Catalytic Asymmetric β-C-H Functionalizations of Ketones via Enamine Oxidation

Article abstract of DOI:10.1021/acs.orglett.8b00508

A chiral primary amine catalyzed oxidative β-C-H functionalization of ketone is described. The reaction proceeds via ketone enamine oxidation by IBX and enables highly enantioselective remote C-H functionalization of both cyclic and acyclic ketones, gener

Full text of DOI:10.1021/acs.orglett.8b00508

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Catalytic Asymmetric β‑C−H Functionalizations of Ketones via
Enamine Oxidation
Lihui Zhu,†,‡ Long Zhang,†,‡,§ and Sanzhong Luo*,†,‡,§
†Key Laboratory of Molecular Recognition and Function, Chinese Academy of Sciences, Beijing 100190, China
‡College of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100490, China
§Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China
S
* Supporting Information
ABSTRACT: A chiral primary amine catalyzed oxidative β-C−H functionalization of ketone is described. The reaction proceeds
via ketone enamine oxidation by IBX and enables highly enantioselective remote C−H functionalization of both cyclic and
acyclic ketones, generating chiral ketones bearing β-stereocenters.
Scheme 1. Tandem Oxidative Iminium Catalysis
unctionalizations and transformations of carbonyl com-
Fpounds are fundamental processes that undergo constant
rebirth in organic synthesis.1 Typical carbonyl chemistry relies
on the polarized ipso-carbon, as well as the resulting acidic α-
C−H. Recent advances in inert bond C−H activation have
allowed for β- or remote C−H bond functionalizations,2 and
enantioselective processes have also been developed by
merging with the established asymmetric catalysis.3 In this
regard, aminocatalysis has also become a viable approach for
enantioselective remote C−H functionalizations of aldehydes
and ketones. On the basis of redox properties of enamine
intermediate,4−7 two strategies, 5πe catalysis6 and oxidative
iminium catalysis,7 have been developed to enable β-C−H
functionalizations of aldehydes and ketones. In the latter case, a
nucleophilic enamine is directly oxidized into an electrophilic
iminium ion, which then participates in typical conjugate
addition processes (Scheme 1). Wang7a and Hayashi7b have
independently developed oxidative iminium catalysis of
aldehydes. However, the reactions with ketones have not
been achieved so far.
Our group has developed chiral primary amines as viable
catalysts for enantioselective transformations of aldehydes and
ketones.8 Recently, we developed a dehydrogenative desym-
metrization of 4-substituted cyclohexanones via a ketone−
enamine oxidaton.8f In the process of further explorations of
this catalytic procedure, it was realized that the asymmetric β-
C−H functionalization of ketones remained an unsolved issue
in general. Herein, we report a chiral primary amine catalyzed
enantioselective β-C−H functionalization of simple ketones
utilizing commercially available IBX (2-iodoxybenzoic acid) as
oxidant under mild conditions (Scheme 1).
In this work, 4-hydroxycoumarin, a classic nucleophile in the
conjugate addition chemistry,9 was chosen as a test nucleophile
due to its importance as a versatile intermediate in both
pharmaceutical ingredients and natural product synthesis.10
Ultimately, the oxidative β-functionalization process was found
to proceed effectively under the catalysis of our previously
developed chiral primary amine catalyst with commercially
available IBX as oxidant (see the Supporting Information for
optimization details). Under the standard conditions, we chose
cyclohexanone 2a and 4-hydroxycoumarine 3a as the model
substrates with IBX as oxidant under the catalysis of primary
amine 1, generating the desired product 4a in 97% yield and
94% ee at 0 °C in air (Table 1, entry 1). Both amine catalyst 1
and IBX were essential for the reaction and their absence
resulted in virtually no reaction (Table 1, entries 2 and 3).
