DMF ultimately led to the following optimum reaction conditions: 10 mol % Fe(OAc)2, 13 mol % 76 bis(aldimine) pyridyl ligand L12, 0.4 M alkynenitrile, and 0.4 M alkyne in DMF at 85 °C (Equation 3.13) The cycloaddition of alkynenitriles and alkynes is a general reaction as a variety of alkynenitriles and alkynes can be used as substrates (Table 3.1). The reaction of alkynenitriles 1a and 1b with 5-decyne 2a afforded good isolated yields of the pyridine products with alkynenitrile 1b affording slighlty higher yields (Table 3.2, entries 1-2). Similarly, the reaction of phenyl-substituted alkynenitrile 1c also afforded the corresponding pyridine in good yield (entry 3). Although the cycloaddition of terminal alkynenitrile 1d resulted in low yield (Table 3.2, entry 4), reasonable yields were obtained when TMS-substituted alkynenitrile 1e was employed (Table 3.2, entry 5). Next, the substrate scope of alkynes in this reaction was studied. Not surprisingly, 3- hexyne (2b) is an effective alkyne substrate (Table 3.2, entry 6). The cycloaddition of diphenylacetylene 2c and alkynenitrile 1a requires 2 equiv. of 2c to afford the pyridine product in appreciable yield (Table 3.2, entry 7) due to competing cyclotrimerization of the alkyne. Alkynenitriles containing either an oxygen or a nitrogen backbone (1f, 1g, and 1h) also react with decyne 2a to afford the pyridine product, albeit in moderate yields (Table 3.2, entries 8 and Table 3.3, entries 1 and 2). In contrast, alkynenitrile 1h, which possesses an all-carbon backbone, reacted with decyne 2a and afforded better yields of the pyridine cycloaddition product (Table 2.3, entry 3). A tricyclic indenylpyridine was prepared in good yield from the coupling of 1j and 2b (Table 2.3, entry 4). In addition, the reaction of 1,6-alkynenitrile 1k, which possesses a 6-carbon chain tether affords pyridine product 3k, albeit in lower yields than the corresponding 1,5-alkynenitrile (Table 3.3, entry 5 vs. Table 3.2, entry 1, respectively). 77 Unsymmetrical alkynes were also employed as coupling partners in the cycloaddition reaction (Table 3.4, equation 3.14). Methyl phenyl acetylene 2d and alkynenitrile 1a afford the pyridine product with 1.2:1 ratio of regioisomers (Table 3.4, entry 1). With the regioisomer having the phenyl group distal to the pyridine nitrogen slightly favored. Interestingly, changing the electronics on the phenyl ring improved the regioselectivity. Aryl-alkyl alkyne 2f possesing an electron withdrawing group (-CF3) (Table 3.4, entry 3) at the para position of the phenyl ring of alkyne 2f affords a higher ratio of the major regioisomer where the phenyl ring is distal from the pyridine nitrogen as compared to an alkyne 2g possessing an electron donating group (-OMe) at the para position of the phenyl ring (Table 3.4, entry 2). The reaction of alkynenitrile 1a and alkyne 2g, possessing a pyridyl substituent, affords better selectivity where the aryl ring is distal to the pyridine nitrogen as the major regioisomer (Table 3.4, entry 4). A relatively equal mixture of regioisomers were obtained in the reactions of aryl-alkyl alkynes 2h and 2i (Table 3.4, entries 5-6). The cycloaddition of unsymmetrical alkyl-alkyl alkyne 2j and alkynenitrile 1a afforded a 1:1 ratio of the pyridine products in a good yield (table 2.4, entry 7). The pyridine product was obtained as a single regioisomer in the reaction of a sterically hindered alkyne 2k (Table 3.4, entry 8). Interestingly, tBu-group is proximal to the nitrogen of the pyridine (entry 8). The catalytic system is also effective in the intramolecular cycloaddition of dialkynenitriles. Specifically, addition of 20 mol % Fe(OAc)2 and 32 mol % L12 to substrate 1l afforded tricyclic product 3v in 74 % isolated yield (Equation 3.15). Efforts to isolate an (L12)Fe(OAc)n complex proved unsuccessful. However, the analogous (L12)FeBr2 complex16d was prepared and used as a catalyst for the 78 cycloaddition of 1a and 2a (Equation 3.16). Importantly, the Fe-ligand complex did catalyze the coupling and afforded pyridine 3a in 58 % isolated yield. For comparison, reactions run with 10 mol % FeBr2, in lieu of Fe(OAc)2, provided pyridine 3a in 54 % (GC yield). Conclusions We have developed a methodology for the synthesis of pyridines from alkynenitriles and alkynes by employing catalytic amounts of iron acetate and a pyridyl bisimine ligand. This reaction is general for symmetrical and unsymmetrical alkynes. Various