Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Formation of Tertiary Alcohols from the Rhodium-Catalyzed Reactions of Donor/Acceptor Carbenes with Esters Liangbing Fu, Kevin Hoang, Cecilia Tortoreto, Wenbin Liu, and Huw M. L. Davies* Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States S Supporting Information *
ABSTRACT: Rhodium(II)-catalyzed reactions between isopropyl acetate and trichloroethyl aryldiazoacetates result in the formation of oxirane intermediates that ring open under the reaction conditions to form tertiary alcohols. When the reaction is catalyzed by the dirhodium tetrakis(triarylcyclopropanecarboxylate) complex, Rh2(S2-Cl,4-BrTPCP)4, the tertiary alcohols are formed with good asymmetric induction (80−88% ee).
R
Scheme 1. Trapping of Donor/Acceptor Carbenes by Esters
hodium-stabilized donor/acceptor carbenes have found extensive applications in organic synthesis.1,2 The donor group attenuates the reactivity of the carbene, enabling a wide variety of selective intermolecular reactions to be feasible. These include cyclopropanation,2a tandem cyclopropanation Cope rearrangement,2a,3 C−H insertion,2b−e and a wide variety of reactions initiated by formation of ylide intermediates.4 Even though the reaction scope is broad, it is still possible to achieve reactions in the presence of a variety of functional groups. It has been suggested that one reason for this broad scope is the reactions with some nucleophilic functional groups, such as esters, are reversible.5 This would explain, for example, why intermolecular functionalization of unactivated C−H bonds can be achieved, even when the substrates contain nucleophilic sites.2b−e Furthermore, many examples known of carbene reactions were conducted in relatively polar solvents such as ethyl acetate or diethyl ether,6 and even water.7 This paper describes an unexpected reaction of rhodium-stabilized donor/ acceptor carbenes with simple ester solvents. For some time, we have been developing enantioselective C−H functionalization strategies by means of rhodiumcatalyzed intermolecular C−H insertions.2a−e The original chiral catalyst used in these studies, Rh2(S-DOSP)4, gave high asymmetric induction only in nonpolar solvents,8 but the newer chiral catalysts also performed well in more polar solvents such as dichloromethane.9 A further advance has been the use of the trichloroethyl ester (Troc) derivatives of the carbene precursors, because they tend to give much cleaner transformations, especially with challenging C−H functionalization reactions.10 During exploratory studies using isopropyl acetate as an industrially more favored solvent, we discovered an unexpected result in the reaction of the trichloroethyl aryldiazoacetate 1 with cumene. In addition to the expected C−H functionalization product, a significant amount (10− 20%) of the tertiary alcohol 2 was formed, whose structure was confirmed by X-ray crystallography. When the Rh2(S-DOSP)4catalyzed reaction was conducted without a trapping agent with isopropyl acetate as solvent, 2 was generated in 38% yield and 35% ee (Scheme 1). © XXXX American Chemical Society
