Diastereoselective multi-component tandem condensation: Synthesis of 2-amino-4-(2-furanone)-4H-chromene-3-carbonitriles

Article abstract of DOI:10.1039/c9ob01345h

A general strategy for a one-pot stereoselective synthesis of 2-amino-4-(2-furanone)-4H-chromene-3-carbonitriles by reaction of salicylaldehyde, malononitrile and butenolides via a tandem Knoevenagel/Pinner/vinylogous Michael condensation is presented. Th

Full text of DOI:10.1039/c9ob01345h

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DOI: 10.1039/C9OB01345H
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Diastereoselective Multi-Component tandem condensation:
Synthesis of 2-amino-4-(2-furanone)-4H-chromene-3-carbonitriles
Vijay Gupta,a Debashish Sahu,a Shailja Jain,b Kumar Vanka,b and Ravi P. Singh*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A general strategy for one-pot stereoselective synthesis of 2-amino-4-(2-furanone)-4H-chromene-3-carbonitriles by
reaction of salicylaldehyde, malononitrile and butenolides via tandem Knoevenagel/Pinner/vinylogous Michael
condensation is presented. The β,γ-butenolides gave syn-selective MCR adduct with dr up to 11.5:1. The mechanistic
insight of MCR was obtained by DFT calculations.
Multicomponent reactions (MCRs) are emerging as a valuable
approach for synthesis of novel heterocyclic compounds,
natural products and biosimilars.1 Utilization of MCRs provides
tremendous advantage over classical linear type approach and
yields complex molecule with high chemical efficiency, atom
economy and diversity.2 A simple example of effective
utilization of MCRs is the reaction of ethylcyanoacetate and
salicylaldehyde with aliphatic aldehydes in the presence of
A. Multi-component reactions involving 3-amidinocoumarin intermediate
R'
N
NH2
NH
R'
CHO CN
CH3CO2NH4
NH2
CH2
CHO
CH2
+
OH CO2Et
+
O
O
O
O
B. Multi-component reactions involving 2-Iminochromenes intermediate
NH
CN
NH
CHO
CN
CN
CN
cat. Zn/L*
R1
R2
ammonium
acetate,
which
yields
1-substituted
R1
+
+
N
O
OH
benzopyranopyridines via 3-amidinocoumarin intermediate
(the Hashimoto three-component coupling, Scheme 1A).3 This
simple example beautifully exemplifies the power of such
transformations to affect strategic fragment coupling. Similarly
in an another example, chiral 2-amino-4-(indol-3-yl)-4H-
chromenes were obtained by the reaction of salicylaldehyde,
malononitrile and indole with an N,N’-dioxide-Zn(II) complex
as the catalyst.4 The chromenes, an interesting class of
compounds, have attracted wide attention for their biological
properties such as anti-HIV,5 anticancers,6a antibiotics,6b
anticoagulant,6c cytotoxic,6d antianaphylactic, diuretic and
spasmolytic activity.6e Among the chromene family members,
4-substituted, 2-amino-4H-chromenes are privileged medicinal
scaffolds and their facile synthesis has gathered special
attention from chemists.7 In the last decade, various Brønsted
acids,8a Lewis acids,8b solid supported Lewis acids,8c organic bases,9
inorganic bases,10 water11 and ionic liquid12 mediated MCR based
synthesis of 2-amino-3- cyano-4H-pyran derivatives have been
realized. However, methods for the synthesis of 2-amino-3-cyano-
4H-chromenes with highly functionalized core at 4-position by a
three-component coupling strategy is still elusive and much
required, as a functionalized core can offer opportunity to explore
synthesis of chromene embedded other small molecules by MCRs.
Inspired by the aforesaid biological activities of chromene moieties,
O
NH2
H
O
C. Stereoselective three-component coupling
O
CHO
CN
CN
This work
H
R1
+
CN
+
O
O
R1
OH
O
NH2
Scheme 1 : (A) Ternary condensation of ethyl cyanoacetate and
salicylaldehyde with aliphatic aldehydes. (B) Asymmetric synthesis
2-amino-4(indol-3-yl)-4H-chromenes
Knoevenagel/Pinner/Friedel-Crafts reaction. (C) Three-component
coupling to establish two contiguous stereocenters
of
via
as well as demand of a highly functionalized 4-substituted
chromene synthon, we envisioned incorporating
a
functionalized core of a heterocyclic ring such as butenolide to
iminochromene. Chiral γ-butenolides and their derivatives are
ubiquitous architectural subunits of numerous natural
products and also serve as important building blocks for the
synthesis of biologically active compounds.13 We ventured to
explore, if the butenolide can be incorporated into 2-amino-
4H-chromene by one-pot MCR strategy. Although concise and
attractive, the proposed sequential transformation is
challenging and involves three important reactions: (i)
Knoevenagel condensation reaction of salicylaldehyde with
malononitrile in the presence of base; (ii) Pinner cyclization to
give iminochromene intermediate; and (iii) Michael addition of
butenolide derived anion to afford fused 2-amino-4H-
chromene derivatives (Scheme 2). The Michael-addition if
carried out in one pot will have three possibilities for the
reaction of β,γ-butenolide, (i) α-attack due to abstraction of
proton from α-position; (ii) β-attack by resonating structure of
a. Address here.
b. Address here.
c. Address here.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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β,γ-butenolide; and (iii) vinylogous γ-site attack.14 Thus, Table 1. Optimization of reaction conditionsa-c
controlling regio- and stereo-selectivities for the β,γ-
View Article Online
DOI: 10.1039/C9OB01345H
butenolide attack would be a major challenge in this MCR
strategy. Herein, we report the successful application of such
an approach in one-pot three-component reaction where
another privileged heterocyclic moiety of β,γ-butenolides and
α,β-butenolides have been incorporated in regio- and stereo-
selective manner.
O
O
CHO
O
CN
O
Base, Solvent
r.t.
+
+
H
CN
CN
OH
NH2
O
3a
1a
2
4a
Yieldb (%)
drc
--
Entry
Base (equiv)
Solvent
CH2Cl2
--
0
1.
2.
3.
4.
5.
O
O
O
NC
CN
R
R
O
O
O
Base

