Augmentation of Enantioselectivity by Spatial Tuning of Aminocatalyst: Synthesis of 2-Alkyl/aryl-3-nitro-2 H-chromenes by Tandem Oxa-Michael-Henry Reaction

Article abstract of DOI:10.1021/acs.joc.9b03366

The asymmetric oxa-Michael addition of salicylaldehyde to conjugated nitroalkenes often suffers from poor reactivity and selectivity and a long reaction time. Because of the formation of an iminium ion with aminocatalyst, the nucleophilicity of the phenol

Full text of DOI:10.1021/acs.joc.9b03366

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Article
Augmentation of enantioselectivity by spatial tuning
of aminocatalyst: Synthesis of 2-alkyl/aryl-3-nitro-2H-
chromenes by tandem oxa-Michael Henry reaction
Rahul Mohanta, and Ghanashyam Bez
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03366 • Publication Date (Web): 09 Mar 2020
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Augmentation of enantioselectivity by spatial tuning
of aminocatalyst: Synthesis of 2-alkyl/aryl-3-nitro-
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H-chromenes by tandem oxa-Michael Henry
reaction
Rahul Mohanta and Ghanashyam Bez*
Department of Chemistry, North-Eastern Hill University, Shillong-793022, Meghalaya,
India
ABSTRACT: Asymmetric oxa-Michael addition of salicylaldehyde to conjugated
nitroalkenes often suffers from poor reactivity, selectivity and long reaction time. Because
of formation of an iminium ion with aminocatalyst, the nucleophilicity of the phenolic
hydroxy group in salicylaldehyde reduces further to make the oxa-Michael reaction
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reversible. Here we report a structurally simple and easily accessible L-proline derived
aminocatalyst, phenyl L-prolinamide for asymmetric tandem oxa-Michael Henry reaction
of salicylaldehyde with conjugated nitroalkene to give 2-alkyl/aryl-3-nitro-2H-chromenes
in excellent enantioselectivity within a short reaction time.
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KEYWORDS: Phenyl L-prolinamide, salicylaldehyde, nitroalkene, asymmetric 1,4-
addition, tandem oxa-Michael-Henry, 2-alkyl/aryl-3-nitro-2H-chromenes
Introduction
Asymmetric synthesis of enantiomerically pure compounds has experienced phenomenal
growth due their applications in electronic and optical devices, polymers and, more
importantly, as drug and biological probe. Since absolute purity of single enantiomer
dictates the efficacy and specificity of a drug, asymmetric synthesis always strives for
cent percent enantioselectivity, which is easier said than done. The factors such as
structural complexity, accessibility and cost of the catalysts, catalyst loading, and the
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reaction conditions often become secondary in the quest of achieving optimum
enantioselectivity. Recently, small molecule organocatalysis has shown great promise in
asymmetric synthesis after discovery of L-proline as an efficient organocatalyst by List et
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al. But, there are only a handful of asymmetric aminocatalysts which are structurally
simple, easily accessible, cost-effective, and yet efficient. Given its application of
asymmetric synthesis in drug development, pharmaceutical companies require catalytic
methods which are cost effective, easy to handle, and give highly optically purity.
Therefore, development of new asymmetric methodology, improvement of existing
method by either modifying the existing processes or employing structurally simpler
catalyst to achieve greater enantioselectivity are very important dimensions of
asymmetric synthesis.
Asymmetric oxa-Michael addition reaction is considered as one of the most difficult
reactions in organic chemistry due to poor nucleophilicity of oxygen and reversible nature
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of the reaction. Due to delocalization of the oxygen lone pair in the aryl ring, phenolic -
OH behaves as a very poor nucleophile for oxa-Michael reaction. Among the phenols, the
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nucleophilicity of salicylaldehyde is one of the worsts; it is an extremely poor and hard
oxygen nucleophile. Therefore, nucleophilic 1,4-additions of salicylaldehyde to
conjugated aldehyde or nitroalkene are often challenging and their asymmetric versions
are extremely limited.4-9 In the aminocatalytic addition of salicylaldehyde to conjugated
aldehyde, the poor nucleophilicity of salicylaldehyde is compensated by activation of the
aldehyde via formation of a more electrophilic and hard conjugated iminium ion that
facilitates the addition of the ‘hard’ phenolic oxygen (Figure 1). Whereas, in case of
addition to conjugated nitroalkene, the reaction of salicylaldehyde with the catalyst forms
an iminium ion to reduce the nucleophilicity further. As a result, addition of salicylaldehyde
to ,-unsaturated nitroalkene is extremely difficult leading to poor enantioselectivity, and
longer reaction time.
