Organocatalytic asymmetric synthesis of polyfunctionalized cyclohexene-carbaldehydes via dominom reaction between 3-(benzyloxy)propanal and β-nitroalkenes

Article abstract of DOI:10.1016/j.tetlet.2017.05.002

A novel domino Michael/retro-oxa-Michael/Michael/Aldol condensation reaction was developed via the reaction of 3-(benzyloxy)propanal with β-nitroalkenes catalyzed by secondary amine. Using this methodology, optically pure polyfunctionalized cyclohexene-carbaldehydes were prepared straightforwardly from two simple starting materials in good yield with excellent stereoselectivity.

Full text of DOI:10.1016/j.tetlet.2017.05.002

Accepted Manuscript
Organocatalytic Asymmetric Synthesis of Polyfunctionalized Cyclohexene-
carbaldehydes via Domino Reaction between 3-(benzyloxy)Propanal and β-
Nitroalkenes
Hong-tao Jiang, Qun Jiang, Cheng-sheng Ge
PII:
S0040-4039(17)30577-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.05.002
TETL 48895
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
24 February 2017
29 April 2017
4 May 2017
Please cite this article as: Jiang, H-t., Jiang, Q., Ge, C-s., Organocatalytic Asymmetric Synthesis of
Polyfunctionalized Cyclohexene-carbaldehydes via Domino Reaction between 3-(benzyloxy)Propanal and β-
Nitroalkenes, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.05.002
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Organocatalytic Asymmetric Synthesis of Polyfunctionalized Cyclohexene-carbaldehydes via
Domino Reaction between 3-(benzyloxy)Propanal and β-Nitroalkenes
Hong-tao Jiang,a*Qun Jiang,a Cheng-sheng Gea,b*
aCollege of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014,
P.R.China
bCollege of Chemistry and Materials Engineering, Quzhou University; Quzhou 324000, P.R.China
Fax: +86- 571-88320598,E-mail:jht@zjut.edu.cn
Fax: +86-570-8015339, E-mail: gechengsheng@qzu.zj.cn
Abstract:
A novel domino Michael/retro-oxa-Michael/Michael/Aldol condensation reaction was developed
via the reaction of 3-(benzyloxy)propanal with β-nitroalkenes catalyzed by secondary amine.
Using this methodology, optically pure polyfunctionalized cyclohexene-carbaldehydes were
prepared straightforwardly from two simple starting materials in good yield with excellent
stereoselectivity.
Polysubstituted cyclohexene-carbaldehydes represent important substructures widely found in
biologically active natural compounds and medicines.1 They are useful building blocks in organic
synthesis.2 These complex molecules with multiple stereocenters can be constructed via
biomimetic approaches from simple precursors.3 In particular, organocatalytic asymmetric domino
reactions may enable the construction of complex molecules in one-pot avoiding the purification
of intermediates and protecting/deprotecting manipulation.4 A variety of efficient organocatalytic
multi-component domino reactions through enamine and iminium activation were reported.5 In
2008, Enders developed an elegant three-component domino reaction of α,β-unsaturated
aldehydes, nitroalkenes and aldehydes via a Michael/Michael/aldol condensation sequence to
make tri- and tetrasubstituted cyclohexene carbaldehydes with excellent enantioselectivity.6 Gong
found a three-component oxa-Michael/Michael/Michael/Adol cascade condensation reaction
catalyzed by secondary amine of simple alcohol, acrolein and β-nitroalkene to give
multifunctional cyclohexene-carbaldehydes with excellent enantioselectivity in moderate yield.7
Chen constructed multifunctional cyclohexene-carbaldehydes via an asymmetric
α,γ-regioselective [3+3] formal cycloaddition of α,β-unsaturated aldehyde and 2-nitroallylic
acetate catalyzed by a secondary amine.8 Very recently, Enders disclosed a stereoselective
synthesis of functionalized complex tricyclic polyethers using the combination of secondary
amine and lanthanide catalysis in one-pot quadruple reaction/Hetero-Diels–Alder sequence.9 The
reported domino reactions involved the aza-Michael addition of alcohols, phenols, amines, thiols
to α,β-unsaturated aldehydes.7.10 However asymmetric multi-component domino reaction
involving retro-oxa-Michael addition of β-alkoxy propanal was not investigated to the best of our
knowledge. In this paper， we disclosed a novel Michael/retro-oxa-Michael/Michael/Aldol
condensation reaction between 3-(benzyloxy)propanal and β-nitroalkenes to provide
polyfunctionalized cyclohexene-carbaldehydes in good yield with excellent stereoselectivity，as
outlined in Scheme 1.

