Formal Bimolecular [2 + 2 + 2] Cycloaddition Strategy for the Synthesis

Sep 24, 2018 - Forneris, Wang, Mamaliga, Willumstad, and Danheiser. 2018 20 (19), pp 6318–6322. Abstract: The first synthesis of the tetracyclic aroma...
0 downloads 0 Views 816KB Size
Download PDF
Letter Cite This: Org. Lett. 2018, 20, 6244−6249

pubs.acs.org/OrgLett

Formal Bimolecular [2 + 2 + 2] Cycloaddition Strategy for the Synthesis of Pyridines: Intramolecular Propargylic Ene Reaction/Aza Diels−Alder Reaction Cascades Michiko Sasaki, Philip J. Hamzik, Hidaka Ikemoto, Samuel G. Bartko, and Rick L. Danheiser* Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States

Org. Lett. 2018.20:6244-6249. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 10/05/18. For personal use only.

S Supporting Information *

ABSTRACT: Two methods for the synthesis of multisubstituted pyridines are described. In each strategy, a highly reactive vinylallene is generated via an intramolecular propargylic ene reaction in the presence of an azadienophile. Reactions employing ethyl N-(tosyl)iminoacetate furnish an intermediate that undergoes elimination and isomerization upon the addition of DBU. The reaction of the intermediate vinylallene with TsCN leads to the isolation of a 2-sulfonylpyridine that serves as a versatile intermediate undergoing substitution reactions with oxygen and carbon nucleophiles.

T

Scheme 1. Synthesis of Pyridines via Diels−Alder Cycloadditions of Vinylallenes with Azadienophiles

he invention of efficient, atom-economical methods for the synthesis of highly substituted pyridines continues to command attention due to the importance of this heterocycle in coordination chemistry and in the structures of functional materials and biologically active compounds.1,2 Convergent annulation strategies have been a focus of particular interest,3 especially transition-metal-catalyzed [2 + 2 + 2] cycloadditions involving nitriles4 and imine derivatives. 5 Diels−Alder reactions employing azadienophiles provide the basis for another attractive strategy for the synthesis of pyridines, as these cycloadditions generally proceed with excellent regioselectivity and under metal-free conditions simply upon heating.6 A drawback associated with the Diels−Alder approach is that it leads to di- and tetrahydropyridines, necessitating one or more subsequent steps to access the aromatic oxidation state. This process can be achieved by dehydrogenation, which often requires harsh conditions, or by employing cycloaddition partners equipped with functionality that enables postcycloaddition elimination or cycloreversion reactions. The design of Diels−Alder strategies that deliver pyridines directly without the need for additional steps thus constitute a significant goal in this area. Vinylallenes are intrinsically reactive Diels−Alder dienes,7 and their cycloadditions with triple bonds lead to isoaromatic systems that undergo isomerization to aromatic rings spontaneously or under very mild conditions. Recently, we reported the application of vinylallenes in a formal [2 + 2 + 2] cycloaddition strategy8 for the synthesis of polycyclic pyridines, which proceeds via a two-stage pericyclic cascade mechanism. In the first step, an intramolecular propargylic ene reaction generates a vinylallene necessarily locked in an s-cis conformation. This vinylallene exhibits exceptional reactivity as a Diels−Alder reaction partner and engages in [4 + 2] cycloadditions (Scheme 1) with normally unreactive azadienophiles including unactivated cyano groups9 and hetero© 2018 American Chemical Society

substituted imine derivatives such as dimethylhydrazones and oximino ethers10 (2, LG = NMe2 and OMe). These cycloadditions lead to isopyridines of type 3, which then isomerize to pyridines upon further heating or upon the addition of base.11 As in the case of many transition-metalcatalyzed [2 + 2 + 2] cycloadditions, these are fully intramolecular processes in which the third π bond is tethered to the 1,6-diyne moiety in the initial reaction substrate. With the aim of expanding the scope and generality of this methodology, we turned our attention to the challenge of developing a bimolecular variant of this formal [2 + 2 + 2] cycloaddition strategy. It was our hope that the unusual reactivity of the s-cis-constrained vinylallenes generated by these propargylic ene reactions would enable efficient intermolecular [4 + 2] cycloadditions with azadienophiles such as those we employed previously. This would provide access to an expanded range of pyridine derivatives and would complement transition-metal-catalyzed [2 + 2 + 2] cycloadditions, which often are inefficient and do not proceed with good regioselectivity in the case of bimolecular reactions. Received: August 25, 2018 Published: September 24, 2018 6244

