Primary-Secondary Diamine Catalyzed Enantioselective Synthesis of Substituted Cyclohex-2-enones by Cascade Michael-Aldol-Dehydration of Ketones with Chalcones

Article abstract of DOI:10.1055/s-0036-1588976

A simple primary-secondary diamine organocatalyst catalyzes the cascade Michael-aldol-dehydration of chalcones and unmodified ketones to produce substituted cyclohex-2-enones under mild conditions with good yields and high enantio- and/or diastereoselectivities. The success of the catalyst system is possibly due to simultaneous activation of the electrophilic chalcone by iminium formation and the nucleophilic ketone by enamine formation with an overall intramolecular iminium-di-enamine mechanism.

Full text of DOI:10.1055/s-0036-1588976

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
A
S. J. Wagh, G. R. Dhage
Letter
Synlett
Primary-Secondary Diamine Catalyzed Enantioselective Synthesis
of Substituted Cyclohex-2-enones by Cascade Michael–Aldol–
Dehydration of Ketones with Chalcones
Sandip J. Wagh*a
Ganesh R. Dhageb
H2N
(30 mol%)
O
N
R2
O
H
O
R2
a Bio-Organic Division, Bhabha Atomic Research Centre, Trombay,
Mumbai, 400085, India
sandipwagh10@gmail.com
b Department of Chemistry, Ahmednagar College, Ahmednagar,
Station Road, Ahmednagar, Maharashtra, 414001, India
R1
R1 = Ar, Me
Ar
+
R1
Ar
3,5-dinitrobenzoic acid (40 mol%)
28 °C
R2 = H, Me
16 examples;
up to 92% yield;
de = >99%;
ee = 74–99%
Received: 06.02.2017
Accepted after revision: 27.02.2017
Published online: 20.03.2017
compounds8 or a Robinson annelation, comprising consecu-
tive asymmetric Michael addition of an activated methy-
lene/methyne substrate to an α,β-unsaturated ketone or al-
dehyde followed by an intramolecular aldol reaction and
subsequent dehydration.9,10
DOI: 10.1055/s-0036-1588976; Art ID: st-2017-d0088-l
Abstract A simple primary-secondary diamine organocatalyst catalyz-
es the cascade Michael–aldol–dehydration of chalcones and unmodi-
fied ketones to produce substituted cyclohex-2-enones under mild con-
ditions with good yields and high enantio- and/or diastereoselectivities.
The success of the catalyst system is possibly due to simultaneous acti-
vation of the electrophilic chalcone by iminium formation and the nu-
cleophilic ketone by enamine formation with an overall intramolecular
iminium–di-enamine mechanism.
Michael additions of simple ketones to chalcones have
received less attention because of the lower reactivity of
the later.11 Furthermore, Michael–aldol or Michael–aldol–
dehydration cascades on chalcone substrates leading to cy-
clohexanone or cyclohex-2-enone systems are limited to β-
keto ester nucleophiles.9 Jørgensen et al.9a were among the
first to show an enantio- and diastereoselective Michael–
aldol reaction of β-keto esters and enones that provided
functionalized cyclohexanones. A separate dehydration
step then provided chiral cyclohex-2-enones. Chiral phos-
phoric acids have been shown9b to catalyze the Robinson
annulation reaction between β-keto esters and enones to
provide substituted chiral cyclohex-2-enones with excel-
lent enantioselectivities. Substituted chiral cyclohex-2-
enones can be obtained by Michael–aldol–dehydration se-
quence from a β-keto ester such as benzoyl acetate and
chalcones.9d More recent studies9f–i have shown that prima-
ry amine catalyzed Robinson annelation of β-keto esters
with enones can provide substituted chiral cyclohex-2-
enones with good diastereo- and enantioselectivities. In
continuation with our previous study12 on organocatalyzed
Michael–aldol–dehydration sequence reactions for the di-
rect synthesis of nonchiral 3,5-diaryl-cyclohexenones from
acetone and chalcones, we herein disclose an organocata-
lyzed enantioselective cascade Michael–aldol cyclization–
dehydration reaction of chalcones and ketones to give syn-
thetically useful functionalized cyclohex-2-enones in high
yields, and good to high regio- and enantioselectivities
(Scheme 1).