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H
R
CHO
OH
R1
N
NHR1R2
O
R
O
R
R2
Activation
of electrophile
O
Better
electrophile
R1
R2
H
N
CHO
1
NHR R2
R
NO2
R
NO2
Deactivation
of nucleophile
OH
OH
Less nucleophilic
O
Figure 1. 1,4-Addition of salicylaldehyde
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One of the major applications of asymmetric oxa-Michael addition of phenols to ,-
unsaturated olefins is the synthesis of chromenes or benzo-pyrans.4-13 They are useful
building blocks for synthesis of many biologically active heterocyclic compounds having
antitumor, antiviral, antimicrobial, anti-anaphylactic, antidiabetic, anticoagulant, and
diuretic properties.14-22 Among the 2H-chromenes, 3-nitro-2H-chromenes have attracted
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attention from synthetic chemist due to their diverse applications. 3-Nitro-2H-chromenes
have shown second harmonic generation for potential application as nonlinear optical
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materials. It also acts as precursors to a variety of medicinally important 2H-benzopyran
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derivatives such as flavonols, and amines. Moreover, the scope of manipulating the
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nitroalkene moieties for the synthesis of important target molecules, and the extent of
difficulty to achieve good enantioselectivity in their asymmetric synthesis have unleashed
an opportunity and a challenge.
It is pertinent to note that asymmetric synthesis of 2-aryl-3-nitro-2H-chromenes via the
tandem oxa-Michael Henry reaction of salicylaldehyde with β-nitrostyrenes is extremely
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limited and gives only moderate enantioselectivity. Xu and coworkers employed 1-methyl-
2-((pyrrolidin-2-ylmethyl) thio)-1H-imidazole (2) derived from L-proline to catalyze the
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reaction of salicylaldehyde with -nitrostyrene to observe moderate enantioselectivities in
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most of the cases. Given the ready accessibility of L-proline, they tested the catalytic
activity of L-proline for the said reaction and observed poor yield with no enantioselectivity.
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Chen and coworker employed a tertiary amide derivative of 4-hydroxy L-proline (3) as
catalyst to achieve mostly moderate enantioselectivity. Additionally, these methods6,7
suffer from high catalyst loading (20 mol%) and long reaction time (3-5 days). Although
Schreiner and coworkers used a cinchona derived bifunctional thiourea (4) catalyst to
synthesize chiral 2-aryl-3-nitro-2H-chromenes directly from the reaction of
salicylaldehyde and -nitrostyrene, they observed low yields along with negligible
stereoinduction. By using salicyl-N-tosylimine in place of salicylaldehyde, they could
synthesize chiral 2-aryl-3-nitro-2H-chromenes in moderate to good yields and
enantioselectivities via a tandem oxa-Michael-aza-Henry-desulfonamidation pathway.8
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Since kinetic resolution is one of mainstays in asymmetric synthesis, Xi et al. employed
a bifunctional thiourea catalyzed kinetic resolution of racemic 3-nitro-2H-chromenes to
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achieve optically active (R)-3-nitro-2H-chromene derivatives with moderate to good
enantioselectivities (Scheme 1). Unlike the methods for usual kinetic resolution, where
the synthesis of both the enantiomers remains the primary target, this reaction led to
irreversible formation of moderately enantioselective multifunctional 3,4-diphenyl-3a-
nitrobenzo-pyrano-[3,4-c]pyrrolidine-1,1-dicarboxylate derivatives and hence the
opposite enantiomers did not form.
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Scheme 1. Enantioselective synthesis of 2-aryl-3-nitro-2H-chromenes
(A) Via tandem oxa-Michael Henry reaction:
NO2
NO2
Ar
X
Catalyst
R
+
R
OH
Ar
O
N
S
Schreiner et al.8:
6
Xu et al. (X=O):
N
(45-85%ee)
Me
N
H
2
(20 mol%)
O
H
H
N
N
CF3
HO
7
MeO
S
Chen et al. (X=O):
N
NH
(54-90%ee)
CF3
N
O
3
(20 mol%)
4 (10 mol%)
X = O; Not selective
O
o
=
NTs; 46-97%ee at 0 C
This method (X=O):
(90- >99%ee)
N
NHPh
H
1a (10 mol%)
CF3
(B) By kinetic resolution (Xi et al.)9
S
F3C
N
N
NO2
CO2Et
N
CO Et
H
H
NO2
Ar
NH2
R
+
R
Ph
2
O
Ar
O
(68-87%ee)
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Results and Discussion
The fact that asymmetric synthesis of 2-aryl-3-nitro-2H-chromenes suffers from poor
2
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reactivity and the reversible nature of the reaction, the development of an effective
catalyst that can stabilize the oxa-Michael intermediate and facilitates rapid Henry
reaction in the subsequent step is critical to achieve high enantioselectivity. The efficiency
of asymmetric catalysis ideally depends on spatial interactions between the reactants and
catalyst. Therefore, optimization of these interactions is often dictated by position and
orientation of interacting groups rather than steric congestion in the catalytic site. We
proposed that a stable H-bond donor functional group nearer to the asymmetric centre of
L-proline core might help in having a better asymmetric 1,4-addition of salicylaldehyde
with the -nitroalkene acceptor, which may in turn lead to better enantioselectivity in the
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aforesaid tandem oxa-Michael-Henry reaction. Since L-prolinamides offer such structural
features and are among the most easily accessible L-proline derivatives, we planned to
employ a secondary amide derived from L-proline to catalyze the reaction of
salicylaldehyde with -nitroalkene. We reasoned that the N-H group in a conformationally
rigid secondary amide might activate the -nitroalkene via H-bonding to dictate the si-face
attack by the phenolic oxygen of salicylaldehyde on the -nitroalkene to give one
enantiomer preferentially (Figure 2).