DOI: 10.1021/acs.orglett.8b02728 Org. Lett. 2018, 20, 6244−6249

Letter

Organic Letters Disappointingly, our attempts to engage vinylallenes generated by propargylic ene reactions in intermolecular cycloadditions with unactivated nitriles, dimethylhydrazones, and oximino ethers were not fruitful. For example, acetonitrile failed to intercept the vinylallene even when employed as a reaction solvent, leading us to conclude that the application of more reactive dienophiles would be required to achieve efficient trapping of the intermediate vinylallene. Note that previous work in our laboratory had shown that vinylallenes produced by propargylic ene reactions undergo rapid [4 + 2] dimerization when generated in the absence of sufficiently reactive dienophiles.12 After further unsuccessful screening of a number of azadienophiles including ethyl cyanoformate and the oximinosulfonate derivative of Meldrum’s acid,13 we turned our attention to more highly activated azadienophiles such as glyoxylate imines of type 7 and commercially available arylsulfonyl cyanides (10). As outlined in Scheme 2, we

Table 1. Bimolecular, Formal [2 + 2 + 2] Cycloadditions with Ethyl N-(Tosyl)iminoacetate

entry 1 2 3 4c

14 15 16 17

Z

R

product

yield (%)a

O NTs O O

Bu Bu Me CH2OSit-BuMe2

18 19 20 21

40, 47b 37 38 22

a

Isolated yield of products purified by column chromatography. Yield when 2 equiv of 13 is used. cHeating at 160 °C (bath temperature) for 30 min in a tube sealed with a threaded Teflon cap. b

dienophile.18 Unfortunately, attempts to extend the scope of the reaction to include a wider range of enophile G groups (e.g., G = H, CO2Et) were not successful, and in light of this limitation and the modest yields obtained for these reactions, we turned our attention to the application of other classes of azadienophiles. The application of tosyl cyanide as an azadienophile in hetero Diels−Alder reactions is well documented.6 Pioneering studies were carried out by van Leusen in the 1970s,19 and this commercially available reagent has since been employed for the construction of a variety of nitrogen heterocyclic systems.20 Several considerations identified tosyl cyanide as a particularly attractive azadienophile partner for our strategy. First, we anticipated that the additional degree of unsaturation in isopyridine cycloadducts 11 would facilitate their rapid aromatization and thus minimize the formation of lactam byproducts from hydrolysis of these intermediates. Note that we have found that the reaction of TsCN with acyclic dienes such as isoprene and 2,3-dimethylbutadiene is complicated by the formation of such lactam byproducts resulting from hydrolysis of the intermediate dihydropyridines. 21 The increased acidity of the ring proton in 11 conferred by the electron-withdrawing sulfonyl group would also serve to increase the facility of the isomerization step. Most importantly, the products of these formal [2 + 2 + 2] cycloadditions would be 2-sulfonylpyridines, compounds that have been demonstrated to possess useful medicinal activity22 and which are known to undergo a variety of nucleophilic aromatic substitution reactions, providing the basis for further useful synthetic elaboration (vide infra). We evaluated the ability of tosyl cyanide to serve as an effective dienophilic partner for vinylallenes generated in propargylic ene reactions through a competition experiment in which the 1,6-diyne 14 was heated at reflux in toluene in the presence of 1 equiv each of N-methylmaleimide (NMM) and tosyl cyanide. This reaction resulted in the formation of a 75:25 mixture of the NMM adduct and pyridine 32, demonstrating the competence of tosyl cyanide to serve as an azadienophile in our strategy. Scheme 3 outlines the scope of the bimolecular formal [2 + 2 + 2] cycloaddition strategy based on tosyl cyanide.17 Several features of this variant of our strategy for the synthesis of highly substituted pyridines are noteworthy. Heating the 1,6diyne propargylic ene substrates in the presence of 1.1 equiv of

