Letter pubs.acs.org/OrgLett
Copper-Catalyzed Synthesis of Indol-3-yl α‑(Difluoromethyl)-α(trifluoromethyl)carbinols: Construction of Difluoromethylated sp3 Carbon Centers Yunxiao Zhang, Weitao Yan, Yukang Wang, and Zhiqiang Weng* State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fujian 350108, China S Supporting Information *
ABSTRACT: An efficient copper-catalyzed synthesis of indol-3-yl α-(difluoromethyl)-α-(trifluoromethyl)carbinols is developed. The reaction proceeds in good to excellent yields through a Friedel−Crafts-type mechanism, and a variety of indoles with commonly occurring functional groups such as formyl, cyano, nitro, alkyloxide, and halogen are well tolerated. In addition, these carbinol products are readily transformed into diversified difluoromethylated dinitrile indol-3-yl derivatives. This strategy provides a general synthetic method for ready construction of difluoromethylated sp3 carbon centers.
O
position is an effective strategy for synthesis of this class of compounds. For example, numerous elegant methods have been developed for their synthesis, which include alkylation,17−22 arylation,23 acylation,24−26 sulfonylation,27 and trifluoromethylthiolation28,29 of indoles. Due to the importance of the (difluoromethyl)-α(trifluoromethyl)carbinol motifs, the development of facile and practical synthetic approaches for their incorporation is still of great interest. Herein we describe a novel copper-catalyzed method for the incorporation of (difluoromethyl)-α(trifluoromethyl)carbinol motifs into indoles, as well as their derivatives. For our initial studies (Table 1), 1-methyl-1H-indole (2a) was used as the substrate in combination with 1,1,3,3,3pentafluoro-2-trimethylsiloxypropene (1) as fluorinating reagent.30,31 The use of CuI as catalyst and wet dichloroethane (DCE) as the solvent at 80 °C allowed the formation of carbinol 3a in 90% yield (entry 1). Gratifyingly, better yield was observed with other copper salts, such as CuBr, CuCl, CuCN, and CuSCN (entries 2−5). The use of other commonly used Lewis acid catalysts such as CuCl2, ZnCl2, Zn(OTf)2, AlCl3, InCl3, and FeCl2 gave lower yield (entries 6−11). It was found that while an uncatalyzed reaction did yield the product 3a, the reaction was only moderate (entry 12). Further optimization of the reaction conditions was performed with the economical and easily available CuCl. A solvent screen was then carried out, and low conversion was observed in THF (entry 13). Other solvents, such as CH3CN, DMF, and DMSO, were found to be ineffective for this transformation (entries 14−16). Decreasing
rganofluorine compounds have been widely applied in medicinal, agricultural, and material sciences.1−4 The unique physical and biological properties of fluorinated compounds are attributed to their metabolic stability, lipophilicity, and electron-withdrawing nature of the fluorinated substituent. Therefore, selective incorporation of fluorinecontaining moieties into organic molecules has become a powerful and widely employed strategy in drug design and new functional-material development.5−9 In this context, introduction of an α-(difluoromethyl)-α-(trifluoromethyl)carbinol moiety into organic molecules is a useful protocol for the synthesis of fluorine-containing bioactive molecules and materials (Figure 1). For instance, carbinol I and its derivatives
Figure 1. Pharmacologically active α-(difluoromethyl)-α(trifluoromethyl)carbinols and their derivatives.
