DOI: 10.1002/chem.201402981
Communication
& Synthetic Methods
Sequential Hydroformylation/Diels–Alder Processes: One-Pot Synthesis of Polysubstituted Cyclohexenes, Cyclohexadienes, and Phthalates from Alkynes Xianjie Fang, Ralf Jackstell, and Matthias Beller*[a] Abstract: A novel, one-pot hydroformylation/Diels–Alder sequence for the synthesis of multisubstituted cyclohexenes, cyclohexadienes, and phthalates has been developed. Various alkynes were efficiently converted into the corresponding products in good yields and with excellent diastereoselectivity through palladium-catalyzed hydroformylation followed by an AAD-type reaction (AAD: Amides–Aldehydes–Dienophiles). In view of the availability of the substrates, the atom-efficiency of the overall process, and the convenient introduction of substituents in the cyclohexene ring, this method complements current methods for the preparation of polysubstituted cyclohexane derivatives. Scheme 1. Schematic representation of the AAD, ANAD, ALAD, and IAD reaction protocols.
In recent years, research in academia and industry has increasingly emphasized the search for atom-efficient transformations of easily available starting materials into complex organic molecules.[1] In this respect, reactions that provide maximum diversity are especially desirable. Here, expeditious multicomponent reactions (MCR)[2] as well as domino reaction sequences offer significant advantages over stepwise procedures.[3] In this context, our group has developed multicomponent reactions in which amides (AAD-reaction: Amides–Aldehydes–Dienophiles), anhydrides (ANAD-reaction: Anhydrides–Aldehydes–Dienophiles), orthoesters (OAD-reaction: Orthoesters–Aldehydes–Dienophiles) and even isocyanates (IAD-reaction: Isocyanates–Aldehydes–Dienophiles) react with aldehydes and dienophiles to afford a variety of multisubstituted cyclohexene and cyclohexadiene derivatives.[4] As shown in Scheme 1, these transformations take advantage of an initial condensation reaction of amides and aldehydes to give amido-substituted 1,3-butadienes (A, Scheme 1) as key intermediates, which are subsequently converted with electron-deficient dienophiles into the corresponding MCR products. The versatility of functionalized 1,3-butadienes for Diels–Alder chemistry[5] has also been demonstrated in the preparation of important natural products such as pumiliotoxin,[6] gephyrotoxin,[7] dendrobine,[8] and tab-
ersonine.[9] Furthermore, we have demonstrated the synthetic applicability of MCRs in the preparation of highly substituted anilines,[10 ] bicyclo[2.2.2]oct-2-enes,[11] enantiomerically pure cyclohexenols,[12] and cyclohexenylamines,[13] phthalic acids,[14] luminol,[15] phenanthridones[16] as well as lactam derivatives.[17] Based on our long-standing interest in hydroformylation reactions,[18] we recently set out to study less common hydroformylation catalysts. Here, we have demonstrated that metals besides rhodium and cobalt[19] can be successfully applied in the hydroformylation of olefins. More specifically, we showed that palladium complexes with heterocyclic phosphine ligands are efficient catalysts for the hydroformylation of alkynes to selectively give a,b-unsaturated aldehydes.[20] On the basis of the latter work, we utilized this protocol for the synthesis of more complex organic molecules. Advantageously, both the palladi-
[a] X. Fang, Dr. R. Jackstell, Prof. Dr. M. Beller Leibniz-Institut fr Katalyse e.V. an der Universitt Rostock Albert-Einstein-Str. 29 a, 18059 Rostock (Germany) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201402981. Chem. Eur. J. 2014, 20, 7939 – 7942
Scheme 2. Sequential hydroformylation/AAD reactions.
