Organocatalytic Para-Selective Amination of Phenols with

Letter pubs.acs.org/OrgLett

Organocatalytic Para-Selective Amination of Phenols with Iminoquinone Monoacetals Liu Liu,† Kun Chen,† Wen-Zhen Wu, Peng-Fei Wang, Hang-Yu Song, Hongbin Sun, Xiaoan Wen,* and Qing-Long Xu* Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China S Supporting Information *

ABSTRACT: A highly selective para C−H amination of unprotected phenols with iminoquinone acetals was realized, giving the functional phenols in good to excellent yields. Overall, this transformation is operationally simple, proceeds with readily available phenols, and has wide substrate scope and low catalyst loading. The biarylamine product is stochastically formed via [5,5]-sigmatropic rearrangement of a mixed acetal species which is generated in situ under the reaction conditions.

S

ite-selective C(sp2)−H functionalizations of monosubstituted benzenes have attracted considerable interest from the organic community since they provide rapid and straightforward access to many structurally different analogues. Its importance in the late-stage modification of pharmaceutically active molecules is especially noteworthy.1 The development of direct C−H functionalization approaches of unprotected phenols has received significant attention in recent years2 due to their wide occurrence in natural products and medicinal drugs. They also serve as common and versatile building blocks involved in numerous organic reactions.3 Over the past decade, the indirect ortho-selective C−H functionalization of phenols has been extensively investigated by installing the directing group on the hydroxyl group.4 On the other hand, the development of new methods for site-selective direct C−H functionalization of unprotected phenols is highly interesting but more challenging, since the unprotected phenols contain several possible reaction sites. Thus far, only limited approaches to site-selective C−H functionalization of unprotected phenols have been reported. Among the reported examples, the paraselective C−H functionalization of unprotected phenols was focused on C−C bond couplings (Figure 1). In 2011, Gaunt’s group developed a highly para-selective copper-catalyzed direct arylation of unprotected phenol, but with low yield.5 Later, Zhang and co-workers reported highly para-selective direct C− H bond functionalization of unprotected phenols with α-aryl αdiazoacetates via gold catalysis.6 Recently, Wu and co-workers realized para-selective direct C−C bond couplings reaction between phenols and acetophenones, affording 4-hydroxybenzil derivatives.7 Kita and co-workers reported para-selective direct C−C bond cross-couplings of quinone monoacetal with phenols.8 Given the importance of phenolic compounds, the development of novel approaches to para-selective direct C−H functionalization of unprotected phenols is highly desirable, © 2017 American Chemical Society

Figure 1. Para-selective C−H functionalization of phenols.

especially C−H amination. Until now, only electrophilic amination of unprotected phenol was realized, but with low site selectivity.9 As part of our interest in developing siteselective direct C−H functionalization of unprotected phenols via rearrangement, we recently utilized iminoquinones as arylating reagents to give access to chiral non-C2-symmetric BINOL-type biaryls from 2-naphthols.10 Encouraged by this result, we envisioned that using new iminoquinone acetal structures might lead to the para-selective C−H amination of phenols via [5,5]-rearrangement.11 This constitutes a novel Received: June 6, 2017 Published: July 11, 2017 3823

DOI: 10.1021/acs.orglett.7b01700 Org. Lett. 2017, 19, 3823−3826

Letter

Organic Letters approach to para-selective C−H functionalization of unprotected phenol, and it is completely different from the reported examples. On the basis of our previous work, we selected N-Msprotected iminoquinone acetal (2a) as the substrate that reacted with 1-naphthol (1a). Gladly, a 10 mol % loading of TsOH·H2O catalyzed the para-selective C−H amination of 1a with 2a under mild conditions (room temperature) to afford the desired amination product (3aa) in 31% yield. The structure of 3aa was confirmed by single-crystal X-ray crystallography (see the Supporting Information for details).12 Encouraged by this interesting result, we investigated different acids to optimize the reaction condition further, and the results are summarized in Table 1. DPP was found to be the best

Table 2. Examination of Different Iminoquinone Monoacetalsa

Table 1. Reaction Optimizationa

entry

acid

solvent

yieldb (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15c 16d 17e 18f 19g 20h

Sc(OTf)3 AlCl3 PhCO2H p-NO2C6H4CO2H TsOH·H2O TFA DPP DPP DPP DPP DPP DPP DPP DPP DPP DPP DPP DPP DPP DPP

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CHCl3 DCE THF MeCN toluene MeOH DMF CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2

61 48 34 77 31 86 93 83 92 89 74 61 74 0 85 86 89 94 83 98

entry

2

3

time (h)

yieldb (%)