groups like alkyl, aryl, trimethylsilyl, and terminal alkynenitriles are reactive in this cycloaddition reaction. Protecting groups like Boc and tosyl are tolerated under the cycloaddition reaction conditions. Alkynenitriles with and without Thorpe-Ingold assistance undergo cycloaddition reactions to afford the pyridine products. Five- and six- Membered bicyclic pyridines can be prepared by this methodology. However, greater than 6-membered tethered bicyclic systems cannot be prepared by this methodology. Exogenous alkynes possessing free hydroxyl or secondary amino groups are not tolerated under these reaction conditions. Efforts to understand the reactivity pattern of the different pyridyl bisimine ligands in the cycloaddition reaction are currently underway. Alkynenitriles 1a and other coupling partners are also being tested with alkynenitrile using a similar iron catalyst systems in an attempt to discover new reaction methodologies. 2-Aminopyrimidines17 are structurally important cores and present in various pharmaceutically active compounds. We envisoned a metal catalyzed [2+2+2] 79 cycloaddition of alkynenitriles and cyanamides (Equation 3.17). Our initial ligand screen has shown that we can synthesize 2-aminopyrimidines in 20 % isolated yield under iron-catalyzed cycloaddition conditions with ligand L12. 1H-NMR and gas chromatography-mass spectrometry (GC-MS) data suggests that the 2-aminopyrimidine is formed. Furthur ligand screening and optimization studies are underway. Experimental All reactions were conducted under an inert atmosphere of N2 using standard Schlenk techniques or in a N2 filled glove-box unless otherwise noted. Dimethyl formamide (DMF) was purchased from Sigma Aldrich in a sure-seal® bottle. Tetrahydrofuran (THF) was freshly distilled from Na/benzophenone still. Iron acetate (99.995% purity) was purchased from Sigma Aldrich. Alkynenitriles 1a18a 1b,18b 1i,19 and 1j,20 were prepared by known literature procedures. 1H and 13C Nuclear Magnetic Resonance spectra of pure compounds were acquired at 400 and 300 MHz, instruments unless otherwise noted (Inova-400 and Varian VXL-300 spectrometers). All spectra are referenced to residual proteated CHCl3 via a singlet at 7.27 ppm for 1H and to the center line of a triplet at 77.26 ppm for 13C. All 13C NMR spectra are proton decoupled. The infra-red spectra were recorded on a Bruker Tensor 27 FT-IR spectrometer. Gas Chromatography was performed on an Agilent 6890 gas chromatography with a 30 meter HP-5 column using the following conditions: initial oven temperature: 100 ºC; temperature ramp rate 10 ºC/min.; final temperature: 300 ºC 80 held for 12 min.; detector temperature: 250 ºC. High Resolution Mass Spectroscopy analyses were performed at the University of Utah Mass Spectrometry facility. Ligands L1-L6 23a and L7-L10 23b were synthesized using reported methods. Ligands L11 and L12 were synthesized as follows: Step1 The general procedure was adapted from the literature procedure.22a To a stirring mixture of 2,6-substituted aniline and NaHCO3 (3 equiv) in methanol, a solution of iodinemonochloride (1.1 equiv) in CH2Cl2 was added dropwise over 1 h (Scheme 3.3, equation 3.18). The reaction was stirred at room temperature for 24 h. Solids were filtered from the mixture and rinsed with diethyl ether. The filtrate was reduced under reduced presure to afford a dark red oil to which a 300 ml solution of saturated sodium thiosulfate was added. The solution was stirred for 10 min then extracted with 3 x 200 mL portions of diethyl ether. The organic extracts were dried with anhydrous Na2SO4, filtered, and reduced in vacuo. Step 2 The general procedure was adapted from the literature procedure.22c In a nitrogen glove box, a 20 ml scintillation vial was filled with CuI (7 mol %) 3,4,7,8- tetramethyl-1,10-phenanthroline (Me4Phen, 14 mol %), Cs2CO3 (2.0 equiv), and 4-iodo- 2,6-dialkyl aniline (1.0 equiv) (Scheme 3.3, Equation 3.19). The vial was sealed with a rubber septum, removed from the glove box then evacuated and backfilled with Argon three times. Toluene was added and the mixture was stirred at 80 °C for 20 min. Benzyl alcohol (2.0 equiv) was added and the rubber septum was quickly replaced with a vial cap. The reaction was stirred for 24 h at 80 °C then cooled to room temperature, filtered through a silica gel plug, and flushed with 150 ml of ethyl acetate. The resulting solution 81 was removed under educed pressure and purified