Catalytic Desymmetrizing Dehydrogenation of 4-Substituted Cyclohexanones through Enamine Oxidation

Article abstract of DOI:10.1002/anie.201713327

A desymmetrizing dehydrogenation process catalyzed by a chiral primary amine is described herein. The reaction proceeds through the oxidation of a ketone enamine by IBX and enables the highly enantioselective desymmetrization of 4-substituted cyclohexanones with the generation of chiral 4-substituted cyclohexenones containing a remote γ-stereocenter.

Full text of DOI:10.1002/anie.201713327

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Accepted Article
Title: Catalytic Desymmetrizing Dehydrogenation of 4-Substituted
Cyclohexanones through Enamine Oxidation
Authors: Lihui Zhu, Long Zhang, and Sanzhong Luo
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201713327
Angew. Chem. 10.1002/ange.201713327
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10.1002/anie.201713327
Angewandte Chemie International Edition
COMMUNICATION
Catalytic Desymmetrizing Dehydrogenation of 4-Substituted
Cyclohexanones through Enamine Oxidation
Lihui Zhu, Long Zhang and Sanzhong Luo*
Dedicated to Prof. Jin-Pei Cheng on the occasion of his 70’s birthday
Abstract:
A
chiral primary amine catalyzed desymmetric
compounds would install unsaturation and meanwhile generate
remote -stereocenters, an appealing yet unachieved process to
access synthetically versatile 4-substituted cycohenxe-2-ones. A
sequence of chiral enolate formation and oxidation was reported
for the synthesis of 4-substituted cyclohenxe-2-ones from
cyclohexanones, but the produce required stoichiometric amount
of chiral amine under rather low temperature.7 Though
desymmetrization of 4-substituted cyclohexanones have been
frequently explored,8 an enantioselective direct dehydrogenation
strategy remains to be developed.
dehydrogenation process is herein described. The reaction proceeds
via ketone enamine oxidation by IBX and enables highly
enantioselective desymmetrization of 4-substituted cyclohexanones,
generating chiral 4-substituted cyclohexanones bearing remote γ-
stereocenter.
As electron-rich species, enamine is inherently nucleophilic and
redox-labile. These features, together with their readily
accessibility and relative stability, make enamines versatile
synthon and catalytic intermediates in carbonyl transformations.1
Compared with the now well-received nucleophilic enamine
catalysis, redox transformation of enamine remains less
developed, particularly in a catalytic asymmetric manner. Single-
electron transfer (SET) with enamine has been known to form an
open shell radical cation, setting basis of SOMO catalysis that
significantly expands the domain of enamine catalysis (Scheme
1).2 On the other hand, nucleophilic enamine could be directly
oxidized into electrophilic iminium ion in both stoichiometric and
catalytic context (Scheme 1, I).3 However, both SOMO catalysis
and oxidative iminium catalysis have been limited to aldehydes,
enantioselective oxidative enamine transformation with ketones
has not been achieved.4 Herein, we reported a chiral primary
amine catalyzed ketone enamine oxidation process, resulting in
I. Oxidative enamine transformation: aldehydes
N
N
N
N
-1e
-2e, -H
H
H
H
H
SOMO catalysis
oxidative iminium catalysis
 or  stereogenic
aldehydes only
II. This work: oxidative ketone enamine transformation
O
O
N
H
NH2


(cat.)


Catalytic Asymmetric
Dehydrogenation
R'
R
R'
R
N
NH
[O]
a
highly desymmetric dehydrogenation of 4-substituted



