Enantioselective aminocatalysis: Michael addition of unactivated ketones to nitroolefins catalyzed by D-fructose derived monofunctional primary amine

Article abstract of DOI:10.1007/s12039-017-1371-6

Abstract: Organocatalytic asymmetric Michael addition is considered among the most extensively studied, yet challenging stereoselective reactions due to the fact that the electrophilic prochiral carbon in Michael acceptor lies away from stereodirecting gr

Full text of DOI:10.1007/s12039-017-1371-6

J. Chem. Sci.
© Indian Academy of Sciences
DOI 10.1007/s12039-017-1371-6
RAPID COMMUNICATION
Enantioselective aminocatalysis: Michael addition of unactivated
ketones to nitroolefins catalyzed by D-fructose derived
monofunctional primary amine
KHIANGTE VANLALDINPUIAa,b, PORAG BORAa, GRACE BASUMATARYa,
RAHUL MOHANTAa and GHANASHYAM BEZa,∗
aDepartment of Chemistry, North Eastern Hill University, Shillong, Meghalaya 793 022, India
bDepartment of Chemistry, Pacchunga University College, Aizawl, Mizoram 796 001, India
E-mail: ghanashyambez@yahoo.com
MS received 31 July 2017; revised 24 August 2017; accepted 3 September 2017
Abstract. Organocatalytic asymmetric Michael addition is considered among the most extensively studied, yet
challenging stereoselective reactions due to the fact that the electrophilic prochiral carbon in Michael acceptor
lies away from stereodirecting groups of the catalyst. Although there is a report on stereoselective organocatalysis
in Michael addition employing monofunctional secondary amine, the use of monofunctional primary amine for
the said reaction is not reported till date. In fact, no monofunctional aminocatalyst is reported yet for the synthesis
γ
-nitro carbonyl compounds. Here we report our preliminary results on the enantioselective Michael addition
of different ketones to nitro olefins catalysed by monofunctional primary amine (1) derived from d-fructose.
Keywords. Stereoselective aminocatalysis; monofunctional amine; d-fructose; Michael addition; nitroalkene.
α
1. Introduction
derived from -amino acids and carbohydrates for
asymmetric Michael addition in solvent-free conditions.
Given the importance of stereoselective Michael addi-
tion of carbonyl compounds to nitroalkenes42 in the
Organocatalytic asymmetric Michael addition is one of
the most extensively studied stereoselective reactions in
recent years. The pioneering works of List1 and Barbas2
on organocatalytic asymmetric Michael additions have
inspired many investigations3–5 employing multifunc-
tional amine catalysts such as amine-thioureas6–14 and
substituted pyrrolidines.15–36 Carbohydrate is one of the
most enticing class of nature’s chiral pools due to their
chiral backbone that helps in stereochemical induction.
In 2008, Zhou et al., reported the advantage of using
γ
synthesis of synthetically useful -nitro carbonyl com-
pounds,43–45 Ma and co-workers reported bifunctional
thiourea catalysts prepared from commercially avail-
able β-D-glucopyranose for a highly enantioselective
Michael addition of aromatic ketones to nitroolefins.46
Even though the use of bifunctional amino catalysts is
routine, there is only one report on the use of monofunc-
tional amine for the said reaction. Gellman and Chi47
used diphenylprolinol methyl ether, a monofunctional
secondary amine to catalyze intermolecular Michael
addition of simple aldehydes to relatively non-activated
enones with enantioselectivities up to 99% with cata-
lyst loading of 1–5 mol%. But the method worked best
with catechol as a co-catalyst, which was believed to
electrophilically activate the enone via hydrogen-bond
donation to the carbonyl oxygen. Interestingly, stere-
oselective organocatalysis employing monofunctional
primary amine is not reported till date. To our knowl-
edge, no monofunctional aminocatalyst is reported yet
α
bifunctional thiourea organocatalysts derived from -
D-glucopyranose, galactose and lactose for asymmetric
Michael addition of acetyl acetone to nitro olefins
giving up to >99% yield and up to 96% enantiose-
lectivity.37 Benaglia et al.,38 used another new class
of glucosamine-based bifunctional organocatalysts for
nucleophilic Michael addition of acetylacetone to nitro
olefins and N-Boc imines of benzaldehyde to achieve
up to 93% yield and 83% ee. More recently, Peddinti
et al.,39 and Shao et al.,40,41 reported organocatalysts
*
γ
For correspondence
for the synthesis -nitro carbonyl compounds as well.
Electronic supplementary material: The online version of this article (doi:10.1007/s12039-017-1371-6) contains supplementary material,
which is available to authorized users.

