Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Metal-Free C−B Bond Cleavage: An Acid Catalyzed ThreeComponent Reaction Construction of Imidazole-Containing Triarylmethanes Changcheng Wang,† Yue Yu,† Zhengquan Su,† Xuechen Li,*,‡ and Hua Cao*,† †
School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan, 528458, P. R. China Department of Chemistry, State Key Lab of Synthetic Chemistry, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
‡
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S Supporting Information *
ABSTRACT: An efficient acid-catalyzed strategy to prepare imidazole-containing triarylmethanes from amidines, ynals, and boronic acids has been developed. It represents an unprecedented and novel metal-free C−B bond cleavage strategy as a workable route to form new carbon−carbon bonds.
T
Scheme 2. Different Strategies for the Formation of C−C Bond
riarylmethanes and related compounds are the basic skeletons of many synthetic dyes,1 some of which have wide applications in pH indicators and medicine2 and display fluorescence.3 Heteroaryl-substituted triarylmethanes, especially N-containing heterocyclic compounds such as Letrozole, Vorozole, and 1-(phenyl(1-phenyl-1H-pyrrol-3-yl)methyl)-1Himidazole, are ubiquitous structural motifs in many pharmaceuticals and bioactive molecules,4 representing an important class of heterocycles (Scheme 1). The development of a facile method to synthesize triarylmethanes has attracted wide attention for potential applications. Scheme 1. Pharmaceutically and Material Relevant Triarylmethanes
Ackermann.8b Recently, a convenient rhodium-catalyzed C−B bond cleavage route has been reported by Willis9 to construct highly functionalized β′-aryl-α,β-unsaturated ketones. It can be seen that a transition metal has a deep impact on the method of C−B bond cleavage. Compared to transition-metalcatalyzed C−B bond cleavage, few metal-free C−B bond transformations have been reported. And no metal-free method has been developed to construct triarylmethanes via C−B bond cleavage.10 Herein, we report a novel metal-free C− B bond cleavage reaction to prepare imidazole-containing triarylmethanes which appeared as key structural units in many important bioactive compounds. Obviously, our method is simple, highly efficient, and environmental friendly. As listed in Table 1, the substrates of N-phenyl-benzamidine 1a, 3-phenylpropiolaldehyde 2a, and phenylboronic acid 3a
Boronic acid is an important synthetic synthon, which is widely used in the Suzuki−Miyaura cross-coupling to synthesize polyolefins, styrenes, and substituted biphenyls via Pd-catalyzed C−B bond cleavage.5 Transition-metal-catalyzed reactions are a powerful tool for converting C−B bonds to C− C bonds (Scheme 2). Over the past few years, Lu,6a Kuwano,6b and Crudden6c have demonstrated a palladium-catalyzed pathway through C−B bond cleavage to form a C−C bond for the synthesis of triarylmethanes. Moreover, Reddy7a and Cheng7b have achieved this transformation via nickel catalysis. Other elegant work to construct C−C bonds with boronic acids has been reported using ruthenium by Wan8a and © XXXX American Chemical Society
Received: March 19, 2019
A
DOI: 10.1021/acs.orglett.9b00969 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Screening for the Reaction Conditionsa
Scheme 3. Reaction Scope of Aryl Boronic Acidsa
entry
additive
T (°C)
solvent
time (h)
yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
FeCl3 AlCl3 ZnCl2 PivOH AcOH L-proline PivOH PivOH PivOH PivOH PivOH PivOH PivOH PivOH PivOH PivOH −
60 60 60 60 60 60 80 100 rt 80 80 80 80 80 80 80 80
toluene toluene toluene toluene toluene toluene toluene toluene toluene n-hexane DCE C2H5OH DMF H2O n-hexane n-hexane n-hexane
8 8 8 8 8 8 8 8 8 8 8 8 8 8 6 4 4
22 n.d. trace 55 n.d. n.d. 61 58 trace 71 54 n.d. n.d. n.d. 71 71 n.d.
a Reaction condition: 1a (0.2 mmol), 2a (0.2 mmol), 3a (0.6 mmol), additive (5.0 mol %), and solvent (2 mL). bDetermined by GC analysis.
a
Isolated yields.