Received: February 11, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00508
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Screening and Optimization
Scheme 2. Substrate Scope
b
c
entry
variation from standard conditions
yield (%)
ee (%)
1
none
97
6
94
2
without 1
3
without IBX
without PFBA
TsOH instead of PFBA
50 mol % K2CO3
rt
NR
79
trace
43
95
96
83
55
76
95
4
73
5
6
racemic
87
7
d
8
−20 °C
DCM
95
9
82
10
11
12
Et2O
72
2a/3a = 1:1
2a/3a = 3:1
91
94
a
Reactions were performed at 0 °C in 0.5 mL of MeCN with 2a (0.2
mmol), 3a (0.1 mmol), IBX (0.12 mmol), 1 (20 mol %), and PFBA
b
(30 mol %) in air, 24 h. 1H NMR yield based on coumarine with
c
trimethoxybenzene as internal standard. Enantioselectivity deter-
mined via HPLC analysis. 72 h. IBX = 2-iodoxybenzoic acid, PFBA =
d
pentafluorobenzoic acid.
Weak acid additive was found to be critical for both activity and
enantioselectivity (entry 4 vs 1) and the use of strong acid or
base additive led to no reaction or racemic product, respectively
(Table 1, entries 5 and 6). When the reaction temperature (0
°C) was raised to ambient temperature, the enantioselectivity
dropped to 87% ee (Table 1, entry 7). Further decrease of the
reaction temperature only slightly improved enantioselectivity
with serious sacrifice of reaction rate (Table 1, entry 8).
Acetonitrile was identified as the optimal solvent, and the
reaction in other solvents such as DCM and Et2O led to
inferior results in terms of both yield and enantioselectivity
(Table 1, entries 9 and 10). The optimal ratio of 2a/3a was
found to be 2:1, further increase the ratio did not lead to any
improvements (Table 1, entries 12). It is noted that when
cyclohexenone, instead of the saturated cyclohexanone, was
used as substrate in the absence of IBX, the reactivity was
comparable but the enantioselectivity was dropped due to
background reaction (Figure 1), highlighting the appeal of this
oxidative sequence.
a
Reactions were performed at 0 °C in 0.5 mL of MeCN with 2a (0.2
mmol), 3a (0.1 mmol), IBX (0.12 mmol), 1 (20 mol %), and PFBA
(30 mol %) in air, 24 h. Isolated yield. Enantioselectivity determined
b
c
via HPLC analysis. 48 h. See the SI for details.
very well. The reaction also tolerated 4-disubstituted cyclo-
hexanones (Scheme 2, 4m and 4n). Larger cyclic ketones were
also tested, showing good reactivity and high enantioselectivity
(Scheme 2, 4o and 4p). Unfortunately, cyclopentanone did not
work, and no reaction was observed under the present
conditions. To our delight, aliphatic acyclic ketones could
also be applied to the reaction conditions with equally good
performance in extended reaction period (Scheme 2, 4q−u),
significantly expanding the utility of this process. In an one-pot
two-stage reaction, the desymmetrization of 4-substituted
cyclohexanone could also be coupled with conjugated addition
to afford the desired product in 86% yield and with 82% ee as a
single diastereoisomer (Scheme 2, 4v). To further illustrate the
reaction scope, other nucleophiles such as 1H-benzotrizaole
and dimethyl malonate were also tested, showing good yield
and moderate enantioselectivity (Figure 2). To demonstrate
the practicability of this transformation, we performed a scale-
up example with 5 mmol of 3a and 10 mmol of 2a as substrate,
generating 1.23 g product without loss of yield or
enantioselectivity (Figure 3).
Figure 1. Conjugate addition using cyclohexenone.
With the optimized conditions in hand, we then explored the
scope of the substrates. The electronic effect on the coumarin
ring was shown to be fully tolerable, both electron-rich and
electron-deficient coumarins could be applied to give good
yield and high enantioselectivity (Scheme 2, 4a−i). Other
coumarin analogues, such as quinolinone derivative, pyran-2-
one, and 4-naphthopyran-2-one (Scheme 2, 4j−l), also worked
On the basis of experimental observation and previous
studies of IBX-mediated enamine dehydrogenation, a detailed
catalytic cycle is proposed in Scheme 3.11 Enamine A is formed
from substrate 2a and primary amine 1, which would be readily
dehydrogenated to unsaturated iminium B by IBX through a
covalent intermediate.8f Primary amine is considered to be
B
DOI: 10.1021/acs.orglett.8b00508
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
Experimental procedures, characterization data, and H
NMR and 13C NMR spectra and HPLC traces (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: luosz@iccas.ac.cn.