Khiangte Vanlaldinpuia et al.
Scheme 1. Michael reaction catalysed by primary amine.
Therefore, we wish to report our preliminary results
on the enantioselective Michael addition of different
ketones to nitro olefins catalysed by monofunctional pri-
mary amine (1) derived from d-fructose (Scheme 1).
2. Experimental
2.1 General remarks
Figure 1. Aminocatalysis with
bifunctional amine.
Chemicals and reagents were purchased from commercial
sources and used without further purification. IR spectra were
recorded on a Perkin–Elmer Spectrum One FTIR spectrom-
eter. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra
were obtained on a Bruker AC-400 using CDCl3 as solvent
and TMS as internal standard, unless otherwise stated. Mass
spectra were obtained from Waters ZQ 4000 mass spectrom-
eter by the ESI method, while the elemental analyses of the
complexes were performed on a Perkin–Elmer-2400 CHN/S
analyzer. Reactions were monitored by thin layer chromatog-
raphy (TLC). The melting points of the compounds were
recorded by open capillary method and were uncorrected.
HPLC analysis was carried out on a Waters M515 equipped
with Chiracel OD-H and Chiralcel AD-H columns using n-
hexane and 2-propanol as mobile phase at room temperature.
EW
G
R1
N
R2
R
Figure 2. Aminocatalysis with
monofunctional secondary amine.
3. Results and Discussions
In continuation of our report48 on aldol reaction employ-
ing d-fructose based amine 1 as organocatalyst, we
wanted to extend the application of the catalysts 1–6 for
direct Michael addition reactions. It may be noted that
unlike aminocatalytic stereoselective Aldol and Henry
reactions, where the stereodirecting group binds with
carbonyl compound to facilitate the stereoselective 1,
2-addition reaction, the stereodirecting group bound to
the Michael acceptor stays away from the electrophilic
reaction centre, i.e., the carbon-carbon double bond. As
a result, use of bifunctional organocatalysts is an abso-
lute necessity in Michael type addition reaction where
both the donor and acceptor molecule bind with the
organocatalyst that comprises strategically placed stere-
odirecting cum activating groups to achieve the desired
selectivity (Figures 1, 2).
2.2 General procedure for Michael reaction
A mixture of d-fructose derived amine 1 (0.15 mmol), ben-
zoic acid (0.15 mmol) and ketone (4 mmol; 10 mmol in
the case of acetone) were stirred at room temperature for
30 min. Nitroolefin (1 mmol) was then added. The reaction
was allowed to run at room temperature and the progress
of the reaction was monitored by thin layer chromatogra-
phy. After the reaction was completed, saturated solution of
ammonium chloride was added to the reaction mixture and
stirred for another 10 min. The compound was extracted with
ethyl acetate (3 x 20 mL), washed with water (3 times), dried
over Na2SO4 and concentrated to get the crude product. The
productobtainedwasfurtherpurifiedusingflashcolumnchro-
matography to obtain the pure Michael adduct.

Enantioselective aminocatalysis in Michael addition
Figure 3. d-fructose derived amines.
Table 1. Solvents effect of asymmetric Michael reaction using sugar derived organocatalysts.
Entry
Catalyst (15 mol%)
Solvent
t (h)
Yield %a
drb(syn:anti)
eecsyn anti
1
2
3
4
5
6
1
2
Neat
Neat
Neat
CH2Cl2
CHCl3
96
96
120
120
120
120
45
57
Trace
21
Trace
Trace
77:23
47:53
–
71:29
64:36
–
62
16
–
47
21
–
21
31
3/4/5/6
1
1
1
19
23
DMSO/DMF/CH3CN/H2O
Reaction condition: p-methoxy-β-nitrostyrene (0.2 mmol), catalyst (15 mol%) and cyclohexanone (0.8 mmol).
aIsolated yields.
bDiastereoselectivity was determined by 1HNMR of the crude product or HPLC analysis of the pure product.
cDetermined by HPLC analysis.
Given the fact that d-fructose based amines 1–6 pos- congestion in secondary amines 3–6, the catalysts carry-
sess the sugar backbone with two adjacent isopropyli- ing the primary amine may be more suitable to catalyze
dene rings which may control the stereoselectivity of the the reaction.
Michael addition reaction similar to that of diphenylpro-
A series of solvents were screened (Table 1, entries
linol methyl ether,47 we screened the catalytic activity 4–6) to confirm that the reaction gave the best result in
and stereoselectivity of the catalysts 1–6 (Figure 3) by the absence of solvents. Dichloromethane gave the best
taking the reaction of cyclohexanone and 4-methoxy β- result among the solvents under scrutiny (Table 1, entry
nitrostyrene as the model reaction (Table 1). Moderate 4) giving 21% yield with 47% ee for the syn adduct.
yield (45%) with moderate diastereoselectivity (77:23 Although the reaction gave trace amount of the desired
dr) and enantioselectivity (62%) were obtained for syn product with inferior stereoselectivity in CHCl3, the
product when the reaction was catalysed by 1 (Table 1, reaction did not work in other solvents at all (Table 1,
entry 1).
entry 6). Catalyst 2 gave better result in term of yield, but
When the model reaction was carried out with cat- the selectivity was rather poor (Table 1, entry 2). Cat-
alysts 2 under the neat reaction conditions, Michael alysts 3–6 having secondary amine functionality gave
product was obtained in 57% yield with 47:53 diastere- only trace amount of conversion even after stirring for
omeric ratio and 31% ee for the anti adduct. Consistent 120 h which may be accounted for the high steric crowd-
with our earlier observations in Aldol reaction, the fruc- ing around the amine group of the catalysts.
tose derived secondary amines 3–6 did not give any
The influences of the amount of catalyst loading and
product under this reaction conditions (Table 1, entry addition of additive on a reaction were then examined.
3) which led us to conclude that because of high steric 15 mol% catalyst loading was found to be optimum,

