ChemComm View Article Online
Published on 04 November 2013. Downloaded by Temple University on 28/10/2014 13:36:43.
COMMUNICATION
Cite this: Chem. Commun., 2014, 50, 484 Received 28th August 2013, Accepted 2nd November 2013
View Journal | View Issue
Pd-catalyzed allylic alkylation of dienyl carbonates with nitromethane with high C-5 regioselectivity† Xiao-Fei Yang,a Xiao-Hui Li,a Chang-Hua Ding,*a Chao-Fan Xu,a Li-Xin Daia and Xue-Long Hou*ab
DOI: 10.1039/c3cc46574h www.rsc.org/chemcomm
A highly regioselective palladium-catalyzed allylic alkylation of dienyl esters with nitromethane has been developed, providing selective access to the C-5 attacked products. The structures of the ligands as well as the steric effect of the substrates are important factors in determining the regiochemical outcome of the reaction.
The regioselectivity in the palladium-catalyzed allylic substitution reaction of mono-substituted allyl substrates has represented a significant issue for a long time because the nucleophile could attack the substituted carbon or terminal carbon of a Pd–allyl complex to provide linear or branched products.1a–e In spite of the great achievements made recently,1f–m,2 the problem has not been fully resolved. Even more of a challenge appears when dienyl substrates are used since they contain more electrophilic sites than allyl compounds. The reaction of a dienyl substrate with a transition-metal catalyst leads to the formation of the vinyl(p-allyl) complexes, a 1-(1-alkenyl)-p-allylmetal intermediate (Int-A) and a 1-alkyl-3-vinyl-p-allylmetal intermediate (Int-B) through p–s–p interconversion, which can undergo nucleophilic attack at the C-1, C-3 or C-5 position to give rise to different regioisomers (Scheme 1).1a–e,3 The use of a Pd-catalyst in this reaction has been reported to favor nucleophilic attack at the C-1 position,3,4a whereas the use of several other metals, including Ir,4c–e Cu,4f,g W,6a and Mo,4b predominantly afforded the regioisomers resulting from the nucleophilic attack at the C-3 position. To date, however, there have been few reports concerning the regioselective attack of nucleophiles at the C-5 positions of polyenyl substrates,5 although several early studies in this area indicated that it might be possible to develop a strategy allowing for regioselective attack at the C-5 position.4a,6 Reaction towards
Scheme 1 Regioselectivity in the transition-metal catalyzed allylic substitution reaction of polyenyl substrates.
controlling the regioselectivity of the reaction to give C-5 substituted products remains therefore to be explored. We recently developed a series of 1,1 0 -P,N-ferrocene ligands, SIOCPhox (Fig. 1), which provided high levels of regioselectivity in the Pd-catalyzed allylic alkylation of monosubstituted allyl substrates.2 In addition, the C-3 substituted products were obtained with excellent levels of regioselectivity in the reaction of polyenyl substrates with malonate and benzyl amine.2b Further investigations revealed that different regioisomers could be obtained regioselectively from the reaction of polyenyl substrates with different types of nucleophiles. In this communication, we report our preliminary results for the Pd-catalyzed reaction of polyenyl carbonates with nitromethane to give the corresponding C5-attacked products with excellent regioselectivity. Based upon the results obtained from our Pd-catalyzed reaction of monosubstituted allyl substrates with nitroalkanes,2f,7 we decided
a
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry (SIOC), Chinese Academy of Sciences (CAS), 345 Lingling Road, Shanghai 200032, China. E-mail: [email protected], [email protected]; Fax: +86 21 54925100; Tel: +86 21 54925144 b Shanghai–Hong Kong Joint Laboratory in Chemical Synthesis, SIOC, CAS, China † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c3cc46574h
484 | Chem. Commun., 2014, 50, 484--486
Fig. 1
P,N-Ferrocene-based SIOCPhox ligands.
This journal is © The Royal Society of Chemistry 2014
View Article Online
Communication
ChemComm
Published on 04 November 2013. Downloaded by Temple University on 28/10/2014 13:36:43.
