NHC-Catalyzed Desymmetrization of N-Aryl Maleimides Leading to the Atroposelective Synthesis of N-Aryl Succinimides

Article abstract of DOI:10.1002/anie.202016938

Although the construction of axially chiral C?C bonds leading to the atroposelective synthesis of biaryls and allied compounds are well-known, the related synthesis of compounds bearing axially chiral C?N bonds are relatively rare. Described herein is the N-heterocyclic carbene-catalyzed atroposelective synthesis of N-aryl succinimides having an axially chiral C?N bond via the desymmetrization of N-aryl maleimides. The NHC involved intermolecular Stetter-aldol cascade of dialdehydes with prochiral N-aryl maleimides followed by oxidation afforded N-aryl succinimides in good yields and ee values. Preliminary studies on rotation barrier for the C?N bond, the temperature dependence, and detailed DFT studies on mechanism are also provided.

Full text of DOI:10.1002/anie.202016938

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Communications
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How to cite:
International Edition: doi.org/10.1002/anie.202016938
German Edition: doi.org/10.1002/ange.202016938
Asymmetric Catalysis
NHC-Catalyzed Desymmetrization of N-Aryl Maleimides Leading to
the Atroposelective Synthesis of N-Aryl Succinimides
Soumen Barik, Sayan Shee, Soumik Das, Rajesh G. Gonnade, Garima Jindal,*
Subrata Mukherjee,* and Akkattu T. Biju*
hypnotic activity,[3] and metolachlor is a C-N axially chiral
aniline derivative having potential as herbicides.[4] In addi-
tion, some of these compounds are useful ligands in asym-
metric catalysis.[5] Given the importance of C-N axially chiral
molecules, selective synthesis of such molecules are highly
desirable.
À
Abstract: Although the construction of axially chiral C C
bonds leading to the atroposelective synthesis of biaryls and
allied compounds are well-known, the related synthesis of
À
compounds bearing axially chiral C N bonds are relatively
rare. Described herein is the N-heterocyclic carbene-catalyzed
atroposelective synthesis of N-aryl succinimides having an
À
axially chiral C N bond via the desymmetrization of N-aryl
Even since the seminal work of Curran and co-workers
demonstrating the C-N axial chirality in maleimides and N-
alkyl anilides,[6] catalytic, enantioselective synthesis of C-N
axially chiral molecules has received considerable attention.
A variety of transition-metal catalyzed[7] and organocatalytic
techniques are known for the synthesis of C-N axially chiral
molecules.[8] Although the N-heterocyclic carbene (NHC)-
catalyzed transformations[9] leading to atroposelective syn-
maleimides. The NHC involved intermolecular Stetter-aldol
cascade of dialdehydes with prochiral N-aryl maleimides
followed by oxidation afforded N-aryl succinimides in good
yields and ee values. Preliminary studies on rotation barrier for
À
the C N bond, the temperature dependence, and detailed DFT
studies on mechanism are also provided.
À
À
C
ompounds having axially chiral C N bonds have found
thesis of biaryls and related C C axially chiral compounds are
widespread application as natural products, pharmaceuticals,
agrochemicals, and as ligands.[1] For example, marinopyrrole
A is a marine alkaloid having a 1,3’-bipyrrole core and is used
as an antibiotic (Figure 1).[2] Moreover, methaqualone is
a quinazolinone class of compound, known for its sedative-
known,[10] the application of NHC catalysis for the synthesis of
C-N axially chiral compounds has received only scant
attention. In 2018, Wang and co-workers reported the
NHC-catalyzed kinetic resolution of anilides for the C-N
axially chiral compounds,[11] where the reaction proceeds via
the chiral a,b-unsaturated acylazoliums [Scheme 1,
Eq. (1)].[12] Given the limitations of kinetic resolution strat-
egies and considering the applications of C-N axially chiral
compounds, we envisaged the NHC-catalyzed desymmetriza-
tion of N-aryl maleimides as a strategy for the atom-economic
and atroposelective synthesis of N-aryl succinimides.[13]
Herein, we demonstrate the reaction of dialdehydes with
prochiral maleimides where the enantio-determining NHC-
catalyzed intermolecular Stetter reaction is followed by an
aldol and a subsequent oxidation to furnish the axially chiral
N-aryl succinimides [Eq. (2)]. It may be mentioned in this
context that related NHC-catalyzed desymmetrization of
Figure 1. Selected important molecules having chiral C-N axis.