2
Et3N (0.2)
DBU (0.2)
DBN (0.2)
DIPEA (0.2)
DABCO (0.2)
DMAP (0.2)
LiOtBU (0.2)
NaOtBu (0.2)
KOtBu (0.2)
MeONa (0.2)
NaOtBu (0.2)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
52
51
49
52
2.6:1
3:1

H

H
Base
NC
2.7:1
3.2:1
CHO
OH
CN
CN
NH
CN
Pinner
Cyclization
6.
7.
8.
CH2Cl2
CH2Cl2
CH2Cl2
48
45
48
1.3:1
1.4:1
4.3:1
N
O
O
H2O
Knoevenagel
Condensation
1a
H
Michael
Attack
9.
CH2Cl2
CH2Cl2
48
45
4.6:1
1.2:1
O
O
R
10.
O
O
O
R
O
11.
12.
CH2Cl2
CH3CN
45
54
4.6:1
3:1
R
CN
CN
CN
O
NH2
O
NH2
O
NH2
NaOtBu (0.2)
NaOtBu (0.2)
NaOtBu (0.5)
NaOtBu (1.0)
THF
52
57
65
13.
14.
15.
5.2:1
5.2:1
5.3:1
7.3:1
2.6:1
I
II
III
Michael attack
Michael attack
Michael attack
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
81
16.
17.
Scheme 2. Synthetic strategies for butenolide containing 2-amino-
4H-chromene-3-carbonitrile
56
Et3N (1.0)
aReaction conditions: Salicylaldehyde 1a (0.2 mmol), malononitrile 2 (0.2 mmol),
α-Angelica lactone 3a (0.3 mmol) and Bases (equiv) were taken in 1 ml solvents
for 16 h at room temperature. bIsolated yield. cDiastereomeric ratio (syn:anti)
We commenced our optimization studies by investigating the
reaction of salicycladehyde 1a (1.0 equiv), malononitrile 2 (1.0
equiv) and α-Angelica lactone 3a (1.5 equiv), in methylene was determined by 1H NMR spectroscopy.
chloride solvent at room temperature (Table 1). To facilitate
conditions (Table 1, entry 16), scope of the reaction with
the condensation via iminochromene intermediate, we carried
out the reaction in a basic environment. The expected product
4a was not observed in the absence of a base (Table 1, entry
1). However, in the presence of catalytic amount of organic
base Et3N (20 mol%), the reaction proceeded smoothly to
afford desired product 4a in 52% yield of inseparable
diastereomer with low diastereoselectivity of 2.6:1 (Table 1,
entry 2). Encouraged with this lead, other organic bases were
also screened. When DBU, DBN, DIPEA, DABCO and DMAP
were examined, the desired product 4a was observed with
most of the organic bases in poor diastereoselectivities and
yield (Table 1, entries 3-7, 1.3:1-3.2:1 dr; 45-52% yield).
Fortunately, alkoxides (LiOtBu, NaOtBu, KOtBu and NaOMe)
showed potential activity in this reaction (Table 1, entries 8-
11). Particularly, in the case of NaOtBu (20 mol%), very good
selectivity of the desired product 4a with moderate yield
(Table 1, entry 9, 4.6:1 dr; 48% yield) was observed. Further
optimization indicated aprotic polar solvent such as 1,4-
