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Multicomponent decarboxylative allylations† Cite this: Chem. Commun., 2014, 50, 14049
Yamuna Ariyarathna and Jon A. Tunge*
Received 13th September 2014, Accepted 24th September 2014 DOI: 10.1039/c4cc07253g www.rsc.org/chemcomm
The reaction of Meldrum’s acid, pyrrolide, and allyl carbonates allows a multicomponent decarboxylative coupling to form allylated acyl pyrroles. This strategy is made possible by the in situ formation of b-oxo carboxylates from Meldrum’s acid. Subsequent decarboxylative enolate formation and electrophilic allylation complete the reaction. Addition of benzylidene malononitriles as good Michael acceptors allow a 4-component interceptive decarboxylative allylation.
Formation of C–C bonds via palladium-catalyzed decarboxylative coupling has received much attention as an alternative to traditional metal-catalyzed cross-coupling reactions.1 For example, decarboxylative allylation (DcA) provides for the allylation of relatively non-stabilized ketone enolates via elimination of CO2 from allyl b-ketoesters or allyl enol carbonates.2 However, DcA reactions often suffer from the need to incorporate the allyl electrophile and the nucleophile into the same reactant molecule via an ester linkage. Thus, we became interested in developing methods that would allow more rapid intermolecular allylation of enolates. Herein we report the successful development of 3- and 4-component decarboxylative allylations that give rise to useful allylated acyl pyrroles (Scheme 1). In order to develop a more rapid intermolecular reaction for the synthesis of a-allylated carbonyl compounds, it was necessary to identify components that would give rise to b-oxo carboxylates via in situ reaction. Meldrum’s acid derivatives seemed ideal since they are readily available and are known to undergo ring-opening with nucleophiles to generate b-oxo carboxylates.3,4 If a nucleophile could be identified that preferentially reacts with Meldrum’s acid derivatives rather than palladium-p-allyl electrophiles, then it should be possible to form homoallylic carbonyl compounds from the combination of nucleophile, Meldrum’s acid, and allyl electrophile according to Scheme 2. Given that palladium p-allyl The University of Kansas Department of Chemistry, 2010 Malott Hall, 1251 Wescoe Hall Dr., Lawrence, KS, 66045, USA. E-mail: [email protected] † Electronic supplementary information (ESI) available: Experimental procedures and spectral characterization of all new compounds. CCDC 1021515. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/ c4cc07253g
This journal is © The Royal Society of Chemistry 2014
Scheme 1
Scheme 2
complexes are soft electrophiles, we envisioned that a hard nucleophile would preferentially attack the relatively hard Meldrum’s acid derivative. Having recently developed decarboxylative allylations of acyl pyrroles as ester enolate equivalents, pyrrolide was chosen as the nucleophile to initiate our investigations.5,6 Aside from the potential for unwanted allylation of pyrrole, other possible pitfalls involve reactions of the acetone that is liberated from Meldrum’s acid; reaction of acetone with the pyrrolide nucleophile or by protonation of our desired enolate would derail the desired 3-component coupling.
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Table 2
Optimization of reaction conditions
Entry Pd source 1 2 3 4 5 6 7 8 9
ChemComm
Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd2dba3 Pddba2 PdCp(allyl) Pd(PPh3)4 Pd2dba3
L
Solvent
R
2:3
None None None None dppf PtBu3 dppf None dppe
THF-d8 Toluene-d8 CD2Cl2 Dioxane Dioxane Dioxane Dioxane Dioxane Dioxane
CH3 80 : 20 CH3 80 : 20 CH3 87 : 13 CH3 91 : 9 CH3 67 : 13 CH3 17 : 83 67 : 13 CH3 OCH3 495 : o5 OCH3 495 : o5
Three-component decarboxylative allylationa
Conv.a (%) 67 50 64 71 50 15 40 99 86
a
Based on % conversion of Meldrum’s acid to product on 1H NMR spectroscopic analysis of crude reaction mixtures, reaction conditions – 10 mol% catalyst, 0.2 M, rt, 16 h.