Ph
Ph
Bn
O
O
N
(10 mol%)
H
OTMS
I
Ar
+
OBn
2 O
NO2
Ar
NO2
1a
2
3
Scheme 1. Organocatalytic domino reaction between 3-(benzyloxy)propanal and β-nitroalkenes
In our proposal as shown in Scheme 2, the reaction between 3-(benzyloxy)propanal 1a and
β-nitrostyrene 2a could afford Michael adduct 4, which could be converted into
(3S,4R)-4-phenylpyrrolidine-3-carboxylic acid, a key intermediate for the synthesis of
class-selective histone deacetylase inhibitor.11 To prove our hypothesis, the mixture of
3-(benzyloxy)propanal 1a (2.5 equiv) and β-nitrostyrene 2a (1 equiv) was stirred in the presence
0
of 10 mol% of (S)-diphenylprolinol silyl ether I in n-hexane at 0 C for 24 hours. To our
disappointment, none of desired Michael adduct 4 was obtained. Unexpectedly, compound 3a
was isolated in good yield (74%) and excellent stereoselctivity (>20:1 d.r.; >99% ee). The
structure of 3a was confirmed by the comparison with that of literature7 and the absolute
configuration of 3a was unambiguously revealed as 3S,4S,5S ([α]D 20 =+78.40 (C = 2 in CHCl3); lit.
[α]D 20 =+80.90 (C = 2 in CHCl3)).
Ph
Bn
Ph
O
O
O
N
(20 mol%)
H
OTMS
I
Ph
+
OBn
2 O
NO2
Ph
OBn
NO2
Ph
NO2
3a
1a
2a
4 (not detected)
Scheme 2. Domino reaction between 3-(benzyloxy)propanal and β-nitrostyrene
The unexpected results propelled us to further optimize this domino reaction conditions. First,
different solvents were screened. In dichloromethane (DCM) and toluene (Table 1), the domino
product 3a can be formed, however yield is low (26% and 45% respectively, entries 2 and 3). In
isopropanol, 3a was isolated in 71% yield (entry 4). In all above screened solvents, Product 3a
was obtained in excellent enatio- and diastereoselectivity with benzyl alcohol as a main byproduct.
Furthermore, the different substrate 1 was also investigated in this reaction. When the oxygen
atom of β-position of substrate 1 was protected with electron-donating p-methoxyphenyl other
than benzyl, the domino product 3b was obtained in 79% yield (entry 5). However, when the
oxygen atom of β-position of substrate 1 was protected with electron-withdrawing benzoyl, the
expected domino product could not be observed and isolated when n-hexane was used as solvent.
Interestingly, an unexpected product 3c was found in 64% yield when the solvent was isopropanol
(entry 6). However, when β-bromopropanal was chosen as substrate for this domino reaction, only
messy reaction mixture was observed in n-hexane, isopropanol and DCM.