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N
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H
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H
Figure 2. Mechanistic perspective on H-bonding directed oxa-Michael addition
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CF3
CF3
N
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H
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HN
N
H
N
N
HN
OMe
H
H
1h
1i
1j
Figure 3. L-Proline derived amidoamine catalysts
Therefore, we synthesized a series of amides (Figure 3, 1a-g, 1j) starting from the reaction
of Boc-L-proline and aromatic/hetero-aromatic amines following literature protocol29,30 and
tested their catalytic efficiency for asymmetric synthesis of 2-aryl-3-nitro-2H-chromenes.
Our studies led to discovery of one of the simplest, efficient and highly enantioselective
methods for the said synthesis employing a catalytic amount of phenyl L-prolinamide
(Scheme 2).
Scheme 2. Synthesis of 2-aryl/furyl-3-nitro-2H-chromene
CHO
NHCOPh
a(10 mol%)
R
N
1
NO2
R1
H
OH
R
+
p-nitrophenol (10 mol%),
o
O
NO2
molecular sieves 4A, RT
R1
-
2a u
(90- 99 %ee)
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The L-proline derived arylamides (1a-e) were employed to understand the effect of the N-
H in governing the enantioselectivity of the reaction. We proposed that if a tertiary amide
is used, the nitroalkene should approach the iminium salt from the opposite side of the
sterically hindered amide functionality due to the absence of the NH in the tertiary amide
group to generate the opposite stereoisomer. Therefore, the L-proline derived tertiary
amide analogues (1f-g) were synthesized to evaluate if a tertiary amide group in the
catalyst facilitates the binding of the nitroalkene with the catalyst. To evaluate the efficacy
of amidoamines, a model reaction of salicylaldehyde with -nitrostyrene was carried out
in the presence of a catalytic amount of phenyl-L-prolinamide, 1a (10 mol%) and p-
nitrophenol (10 mol%) in chloroform (Table 1, entry 1). The reaction took almost 36 h at
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ambient temperature (22 C) to undergo complete conversion. The structure of the
product confirmed by IR, NMR, and MS. HPLC analysis of the compound employing
Chiralcel AS-H column revealed excellent formation of (R)-isomer in 99% ee. To
understand the role of the Bronsted acid better, we screened some other protic acids
(Table 1, entries 1-7) to find that reaction rate and the extent of enantioselectivity is barely
dependent on the nature of the Bronsted acid under our reaction conditions, while the
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3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
reaction time was found shortest when p-nitrophenol was used. Therefore, we screened
all the other catalysts in the presence of p-nitrophenol as an additive. Substitution on the
phenyl ring with electron withdrawing groups (1b-c) and H-bond donor (1d) and acceptor
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(1e) groups hardly helped in enhancing catalytic efficiency of the model reaction under
similar reaction conditions.
Table 1. Screening of catalyst and additivesa-c
CHO
NO2
Ph
NO2
Catalyst 1a-j
+ Ph
OH
Additives (10 mol%o),
molecular sieves 4A
O
CHCl , RT
3
Entry catalyst
additives
p-nitrophenol
PhCOOH
TFA
t/h
36
60
60
60
60
60
60
36
%yieldd %eee
1
2
3
4
5
6
7
8
1a (10)
92
90
88
90
92
87
40
88
>99
>99
>99
>99
99
CH COOH
3
p-NO C H CO H
2
6
4
2
p-TsOH
>99
92
None
1b (10)
p-nitrophenol
76
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1
1c (10)
1d (10)
1e (10)
1f (10)
1f (10)
1g (10)
1h (10)
1i (10)
1j (10)
1a (15)
1a (5)
p-nitrophenol
p-nitrophenol
p-nitrophenol
p-nitrophenol
None
36
90
89
92
80
25
84
87
91
79
96
80
90
15
0
36
96
11
36
24
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
12
120
120
120
120
120
120
36
>99
90
13
14
15
16
17
p-nitrophenol
p-nitrophenol
p-nitrophenol
p-nitrophenol
p-nitrophenol
p-nitrophenol
p-nitrophenol
10
20
05
10
18
>99
90
19
36
20
1a (10)
120
92f
a
b
c
Salicylaldehyde (0.5 mmol): Nitroalkene= 1:1. Catalyst: Additive= 1:1. 50 mg of
d
e
molecular sieves was used. Isolated yields. Stereoselectivity was determined by HPLC
f
analysis of the crude mixture using Chiralcel AS-H column. In the absence of 4Å
molecular sieves.