[*] S. Barik, S. Shee, S. Das, Prof. Dr. G. Jindal, Dr. S. Mukherjee,
Prof. Dr. A. T. Biju
Department of Organic Chemistry, Indian Institute of Science
Bangalore-560012 (India)
E-mail: gjindal@iisc.ac.in
subrata.bilu@gmail.com
atbiju@iisc.ac.in
Homepage: https://orgchem.iisc.ac.in/atbiju/
Dr. R. G. Gonnade
Centre for Materials Characterization
CSIR-National Chemical Laboratory
Dr. Homi Bhabha Road, Pune-411008 (India)
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.202016938.
Scheme 1. NHC-catalyzed synthesis of C-N axially chiral compounds.
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cyclic 1,3-diketones leading to spirocyclic compounds are
uncovered recently by Chi and co-workers.[14]
but the use of thiourea as additive improved the yield to 72%
retaining the high selectivity (entry 12). Finally, employing
20 mol% thiourea and 4 ꢂ MS as additives afforded 3a in
70% yield and 95:5 er (entry 13).[19]
The desymmetrization of N-aryl maleimides using an
intermolecular Stetter reaction was our primary focus.[15–17]
Disappointingly, all our efforts towards the NHC-catalyzed
reaction of 4-chlorobenzaldehyde with maleimides did not
afford the desired Stetter product. Interestingly, when the
reaction of phthalaldehyde 1a with the N-aryl maleimide 2a
was carried out using carbene generated from the chiral
triazolium salt 4[18] using Hꢀnigꢁs base followed by the
oxidation of the reaction products using PDC afforded the
desired the C-N axially chiral compound 3a in 67% yield and
94:6 er (Table 1, entry 1). The product 3a was formed by the
intermolecular Stetter reaction followed by the aldol reaction
and a subsequent oxidation of the generated carbinol
intermediate. Compared to the carbene generated from 4,
the NHC formed from other triazolium salts 5 and 6 are less
efficient in catalyzing this reaction (entries 2, 3). The nucle-
ophilic bases such as DBU and DMAP provided comparable
results whereas inorganic bases returned inferior results
(entries 4–7). The reaction performed in THF and DME
furnished 3a in reduced yield, and the use of CH2Cl2
improved the yield but reduced the er of the product
(entries 8–10). At this stage, supplement of additives was
considered. The use of LiCl returned same results (entry 11),
Having the optimized reaction conditions in hand, we
then examined the substrate scope of this desymmetrization
reaction. Initially, the scope of maleimides were analyzed
(Scheme 2). A series of maleimides bearing electron-releas-
ing and neutral groups at the 4-position of the N-aryl group
underwent smooth symmetry breaking upon treatment with
1a leading to the formation of the desired N-aryl succinimides
in moderate to good yields and high enantioselectivity (3a–
3k). Our efforts to prepare a substrate with electron-with-
drawing group failed. In the case of 3a, the structure and the
Table 1: Optimization of the reaction conditions.[a]
Entry Variation of the standard condi-
tions[a]
Yield of
er of 3a[c]
3a [%][b]
1
2
3
4
5
6
7
8
none
5 instead of 4
6 instead of 4
67
49
56
64
62
58
45
23
74
25
67
72
94:6
91:9
7:93
93:7
94:6
93:7
94:6
98:2
88:12
96:4
94:6
95:5
95:5
DBU instead of DIPEA
DMAP instead of DIPEA
Cs2CO3 instead of DIPEA
KOt-Bu instead of DIPEA
THF instead of toluene
CH2Cl2 instead of toluene
DME instead of toluene
LiCl as additive (20 mol%)
20 mol% thiourea as additive
9
10
11
12
13
20 mol% thiourea & 4 ꢀ MS additives 74 (70)[d]
Scheme 2. Scope of N-aryl maleimides. General conditions: 1a
(0.5 mmol), 2 (0.25 mmol), 4 (10.0 mol%), DIPEA (20 mol%), thio-
urea (20 mol%), 4 ꢀ MS (100 mg), toluene (2.0 mL), 258C and 12 h,
then PDC (2.0 equiv), CH2Cl2 (2.0 mL), 258C, 12 h. Yields of isolated
products are given and the er value was determined by HPLC analysis
on a chiral stationary phase.[a] Structure and stereochemistry confirmed
by X-ray analysis.[b] Oxidation was performed for 24 h.[c] 15 mol% of 4
was used and the reaction mixture stirred for 24 h.