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Communication Table 1. Synthesis of multisubstituted cyclohexenes and cyclohexadienes from alkynes by a one-pot hydroformylation/Diels–Alder process.[a]
Entry 1
2
3
MCR product (yield)[b]
1
2
3
4
5
6
7
8[c]
Herein, we report our recent efforts to develop a two-step, one-pot synthesis of diverse multisubstituted cyclohexenes and cyclohexadienes by combining hydroformylation and Diels–Alder reactions. Notably, this methodology provides an interesting option to synthesize new organic products because the corresponding a,b-unsaturated aldehydes are traditionally difficult to synthesize and only a few examples are commercially available. Initially, we investigated the formation of 4 a by using a one-pot hydroformylation/Diels–Alder process starting from 3-hexyne (1 a). This substrate was treated under the standard hydroformylation reaction conditions recently reported by our research group, which allow the direct conversion of alkynes into a,b-unsaturated aldehydes.[20a] The a,b-unsaturated aldehyde was directly subjected to the multicomponent Diels–Alder reaction conditions (including one equivalent of methanesulfonamide (2 a), Nmethylmaleimide (3 a), and 3 mol % p-TsOH). To our delight, an excellent 87 % isolated yield of the desired product 4 a was obtained [Eq. (1)]. This yield is comparable to that observed for the individual AADreaction. We then extended this straightforward synthesis of 4 a to a wider range of alkynes, amides, and dienophiles. As depicted in Table 1, the present one-pot process was surprisingly versatile. In general, both symmetrical and unsymmetrical alkynes underwent efficient hydroformylation/Diels–Alder reactions to afford the corresponding multisubstituted cyclohexenes in good yields. Notably, functionalized a,b-unsaturated aldehydes are traditionally difficult to synthesize and they are not usually commercially available. Gratifyingly, alkynes having different functional groups such as phthalimide and ester were well tolerated, and were smoothly transformed into the corresponding functionalized cyclohexenes in good yields (Table 1, entries 8 and 9). Furthermore, various carboxamides were stable under the standard reaction conditions. Employment of 2-oxazolidinone 2 d with a tertiary amide moiety, gave the corresponding product 4 k in 69 % yield (Table 1, entry 11). Benzyloxycarbonyl (Cbz) protection of the amino function was realized for 4 g and 4 m (Table 1, entries 7 and 13). In addition to amides, anhydrides (ANAD reaction) and orthoesters (OAD reaction) also served as coupling partners, which led to an increase in structural diversity (Table 1, entries 10 and 12). To
um-catalyzed hydroformylation and the AAD-type reactions require acid as co-catalyst. From this point of view, it should be possible to combine them as postulated in Scheme 2. Chem. Eur. J. 2014, 20, 7939 – 7942
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Communication Table 1. (Continued)
Entry 1
2
3
MCR product (yield)[b]
9[c]
10
11
12
13
14[d]
study the influence of other dienophiles, dimethyl acetylenedicarboxylate (3 b), trans-b-nitrostyrene (3 c), and acrylonitrile (3 d), were employed and the reaction gave yields of 65, 51, and 65 %, respectively (Table 1, entries 14–17). For all products, one- and two-dimensional NMR experiments established the stereochemical structure. In all cases, we observed selective endo-addition of the dienophile during the Diels–Alder step. To enhance product diversity of the present reaction protocol further on, tri- and tetra-substituted dimethyl phthalates 5 were prepared in good yields after 48 h at 160 8C from alkynes, acetamide (2 f) and dimethyl acetylenedicarboxylate (3 b) (Scheme 3). Both short- and longchained symmetrical aliphatic alkynes provided the corresponding substituted dimethyl phthalates in good yields through acylamine elimination from the intermediate cyclohexadienes. In conclusion, several one-pot procedures for diversity-oriented syntheses of multisubstituted cyclohexenes, cyclohexadienes, and phthalates have been developed. Key to success is the combination of hydroformylation of alkynes followed by Diels–Alder reactions. This methodology shows broad scope and starts from alkynes, which are very versatile substrates. Compared with related multicomponent reactions, the scope for substituted cyclohexene derivatives is improved. Considering the ready availability of the substrates, the atom-efficiency, and the good yield with excellent diastereoselectivity, we believe that the present sequential hydroformylation/AAD-reactions complement known methodologies for the synthesis of substituted cyclohexenes, cyclohexadienes, and phthalates.