Table 1 Optimization of reaction conditions.a
Ph
Ph
X
O
N
(10 mol%)
H
OTMS
I
Ph
+
2
X
O
NO2
Ph
1a, X = BnO; 1b, X = p-MeOPhO
NO2
1c, X = PhCOO; 1d, X = Br
1
2a
3
Entry
1
Solvent
Substrate
Product
Yieldb(%)
74
d.r.b
eec,d(%)
>99
n-hexane
>20:1
>20:1
>20:1
>20:1
>20:1
Bn
OBn
O
O
O
1a
1a
1a
1a
Ph
3a
NO2
2
3
4
5
DCM
toluene
26
45
71
79
>99
>99
>99
>99
Bn
OBn
OBn
O
O
O
3a
Ph
NO2
Bn
O
O
O
3a
Ph
NO2
isopropanol
hexane
Bn
OBn
O
O
O
3a
Ph
NO2
O
OMe
MeO
O
2a
O
O
3b
Ph
NO2
6
isopropanol
64
>20:1
>99
O
O
O
O
Ph
O
1c
3c
Ph
NO2
a
Reactions were carried out with 1 (0.5 mmol), nitrostyrene 2a (0.2 mmol) and catalyst I (0.02
mmol) in solvent (2 mL) at 0 0C for 24 h.
b Yield of isolated diastereomer; d.r. >20:1 by 1H NMR analysis.
c Determined by HPLC analysis on chiral stationary phase.
d Absolute configurations were confirmed with that of the reported compounds7.
n.d.: not determined.
To construct a variety of polysubstituted cyclohexene-carbaldehydes, We further explored the
substrate scope of the Michael/retro-oxa-Michael/Michael/Aldol condensation reaction between
3-(benzyloxy)propanal 1 and various β-nitroalkenes 2 (Table 2). For both β-nitroalkenes with
electon-rich aromatic substituents (such as m-methylphenyl, p-methylphenyl, o-methylphenyl,
1-naphthyl and 2-naphthyl; entries 2, 3, 4, 10 and 11) and electron-deficient aromatic substituents

(such as p-chlorophenyl, p-fluorophenyl, m-fluorophenyl, m-bromophenyl and p-nitrophenyl;
entries 5-9), the domino reaction proceeded efficiently with good yield in high enatio- and
diastereoselectivity. However, for β-nitroalkenes with aliphatic substituents (such as amyl and
propyl), we only obtained complex mixtures. The reaction between 3-(benzyloxy)propanal and
β-nitroalkenes with other strong electron-deficient substrates (such as CF3, CN, CHO) could not
happen and we just recovered starting materials. β-nitroalkenes with heteroaromatic substituents
(such as 4-pyridyl, 3-thienyl, 2-furanyl) was also tested as substrates, only
(E)-2-(2-nitrovinyl)furan 2i gave target product in 36% yield without compromising enatio- and
diastereoselectivity (entry 12).
Table 2 Scope of the domino reactionsa
Bn
O
O
I
(10 mol%)
n-hexane, 0 0C, 24 h
Ar
+
OBn
O
NO2
Ar
NO2
3
1a
Entry
2
Substrate
Product
Yield b(%)
74
d.r.b
ee c(%)
>99
NO2
2a
Bn
1
2
3
4
5
>20:1
>20:1
>20:1
>20:1
>20:1
O
O
3a
NO2
70
73
43
68
>99
>99
>99
>99
Bn
O
O
NO2
2b
3d
NO2
NO2
Bn
O
O
2c
3e
NO2
Bn
O
O
NO2
2d
3f
NO2
Bn
NO2
2e
O
O
Cl
3g
NO2
Cl
NO2
2f
Bn
6
67
>20:1
>99
O
O
F
3h
NO2
F

7
8
Bn
65
62
54
74
75
>20:1
>20:1
>20:1
>20:1
>20:1
>99
>99
>99
>99
>99
F
O
O
NO2
2g
3i
F
NO2
Bn
Br
O
O
NO2
2h
3j
Br
NO2
Bn
NO2
2i
9
O
O
O2N
3k
NO2
O2N
Bn
10
11
O
O
NO2
3l
2j
NO2
Bn
O
O
NO2
2k
3m
NO2
NO2
Bn
12
36
>20:1
>99
O
O
2l
O
3n
O
NO2
a
Reactions were performed with 3-(benzyloxy)propanal 1 (0.5 mmol), nitroalkene 2 (0.2 mmol)
and catalyst I (0.02 mmol) in n-hexane (2 mL) at 0 0C for 24 h.
b Yield of isolated diastereomer; dr >20:1 by 1H NMR analysis.
c
Determined by HPLC analysis on chiral stationary phase and absolute configuration was
deduced from that of 3a.
A tentative reaction mechanism is proposed in Scheme 3. We assume that intermediary enamine
A was first formed from the condensation of 3-(benzyloxy)propanal 1 and (S)-diphenylprolinol
silyl ether I (Scheme 3). Subsequently, the Michael addition of intermediate A with β-nitroalkenes
2 afforded Michael adduct B. Meanwhile, through retro-oxa-Michael addition, intermediate A was
decomposed into intermediary iminium ion C and BnO anion, which deprotonated α-carbon of
nitro on B to get B anion D and benzyl alcohol. Then Michael reaction of intermediate C with D
generated enamine intermediate E, which provided the desired trisubsituted cyclohexene-
carbaldehyde 3 and regenerated catalyst I through an intramolecular Aldol condensation. Indeed,
the good yields compared with that of the reported three-component domino reactions by Gong
and Enders can be explained by the in situ formation of iminium ion and the avoidance of using
unstable acrolein. Based on the proposed mechanism, the outcome of domino reaction between 1c
and 2a can be explained that the retro-oxa-Michael addition of 1c gave intermediary iminium ion
C in the first step, and the intermediary enamine A’’ was formed via oxa-Michael addition