Table 1 Impact of specific reaction parameters on the Pd-catalyzed reaction of dienyl carbonate 1a with nitromethanea
Entry
Base
Solvent
Ligand
2a : 3a : 4ab
Yieldc (%)
1 2 3 4 5 6 7 8 9 10 11 12d 13 14
Cs2CO3 DABCO DABCO DABCO TEA DABCO DABCO DABCO DABCO DABCO DABCO DABCO DABCO DABCO
DCM DCM DMSO THF THF THF THF THF THF THF THF THF THF THF
(Rphos,Ra)-L1 (Rphos,Ra)-L1 (Rphos,Ra)-L1 (Rphos,Ra)-L1 (Rphos,Ra)-L1 (Sphos,Ra)-L2 i Pr-(Sc,Rphos,Ra)-L3 i Pr-(Sc,Sphos,Ra)-L4 i Pr-(Sc,Sphos,Sa)-L5 i Pr-(Sc,Rphos,Sa)-L6 Bn-(Sc,Sphos,Ra)-L7 Bn-(Sc,Sphos,Ra)-L7 DPPE DPPF
4 : 68 : 28 46 : 34 : 20 15 : 35 : 50 22 : 34 : 44 9 : 49 : 42 15 : 12 : 73 15 : 18 : 67 4 : 1 : 95 6 : 8 : 86 2 : 3 : 95 1 : 3 : 96 41 : 1 : 58 — 34 : 61 : 5
13 13 27 45 10 78 85 87 85 80 84 53 Trace 60
a 1 equiv. base, 0.5 mL of CH3NO2, 2.0 mL of solvent. b Determined by GC. c Isolated yields of 3a and 4a. d Dienyl acetate as the substrate.
to investigate the reaction of pentadienyl methyl carbonate 1a with nitromethane using Pd2(dba)3CHCl3/(Rphos,Ra)-SIOCPhox L1 as a catalyst in CH2Cl2 (DCM) with Cs2CO3 as a base. The reaction afforded the three alkylation products 2a, 3a, and 4a in a ratio of 4 : 68 : 28 and a combined yield of 13% (Table 1, entry 1). In an attempt to improve the regioselectivity of the reaction, we investigated the influences of several different reaction parameters on the outcome of the reaction. The use of DABCO as a base in DCM gave the linear regioisomer 2a as the major product (Table 1, entry 2), whereas the use of triethylamine in THF led to a poor yield of products, with the C-3 and C-5 attacked products being formed as the major regioisomers (Table 1, entry 5). Pleasingly, the ratio of the C-5 attacked product 4a increased significantly when the reaction was carried out in DMSO or THF using DABCO as a base (Table 1, entries 3 and 4). The evaluation of SIOCPhox ligands revealed the importance of their structure in controlling the regioselectivity of the reaction. Thus, the reaction provided a much higher level of selectivity for the C-5 addition product when it was conducted in the presence of the (Sphos,Ra)-SIOCPhox L2 ligand than it did with the (Rphos,Ra)-SIOCPhox L1 ligand, suggesting that the configuration of the P atom and the axial chirality of the BINOL played a critical role in the regioselective attack of the nitrate to the distal position of the allyl substrate (Table 1, entry 6 vs. entry 4). Further improvement in the C5-selectivity was achieved when (Sc,Rphos,Ra)SIOCPhox L3 or (Sc,Sphos,Sa)-SIOCPhox L5 was used as the ligand, suggesting that the substituent on the oxazoline ring of the ligand presumably suppresses the nucleophilic attack at C1- and C3-positions of the dienyl substrate (Table 1, entries 7 and 9 vs. entry 4). Excellent regioselectivity was achieved when the (Sc,Sphos,Ra)-SIOCPhox L4 ligand bearing an isopropyl group on the oxazoline ring was used in the reaction, with the products 2a, 3a and 4a being formed in a ratio of 4 : 1 : 95 (Table 1, entry 8). The replacement of the iPr group on the oxazoline ring of (Sc,Sphos,Ra)-L4 with a Bn group to give Bn-(Sc,Sphos,Ra)-L7 did
This journal is © The Royal Society of Chemistry 2014
not have a discernible impact on the regioselectivity (Table 1, entry 11 vs. entry 8). A significant reduction in the yield and regioselectivity was observed when dienyl acetate was used as the substrate and Bn-(Sc,Sphos,Ra)-L7 was used as the ligand (Table 1, entry 12). The application of other phosphine ligands, such as DPPE, provided only a trace amount of the desired alkylated product (Table 1, entry 13), whereas the ferrocene-based ligand DPPF induced the favored attack at the C-3 position of 1a (Table 1, entry 14). It is important to note that the products formed from this reaction were nearly racemic (for example, 7% ee for 4a, entry 8) even though chiral ligands were used (vide infra). We then proceeded to examine the substrate scope of the reaction using iPr-(Sc,Sphos,Ra)-SIOCPhox L4 as the ligand (Table 2). The reaction proceeded well for a wide range of dienyl carbonates, providing the corresponding alkylation products in high yields with excellent C5-regioselectivity. The introduction