1 2 3 4 5 6 7 8 9

2a 2b 2c 2d 2e 2f 2g 2h 2i

3aa 3ab 3ac 3ad 3ae 3af 3ag 3ah 3ai

2 2 168 2 2 2 2 2 2

98 trace 20 80 88 76 85 97 70

a Reaction conditions: 1a (1.2 equiv), 2 (0.2 mmol), DPP (1 mol %), CH2Cl2 (3.0 mL), rt. bIsolated yield.

substituents on the iminoquinone ring and nitrogen atom of acetal 2 were evaluated. It was found that compound 2b without substitution on the iminoquinone ring was unstable and easy to be hydrolyzed. When 3,5-dimethyl-substituted acetal (2c) was employed for this reaction, the desired product was obtained in only 20% yield even with longer reaction time, probably due to its steric hindrance (entry 3, Table 2), and 2,3dimethyl-substituted acetal (2d) with less steric hindrance afforded the desired product in 80% yield (entry 4, Table 2). The monosubstituted acetals (2e and 2f) were found to react smoothly with 1-naphthol to furnish the corresponding products in acceptable yields. Moreover, acetals (2g and 2h) with electron-withdrawing groups (Boc and Ts) adjacent to the nitrogen atom were found to be good substrates for this transformation, affording the desired products in 85% and 97% yields, respectively (entries 7 and 8, Table 2). It is noted that 1naphthol-derived iminoquinone acetal (2i) could be also introduced to this transformation, affording the desired product 3ai in 70% yield (entry 9, Table 2). Subsequently, a variety of substituted 1-naphthols (1) were evaluated in the reaction with 2a, and the results are summarized in Scheme 1. When the methyl group was introduced at the β-position of 1-naphthol (1b), the reaction proceeded smoothly, giving the amination product in 73% yield. Electron-donating (3-Me, 6-OMe, 7-Ph) or electronwithdrawing groups (7-Br) on the aryl ring were well tolerated, and the corresponding products were obtained in excellent yields (89−95%, 3ca−fa). Notably, reaction of naphthalene1,8-diol (1g) with 2a provided the corresponding product (3ga) in 65% yield. Interestingly, reaction of 4-methyl-1naphthol (1k) possessing a blocked para-position afforded ortho-amination product (3ka), albeit in low yield (36%).

a

Reaction conditions: 1a (1.5 equiv), 2a (0.2 mmol), acid (10 mol %), solvent (3.0 mL), rt. bIsolated yield. cUsing DPP (5 mol %). dUsing DPP (2 mol %). eUsing DPP (1 mol %). fUsing 1a (1.2 equiv). gUsing 1a (1.0 equiv). hReacted at 0 °C, using 1a (1.2 equiv) and DPP (1 mol %). TFA = trifluoroacetic acid. DPP = diphenyl phosphate.

organocatalyst, giving the amination product in 93% yield (entry 7, Table 1). Subsequently, common solvents were evaluated in this transformation, and we found that most of the solvents could be applied to the reaction, except DMF (entry 14, Table 1). CH2Cl2 was chosen as the optimal solvent due to its simplicity for the operation. It was found that 1.2 equiv of 1a and 1 mol % of DPP were sufficient for this transformation. When the reaction was performed at 0 °C, the reaction proceeded smoothly to give the product in high yield (entry 20, Table 1). With the optimal conditions in hand, we then examined the generality of this para-selective C−H amination reaction. First, the reaction of various iminoquinone acetals (2) with 1a was investigated. The results are summarized in Table 2. Different 3824

DOI: 10.1021/acs.orglett.7b01700 Org. Lett. 2017, 19, 3823−3826

Letter

Organic Letters Scheme 1. Substrate Scope of Substituted 1-Naphtholsa

providing moderate to excellent yields of the corresponding C− H amination products (5a−o) in a regioselective manner. Different electron-withdrawing and electron-donating substituents were well tolerated in this transformation. However, the substrates with electron-withdrawing groups provided the desired products in lower yields (e.g., 2,6-Cl2, 57%; 2-Br, 81%). It is noteworthy that the reaction of 3,5-dimethoxyl phenol (4d) bearing a sterically hindered para C−H bond still furnished the corresponding para C−H amination product (5d) in 76% yield. Thymol (4l) and carvacrol (4m), two small naturally occurring phenols, were evaluated in this transformation, affording the desired products in 60% and 81% yield, respectively. The reaction seems to tolerate the substrates bearing dihydroxy groups such as catechol (4n) and resorcinol (4o), leading to the direct para C−H amination products in good yields (5n, 89% and 5o, 78%). Furthmore, the selective ortho C−H amination products were obtained when substituted 2-naphthols (6) were employed in the reaction as shown in Scheme 3. The reaction of 6 with 2,5-dimethyliminoquinone acetal (2a) produced the corresponding ortho C−H amination products in moderate yields (44−60% yields).

a Reaction conditions: 1 (1.2 equiv), 2a (0.2 mmol), DPP (1 mol %), CH2Cl2 (3.0 mL), rt.