Our initial studies began by screening catalysts and solvents with respect to their ability to provide complete conversion of starting materials and avoid the anticipated byproduct of protonation (3, Table 1). Initial screening experiments with Pd(PPh3)4 catalyst in THF indeed produced the desired product (2), but incomplete conversion of the Meldrum’s acid and substantial production of the protonation product 3 indicated that these reaction conditions were not ideal (entry 1). Although the product is observed in solvents like THF, toluene and CH2Cl2 (entries 1–3), protonation and unconsumed Meldrum’s acid were prominent. Interestingly, switching the solvent to 1,4-dioxane improved both the conversion and the product ratio (entry 4). Hence 1,4-dioxane was chosen as the most suitable solvent and further catalyst screening was carried out in 1,4-dioxane. Unfortunately other palladium catalysts and ligand combinations were not able to improve the product ratio (entries 5–7). Gratifyingly, switching the allyl electrophile from cinnamyl acetate to cinnamyl methyl carbonate enabled excellent conversion to the desired product without any observable protonated byproduct (entry 8). With the optimized reaction conditions, several other substituted Meldrum’s acids and allyl carbonates were investigated for their ability to undergo 3-component DcA with pyrrolide. It was pleasing to see that a-aryl substituted Meldrum’s acids and a range of allyl carbonates are capable of undergoing DcA under these conditions (Table 2). For example, a,a-methyl,phenyl Meldrum’s acid underwent decarboxylative allylation with allyl methyl carbonate to provide product 2a in 85% isolated yield. The a-methyl group can be substituted for other alkyl groups with only a small effect on the yield (2g,m). In order to probe the scope of allyl methyl carbonate substrate, several differentially substituted carbonates were subjected to the standard reaction conditions. Interestingly, all the tested allyl methyl carbonates including: allyl (2a,g,m), cinnamyl (2b,c,i), substituted cinnamyl (2f,h,j), 2-phenallyl (2l,n), and 2-hexenyl (2d,e,k) carbonates participated in DcA to provide good yields of products. With these promising results we turned our attention towards the reactivity of a,a-di-alkyl substituted Meldrum’s acid derivatives. These substrates reacted sluggishly under our standard conditions, but brief optimization revealed
14050 | Chem. Commun., 2014, 50, 14049--14052
a Yields of isolated product for reactions performed at 0.2 M. b 5 mol% Pd2dba3/13 mol% dppe, dioxane 40 1C, 16 h. c Isolated as an inseparable 5 : 1 mixture of 2p : protonation.
that the Pd2dba3/dppe catalyst combination provided good conversion of starting materials. Unfortunately, protonation of the intermediate enolate was problematic, leading to lower yields of product (2o,p). Previously, we and others have developed interceptive decarboxylative allylations (IDcA) based on the ability to intercept intermediate enolate nucleophiles with good Michael acceptors.2a,7 With this in mind, we became curious whether the inclusion of a Michael acceptor would allow a 4-component IDcA reaction. Thus, the development of a four component reaction was initiated by introducing an electron poor olefin to the reaction mixture of the 3-component couplings. Benzylidene malononitriles were seen as ideal Michael acceptors since they have been successfully utilized in related 2-component IDcA reactions of ketone enolates.7,8 However, the addition of a Michael acceptor to the mixture results in the likely presence of four different electrophiles at any given time: Meldrum’s acid, acetone, (p-allyl)palladium and benzylidene malononitrile. Thus, effective four-component coupling would require highly chemoselective bond forming reactions. Catalyst screening was conducted with 1 equivalent of Meldrum’s acid and benzylidene malononitrile combined with 1.2 equivalents of lithium pyrrolide and allyl methyl carbonate in 1,4-dioxane. Under these conditions the Pd(PPh3)4 catalyst was inactive, but the combination of Pd2dba3 with bidentate ligands dppm, dppe, and dppp provided moderate conversion
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at 40 1C (Table 3, entries 1, 4 and 5). Attempts to increase the conversion using dppe as a ligand by raising the temperature to 60 or 100 1C failed, but revealed that significant decomposition takes place at higher temperatures (entries 2 and 3). Thus, the temperature was lowered to room temperature, which provided 78% conversion of the Meldrum’s acid to desired product in 16 hours (entry 6). This conversion could be significantly increased by batchwise addition of lithium pyrrolide over the course of 3 days (entry 7). While the reaction time was somewhat long, the ability to achieve such selective product formation in this 4-component coupling is noteworthy. Under the optimized conditions, the high conversion allowed the isolation of the desired product (4a) in 76% yield as a mixture of diastereomers (Table 4). In this case, the minor diastereomer could be obtained in pure form by Table 3
Optimization of reaction conditions
Entry
Ligand
Temperature (1C)
Conversiona (%)
1 2 3 4 5 6 7b
dppe dppe dppe dppm dppp dppe dppe
40 60 100 40 40 rt rt
58 38 Decomp. 50 50 78 495
a
1.2 eq. of lithium pyrrolide, 1.0 eq. of Meldrum’s acid, 1.0 eq. of benzylidene malononitrile and 1.2 eq. of allyl methyl carbonate at 0.1 M, 16 h, conversion of Meldrum’s acid to product is based on crude 1 H NMR spectroscopic analysis. b 2.3 eq. of lithium pyrrolide was used in 4 batches (1.2 eq., 0.5 eq., 0.3 eq., and 0.3 eq.) through 3 days.