of a variety of different electron withdrawing or electron donating substituents at the para, meta, or ortho position of the phenyl ring on the dienyl carbonates 1 was well tolerated (Table 2, entries 2–8). The reaction of the alkyl substituted dienyl carbonate 1i also proceeded smoothly to give 4i with a regioselectivity of 97 : 3 in favor of the C-5 attacked product (Table 2, entry 9). The application of the reaction conditions to the dienyl carbonate 1j bearing a cyclohexane substituent led to a considerable reduction in the regioselectivity (Table 2, entry 10). The presence of a substituent on the proximal double bond was found to have no effect on the selectivity, although it did have an impact on the rate of the reaction, which was slower (Table 2, entry 11). In our previous study, we achieved a high level of C3-regioselectivity in the Pd-catalyzed allylic alkylation of polyenyl substrates with malonate using (Sc,Sphos,Ra)-SIOCPhox L7 as a ligand.2b In contrast, the use of nitromethane as a nucleophile in the current study under the same conditions afforded the C5-attacked products with high levels of regioselectivity. These results suggest that the steric effect of the nucleophile could be an important factor in determining the regiochemical outcome of the reaction. To evaluate the impact of the steric bulk of the nucleophile on the regiochemical outcome of the reaction, we
Table 2 Substrate scope of the Pd-catalyzed reaction of dienyl esters 1 with nitromethanea
Entry
1, R1, R2, R3
(2 + 3) : 4b
Yieldc (%)
1 2 3 4 5 6 7 8 9 10 11
C6H5, H, H p-FC6H4, H, H p-BrC6H4, H, H p-CH3OC6H4, H, H m-FC6H4, H, H m-CH3C6H4, H, H o-BrC6H4, H, H o-CH3OC6H4, H, H Me, H, H –(CH2)5–, H C6H5, H, Me
5 : 95 5 : 95 3 : 97 3 : 97 3 : 97 3 : 97 2 : 98 2 : 98 3 : 97 20 : 80 3 : 97
4a, 87 4b, 91 4c, 96 4d, 65 4e, 95 4f, 94 4g, 83 4h, 93 4i, 63 4j, 64 4k, 56
a c
1 equiv. base, 0.5 mL of CH3NO2, 2.0 mL of THF. Isolated yield of product 4.
b
Determined by GC.
Chem. Commun., 2014, 50, 484--486 | 485
View Article Online
Published on 04 November 2013. Downloaded by Temple University on 28/10/2014 13:36:43.
ChemComm
Communication
nitromethane, providing access to the C-5 attacked products in high regioselectivity. The structure of the ligand as well as the steric effect of the nucleophile and allyl substrates have a significant impact on the regioselectivity of the reaction. Further investigation of the reaction mechanism, the work towards the asymmetric version of the reaction and the extension of the scope to other nucleophiles are currently underway in our laboratory. This work was financially supported by the Major Basic Research Development Program (2011CB808706), NNSF China (21272251, 21121062, and 21032007), Chinese Academy of Sciences, the Technology Commission of Shanghai Municipality, and the Croucher Foundation of Hong Kong.
Notes and references Scheme 2
Proposed mechanism of C-5 attack during the reaction.
tested the reaction using a variety of different nitroalkanes as the nucleophiles. As expected, the use of nitroethane or 2-nitropropane as the nucleophile afforded the C-3 or C-1 addition product as the major regioisomer (eqn (1)). The importance of the steric bulk of the substrates to the regiochemical outcome of the reaction was demonstrated further in the reaction of terminally disubstituted polyenyl carbonate 1m with nitromethane. This reaction provided the C-3 attacked regioisomer as the major product with a C-5 : C-3 : C-1 attack ratio of 25 : 71 : 4, albeit in a low combined yield (less than 5%, eqn (2)). It is well known that different intermediates are formed during the Pd-catalyzed allylic substitution reaction, including the exo- and endo-forms. Importantly, only one form should be the active intermediate, which is responsible for the enantioselectivity of the reaction.1a We found that the C-5 attacked products with very low ee (less than 10%) were obtained in the current work,8 whereas C-3 attacked products were formed with high enantioselectivities when malonate and benzylamine were used as the nucleophiles.2b The mechanism of Pd-catalyzed allylic substitution of polyenyl substrates was studied before,3,4a the equilibrium