When the catalytic efficacy of the L-proline derived tertiary amides (1f-g) were screened
in the model reaction keeping the other reaction parameters unchanged, surprisingly, the
extent of enantioselectivity was found to be extremely good (>99%) with 1f to give the
(R)-isomer preferentially, despite taking longer reaction time (5 d) for completion. Since
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
1
the nitrogen of tertiary amide group is very difficult to protonate, such finding is possible
only when the oxygen of the amide is protonated.32 Therefore, we concluded that the
amide oxygen might have been protonated by p-nitrophenol to facilitate the si-face attack
on the -nitroalkene to give stereoselective oxa-Michael addition product. To reaffirm the
possible role of the protonated carbonyl of the amide group in stereoinduction, we
conducted the model reaction with a catalytic amount of 1f (10 mol%) in the absence of
p-nitrophenol keeping the other parameters unchanged (entry 13). The reaction was very
slow and gave hardly 25% yield in 5 days. But we were very happy to note that, here too,
the (R)-isomer was the major product with 90%ee. The role of the carbonyl group was
further investigated by carrying out the model reaction in the presence of the diamines 1h
and 1i. Here, the model reaction was very slow and gave poor enantioselectivities upon
using 1h and 1i (Entries 15 and 16). These findings made it abundantly clear that the
amide carbonyl has provided additional directional rigidity besides accelerating the
reaction rate by getting protonated under our reaction conditions. Interestingly, when p-
methoxyphenyl L-prolinamide (1j) bearing an electron-donating OMe group at the phenyl
ring was tested as catalyst in the model reaction, the efficacy of the catalyst was found to
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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be very low (10% ee). The fact that the result was reminiscent of the reaction catalyzed
by 1g led us believe that there may be a competition of the protonated oxygen of the
morpholine moiety (and p-methoxyphenyl) with the amide N-H of the catalyst to directs
the approach of the nitroalkene. The catalyst loading was also optimized to observe that
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
10 mol% of catalyst loading serves the best (Entries 1, 18, 19). Our next step was to study
the effect of solvent in the phenyl-L-prolinamide catalysed asymmetric synthesis of 2-aryl-
3-nitro-2H-chromenes. All other solvents such as 1,2-dichloroethane, dichloromethane,
THF, acetonitrile, and DMSO showed inferior results in terms of reaction rate, yield and
enantioselectivity (Table 2). It is interesting to note that the model reaction showed very
good enantioselectivity (96%) in methanol despite the solvent can potentially compete
with the amide N-H to activate the nitroalkene via formation of H-bond. We reason that
the amide group plays a dual role of activating the nitroalkene in oxa-Michael addition
and subsequent Henry reaction for the formation of 3-nitro-2H-chromene derivatives. The
fact that the oxa-Michael step is highly reversible, the formation of the 1,2-addition product
is very critical to achieve a thermodynamically stable product. Even if methanol may
activate the -nitroalkene via H-bond to form the rapidly reversible oxa-Michael adduct, it
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
may not be able to bring the reacting sites close enough to facilitate the subsequent Henry
reaction to generate the product. Moreover, the ambient temperature was found to be
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
optimum to achieve good enantioselectivity and yields. While the reaction at 10 C for 5
o
days gave 53% yield with >99% enantiomeric excess, the reaction at 40 C showed the
opposite effect despite reducing the reaction time considerably (Table 2).
Table 2. Screening of solventsa
CHO
OH
NO2
Ph
Catalyst 1a (10 mol%)
NO2
Ph
4-nitrophenol (10 mol%)
o
O
molecular sieves 4A
solvent (0.5 mL), RT
2a
o
Yieldb
90
ee%c
Entry
Solvent
Temp ( C)
t/h
36
36
36
36
36
36
36
36
120
48
1
2
3
4
5
6
7
.
.
.
.
.
.
.
C H Cl
2
20
20
20
20
20
20
20
20
10
40
80
96
2
4
CH Cl
92
2
2
CHCl3
96
>99
92
THF
90
CH CN
80
>99
42
3
DMSO
MeOH
97
82
96
8.
Isopropyl alcohol
CHCl3
84
96
9.
53
>99
54
10.
CHCl3
70
aReactions were carried out at 0.5 mmol scale and 50 mg molecular sieves was used.
b
c
Isolated yields are reported. Stereoselectivity was determined by HPLC analysis of the
crude mixture using Chiralcel AS-H columns.
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9
After optimizing the reaction parameters, the substrate scopes were studied to explore
the versatility of our protocol (Table 3). To our pleasure, the reaction of salicylaldehyde
with various -nitrostyrene derivatives gave excellent yields and enantioselectivity at
room temperature reaction conditions. Electron withdrawing or electron donating
substituents on the phenyl ring of the -nitrostyrene derivatives did not affect the yields
and enantioselectivity. Some substrate and solvent specific enantioselectivity were also
noted. For example, the reaction of salicylaldehyde with p-fluoro--nitrostyrene gave the
corresponding 3-nitro-2H-chromene in 86%ee in chloroform (Entry 8) and 99%ee in
acetonitrile medium (Entry 9). When 5-methoxy salicylaldehyde (Entries 13-19) was taken
as the starting material, excellent yield and enantioselectivity were observed. Most
importantly, the reaction works for highly docile nucleophile such as 5-chloro
salicylaldehyde (entries 21, 22) to give excellent yield and enantioselectivity. The reaction
of a β-nitroalkene with heterocyclic substituent, namely (E)-2-(2-furyl)nitroethene with
salicylaldehyde under the optimized conditions gave the desired product in 99% ee (Entry
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
23).