using silica gel flash chromatography with 10 % ethyl acetate in hexanes. Step 3 The general procedure was adapted from the literature procedure.22a 4- benzyloxy-2,6-dialkyl aniline (2.0 equiv.) and 2,6-pyridinedicarboxaldehyde (1.0 equiv) and a catalytic amount glacial acetic acid were stirred in 100 % ethanol overnight at room temperature (Scheme 3.3, Equation 3.20). The mixture was cooled to 0 °C, filtered, and rinsed with cold 100 % ethanol. Synthesis of 4-iodo-2,6-dimethylaniline: 4-iodo-2,6-dimethylaniline was prepared using the Step 1 general procedure with 2,6-dimethylaniline (10.0 g, 83 mmol), iodinemonochloride (14.7 g, 91 mmol), sodium bicarbonate (20.8 g, 248 mmol). The reaction was stirred at room temperature with 115 ml of methanol and 90 mL of dichloromethane to yield 4-iodo-2,6-dimethylaniline (19.2 g, 93 %) as a dark red oil. Spectral data were compared with known literature value.24b Synthesis of 4-iodo-2,6-diisopropylaniline: 4-iodo-2,6-diisopropyl-aniline was prepared using the Step 1 general procedure with 2,6- diisopropylaniline (10.0 g, 56 mmol), iodinemonochloride (10.1 g, 62 mmol), sodium bicarbonate (14.2 g, 169 mmol). The reaction was stirred at room temperature with 80 ml of methanol and 60 ml of dichloromethane to yield 4-iodo-2,6- diisopropylaniline (16.8 g, 93 %) as a dark red oil. Spectral data were compared with known literature value. 22c Synthesis of 4-(benzyloxy)-2,6-dimethylaniline: 4-(benzyloxy)-2,6- dimethyl aniline was prepared using the general procedure in Step 2 with 82 CuI (57.8 mg, 0.30 mmol), Me4Phen (144 mg, 0.61 mmol), cesium carbonate (1.56 g, 8.1 mmol), 4-iodo-2,6-dimethylaniline (1.0 g, 4.0 mmol), and benzyl alcohol (875 mg, 8.1 mmol). The reaction was run for 24 h at 80 °C in 1.9 ml of toluene to yield 4- (benzyloxy)-2,6-dimethylaniline (363 mg, 40 %) as a blue solid. Mp: 71-73 °C. 1H NMR (300 MHz, CDCl3): δ (ppm) 7.48-7.33 (m, 5H), 6.68 (s, 2H), 5.01 (s, 2H), 3.35 (s, 2H), 2.20 (s, 6H). 13C NMR (75 MHz, CDCl3): δ (ppm) 151.5, 137.9, 136.9, 128.7, 127.9, 127.7, 123.4, 115.2, 70.9, 18.2. IR (cm-1) 3450, 3375, 3032, 2969, 2908, 2735, 1602, 1489, 1380, 1328, 1298, 1242, 1150, 1054, 856, 738, 698. HRMS (ESI) calcd for C15H17NO [M+H]+ 228.1388, found 228.1385. Synthesis of 4-(benzyloxy)-2,6-diisopropylaniline: 4-(benzyloxy)-2,6- diisopropylaniline was prepared using the Step 2 general procedure with CuI (57.8 mg, 0.30 mmol), Me4Phen (143 mg, 0.61 mmol), cesium carbonate (1.56 g, 8.1 mmol), 4-iodo-2,6-diisopropylaniline (1.0 g, 4.0 mmol), and benzyl alcohol (875 mg, 8.1 mmol). The reaction was run for 24 h at 80 °C in 1.9 ml of toluene to yield 4-(benzyloxy)-2,6-diisopropylaniline (949 mg, 84 %) as a dark red oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.48-7.27 (m, 5H), 6.74 (s, 2H), 3.48 (s, 2H), 3.01- 2.94 (m, 2H), 1.28 (d, J = 6.8 Hz, 12H). 13C NMR (75 MHz, CDCl3): δ (ppm) 152.4, 138.0, 134.5, 134.4, 128.7, 128.01, 127.96, 110.1, 71.0, 28.4, 22.7. IR (cm-1) 3382, 2960, 1599, 1463, 1347, 1218, 1175, 1100, 1027, 737, 696. HRMS (ESI) calcd for C19H26NO [M+H]+ 284.2014, found 284.2013. Synthesis of (N,N'E,N,N'E)-N,N'-(pyridine-2,6-di ylbis(methanylylidene))bis(4-(benzyloxy)-2,6- 83 dimethylaniline) (L11): Compound L11 was pre- pared using the Step 3 general procedure with 4-(benzyloxy)-2,6-dimethylaniline (195 mg, 0.86 mmol), 2,6- pyridinedicarboxaldehyde (57.8 mg, 0.43 mmol), and 5 drops of glacial acetic acid. The reaction was run at room temperature in 10 ml of 100 % ethanol yielding L11 (108 mg, 46 %) as a yellow solid. Mp: 174-177 °C. 1H NMR (500 MHz, CDCl3): δ (ppm) 8.40 (s, 2H), 8.38 (d, J = 8.0 Hz, 2H), 7.97 (t, J = 7.8 Hz, 1H), 7.47-7.33 (m, 10H), 7.76 (s, 4H), 5.06 (s, 4H), 2.20 (s, 12H). 13C NMR (75 MHz, CDCl3): δ (ppm). IR (cm-1) 3087, 2970, 2948, 1602, 1584, 1480, 1455, 1379, 1332, 1312, 1198, 1052, 738, 698. HRMS (ESI) calcd. for C37H35N3O2 [M+H]+ 576.2627, found 576.2633. Synthesis of (N,N'E,N,N'E)-N,N'-(pyridine-2,6- diylbis(methanylylidene))bis(4-(benzyloxy)-2,6- diisopropylaniline) (L12): Compound L12 was prepared using the Step 3 general procedure with 4-(benzyloxy)-2,6-diisopropylaniline (2.35 g, 8.3 mmol), 2,6-pyridinedicarboxaldehyde (600 mg, 4.1 mmol), and 10 drops of glacial acetic acid. The reaction was run at room temperature in 10 ml of 100 % ethanol to yield L12 (2.48 g, 85%) as a yellow solid. M.p. 170-173 °C. 1H NMR (300 MHz, CDCl3): δ (ppm) 8.40-8.38 (m, 4H), 7.99 (t, J = 8.0 Hz, 1H), 7.51-7.28 (m, 10H), 6.83 (s, 4H), 5.08 (s, 4H), 3.07-2.98 (m, 4H), 1.18 (d, J = 7.2 Hz, 24H). 