Even though intramolecular reactions between carbenes and esters and intermolecular reactions with aldehydes and ketones11 are well established, intermolecular reactions with esters are rare.12 Therefore, we conducted a survey of the most common achiral catalysts to determine if the reaction can be developed into a synthetically useful process. The results are summarized in Table 1. The initial evaluation of the catalysts was conducted with isopropyl acetate as solvent at room temperature (entries 1−6), and under these conditions, Rh2(OAc)4 and Rh2(OOct)4 were the most effective. The yield could be improved if a mixture of isopropyl acetate/ dichloromethane with a 1/1 volume ratio was used as the solvent (entries 7 and 8), and further improvement occurred when the reaction was conducted under reflux (entries 9 and 10). Comparison studies were conducted between different diazo esters (Scheme 2). When the diazo compound was switched from the trichloroethyl ester to the methyl ester 3, the corresponding product 4 was only formed in trace amounts. Ethyl acetate was also an effective trapping agent, generating the tertiary alcohol 5 in 53% yield, but the yield was much lower when tert-butyl acetate was used as the trapping agent. The observation of a very small amount of the tertiary alcohol 4 may explain why intermolecular ester trapping of rhodium carbenes is rare, because the use of the trichloroethyl esters is a relatively new phenomenon in rhodium carbene chemistry. The scope of the reaction was then explored with more elaborate substrates. A series of trichloroethyl aryldiazoacetates 7 were examined, and the results are summarized in Scheme 3. Received: March 5, 2018
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DOI: 10.1021/acs.orglett.8b00739 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization Studiesa
Scheme 3. Substrate Scope
entry
catalyst
solvent
temp (°C)
yield (%)b
1 2 3 4 5 6 7 8 9 10
Rh2(OAc)4 Rh2(OPiv)4 Rh2(TPA)4 Rh2(TFA)4 Rh2(OOct)4 Rh2(esp)2 Rh2(OOct)4 Rh2(OAc)4 Rh2(OOct)4 Rh2(OAc)4
PrOAc PrOAc i PrOAc i PrOAc i PrOAc i PrOAc i PrOAc/CH2Cl2 i PrOAc/CH2Cl2 i PrOAc/CH2Cl2 i PrOAc/CH2Cl2
rt rt rt rt rt rt rt rt 40 40
48 5 16 10 36 10 52 51 68 64
i
i
a
Reaction conditions: diazo compound 1 (0.3 mmol) was added in one portion to a mixture of the catalyst Rh2L4 (1 mol %) in 2 mL of the solvent at the indicated temperature. The reaction was further stirred for 30 min. bIsolated yield.
Scheme 2. Control Studies
Scheme 4. Enol Ether Hydrolysis
A one-pot, two-step procedure was further developed for this transformation. Diazoacetate 1 was reacted with either isopropyl acetate or ethyl acetate under the catalysis of Rh2(OOct)4, followed by direct hydrolysis of the reaction mixture (Scheme 5). When isopropyl acetate was used,
Diazo ester substrates with different substitution patterns such as para-, meta-, 3,5-, and 3,4-substitution were all capable substrates in this transformation. The yields of the reactions were found to be greatly influenced by the nature of the substituent on the aryl ring. The yields of the reactions were generally much higher for substrates with electron-withdrawing groups on the aryl ring (51−90%), compared to those with an electron-donating para substituent (29−31%). When a subsrate bearing a strong electron-donating p-NMe2 on the pheyl ring was employed, none of the desired products was observed, further confirming the influence of electronics on the efficiency of the transformation. The quaternary hydroxyl-enoate thus obtained can be hydrolyzed under acidic conditions. When compound 2 was treated with hydrochloric acid in dichloromethane, product 9 was obtained in quantitative yield (Scheme 4). No column chromatographic purification was required for this hydrolysis reaction. The scope of the hydrolysis was explored with the optimized hydrolysis conditions. Gratifyingly, and unsurprisingly, when the pure products 8 obtained from the last step were employed, all reactions gave the expected hydrolysis products in high yields, without the need for column chromatographic purifications (see Supporting Information (SI)).