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6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 3. Synthesis of 2-aryl-3-nitro-2H-chromenesa
CHO
NO2
R1
Cat. 1a (10 mol%)
NO2
R
R
+
OH
R1
p-nitrophenol (10 mol%),
molecular sieves 4A
RT, CHCl3
o
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Entry
R
R1
Ph
4-CH C H
Product t/h
%yieldb
96
%eec
>99
1
2
3
4
5
6
7
8
9
9
10
H
2a
2b
2b
2c
2d
2e
2f
36
36
36
36
36
36
36
36
36
48
48
48
36
36
36
36
H
92
84
3
6
4
4
>99d
H
4-CH C H
94
3
6
H
4-CH OC H
90
98
3
6
4
H
4-ClC H
93
94
6
4
H
2-ClC H
98
>99
>99
86
6
4
H
3-BrC H
92
6
4
H
4-FC H
2g
2g
2h
94
6
4
H
4-FC H
92
>99e
>99
>99
90
6
4
H
2-MeO C H
97
6
4
H
2,4-(OCH O)C H 2i
91
2
6
3
1
1
1
1
2
3
4
5
H
1-naphthyl
2j
90
5-OMe
5-OMe
5-OMe
5-OMe
4-CH C H
2k
2l
92
98
3
6
4
2-ClC H
95
94
6
4
4-CH OC H
2m
2n
90
>99
98
3
6
4
16
2-CH OC H
94
3
6
4
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5
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7
8
9
1
7
8
5-OMe
5-OMe
5-OMe
3-OMe
5-Cl
4-FC H
2o
2p
2q
2r
36
36
36
36
60
60
60
91
95
93
90
92
90
91
>99
>99
99
6
4
1
C H
6
5
19
4-ClC H
6
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
20
C H
99
6
5
21
C H
2s
2t
98
6
5
2
2
3
5-Cl
4-ClC H
90
6
4
2
H
2-furyl
2u
99
aReactions were carried out at 0.5 mmol scale and 50 mg molecular sieves was used.
b
c
Isolated yields are reported. Stereoselectivity was determined by HPLC analysis of the
d
e
crude mixture using Chiralcel AS-H columns. Solvent is dichloromethane. Solvent is
acetonitrile
The fact that our reaction conditions work well for the reaction of salicylaldehyde with 1-
nitropent-1-ene to give 2-butyl-3-nitro-2H-chromene (3a) in 90% yield with 96%ee
(Scheme 3), the reaction does not depend on the nature of -nitroalkene.
Scheme 3. Synthesis of 2-butyl-3-nitro-2H-chromenes
R
CHO
R
NO2
1
a(10 mol%)
OH
p-nitrophenol (10 mol%)
O
+
o
NO2
molecular sieves 4A
3a: R =H (90% yield, 96 %ee)
3b: R =OMe (93% yield, 92 %ee)
CHCl , 36 h, RT
3
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5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
We conducted an experiment to HNMR experiment by mixing the catalyst 1a with -
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
nitrostyrene in CDCl to understand their nature of interaction between them. We have
3
noted significant downfield shift in  value of the amide proton upon addition of the -
nitrostyrene to suggest that the nitro group of the nitroalkene might be forming H-bond
with amide proton (Figure 4).
NO2
5
4a
O
N
HN
4
H
1a
3
1a (10 mol%) + 4a
1a (20 mol%) + 4a
a (50 mol%) + 4a
2
1
1
1
1.5
10.5
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
f1 (ppm)
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Figure 4. H-bonding interaction of the catalyst 1a with -nitrostyrene
Conclusion
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
In summary, the catalyst efficiency of an asymmetric organocatalyst can be improved by
tuning the position and spatial orientation of the interacting functional groups. Here, a
highly enantioselective asymmetric oxa-Michael addition of salicyaldehyde to -
nitroalkene to synthesize biologically important 2-alkyl/aryl/furyl-3-nitro-2H-chromenes
was achieved by employing a simpler and readily accessible phenyl L-prolinamide. Poor
reactivity of oxygen nucleophile towards 1,4-addition and low stereoselectivity due to the
reversible nature of the oxa-Michael step of the reaction could be circumvented by
employing a secondary amide bearing L-prolinamide derivative. The N-H of the
conformationally rigid amide group might have played a profound role on the extent of
enantioselective induction and the reaction rate in the asymmetric tandem oxa-Michael
Henry reaction of salicylaldehyde with β-nitroalkenes. Given the difficulty attached to oxa-
Michael reaction, achieving more than 99 %ee for many 2-aryl-3-nitro-2H-chromenes is
an extremely good result. The reaction worked equally with 5-cholorosalicylaldehyde
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6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
which is extremely significant. Structural simplicity of the catalyst and its easy
accessibility, wide substrate scope, low catalyst loading, short reaction time and excellent
enantioselectivity are some of the salient features of this reaction.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Experimental Section
General Information. Unless otherwise mentioned, all chemicals and solvents were
purchased from commercial suppliers and were used as received. Benzaldehyde was
distilled before use. IR spectra were recorded on a Perkin–Elmer Spectrum One FTIR
1
spectrometer. H NMR spectra were recorded on a Bruker 400 MHz spectrometer using
TMS as internal reference with CDCl as solvent, while the 13CNMR spectra were
3
recorded at 100 MHz. Mass spectra were obtained from Waters ZQ 4000 mass
spectrometer by the ESI method, while the elemental analyses of the complexes were
performed on a Perkin–Elmer-2400 CHN/S analyzer. Analytical HPLC was performed on
a WATERS Series instrument using chiral stationary phase CHIRALPAK AS. Silica gel G
and Silica gel 230-400 Mesh (E. Merck) was used for thin-layer chromatography (TLC)
and flash column chromatography respectively. TLC plates were visualized by UV or
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iodine or by immersion in anisaldehyde stain (by volume: 95% ethanol, 3.5% sulfuric acid,
1% acetic acid and 2.5 % anisaldehyde) followed by heating. All the nitroolefins were
1
1
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33
29,30,34
7
35
prepared freshly using reported procedure. The catalysts 1a-e
, 1f-g and 1j were
synthesized by following literature protocols. Racemic compounds were prepared by
using DABCO as catalyst.36 (S)-N-(pyrrolidin-2-ylmethyl)aniline and (S)-1-(pyrrolidin-2-
ylmethyl)piperidine were purchased from Sigma-Aldrich.