[a] Standard conditions: i) 1a (0.25 mmol), 2a (0.125 mmol), 4
(10 mol%), DIPEA (20 mol%), toluene (1.0 mL), 258C and 12 h; ii) PDC
(2.0 equiv), CH2Cl2 (1.0 mL), 258C, 12 h. [b] Determined by 1H NMR
analysis of crude products using CH2Br2 as the internal standard. [c] The
er value was determined by HPLC analysis on a chiral stationary phase.
[d] Isolated yield.
2
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stereochemistry were confirmed by X-ray analysis.[20] The
presence of heteroaryl moiety (3g), halogens (3d–3 f), and
carbon-carbon multiple bonds (3h–3j) did not affect the
outcome of the reaction. Moreover, substrates having amino,
iodo and nitro groups para to the tert-butyl moiety afforded
the desired products in moderate to good yield and selectivity
(3l–3n). The tert-butyl group was required to restrict the
rotation about the C-N axis. Replacement of tert-butyl with
dimethyl phenyl afforded the product 3o in 43% yield and
93:7 er. Notably, use of isopropyl group considerably reduced
the selectivity (3p).
Next, we evaluated the scope of dialdehydes. Various
symmetric aromatic 1,2-dialdehydes were well tolerated
under the present conditions and the desired N-aryl succini-
mides 3q–3t were formed in moderate to good yields and high
selectivity (Figure 2). Notably, the naphthalene- and anthra-
cene-derived 1,2-dialdehydes afforded the desired chiral
products 3s and 3t, respectively in good yields and excellent
er values.
Scheme 3. Tentative mechanism of the reaction and the possible
transition states. The distances are in ꢀ.
Figure 2. Scope of the dialdehydes. See the footnote of Scheme 2 for
the reaction conditions.[a] For the NHC-catalyzed step, the reaction
mixture was stirred for 24 h.[b] The reaction performed in 0.1 mmol
scale.
Finally, the carbinol VI was oxidized by PDC to form the
desired product 3a. Our efforts to isolate the Stetter adduct
by varying the second CHO group with other electron-
withdrawing groups failed, which sheds light on the impor-
tance of the intramolecular aldol reaction to derive at the
thermodynamically more stable product.
To get insight into the origin of C-N axial chirality, we
have performed additional experiments. When the reaction
was performed using 2q where the tert-butyl group at the 2-
position of N-aryl ring was replaced by a methyl group, the
reaction afforded the desired product 3u in 52% yield, but
the product was racemic (Scheme 4). It is likely that replacing
the tert-butyl with a methyl group allows the unrestricted
The proposed mechanism of the reaction is presented in
Scheme 3. The free carbene I generated from the chiral
triazolium salt 4 adds to the dialdehyde 1a to form the
tetrahedral intermediate II,[21] which undergoes a proton
transfer to deliver the Breslow intermediate III.[22] The
nucleophilic addition of III to the electron-poor double
bond of maleimide 2a in an enantio-determining step (Re-
face addition)[19] forms the enolate intermediate IV, which
undergoes a proton transfer to form the amide enolate V. The
formation of a stable and more substituted V is likely a reason
for the proton transfer. The amide enolate V can be converted
to carbinol VI[23] in two pathways. In pathway I, the NHC
remains coordinated during the intramolecular aldol reaction
and results in the formation of VI via the transition state TS-
1.[24] In an alternative scenario, where the aldol reaction takes
place after the NHC dissociation, pathway II would be
followed. In this pathway, a proton abstraction from the base
and concomitant NHC dissociation leads to intermediate VII.