13C NMR (75 MHz, CDCl3): δ (ppm) 163.4, 156.3, 154.8, 142.4, 139.1, 137.6, 137.5, 128.1, 128.2, 128.0, 122.8, 109.9, 70.5, 28.4, 23.7. IR (cm-1) 3391, 2961, 2869, 1637, 1600, 1458, 1326, 1190, 1026, 736. HRMS (ESI) calcd. for C45H51N3O2 [M+H]+ 688.3879, found 688.3882. 84 Synthesis of dimethyl-2-(cyanomethyl)malonate: To a stirring suspension of NaH (1.8 g, 75.7 mmol) in 150 ml THF was added dimethylmalonate (10 g, 75.7 mmol) (Equation 3.21) under N2 counter-flow. The resulting solution was stirred at room temperature for 1 h after which time bromoacetonitrile (5.0 g, 42.1 mmol) was added. The mixture was stirred at room temperature for 24 h at which time the solution was quenched with 100 ml of a saturated NH4Cl solution. The layers were separated and aqueous layer was extracted with Et2O (3 x 100 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous MgSO4, and concentrated under reduced pressure. The resulting crude yellow oil was purified by flash column chromatography (20 % EtOAc/hexanes) to yield dimethyl-2-(cyanomethyl) malonate (4.1 g, 57 %) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ (ppm) 3.78 (s, 6H), 3.73 (t, J = 7.2 Hz, 1H), 2.89 (d, J = 7.2 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ (ppm) 167, 116.8, 53.5, 47.8, 17.1 Synthesis of dimethyl 2-(cyanomethyl)-2-(prop-2-yn-1-yl)malonate (1d): Dimethyl-2-(prop-2-yn-1-yl)malonate was prepared by known literature procedure.23 To a stirring suspension of NaH (0.21 g, 8.82 mmol) in 50 ml THF was added dimethyl-2-(prop-2-yn-1-yl)malonate (1.0 g, 5.88 mmol) (Equation 3.22) under N2 counter-flow. The resulting solution was stirred at room temperature for 1 h after which time bromoacetonitrile (1.0 g, 8.82 mmol) was added. A reflux condenser was attached and the mixture was stirred at reflux for 8-12 h at which time GC analysis showed no starting material. The solution was cooled to room temperature and quenched with 100 ml of a saturated NH4Cl solution. The layers were separated and aqueous layer was extracted with Et2O (3 x 100 ml). The combined 85 organics were washed with brine (100 ml), dried over anhydrous MgSO4 and concentrated under reduced pressure. The resulting crude yellow oil was purified by flash column chromatography (10 % EtOAc/hexanes then 12 % EtOAc/ hexanes) to yield 1d (0.6 g, 49 %) as pale yellow oil. 1H (400 MHz, CDCl3): 3.83 (s, 6H), 3.17 (s, 2H), 3.03 (d, J = 2.8 Hz, 2H), 2.13 (t, J = 2.8 Hz, 1H). 13C (100 MHz, CDCl3) δ (ppm) 168.3, 116.4, 81.0, 71.8, 53.9, 24.2, 22.1, 3.7. IR (cm-1) 3288, 2960, 2253, 1743, 1483, 1327, 1217, 971, 892. HRMS calculated for C10H11NO4Na 232.0586, found 232.0592. Synthesis of dimethyl-2-(cyanomethyl)-2-(3-phenylprop-2-yn-1- yl)malonate (1c): Pd(PPh3)2Cl2 (28.4 mg, 0.04 mmol) and CuI (27.7 mg, 0.14 mmol) were added to a solution of 1d (3.0 g, 14.5 mmol) in Et3N (17 ml) (Equation 3.23). To the mixture was added a solution of phenyl iodide (1.6 g, 8.1 mmol). The resulting mixture was stirred at 50 °C for 6 h. The reaction was quenched by the addition of water and extracted with Et2O. The organic layer was washed with saturated aqueous NH4Cl, and the water layer was extracted with Et2O. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified on a silica gel column chromatography (10 % EtOAc/hexanes) which furnished 1c (1.2 g, 52 % yield) as a dark brownish yellow oil. 1H (400 MHz, CDCl3): δ (ppm) 7.34 (m, 5H), 3.85 (s, 6H), 3.25 (s, 2H) 3.22 (s, 2H). 13C NMR (100 MHz, CDCl3) δ (ppm) 168.1, 132.0, 128.7, 128.5, 122.6, 116.2, 85.2, 82.3, 55.5, 54.0, 24.7, 22.3. IR (cm-1) 2957, 2253, 1743, 1438, 1295, 1215, 1030. HRMS (ESI) calculated for C16H15NO4Na (M+Na)+ 308.0899, observed 308.0895. 86 Synthesis of dimethyl 2-(cyanomethyl)-2-(3-(trimethylsilyl)prop-2- yn-1-yl)malonate (1e): To a stirring suspension of NaH (0.12 g, 4.82 mmol) in 30 ml THF was added dimethyl-2-(cyanomethyl)malonate (0.55 mg, 3.21 mmol) under N2 (Equation 3.24). The resulting solution was stirred at room temperature for 1 h after which time (3-bromoprop-1-yn-1- yl)trimethylsilane (0.50 g, 4.82 mmol) was added. A reflux condenser was attached and the mixture was stirred at reflux for 12 h at which time GC analysis showed no starting material. The solution was cooled to room temperature and quenched with 70 ml of a saturated NH4Cl solution. The layers were separated and aqueous layer was extracted with Et2O (3 x 70 ml). The combined organics were washed with brine (100 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude yellow oil was purified by flash column chromatography (20 % EtOAc/hexanes) to yield 1e (0.79 g, 87 %) as a colorless solid. Mp: 34-36 °C. 1H NMR (400 MHz, CDCl3): δ (ppm) 3.82 (s, 6H), 3.14 (s, 2H), 3.03 (s, 2H), 0.15 (s, 9H). 