Khiangte Vanlaldinpuia et al.
Table 2. Monofunctional amine catalysed Michael addition reaction between cyclohexanone and p-methoxy-β-nitrostyrene.
Entry
Catalyst 1 (mol%)
Additive
t (h)
Yield %a
drb (syn:anti)
eec syn
eec anti
1
2
3
4
5
6
7
15
15
15
15
20
10
5
TFA
p-TsOH
HOAc
PhCOOH
PhCOOH
PhCOOH
PhCOOH
36
120
72
36
36
48
72
67
<10
78
86
86
76
53
60:40
–
57:43
88:12
85:15
82:18
83:17
33
–
32
89
84
79
78
11
12
65
57
59
51
Reaction conditions: p-Methoxy-β-nitrostyrene (0.2 mmol), catalyst (15 mol%), additive (15 mol%) and cyclohexanone (0.8
mmol).
aIsolated yields.
bDiastereoselectivity was determined by 1HNMR of the crude product and validated with HPLC data.
cDetermined by HPLC analysis.
while its decrease to 5 mol% and 10 mol% negatively conditions were applied to the addition of cyclopen-
affected the reactivity as well as selectivity of the reac- tanone to nitroolefins the time taken for completion of
tion (Table 2, entries 6–7). On the other hand, increasing the reaction was much shorter in comparison to those
the catalyst loading to 20 mol% remained essentially the with cyclohexanone (Table 3, entries 6–9). The reaction
same as that of the reaction catalyzed by 15 mol% of of various nitroalkenes with acetone in the presence of
1, while the enantioselectivity decreased slightly from catalyst 1 showed excellent conversion with good enan-
91% ee to 84% ee. Addition of additives such as TFA, tioselectivity, albeit taking longer time than in the cases
HOAc and benzoic acids greatly enhanced the catalytic of cyclopentanone or cyclohexanone.
performance, probably by accelerating the formation of
As far as the plausible mechanism of the reaction is
the enamine intermediate between the catalyst and the concerned, it may be noted that the secondary amine can
substrate. In fact, use of 15 mol% catalyst 1 in the pres- bind with carbonyl group to form iminium salt which
ence of 15 mol% of benzoic acid under solvent free readily tautomerizes to nucleophilic enamine. On the
conditions was found to be optimum giving Michael other hand, unless the enamine form is stabilized by fur-
adducts in 86% yield with 88:12 diastereoselective ratio ther conjugation, either with an electron-withdrawing
and 89% enantiomeric excess in favour of the syn adduct group49 or an aromatic nucleus,50 or by other less def-
(Table 2, entry 4). It is inexplicable to note that addition inite stabilizing factors, the reaction of primary amine
of p-TsOH deactivates the reaction as it gave the product with carbonyl compound leads to unfavourable imine-
in less than 10% yield (Table 2, entry 2).
enamine equilibrium that prefers the less nucleophilic
Withtheoptimalreactionconditionsinhand, thereac- imine form. Therefore, the use of monofunctional pri-
tion was carried out on a diverse range of substrates mary amine for stereoselective Michael addition poses
to explore the general applicability of this asymmet- considerable challenge with respect to (a) the lack of an
ric transformation. As shown in Table 3 (entries 1–13), activation site and stereodirecting group in the catalyst
high isolated yields were obtained for all the products, (Figure 2) for the Michael acceptor which is attacked by
regardless of the electronic nature of the aromatic sub- the Michael donor, i.e., the imine or enamine generated
stituents, and in most of the cases, syn products were from the reaction of ketone with the amine catalyst; (b)
obtained as the major product with moderate to high formation of less reactive Michael donor in the form of
enantioselectivities.
imine (Figure 4).
When 1-[(E)-2-nitrovinyl]benzene was treated with
The fact that the reaction of primary amine with car-
cyclohexanone and benzoic acid in the presence of d- bonyl compound favours the less nucleophilic imine
fructose derived 1,2:4,5-di-O-isopropylidene-3-amino- form, we carried out DFT calculation to see the sta-
3-deoxy-α-d-fructopyranose (1) as a catalyst, the prod- bility of imine and enamine derived from the reaction
uct 7a was obtained in 92% yield after 24 h of of cyclohexanone with the catalyst 1. To our pleasure, it
stirring (Table 3, entry 1). When the same reaction was observed that the enamine form 1b is more stable by

