Fe(III)-mediated isomerization of α,α-diarylallylic alcohols to ketones via radical 1,2-aryl migration

Abstract

An Fe(III)-mediated radical 1,2-aryl migration of α,α-diarylallylic alcohols for the isomerization to ketones is described. The Fe(acac)₃–silane would convert the alkene to an alkyl radical and initiates a 1,2-aryl migration-oxidation process. Thus Fe(acac)₃ serves as an olefin hydrogen atom transfer initiator and oxidant, while various allylic alcohols could isomerize to ketones in moderate to good yields.

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Recently, the Fe(III)-catalyzed radical olefin hydrofunctionalization has become a versatile and efficient method in C–C and C–N bond formation.¹ The seminal work reported by Mukaiyama concerned the hydroamination of unactivated alkenes.² In recent years, Baran has contributed elegant work on Fe(III)-catalyzed olefin reductive coupling and hydroamination, which exhibited remarkable synthetic utility in medicinal chemistry.³ Meanwhile, Boger and Shen independently developed the valuable hydrofluorination and hydrotrifluoromethylthiolation of unactivated alkenes.^4,5 While the mechanism of Fe(III)-catalyzed olefin hydrofunctionalization refers to a hydrogen atom transfer (HAT) radical process, Shenvi applied this protocol to the arylation of isopulegol for accessing privileged 8-arylmenthols using Mn(dpm)₃ as a catalyst.⁶ Therefore, the development of Fe(III)-catalyzed radical olefin hydrofunctionalization with new modes of C–C bond formation remains of continuous interest and importance in organic synthesis.

The α,α-diarylallylic alcohols are a typical class of compounds which could undergo intermolecular radical neophyl rearrangements. Recently, the reports concerning the functionalization of α,α-diarylallylic alcohols via radical pathway has been investigated to incorporate CF₃,⁷ CN,⁸ alkyl,⁹ difluoroalkyl,¹⁰ silyl,¹¹ phosphonates,¹² phosphonyl,¹³ and sulfone¹⁴ groups to ketones (Scheme 1, eqn (1)). During the course of our efforts in Fe(III)-catalyzed alkene functionalization,¹⁵ we proposed that the HAT of α,α-diarylallylic alcohols could generate alkyl radical, which would probably undergo sequential aryl migration to deliver interesting compounds. Herein, we report a Fe(III)-mediated isomerization of α,α-diarylallylic alcohols to ketones via radical 1,2-aryl migration (Scheme 1, eqn (2)).

Scheme 1 Radical 1,2-aryl migration of α,α-diarylallylic alcohols.

We commenced our study by investigating diphenylallyl alcohol 1a using Fe(acac)₃ as catalyst and phenylsilane as the reductant in ethanol at 60 °C. Gratifyingly, an isomerization ketone product 2a was obtained in 40% yield and diphenyl ketone 3a was obtained in 30% yield (Table 1, entry 1). This result indicated that the aryl migration did occur, and the ketone moiety should be attributed to an oxidation process. We next screened the solvents, such as THF and TFE, and found inferior to generate only trace amount of 2a (entries 2–3). The attempt to use 0.5 equivalent amount of Fe(acac)₃ gave a yield increasement of 2a to 47% yield, and the formation of 3a could be dramatically suppressed to trace amount (entry 4). The next 1 equivalent amount addition of Fe(acac)₃ was found to improve the yield significantly to 81% (entry 5), while further increasing the amount of Fe(acac)₃ could slightly improve the yield (entries 6–7). The variation of solvent to THF was also effective but to give a lower yield (entry 9).