Table 4
a
Fig. 1
Crystal structure of the minor diastereomer of 4a.
recrystallization (Fig. 1). In addition to benzylidene malononitrile, a variety of substituted benzylidene malononitriles exhibited good reactivity in the 4-component coupling (4b,c,e, Table 4). Heteroaromatic Michael acceptors containing furan, benzofuran, and pyrrole were also effective in the coupling (4d,f,g), resulting in complex products from simple, readily available reactants. The hypothetical mechanism for the catalytic fourcomponent coupling is similar to that shown in Scheme 2. However, the enolate that forms upon decarboxylation undergoes Michael addition to the benzylidene malononitrile (Scheme 3). The resulting stabilized carbanion subsequently reacts with the (p-allyl)palladium complex in a Tsuji–Trost type reaction. Three and four-component couplings are made possible by the chemoselective reaction of pyrrolide with Meldrum’s acid as opposed to palladium-p-allyl electrophiles. Thus, Meldrum’s acid is a versatile reactant for the in situ generation of b-oxo carboxylates that can participate in decarboxylative allylation. Decarboxylation provides ester enolate equivalents that either undergo allylation (3-component DcA) or can be intercepted by Michael acceptors followed by allylation (4-component IDcA).
Four-component decarboxylative allylation
Yields of diastereopure compounds shown in parentheses.
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Scheme 3
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Notes and references 1 (a) E.-i. Negishi, G. Wang, H. Rao and Z. Xu, J. Org. Chem., 2010, 75, 3151–3182; (b) J. Terao and N. Kambe, Acc. Chem. Res., 2008, 41, 1545–1554; (c) R. Martin and S. L. Buchwald, Acc. Chem. Res., 2008, 41, 1461–1473; (d) N. Marion and S. P. Nolan, Acc. Chem. Res., 2008, 41, 1440–1449; (e) S. E. Denmark and C. S. Regens, Acc. Chem. Res., 2008, 41, 1486–1499; ( f ) E. A. B. Kantchev, C. J. O’Brien and M. G. Organ, Angew. Chem., Int. Ed., 2007, 46, 2768–2813; ( g) N. T. S. Phan, D. S. M. Van and C. W. Jones, Adv. Synth. Catal., 2006, 348, 609–679; (h) J.-P. Corbet and G. Mignani, Chem. Rev., 2006, 106, 2651–2710; (i) B. M. Trost, J. Org. Chem., 2004, 69, 5813–5837; ( j) B. M. Trost and M. L. Crawley, Chem. Rev., 2003, 103, 2921–2943; (k) J. Hassan, M. Sevignon, C. Gozzi, E. Schulz and M. Lemaire, Chem. Rev., 2002, 102, 1359–1469. 2 (a) J. D. Weaver, A. Recio, A. J. Grenning and J. A. Tunge, Chem. Rev., 2011, 111, 1846–1913; (b) A. J. Grenning and J. A. Tunge, Org. Lett., 2010, 12, 740–742; (c) A. Recio and J. A. Tunge, Org. Lett., 2009, 11, 5630–5633; (d) E. C. Burger and J. A. Tunge, J. Am. Chem. Soc., 2006, 128, 10002–10003; (e) R. M. McFadden and B. M. Stoltz, J. Am. Chem. Soc., 2006, 128, 7738–7739; ( f ) B. M. Trost, R. N. Bream and J. Xu, Angew. Chem., Int. Ed., 2006, 45, 3109–3112; ( g) V. Ragoussis and A. Giannikopoulos, Tetrahedron Lett., 2006, 47, 683–687; (h) J. T. Mohr, D. C. Behenna, A. M. Harned and B. M. Stoltz, Angew. Chem., Int. Ed., 2005, 44, 6924–6927; (i) J. Tsuji, T. Yamada, I. Minami, M. Yuhara, M. Nisar and I. Shimizu, J. Org. Chem., 1987, 52, 2988–2995. 