Scheme 2. Synthesis of Pyridines via Bimolecular, Formal [2 + 2 + 2] Cycloaddition Reaction Cascades

hoped that these activated azadienophiles would react with our vinylallenes to afford Diels−Alder adducts of type 8 and 11. Treatment of sulfonamide 8 with base would then effect beta elimination and isomerization to furnish 2-carboethoxypyridines (9), and adducts of type 11 were expected to undergo facile isomerization to furnish 2-sulfonylpyridines (12). We considered the latter variant to be especially attractive due to the potential utility of 2-sulfonylpyridines as substrates for further synthetic elaboration via nucleophilic aromatic substitution reactions (vide infra). Reactions of ethyl N-(tosyl)iminoacetate (13)14 were examined first. The use of this sulfonylimine as a Diels− Alder dienophile was pioneered by Kresze,15 and the imino ester was conveniently prepared in one step using Holmes’ method16 and was purified by distillation. Optimal conditions for the cycloaddition were investigated using the propargylic ene substrate 1417 and were found to involve heating 14 overnight in the presence of 1.1 equiv of 13 in toluene at reflux (Table 1, entry 1). Cooling the reaction mixture to room temperature and the addition of DBU effected elimination and isomerization to afford pyridine 18 in 40% yield, and the yield could be increased to 47% by employing 2 equiv of the 6245

DOI: 10.1021/acs.orglett.8b02728 Org. Lett. 2018, 20, 6244−6249

Letter

Organic Letters

have since been applied to the synthesis of a variety of pyridine derivatives.26 2-Sulfonylpyridines 31 and 3927 were chosen as substrates for investigation of the application of nucleophilic aromatic substitution reactions to the products of our [2 + 2 + 2] cycloaddition reactions. Table 2 summarizes our results.

Scheme 3. Bimolecular, Formal [2 + 2 + 2] Cycloadditions with Tosyl Cyanide

Table 2. Ipso-Substitution Reactions of 2-Sulfonylpyridine Cycloadducts

a

Isolated yields of products purified by column chromatography. Reactions conducted at indicated temperature (bath temperature) in a tube sealed with a threaded Teflon cap. cReaction scaled to provide >2 g of product in a single run.

b

tosyl cyanide produces the desired 2-sulfonylpyridines directly without the need for added base to promote isomerization of intermediate 11 to pyridine 12. Activating substituents G on the enophilic π bond are required to promote the propargylic ene step and also serve to facilitate the aromatization step. As in our previous studies, particular attention was devoted to substrates with alkynes as G groups because they serve as excellent activating groups for the propargylic ene step and can also function as synthetic equivalents for a variety of substituents on the pyridine ring via elaboration through hydrogenation, hydration, and hydroboration reactions.9,10 Finally, the [4 + 2] cycloaddition of tosyl cyanide with these vinylallenes proceeded with a high level of regioselectivity, and in all cases, only a single regioisomer was detected.23 No significant byproducts were isolated from these reactions in which the bulk of the mass balance consisted of polymeric materials. The 2-sulfonyl substituents incorporated in these pyridines can serve as synthetic handles for the further elaboration of the cycloaddition products. Nucleophilic aromatic substitution reactions of 2- and 4-halopyridines are well-documented,24 and analogous ipso-substitution reactions involving sulfonyl derivatives are also well-known. Key early contributions in this area were made by Barlin and Furukawa,25 and these reactions

a

Isolated yield of products purified by column chromatography.

Reactions with Grignard reagents effect replacement of the sulfonyl group with alkyl, aryl, and vinyl substituents (entries 1−6), although no reaction was observed with ethynylmagnesium bromide. The optimal results were obtained by employing excess organomagnesium reagent, and considerable unreacted sulfonylpyridine was recovered when only one equivalent of the nucleophile was used. The reaction of 39 with n-butyllithium resulted in a complex mixture of products, presumably arising from metalation at benzylic positions. The ipso-substitution reaction can also be accomplished with heteroatom nucleophiles. For example, the reaction of 39 with sodium ethoxide gave 2-ethoxyopyridine 47 in good yield, and the reaction with alkynylpyridine 31 occurred selectively at 6246

DOI: 10.1021/acs.orglett.8b02728 Org. Lett. 2018, 20, 6244−6249

Letter

Organic Letters ORCID

the alkynyl group to give a ketal, which was further elaborated to 46 by substitution of the sulfonyl group with methylmagnesium bromide. Finally, 2-pyridones such as 48 can be obtained by reaction with potassium hydroxide generated according to the procedure developed by Gassman and coworkers.28 To date, however, we have not identified conditions that allow efficient substitution reactions with nitrogen nucleophiles or fluoride. If desired, desulfonylation29 of the cycloadducts can also be carried out to provide access to pyridines lacking the sulfonyl substituent. As shown in Table 3, exposure of alkynylpyridines

Rick L. Danheiser: 0000-0002-9812-206X Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We thank the National Science Foundation (CHE-1111567 and CHE-1464799) for generous financial support. P.H. was supported in part by an Amgen Summer Graduate Fellowship as well as a Kenneth M. Gordon Summer Fellowship. M.S. thanks the JSPS Excellent Young Researcher Overseas Visitor Program for financial support. H.I. was supported by the Institutional Program for Young Researcher Overseas Visits of Hiroshima University.

