Asymmetric Reaction of p-Quinone Diimide: Organocatalyzed Michael Addition of α-Cyanoacetates

Article abstract of DOI:10.1021/acs.orglett.8b00771

Hitherto unknown catalytic enantioselective transformation of p-quinone diimides is achieved using chiral bifunctional organic molecules. Bifunctional thiourea compounds catalyze the Michael addition of cyanoacetates with excellent yields and enantioselec

Full text of DOI:10.1021/acs.orglett.8b00771

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Asymmetric Reaction of p‑Quinone Diimide: Organocatalyzed
Michael Addition of α‑Cyanoacetates
Sivakumar N. Reddy,†,∥ Venkatram R. Reddy,†,∥ Shrabani Dinda,‡,∥ Jagadeesh Babu Nanubolu,§,∥
and Rajesh Chandra*,†,∥
‡
§
†Organic Chemistry Division II (CPC), Centre for Molecular Modelling, and Centre for X-ray Crystallography, CSIR - Indian
Institute of Chemical Technology, Hyderabad 500007, India
∥Academy of Scientific and Innovative Research, Indian Institute of Chemical Technology, Hyderabad 500007, India
S
* Supporting Information
ABSTRACT: Hitherto unknown catalytic enantioselective
transformation of p-quinone diimides is achieved using chiral
bifunctional organic molecules. Bifunctional thiourea com-
pounds catalyze the Michael addition of cyanoacetates with
excellent yields and enantioselectivities. The initially formed
Michael adducts undergo cyclization to yield functionally rich,
fused cyclic imidines bearing a quaternary benzylic chiral
center. Density functional theory calculations of the competing
transition states (TSs) were carried out to explain the observed stereochemical outcome.
uinones are interesting structural motifs and have
organocatalysis is the conjugate addition of nucleophiles to
electron-deficient alkenes,16 and a large number of carbon and
heteroatom nucleophiles have been utilized in these reactions.
However, literature reports on the organocatalyzed asymmetric
transformations of benzoquinonoid compounds are few and far
between, probably due to their propensity to form electron/
charge transfer complexes with many of the catalyst classes.
Among the quinonoids, quinones have attracted the most
attention,17 while quinone monoimides18 have also garnered
some interest (Scheme 1). It is worth noting that in the majority
of the reports available in the literature, p-naphthoquinone is the
quinonoid compound of choice. More recently, enantioselective
transformations of o-quinones, o-quinone monoimides, and o-
quinone diimides have been achieved by Lectka’s group.19
Q attracted immense attention due to their biological
relevance, chemical versatility, and industrial importance.1
Their unique electronic properties, which play a crucial role in
the biological world, often render quinones nonamenable to a
variety of chemical reactions that proceed well with other
electron-deficient alkenes. Cycloaddition and nucleophilic
addition are the most widely used functional transformations
of quinones. The chemistry of p-quinone diimines/diimides, in
stark contrast to quinones, has garnered only limited attention,
although their existence dates back to the early 20th century.2
The bulk of the quinone imide chemistry, akin to their oxa
analogues, has centered around cycloaddition and nucleophilic
addition. Nucleophilic additions of phenol and thiophenol, [3 +
2] cycloaddition of diazomethane, Freidel−Crafts reaction with
benzene, etc. were reported by Adam’s group.3 Silyl enol ethers,4
enamines,5 sodium arenesulfinate,6 azide,7 ketene S,N-acetals,8
and piperidine9 have been reported to add to quinone diimides,
often promoted by Lewis/mineral acids. Recent reports indicate
that allyltin10 and allylsilane11 undergo conjugate addition to p-
quinone diimides. The addition of active methylene compounds,
under alkaline conditions, to p-quinone imides was also studied
by Adams et al., although the exact nature of the adducts was not
fully established.12 Catalytic enantioselective transformation of
p-quinone diimides is one area that still remains in total oblivion,
despite some data indicating that more than 80% of FDA-
approved small molecule drugs bear at least one nitrogen atom.13
Moreover, the direct functionalization of diiminoquinonoid has
been employed to improve the poor processability of polyaniline
(PAN), which is an important conducting polymer.14
Scheme 1. Organocatalyzed Carbon Acid Addition to p-
Quinonoids
Organocatalysis, in general, and the enantioselective variant, in
particular, has recently garnered a lot of interest.15 One class of
reactions that has benefited immensely with the advent of
Received: March 7, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00771
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Jørgensen’s group has studied the enantioselective addition of
enamines to in situ generated p-quinonoids. p-Quinone and p-
quinone monoimide furnished the corresponding Michael
adducts, while p-benzoquinone diimides did not participate in
the reaction.17d Intrigued by the conspicuous absence of
literature on p-quinone diimides as substrates in catalytic
asymmetric transformations, we initiated a study on the
enantioselective reactions of this class of compounds catalyzed
by chiral organic molecules, and our initial findings are reported
herein.
complementary hydrogen-bonding functionalities, these chiral
bifunctional molecules can, in principle, activate both the
electrophilic and nucleophilic counter partsthe p-quinone
diimide and the active methylene compoundwhile possibly
transferring the inherent stereochemical information. To identify
the best conditions, we carried out a catalyst screen, and our
results are compiled in Table 2.