Analytical data of the catalysts
N-Phenylpyrrolidine-2-carboxamide (1a). White solid. Yield 85%. M.p. 74-76 C. [α]D22=
3
4
o
20
6
-1
−
74.2 (c, 1.0, CHCl ) [Lit. [α] = −77.0 (c, 1.0, CHCl )]. IR (KBr cm ):  3266, 3134,
3
D
3
1
3057, 2969, 2871, 1670, 1599, 1525, 1443, 1384. H NMR (CDCl , 400 MHz): δ 1.73-
3
1.82 (m, 2H), 1.91 ( br s, 1H), 2.01-2.09 (m, 1H), 2.18-2.27 (m, 1H), 2.96-3.02 (m, 1H),
3.06-3.12 (m, 1H), 3.87 (dd, J = 5.2, 9.2 Hz, 1H), 7.07-7.11 (m, 1H), 7.30-7.34 (m, 2H),
13
1
7
3
6
.60 (dd, J = 1.2, 8.8Hz, 2H), 9.74 (s, 1H) ppm. C{ H} NMR (CDCl , 100 MHz): δ 26.1,
3
0.6, 47.2, 60.8, 119.3, 123.9, 128.9, 137.7, 173.0 ppm. Anal. Calcd for C H N O: C,
11 14
2
9.45; H, 7.42; N, 14.73. Found: C, 69.42; H, 7.36; N, 14.86.
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N-(4-Bromophenyl) pyrrolidine-2-carboxamide (1b).34 Brown gum. Yield 84%. [α]D22=
20
7
-1
−
3
1
3
27.3 (c, 0.3, CHCl ) [Lit. [α] = −20.0 (c, 0.59, MeOH)]. IR (KBr, cm ):  3257, 3104,
3
D
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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0
1
2
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7
8
9
0
1
043, 2973, 1676, 1590, 1517, 1395. H NMR (CDCl , 400 MHz): δ 1.72-1.78 (m, 2H),
3
.98-2.06 (m, 1H), 2.14 (br, 1H), 2.18-2.26 (m, 1H), 2.94-3.00 (m, 1H), 3.05-3.11 (m, 1H),
.83-3.86 (dd, J = 4.8, 8.8 Hz, 1H), 7.41 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.8 Hz, 2H), 9.81
1
(
s, 1H) ppm. 13C{ H} NMR (CDCl , 100 MHz): δ 26.0, 30.5, 47.1, 60.7, 116.6, 121.0,
3
1
31.8, 136.8, 172.1 ppm. Anal. Calcd for C H BrN O: C, 49.09; H, 4.87; N, 10.41.
11
13
2
Found: C, 48.99; H, 4.80; N, 10.44.
N-(3,5-Bis(trifluoromethyl)phenyl) pyrrolidine-2-carboxamide (1c).34 Colourless gum.
Yield 80%. [α]D22= −42.1 (c, 1.0, CHCl ) [Lit. [α] = −37.0 (c, 0.05, CHCl )]. IR (KBr, cm
20
8
-
3
D
3
1)
:  3246, 2977, 1693, 1531, 1473, 1441, 1383. H NMR (CDCl , 400 MHz): δ 1.76-1.82
1
3
(m, 2H), 2.01-2.09 (m, 1H), 2.21-2.3 (m, 1H), 2.55 (br, 1H), 2.99-3.05 (m, 1H), 3.10-3.16
(m, 1H), 3.92 (dd, J = 5.2, 8.8 Hz, 1H), 7.57 (s, 1H), 8.13 (s, 2H), 10.26 (s, 1H) ppm.
13
1
C{ H} NMR (CDCl , 100 MHz): δ 26.2, 30.6, 47.3, 60.8, 116.9-117.0 (unresolved),
3
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18.8-118.9 (unresolved), 121.7, 124.4, 127.2, 131.6-132.6, 139.2, 174.3 ppm. Anal.
Calcd for C H F N O: C, 47.86; H, 3.71; N, 8.59. Found: C, 47.91; H, 3.78; N, 8.58.
