Asymmetric Carbene-Catalyzed Oxidation of Functionalized Aldimines as 1,4-Dipoles

Article abstract of DOI:10.1002/anie.202017017

The use of functionalized aldimines has been demonstrated as newly structural 1,4-dipole precursors under carbene catalysis. More importantly, enantiodivergent organocatalysis has been successfully developed using carbene catalysts with the same absolute configuration, leading to both (R)- and (S)- enantiomers of six-membered heterocycles with quaternary carbon centers. This strategy features a broad substrate scope, mild reaction conditions, and good enantiomeric ratio. DFT calculation results indicated that hydrogen bond C?H???F interactions between the catalyst and substrate are the key factors for controlling and even switching the enantioselectivity. These new 1,4-dipoles can also react with isatin and its imines under carbene catalysis, allowing for access to the spiro oxindoles with excellent enantiomeric ratios.

Full text of DOI:10.1002/anie.202017017

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 7913–7919
International Edition: doi.org/10.1002/anie.202017017
German Edition: doi.org/10.1002/ange.202017017
Heterocycles
Hot Paper
Asymmetric Carbene-Catalyzed Oxidation of Functionalized
Aldimines as 1,4-Dipoles
Guanjie Wang, Qiao-Chu Zhang, Chenlong Wei, Ye Zhang, Linxue Zhang, Juhui Huang,
Donghui Wei,* Zhenqian Fu,* and Wei Huang
Abstract: The use of functionalized aldimines has been
demonstrated as newly structural 1,4-dipole precursors under
carbene catalysis. More importantly, enantiodivergent organo-
catalysis has been successfully developed using carbene
catalysts with the same absolute configuration, leading to both
(R)- and (S)- enantiomers of six-membered heterocycles with
quaternary carbon centers. This strategy features a broad
substrate scope, mild reaction conditions, and good enantio-
meric ratio. DFT calculation results indicated that hydrogen
electrophilic substrates; this area of research is still in its
infancy. Further development of new activation modes of
aldimines catalyzed by NHC, especially in an enantioselective
manner, is of high importance.
As part of our ongoing interest in organocatalysis,[5] on the
basis of our previous work on carbene-activated aldimines or
iminiums,[4h,i,o] we planned to design a new type of aldimine
containing a nucleophile moiety. We envisaged that this
functionalized aldimine could be used as a new dipole via
reverse polarity of the imine moiety to form an aza-Breslow
intermediate, followed by its oxidation. Importantly, the
proposed new dipole intermediate derived from the aldimine,
is radically different from the well-known intermediates
derived from aldehydes, and esters. Compared with the
well-developed strategy of connecting a nucleophilic (or
eletrophilic) moiety to the carbon atom of a carbonyl group,[3-
h,i,6] connecting a nucleophilic moiety to the nitrogen atom of
an imine moiety remains underdeveloped. However, the
distinct difference in their structures may lead to big differ-
ences in their chemical properties. If successful, this method-
ology will undoubtedly greatly enhance the development of
carbene chemistry.
À
bond C H···F interactions between the catalyst and substrate
are the key factors for controlling and even switching the
enantioselectivity. These new 1,4-dipoles can also react with
isatin and its imines under carbene catalysis, allowing for
access to the spiro oxindoles with excellent enantiomeric ratios.