cyclohexanones.
R'
R
R'
-stereogenic reaction
both tertiary and quaternary stereocenters
R
Direct dehydrogenation represents the most ideal and
straightforward method to build an unsaturated bond from
alkanes. Prominent advances have been made in synthetic
methodology studies.5, 6 Among these significant contributions,
practical ketone dehydrogenation was mainly achieved through
hypervalent iodine chemistry developed by Nicolaou6a-6c and
Ishihara6d, as well as Pd(II) species catalyzed aerobic Saegusa-
type oxidation reported by Stahl6e-6h. Despite elegant procedures
reported, no enantioselective processes have been reported for
ketone dehydrogenation. As in the cases with 4-substituted
cyclohexanones, direct dehydrogenation of these prochiral
ketone enamine oxidation
Scheme 1. Oxidative enamine transformation with Cyclohexanones
We have tried to develop enamine ketone oxidative processes
on the basis of our primary amine catalysis.9 The desymmetric
dehydrogenation of cyclohexanones was initially explored. The
primary concern would be the oxidant tolerability of primary
amine catalyst as well as the issues in attaining chemoselective
ketone enamine oxidation in preference to amine oxidation. In
addition, the targeted reaction also poses a daunting challenge
in stereocontrol as the stereocenter is generated remote to the
reaction center at -position, a feature departure from the typical
- or - stereogenic aminocatalysis (Scheme 1, II). Ultimately,
we accomplished a primary amine catalyzed desymmetrization
of cyclohexanone utilizing commercially available IBX (2-
iodoxybenzoic acid) as oxidant under mild conditions. IBX was
known to be able to oxidize aldehyde and ketone to its
unsaturated analogue.6,10 Previous work by Wang have
demonstrated that amine catalyst was compatible with IBX
oxidation.3a Hence, the first difficulty in our case is to suppress
uncontrolled reaction in order to ensure a completely catalyst
controlled pathway.
[a]
L. Zhu, Dr. L. Zhang, Prof. Dr. S. Luo
Key Laboratory of Molecular Recognition and Function
Institute of Chemistry, Chinese Academy of Sciences
Beijing, 100190 (China);
University of Chinese Academy of Sciences
Beijing, 100490
E-mail: luosz@iccas.ac.cn
Homepage: http://luosz.iccas.ac.cn
[b] Dr. L. Zhang, Prof. Dr. S. Luo
Department of Chemistry, Center of Basic Molecular Science
Tsinghua University, Beijing, 100084 (China).
Collaborative Innovation Center of Chemical Science
and Engineering, Tianjin, 300071 (China).
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201713327
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Screening and Optimization[a]
resulted in serious reduction of enantioselectivity (entry 7). As
the reaction was generally clean, the excess cyclohexanone
Table 2. Scopes of 4-Substituted Cyclohexanones[a]
R3
O
N
O
1a, R3=R4=Et
1b
, R = Bu, R =H
OH
O
O
NH2 R4 HOTf
1, (10 mol%)
I
3
t
4
+
R1 R2
Pentanedioic acid (15 mol %)
Et2O, air, 20 o
R1 R2
O
C
2a-2aj
3a-3aj
4 (0.5 eq.)
variation
conditions
from
standard yield
(%)b
entry
ee (%)c
O
O
1
2
8
O
O
3
9
3a
3c
3b
1
2
none
45 (95)d
91
45% (95%)b yield
47% (97%) yield
91% ee
39% (85%) yield
81% ee
91% ee
DCM
22
56
O
3
Toluene
DMSO
15
77
3d
n=1,
4-7
O
40% (91%) yield, 81% ee
n=3, 3e
3i
3h
4
35
racemic
90
43% (92%) yield
84% ee
41% (91%) yield
87% ee
40% (88%) yield, 83% ee
n=4, 3f
41% (90%) yield, 82% ee
n
5
Et2O (0.5 M)
Et2O (0.1 M)
2a:4a = 1:1
2a:4a = 3:1
without 1
27
3g
n=6,
43% (90%) yield, 83% ee
6
13
87
O
O
O
10
11
12
7
60
48
3j
3l
3k
46% (94%) yield