between Int-A and Int-B was found, C5-regioisomers were minor in all cases. On the basis of the results we obtained, we propose that Int-B is more active than Int-A because no C-5 addition products were found in the reactions of 1 with different malonates using L7 as a ligand, whereas the corresponding C-3 attacked products were formed with high regio- and enantio-selectivities.2b Taken together, these results suggest that the nucleophile attacks both the exo- and endo-forms of Int-B via an SN2 0 mechanism regioselectively to give the C-5 attacked product with almost no enantioselectivity (Scheme 2).4a,9 Further studies are currently underway in our laboratory to determine the mechanism responsible for the formation of the C-5 attacked regioisomer. In summary, we have successfully developed a regioselective palladium-catalyzed allylic alkylation of dienyl esters with
486 | Chem. Commun., 2014, 50, 484--486
1 For some reviews: (a) A. Pfaltz and M. Lautens, in Comprehensive Asymmetric Catalysis, ed. E. N. Jacobsen, A. Pfaltz and H. Yamamoto, Springer, New York, 1999, vol. 2, p. 833; (b) B. M. Trost and D. L. Van Vranken, Chem. Rev., 1996, 96, 395; (c) B. M. Trost and M. L. Crawley, Chem. Rev., 2003, 103, 2921; (d) Pd(0)-Catalyzed Reactions of Allylic Compounds via p-Allylpalladium Complexes, Palladium Reagents and Catalysts: New Perspectives for the 21st Century, ed. J. Tsuji, John Wiley & Sons, Ltd, Chichester, 2004, ch. 4, p. 431; (e) Z. Lu and S. M. Ma, Angew. Chem., Int. Ed., 2008, 47, 258. For some examples, see: ( f ) T. Hayashi, M. Kawatsura and Y. Uozumi, Chem. Commun., ´to ˆt and A. Pfaltz, Angew. Chem., Int. Ed., 1998, 1997, 561; ( g) R. Pre 37, 323; (h) R. Hilgraf and A. Pfaltz, Synlett, 1999, 1814; (i) K. Itami, T. Koike and J.-i. Yoshida, J. Am. Chem. Soc., 2001, 123, 6957; ( j) I. D. G. Watson, S. A. Styler and A. K. Yudin, J. Am. Chem. Soc., 2004, 126, 5086; (k) O. Pamies, M. Dieguez and C. Claver, J. Am. Chem. Soc., 2005, 127, 3646; (l ) A. M. Johns, Z. Liu and J. F. Hartwig, Angew. Chem., Int. Ed., 2007, 46, 7259; (m) Z. Hu, Y. Li, K. Liu and Q. Shen, J. Org. Chem., 2012, 77, 7957. 2 (a) S.-L. You, X.-Z. Zhu, Y.-M. Luo, X.-L. Hou and L.-X. Dai, J. Am. Chem. Soc., 2001, 123, 7471 and references cited therein; (b) W.-H. Zheng, N. Sun and X.-L. Hou, Org. Lett., 2005, 7, 5151; (c) J.-P. Chen, C.-H. Ding, W. Liu, X.-L. Hou and L.-X. Dai, J. Am. Chem. Soc., 2010, 132, 15493; (d) B.-H. Zheng, C.-H. Ding and X.-L. Hou, Synlett, 2011, 2262; (e) J. P. Chen, Q. Peng, B.-L. Lei, X.-L. Hou and Y.-D. Wu, J. Am. Chem. Soc., 2011, 133, 14180; ( f ) X.-F. Yang, C.-H. Ding, X.-H. Li, J.-Q. Huang, X.-L. Hou, L.-X. Dai and P.J. Wang, J. Org. Chem., 2012, 77, 8980. ¨ckvall, J. Org. Chem., 1991, 56, 5349; 3 (a) P. G. Andersson and J. E. Ba ¨ckvall, J. Am. Chem. (b) Y. I. M. Nilsson, P. G. Andersson and J. E. Ba Soc., 1993, 115, 6609. 4 (a) B. M. Trost and R. C. Bunt, J. Am. Chem. Soc., 1998, 120, 70; (b) B. M. Trost, S. Hildbrand and K. Dogra, J. Am. Chem. Soc., 1999, 121, 10416; (c) R. Takeuchi and K. Tanabe, Angew. Chem., Int. Ed., 2000, 39, 1975; (d) G. Lipowsky, N. Miller and G. Helmchen, Chem. Commun., 2004, 116; (e) G. Lipowsky, N. Miller and G. Helmchen, Angew. Chem., Int. Ed., 2004, 43, 4595; ( f ) H. Li and A. Alexakis, Angew. Chem., Int. Ed., 2012, 51, 1055; ( g) M. Magrez, Y. L. Guen, ´, C. Cre ´visy and M. Mauduit, Chem.–Eur. J., 2013, 19, 1199. O. Basle 5 An example of C-5 attack using an Ir-catalyst with only one substrate was reported very recently: S. Krautwald, D. Sarlah, M. A. Schafroth and E. M. Carreira, Science, 2013, 340, 1065. 6 (a) B. M. Trost and M. H. Hung, J. Am. Chem. Soc., 1984, 106, 6837; (b) B. M. Trost, C. J. Urch and M. H. Hung, Tetrahedron Lett., 1986, 27, 4949. 7 X.-F. Yang, W.-H. Yu, C.-H. Ding, Q.-P. Ding, S.-L. Wan, X.-L. Hou, L.-X. Dai and P.-J. Wang, J. Org. Chem., 2013, 78, 6503. 8 The optically active C-3 attacked product was obtained in the reaction of 1m with nitromethane in 90% ee using L3 as the ligand, the ratio of C-5 : C-3 : C-1 attacked isomers being 2 : 88 : 10. 9 The steric effect should be smaller when a nucleophile attacks the C-5 position of both exo- and endo-forms of Int-B.