exhibited potential as antihypertensive compounds.10 Carbinol II derivatives have been reported for their potential antiinflammatory activity.11 Compound III has been used as positive-working vacuum UV-sensitive photoresist material.12 3-Substituted indoles are very important structural motifs in biologically active natural products and drug molecules because they are capable of binding many receptors with high affinity.13−16 Direct functionalization of indoles at the C3 © 2017 American Chemical Society
Received: September 10, 2017 Published: September 28, 2017 5478
DOI: 10.1021/acs.orglett.7b02828 Org. Lett. 2017, 19, 5478−5481
Letter
Organic Letters Table 1. Optimization of the Reaction Conditionsa
Scheme 1. Scope of the Reactiona
entry
cat. (20 mol %)
solvent
temp (°C)
time (h)
yieldc (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
CuI CuBr CuCl CuCN CuSCN CuCl2 ZnCl2 Zn(OTf)2 AlCl3 InCl3 FeCl2 CuCl CuCl CuCl CuCl CuCl CuCl CuCl
DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE THF CH3CN DMF DMSO DCE DCE DCEb DCEb
80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 60 80 80 80
16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 8 16 16
90 96 99 95 98 40 46 41 47 44 70 57 40 trace trace trace 56 77 12 6
a
Reaction conditions: 1 (0.011 mmol), 2a (0.010 mmol), solvent (1.2 mL), N2. bExtra dry 1,2-dichloroethane with molecular sieves. cThe yield was determined by 19F NMR spectroscopy with PhOCF3 as internal standard.
the reaction temperature to 60 °C or shortening time to 8 h resulted in a drop in yield of product 3a (entries 17 and 18). The reaction was also tested in extra dry DCE with or without copper catalyst, and a very low yield of 3a was observed (entries 19 and 20), thus implying that the presence of trace amounts of water greatly enhanced this transformation. In order to explore the scope of this novel procedure, diverse indoles 2a−w were prepared and subjected to the optimized conditions (Scheme 1). The reactions with C-4, -5, and -7 methyl-substituted indoles 2b−d with 1 proceeded well to give the corresponding products 3b−d in excellent yields, respectively. The reactions of indoles having electron-donating groups such as 5-methoxy-1-methyl-1H-indole 2e, 5-(benzyloxy)-1-methyl-1H-indole 2f, and 5-([1,1′-biphenyl]-4-yloxy)-1methyl-1H-indole 2g proceeded to give 3e, 3f, and 3g in excellent yields, respectively. Moreover, product 3e was isolated in 87% yield (1.35 g) upon performing the reaction on a 5.0 mmol scale. The structure of 3f was established unequivocally by X-ray crystallography (Figure 2).32 Furthermore, an indole bearing a deficient group such as 1methyl-1H-indole-5-carbaldehyde 2h was converted to the corresponding product 3h in good yield (77%). However, when an indole having a strong electron-withdrawing group such as 1-methyl-1H-indole-5-carbonitrile 2i was subjected to the reaction, the yield of the corresponding product 3i is decreased to 34%. These results implied that the sufficient electron density on the pyrrole ring of indole promotes the electrophilic substitution. The halogen substituents, such as fluoro (3j and 3k), chloro (3l), and bromo (3m), were compatible with this protocol, providing the corresponding products in excellent yields, which
a
Reaction conditions: 1 (0.44 mmol), 2 (0.40 mmol), CuCl (0.08 mmol), DCE (4.0 mL), N2; isolated yields. bPerformed on 5.0 mmol scale.
Figure 2. ORTEP diagrams of 3f (left) and 4e (right).
