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Direct N-acylation of azoles via a metal-free catalyzed oxidative cross-coupling strategy† Jingjing Zhao,ab Pan Li,a Chungu Xiaa and Fuwei Li*a
Received 3rd March 2014, Accepted 18th March 2014 DOI: 10.1039/c4cc01587h www.rsc.org/chemcomm
The KI-catalyzed N-acylation of azoles via direct oxidative coupling of C–H and N–H bonds has been developed. It could be smoothly scaled up to gram synthesis of acyl azoles. The reaction occurred by the coupling of acyl radicals and azoles to form the acyl azole radical anion, followed by its further oxidation.
The amide unit is a key structural moiety in pharmaceuticals, natural products, polymers, and agrochemicals.1 Traditionally, the amides are often prepared from carboxylic acids or their activated analogues like acyl chlorides, anhydrides, and azides, etc.2 Recently, direct oxidative coupling of two different X–H (X = C, N, O) bonds has attracted much attention from the synthetic organic chemistry community.3 Especially, the oxidative cross-coupling between aldehydes and amines (including primary, secondary, and tertiary) was developed rapidly.4 This C–N bond formation occurred via a hemiaminal intermediate, followed by its oxidation (Scheme 1, path A). In addition, amidations of aldehydes with N-chloroamines were investigated.5 These processes were proposed to be involved in the coupling of acyl radicals and amino radical cations (Scheme 1, path B). Azoles are ubiquitous motifs in nature and exhibit potential biological activities and medicinal significance.6 Therefore, the
Scheme 1
Synthesis of amides from aldehydes.
a
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou, 730000, China. E-mail: [email protected]; Fax: +86-931-4968129 b Graduate University of Chinese Academy of Sciences, Beijing, 100049, China † Electronic supplementary information (ESI) available. See DOI: 10.1039/c4cc01587h
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development of new methods for the preparation of functional azoles is highly desirable in organic synthesis.7–9 Recently, with the increasing concerns on the development of practical and green methodology in synthetic chemistry, organic chemists have also paid much attention to screening non-metal catalysts to form C–N bonds.10 As our continuing interest on the development of new methods to prepare functionalized heterocycles,11 we herein report a KI-catalyzed N-acylation of azoles by an oxidative cross-coupling strategy. With this in mind, our initial investigation focused on the reaction of 3-phenyl-1H-pyrazole (1a) with 3,4-dimethoxybenzaldehyde (2a), selected results are summarized in Table 1. To our delight,
Table 1
Optimization of reaction conditionsa
Entry
Catalyst
Peroxide
Solvent
T (1C)
Yield (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14b 15b,c 16b,d 17b,e 18b,e 19b,e 20b,e
— TBAI NaI KI I2 KI KI KI KI KI KI KI KI KI KI KI CuI CuBr2 FeCl3.6H2O FeCl2.4H2O
TBHP TBHP TBHP TBHP TBHP DTBP TBPB H 2 O2 TBHP TBHP TBHP TBHP TBHP TBHP TBHP TBHP TBHP TBHP TBHP TBHP
DCE DCE DCE DCE DCE DCE DCE DCE Toluene Chlorobenzene H2O DCE DCE DCE DCE DCE DCE DCE DCE DCE
100 100 100 100 100 100 100 100 100 100 100 80 50 100 100 100 100 100 100 100
16 45 68 81 76 23 65 0 74 80 0 68 10 83 84 68 26 51 27 36
a
All reactions were carried out on a 0.3 mmol scale in 3 mL of solvent for 12 h. 1a/2a/peroxide = 1 : 2 : 4. Isolated yield. b 1.5 equiv. of aldehydes. c 3 equiv. of TBHP. d 2 equiv. of TBHP. e 10 mmol% catalyst.