Scheme 3. Substrate Scope of Substituted Phenolsa

Next, the reactions of various substituted phenols (4a−o) with 2,5-dimethyliminoquinone acetal (2a) were then examined. As shown in Scheme 2, the reactions proceeded smoothly, Scheme 2. Substrate Scope of Substituted Phenolsa

a Reaction conditions: 6 (1.2 equiv), 2a (0.2 mmol), DPP (1 mol %), CH2Cl2 (3.0 mL), rt.

Notably, the DPP-catalyzed selective para C−H amination of unprotected phenols was practical for scale-up. A gram-scale reaciton of 4h (1.0 g) and 2a proceed smoothly with only low catalyst loading (1 mol %), giving the desired product (5h) in 95% yield (Scheme 4). Importantly, the product (5h) could be Scheme 4. Gram-Scale Preparation of Product 5h and Transformation

easily converted to carbazole derivative (9) in two steps (protected hydroxy group and Pd-catalyzed C−H fuctionalization) in moderate yield. On the basis of previous studies,10 a probable reaction pathway of this transformation is illlustrated in Scheme 5. 2,5Dimethyliminoquinone acetal (2a) is converted to Int-1 or Int2 under acid condition. For pathway (a), the acetal exchange reaction occurs, leading to the mixed acetal Int-1 that

a

Reaction conditions: 4 (1.2 equiv), 2a (0.2 mmol), DPP (1 mol %), CH2Cl2 (3.0 mL), rt. 3825

DOI: 10.1021/acs.orglett.7b01700 Org. Lett. 2017, 19, 3823−3826

Letter

Organic Letters

State Administration of Foreign Expert Affairs of China (No. 111-2-07) and program for Changjiang Scholars and Innovative Research Team in University (IRT1193), Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University (No. SKLNMZZYQ201607), and the Program for Jiangsu Province Innovative Research Team.