Table 3. Desulfonylation of 2-Sulfonylpyridine Cycloadducts

■

entry

sulfonylpyridine

R1

R2

product

yield (%)b

1 2 3

31 32 49a

Me Bu Bu

Si(i-Pr)3 Si(i-Pr)3 CH2CH2OH

50 51 52

78c 99 98

a

Prepared from 36 in 85% yield via the following conditions: TBAF (1.0 equiv), THF, 0 °C, 10 min. bIsolated yields of products purified by column chromatography. cThis reaction was run in 2:1 MeOH/ THF.

31, 32, and 49 to the action of sodium amalgam in methanol furnished pyridines 50−52 in high yield. Note that, in addition to removal of the sulfonyl group, these conditions also resulted in the reduction of the alkynyl substituents. In summary, we have described a metal-free, formal [2 + 2 + 2] cycloaddition strategy for the synthesis of bicyclic pyridines based on a pericyclic reaction cascade involving an intramolecular propargylic ene reaction and an intermolecular azaDiels−Alder reaction. Glyoxylate imines and commercially available tosyl cyanide participate as azadienophiles in the second step affording 2-carboalkoxy and 2-sulfonylpyridines, respectively. The 2-sulfonylpyridine cycloaddition products are substrates for further synthetic elaboration via nucleophilic aromatic substitution and desulfonylation reactions, providing access to a wide range of substituted pyridines. Further studies are underway in our laboratory aimed at the preparation of highly substituted pyridines via [4 + 2] cycloadditions of other classes of vinylallenes with azadienophiles.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02728. Experimental procedures, characterization data, and 1H and 13C NMR spectra for all new compounds (PDF)

■

REFERENCES

(1) (a) Jones, G. In Comprehensive Heterocyclic Chemistry II; Katritsky, A. R., Rees, C. W., Scriven, E. F. V., McKillop, A., Eds.; Oxford: Pergamon, 1996; Vol. 5, pp 167−243. (b) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th ed.; Wiley-Blackwell: New York, 2010. (2) For general reviews on the de novo synthesis of pyridines, see: (a) Henry, G. D. De Novo Synthesis of Substituted Pyridines. Tetrahedron 2004, 60, 6043−6061. (b) Hill, M. D. Recent Strategies for the Synthesis of Pyridine Derivatives. Chem. - Eur. J. 2010, 16, 12052−12062. (c) Allais, C.; Grassot, J.