This journal is © The Royal Society of Chemistry 2014
Published on 04 November 2013. Downloaded by Temple University on 28/10/2014 13:36:43.
COMMUNICATION
Cite this: Chem. Commun., 2014, 50, 484 Received 28th August 2013, Accepted 2nd November 2013
View Journal | View Issue
Pd-catalyzed allylic alkylation of dienyl carbonates with nitromethane with high C-5 regioselectivity† Xiao-Fei Yang,a Xiao-Hui Li,a Chang-Hua Ding,*a Chao-Fan Xu,a Li-Xin Daia and Xue-Long Hou*ab
DOI: 10.1039/c3cc46574h www.rsc.org/chemcomm
A highly regioselective palladium-catalyzed allylic alkylation of dienyl esters with nitromethane has been developed, providing selective access to the C-5 attacked products. The structures of the ligands as well as the steric effect of the substrates are important factors in determining the regiochemical outcome of the reaction.
The regioselectivity in the palladium-catalyzed allylic substitution reaction of mono-substituted allyl substrates has represented a significant issue for a long time because the nucleophile could attack the substituted carbon or terminal carbon of a Pd–allyl complex to provide linear or branched products.1a–e In spite of the great achievements made recently,1f–m,2 the problem has not been fully resolved. Even more of a challenge appears when dienyl substrates are used since they contain more electrophilic sites than allyl compounds. The reaction of a dienyl substrate with a transition-metal catalyst leads to the formation of the vinyl(p-allyl) complexes, a 1-(1-alkenyl)-p-allylmetal intermediate (Int-A) and a 1-alkyl-3-vinyl-p-allylmetal intermediate (Int-B) through p–s–p interconversion, which can undergo nucleophilic attack at the C-1, C-3 or C-5 position to give rise to different regioisomers (Scheme 1).1a–e,3 The use of a Pd-catalyst in this reaction has been reported to favor nucleophilic attack at the C-1 position,3,4a whereas the use of several other metals, including Ir,4c–e Cu,4f,g W,6a and Mo,4b predominantly afforded the regioisomers resulting from the nucleophilic attack at the C-3 position. To date, however, there have been few reports concerning the regioselective attack of nucleophiles at the C-5 positions of polyenyl substrates,5 although several early studies in this area indicated that it might be possible to develop a strategy allowing for regioselective attack at the C-5 position.4a,6 Reaction towards
Scheme 1 Regioselectivity in the transition-metal catalyzed allylic substitution reaction of polyenyl substrates.
controlling the regioselectivity of the reaction to give C-5 substituted products remains therefore to be explored. We recently developed a series of 1,1 0 -P,N-ferrocene ligands, SIOCPhox (Fig. 1), which provided high levels of regioselectivity in the Pd-catalyzed allylic alkylation of monosubstituted allyl substrates.2 In addition, the C-3 substituted products were obtained with excellent levels of regioselectivity in the reaction of polyenyl substrates with malonate and benzyl amine.2b Further investigations revealed that different regioisomers could be obtained regioselectively from the reaction of polyenyl substrates with different types of nucleophiles. In this communication, we report our preliminary results for the Pd-catalyzed reaction of polyenyl carbonates with nitromethane to give the corresponding C5-attacked products with excellent regioselectivity. Based upon the results obtained from our Pd-catalyzed reaction of monosubstituted allyl substrates with nitroalkanes,2f,7 we decided
a
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry (SIOC), Chinese Academy of Sciences (CAS), 345 Lingling Road, Shanghai 200032, China. E-mail: [email protected], [email protected]; Fax: +86 21 54925100; Tel: +86 21 54925144 b Shanghai–Hong Kong Joint Laboratory in Chemical Synthesis, SIOC, CAS, China † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c3cc46574h
484 | Chem. Commun., 2014, 50, 484--486
Fig. 1
P,N-Ferrocene-based SIOCPhox ligands.
This journal is © The Royal Society of Chemistry 2014
View Article Online
Communication
ChemComm
Published on 04 November 2013. Downloaded by Temple University on 28/10/2014 13:36:43.