respect to salicylaldehyde and butenolide was explored (Table
2). Interestingly, the reactivity and selectivity was found to be
sensitive to the electronic property of salicylaldehydes. First,
we explored salicylaldehyde with electron withdrawing
substituents such as halogens at 5-position. The 5-Cl and 5-Br
salicylaldehydes, afforded 4b and 4c in 63% and 65% yields
respectively, with high selectivities (Table 2). Also, 3,5-
dichloro- and 3,5-dibromo salicylaldehydes gave 4d and 4e in
64% and 71% yields respectively, with high stereocontrol while
4-F substituted salicylaldehyde gave 4f in good yield and
selectivity. Surprisingly, 5-nitrosalicylaldehyde afforded 4g in
low yield and poor selectivity (Table 2, 46%, 1.2:1 dr), this may
be due to strong electron withdrawing nature of NO2 group
which makes benzylic proton acidic which can lead to
isomerization at the stereogenic center. Thereafter, we
screened the effects of electron donating substituents on
dioxane as the most efficient (Table 1, entry 14, 5.2:1 dr; 57% reactivity and selectivity of the MCR reaction where
yield) solvent for these reactions. Variation in the base loading
was indicated that 0.5 equiv of NaOtBu in 1,4-dioxane provided
high yield with similar selectivity (Table 1, entry 15, 5.3:1 dr).
Further increasing the base loading of NaOtBu to 1.0 equiv.
improved the yield to 81% with high diastereomeric ratio
(Table 1, entry 16, 7.3:1 dr). However, same reaction in the
presence of 1.0 equiv. Et3N in 1,4-dioxane solvent at room
temperature afforded 4a in 56% yield with 2.6:1 dr. At higher
temperature such as 60 oC, yield and diastereoselectivity
of the product decreases. With this optimal reaction
salicylaldehyde with methoxy, diethylamine, and alkyl
substituents (1h-l), were subjected to the optimized reaction
conditions. Interestingly, methoxy substitution at the C4
position of the salicylaldehyde gave high yield and dr whereas;
substitution at the C3 gave very poor dr (Table 2, 4h and 4i).
While 4-diethylaminesalicylaldehyde did not show any
reactivity, it was found that 5-methyl and 3,5-di-tert-butyl
gave 4u with 65% yield and 7.3:1 dr. The more hindered β,γ-
2 | J. Name., 2012, 00, 1-3
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Table 3. Scope of α,β-Butenolidesa-c
Table 2. Scope of MCR for various salicylaldehydes and β,γ-
Butenolidesa-g
View Article Online
DOI: 10.1039/C9OB01345H
O
O
R2
O
R2
CHO
CN
NaOtBu
*
R1
O
+
H
H
+
O
1,4-Dioxane
r.t.
CN
O
CN
CHO
OH
O