Introduction
Asymmetric catalysis has proven to be the best method
for the construction of chiral molecules from simple racemic
raw materials.[1] In this field, N-heterocyclic carbene (NHC, or
carbene) catalysis, one of the most powerful methods of
organocatalysis, has been studied extensively with impressive
advances over recent decades.[2,3] In sharp contrast to the well-
developed activation of aldehydes, enals and esters promoted
by carbene organocatalysis, similar activation of easily
available aldimines has been largely unrecognized due to
their relatively low reactivity.[4] Although considerable effort
has been devoted to this field, the reactions involving NHC-
activated aldimines are mainly limited to Stetter and oxida-
tive reactions.[4] Surprisingly, only two enantioselective reac-
tions, intramolecular cyclization and aza-Stetter reaction
based on an umpolung reaction of imines with a chiral
carbene, have been successfully developed to date.[4k,l] Fur-
thermore, in all the developed reactions the in situ carbon of
the imine moiety acts as the nucleophile and reacts with other
We envisaged that aldimines 1 derived from 2-amino
imidazoles and benzaldehydes, with a free amino group, might
be suitable aldimines as 1,4-dipole precursors. The carbene
would attack aldimines 1 to generate aza-Breslow intermedi-
ate I following deprotonation under basic conditions, which
could be oxidized to give intermediate II, demonstrated by
our group.[4o] Deprotonation of intermediate II forms 1,4-
dipolar intermediate III, which would undergo [4+2] annu-
lation with activated ketones 2 to deliver the products 3 and
release the carbene. Some challenges must be overcome for
this strategy to be successful, including (i) avoiding back-
ground reactions. Aldimines 1 could form a 1,4-dipole via
deprotonation under basic condtions in absence of carbene
catalyst, and this might reacted directly with activated
ketones 2. (ii) realizing good enantioselectivity. The nucleo-
philic nitrogen anion in intermediate III is not only far away
from the chiral carbene moiety, but is also different from
previously reported intermediates generated from aldehydes
under carbene catalysis, meaning that achieving satisfactory
enantioselectivity may be challenging. Herein, we present the
successful development of a novel strategy for asymmetric
NHC-catalyzed 1,4-dipolar cycloaddition of aldimines under
mild conditions. More importantly, enantiodivergent carbene
organocatalysis was realized with the same absolute config-
uration catalyst when trifluoromethyl ketone was used in this
transformation.
[*] G. Wang, C. Wei, Y. Zhang, L. Zhang, J. Huang, Prof. Dr. Z. Fu,
Prof. Dr. W. Huang
Key Laboratory of Flexible Electronics & Institute of Advanced
Materials, Nanjing Tech University
30 South Puzhu Road, Nanjing 211816 (China)
E-mail: iamzqfu@njtech.edu.cn
Q. Zhang, Prof. Dr. D. Wei
College of Chemistry, Zhengzhou University
100 Science Avenue, Zhengzhou, Henan Province, 450001 (China)
E-mail: donghuiwei@zzu.edu.cn
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under https://doi.org/10.
1002/anie.202017017.
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Figure 1. Activation of aldimines under carbene organocatalysis.
Figure 2. Catalyst Screening.
Results and Discussion
(2, 6-MeO2C6H3) substituent and NHC L with an N-(2,4,6-
Ph3C6H2) substituent also gave the enantiomeric ratios to
catalyst J. Encouraged by these unexpected results, NHCs K–
N, with variation of N-substituents, were prepared and further
investigated. The results indicated that this interesting
enantiodivergent phenomenon still exists; however, it seems
that there is no predictable pattern from looking at the
current results. These surprising results prompted us to
further optimize the reaction conditions; the key results are
summarized in Table 1. Increasing the loading of NHC J to
20 mol% significantly improved the product yield (85%).
Subsequently, several additives, such as Sc(OTf)3, LiCl,
Mg(OTf)2, Mg(Ot-Bu)2, Cu(OTf)2, HOBt, Ti(Oi-Pr)4, P, and
Q were screened, showing that the enantiomeric ratio could
not be further improved in this way. We also investigated the
influence of the additives on the catalysts which gave the
opposite enantiomeric ratio. Delightingly, the enantiomeric
ratio could be significantly improved when the NHC G was
used with thiourea Q as a co-catalyst, delivering the product
3a in 90% yield with 10:90 er. However, co-catalyst Q proved
to be detrimental to this transformation for other catalysts.
Lowering the temperature to 08C improved the enantiomeric
ratio considerably. Using a mixed solvent (DCM: hexane =
1:1) further improved enantiomeric ratio (6:94 er).
We initially tested this design with easily available
aldimine 1a, derived from 2-amino benzimidazole and
benzaldehyde, and trifluoroacetophenone 2a in presence of
the racemic triazolium NHC A with K2CO3 as the base in
THFat room temperature. To our delight, the desired product
3a was obtained in 73% yield. Encouraged by this promising
result, the enantioselectivity of the catalytic reaction was
investigated. Base and solvent screening showed that K3PO4
and DCM were the most effective, respectively, affording
product 3a in 86% yield with an enantiomeric ratio (er) of
82:18 when aminoindanol-derived triazolium NHC B was
used (for details, see Supporting Information). To further
improve the enantiomeric ratio, we subsequently investigated
chiral catalysts as shown in Figure 2.