Scheme 4. Reaction Scope of Amidinesa
were selected to screen the reaction conditions. Initial experiments were carried out using FeCl3 as the catalyst in toluene at 60 °C. The product 4a was observed in 22% yield (entry 1). Next, five more acids were evaluated (entries 2−6). In comparison with AlCl3, ZnCl2, AcOH, and L-proline, the yield improved considerably when PivOH was used (entry 4). The effect of temperature on reaction yield was then studied. It was observed that 80 °C is the most effective temperature for this C−B bond cleavage approach. Among the solvents, we were surprised to find that the yield of product 4a had a correlation with the solvent polarity (entries 10−14). Lower polarity solvent was beneficial to generate the desired product 4a. Other solvents, such as C2H5OH, DMF, and H2O, did not detect the desired product. Besides, shortening the reaction time to 4 h could also work with a 71% yield (entry 16). Finally, no product was detected without PivOH (entry 17). After the optimized reaction conditions were established (Table 1, entry 16), we proceeded to test the scope and limitations of this metal-free C−B bond cleavage. A series of arylboronic acids were examined in Scheme 3. As it suggested, under the optimized conditions, reaction conditions with different arylboronic acids all yielded the desired products 4a− 4k in 65−80%. It was observed that there was a marginal influence on the reaction with different positions of the substituents on the arylboronic acids. Meanwhile, electrondonating and electron-withdrawing groups in a phenyl ring of arylboronic acids also successfully afforded products without any difficulties. Furthermore, naphthalen-1-ylboronic acid was also employed to synthesize 4l in 65% yield. Encouraged by the results above in Scheme 3, we tried to use propylboronic acid as the substrate, and the yield of the desired product was detected in less than 8% yield by GC-MS. The scope of this metal-free C−B bond cleavage was further investigated using different amidines for the synthesis of imidazoles in Scheme 4. The amidines with a diverse range of
a
Isolated yields.
substituent groups such as CH3, F, Cl, and Br in a phenyl ring of N-substituted amidines could react smoothly, and the desired products (5a−5p) were obtained in 62−82% yields. First, electron-donating N-(3- or 4-methyl) substituted B
DOI: 10.1021/acs.orglett.9b00969 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters amidines reacted well with 2a and 3a to obtain 5a or 5b in 66% or 70% yields, respectively. Furthermore, N-substituted amidines (Ar1) with electron-deficient or electron-rich groups such as F, Cl, or Br were suitable substrates, delivering the expected products 5c−5i in good yields. Otherwise, different substituents (Ar2) of amidines also reacted well and afforded desired products in excellent yields 5j−5p. Different ynals were next investigated, and the results are illustrated in Scheme 5. Notably, the substituents on the
Scheme 7. Plausible Mechanism for the Observed Transformation
Scheme 5. Reaction Scope of Ynalsa
B,13 which, with the help of hydrion, is concerted into the desired product 4a in the end. In conclusion, we have successfully developed a novel and new metal-free C−B bond cleavage method to synthesize imidazole-containing triarylmethanes. This acid-catalyzed three-component reaction presents high regioselectivity under mild conditions. The transformation features excellent functional group tolerance, simple operation, and mild conditions. This strategy is anticipated to be an important approach to imidazole-containing triarylmethanes, which would be useful to construct bioactive molecules.
a
Isolated yields.
aromatic ring, such as methyl, methoxyl, and bromo, smoothly underwent this transformation, delivering the expected product 6a−6c in 69−75% yields. To understand the mechanism of this metal-free C−B bond cleavage, we added TEMPO or BHT; the yield of the reaction dropped insignificantly. This result suggests that the radical process may not be involved in this transformation11 (Scheme 6, eq 1). Futhermore, the imine intermediate A was oberved by
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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.9b00969. Experimental procedures and spectral data (PDF)
Scheme 6. Control Experiments
Accession Codes
CCDC 1865739 contains 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 Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Xuechen Li: 0000-0001-5465-7727 Hua Cao: 0000-0001-8825-0175 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The work was financially supported by the National Natural Science Foundation of China (21302023), the Innovation and Strong School Project of Guangdong Pharmaceutical University (2015cxqx212), the Science and Technology Planning Project of Guangzhou (2016A010103039, 201806040009, 201804010349), the University Grants Committee of Hong Kong (Grant AoE/P-705/16), and Provincial Experimental
GC-MS upon treatment of 1a and 2a with PivOH or TsOH in n-hexane, which could subsequently be reacted with phenylboronic acid by interaction with PivOH and transformed to 4a in 71% yield (eqs 2 and 3). The plausible mechanism is provided in Scheme 7. First, PivOH-promoted intermolecular dehydration of 1a and 2a gave product A.12 The borate complex attacks intermediate A and undergoes conjugated addition to produce intermediate C
DOI: 10.1021/acs.orglett.9b00969 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
(13) (a) Asao, N.; Takahashi, K.; Lee, S.; Kasahara, T.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 12650. (b) Wang, C.; Wang, E.; Chen, W.; Zhang, L.; Zhan, H.; Wu, Y.; Cao, H. J. Org. Chem. 2017, 82, 9144. (c) Gao, H.; Zhang, J. Adv. Synth. Catal. 2009, 351, 85. (d) Lee, S.; MacMillan, D. J. Am. Chem. Soc. 2007, 129, 15438.
Teaching Demonstration Center of Chemistry & Chemical Engineering.
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DOI: 10.1021/acs.orglett.9b00969 Org. Lett. XXXX, XXX, XXX−XXX