15[d]
Experimental Section General procedure for the preparation of 4
16
17[e]
[a] Reaction conditions: 1) 1 (7.5 mmol), Pd(acac)2 (1 mol %), L (4 mol %), p-TsOH (4 mol %), CO/H2 (40 bar), toluene (30 mL), 100 8C, 10 h; 2) p-TsOH (3 mol %), 2 (7.5 mmol), 3 (7.5 mmol), 110 8C, 16 h. [b] Yield of isolated product after column chromatography. [c] Experiments were carried out on a 1.5 mmol scale. [d] 3 b (11.25 mmol). [e] 3 d (37.5 mmol), the reaction temperature and time of the second step were 160 8C and 48 h, respectively.
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A 100 mL steel autoclave was charged under argon atmosphere with Pd(acac)2 (22.8 mg, 1 mol %), ligand (160.7 mg, 4 mol %), and p-TsOH (57 mg, 4 mol %). Toluene (30 mL) and alkyne 1 (7.5 mmol) were then added and the autoclave was pressurized with 40 bar synthesis gas and heated to 100 8C. The reaction was carried out for 10 h. After the reaction time, the autoclave was cooled to RT, the pressure was released, and p-TsOH (42.7 mg, 3 mol %), 2 (7.5 mmol), and 3 (7.5 mmol) were consecutively added into the autoclave under an argon atmosphere. The resulting mixture was stirred at 110 8C for 16 h. After the reaction time, the autoclave was cooled to RT, the solvent was removed under vacuum, and the residue was directly purified by flash chromatography on silica gel (heptane/ethyl acetate 2:1) to give the desired product 4. 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Communication
[5]
[6]
[7] Scheme 3. Synthesis of multisubstituted phthalates from alkynes by a onepot hydroformylation/Diels–Alder process. Reaction conditions: 1) 1 (7.5 mmol), Pd(acac)2 (1 mol %), L (4 mol %), p-TsOH (4 mol %), CO/H2 (40 bar), toluene (30 mL), 100 8C, 10 h; 2) p-TsOH (3 mol %), 2 f (7.5 mmol), 3 b (11.25 mmol), 160 8C, 48 h, yield of isolated product after column chromatography.
[8] [9]
[10]
Acknowledgements [11]
This work has been funded by the BMBF (Germany) and the State of Mecklenburg-Vorpommern. We thank Dr. Christine Fischer, Susann Buchholz, and Susanne Schareina for their technical and analytical support. We are grateful to Dr. Abhishek Dutta Chowdhury for helpful discussions. Keywords: alkynes · a,b-unsaturated aldehydes cycloaddition · diastereoselectivity · hydroformylation palladium
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[13]
[14]
[15] [16]
[1] a) B. M. Trost, Science 1991, 254, 1471; b) B. M. Trost, Angew. Chem. 1995, 107, 285; Angew. Chem. Int. Ed. Engl. 1995, 34, 259; c) B. M. Trost in Transition Metals for Organic Synthesis (Eds.: M. Beller, C. Bolm), WileyVCH, Weinheim, 1998, p. 1. [2] a) Multicomponent Reactions (Eds.: J. Zhu, H. Bienayme), Wiley-VCH, Weinheim, 2005; b) L. F. Tietze, G. Brasche, K. Gericke, Domino Reactions in Organic Synthesis, Wiley-VCH, Weinheim, 2006; c) E. Ruijter, R. Scheffelaar, R. V. A. Orru, Angew. Chem. 2011, 123, 6358; Angew. Chem. Int. Ed. 2011, 50, 