3 (a) D. Craig and F. Grellepois, Org. Lett., 2005, 7, 463–465; (b) P. C. Bulman Page, J. P. G. Moore, I. Mansfield, M. J. McKenzie, W. B. Bowler and J. A. Gallagher, Tetrahedron, 2001, 57, 1837–1847; (c) D. Craig and N. K. Slavov, Chem. Commun., 2008, 6054–6056; (d) D. W. Brooks, L. N. C. De and R. Peevey, Tetrahedron Lett., 1984, 25, 4623–4626; (e) S. Ghosh, S. De, B. N. Kakde, S. Bhunia, A. Adhikary and A. Bisai, Org. Lett., 2012, 14, 5864–5867; ( f ) S. Bhunia, S. Ghosh, D. Dey and A. Bisai, Org. Lett., 2013, 15, 2426–2429; (g) K. L. Kimmel, J. D. Weaver, M. Lee and J. A. Ellman, J. Am. Chem. Soc., 2012, 134, 9058–9061; (h) J. Svetlik, I. Goljer and F. Turecek, J. Chem. Soc., Perkin Trans. 1, 1990, 1315–1318.
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ChemComm 4 (a) Z. Xiao, M. Lei and L. Hu, Tetrahedron Lett., 2011, 52, 7099–7102; (b) V. V. Lipson and N. Y. Gorobets, Mol. Diversity, 2009, 13, 399–419; (c) A. Shaabani, E. Soleimani, A. H. Rezayan, A. Sarvary and H. R. Khavasi, Org. Lett., 2008, 10, 2581–2584; (d) J. Gerencser, G. Dorman and F. Darvas, QSAR Comb. Sci., 2006, 25, 439–448; (e) C.-Y. Yu, P.-H. Yang, M.-X. Zhao and Z.-T. Huang, Synlett, 2006, 1835–1840; ( f ) L. F. Tietze and Y. Zhou, Angew. Chem., Int. Ed., 1999, 38, 2045–2047; ( g) Y. Verdecia, M. Suarez, A. Morales, E. Rodriguez, E. Ochoa, L. Gonzalez, N. Martin, M. Quinteiro, C. Seoane and J. L. Soto, J. Chem. Soc., Perkin Trans. 1, 1996, 947–951; (h) M. Adib, S. Ansari and H. R. Bijanzadeh, Synlett, 2011, 619–622; (i) D. B. Ramachary and C. F. Barbas, III, Chem. – Eur. J., 2004, 10, 5323–5331. 5 (a) Y. Ariyarathna and J. Tunge, Org. Biomol. Chem., 2014, DOI: 10.1039/ C4OB01752H; (b) D. Imao, A. Itoi, A. Yamazaki, M. Shirakura, R. Ohtoshi, K. Ogata, Y. Ohmori, T. Ohta and Y. Ito, J. Org. Chem., 2007, 72, 1652–1658; (c) K. Chattopadhyay, R. Jana, V. W. Day, J. T. Douglas and J. A. Tunge, Org. Lett., 2010, 12, 3042–3045; (d) L. P. Tardibono, J. Patzner, C. Cesario and M. J. Miller, Org. Lett., 2009, 11, 4076–4079; (e) B. M. Trost, K. Lehr, D. J. Michaelis, J. Xu and A. K. Buckl, J. Am. Chem. Soc., 2010, 132, 8915–8917; ( f ) B. M. Trost, D. J. Michaelis, J. Charpentier and J. Xu, Angew. Chem., Int. Ed., 2012, 51, 204–208. 6 (a) D. A. Evans, G. Borg and K. A. Scheidt, Angew. Chem., Int. Ed., 2002, 41, 3188–3191; (b) D. A. Evans, K. A. Scheidt, J. N. Johnston and M. C. Willis, J. Am. Chem. Soc., 2001, 123, 4480–4491; (c) B. L. Hodous and G. C. Fu, J. Am. Chem. Soc., 2002, 124, 10006–10007; (d) Y. Arai, T. Masuda and Y. Masaki, Chem. Lett., 1997, 145–146. 7 (a) N. T. Patil and Y. Yamamoto, Synlett, 2007, 1994–2005; (b) C. Wang and J. A. Tunge, Org. Lett., 2005, 7, 2137–2139; (c) J. A. Tunge and E. C. Burger, Eur. J. Org. Chem., 2005, 1715–1726; (d) J. Streuff, D. E. White, S. C. Virgil and B. M. Stoltz, Nat. Chem., 2010, 2, 192–196; (e) H. Nakamura, M. Sekido, M. Ito and Y. Yamamoto, J. Am. Chem. Soc., 1998, 120, 6838–6839. 8 (a) T. Lemek and H. Mayr, J. Org. Chem., 2003, 68, 6880–6886; (b) O. Kaumanns, R. Lucius and H. Mayr, Chem. – Eur. J., 2008, 14, 9675–9682; (c) O. Kaumanns and H. Mayr, J. Org. Chem., 2008, 73, 2738–2745.
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Multicomponent decarboxylative allylations† Cite this: Chem. Commun., 2014, 50, 14049