ORCID
Sanzhong Luo: 0000-0001-8714-4047
Notes
Figure 2. Other nucleophiles.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Natural Science Foundation of China (21390400,
21521002, 21572232, and 21672217) and the Chinese
Academy of Science (QYZDJ-SSW-SLH023) for financial
support. S.L. is supported by the National Program of Top-
notch Young Professionals.
Figure 3. Scale-up reaction.
REFERENCES
Scheme 3. Proposed Mechanism
■
(1) For selected reviews, see: (a) Huang, Z.; Dong, G. Tetrahedron
Lett. 2014, 55, 5869−5889. (b) Jensen, K. L.; Dickmeiss, G.; Jiang, K.;
Albrecht, L.; Jørgensen, K. A. Acc. Chem. Res. 2012, 45, 248−264.
(c) Hopkinson, M. N.; Richter, C.; Schedler, M.; Glorius, F. Nature
2014, 510, 485−496. (d) Allen, A. E.; MacMillan, D. W. C. Chem. Sci.
2012, 3, 633−658. (e) Deng, Y.; Kumar, S.; Wang, H. Chem. Commun.
2014, 50, 4272−4284. (f) Kim, D.-S.; Park, W.-J.; Jun, C.-H. Chem.
Rev. 2017, 117, 8977−9015.
(2) For selected reviews, see: (a) Qin, Y.; Zhu, L.; Luo, S. Chem. Rev.
2017, 117, 9433−9520. (b) Inamdar, S. M.; Shinde, V. S.; Patil, M. T.
Org. Biomol. Chem. 2015, 13, 8116−8162. (c) Oliveira, M. T.; Luparia,
M.; Audisio, D.; Maulide, N. Angew. Chem., Int. Ed. 2013, 52, 13149−
13152. (d) Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.;
Rovis, T. Chem. Rev. 2015, 115, 9307−9387. (e) He, J.; Wasa, M.;
Chan, K. S. L.; Shao, Q.; Yu, J.-Q. Chem. Rev. 2017, 117, 8754−8786.
(3) For selected examples on asymmetric remote C−H functionaliza-
tion of carbonyls, see: (a) Zhang, F.-L.; Hong, K.; Li, T.-J.; Park, H.;
Yu, J.-Q. Science 2016, 351, 252−256. (b) Fu, Z.; Xu, J.; Zhu, T.;
Leong, W. W. Y.; Chi, Y. R. Nat. Chem. 2013, 5, 835−839. (c) Chen,
G.; Gong, W.; Zhuang, C.; Andra, M. S.; Chen, Y.-Q.; Hong, X.; Yang,
Y.-F.; Liu, T.; Houk, K. N.; Yu, J.-Q. Science 2016, 353, 1023.
(4) For selected reviews on aminocatalysis, see: (a) Mukherjee, S.;
Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471−5569.
crucial to achieve this nontrivial ketone-enamine dehydrogen-
ation for its space tolerance. Subsequent Si-facial nucleophilic
addition to iminium B via transition state C affords the S-
selective product 4a. A steric mode can be applied to account
for the facial selectivity. In this model, the charged N−H−N H-
bonding fixes the comformation of iminium ion and meanwhile
renders the tertiary amine moiety block the Re-face. The role of
weak acid additive is to facilitate enamine formation as
previously verified,8a,b thus favoring enamine-based catalytic
turnover. As a result, the enol-based background reaction was
largely overrode, leading to better stereocontrol.
In conclusion, we have developed a catalytic asymmetric β-
C−H functionalization of ketones via enamine oxidation. The
reaction proceeds smoothly with both cyclic and acyclic
ketones under mild conditions in high yield with excellent
enantioselectivity. This unique cascade process is expected to
achieve wide application in natural product synthesis and the
pharmaceutical industry.
(b) Erkkila, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107,
̈
5416−5470. (c) Marigo, M.; Jørgensen, K. A. Chem. Commun. 2006,
2001−2011. (d) Lelais, G.; MacMillan, D. W. C. Aldrichimica Acta
2006, 39, 79−87. (e) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev.