Enantioselective aminocatalysis in Michael addition
Table 3. Asymmetric Michael addition reaction catalyzed by 1.
Entry
Substrate
Ketone
Product
t(h)
%Yieldb
drc
%eed
syn:anti
1
2
3
4
5
24
12
30
36
10
92
95
85
86
96
69:31
76:24
78:22
88:12
59:41
92
76
90
89
78
7a
7b
7c
7d
7e
6
7
8
7
6
93
92
90
69:31
60:40
69:31
99
63
47
7f
7g
7h
16
9
20
87
69:31
79
7i
10
11
12
36
36
48
89
91
79
-
-
-
63
58
67
7j
7k
7l
13
48
77
-
80
7m
Reaction condition: Nitroolefin (0.2 mmol), catalyst 1 (15 mol%), PhCOOH (15 mol%) and ketones (0.8 mmol).
aIsolated yields.
bDiastereoselectivity was determined by 1HNMR of the crude product.
cEnantioselectivity of the syn-diastereomer was determined by chiral HPLC analysis.

Khiangte Vanlaldinpuia et al.
In conclusion, we have reported for the first time
a stereoselective organocatalyst having only one acti-
vating group in the form of amine for asymmetric
Michael addition of ketones to nitroolefins. Given the
fact enamine derived from secondary amine is more
nucleophilic, the favourable imine-enamine equilib-
rium in primary amine derived enamine is explained
by DFT studies. While the d-Fructose derived pri-
mary amine, 1,2:4,5-di-O-isopropylidene-3-amino-3-
deoxy- α-d-fructopyranose (1) has been found to be
an effective catalyst for asymmetric Michael addition
of ketones to nitroolefins giving up to 96% yield,
88:12 dr and 89% ee,while its opposite stereoisomer (2)
was less reactive and selective under similar reaction
conditions. Interestingly, fructose derived secondary
amines 3, 4, 5 and 6 were found to be ineffective for
this transformation which may be due to steric hin-
drance.
Figure 4. Enamine formation.
Figure 5. Structure of imine and enamine.
Supporting Information
1
The spectroscopic data, HNMR and 13CNMR spectra of
selected compounds, HPLC data and chromatogram, and
computational data etc., are available free of charge via the
Internet at http://www.ias.ac.in/chemsci.
Acknowledgements
Authors acknowledge the Council of Scientific and Indus-
trial Research (CSIR), New Delhi, India for financial support
(Scheme No. 1 (1992)/05/EMR-II). The analytical service
provided by Sophisticated Analytical Instrument Facility,
North Eastern Hill University, Shillong is gratefully acknowl-
edged.
Figure 6. Plausible mechanism of syn-selectivity.
0.377Kcal/mol51 thantheimineform 1a(Figure 5). The
shift in imine-enamine equilibrium to more nucleophilic
enamine can be attributed to the lesser conformational
restriction in enamine form in comparison to the imine.
As for the plausible mechanism of syn-selectivity, a
tentative model representing the prototypical addition of
cyclohexanone to trans-β-nitrostyrene in the presence
of organocatalyst 1a might explain that the NH group of
the enamine interacts through hydrogen bonding with
the nitrogroup of the nitroalkene and enhances their
electrophilicity. The si-face approach to the nitroolefin,
where the plan of the nitroolefin lies below plane of
the enamine, generates syn-product while the re-face
approach to the nitroolefin may be less favourable
due steric interaction between the five-membered ace-
tonide ring with the substituent on the β-position of the
nitroolefin (Figure 6).
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