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Table 2
KI-catalyzed N-acylation of pyrazolesa
ChemComm Table 3
KI-catalyzed N-acylation of other azolesa
a
A mixture of pyrazoles (0.3 mmol), aldehyde (0.45 mmol), KI (0.06 mmol), and TBHP (0.9 mmol) in 3 mL of DCE was stirred in 15 mL pressure tubes at 100 1C for 12 h. Isolated yields. a
the desired product 3a was obtained in 16% yield using tertbutylhydroperoxide (70% aqueous) as the oxidant (Table 1, entry 1). Upon using various iodides as the catalysts,12 KI showed the best activity (Table 1, entries 2–5). Similar to tert-butylhydroperoxide (TBHP), tert-butyl peroxide (DTBP) or tert-butyl peroxybenzoate (TBPB) was also effective for this reaction (Table 1, entries 6 and 7). However, H2O2 was an inactive oxidant for this transformation (Table 1, entry 8). Present acylation proceeded smoothly in toluene and chlorobenzene (Table 1, entries 9 and 10). Unfortunately, the reaction did not occur in H2O (Table 1, entry 11). In addition, the temperature variation could obviously affect the catalytic performance (Table 1, entries 12 and 13). Reducing the amount of aldehydes and TBHP (1.5 equiv. of aldehydes and 3 equiv. of TBHP) also worked efficiently, affording 84% yield of the desired product 3a (Table 1, entry 15). To our delight, the present KI catalyst showed much higher reactivity than the metallic copper and iron catalysts (Table 1, entries 17–20). With these satisfactory conditions in hand, we then turned to examine the scope of aldehydes and pyrazoles (Table 2). The benzaldehydes with electron-donating (OMe and tert-butyl) and -withdrawing groups (Cl, Br, F, and CN) all worked well with 3-phenyl pyrazole, affording the desired N-acyl pyrazoles in 51% to 95% yields, respectively (3b–j). Other representative aromatic aldehydes, such as 2-naphthaldehyde and thiophene-2-carbaldehyde, were also found to be suitable for this transformation (3k and l). To our delight, use of benzil instead of benzaldehyde also afforded the desired product 3b in 39% yield under the standard conditions.13 Furthermore, other pyrazoles could react with aldehydes to give the desired products in moderate yields (3m and n). Encouraged by the above results, we then extended the azole scope to other heterocycles bearing a N–H group (Table 3). The reactions of benzimidazole with benzaldehyde and its electrondonating substituted analogues proceeded efficiently, giving the expected products 5a, 5d, and 5f in 85% to 98% yields.
Chem. Commun.
A mixture of pyrazoles (0.3 mmol), aldehyde (0.45 mmol), KI (0.06 mmol), and TBHP (0.9 mmol) in 3 mL of DCE was stirred in 15 mL pressure tubes at 100 1C for 12 h. Isolated yields.
However, the benzaldehyde with electron-withdrawing substituents afforded 5b, 5c, 5e, and 5g in 24% to 78% yields. The N-acylation with other representative aromatic aldehydes such as 2-naphthaldehyde and thiophene-2-carbaldehyde also worked well and provided the products 5h and 5i in 76% and 55% yields, respectively. For benzotriazole, surprisingly, only benzaldehyde and its ortho-substituted analogues were fit for this procedure, and the aromatic aldehydes with para-substitutions only gave the corresponding tert-butyl esters (5j–5n).14 Moreover, the indazole was also found to be suitable for this catalytic system and provided the corresponding product 5o in 44% yield. Regretfully, aliphatic aldehydes (such as 3-phenylpropanal, cyclohexanealdehyde and pivalaldehyde) were not suitable for our system (ESI,† eqn (S1) and (S2)).15 In order to prove the practicality of this approach, a gram-scale synthesis of the N-benzoyl benzoimidazole 5a (3.77 g, 85% yield) was performed, suggesting that such a new and facile methodology could also be efficiently scaled up (Scheme 2). To validate the proposed mechanism, a series of control experiments were carried out. The addition of TEMPO (2,2,6,6tetramethylpiperidinooxy) prevented the reaction and product 6 generated from the coupling of acyl radical and TEMPO was obtained in a near quantitative yield (Scheme 3, a). Additionally, the reaction was also inhibited by another radical scavenger,
Scheme 2
Gram scale synthesis of N-benzoyl benzoimidazole.
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Scheme 3
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Radical trapping experiments.