Scheme 5. One-Pot Rhodium-Catalyzed Reaction and Enol Ether Hydrolysis
compound 9 was obtained in 56% yield for two steps. When ethyl acetate was used, compound 9 was obtained in 53% yield. The reaction was found to be applicable to isopropyl propionate. When isopropyl propionate was subjected to the same reactions, tertiary alcohol 10 was obtained, although the yield was a bit lower (42%). B
DOI: 10.1021/acs.orglett.8b00739 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters The likely mechanism of this transformation involves ylide intermediates. Dirhodium-catalyzed reactions are known to give variable levels of enantioselectivity when ylides are involved because the metal may have already dissociated when the ylide reacts or the reaction proceeds via enol intermediates.13 As already discussed in the introduction, the Rh2(S-DOSP)4catalyzed reaction gave the product in 35% ee (Table 2). The
Scheme 6. Enantioselective Reaction
Table 2. Evaluation of Chiral Dirhodium Catalystsa
entrya
Rh2L*4
yield (%)b
ee (%)c
1 2 3 4 5 6 7
Rh2(S-DOSP)4 Rh2(S-PTAD)4 Rh2(S-TCPTAD)4 Rh2(S-p-BrTPCP)4 Rh2(S-2-CITPCP)4 Rh2(S-2-CI,5-BrTPCP)4 Rh2(S-2-CI,4-BrTPCP)4
38 57 39 7 10 32 49
35 −5 −19 26 51 24 88
the asymmetric reactions were assigned by analogy. These results open up the possibility of achieving enantioinduction for the intermolecular reactions between carbenes and esters, even though further development of chiral dirhodium catalysts is still required for the reaction to be more broadly applicable. A possible mechanistic pathway for the formation of tertiary alcohols is shown Scheme 7. Decomposition of the Scheme 7. Proposed Mechanistic Pathway
a
Reaction conditions: a solution of 1 (0.3 mmol) in 3 mL of isopropyl acetate was added over 30 min to the catalyst (1 mol %) in 2 mL of isopropyl acetate at room temperature. The reaction was allowed to stir for an additional 30 min. bIsolated yield. cDetermined by chiral HPLC analysis.
trichloroethyl aryldiazoacetate 11 by the dirhodium catalyst generates a rhodium-bound carbene 12. The carbonyl group of the isopropyl acetate then attacks the carbene 12 to form a rhodium-bound carbonyl ylide intermediate 13. The intermolecular reaction of esters with donor/acceptor carbenes has been proposed to be reversible,5 but in this case, the ylide collapses to form an epoxide 14. The epoxide contains a ketal functional group and, thus, is prone to ring opening to form a new ylide intermediate 15, which undergoes proton transfer, possibly in an intermolecular fashion to generate the final products 16. The stereogenic center is initially generated during the formation of the ylide 13, and is then at least mostly retained during the cyclization to the epoxide 14. This result is different from what was observed in the reactions of aldehydes with aryldiazoacetates in the presence of chiral dirhodium catalysts, which resulted in the formation of racemic epoxides, presumably because the rhodium is no longer bound when cyclization to the epoxide occurs.16 In summary, these studies demonstrate that even though rhodium-bound donor/acceptor carbenes are capable of a wide range of selective transformations, relatively innocuous solvents such as isopropyl acetate can interfere with the reactions. The carbene derived with a trichoroethyl ester appears to be more reactive than the corresponding carbene with a methyl ester. The rhodium-catalyzed reaction can be used to synthesize tertiary alcohols by a cascade reaction involving epoxide intermediates. Rh2(OOct)4 is the optimum achiral catalyst,