Table 1 Impact of specific reaction parameters on the Pd-catalyzed reaction of dienyl carbonate 1a with nitromethanea
Entry
Base
Solvent
Ligand
2a : 3a : 4ab
Yieldc (%)
1 2 3 4 5 6 7 8 9 10 11 12d 13 14
Cs2CO3 DABCO DABCO DABCO TEA DABCO DABCO DABCO DABCO DABCO DABCO DABCO DABCO DABCO
DCM DCM DMSO THF THF THF THF THF THF THF THF THF THF THF
(Rphos,Ra)-L1 (Rphos,Ra)-L1 (Rphos,Ra)-L1 (Rphos,Ra)-L1 (Rphos,Ra)-L1 (Sphos,Ra)-L2 i Pr-(Sc,Rphos,Ra)-L3 i Pr-(Sc,Sphos,Ra)-L4 i Pr-(Sc,Sphos,Sa)-L5 i Pr-(Sc,Rphos,Sa)-L6 Bn-(Sc,Sphos,Ra)-L7 Bn-(Sc,Sphos,Ra)-L7 DPPE DPPF
4 : 68 : 28 46 : 34 : 20 15 : 35 : 50 22 : 34 : 44 9 : 49 : 42 15 : 12 : 73 15 : 18 : 67 4 : 1 : 95 6 : 8 : 86 2 : 3 : 95 1 : 3 : 96 41 : 1 : 58 — 34 : 61 : 5
13 13 27 45 10 78 85 87 85 80 84 53 Trace 60
a 1 equiv. base, 0.5 mL of CH3NO2, 2.0 mL of solvent. b Determined by GC. c Isolated yields of 3a and 4a. d Dienyl acetate as the substrate.
to investigate the reaction of pentadienyl methyl carbonate 1a with nitromethane using Pd2(dba)3CHCl3/(Rphos,Ra)-SIOCPhox L1 as a catalyst in CH2Cl2 (DCM) with Cs2CO3 as a base. The reaction afforded the three alkylation products 2a, 3a, and 4a in a ratio of 4 : 68 : 28 and a combined yield of 13% (Table 1, entry 1). In an attempt to improve the regioselectivity of the reaction, we investigated the influences of several different reaction parameters on the outcome of the reaction. The use of DABCO as a base in DCM gave the linear regioisomer 2a as the major product (Table 1, entry 2), whereas the use of triethylamine in THF led to a poor yield of products, with the C-3 and C-5 attacked products being formed as the major regioisomers (Table 1, entry 5). Pleasingly, the ratio of the C-5 attacked product 4a increased significantly when the reaction was carried out in DMSO or THF using DABCO as a base (Table 1, entries 3 and 4). The evaluation of SIOCPhox ligands revealed the importance of their structure in controlling the regioselectivity of the reaction. Thus, the reaction provided a much higher level of selectivity for the C-5 addition product when it was conducted in the presence of the (Sphos,Ra)-SIOCPhox L2 ligand than it did with the (Rphos,Ra)-SIOCPhox L1 ligand, suggesting that the configuration of the P atom and the axial chirality of the BINOL played a critical role in the regioselective attack of the nitrate to the distal position of the allyl substrate (Table 1, entry 6 vs. entry 4). Further improvement in the C5-selectivity was achieved when (Sc,Rphos,Ra)SIOCPhox L3 or (Sc,Sphos,Sa)-SIOCPhox L5 was used as the ligand, suggesting that the substituent on the oxazoline ring of the ligand presumably suppresses the nucleophilic attack at C1- and C3-positions of the dienyl substrate (Table 1, entries 7 and 9 vs. entry 4). Excellent regioselectivity was achieved when the (Sc,Sphos,Ra)-SIOCPhox L4 ligand bearing an isopropyl group on the oxazoline ring was used in the reaction, with the products 2a, 3a and 4a being formed in a ratio of 4 : 1 : 95 (Table 1, entry 8). The replacement of the iPr group on the oxazoline ring of (Sc,Sphos,Ra)-L4 with a Bn group to give Bn-(Sc,Sphos,Ra)-L7 did
This journal is © The Royal Society of Chemistry 2014
not have a discernible impact on the regioselectivity (Table 1, entry 11 vs. entry 8). A significant reduction in the yield and regioselectivity was observed when dienyl acetate was used as the substrate and Bn-(Sc,Sphos,Ra)-L7 was used as the ligand (Table 1, entry 12). The application of other phosphine ligands, such as DPPE, provided only a trace amount of the desired alkylated product (Table 1, entry 13), whereas the ferrocene-based ligand DPPF induced the favored attack at the C-3 position of 1a (Table 1, entry 14). It is important to note that the products formed from this reaction were nearly racemic (for example, 7% ee for 4a, entry 8) even though chiral ligands were used (vide infra). We then proceeded to examine the substrate scope of the reaction using iPr-(Sc,Sphos,Ra)-SIOCPhox L4 as the ligand (Table 2). The reaction proceeded well for a wide range of dienyl carbonates, providing the corresponding alkylation products in high yields with excellent C5-regioselectivity. The introduction of a variety of