1,1-diphenylethylene (Scheme 3, b). Besides, upon using benzil instead of benzaldehyde, product 3b was also not detected when TEMPO was added (Scheme 3, c). All these results suggested that an acyl radical intermediate was involved in the present catalytic cycle. On the other hand, some control experiments with respect to the previous reported N-acylation of primary and secondary aliphatic amines were also performed (ESI,† eqn (S3)–(S6)).3b,c The addition of TEMPO inhibited these N-acylations. Interestingly, the imine product was observed in the reaction of aldehydes and primary amines, which was generated from the dehydration of a hemiaminal intermediate, suggesting again that the reported N-acylation reactions occur via a hemiaminal intermediate followed by its further oxidation which may involve a radical process. Therefore, our method is much different from the reported procedures in terms of the mechanism and the reaction process. Correspondingly, the reported procedures did not work for the present N-acylation of azoles with aldehydes (ESI,† eqn (S7) and (S8)). It has been reported that the amides are formed from aldehydes and amines via N-chloroamine intermediates,5 which reminded us that such transformation might be via a N-iodineazole intermediate in our oxidation system. Subsequently, some control experiments were carried out (ESI,† eqn (S9)–(S11)). However, N-iodineazole was not detected. Therefore, the possibility via a N-iodineazole intermediate was ruled out in the present N-acylation reaction. Based on the above control experiments, a proposed mechanism is shown in Scheme 4. Initially, the tert-butoxyl and tert-butylperoxy radicals were generated in the catalytic system,16 and they could abstract a hydrogen atom from aldehydes to generate the acyl radical A,17 which reacted with azole to give the acyl azole radical anion B,18 followed by a SET process by losing an electron with the assistance of tert-butoxyl or tert-butylperoxy radicals to afford the desired N-acyl azoles (Scheme 4, path A).19 On the other hand, the tert-butoxyl and tert-butylperoxy radicals could capture a single electron from azoles to form azole radical cation species C1,20 which could also convert to azole radical C2 via a deprotonation reaction with the assistance of the tert-butoxyl anion. Ultimately, the acyl radical A and azole radical cation C1 or azole radical C2 were coupled to provide the desired amide (Scheme 4, path B). Although the acyl radical was captured, the coupling of TEMPO and radical C1 or C2 was not detected. Therefore, present N-acylation was preferred to react following the path A, however, the possibility via path B was not excluded. According to our
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Scheme 4
Plausible reaction mechanism.
proposed mechanism, theoretically, present N-acylation needs two equiv. of the oxidant. In summary, we have developed a KI-catalyzed N-acylation of azoles using aldehydes as the acyl sources. Different from the synthesis of amides from aliphatic amines using aldehydes via a nucleophilic addition/oxidation mechanism, the present catalytic cycle appears to involve the coupling of the acyl radical intermediate and azole. Interestingly, such transformation was tolerant with different azoles and could be efficiently scaled up. The reactions of acyl radicals with other coupling partners are under investigation in our laboratory. Financial support from the Chinese Academy of Sciences and the National Natural Science Foundation of China (21002106, 21133011 and 21373246) is gratefully acknowledged.