13
12
6
2
1
1
1
1
1
1
1
1
1
1
2
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0
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34
N-(2-Hydroxyphenyl) pyrrolidine-2-carboxamide (1d). Brown solid. Yield 84%. M.p. 164-
o
22
20
9
-1
166 C. [α] = −41.9 (c, 1.0, CHCl ) [Lit. [α] = −45.6 (c, 1.0, CH Cl )]. IR (KBr, cm ):
D
3
D
2
2
1

3354, 3225, 3065, 2971, 2871, 1640, 1586, 1537, 1455, 1384. H NMR (CDCl , 400
3
MHz): δ 1.76-1.83 (m, 2H), 2.02-2.10 (m, 1H), 2.18-2.3 (m, 1H), 2.99-3.05 (m, 1H), 3.10-
3.15 (m, 1H), 3.94 (dd, J = 4.8, 9.6 Hz, 1H), 6.84 (dt, J = 1.6, 7.2 Hz, 1H), 6.91 (dd, J =
13
1
1.6, 8 Hz, 1H), 7.01 (dd, J = 1.6, 8 Hz, 1H), 7.09-7.14 (m, 1H), 9.99 (s, 1H) ppm. C{ H}
NMR (CDCl , 100 MHz): δ 25.9, 30.6, 47.0, 60.4, 117.1, 119.5, 120.7, 125.1, 125.4,
3
+
147.5, 174.4 ppm. MS (ESI) calcd for C H N O 207.1, found m/z 207.05 [M+H] . Anal.
11
14
2
2
Calcd for C H N O : C, 64.06; H, 6.84; N, 13.58. Found: C, 63.97; H, 6.78; N, 13.61.
11
14
2
2
34
N-(Quinolin-8-yl) pyrrolidine-2-carboxamide (1e). Beige solid. Yield 88%. M.p. 145-147
oC. [α]D22= +24.4 (c, 1.0, CHCl ) [Lit. [α] = +18.6 (c, 1.0, CHCl )]. IR (KBr cm ):  3400,
20
8
-1
3
D
3
1
3302, 2972, 2868, 1677, 1528, 1486, 1424, 1384. H NMR (CDCl , 400 MHz): δ 1.72-
3
1.89 (m, 2H), 2.08-2.14 (m, 1H), 2.23-2.32 (m, 2H), 3.11-3.2 (m, 2H), 4.01 (dd, J = 5.2,
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.2 Hz, 1H), 7.43 (dd, J = 4, 8 Hz, 1H), 7.48-7.55 (m, 2H), 8.13 (dd, J = 1.6, 8 Hz, 1H),
13
1
8.83 (dd, J = 1.6, 7.2 Hz, 1H), 8.87 (dd, J = 1.6, 4.4 Hz, 1H), 11.60 (s, 1H) ppm. C{ H}
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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9
0
NMR (CDCl , 100 MHz): δ 26.0, 31.0, 47.4, 61.8, 116.3, 121.3, 121.6, 127.1, 128.0,
3
134.3, 136.1, 139.0, 148.5, 174.2 ppm. MS (ESI) calcd for C H N O 241.1, found m/z
14
15
3
+
242.0 [M+H] . Anal. Calcd for C H N O: C, 69.69; H, 6.27; N, 17.41. Found: C, 69.57;
14
15
3
H, 6.21; N, 17.45.
Piperidin-1-yl(pyrrolidin-2-yl)methanone (1f). Yellow gum. Yield 80 %. [α]D22= -47.2 (c,
7
20
10
-1
1.0, CHCl ) [Lit. [α] = -53.0 (c, 0.54, MeOH)]. IR (KBr cm ):  3445, 2948, 2866, 1642,
3
D
1
1482, 1449, 1418. H NMR (CDCl , 400 MHz): δ 1.6-1.69 (m, 6H), 1.88-1.96 (m, 1H),
3
1.99-2.08 (m, 1H), 2.10-2.21 (m, 1H), 2.47-2.56 (m, 1H), 3.41-3.59 (m, 7H), 4.81 (s, 1H)
13
1
ppm. C{ H} NMR (CDCl , 100 MHz): δ 23.9, 24.8, 25.2, 25.8, 29.7, 44.2, 46.4, 46.6,
3
58.1, 166.3 ppm. Anal. Calcd for C H N O: C, 65.90; H, 9.95; N, 15.37. Found: C,
10
18
2
65.86; H, 9.90; N, 15.46.
Morpholino(pyrrolidin-2-yl)methanone (1g). Light brown gum. Yield 84 %. [α]D22= -62.4
7
20
-1
(c, 1.0, CHCl ) [Lit. [α] = -59.1 (c, 2.0, MeOH)]. IR (KBr, cm ):  3441, 2952, 2862,
3
D
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8
643, 1482, 1449, 1419. H NMR (CDCl , 400 MHz): δ 1.88-1.96 (m, 1H), 2.00-2.07 (m,
3
H), 2.11-2.18 (m, 1H), 2.45-2.54 (m, 1H), 3.45-3.57 (m, 6H), 3.70-3.75 (m, 5H), 4.83 (s,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
H) ppm. C{ H} NMR (CDCl , 100 MHz): δ 24.6, 29.5, 43.1, 45.7, 46.8, 57.9, 66.0, 66.3,
3
67.0 ppm. Anal. Calcd for C H N O : C, 58.67; H, 8.75; N, 15.21. Found: C, 59.51; H,
9
16
2
2
.68; N, 15.36.
35
o
N-(4-Methoxyphenyl)pyrrolidine-2-carboxamide. Beige solid. Yield 84%. M.p. 80-81 C.