different electron withdrawing or electron donating substituents at the para, meta, or ortho position of the phenyl ring on the dienyl carbonates 1 was well tolerated (Table 2, entries 2–8). The reaction of the alkyl substituted dienyl carbonate 1i also proceeded smoothly to give 4i with a regioselectivity of 97 : 3 in favor of the C-5 attacked product (Table 2, entry 9). The application of the reaction conditions to the dienyl carbonate 1j bearing a cyclohexane substituent led to a considerable reduction in the regioselectivity (Table 2, entry 10). The presence of a substituent on the proximal double bond was found to have no effect on the selectivity, although it did have an impact on the rate of the reaction, which was slower (Table 2, entry 11). In our previous study, we achieved a high level of C3-regioselectivity in the Pd-catalyzed allylic alkylation of polyenyl substrates with malonate using (Sc,Sphos,Ra)-SIOCPhox L7 as a ligand.2b In contrast, the use of nitromethane as a nucleophile in the current study under the same conditions afforded the C5-attacked products with high levels of regioselectivity. These results suggest that the steric effect of the nucleophile could be an important factor in determining the regiochemical outcome of the reaction. To evaluate the impact of the steric bulk of the nucleophile on the regiochemical outcome of the reaction, we
Table 2 Substrate scope of the Pd-catalyzed reaction of dienyl esters 1 with nitromethanea
Entry
1, R1, R2, R3
(2 + 3) : 4b
Yieldc (%)
1 2 3 4 5 6 7 8 9 10 11
C6H5, H, H p-FC6H4, H, H p-BrC6H4, H, H p-CH3OC6H4, H, H m-FC6H4, H, H m-CH3C6H4, H, H o-BrC6H4, H, H o-CH3OC6H4, H, H Me, H, H –(CH2)5–, H C6H5, H, Me
5 : 95 5 : 95 3 : 97 3 : 97 3 : 97 3 : 97 2 : 98 2 : 98 3 : 97 20 : 80 3 : 97
4a, 87 4b, 91 4c, 96 4d, 65 4e, 95 4f, 94 4g, 83 4h, 93 4i, 63 4j, 64 4k, 56
a c
1 equiv. base, 0.5 mL of CH3NO2, 2.0 mL of THF. Isolated yield of product 4.
b
Determined by GC.
Chem. Commun., 2014, 50, 484--486 | 485
View Article Online
Published on 04 November 2013. Downloaded by Temple University on 28/10/2014 13:36:43.
ChemComm
Communication
nitromethane, providing access to the C-5 attacked products in high regioselectivity. The structure of the ligand as well as the steric effect of the nucleophile and allyl substrates have a significant impact on the regioselectivity of the reaction. Further investigation of the reaction mechanism, the work towards the asymmetric version of the reaction and the extension of the scope to other nucleophiles are currently underway in our laboratory. This work was financially supported by the Major Basic Research Development Program (2011CB808706), NNSF China (21272251, 21121062, and 21032007), Chinese Academy of Sciences, the Technology Commission of Shanghai Municipality, and the Croucher Foundation of Hong Kong.
Notes and references Scheme 2
Proposed mechanism of C-5 attack during the reaction.
tested the reaction using a variety of different nitroalkanes as the nucleophiles. As expected, the use of nitroethane or 2-nitropropane as the nucleophile afforded the C-3 or C-1 addition product as the major regioisomer (eqn (1)). The importance of the steric bulk of the substrates to the regiochemical outcome of the reaction was demonstrated further in the reaction of terminally disubstituted polyenyl carbonate 1m with nitromethane. This reaction provided the C-3 attacked regioisomer as the major product with a C-5 : C-3 : C-1 attack ratio of 25 : 71 : 4, albeit in a low combined yield (less than 5%, eqn (2)). It is well known that different intermediates are formed during the Pd-catalyzed allylic substitution reaction, including the exo- and endo-forms. Importantly, only one form should be the active intermediate, which is responsible for the enantioselectivity of the reaction.1a We found that the C-5 attacked products with very low ee (less than 10%) were obtained in the current work,8 whereas C-3 attacked products were formed with high enantioselectivities when malonate and benzylamine were used as the nucleophiles.2b The mechanism of Pd-catalyzed allylic substitution of polyenyl substrates was studied before,3,4a the equilibrium between Int-A and Int-B was