Table 1 Optimization of reaction conditions^a

Entry	Amount of Fe(acac)3	Solvent	t (°C)	Yield^b (%)
				2a	3a
a Reaction conditions: 1a (0.2 mmol), PhSiH3 (0.4 mmol), solvent (2 mL), 2 h.b Isolated yields.c EtOH (2 equiv.) was added as additive.d TFE = trifluroethyl alcohol.e (CH2OH)2 (2 equiv.) was added as additive.
1	10 mol%	EtOH	60	40	30
2	10 mol%	THF^c	60	Trace	Trace
3	10 mol%	TFE^d	60	Trace	85
4	0.5 equiv.	EtOH	60	47	Trace
5	1 equiv.	EtOH	60	81	Trace
6	2 equiv.	EtOH	60	87	Trace
7	3 equiv.	EtOH	60	87	Trace
8	1 equiv.	THF^e	60	65	Trace

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With the optimized reaction in hand, we set out to explore the substrate scope of this isomerization transformation (Table 2). Various symmetrical α,α-diarylallylic alcohols could react smoothly in this process to deliver the isomerization ketone products in good yields (2b–2f), with valuable substitution like methyl, methoxy, fluoro, chloro and bromo. Respecting to those unsymmetrical α,α-diarylallyl alcohols, the literatures revealed that the aryl group radical migration occurs depend on the electronic properties and steric hindrance.^7–13 The electron-withdrawing group substituted aromatic rings were favored in migration, and the migration reactivity decreased from para-substitution to meta-substitution to ortho-substitution.^7–13 In this isomerization protocol, we found the same migration rule. For example, the alcohols 1g–1j with a Ph group and an electron-deficient aromatic ring, could isomerize to the sole ketones (2g–2j) with substituted electron-deficient aromatic ring migration. And the functional group like CN, CF₃ and pyridine ring were well amenable in this process. Respecting to alcohols 1k–1m, the two aromatic rings were both substituted, and the electron-deficient rings were also prior to electron-rich and ortho-substituted aromatic rings, furnishing the products in good yields (2k–2m). Morever, when the two aromatic rings did not have significant difference in electron property and steric hindrance (1n–1s), the isomerization process furnished two ketone products (2n–2s) and the major products were predictable to well follow the migration rule.

Table 2 Substrate scope^a

a Reaction conditions: 1 (0.2 mmol), Fe(acac)₃ (0.4 mmol), PhSiH₃ (0.4 mmol), EtOH (2 mL), 2 h, isolated yields are shown.b The ratio refers to isolated yields.

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Next, a variety of α,α-diaryl 2-methylallyl alcohols were also investigated in this protocol to deliver the 2,2-dimethyl diarylethanones in good to excellent yields (Scheme 2). And the aryl migration rule was also well obeyed. For example, the 4-cyanophenyl ring of alcohol 1u underwent migration to furnish the sole product 3b, and the 3,4-dichlorophenyl ring of alcohol 1v underwent isomerization to give 3c as major product.

Scheme 2 Scope of α,α-diaryl 2-methylallyl alcohols.

Based on these results and literatures,^7–16 a possible reaction mechanism was proposed in Scheme 3. At the beginning, the Fe(acac)₃ would convert to Fe hydride species A in the presence of phenylsilane and ethanol. Then A regioselectively adds to allylic alcohols 1 to form intermediate B, which dissociates quickly to form radical C. At this stage, a 1,2-migration of aryl group occurs via spiro[2,5]octadienyl radical D to produce E. E is further oxidized by additional Fe(acac)₃ to furnish the final ketone product. Definitely, Fe(acac)₃ served both as olefin hydrogen atom transfer initiator and oxidant. Therefore the equivalent amount use of Fe(acac)₃ would facilitate this isomerization process.

Scheme 3 Proposed mechanism.

In conclusion, we have developed a Fe(III)-mediated isomerization of α,α-diarylallylic alcohols to ketones via radical 1,2-aryl migration. The migration rule was clear and the isomerization products were predictable. Morever, the Fe(acac)₃ served both as olefin hydrogen atom transfer initiator and oxidant.

Acknowledgements

We acknowledge for the financial support from NSFC (21472163).