-M.; Rodriguez, J.; Constantieux, T. Metal-Free Multicomponent Syntheses of Pyridines. Chem. Rev. 2014, 114, 10829−10868. (3) For notable recent examples, see: (a) Movassaghi, M.; Hill, M. D.; Ahmad, O. K. Direct Synthesis of Pyridine Derivatives. J. Am. Chem. Soc. 2007, 129, 10096−10097. (b) Liu, S.; Liebeskind, L. S. A Simple, Modular Synthesis of Substituted Pyridines. J. Am. Chem. Soc. 2008, 130, 6918−6919. (c) Manning, J. R.; Davies, H. M. L. One-Pot Synthesis of Highly Functionalized Pyridines via a Rhodium Carbenoid Induced Ring Expansion of Isoxazoles. J. Am. Chem. Soc. 2008, 130, 8602−8603. (d) Martin, R. M.; Bergman, R. G.; Ellman, J. A. Synthesis of Pyridines from Ketoximes and Terminal Alkynes via C−H Bond Functionalization. J. Org. Chem. 2012, 77, 2501−2507. (e) Neely, J. M.; Rovis, T. Rh(III)-Catalyzed Decarboxylative Coupling of Acrylic Acids with Unsaturated Oxime Esters: Carboxylic Acids Serve as Traceless Activators. J. Am. Chem. Soc. 2014, 136, 2735−2738. (f) Anderson, E. D.; Duerfeldt, A. S.; Zhu, K.; Glinkerman, C. M.; Boger, D. L. Cycloadditions of Noncomplementary Substituted 1,2,3-Triazines. Org. Lett. 2014, 16, 5084−5087. (g) Wu, J.; Xu, W.; Yu, Z.-X.; Wang, J. Ruthenium-Catalyzed Formal Dehydrative [4 + 2] Cycloaddition of Enamides and Alkynes for the Synthesis of Highly Substituted Pyridines: Reaction Development and Mechanistic Study. J. Am. Chem. Soc. 2015, 137, 9489−9496. (4) For recent reviews of pyridine syntheses based on transitionmetal-catalyzed [2 + 2 + 2] cycloadditions of nitriles, see: (a) Heller, B.; Hapke, M. The fascinating construction of pyridine ring systems by transition metal-catalysed [2 + 2 + 2] cycloaddition reactions. Chem. Soc. Rev. 2007, 36, 1085−1094. (b) Shaaban, M. R.; El-Sayed, R.; Elwahy, A. H. M. Construction of fused heterocycles by metalmediated [2 + 2 + 2] cyclotrimerization of alkynes and/or nitriles. Tetrahedron 2011, 67, 6095−6130. (c) Broere, D. L. J.; Ruijter, E. Recent Advances in Transition-Metal-Catalyzed [2 + 2 + 2]Cyclo(co)trimerization Reactions. Synthesis 2012, 44, 2639−2672. (5) For recent examples of transition-metal-catalyzed [2 + 2 + 2] cycloadditions of imino compounds, see: (a) Xu, F.; Wang, C.; Wang, D.; Li, X.; Wan, B. Rhodium-Catalyzed [2 + 2 + 2] Cycloaddition of Oximes and Diynes To Give Pyridines. Chem. - Eur. J. 2013, 19, 2252−2255. (b) Amatore, M.; Leboeuf, D.; Malacria, M.; Gandon, V.; Aubert, C. Highly Enantioselective Rhodium-Catalyzed [2 + 2 + 2] Cycloaddition of Diynes to Sulfonimines. J. Am. Chem. Soc. 2013, 135, 4576−4579. (c) Xu, F.; Wang, C.; Wang, H.; Li, X.; Wan, B. Eco-