Key words cascade reaction, chalcone, chiral cyclohex-2-enone, or-
ganocatalysis
Asymmetric organocatalysis1 has now become a com-
plement to metal- and enzyme-catalyzed reactions,
spurred by the development of a number of highly enantio-
selective transformations of carbonyl substrates catalyzed
by chiral secondary amines involving enamine2 or iminium
intermediates.3
Cascade reactions,4 in which more than one bond is
formed in a multistep one-pot reaction sequence, are an at-
tractive tool for quick assembly of complex structures with-
out isolation and purification of the intermediates. Recent-
ly, organocatalyzed cascade reactions are gaining populari-
ty because they can be performed in an asymmetric fashion
with high levels of stereocontrol.5
Chiral cyclohex-2-enones are an important class of scaf-
folds and are important starting materials for organic syn-
thesis.6 Thus, considerable attention has been paid to the
development of simple but efficient methods for the syn-
thesis of chiral cyclohex-2-enones using organocatalysis.7
Two approaches described involve either an asymmetric al-
dol cyclization–dehydration of prochiral 1,5-dicarbonyl
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
S. J. Wagh, G. R. Dhage
Letter
Synlett
O
Previous works:
O
Catalyst (30 mol%)
O
O
+
Chiral organocatalyst
O
R1
O
Ph
Ph
Ph
Ph
Ref: 8
R2
4a
6a
5a
R1 = alkyl, aryl
2 = Me, aryl
R1
R2
R
Scheme 2 Michael–aldol–dehydration cascade of chalcone 4a and ac-
etone 5a
O
O
O
O
O
Chiral organocatalyst
R1
CO2R2
R4
R1
R3
+
Ref: 9
CO2R2
R4
R3
The generality of the catalytic system was examined
under the optimized reaction conditions using chalcones
4a–l and acetone (Table 1). The 3,5-diarylcyclohex-2-
enones 6a–l were obtained in moderate to good yields (54–
92%) with good to excellent enantioselectivities (74–98%
ee).
O
Chiral organocatalyst
+
Ar
Ref: 9d
Ar
R1
CO2R2
R1
CO2R2
Present work:
O
O
O
Chiral organocatalyst
R2
Ar
R1
+
R2
Table 1 Organocatalyzed Tandem Michael-Aldol Dehydration of Chal-
cones and Acetonea
Ar
R1
Scheme 1 Preparation of cyclohex-2-enone systems
Catalyst 3 (30 mol%)
O
3,5-Dinitrobenzoic acid
O
O
(40 mol%), t-BuOH
+
Ar1
Ar2
28 °C, 4 d
Secondary amines have proved to be useful for genera-
tion of activated enamines from aldehydes and ketones or
iminium activation of α,β-unsaturated aldehydes.2,3 Chiral
primary amines have recently been extensively used in
enamine activation of aldehyde and ketones.13 However,
α,β-unsaturated ketones do not tend to form iminium ions
with secondary amines due to steric reasons but do so with
primary amines derived from natural cinchona alkaloids
and other molecules.14 We proposed that, for a successful
organocatalytic cascade annelation of simple ketones and
chalcones, simultaneous enamine activation of the ketone
and iminium activation of chalcone would probably be nec-
essary in an intramolecular fashion to facilitate the process.
Based on this hypothesis, we selected commercially avail-
able chiral primary diamines 1,15 216, and primary-second-
ary diamine 317 (Figure 1).