6234; d) D. M. D’Souza, T. J. J. Mller, Chem. Soc. Rev. 2007, 36, 1095; e) B. Willy, T. J. J. Mller, Curr. Org. Chem. 2009, 13, 1777; f) A. Dçmling, I. Ugi, Angew. Chem. 2000, 112, 3300; Angew. Chem. Int. Ed. 2000, 39, 3168; g) H. Bienaym, C. Hulme, G. Oddon, P. Schmitt, Chem. Eur. J. 2000, 6, 3321. [3] a) L. F. Tietze, Chem. Rev. 1996, 96, 115; b) L. F. Tietze, A. Modi, Med. Res. Rev. 2000, 20, 304; c) L. F. Tietze, F. Haunert in Stimulating Concepts in Chemistry (Eds.: M. Shibasaki, J. F. Stoddart, F. Vçgtle), Wiley-VCH, Weinheim, 2000, p. 39; d) J. E. Rixson, T. Chaloner, C. H. Heath, L. F. Tietze, S. G. Stewart, Eur. J. Org. Chem. 2012, 544; e) D. L. Priebbenow, S. G. Stewart, F. M. Pfeffer, Org. Biomol. Chem. 2011, 9, 1508; f) D. L. Priebbenow, S. G. Stewart, F. M. Pfeffer, Tetrahedron Lett. 2012, 53, 1468; g) C. Hulme, V. Gore, Curr. Med. Chem. 2003, 10, 51; h) J. Zhu, Eur. J. Org. Chem. 2003, 1133; i) E. Merkul, T. Oeser, T. J. J. Mller, Chem. Eur. J. 2009, 15, 5006; j) A. V. Rotaru, I. D. Druta, T. Oeser, T. J. J. Mller, Helv. Chim. Acta 2005, 88, 1798. [4] a) H. Neumann, A. Jacobi von Wangelin, D. Gçrdes, A. Spannenberg, M. Beller, J. Am. Chem. Soc. 2001, 123, 8398; b) A. Jacobi von Wangelin, H. Neumann, D. Gçrdes, A. Spannenberg, M. Beller, Org. Lett. 2001, 3, 2895; c) H. Neumann, A. Jacobi von Wangelin, D. Gçrdes, A. Spannenberg, W. Baumann, M. Beller, Tetrahedron 2002, 58, 2381; d) D. Strbing, H. Neumann, S. Hbner, S. Klaus, M. Beller, Org. Lett. 2005, 7, 4321; e) D. Strbing, H. Neumann, A. Jacobi von Wangelin, S. Klaus, S. Hbner, M.
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[17] [18]
[19]
[20]
Beller, Tetrahedron 2006, 62, 10962; f) R. Fichtler, J.-M. Neudçrfl, A. Jacobi von Wangelin, Org. Biomol. Chem. 2011, 9, 7224. a) J. M. Janey, T. Iwama, S. A. Kozmin, V. H. Rawal, J. Org. Chem. 2000, 65, 9059; b) M. B. Smith, Org. Prep. Proced. Int. 1990, 22, 315; c) L. E. Overman, R. L. Freerks, C. B. Petty, L. A. Clizbe, R. K. Ono, G. F. Taylor, P. J. Jessup, J. Am. Chem. Soc. 1981, 103, 2816; d) W. Oppolzer, L. Bieber, E. Francotte, Tetrahedron Lett. 1979, 20, 4537; e) For antibody-catalysis, see: M. R. Tremblay, T. J. Dickerson, K. D. Janda, Adv. Synth. Catal. 2001, 343, 577. a) W. Oppolzer, W. Frçstl, H.-P. Weber, Helv. Chim. Acta 1975, 58, 593; b) W. Oppolzer, E. Flaskamp, Helv. Chim. Acta 1977, 60, 204; c) W. Oppolzer, E. Flaskamp, L. W. Bieber, Helv. Chim. Acta 2001, 84, 141; d) L. E. Overman, P. J. Jessup, Tetrahedron Lett. 1977, 18, 1253. L. E. Overman, D. Lesuisse, M. Hashimoto, J. Am. Chem. Soc. 1983, 105, 5373. a) S. F. Martin, W. Li, J. Org. Chem. 1989, 54, 265; b) S. F. Martin, W. Li, J. Org. Chem. 1991, 56, 642. a) S. A. Kozmin, V. H. Rawal, J. Am. Chem. Soc. 1998, 120, 13523; b) for total syntheses of tabersonine and other aspidosperma alkaloids, see: S. A. Kozmin, T. Iwama, Y. Huang, V. H. Rawal, J. Am. Chem. Soc. 2002, 124, 4628. H. Neumann, A. Jacobi von