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. 6247

DOI: 10.1021/acs.orglett.8b02728 Org. Lett. 2018, 20, 6244−6249

Letter

Organic Letters

Derivaten durch Diels-Alder-Synthese. Chem. Ber. 1965, 98, 1431− 1434. (16) Hamley, P.; Holmes, A. B.; Kee, A.; Ladduwahetty, T.; Smith, D. F. A Convenient Synthesis of Methyl (p-Toluenesulphonylimino)acetate. Addition Reactions with Dienes. Synlett 1991, 1991, 29−30. (17) For full details on the preparation of cycloaddition substrates, see the Supporting Information. (18) Cycloaddition regiochemistry was confirmed by an HMBC experiment on cycloadduct 18 (see Supporting Information) and was consistent with the regiochemical course of vinylallene Diels−Alder reactions reported previously (see refs 7, 9, and 12). (19) (a) van Leusen, A. M.; Jagt, J. C. Cycloaddition reactions of sulfonyl cyanides. Tetrahedron Lett. 1970, 11, 971−973. (b) Jagt, J. C.; van Leusen, A. M. Chemistry of sulfonyl cyanides. Part 4: Diels-alder cycloadditions of sulfonyl cyanides with dienes. Recl. Trav. Chim. PaysBas 1973, 92, 1343−1354. (c) Jagt, J. C.; van Leusen, A. M. DielsAlder cycloadditions of sulfonyl cyanides with cyclopentadiene. Synthesis of 2-azabicyclo[2.2.1]hepta-2,5-dienes. J. Org. Chem. 1974, 39, 564−566. (20) Examples: (a) Pews, R. G.; Nyquist, E. B.; Corson, F. P. The Cycloaddition of Aroyl and Sulfonyl Cyanides with 5,5-Dimethoxy1,2,3,4-tetrahalocyclopentadienes. J. Org. Chem. 1970, 35, 4096− 4100. (b) Rüffer, U.; Breitmaier, E. 5-Alkyl-2-(p-tolylsulfonyl)pyridine durch regioselektive Cyano [4 + 2]-Cycloaddition. Synthesis 1989, 1989, 623−625. (c) Griffiths, G. J.; Previdoli, F. E. Diels-Alder reaction of methanesulfonyl cyanide with cyclopentadiene. Industrial synthesis of 2-azabicyclo[2.2.1]hept-5-en-3-one. J. Org. Chem. 1993, 58, 6129−6131. (d) Hentemann, M. F.; Allen, J. G.; Danishefsky, S. J. Thermal Intermolecular Hetero Diels−Alder Cycloadditions of Aldehydes and Imines via o-Quinone Dimethides. Angew. Chem., Int. Ed. 2000, 39, 1937−1940. (e) McClure, C. K.; Link, J. S. 2Azabicyclo[2.2.2]octa-3,5-dione via a Nitrile Diels−Alder Reaction. J. Org. Chem. 2003, 68, 8256−8257. (f) Hendrickson, J. B.; Wang, J. A Diels-Alder Synthesis of Pyridines. Org. Prep. Proced. Int. 2003, 35, 623−626. (g) Hussain, I.; Yawer, M. A.; Lalk, M.; Lindequist, U.; Villinger, A.; Fischer, C.; Langer, P. Hetero-Diels−Alder reaction of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with arylsulfonylcyanides. Synthesis and antimicrobial activity of 4-hydroxy-2-(arylsulfonyl)pyridines. Bioorg. Med. Chem. 2008, 16, 9898−9903. (h) Grafton, M. W.; Farrugia, L. J.; Sutherland, A. Synthesis of Amino-Substituted Indanes and Tetralins via Consecutive Multibond-Forming Tandem Processes. J. Org. Chem. 2013, 78, 7199−7207. (21) This process is autocatalytic in water, which is generated by disproportionation of the sulfinic acid generated in the hydrolysis. Similar hydrolysis of tosyl cyanide cycloadducts has been observed by van Leusen (ref 19b). (22) See: (a) Hussain, I.; Yawer, M. A.; Lalk, M.; Lindequist, U.; Villinger, A.; Fischer, C.; Langer, P. Hetero-Diels−Alder reaction of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with arylsulfonylcyanides. Synthesis and antimicrobial activity of 4-hydroxy-2-(arylsulfonyl)pyridines. Bioorg. Med. Chem. 2008, 16, 9898−9903. (b) Maloney, K. M.; Kuethe, J. T.; Linn, K. A Practical, One-Pot Synthesis of Sulfonylated Pyridines. Org. Lett. 2011, 13, 102−105. (c) Reeves, J. T.; Tan, Z.; Reeves, D. C.; Song, J. J.; Han, X. S.; Xu, Y.; Tang, W.; Yang, B.-S.; Razavi, H.; Harcken, C.; Kuzmich, D.; Mahaney, P. E.; Lee, H.; Busacca, C. A.; Senanayake, C. H. Development of an Enantioselective Hydrogenation Route to (S)-1-(2-(Methylsulfonyl)pyridin-4-yl)propan-1-amine. Org. Process Res. Dev. 2014, 18, 904− 911. (d) Sun, K.; Chen, X.-L.; Li, X.; Qu, L.-B.; Bi, W.-Z.; Chen, X.; Ma, H.-L.; Zhang, S.-T.; Han, B.-W.; Zhao, Y.-F.; Li, C.-J. Hphosphonate-mediated sulfonylation of heteroaromatic N-oxides: a mild and metal-free one-pot synthesis of 2-sulfonyl quinolines/ pyridines. Chem. Commun. 2015, 51, 12111 and references cited therein . (23) The regiochemical course of the cycloadditions producing pyridines 33 and 41 was confirmed through differential NOE experiments. (24) See ref 1b and references cited therein.