Ar1
Ar2
4a–l
5a
6a–l
Entry
Chalcone
Ar1
Ar2
Product
ee
yield (%)b
(%)c
1
4a
4b
4c
4d
Ph
Ph
6a 80
6b 80
6c 92
89
89
98
96
2
Ph
Ph
Ph
4-ClC6H4
4-BrC6H4
4-MeOC6H4
3
4d
6d 54
[83]e
5f
6
4e
4f
Ph
Ph
Ph
Ph
4-F3CC6H4
4-FC6H4
6e 87
6f 75
6g 80
6h 73
94
80
78
74
82
7f,g
8
4g
4h
4i
4-NCC6H4
3-ClC6H4
9d
4-MeOC6H4
Ph
6i 60
[81]e
10f,g
11
4j
4-O2NC6H4
4-BrC6H4
4-BrC6H4
Ph
6j 81
6k 70
6l 79
88
84
80
Ph
Ph
H2N
N
4k
4l
Ph
H2N
NH2
H
H2N
NH2
12
4-FC6H4
1
2
3
a Unless otherwise specified, the reaction was carried out using optimized
conditions.
Figure 1 Structure of diamine catalysts used in this study
b Yield of the isolated product after flash chromatography.
c Determined by HPLC on a chiral stationary phase.
d The reaction was performed over 6 d.
The reaction of chalcone 4a and acetone 5a to give 3,5-
diphenylcyclohex-2-enone (6a) was chosen as the model
reaction for the catalyst evaluation (Scheme 2). A large
number of experiments was performed to optimize the
process in terms of catalyst, solvent, additive, and condi-
tions (see Supporting Information). The optimum condi-
tions found utilized one equivalent of chalcone 4a, 15
equivalents of acetone 5a, 0.3 equivalents of catalyst 3, and
0.4 equivalents of additive 3,5-dinitrobenzoic acid in t-
BuOH (0.4 M) as solvent at 28 °C for 4, furnishing 3,5-di-
phenylcyclohex-2-enone 6a in 80% yield and with 88% ee.18
e Yield based on recovered starting material.
f The reaction was performed over 3 d.
g The reaction was carried out in t-BuOH/toluene (4:1) to maintain homo-
geneity.
The reaction of acetone and chalcones with electron-
donating substituents on aroyl or styryl components were
sluggish and remained incomplete (Table 1, entries 4 and
9); whereas the reactions of acetone and chalcones substi-
tuted with electron-withdrawing groups on both the aryl
rings were complete and gave very good yields of cyclohex-
2-enones.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
S. J. Wagh, G. R. Dhage
Letter
Synlett
Further applications and scope of the catalytic system
were examined with less reactive chalcones devoid of an
aryl group adjacent to carbonyl functionality. We were
pleased to see that the catalytic system worked well with
chalcones 7a,b and acetone to provide the desired 5-aryl-3-
methylcyclohex-2-enones 8a,b but with lower yield; albeit
better stereoselectivity (Scheme 3).
Catalyst 3 (30 mol%)
O
3,5-Dintrobenzoic
Figure 3 ORTEP diagram of 9b
O
O
acid (40 mol%)
28 °C, 96 h
46–47%
+
Me
Ar
Me
Ar
7a; Ar = Ph
7b; Ar = 4-BrC6H4
5a
8a; Ar = Ph, ee = 90%
8b; Ar = 4-BrC6H4, ee = >99%
N
+
N
O
NH2
O
N
H
H
+
N
H
H
+
Ph
3
N
Scheme 3 Reaction of unreactive chalcones with acetone
5a
Ph
Ph
Ph
Ph
Ph
4a
10
11
We also investigated butan-2-one 5b and chalcones
4a,c. Interestingly, the reaction took place with the exclu-
sive formation of a single regio- and diastereoisomers 9a
and 9b, respectively (Scheme 4). The yields were moderate
but the enantioselectivities were uniformly high.
H2N
Ph
N
N
+
N
H
Ph
Ph
O
Ph
12
13
Catalyst 3 (30 mol%)
O
3,5-Dintrobenzoic
O
acid (40 mol%)
O
Me
Ar
O
H2N
+
N
H2N
+
+
N
28 °C, 96 h
33–43%
Ph
Ar
Ph
5b
Ph
Ph
Ph
HO
4a; Ar = Ph
4c; Ar = 4-BrC6H4
Ph
9a; Ar = Ph, de = >99%, ee = 80%
9b; Ar = 4-BrC6H4, de = >99%, ee = 86%
Ph
Ph
14
15
6a
Scheme 4 Reaction of chalcones with 2-butanone 5b
Scheme 5 Proposed mechanism of diamine-catalyzed Michael–aldol–
dehydration cascade
The absolute configuration of 5-(4-bromophenyl)-3-
phenylcyclohex-2-enone (6c) was established by X-ray
crystallography19 and was found to be 5R (Figure 2).
cone 4a and nucleophilic ketone by the primary-secondary
diamine catalyst 3 via iminium and enamine formation,11c
respectively (Scheme 5).