Wangelin, S. Klaus, D. Strbing, D. Gçrdes, M. Beller, Angew. Chem. 2003, 115, 4641; Angew. Chem. Int. Ed. 2003, 42, 4503. D. Strbing, A. Jacobi von Wangelin, H. Neumann, D. Gçrdes, S. Hbner, S. Klaus, A. Spannenberg, M. Beller, Eur. J. Org. Chem. 2005, 107. D. Strbing, A. Kirschner, H. Neumann, S. Klaus, U. T. Bornscheuer, M. Beller, Chem. Eur. J. 2005, 11, 4210. D. Strbing, H. Neumann, A. Jacobi von Wangelin, D. Gçrdes, S. Klaus, M. Beller, P. Braiuca, C. Ebert, L. Gardossi, U. Kragl, Tetrahedron 2004, 60, 683. A. Jacobi von Wangelin, H. Neumann, D. Gçrdes, S. Klaus, H. Jiao, A. Spannenberg, M. Beller, T. Krger, C. Wendler, K. Thurow, N. Stoll, Chem. Eur. J. 2003, 9, 2273. H. Neumann, S. Klaus, M. Klawonn, D. Strbing, S. Hbner, D. Gçrdes, A. Jacobi von Wangelin, M. Beller, Z. Naturforsch. B 2004, 59, 431. A. Jacobi von Wangelin, H. Neumann, D. Gçrdes, S. Hbner, C. Wendler, S. Klaus, D. Strbing, A. Spannenberg, H. Jiao, L. El Firdoussi, K. Thurow, N. Stoll, M. Beller, Synthesis 2005, 2029. D. Strbing, H. Neumann, S. Klaus, S. Hbner, M. Beller, Tetrahedron 2005, 61, 11345. a) A. Seayad, M. Ahmed, H. Klein, R. Jackstell, T. Gross, M. Beller, Science 2002, 297, 1676; b) M. Ahmed, A. M. Seayad, R. Jackstell, M. Beller, J. Am. Chem. Soc. 2003, 125, 10311; c) M. Ahmed, R. P. J. Bronger, R. Jackstell, P. C. J. Kamer, P. W. N. M. van Leeuwen, M. Beller, Chem. Eur. J. 2006, 12, 8979; d) M. Ahmed, C. Buch, L. Routaboul, R. Jackstell, H. Klein, A. Spannenberg, M. Beller, Chem. Eur. J. 2007, 13, 1594. a) R. Jennerjahn, I. Piras, R. Jackstell, R. Franke, K.-D. Wiese, M. Beller, Chem. Eur. J. 2009, 15, 6383; b) I. Piras, R. Jennerjahn, R. Jackstell, A. Spannenberg, R. Franke, M. Beller, Angew. Chem. 2011, 123, 294; Angew. Chem. Int. Ed. 2011, 50, 280; c) I. Fleischer, L. Wu, I. Profir, R. Jackstell, R. Franke, M. Beller, Chem. Eur. J. 2013, 19, 10589; d) L. Wu, I. Fleischer, R. Jackstell, M. Beller, J. Am. Chem. Soc. 2013, 135, 3989; e) I. Fleischer, K. M. Dyballa, R. Jennerjahn, R. Jackstell, R. Franke, A. Spannenberg, M. Beller, Angew. Chem. 2013, 125, 3021; Angew. Chem. Int. Ed. 2013, 52, 2949; f) L. Wu, I. Fleischer, R. Jackstell, I. Profir, R. Franke, M. Beller, J. Am. Chem. Soc. 2013, 135, 14306. For a review, see: g) J. Pospech, I. Fleischer, R. Franke, S. Buchholz, M. Beller, Angew. Chem. 2013, 125, 2922; Angew. Chem. Int. Ed. 2013, 52, 2852. For hydroformylation of alkynes, see: a) X. Fang, M. Zhang, R. Jackstell, M. Beller, Angew. Chem. 2013, 125, 4743; Angew. Chem. Int. Ed. 2013, 52, 4645; b) J. R. Johnson, G. D. Cuny, S. L. Buchwald, Angew. Chem. 1995, 107, 1877; Angew. Chem. Int. Ed. Engl. 1995, 34, 1760; c) Y. Ishii, K. Miyashita, K. Kamita, M. Hidai, J. Am. Chem. Soc. 1997, 119, 6448; d) B. G. Van den Hoven, H. Alper, J. Org. Chem. 1999, 64, 3964; e) B. G. Van den Hoven, H. Alper, J. Org. Chem. 1999, 64, 9640; f) V. Agabekov, W. Seiche, B. Breit, Chem. Sci. 2013, 4, 2418.