phthalimido catalysts Rh2(S-PTAD)4 and Rh2(S-TCPTAD)414 gave reasonable yields, but even lower levels of enantioselectivity. The newly developed Rh2(S-p-BrTPCP)4 and (S-pPhTPCP)49 gave low yields and enantioselectivity. A promising result was seen with Rh2(S-2-ClTPCP)4,15 as it gave reasonable enantioselectivity, albeit poor yield. Further optimization with two previously unpublished catalysts, Rh2(S-2-Cl,4-BrTPCP)4 and Rh 2 (S-2-Cl,5-BrTPCP) 4 , identified Rh 2 (S-2-Cl,4BrTPCP)4 as the optimum catalyst, generating 2 in 49% yield and 88% ee. With the optimized conditions for the enantioselective reaction in hand, the efficiency of Rh2(S-2-Cl,4-BrTPCP)4 in promoting an enantioselective synthesis of quaternary hydroxyl-enoate was explored (Scheme 6). The yields of these enantioselective reactions were generally inferior to those of reactions catalyzed by Rh2(OOct)4, but reasonably high levels of enantioselectivity were achieved (80−88% ee). The absolute configuration of product 8h was unambiguously assigned by Xray crystallography, and the configurations of other products in C
DOI: 10.1021/acs.orglett.8b00739 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
12422. (c) Schwartz, B. D.; Denton, J. R.; Lian, Y. J.; Davies, H. M. L.; Williams, C. M. J. Am. Chem. Soc. 2009, 131, 8329. (4) For recent reviews on ylide reactions, see: (a) Sheng, Z.; Zhang, Z. K.; Chu, C.; Zhang, Y.; Wang, J. Tetrahedron 2017, 73, 4011. (b) Guo, X.; Hu, W. Acc. Chem. Res. 2013, 46, 2427. (5) (a) Wang, H.; Guptill, D. M.; Varela-Alvarez, A.; Musaev, D. G.; Davies, H. M. L. Chem. Sci. 2013, 4, 2844. (b) Davies, H. M. L.; Huby, N. J. S.; Cantrell, W. R., Jr.; Olive, J. L. J. Am. Chem. Soc. 1993, 115, 9468. (6) For examples of rhodium-catalyzed carbene reactions conducted in ethyl acetate as solvent, see: (a) Jiang, L.; Jin, W.; Hu, W. ACS Catal. 2016, 6, 6146. (b) Fu, L.; Davies, H. M. L. Org. Lett. 2017, 19, 1504. (c) Qin, C.; Davies, H. M. L. Org. Lett. 2013, 15, 310. (d) Wang, C.; Xing, D.; Wang, D.; Wu, X.; Hu, W. J. Org. Chem. 2014, 79, 3908. (e) Lo, M. M.-C.; Fu, G. C. Tetrahedron 2001, 57, 2621. (f) Xu, Z.-H.; Zhu, S.-N.; Sun, X.-L.; Tang, Y.; Dai, L.-X. Chem. Commun. 2007, 1960. (7) (a) Antos, J. M.; McFarland, J. M.; Iavarone, A. T.; Francis, M. B. J. Am. Chem. Soc. 2009, 131, 6301. (b) Candeias, N. R.; Gois, P. M. P.; Afonso, C. A. M. J. Org. Chem. 2006, 71, 5489. (c) Morandi, B.; Cheang, J.; Carreira, E. M. Org. Lett. 2011, 13, 3080. (8) (a) Davies, H. M. L.; Antoulinakis, E. G.; Hansen, T. Org. Lett. 1999, 1, 383. (b) Davies, H. M. L.; Antoulinakis, E. G. Org. Lett. 2000, 2, 4153. (c) Davies, H. M. L.; Ren, P. J. Am. Chem. Soc. 2001, 123, 2070. (d) Hansen, J.; Autschbach, J.; Davies, H. M. L. J. Org. Chem. 2009, 74, 6555. (9) (a) Qin, C.; Boyarskikh, V.; Hansen, J. H.; Hardcastle, K. I.; Musaev, D. G.; Davies, H. M. L. J. Am. Chem. Soc. 2011, 133, 19198. (b) Qin, C.; Davies, H. M. L. J. Am. Chem. Soc. 2014, 136, 9792. (10) (a) Fu, L.; Guptill, D. M.; Davies, H. M. L. J. Am. Chem. Soc. 2016, 138, 5761. (b) Guptill, D. M.; Davies, H. M. L. J. Am. Chem. Soc. 2014, 136, 17718. (c) Liao, K.; Negretti, S.; Musaev, D. G.; Bacsa, J.; Davies, H. M. L. Nature 2016, 533, 