13C NMR (100 MHz, CDCl3) δ (ppm) 167.9, 116.2, 99.1, 90.5, 55.4, 53.9, 25.4, 22.1, 0.1. IR (cm-1): 2960, 2902, 2253, 2181, 1746, 1437, 1322, 1294, 1028, 847. HRMS calculated for C13H19NO4NaSi 304.0981, found 304.0977. Synthesis of 2-(pent-2-yn-1-yloxy)acetonitrile (1f): To a stirring suspension of NaH (0.7 g, 30.9 mmol) in 25 ml THF was added pent-2-yn-1-ol (2.0 g, 23.8 mmol) (Equation 3.25) under N2 counter-flow in two portions. The resulting solution was stirred at room temperature for 1 h after which time bromoacetonitrile (3.7 g, 30.9 mmol) was added. The reaction mixture was stirred at room temperature for 8-12 h at which time GC analysis showed no starting material. The solution was cooled and 87 quenched with 100 ml of a saturated NH4Cl solution. The layers were separated and aqueous layer was extracted with Et2O (3 x 100 ml). The combined organics were washed with brine (100 ml), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The resulting crude yellow oil was purified by flash column chromatography (10 % EtOAc/hexanes) to yield 1f (1.2 g, 42 %) as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 4.34 (s, 2H), 4.28 (t, J = 4.4 Hz, 2H), 2.25 (m, 2H), 1.15 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm) 115.9, 91.3, 72.8, 58.9, 54.0, 13.7, 12.5. IR (cm-1) 2980, 2919, 2292, 1452, 1320, 1140, 1092, 902. HRMS (ESI) calcd for C21H24NO5 [M+H]+ 124.0762, found 124.0776. Synthesis of 2-((3-phenylprop-2-yn-1-yl)oxy)acetonitrile (1g): To a stirring suspension of NaH (0.3 g, 9.1 mmol) in 50 ml THF was added 3-phenylprop-2- yn-1-ol (2.0 g, 7.57 mmol) under N2 counter-flow (Equation 3.26). The resulting solution was stirred at room temperature for 1 h after which time bromoacetonitrile (1.1 g, 9.1 mmol) was added. The mixture was stirred at room temperature for 12 h at which time GC analysis showed no starting material. The solution was cooled and quenched with 100 mL of a saturated NH4Cl solution. The layers were separated and aqueous layer was extracted with Et2O (3 x 100 ml). The combined organics were washed with brine (100 ml), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The resulting crude yellow oil was purified by silica gel flash column chromatography (20 % EtOAc/hexanes) to yield 1g (1.2 g, 92 %) as pale yellow oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.49 (m, 2H), 7.36 (m, 3H), 4.55 (s, 2H), 4.43 (s, 2H). 13C NMR (100 MHz, CDCl3) δ (ppm) 132.0, 129.2, 128.6, 88 121.9, 115.9, 88.8, 82.3, 59.1, 54.3. IR cm-1 3060, 2908, 2857, 2242, 1964, 172.0762, found 172.0728. Synthesis of N-(cyanomethyl)-4-methyl-N-(3-phenylprop-2-yn-1-yl)benzene sulfonamide (1h): To a stirring suspension of NaH (0.05 g, 1.9 mmol) in 20 ml THF was added 4-methyl-N-(3-phenylprop-2-yn-1yl)benzenesulfonamide24 (0.5 g, 1.7 mmol) under N2 (Equation 3.27). The resulting solution was stirred at room temperature for 1 h after which time bromoacetonitrile (0.2 g, 1.9 mmol) was added. A reflux condenser was attached and the mixture was stirred at reflux for 12 h at which time GC analysis showed no starting material. The solution was cooled to room temperature and quenched with 100 ml of a saturated NH4Cl solution. The layers were separated and aqueous layer was extracted with Et2O (3 x 100 ml). The combined organics were washed with brine (100 ml), dried over anhydrous MgSO4, and concentrated under reduced pressure. The resulting crude yellow oil was purified by flash column chromatography (30 % EtOAc/hexanes) to yield 1h (0.34 g, 60 %) as a colorless solid. Mp: 97-99 °C. 1H (400 MHz, CDCl3): δ (ppm) 7.78 (d, J = 8Hz, 2H), 4.28 (t, J = 4.4 Hz, 2H), 2.25 (m, 2H), 1.15 (t, J = 7.6 Hz, 3H). 