offer possibilities for further functionalizations. Notably, the reaction efficiency was not affected by the presence of a methyl or phenyl group into the 2-position of the indole nucleus and gave the desired products 3n and 3o in quantitative yields. The unprotected indole substrates such as 1H-indoles 2p and 2q also furnished the desired products 3p and 3q in excellent yields under the standard conditions. Subsequently, various aryl-protected indoles were examined. It was worth noting that the electronic effect of the substituent on the phenyl ring was apparent. Reactions of N-arylindoles bearing alkyl, phenyl, methoxy, and halogen groups at the para position of phenyl ring proceeded smoothly to furnish the corresponding products 3r−v in good to excellent yields. However, a decreased yield was observed for N-arylindoles containing a strong electronwithdrawing group 3w (55%). To examine the crucial role of H2O for this transformation, a deuteration labeling reaction was conducted (Scheme 2). 5479
DOI: 10.1021/acs.orglett.7b02828 Org. Lett. 2017, 19, 5478−5481
Letter
Organic Letters Scheme 2. Isotope-Labeling Reaction
Scheme 4. Synthesis of Deuterated Difluoromethylated Dinitrile Indol-3-yl Derivative
Hydrolysis of enolate 1 with D2O (4 equiv) formed the active species 1,1,1,3,3-pentafluoroacetone, which readily underwent a Friedel−Crafts-type reaction with indole to afford the desired carbinol. Mass spectrometry and NMR analysis confirmed the incorporation of D in the carbinol product 3l-d1 with 85% deuteration at the difluoromethyl position. The synthetic utility of the carbinol products was then explored through a range of derivatizations. Treatment of carbinols 3 with 1.5 equiv of t-BuOK in CH3CN at 100 °C led to the isolation of difluoromethylated dinitrile indol-3-yl derivatives 4 in good to excellent yields (Scheme 3). The
Scheme 5. Proposed Mechanism for the Formation of 4
difluoromethylene I. Subsequently, the double-nucleophilic attack of cyanomethyl anions onto I and III, followed by elimination of CF3H and protonation of IV, would account for the formation of products 4. Furthermore, the elimination reaction of 3e in the presence of Cs2CO3 gave the corresponding difluoromethyl indol-3-yl ketone 5e in 75% yield (Scheme 6a). The subsequent reaction
Scheme 3. Synthesis of Difluoromethylated Dinitrile Indol-3yl Derivativesa
Scheme 6. Synthetic Utility of 3e
a
Reaction conditions: 3 (0.20 mmol), t-BuOK (0.30 mmol), CH3CN (2.0 mL), N2; isolated yields.
of 5e with t-BuOK in CH3CN at 100 °C did not afford the product 4e, thus suggesting that the difluoromethyl ketone species are not involved as the key intermediates in the formation of 4 from carbinols 3. The nucleophilic substitution reaction of 3-fluorobenzyl bromide with 3e furnished the ether 6 in 97% yield (Scheme 6b). Treatment of 4-chlorobenzoyl chloride with 3e provided the corresponding ester 7 in 96% yield (Scheme 6c). In conclusion, we have developed an efficient coppercatalyzed synthesis of indol-3-yl α-(difluoromethyl)-α(trifluoromethyl)carbinols using 1,1,3,3,3-pentafluoro-2-trimethylsiloxypropene as fluorinating reagent. This strategy has been applied to a variety of electronically and sterically differentiated indole derivatives, bearing a range of functional groups, to give the corresponding carbinols in good yield. Furthermore, a new class of difluoromethylated dinitrile indol3-yl derivatives could be synthesized through a reaction of carbinols with t-BuOK in CH3CN, providing a new method for construction of difluoromethylated sp3 carbon centers.