In the doubly activated species 10, the enamine reacts
intramolecularly at the less hindered Re-face 4-position of
the iminium of chalcone leading to intermediate 11 which
reorganizes to a new iminium–enamine 12. At this stage a
probable hydrolysis of ketone iminium leads to ketone–
enamine 13 which then undergoes an intramolecular aldol
reaction to give the iminium intermediate 14. Dehydration
followed by iminium hydrolysis then leads to the (5R)-3,5-
diphenylcyclohex-2-enone (6a).
Figure 2 ORTEP diagram of 6c
In conclusion, we have developed a cascade Michael–al-
dol–dehydration of chalcones and simple ketones leading to
substituted chiral cyclohex-2-enones using a readily avail-
able primary-secondary diamine derived from proline. The
products were formed in good yield and with acceptable re-
gio-, stereo-, and enantioselectivity. This provides a meth-
od for making chiral 3,5-diarylcyclohex-2-enones where
both the aryl rings sourced from a chalcone substrate.
The absolute configuration of the other products
6a,b,d–l and 8a,b were assigned by analogy. The absolute
configuration of 9b was also established X-ray crystallogra-
phy19 and was assigned to be 5R,6S (Figure 3).
The promotion of the cascade process can be explained
through simultaneous activation of the electrophilic chal-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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S. J. Wagh, G. R. Dhage
Letter
Synlett
Acknowledgment
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S.J.W. is grateful to the Council of Scientific and Industrial Research
(CSIR), New Delhi for a Senior Research Fellowship, Professor Sunil
Kumar Ghosh (BARC, Mumbai) for continuous support and guidance
and Professors Mukesh Kumar (BARC, Mumbai) and S. Mobin (IIT, In-
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588976.
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(18) A mixture of chalcone 4a (0.2 mmol), acetone (3 mmol),
organocatalyst 3 (0.06 mmol), 3,5-dinitrobenzoic acid (0.08
mmol) in t-BuOH (500 μL) was stirred at r.t. for 96 h. After
column chromatography (eluent: 95:5, hexane–EtOAc) a white
solid was obtained (40 mg, 80%). The enantiomeric excess (ee)
1372, 1265, 761 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.69–2.82
(m, 2 H, CH2), 2.95 (ddd, = 2.4, 11.2, 17.8 Hz, 1 H, CHAHBCO), 3.07
(dd, J = 4.4, 17.8 Hz, CHAHBCO, 1 H), 3.43–3.51 (m, 1 H, PhCH),
6.52 (d, J = 1.8 Hz, 1 H, C=CH), 7.29–7.46 (m, 8 H, Ar), 7.53–7.58
(m, 2 H, Ar). 13C NMR (50 MHz, CDCl3): δ = 36.2, 40.9, 43.9,
125.0, 126.1 (2 C), 126.7 (2 C), 127.0, 128.8 (3 C), 130.1, 138.3,
143.1, 158.7 (2 C), 199.2 (CO).
(19) The structures of 6c (CCDC 1041621) and 9b (CCDC 1041622)
were confirmed by single-crystal X-ray data. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/getstructures.
was determined by HPLC using
a Chiralcel OJ-H column
(hexane–i-PrOH = 90:10); flow rate 1.0 mL/min; tR (major) =
26
18.3 min, tR (minor) = 21.3 min (ee 89%); [α]D +34.8 (c 0.5,
CH2Cl2); mp 92–93 °C. IR (KBr): 1663 (CO), 1605, 1497, 1444,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E