2009, 38, 2178−2189. (f) Melchiorre, P.; Marigo, M.; Carlone, A.;
Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138−6171.
(5) For enamine oxidation through SET process, see: (a) Comito, R.
J.; Finelli, F. G.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135,
9358−9361. (b) Jui, N. T.; Garber, J. A.; Finelli, F. G.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2012, 134, 11400−11403. (c) Pham, P. V.;
Ashton, K.; MacMillan, D. W. C. Chem. Sci. 2011, 2, 1470−1473.
(d) Mastracchio, A.; Warkentin, A. A.; Walji, A. M.; MacMillan, D. W.
C. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 20648−20651. (e) Devery,
J. J.; Conrad, J. C.; MacMillan, D. W. C.; Flowers, R. A. Angew. Chem.,
Int. Ed. 2010, 49, 6106−6110. (f) Jui, N. T.; Lee, E. C.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2010, 132, 10015−10017. (g) Van Humbeck,
J. F.; Simonovich, S. P.; Knowles, R. R.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2010, 132, 10012−10014. (h) Um, J. M.; Gutierrez, O.;
Schoenebeck, F.; Houk, K. N.; MacMillan, D. W. C. J. Am. Chem. Soc.
2010, 132, 6001−6005. (i) Rendler, S.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2010, 132, 5027−5029. (j) Wilson, J. E.; Casarez, A. D.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 11332−11334.
(k) Conrad, J. C.; Kong, J.; Laforteza, B. N.; MacMillan, D. W. C. J.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00508.
C
DOI: 10.1021/acs.orglett.8b00508
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Am. Chem. Soc. 2009, 131, 11640−11641. (l) Amatore, M.; Beeson, T.
D.; Brown, S. P.; MacMillan, D. W. C. Angew. Chem., Int. Ed. 2009, 48,
5121−5124. (m) Graham, T. H.; Jones, C. M.; Jui, N. T.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2008, 130, 16494−16495. (n) Kim, H.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2008, 130, 398−399. (o) Jang,
H. Y.; Hong, J. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129,
7004−7005. (p) Beeson, T. D.; Mastracchio, A.; Hong, J. B.; Ashton,
K.; MacMillan, D. W. C. Science 2007, 316, 582−585. (q) Capacci, A.
G.; Malinowski, J. T.; McAlpine, N. J.; Kuhne, J.; Macmillan, D. W. C.
Nat. Chem. 2017, 9, 1073−1077.
́
(6) For 5πe-catalysis, see: (a) Jeffrey, J. L.; Petronijevic, F. R.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2015, 137, 8404−8407.
(b) Terrett, J. A.; Clift, M. D.; MacMillan, D. W. C. J. Am. Chem. Soc.
́
2014, 136, 6858−6861. (c) Petronijevic, F. R.; Nappi, M.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2013, 135, 18323−18326. (d) Pirnot, M.
T.; Rankic, D. A.; Martin, D. B.; MacMillan, D. W. C. Science 2013,
339, 1593−1596.
(7) For oxidative iminium process, see: (a) Zhang, S.-L.; Xie, H.-X.;
Zhu, J.; Li, H.; Zhang, X.-S.; Li, J.; Wang, W. Nat. Commun. 2011, 2,
211−217. (b) Hayashi, Y.; Itoh, T.; Ishikawa, H. Angew. Chem., Int. Ed.
2011, 50, 3920−3924. (c) Zhu, J.; Liu, J.; Ma, R.; Xie, H.; Li, J.; Jiang,
H.; Wang, W. Adv. Synth. Catal. 2009, 351, 1229−1232. (d) Liu, J.;
Zhu, J.; Jiang, H.; Wang, W.; Li, J. Chem. - Asian J. 2009, 4, 1712−
1716. (e) Hayashi, Y.; Itoh, T.; Ishikawa, H. Adv. Synth. Catal. 2013,
355, 3661−3669. (f) Zhao, Y.-L.; Wang, Y.; Hu, X.-Q.; Xu, P.-F. Chem.