13C (100 MHz, CDCl3) δ (ppm) 145.2, 134.3, 131.9, 130.3, 129.2, 128.5, 128.1, 121.8, 113.8, 87.6, 80.1, 38.8, 35.4, 21.8. IR (cm-1) 2958, 2253, 1744, 1438, 1215, 1072, 759. HRMS (ESI) calculated for C18H16N2O2NaS (M+Na) 347.0830, observed: 347.0835. Synthesis of dimethyl-2-(but-2-yn-1-yl)-2-(2-cyanoethyl)malonate (1k): To a stirring suspension of NaH (0.24 g, 10.1 mmol) in 100 ml THF was added dimethyl malonate (2.0 g, 15.1 mmol) under N2 (scheme 3.4). The resulting solution was stirred at room temperature for 1 h after which 89 time bromopropionitrile (1.35 g, 10.1 mmol) was added. A reflux condenser was attached and the mixture was stirred at reflux for 12 h at which time the solution was cooled to room temperature and quenched with 100 ml of a saturated NH4Cl solution. The layers were separated and aqueous layer was extracted with Et2O (3 x 100 ml). The combined organics were washed with brine (100 ml), dried over anhydrous MgSO4, and concentrated under reduced pressure. The resulting crude yellow oil was purified by silica gel flash column chromatography (40 % EtOAc/hexanes) to yield dimethyl-2-(2- cyanoethyl)malonate (1.2 g, 64 %) as a pale yellow oil. Spectral data were compared with known literature values.25 To a stirring suspension of NaH (0.16 g, 6.5 mmol) in 50 ml THF was added dimethyl-2-(2-cyanoethyl)malonate (1g, 5.4 mmol) under N2. The resulting solution was stirred at room temperature for 1 h after which time 1-bromo-2-butyne (0.86 g, 6.5 mmol) was added. A reflux condenser was attached and the mixture was stirred at reflux for 12 h at which time the solution was cooled to room temperature and quenched with 50 ml of a saturated NH4Cl solution. The layers were separated and aqueous layer was extracted with Et2O (3 x 50 ml). The combined organics were washed with brine (50 ml), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The resulting crude yellow oil was purified by silica gel flash column chromatography (40 % EtOAc/hexanes) to yield 1k (0.6 g, 50 %) as a colorless solid. Mp: 62-63 °C. 1H (400 MHz, CDCl3): δ (ppm) 3.78 (s, 6H), 2.79 (q, J = 2.4 Hz, 2H), 2.44 (m, 4H), 1.77 (t, J = 2.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm) 170.0, 119.2, 80.3, 72.4, 56.2, 53.3, 28.9, 24.2, 13.2, 3.7. IR (cm-1) 2957, 2249, 1736, 1441, 1340, 1209. HRMS C12H15NO4Na calculated 260.0899, observed 260.0898. 90 Synthesis of tert-butyl(4-phenylbut-3-yn-1-yl)tosylcarbamate (2i): Under N2, diisopropylazodicarboxylate (1.7 ml, 8.92 mmol, 1.1 equiv) was added to a solution of N-(tert-butyoxycarbonyl)-p-toluene sulfonamide (2.2 g, 8.1 mmol, 1 equiv), triphenylphosphine (8.9 g, 1.3 mmol, 1.1 equiv) and 4-phenylbut-3-yn-1-ol 26 (1.3 g, 8.92 mmol, 1.1 equiv) in a dropwise fashion at 0 °C (Equation 3.28). The reaction mixture was then stirred at room temperature for 15 h. The solvent was removed under reduced pressure. Hexanes (100 ml) were added to the resultant yellow mixture and the white precipitate was filtered. The solid was pre-absorbed on silica gel and purified by flash column chromatography (20 % EtOAc and Hexanes) affording the product 2i as a white solid (3.1 g, 96 %). Mp: 98-99 °C. 1H (400 MHz, CDCl3) δ (ppm) 7.84 (d, J= 6.8 Hz, 2H), 7.38 (m, 2H), 7.28 (m, 5H), 4.10 (t, J = 7.2 Hz, 2H), 2.89 (t, J = 8 Hz, 2H), 2.43 (s, 3H), 1.35 (s, 9H). 13C (100 MHz, CDCl3) δ ppm 151.1, 144.4, 137.6, 131.9, 129.5, 128.4, 128.2, 128.1, 123.7, 86.3, 84.7, 82.8, 45.6, 28.1, 21.8, 21.1. IR (in cm-1): 3058, 2980, 2932, 1739, 1598, 1357, 1287, 1162, 970, 846, 693. HRMS (ESI) calculated for m/z C22H25NO4NaS (M+Na)+ 422.1402, observed 422.1403. Synthesis of tetramethyl-1-cyanoundeca-4,9-diyne-2,2,7,7-tetra carboxylate (1l): Dimethyl-2-(4-bromobut-2-yn-1-yl)-2-(but-2- yn-1-yl)malonate 27 was then added to a solution of NaH (92 mg, 3.85 mmol), THF (40 ml), and dimethyl-2-(cyanomethyl) malonate (0.6 g, 3.5 mmol) which was previously stirred at room temperature for 1 h (Equation 3.30). After the addition was complete the reaction mixture was refluxed for 12-15 h. The completion of the reaction was monitored by gas chromatography. The 91 reaction was later quenched by addition of 50 ml saturated ammonium chloride and distilled water 20 ml and extracted with diethyl ether (3x 100 ml). All organic layers were washed with brine and then dried over magnesium sulfate. The organic layers were concentrated under reduced pressure to afford a crude oil. The crude oil was then purified by silica gel column chromatography using silica gel to afford 1l (1.2 g, 86 %) as yellowish oil. 1H NMR (400 MHz, CDCl3) δ (ppm) 3.81 (s, 6H), 3.75 (s, 6H), 3.12 (s, 2H), 2.98 (t, J = 2 Hz, 2H), 2.93 (t, J = 2.4 Hz, 2H), 2.84 (q, J = 2.4 Hz, 2H), 1.75 (t, J = 2.