Notes and references

1. M. Villa and A. Jacobi vonWangelin, Angew. Chem., Int. Ed., 2015, 54, 11906.
2. K. Kato and T. Mukaiyama, Chem. Lett., 1992, 1137.
3. (a) J. Gui, C.-M. Pan, Y. Jin, T. Qin, J. C. Lo, B. J. Lee, S. H. Pergel, M. E. Mertzman, W. J. Pitts, T. E. L. Cruz, A. M. Schmidt, N. Darvatkar, S. R. Natarajan and P. S. Baran, Science, 2015, 348, 886; (b) J. C. Lo, Y. Yabe and P. S. Baran, J. Am. Chem. Soc., 2014, 136, 1304; (c) J. C. Lo, J. Gui, Y. Yabe, C.-M. Pan and P. S. Baran, Nature, 2014, 516, 343; (d) H. T. Dao, C. Li, Q. Michaudel, B. D. Maxwell and P. S. Baran, J. Am. Chem. Soc., 2015, 137, 8046.
4. T. J. Barker and D. L. Boger, J. Am. Chem. Soc., 2012, 134, 13588.
5. T. Yang, L. Lu and Q. Shen, Chem. Commun., 2015, 51, 5479.
6. S. W. M. Crossley, R. M. Martinez, S. Guevara-Zuluaga and R. A. Shenvi, Org. Lett., 2016, 18, 2620.
7. (a) Z. M. Chen, W. Bai, S. H. Wang, B. M. Yang, Y. Q. Tu and F. M. Zhang, Angew. Chem., Int. Ed., 2013, 52, 9781; (b) H. Egami, R. Shimizu, Y. Usui and M. Sodeoka, Chem. Commun., 2013, 49, 7346; (c) X. Liu, F. Xiong, X. Huang, L. Xu, P. Li and X. Wu, Angew. Chem., Int. Ed., 2013, 52, 6962.
8. (a) A. Bunescu, Q. Wang and J. Zhu, Angew. Chem., Int. Ed., 2015, 54, 3132; (b) Y. Li, B. Liu, H.-B. Li, Q. Wang and J.-H. Li, Chem. Commun., 2015, 51, 1024.
9. (a) Y. Yu and U. K. Tambar, Chem. Sci., 2015, 6, 2777; (b) J. Zhao, H. Fang, R. Song, J. Zhou, J. Han and Y. Pan, Chem. Commun., 2015, 51, 599; (c) X.-Q. Chu, H. Meng, Y. Zi, X.-P. Xu and S.-J. Ji, Chem.–Eur. J., 2014, 20, 17198; (d) R.-J. Song, Y.-Q. Tu, D.-Y. Zhu, F.-M. Zhang and S.-H. Wang, Chem. Commun., 2015, 51, 749; (e) W. Hu, S. Sun and J. Cheng, J. Org. Chem., 2016, 81, 4399; (f) P. Xu, K. Hu, Z. Gu, Y. Cheng and C. Zhu, Chem. Commun., 2015, 51, 7222.
10. H. Peng, J.-T. Yu, Y. Jiang and J. Cheng, Org. Biomol. Chem., 2015, 13, 10299.
11. X. Mi, C. Wang, M. Huang, Y. Wu and Y. Wu, Org. Biomol. Chem., 2014, 12, 8394.
12. X.-Q. Chu, Y. Zi, H. Meng, X.-P. Xu and S.-J. Ji, Chem. Commun., 2014, 50, 7642.
13. X.-Q. Chu, H. Meng, X.-P. Xu and S.-J. Ji, Chem.–Eur. J., 2015, 21, 11359.
14. (a) J. Zheng, D. Wang and S. Cui, Org. Lett., 2015, 17, 4572; (b) J. Zheng, J. Qi and S. Cui, Org. Lett., 2016, 18, 128; (c) Y. Shen, J. Qi, Z. Mao and S. Cui, Org. Lett., 2016, 18, 2722.
15. M. D. Greenhalgh, A. S. Jones and S. P. Thomas, ChemCatChem, 2015, 7, 190.
16. S. W. M. Crossley, C. Obradors, R. M. Martinez and R. A. Shenvi, Chem. Rev., 2016, 116, 8912.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra20007a

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