Scheme 5. Proposed Mechanism

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(1) (a) Dey, A.; Maity, S.; Maiti, D. Chem. Commun. 2016, 52, 12398. (b) Wencel-Delord, J.; Glorius, F. Nat. Chem. 2013, 5, 369. (2) Selected examples, see: (a) Bedford, R. B.; Coles, S. J.; Hursthouse, M. B.; Limmert, M. E. Angew. Chem., Int. Ed. 2003, 42, 112. (b) Ghosh, S.; Kinthada, L. K.; Bhunia, S.; Bisai, A. Chem. Commun. 2012, 48, 10132. (c) Luo, J.; Preciado, S.; Larrosa, I. J. Am. Chem. Soc. 2014, 136, 4109. (3) Tyman, J. H. P. Synthetic and Natural Phenols; Elsevier, 1996. (4) For selected recent examples, see: (a) Boebel, T. A.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 7534. (b) Zhao, X.; Yeung, C. S.; Dong, V. M. J. Am. Chem. Soc. 2010, 132, 5837. (c) Xiao, B.; Fu, Y.; Xu, J.; Gong, T.-J.; Dai, J.-J.; Yi, J.; Liu, L. J. Am. Chem. Soc. 2010, 132, 468. (d) Huang, C.; Chattopadhyay, B.; Gevorgyan, V. J. Am. Chem. Soc. 2011, 133, 12406. (e) Dai, H.-X.; Li, G.; Zhang, X.-G.; Stepan, A. F.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135, 7567. (f) Luo, S.; Luo, F.-X.; Zhang, X.-S.; Shi, Z.-J. Angew. Chem., Int. Ed. 2013, 52, 10598. (5) Ciana, C.-L.; Phipps, R. J.; Brandt, J. R.; Meyer, F.-M.; Gaunt, M. J. Angew. Chem., Int. Ed. 2011, 50, 458. (6) (a) Yu, Z.; Ma, B.; Chen, M.; Wu, H.-H.; Liu, L.; Zhang, J. J. Am. Chem. Soc. 2014, 136, 6904. (b) Xi, Y.; Su, Y.; Yu, Z.; Dong, B.; McClain, E. J.; Lan, Y.; Shi, X. Angew. Chem., Int. Ed. 2014, 53, 9817. (7) Xiang, J.-C.; Cheng, Y.; Wang, M.; Wu, Y.-D.; Wu, A.-X. Org. Lett. 2016, 18, 4360. (8) Kamitanaka, T.; Morimoto, K.; Tsuboshima, K.; Koseki, D.; Takamuro, H.; Dohi, T.; Kita, Y. Angew. Chem., Int. Ed. 2016, 55, 15535. (9) (a) Yadav, J. S.; Reddy, B. V. S.; Veerendhar, G.; Srinivasa Rao, R.; Nagaiah, K. Chem. Lett. 2002, 31, 318. (b) Leblanc, Y.; Boudreault, N. J. Org. Chem. 1995, 60, 4268. (c) Gu, L.; Neo, B. S.; Zhang, Y. Org. Lett. 2011, 13, 1872. (d) Inamdar, S. M.; More, V. K.; Mandal, S. K. Tetrahedron Lett. 2013, 54, 530. (e) Alisi, M. A.; Brufani, M.; Cazzolla, N.; Ceccacci, F.; Dragone, P.; Felici, M.; Furlotti, G.; Carofalo, B.; La Bella, A.; Lanzalunga, O.; Leonelli, F.; Berrolo, R. M.; Maugeri, C.; Migneco, L. M.; Russo, V. Tetrahedron 2012, 68, 10180 and references cited therein. (10) (a) Wang, J.-Z.; Zhou, J.; Xu, C.; Sun, H.; Kürti, L.; Xu, Q.-L. J. Am. Chem. Soc. 2016, 138, 5202. (b) Gao, H.; Xu, Q.-L.; Keene, C.; Yousufuddin, M.; Ess, D. H.; Kürti, L. Angew. Chem., Int. Ed. 2016, 55, 566. (11) (a) Hofmann, A. W. Proc. R. Soc. London 1862, 12, 576. (b) Endo, Y.; Terashima, T.; Shudo, K. Tetrahedron Lett. 1984, 25, 5537. (c) Beno, B. R.; Fennen, J.; Houk, K. N.; Lindner, H. J.; Hafner, K. J. Am. Chem. Soc. 1998, 120, 10490. (d) Kang, H.-M.; Lim, Y.-K.; Shin, I.-J.; Kim, H.-Y.; Cho, C.-G. Org. Lett. 2006, 8, 2047. (e) Kim, H.-Y.; Lee, W.-J.; Kang, H.-M.; Cho, C.-G. Org. Lett. 2007, 9, 3185. (12) CCDC 1540340 (3aa) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam. ac.uk/data_request/cif. (13) When electron-rich nucleophiles 1-methoxynaphthalene and N,N-dimethyl-1-naphthylamine were employed to this transformation, no reaction occurred, since they cannot generate the mixed acetal intermediate.

undergoes [5,5]-rearrangement under acidic conditions, and subsequent rearomatization gives rise to the para-amination product. In another alternative reaction pathway (b), 1naphthol nucleophilic captures the dication intermediate Int2, giving the desired product. However, this reaction pathway cannot account for the nonreactivity of 1-methoxynaphthalene and N,N-dimethyl-1-naphthylamine.13 Thus, the mechanistic proposal of the mixed acetal/[5,5]-sigmatropic rearrangement sequence is more reasonable. In summary, we present here a novel direct and selective para C−H amination of unprotected phenols with iminoquinone acetals catalyzed by simple Brønsted acid, leading to the functionalized phenols in good to excellent yields. We propose a novel mechanism of this transformation via [5,5]-rearrangement. The remarkable features of this reaction include readily available starting materials, wide substrate scope, mild conditions, simple acid catalyst, and low catalyst loading.

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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.7b01700. Detailed experimental procedures and spectral data for all new compounds (PDF) Crystallographic data for compounds 3aa (CIF)

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REFERENCES

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Hongbin Sun: 0000-0002-3452-7674 Xiaoan Wen: 0000-0001-7852-1154 Qing-Long Xu: 0000-0003-4450-6866 Author Contributions †

L.L. and K.C. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from National Natural Science Foundation of China (Grant Nos. 81473080, 81573299, and 21502230) is gratefully acknowledged. This project was also supported by the Jiangsu Province Natural Science Foundation (BK20150688), the “111 Project” from the Ministry of Education of China, the 3826

DOI: 10.1021/acs.orglett.7b01700 Org. Lett. 2017, 19, 3823−3826