This is followed by intramolecular aldol reaction via the
transition state TS-2 and a final proton transfer to afford the
carbinol VI. A comparison of both pathways reveals that the
transition state without the NHC, that is, TS-2 is lower in
energy by 5.4 kcalmolÀ1 than TS-1. This shows that the aldol
reaction is likely to take place in the absence of NHC.[25]
À
rotation of the C N bond. Similar was the observation with
the maleimide 2r bearing an isopropyl group.
To get further insights, we have calculated the rotational
À
barrier for the C N bond in 3a experimentally and using
À
Scheme 4. Studies towards (un)restricted C N bond-rotation.
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density functional theory (DFT) studies. Following the
Conflict of interest
procedure of Curran,[26] DGrot for the C N bond in 3a was
determined as 32.4 kcalmolÀ1 by noting the change in er at
various time intervals maintaining the temperature at 1208C
(Figure 3a).[19] This is in agreement with the calculated value
of 33.9 kcalmolÀ1 using DFT at the SMD(toluene)/M06-2X/6–
311 ++ G(d,p) level of theory at 298 K.[24,27] Moreover, the
calculated free energy barriers for methyl and isopropyl
°
À
The authors declare no conflict of interest.
Keywords: asymmetric catalysis · axial chirality ·
desymmetrization · N-heterocyclic carbenes · organocatalysis
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Figure 3. a) Plot for the determination of C-N rotation barrier; b) Stud-
À
ies on C N bond rotation with temperature.
To get more information on the restriction of rotation
around the C-N axis, the product 3a was heated in toluene for
2 h and noted the change in ee values. Interestingly, up to
À
908C, the restriction in rotation around the C N bond axis
was observed preserving the ee value of 90% (Figure 3b).
Notably, when 3a was heated at 1108C, the ee dropped to
84%. With further increase in temperature, the ee dropped
and at 1508C, the product was almost racemic indicating the
À
unrestricted rotation of the C N bond at this temperature.
In conclusion, we have reported the desymmetrization of
N-aryl maleimides for the enantioselective synthesis of N-aryl
À
succinimides bearing an axially chiral C N bond. This
carbene involved process proceeds via the intermolecular
Stetter reaction followed by an intramolecular aldol reaction
and a subsequent oxidation in tandem. Remote axial chirality
control, broad scope, mild conditions etc are the notable
features of this reaction. The calculated higher barrier with
tert-butyl group using DFT clearly indicates its role in
selectivity.
Acknowledgements
This activity was supported by the SERB, Government of
India (File Number: DIA/2018/000018) in the form of
a Distinguished Investigator Award to A.T.B. G.J. thanks
IISc for a start-up grant. S.B. and S.S. thank IISc and S.D.
thanks KVPY respectively for the research fellowship. We
thank Mr. Arghya Ghosh and Dr. Tamal Kanti Das for their
help in preparing some substrates.
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2020, 22, 5407; b) Z. Huang, X. Huang, B. Li, C. Mou, S. Yang,
4
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[19] See the Supporting Information for details.
[20] Deposition Number 2047469 (for 3a) contains the supplemen-
tary crystallographic data for this paper. These data are provided
Manuscript received: December 21, 2020
Revised manuscript received: March 4, 2021
Accepted manuscript online: March 22, 2021
Version of record online: && &&, &&&&
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Communications
Asymmetric Catalysis
S. Barik, S. Shee, S. Das, R. G. Gonnade,
G. Jindal,* S. Mukherjee,*
A. T. Biju*
&&&& — &&&&
NHC-Catalyzed Desymmetrization of N-
Aryl Maleimides Leading to the
Atroposelective Synthesis of N-Aryl
Succinimides
NHC-catalyzed atroposelective synthesis
of N-aryl succinimides having an axially
chiral N-aryl maleimides followed by oxi-
dation. Preliminary studies on the rota-
À
À
chiral C N bond via the desymmetriza-
tion barrier for the C N bond and
detailed DFT studies on the mechanism
are also provided.
tion of N-aryl maleimides is presented.
The reaction proceeds via the Stetter-
aldol cascade of dialdehydes with pro-
6
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