Received: April 7, 2014 Published online on May 30, 2014
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Communication
& Synthetic Methods
Sequential Hydroformylation/Diels–Alder Processes: One-Pot Synthesis of Polysubstituted Cyclohexenes, Cyclohexadienes, and Phthalates from Alkynes Xianjie Fang, Ralf Jackstell, and Matthias Beller*[a] Abstract: A novel, one-pot hydroformylation/Diels–Alder sequence for the synthesis of multisubstituted cyclohexenes, cyclohexadienes, and phthalates has been developed. Various alkynes were efficiently converted into the corresponding products in good yields and with excellent diastereoselectivity through palladium-catalyzed hydroformylation followed by an AAD-type reaction (AAD: Amides–Aldehydes–Dienophiles). In view of the availability of the substrates, the atom-efficiency of the overall process, and the convenient introduction of substituents in the cyclohexene ring, this method complements current methods for the preparation of polysubstituted cyclohexane derivatives. Scheme 1. Schematic representation of the AAD, ANAD, ALAD, and IAD reaction protocols.
In recent years, research in academia and industry has increasingly emphasized the search for atom-efficient transformations of easily available starting materials into complex organic molecules.[1] In this respect, reactions that provide maximum diversity are especially desirable. Here, expeditious multicomponent reactions (MCR)[2] as well as domino reaction sequences offer significant advantages over stepwise procedures.[3] In this context, our group has developed multicomponent reactions in which amides (AAD-reaction: Amides–Aldehydes–Dienophiles), anhydrides (ANAD-reaction: Anhydrides–Aldehydes–Dienophiles), orthoesters (OAD-reaction: Orthoesters–Aldehydes–Dienophiles) and even isocyanates (IAD-reaction: Isocyanates–Aldehydes–Dienophiles) react with aldehydes and dienophiles to afford a variety of multisubstituted cyclohexene and cyclohexadiene derivatives.[4] As shown in Scheme 1, these transformations take advantage of an initial condensation reaction of amides and aldehydes to give amido-substituted 1,3-butadienes (A, Scheme 1) as key intermediates, which are subsequently converted with electron-deficient dienophiles into the corresponding MCR products. The versatility of functionalized 1,3-butadienes for Diels–Alder chemistry[5] has also been demonstrated in the preparation of important natural products such as pumiliotoxin,[6] gephyrotoxin,[7] dendrobine,[8] and tab-
ersonine.[9] Furthermore, we have demonstrated the synthetic applicability of MCRs in the preparation of highly substituted anilines,[10 ] bicyclo[2.2.2]oct-2-enes,[11] enantiomerically pure cyclohexenols,[12] and cyclohexenylamines,[13] phthalic acids,[14] luminol,[15] phenanthridones[16] as well as lactam derivatives.[17] Based on our long-standing interest in hydroformylation reactions,[18] we recently set out to study less common hydroformylation catalysts. Here, we have demonstrated that metals besides rhodium and cobalt[19] can be successfully applied in the hydroformylation of olefins. More specifically, we showed that palladium complexes with heterocyclic phosphine ligands are efficient catalysts for the hydroformylation of alkynes to selectively give a,b-unsaturated aldehydes.[20] On the basis of the latter work, we utilized this protocol for the synthesis of more complex organic molecules. Advantageously, both the palladi-
[a] X. Fang, Dr. R. Jackstell, Prof. Dr. M. Beller Leibniz-Institut fr Katalyse e.V. an der Universitt Rostock Albert-Einstein-Str. 29 a, 18059 Rostock (Germany) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201402981. Chem. Eur. J. 2014, 20, 7939 – 7942
Scheme 2. Sequential hydroformylation/AAD reactions.