Notes and references 1 (a) C. L. Allen and J. M. J. Williams, Chem. Soc. Rev., 2011, 40, 3450; (b) M. J. Humphrey and R. A. Chamberlin, Chem. Rev., 1997, 97, 2243. 2 Recently, Barbas and coworkers developed organocatalytic amidation of aldehydes with activating reagents, see: B. Tan, N. Toda and C. F. Barbas, Angew. Chem., Int. Ed., 2012, 51, 12538. 3 (a) S. A. Girard, T. Knauber and C.-J. Li, Angew. Chem., Int. Ed., 2014, 53, 74; (b) C.-J. Li, Acc. Chem. Res., 2009, 42, 335; (c) X. W. Guo, Z. Li and C.-J. Li, Prog. Chem., 2010, 22, 1434; (d) C. Liu, H. Zhang, W. Shi and A. Lei, Chem. Rev., 2011, 111, 1780; (e) S. H. Cho, J. Y. Kim, J. Kwak and S. Chang, Chem. Soc. Rev., 2011, 40, 5068; ( f ) C. S. Yeung and V. M. Dong, Chem. Rev., 2011, 111, 1215. 4 (a) W.-J. Yoo and C.-J. Li, J. Am. Chem. Soc., 2006, 128, 13064; (b) K. EkoueKovi and C. Wolf, Org. Lett., 2007, 9, 3429; (c) K. R. Reddy, C. U. Maheswari, M. Venkateshwar and M. L. Kantam, Eur. J. Org. Chem., 2008, 3619; (d) S. C. Ghosh, J. S. Y. Ngiam, C. L. L. Chai, A. M. Seayad, T. T. Dang and A. Chen, Adv. Synth. Catal., 2012, 354, 1407; (e) V. Prasad, R. R. Kale, B. B. Mishra, D. Kumar and V. K. Tiwari, Org. Lett., 2012, 14, 2936; ( f ) K. S. Goh and C.-H. Tan, RSC Adv., 2012, 2, 5536; (g) Y. Li, F. Jia and Z. Li, Chem. – Eur. J., 2013, 19, 82. 5 (a) R. Cadoni, A. Porcheddu, G. Giacomelli and L. D. Luca, Org. Lett., 2012, 14, 5014; (b) A. Porcheddu and L. D. Luca, Adv. Synth. Catal., 2012, 354, 2949; (c) R. Vanjari, T. Guntreddi and K. N. Singh, Green Chem., 2014, 16, 351. 6 (a) D. A. Horton, G. T. Bourne and M. L. Smythe, Chem. Rev., 2003, 103, 893; (b) M. L. McKee and S. M. Kerwin, Bioorg. Med. Chem., 2008, 16, 1775; (c) K. Bahrami, M. M. Khodaei and F. Naali, J. Org. Chem., 2008, 73, 6835. 7 N-Arylation of azoles for representative reviews, see: (a) F. Monnier and M. Taillefer, Angew. Chem., Int. Ed., 2009, 48, 6954; (b) J.-P. Corbet and G. Mignani, Chem. Rev., 2006, 106, 2651;
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9 10 11
12 13 14 15
(c) J. F. Hartwing, Synlett, 2006, 1283; (d) I. P. Beletskaya and A. V. Cheprakov, Coord. Chem. Rev., 2004, 248, 2337. N-Alkylation of azoles for representative reports, see: (a) S. Pan, J. Liu, H. Li, Z. Wang, X. Guo and Z. Li, Org. Lett., 2010, 12, 1932; (b) Q. Xue, J. Xie, P. Xu, K. Hu, Y. Cheng and C. Zhu, ACS Catal., 2013, 3, 1365; (c) Q. Xia, W. Chen and H. Qiu, J. Org. Chem., 2011, 76, 7577; (d) Q. Xia and W. Chen, J. Org. Chem., 2012, 77, 9366; (e) Q. Xue, J. Xie, H. Li, Y. Cheng and C. Zhu, Chem. Commun., 2013, 49, 3700; ( f ) X. Liu, G. Yu, J. Li, D. Wang, Y. Chen, K. Shi and B. Chen, Synlett, 2013, 1588. N-Acylation of azoles for representative reports, see: (a) M. Tang and F.-M. Zhang, Tetrahedron, 2013, 69, 1427; (b) S. K. Verma, B. N. Acharya and M. P. Kaushik, Org. Lett., 2010, 12, 4232. R. Samanta, K. Matcha and A. P. Antonchick, Eur. J. Org. Chem., 2013, 5769. (a) R. Lang, J. Wu, L. Shi, C. Xia and F. Li, Chem. Commun., 2011, 47, 12553; (b) C. Hou, Y. Ren, R. Lang, X. Hu, C. Xia and F. Li, Chem. Commun., 2012, 48, 5181; (c) Q. Xing, L. Shi, R. Lang, C. Xia and F. Li, Chem. Commun., 2012, 48, 11023; (d) R. Lang, L. Shi, D. Li, C. Xia and F. Li, Org. Lett., 2012, 14, 4094. P. Finkbeiner and B. J. Nachtsheim, Synthesis, 2013, 979. (a) W. Zhou, H. Li and L. Wang, Org. Lett., 2012, 14, 4594; (b) W. Adam and R. S. Oestrich, J. Am. Chem. Soc., 1993, 115, 3455; (c) Q. Zhao, H. Li and L. Wang, Org. Biomol. Chem., 2013, 11, 6772. Y. Zhu and Y. Wei, RSC Adv., 2013, 3, 13668. The acyl radicals generated from aliphatic aldehydes could not be captured by TEMPO, possibly suggesting the aliphatic aldehyde undergoes a different reaction mechanism from that of its aromatic analogues.
Chem. Commun.