Commun. 2013, 49, 7555−7556. (g) Kang, Y. K.; Kim, D. Y. Chem.
Commun. 2014, 50, 222−224. (h) Suh, C. W.; Woo, S. B.; Kim, D. Y.
Asian J. Org. Chem. 2014, 3, 399−402. (i) Zeng, X.; Ni, Q.; Raabe, G.;
Enders, D. Angew. Chem., Int. Ed. 2013, 52, 2977−2980. (j) Zhou, X.-
L.; Wang, P.-S.; Zhang, D.-W.; Liu, P.; Wang, C.-M.; Gong, L.-Z. Org.
Lett. 2015, 17, 5120−5123.
(8) (a) Zhang, L.; Luo, S. Synlett 2012, 23, 1575−1589. (b) Zhang,
L.; Fu, N.; Luo, S. Acc. Chem. Res. 2015, 48, 986−997. (c) Yang, Q.;
Zhang, L.; Ye, C.; Luo, S.; Wu, L.-Z.; Tung, C.-H. Angew. Chem., Int.
Ed. 2017, 56, 3694−3698. (d) Fu, N.; Li, L.; Yang, Q.; Luo, S. Org.
Lett. 2017, 19, 2122−2125. (e) Wang, D.; Zhang, L.; Luo, S. Org. Lett.
2017, 19, 4924−4927. (f) Zhu, L.; Zhang, L.; Luo, S. Angew. Chem.,
Int. Ed. 2018, 57, 2253−2258.
(9) (a) Halland, N.; Hansen, T.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2003, 42, 4955−4957. (b) Kim, H.; Yen, C.; Preston, P.; Chin, J.
Org. Lett. 2006, 8, 5239−5242. (c) Xie, J.-W.; Yue, L.; Chen, W.; Du,
W.; Zhu, J.; Deng, J.-G.; Chen, Y.-C. Org. Lett. 2007, 9, 413−415.
(d) Zhu, X.; Lin, A.; Shi, Y.; Guo, J.; Zhu, C.; Cheng, Y. Org. Lett.
2011, 13, 4382−4385. (e) Leven, M.; Neudorfl, J. M.; Goldfuss, B.
̈
Beilstein J. Org. Chem. 2013, 9, 155−165. (f) Xiao, B.-X.; Yan, R.-J.;
Gao, X.-Y.; Du, W.; Chen, Y.-C. Org. Lett. 2017, 19, 4652−4655.
(10) (a) Murray, R. D. H.; Mendez, J.; Brown, R. A. The Natural
Coumarins: Occurrence, Chemistry and Biochemistry; John Wiley &
Sons: New York, 1982. (b) Kennedy, R. O.; Thornes, R. D.
Coumarins: Biology, Applications and Mode of Action; John Wiley &
Sons: Chichester, 1997. (c) Fylaktakidou, K. C.; Hadjipavlou-Litina, D.
J.; Litinas, K. E.; Nicolaides, D. N. Curr. Pharm. Des. 2004, 10, 3813−
3833.
(11) For mechanistic study on IBX as oxidant, see: (a) Nicolaou, K.
C.; Baran, P. S.; Zhong, Y.-L.; Sugita, K. J. Am. Chem. Soc. 2002, 124,
2212−2220. (b) Nicolaou, K. C.; Sugita, K.; Baran, P. S.; Zhong, Y.-L.
J. Am. Chem. Soc. 2002, 124, 2221−2232. (c) Nicolaou, K. C.; Baran,
P. S.; Zhong, Y.-L.; Barluenga, Z. S.; Hunt, K. W.; Kranich, R.; Vega, J.
A. J. Am. Chem. Soc. 2002, 124, 2233−2244. (d) Nicolaou, K. C.;
Montagnon, T.; Baran, P. S.; Zhong, Y.-L. J. Am. Chem. Soc. 2002, 124,
2245−2258. (e) Nicolaou, K. C.; Mathison, J. N.; Montagnon, T. J.
Am. Chem. Soc. 2004, 126, 5192−5201.
D
DOI: 10.1021/acs.orglett.8b00508
Org. Lett. XXXX, XXX, XXX−XXX