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Communication Table 1. Synthesis of multisubstituted cyclohexenes and cyclohexadienes from alkynes by a one-pot hydroformylation/Diels–Alder process.[a]
Entry 1
2
3
MCR product (yield)[b]
1
2
3
4
5
6
7
8[c]
Herein, we report our recent efforts to develop a two-step, one-pot synthesis of diverse multisubstituted cyclohexenes and cyclohexadienes by combining hydroformylation and Diels–Alder reactions. Notably, this methodology provides an interesting option to synthesize new organic products because the corresponding a,b-unsaturated aldehydes are traditionally difficult to synthesize and only a few examples are commercially available. Initially, we investigated the formation of 4 a by using a one-pot hydroformylation/Diels–Alder process starting from 3-hexyne (1 a). This substrate was treated under the standard hydroformylation reaction conditions recently reported by our research group, which allow the direct conversion of alkynes into a,b-unsaturated aldehydes.[20a] The a,b-unsaturated aldehyde was directly subjected to the multicomponent Diels–Alder reaction conditions (including one equivalent of methanesulfonamide (2 a), Nmethylmaleimide (3 a), and 3 mol % p-TsOH). To our delight, an excellent 87 % isolated yield of the desired product 4 a was obtained [Eq. (1)]. This yield is comparable to that observed for the individual AADreaction. We then extended this straightforward synthesis of 4 a to a wider range of alkynes, amides, and dienophiles. As depicted in Table 1, the present one-pot process was surprisingly versatile. In general, both symmetrical and unsymmetrical alkynes underwent efficient hydroformylation/Diels–Alder reactions to afford the corresponding multisubstituted cyclohexenes in good yields. Notably, functionalized a,b-unsaturated aldehydes are traditionally difficult to synthesize and they are not usually commercially available. Gratifyingly, alkynes having different functional groups such as phthalimide and ester were well tolerated, and were smoothly transformed into the corresponding functionalized cyclohexenes in good yields (Table 1, entries 8 and 9). Furthermore, various carboxamides were stable under the standard reaction conditions. Employment of 2-oxazolidinone 2 d with a tertiary amide moiety, gave the corresponding product 4 k in 69 % yield (Table 1, entry 11). Benzyloxycarbonyl (Cbz) protection of the amino function was realized for 4 g and 4 m (Table 1, entries 7 and 13). In addition to amides, anhydrides (ANAD reaction) and orthoesters (OAD reaction) also served as coupling partners, which led to an increase in structural diversity (Table 1, entries 10 and 12). To
um-catalyzed hydroformylation and the AAD-type reactions require acid as co-catalyst. From this point of view, it should be possible to combine them as postulated in Scheme 2. Chem. Eur. J. 2014, 20, 7939 – 7942
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Communication Table 1. (Continued)
Entry 1
2
3
MCR product (yield)[b]
9[c]
10
11
12
13
14[d]
study the influence of other dienophiles, dimethyl acetylenedicarboxylate (3 b), trans-b-nitrostyrene (3 c), and acrylonitrile (3 d), were employed and the reaction gave yields of 65, 51, and 65 %, respectively (Table 1, entries 14–17). For all products, one- and two-dimensional NMR experiments established the stereochemical structure. In all cases, we observed selective endo-addition of the dienophile during the Diels–Alder step. To enhance product diversity of the present reaction protocol further on, tri- and tetra-substituted dimethyl phthalates 5 were prepared in good