88% ee
44% (95%) yield
93% ee
42% (90%) yield
90% ee
8
29
90
42% (86%) yield
90% eec
9
< 5
racemic
36
10
11
12
13
14
15
16
17
without pentanedioic acid
m-NO2PhCO2H
TsOH
12
O
O
13
16
14
15
O
3n
3m
21
61
3o
47% (96%) yield
95% ee
47% (95%) yield
93% ee
45% (93%) yield
91% ee
< 5
< 20
Ph
NaHCO3 (1 eq.)
Cat. 1b instead of 1a
4b instead of 4a
4c instead of 4a
4d instead of 4a
no reaction
39 (85)d
18
O
17
O
O
92
91
3q
3p
3r
41% (88%) yield
87% ee
38% (82%) yield
81% ee
46% (96%) yield
86% ee
43
35% (78%) yield
92% eec
42
90
36
Ph
30
O
19
20
O
O
21
3t
3u
3s
45% (96%) yield
87% ee
41% (82%) yield
81% ee
39% (82%) yield
85% ee
40% (82%) yield
91% eec
OCOPh
CH3
CF3
22
23
24
O
O
O
[a] Reactions were performed at room temperature in 0.1 mL of Et2O with 2a
(0.2 mmol), 4a (0.1 mmol), 1 (10 mol %) and pentanedioic acid (15 mol %) in
air, 60 h. [b] 1H NMR yield based on cyclohexanone with biphenyl as internal
standard. Based on the loading of IBX, the maximum yield is 50%. [c]
Determined by HPLC analysis. [d] Isolated yield based on recovered starting
material.
3ab
3aa
3ac
42% (85%) yield
82% ee
43% (88%) yield
77% ee
41% (83%) yield
83% ee
O
O
27
O
26
25
In our standard conditions, we chose 4-tert-butyl
cyclohexanone 2a as the model substrate with IBX 4 as oxidant
under the catalysis of 1, generating the desired cyclohexanone
3a in 45% yield based on ketone (95% isolated yield based on
recovered starting material) and 91% ee at 20 oC (Table 1, entry
1). The use of concentrated ether suspension of IBX was critical
for both the reactivity and stereoselectlvity, as the reaction in
other solvents such as dichloromethane, toluene or DMSO led to
lower enantioselectivity or even racemic product due to the
background reaction (Table 1, entries 2-4). The use of high
concentration led to a faster reaction (Table 1, entry 5 and 6).
The ratio of 2a and 4 also impacted both reactivity and
enantioselectivity and a 2:1 ratio was identified to be optimal
(Table 1, entry 1 vs entries 7 and 8). Presumably, the use of
excess cyclohexanone would facilitate enamine formation,
hence to suppress background reaction, to note that a 1:1 ratio
3ae
3af
3ad
47% (96%) yield
92% ee
42% (85%) yield
80% ee
45% (92%) yield
83% ee
Cl
O
30
O
28
29
O
3ag
3ah
3ai
44% (90%) yield
88% ee
44% (91%) yield
90% ee
44% (91%) yield
93% ee
40% (82%) yield
92% eec
O
O
H3C
F
31
32
OH
R
R = -Ph
-Halogen
-OMe
3aj
41% (86%) yield
90% ee
-NPhth
Cl
[a] Reactions were performed at room temperature in 0.1 mL of Et2O with 2a
(0.2 mmol), 4 (0.1 mmol), 1a (10 mol %) and pentanedioic acid (15 mol %) in
air, 60 h. Isolated yield based on cyclohexanone. Enantiomeric excess was
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10.1002/anie.201713327
Angewandte Chemie International Edition
COMMUNICATION
determined by HPLC and GC analysis. [b] Yield based on recovered starting
compound showed neglectable effect on the reaction (Table 2,
entries 27 and 31).
material was listed in parentheses. [c] Catalyst 1b was employed instead of 1a.
a)
could be quantitatively recovered and this helps to increase the
reaction economy. In addition, the absence of amine catalyst 1
led to trace product generation (Table 1, entry 9), pinpointing the
critical role of amine catalyst in this reaction. The use of a weak
acid additive such as pentanedioic acid was also essential for
effective reaction. The replacement of pentanedioic acid with m-
nitrobenzoic acid or p-toluenesulfonic acid gave inferior
outcomes in terms of both activity and enantioselectivity (Table 1,