reaction was highly compatible with a variety of functional groups on the phenyl ring such as methoxy (4e), benzyloxy (4f), fluoro (4j), and bromo (4m) groups. However, the C2substituted indolyl carbinol (to 4n) gave a trace amount of product, apparently due to the steric hindrance. The structure of 4e was confirmed unambiguously by X-ray crystallography (Figure 2).32 However, when the unprotected indolyl carbinol 3p was subjected to reaction, a difluoromethyl indol-3-yl ketone 5p was obtained in 45% yield without the formation of the desired dinitrile product. In order to understand the formation of 4, the reaction was performed with deuterated solvent (Scheme 4). Thus, when carbinol 3e was treated with t-BuOK in CD3CN under the otherwise identical conditions of Scheme 3 4e-d5 was obtained with 99% and 97% deuteration at the difluoromethyl and cyanomethyl positions, respectively. On the basis of these results, a plausible reaction mechanism is proposed (Scheme 5). Initially, the intramolecular dehydration of 3 would form 5480
DOI: 10.1021/acs.orglett.7b02828 Org. Lett. 2017, 19, 5478−5481
Letter
Organic Letters
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(26) Yao, S.-J.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-H. J. Org. Chem. 2016, 81, 4226. (27) Xu, X.-H.; Liu, G.-K.; Azuma, A.; Tokunaga, E.; Shibata, N. Org. Lett. 2011, 13, 4854. (28) Chachignon, H.; Maeno, M.; Kondo, H.; Shibata, N.; Cahard, D. Org. Lett. 2016, 18, 2467. (29) Bu, M.-j.; Lu, G.-p.; Cai, C. Org. Chem. Front. 2017, 4, 266. (30) Qian, C.-P.; Nakai, T. Tetrahedron Lett. 1988, 29, 4119. (31) Hass, D.; Holfter, H.; Schröder, U. J. Fluorine Chem. 1994, 69, 89. (32) Crystal structures submitted to the Cambridge Cystallographic Data Centre, CCDC deposition nos. CCDC 1571254 (compound 3f) and CCDC 1571250 (compound 4e), respectively.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02828. Detailed experimental procedures, characterization data, and copies of 1H, 13C and 19F NMR spectra for all new compounds (PDF) X-ray data for 3f (CIF) X-ray data for 4e (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Zhiqiang Weng: 0000-0001-6851-1841 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (21372044 & 21772022). REFERENCES
(1) Uneyama, K., Ed. Organofluorine Chemistry; Blackwell Publishing Ltd., 2006. (2) Begue, J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine; Wiley: Hoboken, 2008. (3) Nakajima, T.; Groult, H. Fluorinated Materials for Energy Conversion; Elsevier: London, 2005. (4) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications; Wiley-VCH: Weinheim, 2014. (5) Chu, L.; Qing, F.-L. Acc. Chem. Res. 2014, 47, 1513. (6) Merino, E.; Nevado, C. Chem. Soc. Rev. 2014, 43, 6598. (7) Xu, X.-H.; Matsuzaki, K.; Shibata, N. Chem. Rev. 2015, 115, 731. (8) Ni, C.; Hu, M.; Hu, J. Chem. Rev. 2015, 115, 765. (9) Alonso, C.; Martínez de Marigorta, E.; Rubiales, G.; Palacios, F. Chem. Rev. 2015, 115, 1847. (10) Aldrich, P. E.; Berezin, G. H. BE872311A4, 1979. (11) Haber, S. B. US4381311A, 1983. (12) Kanna, S.; Mizutani, K. JP2003015298A, 2003. (13) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875. (14) Platon, M.; Amardeil, R.; Djakovitch, L.; Hierso, J.-C. Chem. Soc. Rev. 2012, 41, 3929. (15) Sandtorv, A. H. Adv. Synth. Catal. 2015, 357, 2403. (16) Vasiljevik, T.; Franks, L. N.; Ford, B. M.; Douglas, J. T.; Prather, P. L.; Fantegrossi, W. E.; Prisinzano, T. E. J. Med. Chem. 2013, 56, 4537. (17) Prakash, G. K. S.; Yan, P.; Török, B.; Olah, G. A. Synlett 2003, 527. (18) Wang, T.; Zhang, G.-W.; Teng, Y.; Nie, J.; Zheng, Y.; Ma, J.-A. Adv. Synth. Catal. 2010, 352, 2773. (19) Sigan, A. L.; Gusev, D. V.; Chkanikov, N. D.; Shmidt, E. Y.; Ivanov, A. V.; Mihaleva, A. b. I. Tetrahedron Lett. 2011, 52, 5025. (20) Sasaki, S.; Ikekame, Y.; Tanayama, M.; Yamauchi, T.; Higashiyama, K. Synlett 2012, 23, 2699. (21) Liu, X.-D.; Wang, Y.; Ma, H.-Y.; Xing, C.-H.; Yuan, Y.; Lu, L. Tetrahedron 2017, 73, 2283. (22) Hanakawa, T.; Isa, K.; Isobe, S.-i.; Hoshino, Y.; Zhou, B.; Kawatsura, M. J. Org. Chem. 2017, 82, 2281. (23) Chen, J.; Wu, J. Angew. Chem., Int. Ed. 2017, 56, 3951. (24) Williams, T. J.; Greaney, M. F. Org. Lett. 2014, 16, 4024. (25) Zhang, Z.-W.; Xue, H.; Li, H.; Kang, H.; Feng, J.; Lin, A.; Liu, S. Org. Lett. 2016, 18, 3918. 5481
DOI: 10.1021/acs.orglett.7b02828 Org. Lett. 2017, 19, 5478−5481