ChemComm 16 Recently representative reports on a ‘‘I /TBHP’’ catalytic system, see: (a) Z. Liu, J. Zhang, S. Chen, E. Shi, Y. Xu and X. Wan, Angew. Chem., Int. Ed., 2012, 51, 3231; (b) W. Wei, C. Zhang, Y. Xu and X. Wan, Chem. Commun., 2011, 47, 10827; (c) L. Chen, E. Shi, Z. Liu, S. Chen, W. Wei, H. Li, K. Xu and X. Wan, Chem. – Eur. J., 2011, 17, 4085; (d) E. Shi, Y. Shao, S. Chen, H. Hu, Z. Liu, J. Zhang and X. Wan, Org. Lett., 2012, 14, 3384; (e) H. Li, J. Xie, Q. Xue, Y. Cheng and C. Zhu, Tetrahedron Lett., 2012, 53, 6479; ( f ) K. Xu, Y. Hu, S. Zhang, Z. Zha and Z. Wang, Chem. – Eur. J., 2012, 18, 9793; (g) Y. Yan, Y. Zhang, C. Feng, Z. Zha and Z. Wang, Angew. Chem., Int. Ed., 2012, 51, 8077; (h) W.-P. Mai, H.-H. Wang, Z.-C. Li, J.-W. Yuan, Y.-M. Xiao, L.-R. Yang, P. Mao and L.-B. Qu, Chem. Commun., 2012, 48, 10117; (i) Z.-Q. Lao, W.-H. Zhong, Q.-H. Lou, Z.-J. Li and X.-B. Meng, Org. Biomol. Chem., 2012, 10, 7869. 17 For a review of acyl radicals, see: C. Chatgilialoglu, D. Crich, M. Komatsu and I. Ryu, Chem. Rev., 1999, 99, 1991. 18 (a) H. Zhang, R. Shi, A. Ding, L. Lu, B. Chen and A. Lei, Angew. Chem., Int. Ed., 2012, 51, 12542; (b) A. Studer and D. P. Curran, Angew. Chem., Int. Ed., 2011, 50, 5018. 19 The intramolecular coupling of amines and acyl radicals, see: (a) Y. Uenoyama, T. Fukuyama, O. Nobuta, H. Matsubara and I. Ryu, Angew. Chem., Int. Ed., 2005, 44, 1075; (b) I. Ryu, T. Fukuyama, M. Tojino, Y. Uenoyama, Y. Yonamine and N. Terasoma, Org. Biomol. Chem., 2011, 9, 3780; (c) Y. Uenoyama, T. Fukuyama and I. Ryu, Org. Lett., 2007, 9, 935. 20 From amines to amino radical cations via a single electron transfer process, see: (a) C. Zhang, C. Tang and N. Jiao, Chem. Soc. Rev., 2012, 41, 3464; (b) F. Yang, J. Li, J. Xie and Z.-Z. Huang, Org. Lett., 2010, 12, 5214; (c) Z. Li and C.-J. Li, J. Am. Chem. Soc., 2004, 126, 11810; (d) Z. Li and C.-J. Li, J. Am. Chem. Soc., 2005, 127, 3672; (e) J.-S. Tian and T.-P. Loh, Chem. Commun., 2011, 47, 5458.
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Direct N-acylation of azoles via a metal-free catalyzed oxidative cross-coupling strategy† Jingjing Zhao,ab Pan Li,a Chungu Xiaa and Fuwei Li*a
Received 3rd March 2014, Accepted 18th March 2014 DOI: 10.1039/c4cc01587h www.rsc.org/chemcomm
The KI-catalyzed N-acylation of azoles via direct oxidative coupling of C–H and N–H bonds has been developed. It could be smoothly scaled up to gram synthesis of acyl azoles. The reaction occurred by the coupling of acyl radicals and azoles to form the acyl azole radical anion, followed by its further oxidation.
The amide unit is a key structural moiety in pharmaceuticals, natural products, polymers, and agrochemicals.1 Traditionally, the amides are often prepared from carboxylic acids or their activated analogues like acyl chlorides, anhydrides, and azides, etc.2 Recently, direct oxidative coupling of two different X–H (X = C, N, O) bonds has attracted much attention from the synthetic organic chemistry community.3 Especially, the oxidative cross-coupling between aldehydes and amines (including primary, secondary, and tertiary) was developed rapidly.4 This C–N bond formation occurred via a hemiaminal intermediate, followed by its oxidation (Scheme 1, path A). In addition, amidations of aldehydes with N-chloroamines were investigated.5 These processes were proposed to be involved in the coupling of acyl radicals and amino radical cations (Scheme 1, path B). Azoles are ubiquitous motifs in nature and exhibit potential biological activities and medicinal significance.6 Therefore, the
Scheme 1
Synthesis of amides from aldehydes.