entries 11 and 12). No reaction occurred with the addition of
sodium bicarbonate (Table 1, entry 13). Mechanistically, weak
acid plays a dual role to facilitate enamine formation as we
previously reported, and to enhance the solubility of IBX in ether
as known.11 When catalyst 1b was employed instead of 1a, the
enantioselectivity was raised slightly, albeit with a reduction in
yield (Table 1, entry 14). Other substituted IBX have also been
examined (Table 1, entries 15-17), both fluoro- and methyl-
substituted IBX showed similar performance, indicating the
absence of electronic effect in the oxidation. On the other hand,
IBX bearing ortho-methyl group led to inferior activity and
enantioselectivity, indicating a strong steric effect (Table 1, entry
17).
N
O
O
HOTf
, (20 mol%)
Pentanedioic acid (30 mol %)
Et2O, air, 20 o
OH
O
O
NH2
1a
I
+
O
C
16 mmol
8 mmol
1.08 g,
44% yield, 86% ee
b)
O
O
Ph
(MeO2C)2HC
f)
a)
5f 82%, 86% ee
5a 67%, 86% ee
O
O
O
I
e)
b)
O
R
5e
5b 91%, 86% ee
d)
70%, 86% ee
O
c)
3a: 86% ee
3p: 81% ee
3q: 87% ee
O
5d
85%, 87% ee
5c 78%, 81% ee
a) 3a, Zn(OTf)2, CH2(CO2Me)2, THF, reflux, 24 h.; b) 3a, I2, Py, CCl4, rt,
4h.; c) 3p, Fe(acac)3, PhSiH3, EtOH, 60 oC, 12 h.; d) 3q, Fe(acac)3, PhSiH3,
EtOH, 60 oC, 12 h.; e) 3a, H2O2(aq), PhCOCF3, buffer in MeCN, rt, 3 h.; f) 3a,
Pd(MeCN)4OTf, NaNO3, (PhBO)3, DCE, rt, 12 h.
With the optimized conditions in hand, we then explored the
scope of the substrates. The reactions worked well with
cyclohexanones bearing different 4-alkyl group including those
t
t
i
bulky groups such as Bu, Pent, Pr and cycohexyl, giving the
desired cyclohexen-2-ones with good ee (Table 2, entries 1-9).
The bulky substitutes generally favors stereoselective control
and 4-tertiary alkyl groups such as methylcyclohexyl, adamantyl,
tOctyl, 3-methyl-3-pentyl, 3-ethyl-3-pentyl and cumyl group all
led to > 90% ee with no decline in reactivity (Table 2, entries 10-
15). Allylic substituted cyclohexanones also worked very well to
deliver the desired cycohexen-2-ones (Table 2, entries 16 and
17) and those products can be readily utilized in the synthesis of
terpenoid compounds.12 4-Benzyl substituted cyclohexanone
could also be incorporated to give good yield and high
enantioselectivity (Table 2, entry 18), and substituents on the
benzene ring showed no obvious effect (Table 2, entry 19 and
20). A 4-ester moiety was also tolerated (Table 2, entry 21). In
some cases, amine catalyst 1b has been found to give slightly
Scheme 2. Transformations and Scale-up Reactions
The reaction could be scaled up to gram scale with similar
outcome and the excess cyclohexanone could be quantitatively
recovered for further reactions, demonstrating the practicability.
To demonstrate the synthetic utility, further derivatization were
examined by transforming the enone moiety into different
structural motif. In this regard, conjugate addition, aryl boric acid
addition, α-iodination, radical reductive cyclization and
epoxidation all worked smoothly to give the desired adduct with
maintaining enantioselectivity as single diastereoisomers
(Scheme 2).13
a) Radical inhibition experiments
O
O
with 1 eq. TEMPO
improved enantioselectivity but with
a minor sacrifice of
84% yield, 81% ee
standard condition
productivity (Table 2, entries 10, 17, 20, 27). Unfortunately,
when hetero-atom or aryl group was introduced on the 4-position
(R2 = H), over-oxidation to phenols were obtained, without any
cycohexenone observed (Table 2, entry 32).