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm) 169.6, 168.1, 116.3, 79.7, 79.5, 723.0, 56.9, 55.3, 53.9, 53.2, 24.1, 23.2, 23.1, 22.0, 3.7. IR (cm-1): 2958, 2848, 2251, 1741, 1437, 1294, 1214, 1056, 952, 819. General Procedure for Cycloaddition In a nitrogen filled glove box, a solution of alkynenitrile (>1.0 M in DMF) was added to a vial containing 10 mol % Fe(OAc)2 and 13 mol % L12. Additional DMF was added to make the final concentration of alkynenitrile 0.4 M (accounting for alkyne volume). The mixture was stirred for 10 min then 1 equiv. of alkyne and 20 mol % of zinc dust was added. The vial was capped and removed from the glove box then stirred at 85 °C for the indicated period of time. The crude mixture was purified via silica gel flash chromatography. Synthesis of dimethyl-2,3-dibutyl-4-methyl-5H-cyclopenta [b]pyridine-6,6(7H)-dicarboxylate (3a): Compound 3a was prepared using the general procedure with 1a (51.3 mg, 0.23 92 mmol), 2a (32.8 mg, 0.23 mmol), Fe(OAc)2 (4.0 mg, 2.3 x 10-2 mmol), L12 (20 mg, 3.1 x 10-2 mmol), and zinc (3.0 mg, 4.6 x 10-2 mmol) in 533 μL of N,N-dimethylformamide. The reaction mixture was stirred at 85 °C for 2 h and the resulting brown mixture was purified with silica gel flash chromatography using 10 % ethyl acetate in hexanes to yield 3a (58.2 mg, 70 %) as a viscous, yellow oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 3.75 (s, 6H), 3.70 (s, 2H), 3.64 (s, 2H), 2.72 (t, J = 8 Hz, 2H), 2.56 (t, J = 8 Hz, 2H), 2.19 (s, 3H), 1.62 (m, 2H), 1.42 (m, 2H), 0.93 (m, 6H). 13C NMR (100 MHz, CDCl3): δ (ppm) 172.4, 159.8, 156.6, 141.6, 123.3, 130.3, 57.7, 53.2, 42.2, 38.1, 35.6, 33.0, 32.5, 28.4, 23.4, 23.3, 15.9, 14.2, 14.1. IR (cm-1) 3476, 2963, 2019, 1736, 1582, 1438, 1380, 1241, 1071, 963, 863, 818, 737. HRMS (ESI) calcd for C21H32NO4 [M+H]+ 362.2331, found 362.2338. Synthesis of dimethyl-2,3-dibutyl-4-ethyl-5H-cyclopenta[b] pyridine-6,6(7H)-dicarboxylate (3b): Compound 3b was prepa-red using the general procedure with 1a (81.8 mg, 0.23 mmol), 2a (47.7 mg, 0.35 mmol), Fe(OAc)2 (6.0 mg, 3.5 x 10-2 mmol), L12 (29.9 mg, 4.5 x 10-2 mmol), and zinc (4.5 mg, 6.9 x 10-2 mmol) in 800 μL of dimethylformamide. The reaction was stirred at 85 °C for 4 h and the resulting brown mixture was purified with silica gel flash chromatography using 10 % ethyl acetate in hexanes to yield 3b (103 mg, 86 %) as a viscous, yellow oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 3.75 (s, 6H), 3.63 (s, 2H), 3.51 (s, 2H), 2.76 (q, J = 7.6 Hz, 2H), 2.62 (q, J = 7.2 Hz, 2H), 2.20 (s, 3H), 1.24 (t, J = 7.6 Hz, 3H), 1.10 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 172.3, 160.4, 157.1, 147.4, 131.4, 129.7, 58.1, 53.2, 42.0, 37.5, 42.0, 37.5, 35.5, 33.7, 33.0, 27.9, 23.5, 23.4, 23.3, 14.2, 14.04, 13.98. IR (cm-1) 3476, 2958, 1744, 1580, 1437, 93 1408, 1378, 1253, 1104, 1070, 964, 905, 865, 736. HRMS (ESI) calcd for C22H34NO4 [M+H]+ 376.2488, found 376.2497. Synthesis of dimethyl-2,3-dibutyl-4-phenyl-5H-cyclopenta[b] pyridine-6,6(7H)-dicarboxylate (3c): Compound 3c was prepa red using the general procedure with 1c (98.4 mg, 0.35 mmol), 2a (47.7 mg, 0.35 mmol), Fe(OAc)2 (6.0 mg, 3.5 x 10-2 mmol), L12 (29.9 mg, 4.5 x 10-2 mmol), and zinc (4.5 mg, 6.9 x 10-2 mmol) in 800 μL of N,N-dimethylformamide. The reaction mixture was stirred at 85 °C for 4 h and the resulting brown mixture was purified with silica gel flash chromatography using 10 % ethyl acetate in hexanes to yield 3c (137 mg, 75 %) as a viscous yellow oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.42 (t, J = 8 Hz, 2H), 7.36 (d, J = 7.2, 1H), 7.17 (d, J = 8 Hz, 2H), 3.71 (s, 6H), 3.22 (s, 2H), 2.78 (t, J = 10 Hz, 2H), 2.41 (t, J = 8 Hz, 2H), 1.70 (q, J = 7.2 Hz, 2H), 1.46 (sext, J = 7.2 Hz, 2H), 1.28 (q, J = 6.8 Hz, 2H), 1.15 (q, J = 7.2 Hz, 2H), 0.96 (t, J = 7.2, 3H), 0.71 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 172.1, 160.6, 156.9, 146.8, 138.2, 131.6, 129.7, 128.6, 128.2, 127.7, 57.9, 42.3, 38.4, 35.4, 33.2, 32.9, 28.6, 23.3, 22.9, 14.2, 13.7. IR (cm-1) 2956, 2869, 1783, 1576, 1490, 1437, 1273, 1198, 1073, 964, 739. HRMS (ESI) calcd for C26H34NO4 [M+H]+ 424.2488, found 424.2484. Synthesis of dimethyl 2,3-dibutyl-5H-cyclopenta[b]pyridine- 6,6(7H)-dicarboxylate (3d): Compound 3d was prepared using the general procedure with 1d (32.8 mg, 0.23 mmol), 2a (32.8 mg, 0.23 mmol), Fe(OAc)2 (4.0 mg, 2.3 x 10-2 mmol), L12 (20 mg, 3.1 x 10-2 mmol), and zinc (3.0 mg, 4.6 x 10-2 mmol) in 533 μL of N,N-dimethylformamide. The reaction was stirred at 85 °C for 26 h and the resulting brown mixture was purified with silica gel flash 94 chromatography using 10 % ethyl acetate in hexanes to yield 3d (24.0 mg, 30 %) as a viscous yellow oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.23 (s, 1H), 3.76 (s, 6H), 3.65 (s, 2H), 3.54, (s, 2H), 2.76 (t, J = 8 Hz, 2H), 2.56 (t, J = 8 Hz, 2H), 1.63 (m, 4H), 1.53 (m, 4H), 1.42 (m, 4H), 0.95 (td, J = 7.2 Hz, 1.2 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ (ppm) 172.2, 159.7, 157.7, 133.8, 133.2, 130.6, 58.4, 53.3, 41.9, 38.5, 35.0, 33.4, 32.6, 32.2, 30.6, 23.3, 22.9, 14.24, 14.17. IR (cm-1) 3286, 2958, 2868, 1737, 1603, 1572, 1437, 1379, 1249, 1072, 969, 853, 654. HRMS (ESI) calcd for C26H34NO4 [M+H]+ 348.2175, found 348.2176. Synthesis of dimethyl 2,3-dibutyl-4-(trimethylsilyl)-5H-cyclo penta[b]pyridine-6,6(7H)-dicarboxylate (3e): Compound 3e was prepared using the general procedure with 1e (64.7 mg, 0.23 mmol), 2a (32.8 mg, 0.23 mmol), Fe(OAc)2 (4.0 mg, 2.3 x 10-2 mmol), L12 (20 mg, 3.1 x 10-2 mmol), and zinc (3.0 mg, 4.6 x 10-2 mmol) in 533 μL of N,N-dimethylformamide. The reaction mixture was stirred at 85 °C for 26 h and the resulting brown mixture was purified with silica gel flash chromatography using 10 % ethyl acetate in hexanes to yield 3e (55.0 mg, 57 %) as a viscous, yellow oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 3.75 (s, 6H), 3.60 (s, 4H), 2.72 (t, J = 8 Hz, 2H), 2.66 (t, J = 7.6 Hz, 2H), 1.64 (m, 4H), 1.42 (m, 4H), 0.96 (m, 6H), 0.39 (s, 9H). 13C NMR (100 MHz, CDCl3): δ (ppm) 172.3, 159.3, 156.5, 144.4, 138.8, 136.0, 58.3, 53.2, 41.3, 41.0, 35.4, 35.3, 33.0, 32.2, 29.9, 23.4, 23.3, 14.2, 14.1, 2.4. IR (cm-1) 3476, 2957, 2870, 2179, 1739, 1556, 1436, 1376, 1253, 1200, 1167, 1072, 1049, 965, 877, 843, 762, 695, 633. HRMS (ESI) calcd for C23H38NO4 [M+H]+ 420.2570, found 420.2579. 95 Synthesis of dimethyl 2,3-diethyl-4-methyl-5H-cyclopenta[b] pyridine-6,6(7H)-dicarboxylate (3f): Compound 3f was prepared using the general procedure with 1a (100.0 mg, 0.45 mmol), 2b (36.8 mg, 0.45 mmol), Fe(OAc)2 (7.8 mg, 4.5 x 10-2 mmol), L12 (38.8 mg, 5.8 x 10-2 mmol), and zinc (5.9 mg, 9.0 x 10-2 mmol) in 1.0 mL of N,N-dimethylformamide. The reaction mixture was stirred at 85 °C for 6 h and the resulting brown mixture was purified with silica gel flash chromatography using 10% ethyl acetate in hexanes to yield 3f (97.0 mg, 71%) as a viscous, yellow oil. 1H NMR (300 MHz, CDCl3): δ (ppm) 3.77 (s, 6H), 3.65 (s, 2H), 3.52 (s, 2H), 2.78 (q, J = 7.8 Hz, 2H), 2.64 (q, J = 7.5 Hz, 2H), 2.21 (s, 3H), 1.29-1.23 (m, 3H), 1.11 (t, J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 172.3, 160.6. 156.7, 141.6, 133.4, 130.5, 57.7, 53.2, 42.2, 38.1, 28.7, 21.6, 15.6, 14.9, 14.5. IR (cm-1) 2965, 1737, 1584, 1437, 1377, 1259, 1071, 961, 928, 864, 820, 733. HRMS (ESI) calcd for C17H24NO4 [M+H]+ 306.1705, found 306.1707. Synthesis of dimethyl-4-methyl-2,3-diphenyl-5H-cyclopenta [b]pyridine-6,6(7H)-dicarboxylate (3g): Compound 3g was prepared using the general procedure with 1a (100.0 mg, 0.45 mmol), 2c (159.7 mg, 0.90 mmol), Fe(OAc)2 (7.8 mg, 4.5 x 10-2 mmol), L12 (38.8 mg, 5.8 x 10-2 mmol), and zinc (5.9 mg, 9.0 x 10-2 mmol) in 1.1 mL of N,N-dimethylformamide. The reaction mixture was stirred at 85 °C for 6 h and the resulting brown mixture was purified with silica gel flash chromatography using 10 % ethyl acetate in hexanes to yield 3g (88.0 mg, 54 %) as a viscous, yellow oil. 1H NMR (300 MHz, CDCl3): δ (ppm) 7.27-7.02 (m, 10H), 3.82 (s, 8H), 3.65 (s, 2H), 2.09 (s, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm). IR (cm-1) 3057, 2854, 1737, 1601, 1554, 1495, 1432, 96 1400, 1266, 1201, 1121, 1073, 908, 862, 819, 797, 771, 736, 701, 574. HRMS (ESI) calcd for C25H24NO4 [M+H]+ 402.1705, found 402.1700. Synthesis of 2,3-dibutyl-4-ethyl-5,7-dihydrofuro[3,4-b]pyridine (3h): Compound 3h was prepared using the general procedure with 1f (28.3 mg, 0.23 mmol), 2a (32.8 mg, 0.23 mmol), Fe(OAc)2 (4.0 mg, 2.3 x 10-2 mmol), L12 (20 mg, 3.1 x 10-2 mmol), and zinc (3.0 mg, 4.6 x 10-2 mmol) in 533 μL of N,N-dimethylformamide. The reaction mixture was stirred at 85 °C for 26 h and the resulting brown mixture was purified with silica gel flash chromatography using 10% ethyl acetate in hexanes to yield 3h (25 mg, 41 %) as a yellow viscous oil. 1H NMR (300 MHz, CDCl3): δ (ppm) 5.13 (s, 2H), 5.02 (s, 2H), 2.77, (t, J = 8.4 Hz, 2H), 2.64-2.50 (m, 4H), 1.71-1.6 (m, 2H), 1.50-1.41 (m, 6H), 1.15 (t, J = 7.8 Hz, 3H), 1.00-0.93 (m, 6H). 13C NMR (100 MHz, CDCl3): δ (ppm) 160.9, 156.9, 145.2, 131.6, 128.7, 73.4, 71.9, 35.4, 33.7, 32.8, 27.6, 23.7, 23.4, 23.2, 14.1, 14.02, 13.97. IR (cm-1)