Introducing a Br atom (C) or a nitro group (D) on the
indane moiety did not have a positive influence, and the
catalyst with an N-(2, 6-Et2C6H3) substituent (E) gave similar
outcomes. However, no desired product was found when
catalysts with N-Ph (F) and N-C6F5 (H) substituents were
used. Further catalyst screening indicated that NHC J with N-
(2, 4, 6-i-Pr3C6H2) substituent gives the best enantiomeric
ratio (93:7 er). Surprisingly, the catalyst G with N-(2,4,6-
Cl3C6H2) substituent gave the opposite enantiomeric ratio
(47:53 er). This indicated that it may be possible to realize an
enantiodivergent organocatalytic method by slight modifica-
tion of the structure of a catalyst while keeping the same
absolute configuration. Besides NHC G, NHC I bearing an N-
The above obtained results clearly indicate that these
functionalized aldimines could be enantioselectively activat-
ed by NHC as 1,4-dipole precursors. More importantly,
enantiodivergent organocatalysis, was successfully achieved
using NHC catalysts with the same absolute configuration in
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Table 1: Optimization of the reaction conditions.[a]
with acceptable outcomes. Subsequently, the generation of
trifluoromethyl ketones was evaluated. Trifluoromethyl aryl
ketones bearing substituents with a variety of electronic and
steric properties on the aromatic ring were well tolerated,
generating the corresponding products 3s–3y (72–86% yields
and 87:13–97:3 er for the (R)-enantiomers, and 67–81% yields
and 87:13–93:7 er for the (S)-enantiomers). Heteroaryls (such
as pyridinyl, benzofuryl, benzothienyl, quinolyl, and carba-
zolyl) also worked efficiently, leading to both enantiomers of
3aa–ad (57–93% yields and 67:33–96:4 er for the (R)-
enantiomers, and 53–85% yields and 88:12–94:6 er for the
(S)-enantiomers). Notably, a trifluoromethyl alkyl ketone,
was also a suitable substrate for this transformation, resulting
in the formation of the desired product 3ae with an accept-
able outcome. Pleasingly, CF2H, CF2Cl, and CF2Br groups
were all compatible with this transformation, providing access
to both (R)- and (S)-enantiomers of 3af–3ah (73–90% yields
and 91:9–93:7 er for the (R)-enantiomers, and 45–83% yields
and 83:17–90:10 er for the (S)-enantiomers). It should be
noteworthy that the resulting products 3 bearing CF3-
containing quaternary carbon centers. Actually, trifuorometh-
yl (CF3) are identified as one of most valuable functional
groups and widely used in pharmaceutical chemistry, materi-
als science, and agrochemistry.[8]
Entry
NHC
Additive
Solvent
Yield[%][b]
er[c]
1[d]
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16[e]
17[e,f]
J
J
J
J
J
J
J
J
J
J
G
I
L
M
N
G
G
–
Sc(OTf)3
LiCl
Mg(OTf)2
Mg(Ot-Bu)2
Cu(OTf)2
HOBt
Ti(Oi-Pr)4
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM/Hex.
85
43
40
35
73
n.r.
55
93:7
91:9
91:9
91:9
89:11
–
92:8
91:9
–
–
10:90
–
34:66
–
-
70
P
n.r.
<10
90
<10
32
<10
<10
91
Q
Q
Q
Q
Q
Q
Q
Q
To discover the key factors for determining the enantio-
selectivity, we have performed DFT calculations at the M06-
2X/6-31G(d, p)/IEFPCMDCM/Hex level as well as non-covalent
interaction (NCI) and atoms in molecules (AIM) analyses for
8:92
6:94
88
[a] 1a (0.12 mmol), 2a (0.1 mmol), NHC precursor (10 mol%), K3PO4
(1.5 equiv), DCM (0.1 M), 4 Š MS (100 mg), 308C, 48 h. [b] Isolated
yields after column chromatography. [c] Determined by chiral HPLC.
[d] 20 mol% NHC precursor was used. [e] 08C was used. [f] DCM/
Hexane=(v/v=1:1, 0. 1 M).