between intermediary iminium ion C and isopropanol in the second step. In the end, the domino
reaction between intermediary enamine A’’ and β-nitrostyrene 2a gave unexpected 3c (Scheme 4).
Bn
O
O
OBn
O
Ph
Ph
1a
N
H
OTMS
Ar
3
I
NO2
Ph
Ph
Aldol condensation
N
OTMS
Ph
Ph
OTMS
A
O
N
BnO
BnO
retro-oxa-Michael addition
Ar
Ph
Ph
E
NO2
Ar
2
N
NO2
OTMS
Michael addition
BnO
H
O
C
BnOH
BnO
H
Ar
O
Michael addition
NO2
BnO
B
Ar
NO2
D
Scheme 3. Proposed catalytic mechanism on the domino reaction.
O
O
O
O
Ph
O
Ph
Ph
1c
N
H
OTMS
Ph
3c
I
NO2
Ph
Ph
Aldol condensation
N
OTMS
O
Ph
Ph
OTMS
A'
Ph
O
N
O
O
retro-oxa-Michael addition
Ph
E'
Ph
Ph
OTMS
Ph
Ph
N
N
NO2
OTMS
BnO
H
A''
OH
C
O
BnOH
oxa-Michael addition
Ph
O
Michael addition
NO2
2a
O
Michael addition
O
H
O
Ph
NO2
B'
Ph
D'
NO2
Scheme 4. Proposed catalytic mechanism to generate product 3c.
In conclusion, as a new example of organocatalytic domino reactions, our reaction sequence
consists of two intermolecular Michael reactions, one retro-oxa-Michael reaction and one

intramolecular aldol condensation. A new straightforward and efficient methodology was
developed to construct optically pure polyfunctionalized cyclohexene-carbaldehydes via the
double use of the starting aldehyde substrate as both the Michael donor and the precursor of
acrolein. Compared with the outcome of the reported three-component domino reactions, optically
pure polyfunctionalized cyclohexene-carbaldehydes can be formed in good yield avoiding the use
of unstable and toxic acrolein. It will be very helpful for the construction of
complex polyfunctionalized cyclohexene-carbaldehydes.
Acknowledgement
We acknowledge the financial support for this study from the National Natural Science
Foundation of China (No. 21472110)
Supplementary data
Experimental procedures and characterization data for the new compounds can be found in the
online version.
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Organocatalytic Asymmetric Synthesis of Polyfunctionalized Cyclohexene-carbaldehydes via
Domino Reaction between 3-(benzyloxy)Propanal and β-Nitroalkenes
Hong-tao Jiang,a* Qun Jiang,a Cheng-sheng Gea,b*
Ph
Ph
(10 mol%)
Bn
N
O
O
H
OTMS
n-hexane, 0 0C, 24 h
Ar
+
OBn
O
NO2
Ar
NO2
Ar = Ph, p-methylPh, m-methylPh, o-methylPh, p-chloroPh, p-fluoroPh,
m-fluoroPh, m-bromoPh, p-nitroPh, 1-naphthyl, 2-naphthyl, 2-furanyl
1a
2
3
36-75% yield, >20:1 d.r., >99% ee

Highlights
. Novel domino Michael/retro-oxa-Michael/Michael/Aldol condensation reaction
. Construction of optically pure polyfunctionalized cyclohexene-carbaldehydes
. Double use of the starting aldehyde substrate