Yamuna Ariyarathna and Jon A. Tunge*
Received 13th September 2014, Accepted 24th September 2014 DOI: 10.1039/c4cc07253g www.rsc.org/chemcomm
The reaction of Meldrum’s acid, pyrrolide, and allyl carbonates allows a multicomponent decarboxylative coupling to form allylated acyl pyrroles. This strategy is made possible by the in situ formation of b-oxo carboxylates from Meldrum’s acid. Subsequent decarboxylative enolate formation and electrophilic allylation complete the reaction. Addition of benzylidene malononitriles as good Michael acceptors allow a 4-component interceptive decarboxylative allylation.
Formation of C–C bonds via palladium-catalyzed decarboxylative coupling has received much attention as an alternative to traditional metal-catalyzed cross-coupling reactions.1 For example, decarboxylative allylation (DcA) provides for the allylation of relatively non-stabilized ketone enolates via elimination of CO2 from allyl b-ketoesters or allyl enol carbonates.2 However, DcA reactions often suffer from the need to incorporate the allyl electrophile and the nucleophile into the same reactant molecule via an ester linkage. Thus, we became interested in developing methods that would allow more rapid intermolecular allylation of enolates. Herein we report the successful development of 3- and 4-component decarboxylative allylations that give rise to useful allylated acyl pyrroles (Scheme 1). In order to develop a more rapid intermolecular reaction for the synthesis of a-allylated carbonyl compounds, it was necessary to identify components that would give rise to b-oxo carboxylates via in situ reaction. Meldrum’s acid derivatives seemed ideal since they are readily available and are known to undergo ring-opening with nucleophiles to generate b-oxo carboxylates.3,4 If a nucleophile could be identified that preferentially reacts with Meldrum’s acid derivatives rather than palladium-p-allyl electrophiles, then it should be possible to form homoallylic carbonyl compounds from the combination of nucleophile, Meldrum’s acid, and allyl electrophile according to Scheme 2. Given that palladium p-allyl The University of Kansas Department of Chemistry, 2010 Malott Hall, 1251 Wescoe Hall Dr., Lawrence, KS, 66045, USA. E-mail: [email protected] † Electronic supplementary information (ESI) available: Experimental procedures and spectral characterization of all new compounds. CCDC 1021515. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/ c4cc07253g
This journal is © The Royal Society of Chemistry 2014
Scheme 1
Scheme 2
complexes are soft electrophiles, we envisioned that a hard nucleophile would preferentially attack the relatively hard Meldrum’s acid derivative. Having recently developed decarboxylative allylations of acyl pyrroles as ester enolate equivalents, pyrrolide was chosen as the nucleophile to initiate our investigations.5,6 Aside from the potential for unwanted allylation of pyrrole, other possible pitfalls involve reactions of the acetone that is liberated from Meldrum’s acid; reaction of acetone with the pyrrolide nucleophile or by protonation of our desired enolate would derail the desired 3-component coupling.