friendly synthesis of pyridines via rhodium-catalyzed cyclization of diynes with oximes. Green Chem. 2015, 17, 799−803. (6) For reviews on the construction of nitrogen heterocycles via hetero Diels−Alder reactions, see: (a) Boger, D. L.; Weinreb, S. M. Hetero Diels−Alder Methodology in Organic Synthesis; Academic Press: San Diego, CA, 1987. (b) Buonora, P.; Olsen, J.-C.; Oh, T. Recent developments in imino Diels-Alder reactions. Tetrahedron 2001, 57, 6099−6138. (c) Heintzelman, G. R.; Meigh, I. R.; Mahajan, Y. R.; Weinreb, S. M. Diels-Alder Reactions of Imino Dienophiles. Org. React. 2005, 65, 141−599. (d) Rowland, G. B.; Rowland, E. B.; Zhang, Q.; Antilla, J. C. Stereoselective Aza-Diels-Alder reactions. Curr. Org. Chem. 2006, 10, 981−1005. (e) Blond, G.; Gulea, M.; Mamane, V. Recent Contributions to Hetero Diels-Alder Reactions. Curr. Org. Chem. 2016, 20, 2161−2210. (f) Cao, M.-H.; Green, N. J.; Xu, S.-Z. Application of the aza-Diels−Alder reaction in the synthesis of natural products. Org. Biomol. Chem. 2017, 15, 3105−3129. (7) For a review of Diels−Alder reactions of vinylallenes, see: Murakami, M.; Matsuda, T. Cycloadditions of Allenes. In Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 2, pp 727−815. For a computational study on Diels−Alder reactions of vinylallenes, see: Ferreiro, M. L.; RodríguezOtero, J.; Cabaleiro-Lago, E. M. Ab Initio and DFT Study of the Influence of the Allene Group on the Diels−Alder Reaction. Struct. Chem. 2004, 15, 323−326. (8) For a review of metal-free formal [2 + 2 + 2] cycloadditions, see: Hapke, M. Transition metal-free formal [2 + 2 + 2] cycloaddition reactions of alkynes. Tetrahedron Lett. 2016, 57, 5719−1729. (9) (a) Sakai, T.; Danheiser, R. L. Cyano Diels−Alder and Cyano Ene Reactions. Applications in a Formal [2 + 2 + 2] Cycloaddition Strategy for the Synthesis of Pyridines. J. Am. Chem. Soc. 2010, 132, 13203−13205. (b) Lan, Y.; Danheiser, R. L.; Houk, K. N. Why Nature Eschews the Concerted [2 + 2 + 2] Cycloaddition of a Nonconjugated Cyanodiyne. Computational Study of a Pyridine Synthesis Involving an Ene−Diels−Alder−Bimolecular HydrogenTransfer Mechanism. J. Org. Chem. 2012, 77, 1533−1538. (10) Hamzik, P. J.; Goutierre, A.-S.; Sakai, T.; Danheiser, R. L. Aza Diels-Alder Reactions of Nitriles, N,N-Dimethylhydrazones, and Oximino Ethers. Application in Formal [2 + 2 + 2] Cycloadditions for the Synthesis of Pyridines. J. Org. Chem. 2017, 82, 12975−12991. (11) Palenzuela has reported cycloadditions of vinylallenes with Nbenzylimines to give products that can be converted to pyridines via dehydrogenation by heating with Pd on carbon. See: (a) Regás, D.; Afonso, M. M.; Rodríguez, M. L.; Palenzuela, J. A. Synthesis of Octahydroquinolines through the Lewis Acid Catalyzed Reaction of Vinyl Allenes and Imines. J. Org. Chem. 2003, 68, 7845−7852. (b) Regás, D.; Afonso, M. M.; Palenzuela, J. A. Intramolecular Hetero-Diels-Alder Reaction of Vinylallenes and Imines: Synthesis of 9-Methyl-1,2,3,4,5,6,7,8-octahydroacridine. Synthesis 2004, 2004, 757−760. (c) Regás, D.; Afonso, M. M.; Palenzuela, J. A. Pyridines and pyridine derivatives from vinyl allenes and imines. Tetrahedron 2012, 68, 9345−9349. (12) Robinson, J. M.; Sakai, T.; Okano, K.; Kitawaki, T.; Danheiser, R. L. Formal [2 + 2 + 2] Cycloaddition Strategy Based on an Intramolecular Propargylic Ene Reaction/Diels−Alder Cycloaddition Cascade. J. Am. Chem. Soc. 2010, 132, 11039−11041. (13) (a) Renslo, A. R.; Danheiser, R. L. Synthesis of Substituted Pyridines via Regiocontrolled [4 + 2] Cycloaddition of Oximinosulfonates. J. Org. Chem. 1998, 63, 7840−7850. (b) Danheiser, R. L.; Renslo, A. R.; Amos, D. T.; Wright, G. T. Preparation of Substituted Pyridines via Regiocontrolled [4 + 2] Cycloadditions of Oximinosulfonates: Methyl 5-Methylpyridine-2-carboxylate. Org. Synth. 2003, 80, 133−143. (14) Diels−Alder reactions of N-sulfonyl iminoacetates are reviewed in Weinreb, S. M. N-Sulfonyl Imines − Useful Synthons in Stereoselective Organic Synthesis. Top. Curr. Chem. 1997, 190, 131−184. (15) Kresze, G.; Albrecht, R. Heterocyclen durch Diensynthese, II: N-[Butyloxycarbonylmethylen]-p-toluolsulfonamid, ein neues Dienophil zur Darstellung von Pyridin-, Piperidein- und Piperidin6248