À
comparing the stereoselective C N bond formation transition
À
states. As shown in Figure 3, two C H···F hydrogen bond
interactions (2.22 and 2.40 Š) are identified in TSSMe, but only
this transformation (entry 1 vs. entry 17). Notably, the syn-
thesis of both enantiomers of chiral compounds catalyzed by
the catalyst with the same absolute configuration represents
one of the most fundamental challenges in organic chemis-
try.[3k,7]
With acceptable optimized conditions in hand (Table 1,
entries 1 and 17), we then evaluated the scope of the
enantiodivergent reaction for aldimine substrates by using
trifluoroacetophenone 2a as a model substrate (Table 2). For
aldimine aldehyde moieties with aromatic rings bearing
electron-donating groups (such as Me, MeO) or electron-
withdrawing groups (such as F, Cl, Br, COOEt, CN, CF3), all
the reactions proceeded smoothly to generate both (R)- and
(S)-enantiomers of the cycloaddition products (3a–o) in
acceptable to excellent yields (43–91% for the (R)-enantio-
mers and 51–87% for the (S)-enantiomers) and enantiomeric
ratios (92:8–96:4 er for the (R)-enantiomers and 85:15–95:5
er for the (S)-enantiomers). Aldimine aldehyde moieties
bearing naphthalene or heteroaromatic rings (3-pyridinyl)
also worked efficiently as well, affording the corresponding
products 3p & 3q with good outcomes (86%, 87% yields and
94:6, 91:9 er for the (R)-enantiomers, and 85%, 83% yields
and 92:8, 94:6 er for the (S)-enantiomers, respectively). An
aldimine imine moiety with a symmetric substituent on the
benzoimidazole ring worked efficiently, giving the poduct 3r
À
Figure 3. NCI analyses for the stereoselective C N bond formation
transition states under NHC B catalysis (energy in kcalmolÀ1 and
distance in angstrom).
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Table 2: Scope of reaction.[a,b]
[a] Reaction conditions A: Aldimine 1 (0.12 mmol), ketones 2 (0.1 mmol), NHC precursor G (10 mol%), co-catalyst Q (20 mol%), K3PO4 (1.5 equiv),
DCM/Hexane=(v/v=1:1, 0. 1 M), 4 Š MS (100 mg), 08C, 48 h. [b] Reaction conditions B: Aldimine 1 (0.12 mmol), ketones 2 (0.1 mmol), NHC
precursor J (20 mol%), K3PO4 (1.5 equiv), DCM (0.1 M), 4 Š MS (100 mg), 308C, 48 h. [c] Reaction was performed at rt for 48 h. [d] Reaction was
performed at 08C for 72 h. [e] Reaction was performed at rt for 72 h. [f] Reaction was performed at À108C for 48 h. [g] 1.0 mLTHF was used as solvent.
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Table 3: Scope of reaction.[a]
À
one C H···F hydrogen bond interaction (2.19 Š) exists in
TSRMe according to the AIM analysis (Table S4 of SI),
À
indicating the C H···F hydrogen bond interaction should be
responsible for the favorability of TSSMe. When the Cl groups
were introduced in the catalyst (i.e. NHC G), all the identified
À
C H···F hydrogen bond interactions were significantly weak-
ened in both transition states TSSCl and TSRCl (Table S5 of
SI), and the corresponding R-configured isomer pathway
associated with transition state TSRCl is slightly more
energetically favorable, showing that the enantioselectivity
À
can be switched by weakening the C H···F hydrogen bond
interactions. Inspired by this conclusion, we have assumed
that the enantioselectivity would be unswitchable when the
-CF3 group is excluded in the substrate (such as isatin), which
has been confirmed in both theory (Tables S6,7 of SI) and the
following experiments. The additional calculations demon-
strate that the enantioselectivity can be significantly im-
proved in the presence of urea (Table S8 of SI), which is also
in agreement with the experimental observation. Further-
more, we considered and compared the oxidative processes of
the aldimine with or without the presence of NHC catalyst.
The calculated results (Figures S1 and S2 of SI) indicate that
the oxidation (i.e. the transfer of 1H+ and 2eÀ to DQ oxidant)
only can occur via transition state TSOx with an energy barrier
of 14.4 kcalmolÀ1 with the presence of NHC, which is
consistent with the experimental observation.