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Table 2
Optimization of reaction conditions
Entry Pd source 1 2 3 4 5 6 7 8 9
ChemComm
Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd2dba3 Pddba2 PdCp(allyl) Pd(PPh3)4 Pd2dba3
L
Solvent
R
2:3
None None None None dppf PtBu3 dppf None dppe
THF-d8 Toluene-d8 CD2Cl2 Dioxane Dioxane Dioxane Dioxane Dioxane Dioxane
CH3 80 : 20 CH3 80 : 20 CH3 87 : 13 CH3 91 : 9 CH3 67 : 13 CH3 17 : 83 67 : 13 CH3 OCH3 495 : o5 OCH3 495 : o5
Three-component decarboxylative allylationa
Conv.a (%) 67 50 64 71 50 15 40 99 86
a
Based on % conversion of Meldrum’s acid to product on 1H NMR spectroscopic analysis of crude reaction mixtures, reaction conditions – 10 mol% catalyst, 0.2 M, rt, 16 h.
Our initial studies began by screening catalysts and solvents with respect to their ability to provide complete conversion of starting materials and avoid the anticipated byproduct of protonation (3, Table 1). Initial screening experiments with Pd(PPh3)4 catalyst in THF indeed produced the desired product (2), but incomplete conversion of the Meldrum’s acid and substantial production of the protonation product 3 indicated that these reaction conditions were not ideal (entry 1). Although the product is observed in solvents like THF, toluene and CH2Cl2 (entries 1–3), protonation and unconsumed Meldrum’s acid were prominent. Interestingly, switching the solvent to 1,4-dioxane improved both the conversion and the product ratio (entry 4). Hence 1,4-dioxane was chosen as the most suitable solvent and further catalyst screening was carried out in 1,4-dioxane. Unfortunately other palladium catalysts and ligand combinations were not able to improve the product ratio (entries 5–7). Gratifyingly, switching the allyl electrophile from cinnamyl acetate to cinnamyl methyl carbonate enabled excellent conversion to the desired product without any observable protonated byproduct (entry 8). With the optimized reaction conditions, several other substituted Meldrum’s acids and allyl carbonates were investigated for their ability to undergo 3-component DcA with pyrrolide. It was pleasing to see that a-aryl substituted Meldrum’s acids and a range of allyl carbonates are capable of undergoing DcA under these conditions (Table 2). For example, a,a-methyl,phenyl Meldrum’s acid underwent decarboxylative allylation with allyl methyl carbonate to provide product 2a in 85% isolated yield. The a-methyl group can be substituted for other alkyl groups with only a small effect on the yield (2g,m). In order to probe the scope of allyl methyl carbonate substrate, several differentially substituted carbonates were subjected to the standard reaction conditions. Interestingly, all the tested allyl methyl carbonates including: allyl (2a,g,m), cinnamyl (2b,c,i), substituted cinnamyl (2f,h,j), 2-phenallyl (2l,n), and 2-hexenyl (2d,e,k) carbonates participated in DcA to provide good yields of products. With these promising results we turned our attention towards the reactivity of a,a-di-alkyl substituted Meldrum’s acid derivatives. These substrates reacted sluggishly under our standard conditions, but brief optimization revealed
14050 | Chem. Commun., 2014, 50, 14049--14052
a Yields of isolated product for reactions performed at 0.2 M. b 5 mol% Pd2dba3/13 mol% dppe, dioxane 40 1C, 16 h. c Isolated as an inseparable 5 : 1 mixture of 2p : protonation.