DOI: 10.1021/acs.orglett.8b02728 Org. Lett. 2018, 20, 6244−6249

Letter

Organic Letters (25) (a) Barlin, G. B.; Brown, W. V. Kinetics of Reactions in Heterocycles. Part II. Replacement of the Methylsulphonyl Group in Substituted Pyridines, Pyridazines, and Pyrazine by Methoxide Ion. J. Chem. Soc. B 1967, 648−652. (b) Barlin, G. B.; Brown, W. V. Useful Reactions of Nucleophiles with Some Methylsulphonyl Derivatives of Nitrogen Heterocycles. J. Chem. Soc. C 1967, 2473−2476. (c) Furukawa, N.; Tsuruoka, M.; Fujihara, H. Ipso-substitution Reactions of 2- and 4-Sulfonylpyridines with Nucleophiles. Heterocycles 1986, 24, 3337−3341. (d) Furukawa, N.; Ogawa, S.; Kawai, T.; Oae, S. Selective ipso-substitution in pyridine ring and its application for the synthesis of macrocycles containing both oxa- and thia-bridges. Tetrahedron Lett. 1983, 24, 3243−3246. (e) Furukawa, N.; Ogawa, S.; Kawai, T.; Oae, S. Ipso-Substitution of a sulphinyl or sulphonyl group attached to pyridine rings and its application for the synthesis of macrocycles. J. Chem. Soc., Perkin Trans. 1 1984, 1, 1839−1845. (26) Additional representative examples: (a) Niiyama, K.; Nagase, T.; Fukami, T.; Takezawa, Y.; Takezawa, H.; Hioki, Y.; Takeshita, H.; Ishikawa, K. Novel 4-substituted pyridine derivatives: Practical derivatization and biological profiles of reversible H+K+-ATPase inhibitors. Bioorg. Med. Chem. Lett. 1997, 7, 527−532. (b) Kaupang, Å.; Hildonen, S.; Halvorsen, T. G.; Mortén, M.; Vik, A.; Hansen, T. V. Involvement of covalent interactions in the mode of action of PPARβ/δ antagonists. RSC Adv. 2015, 5, 76483−76490. (c) Qu, B.; Samankumara, L. P.; Savoie, J.; Fandrick, D. R.; Haddad, N.; Wei, X.; Ma, S.; Lee, H.; Rodriguez, S.; Busacca, C. A.; Yee, N. K.; Song, J. J.; Senanayake, C. H. Synthesis of Pyridyl-dihydrobenzooxaphosphole Ligands and Their Application in Asymmetric Hydrogenation of Unfunctionalized Alkenes. J. Org. Chem. 2014, 79, 993−1000. (d) Wei, X.; Qu, B.; Zeng, X.; Savoie, J.; Fandrick, K. R.; Desrosiers, J. N.; Tcyrulnikov, S.; Marsini, M. A.; Buono, F. G.; Li, Z.; Yang, B.-S.; Tang, W.; Haddad, N.; Gutierrez, O.; Wang, J.; Lee, H.; Ma, S.; Campbell, S.; Lorenz, J. C.; Eckhardt, M.; Himmelsbach, F.; Peters, S.; Patel, N. D.; Tan, Z.; Yee, N. K.; Song, J. J.; Roschangar, F.; Kozlowski, M. C.; Senanayake, C. H. Sequential C−H Arylation and Enantioselective Hydrogenation Enables Ideal Asymmetric Entry to the Indenopiperidine Core of an 11β-HSD-1 Inhibitor. J. Am. Chem. Soc. 2016, 138, 15473−15481. (27) Pyridine 39 was prepared from cycloadduct 31 in 78% yield by (a) 1 equiv TBAF, THF, 0 °C, 10 min and (b) H2, Pd/C, MeOH, rt, 24 h. (28) Gassman, P. G.; Hodgson, P. K. G.; Balchunis, R. J. Basepromoted hydrolysis of amides at ambient temperatures. J. Am. Chem. Soc. 1976, 98, 1275−1276. (29) For a review of desulfonylation reactions, see: Alonso, D. A.; Nájera, C. Desulfonylation Reactions. Org. React. 2008, 72, 367−656.

6249

DOI: 10.1021/acs.orglett.8b02728 Org. Lett. 2018, 20, 6244−6249