yields after 48 h at 160 8C from alkynes, acetamide (2 f) and dimethyl acetylenedicarboxylate (3 b) (Scheme 3). Both short- and longchained symmetrical aliphatic alkynes provided the corresponding substituted dimethyl phthalates in good yields through acylamine elimination from the intermediate cyclohexadienes. In conclusion, several one-pot procedures for diversity-oriented syntheses of multisubstituted cyclohexenes, cyclohexadienes, and phthalates have been developed. Key to success is the combination of hydroformylation of alkynes followed by Diels–Alder reactions. This methodology shows broad scope and starts from alkynes, which are very versatile substrates. Compared with related multicomponent reactions, the scope for substituted cyclohexene derivatives is improved. Considering the ready availability of the substrates, the atom-efficiency, and the good yield with excellent diastereoselectivity, we believe that the present sequential hydroformylation/AAD-reactions complement known methodologies for the synthesis of substituted cyclohexenes, cyclohexadienes, and phthalates.
15[d]
Experimental Section General procedure for the preparation of 4
16
17[e]
[a] Reaction conditions: 1) 1 (7.5 mmol), Pd(acac)2 (1 mol %), L (4 mol %), p-TsOH (4 mol %), CO/H2 (40 bar), toluene (30 mL), 100 8C, 10 h; 2) p-TsOH (3 mol %), 2 (7.5 mmol), 3 (7.5 mmol), 110 8C, 16 h. [b] Yield of isolated product after column chromatography. [c] Experiments were carried out on a 1.5 mmol scale. [d] 3 b (11.25 mmol). [e] 3 d (37.5 mmol), the reaction temperature and time of the second step were 160 8C and 48 h, respectively.
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A 100 mL steel autoclave was charged under argon atmosphere with Pd(acac)2 (22.8 mg, 1 mol %), ligand (160.7 mg, 4 mol %), and p-TsOH (57 mg, 4 mol %). Toluene (30 mL) and alkyne 1 (7.5 mmol) were then added and the autoclave was pressurized with 40 bar synthesis gas and heated to 100 8C. The reaction was carried out for 10 h. After the reaction time, the autoclave was cooled to RT, the pressure was released, and p-TsOH (42.7 mg, 3 mol %), 2 (7.5 mmol), and 3 (7.5 mmol) were consecutively added into the autoclave under an argon atmosphere. The resulting mixture was stirred at 110 8C for 16 h. After the reaction time, the autoclave was cooled to RT, the solvent was removed under vacuum, and the residue was directly purified by flash chromatography on silica gel (heptane/ethyl acetate 2:1) to give the desired product 4. 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Communication
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[7] Scheme 3. Synthesis of multisubstituted phthalates from alkynes by a onepot hydroformylation/Diels–Alder process. Reaction conditions: 1) 1 (7.5 mmol), Pd(acac)2 (1 mol %), L (4 mol %), p-TsOH (4 mol %), CO/H2 (40 bar), toluene (30 mL), 100 8C, 10 h; 2) p-TsOH (3 mol %), 2 f (7.5 mmol), 3 b (11.25 mmol), 160 8C, 48 h, yield of isolated product after column chromatography.
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Acknowledgements [11]
This work has been funded by the BMBF (Germany) and the State of Mecklenburg-Vorpommern. We thank Dr. Christine Fischer, Susann Buchholz, and Susanne Schareina for their technical and analytical support. We are grateful to Dr. Abhishek Dutta Chowdhury for helpful discussions. Keywords: alkynes · a,b-unsaturated aldehydes cycloaddition · diastereoselectivity · hydroformylation palladium
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Received: April 7, 2014 Published online on May 30, 2014
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