230. (d) Fu, L.; Mighion, J. D.; Voight, E. A.; Davies, H. M. L. Chem. - Eur. J. 2017, 23, 3272. (11) (a) Padwa, A.; Hornbuckle, S. F. Chem. Rev. 1991, 91, 263. (b) Padwa, A. Acc. Chem. Res. 1991, 24, 22. (c) Bonderoff, S. A.; Padwa, A. J. Org. Chem. 2017, 82, 642. (d) Fu, L.; Wang, H.; Davies, H. M. L. Org. Lett. 2014, 16, 3036. (12) Padwa, A.; Boonsombat, J.; Rashatasakhon, P. Tetrahedron Lett. 2007, 48, 5938. (13) Li, Z.; Davies, H. M. L. J. Am. Chem. Soc. 2010, 132, 396. (14) Reddy, R. P.; Davies, H. M. L. Org. Lett. 2006, 8, 5013. (15) Liao, K.; Liu, W.; Niemeyer, Z. L.; Ren, Z.; Bacsa, J.; Musaev, D. G.; Sigman, M. S.; Davies, H. M. L. ACS Catal. 2018, 8, 678. (16) (a) Davies, H. M. L.; DeMeese, J. Tetrahedron Lett. 2001, 42, 6803. (b) Doyle, M. P.; Hu, W.; Timmons, D. J. Org. Lett. 2001, 3, 933. (c) Russell, A. E.; Brekan, J.; Gronenberg, L.; Doyle, M. P. J. Org. Chem. 2004, 69, 5269.
and the yields are highest for electron-deficient aryldiazoacetates. The yields are lower when chiral catalysts were used, but Rh2(S-2-Cl,4-BrTPCP)4 was able to generate the products in 80−88% ee.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00739. Complete experimental, NMR, chiral HPLC, and X-ray crystallographic data (PDF) Accession Codes
CCDC 1576459−1576460 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Huw M. L. Davies: 0000-0001-6254-9398 Notes
The authors declare the following competing financial interest(s): HMLD is a named inventor on a patent entitled, Dirhodium Catalyst Compositions and Synthetic Processes Related Thereto (US 8,974,428, issued 3/10/2015). The other authors have no competing financial interests.
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ACKNOWLEDGMENTS This work was supported by the National Science Foundation (CHE 1465189). We also thank the Swiss National Science Foundation for the early postdoc grant awarded to Cecilia Tortoreto. Instrumentation used in this work was supported by the National Science Foundation (CHE 1531620 and CHE 1626172). We thank Dr. John Bacsa from Emory X-ray Crystallography Center for the X-ray structure determination. We thank Mark A. Matulenko from AbbVie for encouraging us to examine more benign solvents for carbene transformations.
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REFERENCES
(1) For general reviews on rhodium carbene chemistry, see: (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo Compounds; Wiley: New York, 1998. (b) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704. (c) Doyle, M. P.; Liu, Y.; Ratnikov, M. Org. React. 2013, 80, 1. (d) Ford, A.; Miel, H.; Ring, A.; Slattery, C. N.; Maguire, A. R.; McKervey, M. A. Chem. Rev. 2015, 115, 9981. (2) For selected reviews on donor/acceptor rhodium carbenes, see: (a) Davies, H. M. L.; Antoulinakis, E. G. Org. React. 2001, 57, 1. (b) Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861. (c) Davies, H. M. L.; Pelphrey, P. Org. React. 2011, 75, 75. (d) Davies, H. M. L.; Morton, D. Chem. Soc. Rev. 2011, 40, 1857. (e) Davies, H. M. L.; Lian, Y. Acc. Chem. Res. 2012, 45, 923. (3) For recent examples of the tandem cyclopropanation/Cope rearrangement used in total synthesis, see: (a) Parr, B. T.; Economou, C.; Herzon, S. B. Nature 2015, 525, 507. (b) Lian, Y.; Miller, L. C.; Born, S.; Sarpong, R.; Davies, H. M. L. J. Am. Chem. Soc. 2010, 132, D
DOI: 10.1021/acs.orglett.8b00739 Org. Lett. XXXX, XXX, XXX−XXX