Table 2. Reaction of Cyanoacetate with p-Quinone Diimide:
a
Catalyst Screen
Jørgensen’s seminal paper on the addition cyclic ketoesters to
p-quinones provided us with the starting point, and thus, we
initially employed the cinchona alkaloids as catalysts. Under
various reaction conditions, p-benzoquinone ditoluenesulfoni-
mide (1) and α-substituted cyanoacetate (2a) were reacted in the
presence of a catalytic amount of cinchonine, cinchonidine,
quinine, and quinidine. At −30 °C in toluene, the reaction
afforded the adduct 3a in excellent yield but with poor selectivity
(Table 1).
b
c
entry
cat.
yield (%)
ee
1
2
3
4
5
6
E
F
G
H
I
>90
>90
>90
>90
>90
>90
−38
−41
65
Table 1. Cinchona Alkaloid Catalyzed Cyano Ester Addition
85
a
to p-Quinone Diimide
91
J
−60
a
Reaction conditions: 1 (0.12 mmol), 2a (0.12 mmol), catalyst (20
mol %) in 2 mL of toluene. Isolated yield after column
chromatography. Determined by HPLC using a chiral column
b
c
(Chiralpak-IC3).
b
c
We have employed squaramide and thiourea-derived bifunc-
entry
cat.
solvent
temp (°C)
yield (%)
ee
tional catalysts E−J (Figure 1). Although the squaramide
1
2
A
A
A
B
C
D
B
B
B
B
toluene
toluene
toluene
toluene
toluene
toluene
o-xylene
CH2Cl2
CHCl3
THF
0
−20
−30
−30
−30
−30
−30
−30
−30
−30
>90
>90
>90
>90
>90
>90
>90
80
−14
−20
25
3
4
5
20
6
−25
20
7
8
9
>90
10
a
Reaction conditions: 1 (0.12 mmol), 2a (0.12 mmol), catalyst (20
b
mol %) in 2 mL of solvent. Isolated yield after column
chromatography. Determined by HPLC using a chiral column
c
(Chiralpak-IC3).
The structural analysis of the adduct 3a revealed that the
reaction sequence involved a cyclization step (aza-Pinner type)
subsequent to the initial Michael addition, forming a cyclic
amidine, the bis-nitrogen analogue of γ-lactone. Interestingly, the
functionally rich product bears a quaternary chiral center directly
attached to a phenyl ring.20 The choice of α-substituted
cyanoacetate (2a) as the active methylene compound was
deliberate, as it offers a variety of advantages such as high
reactivity, functional group abundance, and configurational
stability of the newly formed quaternary center.21 It is worth
mentioning that the reaction of α-unsubstituted cyanoacetates
with p-quinone diimide 1 under identical reaction conditions
resulted in an intractable mixture. In spite of the mediocre
selectivity observed, the initial results encouraged us to pursue
the reaction further, since the prior attempts to carry out even the
achiral version of this reaction under various conditions did not
lead to any meaningful products.12 We then turned our attention
to chiral bifunctional organic molecules.22 Endowed with
Figure 1. Bifunctional catalysts employed in the study.
catalysts were better when compared to the cinchona alkaloids
(A−D), the selectivity was only moderate (entries 1−3; Table 2).
Gratifyingly, the thiourea catalysts were proven ideal with
cinchona alkaloid derived molecules H and I affording the
product in excellent yield and selectivity. The selectivity was
moderate with Takemoto catalyst J. Our efforts to isolate the
initial Michael adduct were unsuccessful, and in all cases, the
Michael−aza Pinner product resulted. We believe that the
conjugate acid of the hydrogen-bond acceptor of the bifunctional
catalyst (a quaternary ammonium species) would further act as a
proton source and catalyze the cyclization step.
́
Having identified Soos’ catalyst (I) as the best of the group, we
proceeded to explore the generality of the reaction by employing
B
DOI: 10.1021/acs.orglett.8b00771
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
different cyano esters, as illustrated in Scheme 2. It is evident that
catalyst I is extremely efficient in promoting the reaction. In all
Scheme 2. Reaction of Cyanoacetate with p-Quinone
a
Diimide: Substrate Screen
a
The yields reported are isolated yields; ee values were determined by
chiral HPLC; the absolute configuration of 3b was determined by
single-crystal X-ray analysis.