a
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou, 730000, China. E-mail: [email protected]; Fax: +86-931-4968129 b Graduate University of Chinese Academy of Sciences, Beijing, 100049, China † Electronic supplementary information (ESI) available. See DOI: 10.1039/c4cc01587h
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development of new methods for the preparation of functional azoles is highly desirable in organic synthesis.7–9 Recently, with the increasing concerns on the development of practical and green methodology in synthetic chemistry, organic chemists have also paid much attention to screening non-metal catalysts to form C–N bonds.10 As our continuing interest on the development of new methods to prepare functionalized heterocycles,11 we herein report a KI-catalyzed N-acylation of azoles by an oxidative cross-coupling strategy. With this in mind, our initial investigation focused on the reaction of 3-phenyl-1H-pyrazole (1a) with 3,4-dimethoxybenzaldehyde (2a), selected results are summarized in Table 1. To our delight,
Table 1
Optimization of reaction conditionsa
Entry
Catalyst
Peroxide
Solvent
T (1C)
Yield (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14b 15b,c 16b,d 17b,e 18b,e 19b,e 20b,e
— TBAI NaI KI I2 KI KI KI KI KI KI KI KI KI KI KI CuI CuBr2 FeCl3.6H2O FeCl2.4H2O
TBHP TBHP TBHP TBHP TBHP DTBP TBPB H 2 O2 TBHP TBHP TBHP TBHP TBHP TBHP TBHP TBHP TBHP TBHP TBHP TBHP
DCE DCE DCE DCE DCE DCE DCE DCE Toluene Chlorobenzene H2O DCE DCE DCE DCE DCE DCE DCE DCE DCE
100 100 100 100 100 100 100 100 100 100 100 80 50 100 100 100 100 100 100 100
16 45 68 81 76 23 65 0 74 80 0 68 10 83 84 68 26 51 27 36
a
All reactions were carried out on a 0.3 mmol scale in 3 mL of solvent for 12 h. 1a/2a/peroxide = 1 : 2 : 4. Isolated yield. b 1.5 equiv. of aldehydes. c 3 equiv. of TBHP. d 2 equiv. of TBHP. e 10 mmol% catalyst.
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Table 2
KI-catalyzed N-acylation of pyrazolesa
ChemComm Table 3
KI-catalyzed N-acylation of other azolesa
a
A mixture of pyrazoles (0.3 mmol), aldehyde (0.45 mmol), KI (0.06 mmol), and TBHP (0.9 mmol) in 3 mL of DCE was stirred in 15 mL pressure tubes at 100 1C for 12 h. Isolated yields. a
the desired product 3a was obtained in 16% yield using tertbutylhydroperoxide (70% aqueous) as the oxidant (Table 1, entry 1). Upon using various iodides as the catalysts,12 KI showed the best activity (Table 1, entries 2–5). Similar to tert-butylhydroperoxide (TBHP), tert-butyl peroxide (DTBP) or tert-butyl peroxybenzoate (TBPB) was also effective for this reaction (Table 1, entries 6 and 7). However, H2O2 was an inactive oxidant for this transformation (Table 1, entry 8). Present acylation proceeded smoothly in toluene and chlorobenzene (Table 1, entries 9 and 10). Unfortunately, the reaction did not occur in H2O (Table 1, entry 11). In addition, the temperature variation could obviously affect the catalytic performance (Table 1, entries 12 and 13). Reducing the amount of aldehydes and TBHP (1.5 equiv. of aldehydes and 3 equiv. of TBHP) also worked efficiently, affording 84% yield of the desired product 3a (Table 1, entry 15). To our delight, the present KI catalyst showed much higher reactivity than the metallic copper and iron catalysts (Table 1, entries 17–20). With these satisfactory conditions in hand, we then turned to examine the scope of aldehydes and pyrazoles (Table 2). The benzaldehydes with electron-donating (OMe and tert-butyl) and -withdrawing groups (Cl, Br, F, and CN) all worked well with 3-phenyl pyrazole, affording the desired N-acyl pyrazoles in 51% to 95% yields, respectively (3b–j). Other representative aromatic aldehydes, such as 2-naphthaldehyde and thiophene-2-carbaldehyde, were also found to be suitable for this transformation (3k and l). To our delight, use of benzil instead of benzaldehyde also afforded the desired product 3b in 39% yield under the standard conditions.13 Furthermore, other pyrazoles could react with aldehydes to give the desired products in moderate yields (3m and n). Encouraged by the above results, we then extended the azole scope to other heterocycles bearing a N–H group (Table 3). The reactions of benzimidazole with benzaldehyde and its electrondonating substituted analogues proceeded efficiently, giving the expected products 5a, 5d, and 5f in 85% to 98% yields.