After successfully establishing functionalized aldimines as
1,4-dipole precursors under carbene catalysis, to further
demonstrate the generality of the current strategy, other
activated ketones (such as isatin) were investigated; the result
are summarized in Table 3. Gratifyingly, the desired chiral
product 5a was obtained in 96% yield with excellent
enantiomeric ratio (99:1 er) when NHC G was used with
co-catalyst Q (for details, see Supporting Information).
Unfortunately, enantiodivergent organocatalysis could not
be realized when isatin was used as the reactant. Without the
co- catalyst, both yield and enantiomeric ratio decreased
considerably. With acceptable optimized conditions in hand,
the generation and limitations of the aldimines and isatins for
this transformation were investigated. As expected, aldimines
with both aldehyde and imine moieties bearing various
substituents with diverse electronic and steric properties on
the aromatic ring were well tolerated, generating the corre-
sponding spiro oxindoles 5a–5k in excellent yields and
enantiomeric ratios. Notably, For an aldimine imine moiety
with a methyl group at the 4-position of the benzoimidazole
ring, the nitrogen anion at the 1-position of the benzoimida-
zole ring regioselectively attacked the carbonyl group, gen-
erating a single product 5l in 93% yield with 99:1 er. An
aldimine imine moiety with a symmetric substituent on the
benzoimidazole ring worked efficiently, giving the poduct 5m
in 82% yield with 97:3 er. For aldimines with the imine moiety
bearing a Cl substituent at the 5- position of the benzoimda-
zole ring, the product 5n was obtained in excellent yield and
enantiomeric ratio, albeit with weak regioselectivity (1.28:1).
Replacement of Bn with Me gave a similar outcome.
Variation of substituents at the 4, 5, 6, 7-positions of the
isatin ring did not influence the efficiency, delivering products
[a] Reaction conditions: Aldimine 1 (0.1 mmol), isatins 2 (0.1 mmol),
NHC precursor G (10 mol%), co-catalyst Q (20 mol%), K3PO4
(1.5 equiv), DCM/Hexane=(v/v=1:1, 0. 1 M), 4 Š MS (100 mg), 08C,
48 h. [b] without Q.
5o–5aa in excellent yields with good to excellent enantio-
meric ratios.
To demonstrate the practicality of our method, a gram-
scale reaction was performed (Scheme 1). In the presence of
only 5 mol% of NHC pre-catalyst J and 10 mol% of co
catalyst thiourea Q, the reaction in a gram scale worked
efficiently to afford spiro oxoindole 5a in 82% yield with 97:3
er. Subsequently, further attempt showed that activated imine
6, derived from isatin, also is suitable substrates for this
transformation, generating the spiro product 7 in 73% yield,
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Conflict of interest
The authors declare no conflict of interest.
Keywords: aldimine ·trifluoromethyl ·dipolar cycloaddition ·
enantiodivergent catalysis ·N-heterocyclic carbene
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In summary, we have addressed asymmetric NHC-cata-
lyzed oxidative reaction of functionalized aldimines as 1,4-
dipole precursors. More importantly, enantiodivergent orga-
nocatalysis has been successfully developed by using carbene
catalysts with the same absolute configuration, leading to
both (R)- and (S)- enantiomers of six-membered heterocycles
with quaternary carbon centers. This efficient strategy
features a broad substrate scope, mild reaction conditions,
and good enantiomeric ratio. DFT calculation results indi-
À
cated that hydrogen bond C H···F interactions between the
catalyst and substrate are the key factors for controlling and
even switching the enantioselectivity. These new 1,4-dipoles
can also react with isatin and its imines under carbene
catalysis, allowing for access to the spiro oxindoles with
excellent enantiomeric ratios. Further investigations and
exploration of this catalytic process are underway in our
laboratory.
Acknowledgements
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We acknowledge financial support by the National Key R&D
Program of China (2017YFA0204704), National Natural
Science Foundation of China (21602105), and Natural Science
Foundation of Jiangsu Province (BK20171460). G. Wang is
grateful to Postgraduate Research & Practice Innovation
Program of Jiangsu Province (KYCX20_0988) and Cultiva-
tion Program for Excellent Doctoral Dissertation of Nanjing
Tech University for financial support.
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Manuscript received: December 22, 2020
Accepted manuscript online: January 14, 2021
Version of record online: February 25, 2021
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