Figure 2. (I) Activation mode A; (II) activation mode B; (III−VI) C−C
bond-forming TSs calculated at the M06-2X/def2-TZVPP level of
theory for major and minor products through activation modes A and B.
(Noncritical hydrogen atoms are omitted for clarity. All distances are in
pm. ΔΔG⧧, in kcal mol−1, is the free energy difference with reference to
the mode A TSmajor. Carbon atoms participating in the C−C coupling
are enclosed in red circles.)
cases, cyclic imidine, the addition−cyclization product, is formed
in high yields. Enantioselectivity is also excellent, ranging from 76
to 91%, except for 3k, in which case the reaction proceeds with
moderate selectivity (50% ee). The absolute configuration of 3b
was determined as (S) by single-crystal X-ray structure analysis
(see the Supporting Information, SI). This particular reaction
was carried out on a 1.2 mmol scale, and the yield and the
selectivity obtained were comparable to small-scale reaction (see
the SI).
To gain insight into the mechanism of the reaction, density
functional theory (DFT) calculations were carried out employ-
ing the M06-2X functional. The initial step in the reaction
sequence is the deprotonation of the active methylene
compound, which precedes the rate-determining C−C bond-
forming step. There are at least two distinct activation modes
possible, depending on the substrate−catalyst alignment at the
active space stabilized by multiple hydrogen-bonding inter-
actions. In one of the modes, the quinone diimide (electrophile)
is activated by the thiourea moiety of the catalyst, while the active
methylene compound (nucleophile) binds to the protonated
amine (quinuclidine ring) moiety of the catalyst (mode A, I
Figure 2). In mode B, the quinone diimide is bound to the
protonated quinuclidine ring of the catalyst, and the active
methylene compound interacts with the thiourea part of the
catalyst (II). Since these prereaction complexes I and II
equilibrate rapidly, their relative stabilities are unlikely to play
any role in the outcome of the reaction. Hence, the C−C bond-
forming transition state (TS) energies in both modes are crucial.
The summary of the DFT calculation studies is given in Figure 2
(see the SI for details). The lowest energy TS corresponds to
mode A TSmajor, which leads to the major product formed
experimentally as well. The mode B TS corresponding to major
product, mode B TSmajor, is nearly of the same energy (ΔΔG⧧ =
0.28 kcal mol−1). Unlike the systems with nitroalkane,23 here,
both modes are equally probable. Notably, the TSs in both
modes corresponding to the minor product, TSminor, were
appreciably high in energy with respect to the mode A TSmajor
.
The hydrogen-bonding and π−π stacking interactions are key
components contributing to the relative stability of the TSs.
In summary, we have achieved the first catalytic asymmetric
reaction of p-quinone diimides, the organocatalytic Michael
addition of cyanoacetates. Interestingly, even the achiral version
of this reaction does not have any literature precedence. Chiral
bifunctional molecules efficiently promote the reaction in
excellent yield and selectivity, affording the functionally rich
cyclic imidines with an all-carbon quaternary chiral center
directly attached to a phenyl ring.24 Further, relative energies
C
DOI: 10.1021/acs.orglett.8b00771
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
■
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* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00771.
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Experimental procedures, characterization details, 1H, 13C
NMR spectra and HPLC data of all new compounds, and
computational details and coordinates (PDF)
Accession Codes
CCDC 1457062 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
2007, 46, 5515. (b) Siau, W. − Y.; Li, W.; Xue, F.; Ren, Q.; Wu, M.; Sun,
S.; Guo, H.; Jiang, X.; Wang, J. Chem. - Eur. J. 2012, 18, 9491.
■
Corresponding Author
*E-mail: rajeshc@iict.res.in.
ORCID
́
(c) Aleman, J.; Cabrera, S.; Maerten, E.; Overgaard, J.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2007, 46, 5520. (d) Jensen, K. L.; Franke, P. T.;
Nielsen, L. T.; Daasbjerg, K.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2010, 49, 129.
Rajesh Chandra: 0000-0001-9792-5031
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Department of Biotechnology, New
Delhi, is gratefully acknowledged (6242-P85/RGCB/PMD/
DBT/RJCH/2015). S.N.R. and V.R.R. thank CSIR, New Delhi,
for financial assistance in the form of a research fellowship. S.D.
thanks DST for the WOS-A fellowship. We also acknowledge T.
Ramesh Babu, CPC Division, CSIR-IICT, Hyderabad, for some
of the HPLC data. Manuscript number IICT/Pubs./2018/052.
(21) Liao, Y. − H.; Liu, X. − L.; Wu, Z. J.; Du, X. − L; Zhang, X. − M.;
Yuan, W. C. Adv. Synth. Catal. 2011, 353, 1720.
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