Chem. Commun.
A mixture of pyrazoles (0.3 mmol), aldehyde (0.45 mmol), KI (0.06 mmol), and TBHP (0.9 mmol) in 3 mL of DCE was stirred in 15 mL pressure tubes at 100 1C for 12 h. Isolated yields.
However, the benzaldehyde with electron-withdrawing substituents afforded 5b, 5c, 5e, and 5g in 24% to 78% yields. The N-acylation with other representative aromatic aldehydes such as 2-naphthaldehyde and thiophene-2-carbaldehyde also worked well and provided the products 5h and 5i in 76% and 55% yields, respectively. For benzotriazole, surprisingly, only benzaldehyde and its ortho-substituted analogues were fit for this procedure, and the aromatic aldehydes with para-substitutions only gave the corresponding tert-butyl esters (5j–5n).14 Moreover, the indazole was also found to be suitable for this catalytic system and provided the corresponding product 5o in 44% yield. Regretfully, aliphatic aldehydes (such as 3-phenylpropanal, cyclohexanealdehyde and pivalaldehyde) were not suitable for our system (ESI,† eqn (S1) and (S2)).15 In order to prove the practicality of this approach, a gram-scale synthesis of the N-benzoyl benzoimidazole 5a (3.77 g, 85% yield) was performed, suggesting that such a new and facile methodology could also be efficiently scaled up (Scheme 2). To validate the proposed mechanism, a series of control experiments were carried out. The addition of TEMPO (2,2,6,6tetramethylpiperidinooxy) prevented the reaction and product 6 generated from the coupling of acyl radical and TEMPO was obtained in a near quantitative yield (Scheme 3, a). Additionally, the reaction was also inhibited by another radical scavenger,
Scheme 2
Gram scale synthesis of N-benzoyl benzoimidazole.
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Scheme 3
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Radical trapping experiments.
1,1-diphenylethylene (Scheme 3, b). Besides, upon using benzil instead of benzaldehyde, product 3b was also not detected when TEMPO was added (Scheme 3, c). All these results suggested that an acyl radical intermediate was involved in the present catalytic cycle. On the other hand, some control experiments with respect to the previous reported N-acylation of primary and secondary aliphatic amines were also performed (ESI,† eqn (S3)–(S6)).3b,c The addition of TEMPO inhibited these N-acylations. Interestingly, the imine product was observed in the reaction of aldehydes and primary amines, which was generated from the dehydration of a hemiaminal intermediate, suggesting again that the reported N-acylation reactions occur via a hemiaminal intermediate followed by its further oxidation which may involve a radical process. Therefore, our method is much different from the reported procedures in terms of the mechanism and the reaction process. Correspondingly, the reported procedures did not work for the present N-acylation of azoles with aldehydes (ESI,† eqn (S7) and (S8)). It has been reported that the amides are formed from aldehydes and amines via N-chloroamine intermediates,5 which reminded us that such transformation might be via a N-iodineazole intermediate in our oxidation system. Subsequently, some control experiments were carried out (ESI,† eqn (S9)–(S11)). However, N-iodineazole was not detected. Therefore, the possibility via a N-iodineazole intermediate was ruled out in the present N-acylation reaction. Based on the above control experiments, a proposed mechanism is shown in Scheme 4. Initially, the tert-butoxyl and tert-butylperoxy radicals were generated in the catalytic system,16 and they could abstract a hydrogen atom from aldehydes to generate the acyl radical A,17 which reacted with azole to give the acyl azole radical anion B,18 followed by a SET process by losing an electron with the assistance of tert-butoxyl or tert-butylperoxy radicals to afford the desired N-acyl azoles (Scheme 4, path A).19 On the other hand, the tert-butoxyl and tert-butylperoxy radicals could capture a single electron from azoles to form azole radical cation species C1,20 which could also convert to azole radical C2 via a deprotonation reaction with the assistance of the tert-butoxyl anion. Ultimately, the acyl radical A and azole radical cation C1 or azole radical C2 were coupled to provide the desired amide (Scheme 4, path B). Although the acyl radical was captured, the coupling of TEMPO and radical C1 or C2 was not detected. Therefore, present N-acylation was preferred to react following the path A, however, the possibility via path B was not excluded. According to our
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Scheme 4
Plausible reaction mechanism.