with 1 eq. BHT
83% yield, 86% ee
b)
Kinetic isotope effect
O
O
O
D
(D)/H
D
We then tested 4,4-disubstituted cyclohexanones, and in
these cases, -quaternary stereocenters will be generated. We
first examined the reactions with 4-aryl-4-methylcycohexanones
and in these cases the desired cyclohexanones could be
obtained in good yields and 77-83% ee (Table 2, entries 22-24).
To further enhance synthetic applicability, we tested the
reactions with cyclohexanones bearing spirocarbocyclic
backbone, structural motif in many natural products. The
reaction proceeded smoothly when five- or six- membered ring
was introduced (Table 2, entries 25 and 26). In the meantime,
the electronic nature on the benzene ring attached to spiro-
standard condition
D
D
kH/kD = 1.02
or
2a

2a
-4D-
O
O
O
standard condition
or
D
D
kH/kD = 1.82
D
(D)/H
D
Ph
Ph
2l
Ph
2l

-4D-
Scheme 3. Control Experiments
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10.1002/anie.201713327
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COMMUNICATION
A number of control experiments were carried out to
elucidate this oxidative desymmetrization process. The addition
of typical radical scavenger such as butylated hydroxytoluene
(BHT) or TEMPO showed on obvious inhibition effect (Scheme
3a). This observation together with the notable steric effect of
IBX suggests that a SET initialized radical mechanism is unlikely
operable in our case.14, 3a On this basis, a plausible substitution-
elimination catalytic cycle, similar to the IBX-alcohol oxidation
mechanism,15 was proposed. This pathway involves enamine α-
addition to IBX to form an α-iodic intermediate C1/C2 (Scheme
4), which undergoes a concerted β-H abstraction-elimination to
give the dehydrogenated adduct (Scheme 4). Coordination of
enamine nitrogen or tertiary amine moiety to IBX is electronically
feasible, however, this complex as an active intermediate was
not considered due to its crowded coordination nature. On the
other hand, the protonated tertiary amine moiety may direct the
coupling of enamine and IBX via N-H-O hydrogen bonding in a
chair-chair conformation (Scheme 4, B1 and B2).
via ketone enamine oxidation. The reaction proceed smoothly
with both 4-mono- and 4,4-di-substituted cyclohexanone under
mild conditions in high yield and good enantioselectivity. This
unique desymmetrisation process is expected to achieve wide
application in nature product synthesis and pharmaceutical
industry. More cascade applications and mechanistic studies are
underway in our laboratory.
Acknowledgements
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 National Program of Top-notch Young
Professionals.
Keywords: enamine • desymmetrization • enantioselective
dehydrogenation • ketone enamine oxidation • organocatalysis
[1]
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For recent examples on SOMO catalysis, see: (a) A. G. Capacci, J. T.
Malinowski, N. J. McAlpine, J. Kuhne, D. W. C. MacMillan, doi:
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Science, 2007, 316, 582-585.
Scheme 4. Proposed reaction sequence and stereocontrol mode
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Li, X.-S. Zhang, J. Li, W. Wang, Nat. Commun. 2011, 2, 1-7; b) Y.
Hayashi, T. Itoh, H. Ishikawa, Angew. Chem., Int. Ed. 2011, 50, 3920-
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The intermolecular kinetic isotope effect of α-C-H and β-C-H
bond was determined to be 1.02 and 1.82, respectively (Scheme
3b). This result suggested the rate-limiting step resides in the
oxidation stage (Scheme 4, II), not in the enamine formation
stage (Scheme 4, I) under the present conditions. The
determined zero-order kinetics on cyclohexanone 2a is
consistent with this scenario (SI). The stereocontrol within this
reaction sequence is another intriguing yet complicated issue.
As different enamine conformers equilibrates under the present
conditions (See SI for detailed analysis), both enamine formation
and the oxidation steps could contribute in the stereocontrol.
Shown in Scheme 4 are two equilibrated s-trans enamine A1
and A2 and the possible transition states B1 and B2 on reacting
with IBX. DFT calculations indicated S-configured enamine A1 is
slightly favored over R-configured enamine A2 by 1.0 Kcal/mol.
In the following oxidation steps, steric effect of the 4-substituent
(mono-substitution cases) may further reinforce the S-selective
pathway (Scheme 4 and SI for detailed discussions).
[4] For reviews on asymmetric C-H functionalization of carbonyl groups, see:
a) Y. Qin, L. Zhu, S. Luo Chem. Rev. 2017, 117, 9433-9520; b) J. He,
M. Wasa, K. S. L. Chan, Q. Shao, J.-Q. Yu Chem. Rev. 2017, 117,
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S. Baran, Angew. Chem., Int. Ed. 2002, 41, 1386-1389; d) M. Uyanik,
In conclusion, we have developed the first catalytic
desymmetric dehydrogenation of 4-substituted cyclohexanone
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10.1002/anie.201713327
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10.1002/anie.201713327
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
Lihui Zhu, Long Zhang and Sanzhong
Luo*
Page No. – Page No.
Catalytic Desymmetrizing
Dehydrogenation of 4-Substituted
Cyclohexanones through Enamine
Oxidation
Text for Table of Contents
Desymmetric dehydrogenation: A chiral primary amine catalyzed desymmetric dehydrogenation
process is herein described. The reaction proceeds via ketone enamine oxidation by IBX and enables
highly enantioselective desymmetrization of 4-substituted cyclohexanones.
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