25
-1
[
α]D22= −27.3 (c, 0.3, CHCl ) [Lit. [α] = -20.2 (c, 0.92, MeOH)]. IR (KBr cm ):  3411,
3
D
1
3
1
6
1
301, 2970, 2865, 1672, 1529, 1381. H NMR (CDCl , 400 MHz): δ 1.71-1.76 (m, 2H),
3
.97-2.05 (m, 1H), 2.14-2.21 (m, 2H), 2.93-3.08 (m, 2H), 3.77 (s, 3H), 3.81-3.84 (m, 1H),
13
1
.85 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 9.62 (s, 1H) ppm. C{ H} NMR (CDCl ,
3
00 MHz): δ 26.2, 30.6, 47.2, 55.4, 60.8, 113.9, 120.7, 131, 155.9, 173.1 ppm. MS (ESI)
+
calcd for C H N O 220.1, found m/z 221.1 [M+H] . Anal. Calcd for C H N O : C, 65.43;
12
16
2
2
12 16
2
2
H, 7.32; N, 12.72. Found: C, 65.41; H, 7.33; N, 12.75.
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General procedure for synthesis of 2-alkyl/aryl-3-nitro-2H-chromenes. A 10 mL round
bottom flask equipped with a stirring bar was charged with salicylaldehyde (61 mg, 0.5
mmol), catalyst 1a (10 mg, 0.05 mmol), molecular sieves (4 Å, 0.05 g), 4-nitrophenol (7
mg, 0.05 mmol), and trans-β-nitroalkene (0.5 mmol) in chloroform (0.5 mL) and allowed
to stir at room temperature for specified time. The reaction mixture was then directly
transferred to a silica gel column and purified by using ethyl acetate in hexane as eluent
to get the desired product.
0
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Analytical data of 2-alkyl/aryl/furyl-3-nitro-2H-chromenes
7
3
-Nitro-2-phenyl-2H-chromene (2a). Yellow solid; R = 0.5 (1:9, ethyl acetate: hexane).
f
o
22
25
Yield: 120 mg (96%). M.p. 92-93 C. [α] =-41 (c, 1.0, CHCl ) [Lit. [α]
= -33.0 (c 0.27,
D
3
D
12
-1 1
ethanol)]. IR (KBr):  3071, 3032, 1648, 1605, 1544, 1511, 1325, 1068 cm . H NMR
(400 MHz, CDCl ): δ 6.59 (s, 1H), 6.87(d, J = 8 Hz, 1H), 7.01 (dt, J = 1.2, 7.6 Hz, 1H),
3
13
1
7
.31-7.35 (m, 5H), 7.37-7.40 (m, 2H), 8.07 (s, 1H) ppm. C{ H} NMR (100 MHz, CDCl ):
3
δ 74.2, 117.2, 117.9, 122.5, 127.0, 128.8, 129.3, 129.4, 130.4, 134.3, 136.7, 141.1, 153.5
ppm. The %ee was determined by HPLC using a chiralpak AS column (hexane/iPrOH,
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-
1
9
0:10, 1.0 mL min ): τ
= 8.27 min (100% ee). MS (ESI) calcd for C H NO 253.0,
major
15 11
3
+
found m/z 253.1[M] . Anal. Calcd for C H NO : C, 71.14; H, 4.38; N, 5.53. Found: C,
15
11
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
1.10; H, 4.36; N, 5.56.
6
3-Nitro-2-(p-tolyl)-2H-chromene (2b). Yellow solid; R = 0.54 (1:9, ethyl acetate: hexane).
f
o
22
25
Yield: 122 mg (92%). M.p. 138- 140 C. [α] = -6.89 (c, 1.0, CHCl ) [Lit. [α] = -34.5 (c
D
3
D
11
-1 1
0.35, ethanol)]. IR (KBr):  3066, 3023, 2960, 1650, 1607, 1504, 1333, 1064 cm . H
NMR (400 MHz, CDCl ): δ 3.1 (s, 3H), 6.54 (s, 1H), 6.84 (d, J = 8 Hz, 1H), 6.98 (dt, J =
3
13
1
0.8, 7.6 Hz, 1H), 7.11 (d, J = 8 Hz, 2H), 7.24-7.32 (m, 4H), 8.04 (s, 1H) ppm. C{ H} NMR
(
100 MHz, CDCl ): δ 21.2, 74.1, 117.3, 118.0, 122.4, 127.0, 129.1, 129.5, 130.3, 133.8,
3
134.2, 139.5, 141.2, 153.5 ppm. The ee was determined by HPLC using a chiralpak AS
-1
column (hexane/iPrOH, 90:10, 1.0 mL min ): τ
= 7.41 min, τminor = 10.48 min (84%
major
ee). The %ee was determined by HPLC using a chiralpak AS column (hexane/iPrOH,
-1
9
0:10, 1.0 mL min ): τ
= 7.84 min, (100% ee)(CH Cl as solvent in reaction medium).
major
2
2
+
MS (ESI) calcd for C H NO 267.0, found m/z 267.1[M] . Anal. Calcd for C H NO : C,
16 13
3
16 13
3
7
1.90; H, 4.90; N, 5.24. Found: C, 71.86; H, 4.89; N, 5.25.
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