that the Pd2dba3/dppe catalyst combination provided good conversion of starting materials. Unfortunately, protonation of the intermediate enolate was problematic, leading to lower yields of product (2o,p). Previously, we and others have developed interceptive decarboxylative allylations (IDcA) based on the ability to intercept intermediate enolate nucleophiles with good Michael acceptors.2a,7 With this in mind, we became curious whether the inclusion of a Michael acceptor would allow a 4-component IDcA reaction. Thus, the development of a four component reaction was initiated by introducing an electron poor olefin to the reaction mixture of the 3-component couplings. Benzylidene malononitriles were seen as ideal Michael acceptors since they have been successfully utilized in related 2-component IDcA reactions of ketone enolates.7,8 However, the addition of a Michael acceptor to the mixture results in the likely presence of four different electrophiles at any given time: Meldrum’s acid, acetone, (p-allyl)palladium and benzylidene malononitrile. Thus, effective four-component coupling would require highly chemoselective bond forming reactions. Catalyst screening was conducted with 1 equivalent of Meldrum’s acid and benzylidene malononitrile combined with 1.2 equivalents of lithium pyrrolide and allyl methyl carbonate in 1,4-dioxane. Under these conditions the Pd(PPh3)4 catalyst was inactive, but the combination of Pd2dba3 with bidentate ligands dppm, dppe, and dppp provided moderate conversion
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at 40 1C (Table 3, entries 1, 4 and 5). Attempts to increase the conversion using dppe as a ligand by raising the temperature to 60 or 100 1C failed, but revealed that significant decomposition takes place at higher temperatures (entries 2 and 3). Thus, the temperature was lowered to room temperature, which provided 78% conversion of the Meldrum’s acid to desired product in 16 hours (entry 6). This conversion could be significantly increased by batchwise addition of lithium pyrrolide over the course of 3 days (entry 7). While the reaction time was somewhat long, the ability to achieve such selective product formation in this 4-component coupling is noteworthy. Under the optimized conditions, the high conversion allowed the isolation of the desired product (4a) in 76% yield as a mixture of diastereomers (Table 4). In this case, the minor diastereomer could be obtained in pure form by Table 3
Optimization of reaction conditions
Entry
Ligand
Temperature (1C)
Conversiona (%)
1 2 3 4 5 6 7b
dppe dppe dppe dppm dppp dppe dppe
40 60 100 40 40 rt rt
58 38 Decomp. 50 50 78 495
a
1.2 eq. of lithium pyrrolide, 1.0 eq. of Meldrum’s acid, 1.0 eq. of benzylidene malononitrile and 1.2 eq. of allyl methyl carbonate at 0.1 M, 16 h, conversion of Meldrum’s acid to product is based on crude 1 H NMR spectroscopic analysis. b 2.3 eq. of lithium pyrrolide was used in 4 batches (1.2 eq., 0.5 eq., 0.3 eq., and 0.3 eq.) through 3 days.
Table 4
a
Fig. 1
Crystal structure of the minor diastereomer of 4a.
recrystallization (Fig. 1). In addition to benzylidene malononitrile, a variety of substituted benzylidene malononitriles exhibited good reactivity in the 4-component coupling (4b,c,e, Table 4). Heteroaromatic Michael acceptors containing furan, benzofuran, and pyrrole were also effective in the coupling (4d,f,g), resulting in complex products from simple, readily available reactants. The hypothetical mechanism for the catalytic fourcomponent coupling is similar to that shown in Scheme 2. However, the enolate that forms upon decarboxylation undergoes Michael addition to the benzylidene malononitrile (Scheme 3). The resulting stabilized carbanion subsequently reacts with the (p-allyl)palladium complex in a Tsuji–Trost type reaction. Three and four-component couplings are made possible by the chemoselective reaction of pyrrolide with Meldrum’s acid as opposed to palladium-p-allyl electrophiles. Thus, Meldrum’s acid is a versatile reactant for the in situ generation of b-oxo carboxylates that can participate in decarboxylative allylation. Decarboxylation provides ester enolate equivalents that either undergo allylation (3-component DcA) or can be intercepted by Michael acceptors followed by allylation (4-component IDcA).
Four-component decarboxylative allylation
Yields of diastereopure compounds shown in parentheses.
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Scheme 3
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