proposed mechanism, theoretically, present N-acylation needs two equiv. of the oxidant. In summary, we have developed a KI-catalyzed N-acylation of azoles using aldehydes as the acyl sources. Different from the synthesis of amides from aliphatic amines using aldehydes via a nucleophilic addition/oxidation mechanism, the present catalytic cycle appears to involve the coupling of the acyl radical intermediate and azole. Interestingly, such transformation was tolerant with different azoles and could be efficiently scaled up. The reactions of acyl radicals with other coupling partners are under investigation in our laboratory. Financial support from the Chinese Academy of Sciences and the National Natural Science Foundation of China (21002106, 21133011 and 21373246) is gratefully acknowledged.
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ChemComm 16 Recently representative reports on a ‘‘I /TBHP’’ catalytic system, see: (a) Z. Liu, J. Zhang, S. Chen, E. Shi, Y. Xu and X. Wan, Angew. Chem., Int. Ed., 2012, 51, 3231; (b) W. Wei, C. Zhang, Y. Xu and X. Wan, Chem. Commun., 2011, 47, 10827; (c) L. Chen, E. Shi, Z. Liu, S. Chen, W. Wei, H. Li, K. Xu and X. Wan, Chem. – Eur. J., 2011, 17, 4085; (d) E. Shi, Y. Shao, S. Chen, H. Hu, Z. Liu, J. Zhang and X. Wan, Org. Lett., 2012, 14, 3384; (e) H. Li, J. Xie, Q. Xue, Y. Cheng and C. Zhu, Tetrahedron Lett., 2012, 53, 6479; ( f ) K. Xu, Y. Hu, S. Zhang, Z. Zha and Z. Wang, Chem. – Eur. J., 2012, 18, 9793; (g) Y. Yan, Y. Zhang, C. Feng, Z. Zha and Z. Wang, Angew. Chem., Int. Ed., 2012, 51, 8077; (h) W.-P. Mai, H.-H. Wang, Z.-C. Li, J.-W. Yuan, Y.-M. Xiao, L.-R. Yang, P. Mao and L.-B. Qu, Chem. Commun., 2012, 48, 10117; (i) Z.-Q. Lao, W.-H. Zhong, Q.-H. Lou, Z.-J. Li and X.-B. Meng, Org. Biomol. Chem., 2012, 10, 7869. 17 For a review of acyl radicals, see: C. Chatgilialoglu, D. Crich, M. Komatsu and I. Ryu, Chem. Rev., 1999, 99, 1991. 18 (a) H. Zhang, R. Shi, A. Ding, L. Lu, B. Chen and A. Lei, Angew. Chem., Int. Ed., 2012, 51, 12542; (b) A. Studer and D. P. Curran, Angew. Chem., Int. Ed., 2011, 50, 5018. 19 The intramolecular coupling of amines and acyl radicals, see: (a) Y. Uenoyama, T. Fukuyama, O. Nobuta, H. Matsubara and I. Ryu, Angew. Chem., Int. Ed., 2005, 44, 1075; (b) I. Ryu, T. Fukuyama, M. Tojino, Y. Uenoyama, Y. Yonamine and N. Terasoma, Org. Biomol. Chem., 2011, 9, 3780; (c) Y. Uenoyama, T. Fukuyama and I. Ryu, Org. Lett., 2007, 9, 935. 20 From amines to amino radical cations via a single electron transfer process, see: (a) C. Zhang, C. Tang and N. Jiao, Chem. Soc. Rev., 2012, 41, 3464; (b) F. Yang, J. Li, J. Xie and Z.-Z. Huang, Org. Lett., 2010, 12, 5214; (c) Z. Li and C.-J. Li, J. Am. Chem. Soc., 2004, 126, 11810; (d) Z. Li and C.-J. Li, J. Am. Chem. Soc., 2005, 127, 3672; (e) J.-S. Tian and T.-P. Loh, Chem. Commun., 2011, 47, 5458.
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