found, C5-regioisomers were minor in all cases. On the basis of the results we obtained, we propose that Int-B is more active than Int-A because no C-5 addition products were found in the reactions of 1 with different malonates using L7 as a ligand, whereas the corresponding C-3 attacked products were formed with high regio- and enantio-selectivities.2b Taken together, these results suggest that the nucleophile attacks both the exo- and endo-forms of Int-B via an SN2 0 mechanism regioselectively to give the C-5 attacked product with almost no enantioselectivity (Scheme 2).4a,9 Further studies are currently underway in our laboratory to determine the mechanism responsible for the formation of the C-5 attacked regioisomer. In summary, we have successfully developed a regioselective palladium-catalyzed allylic alkylation of dienyl esters with
486 | Chem. Commun., 2014, 50, 484--486
1 For some reviews: (a) A. Pfaltz and M. Lautens, in Comprehensive Asymmetric Catalysis, ed. E. N. Jacobsen, A. Pfaltz and H. Yamamoto, Springer, New York, 1999, vol. 2, p. 833; (b) B. M. Trost and D. L. Van Vranken, Chem. Rev., 1996, 96, 395; (c) B. M. Trost and M. L. Crawley, Chem. Rev., 2003, 103, 2921; (d) Pd(0)-Catalyzed Reactions of Allylic Compounds via p-Allylpalladium Complexes, Palladium Reagents and Catalysts: New Perspectives for the 21st Century, ed. J. Tsuji, John Wiley & Sons, Ltd, Chichester, 2004, ch. 4, p. 431; (e) Z. Lu and S. M. Ma, Angew. Chem., Int. Ed., 2008, 47, 258. For some examples, see: ( f ) T. Hayashi, M. Kawatsura and Y. Uozumi, Chem. Commun., ´to ˆt and A. Pfaltz, Angew. Chem., Int. Ed., 1998, 1997, 561; ( g) R. Pre 37, 323; (h) R. Hilgraf and A. Pfaltz, Synlett, 1999, 1814; (i) K. Itami, T. Koike and J.-i. Yoshida, J. Am. Chem. Soc., 2001, 123, 6957; ( j) I. D. G. Watson, S. A. Styler and A. K. Yudin, J. Am. Chem. Soc., 2004, 126, 5086; (k) O. Pamies, M. Dieguez and C. Claver, J. Am. Chem. Soc., 2005, 127, 3646; (l ) A. M. Johns, Z. Liu and J. F. Hartwig, Angew. Chem., Int. Ed., 2007, 46, 7259; (m) Z. Hu, Y. Li, K. Liu and Q. Shen, J. Org. Chem., 2012, 77, 7957. 2 (a) S.-L. You, X.-Z. Zhu, Y.-M. Luo, X.-L. Hou and L.-X. Dai, J. Am. Chem. Soc., 2001, 123, 7471 and references cited therein; (b) W.-H. Zheng, N. Sun and X.-L. Hou, Org. Lett., 2005, 7, 5151; (c) J.-P. Chen, C.-H. Ding, W. Liu, X.-L. Hou and L.-X. Dai, J. Am. Chem. Soc., 2010, 132, 15493; (d) B.-H. Zheng, C.-H. Ding and X.-L. Hou, Synlett, 2011, 2262; (e) J. P. Chen, Q. Peng, B.-L. Lei, X.-L. Hou and Y.-D. Wu, J. Am. Chem. Soc., 2011, 133, 14180; ( f ) X.-F. Yang, C.-H. Ding, X.-H. Li, J.-Q. Huang, X.-L. Hou, L.-X. Dai and P.J. Wang, J. Org. Chem., 2012, 77, 8980. ¨ckvall, J. Org. Chem., 1991, 56, 5349; 3 (a) P. G. Andersson and J. E. Ba ¨ckvall, J. Am. Chem. (b) Y. I. M. Nilsson, P. G. Andersson and J. E. Ba Soc., 1993, 115, 6609. 4 (a) B. M. Trost and R. C. Bunt, J. Am. Chem. Soc., 1998, 120, 70; (b) B. M. Trost, S. Hildbrand and K. Dogra, J. Am. Chem. Soc., 1999, 121, 10416; (c) R. Takeuchi and K. Tanabe, Angew. Chem., Int. Ed., 2000, 39, 1975; (d) G. Lipowsky, N. Miller and G. Helmchen, Chem. Commun., 2004, 116; (e) G. Lipowsky, N. Miller and G. Helmchen, Angew. Chem., Int. Ed., 2004, 43, 4595; ( f ) H. Li and A. Alexakis, Angew. Chem., Int. Ed., 2012, 51, 1055; ( g) M. Magrez, Y. L. Guen, ´, C. Cre ´visy and M. Mauduit, Chem.–Eur. J., 2013, 19, 1199. O. Basle 5 An example of C-5 attack using an Ir-catalyst with only one substrate was reported very recently: S. Krautwald, D. Sarlah, M. A. Schafroth and E. M. Carreira, Science, 2013, 340, 1065. 6 (a) B. M. Trost and M. H. Hung, J. Am. Chem. Soc., 1984, 106, 6837; (b) B. M. Trost, C. J. Urch and M. H. Hung, Tetrahedron Lett., 1986, 27, 4949. 7 X.-F. Yang, W.-H. Yu, C.-H. Ding, Q.-P. Ding, S.-L. Wan, X.-L. Hou, L.-X. Dai and P.-J. Wang, J. Org. Chem., 2013, 78, 6503. 8 The optically active C-3 attacked product was obtained in the reaction of 1m with nitromethane in 90% ee using L3 as the ligand, the ratio of C-5 : C-3 : C-1 attacked isomers being 2 : 88 : 10. 9 The steric effect should be smaller when a nucleophile attacks the C-5 position of both exo- and endo-forms of Int-B.
This journal is © The Royal Society of Chemistry 2014