NaOtBu
CN
*
R1
R1
H
R2
O
1,4-Dioxane
16h, r.t.
CN
O
NH2
CN
OH
R1
1
2
5a-c
6
R2
O
O
NH2
O
1a-u
2
3
4
4a
-syn (major)
O
O
O
O
O
O
H
H
H
H
Br
CN
NH2
CN
NH2
O
O
O
O
H
O
O
H
H
H
CN Cl
NH2
CN Br
CN
Cl
CN
6b,
61%, (dr = 1.8:1)
O
6a,
60%, (dr = 3.8:1)
O
O
O
O
O
NH2
O
NH2
O
NH2
Cl
O
O
b
4a
4b
4c
, 81%, (dr = 7.3:1)
, 63%, (dr = 6.1:1)
, 65%, (dr = 5.2:1)
4d
, 64%,(dr = 7.3:1)
H
H
H
H
H
H
Br
CN
CN
O
O
O
O
H3C
CN
O
O
H
O
O
H
O
NH2
O
NH2
O
NH2
H
H
6c
6e
, 56%, (dr = 1.8:1)
, 53%, (dr = 2.3:1)
6d,
51%, (dr = 2.3:1)
Br
CN
CN O2N
NH2
CN
CN
O
O
O
NH2
F
O
O
NH2 MeO
O
NH2
O
O
Br
Ph
c
b
H
H
4h
,72%, (dr = 4.3:1)
H
H
4g
, 46%,(dr = 1.2:1)
4e
4f
,71%, (dr = 4.9:1)
, 61%, (dr = 4.6:1)
O
CN
H3C
CN
O
O
O
O
NH2
O
NH2
O
H
O
H
O
O
H
6g,
54%, (dr = 1.5:1)
6f
, 55%, (dr = 3.3:1)
H
CN
NH2Et2N
CN H3C
NH2
CN
tBu
CN
NH2
O
O
O
NH2
O
aReaction Conditions: Salicylaldehyde 1 (0.2 mmol), malononitrile 2 (0.2
mmol), α,β-butenolide 5 (0.3 mmol) and NaOtBu (0.2 mmol) were taken in
tBu
OMe
d
4i
4j
, 0%
4k
4l
, 75%, (dr = 1.7:1)
, 72%, (dr = 9:1)
, 64%, (dr = 11.5:1)
1
ml 1,4-Dioxane for 16 h
at room temerature. bIsolated yield.
O
O
O
O
cDiastereomeric ratio (major:minor) was determined by crude 1H NMR
O
H
O
O
H
O
F
spectroscopy.
H
H
Br
CN O2N
NH2
CN Ph
NH2
CN
CN
Both the substitutions are well tolerated in the reaction
conditions and yielded MCR adduct (Table 2. 4m, 72%; 2.1:1 dr
and 4n, 45%; 1.8:1 dr). We further extended the scope of the
reaction to include phenyl, p-F-phenyl, p-CF3- phenyl and
theinyl-substituted salicyladehydes at 5-position (Table 2, 4o-
r). In all cases very high reactivity and selectivity was realized.
However, 2-hydroxy-1-naphthaldehyde yielded 4s in 54% yield
and 4:1 dr with longer reaction time of 24h. Further, the
impact of 5-ethyl, 5-propyl, 3-methyl-5-propyl and 5-phenyl
substituted β,γ-butenolides (3b-e) on reactivity and selectivity
with 5-methyl salicylaldehyde was screened. It was observed
that in case of propyl substituted β,γ- butenolides 3c
O
O
O
NH2
O
NH2
OMe
,70%, (dr = 2.1:1)
OMe
, 45%, (dr =1.8:1)
c
4m
4o
4p
, 72%, (dr = 4.6:1)
, 65%, ( dr = 4.9:1)
4n
O
O
O
O
O
O
F3C
S
H
H
H
CN
CN
CN
O
NH2
O
NH2
O
NH2
e
4q
, 75%, (dr = 7.3:1%)
4r
,70%, (dr = 5.7:1)
O
4s
, 54%,(dr =4:1)
O
O
O
O
O
O
H
O
H
H
H
Ph
H3C
CN H3C
NH2
CN H3C
NH2
CN
H3C
CN
O
O
O
NH2
O
NH2
configuration of major product corresponds to syn and the
stereochemistry of all other products obtained from β,γ-
butenolides 4a-v was assigned by analogy. Further α,β-
butenolides 5a-c were explored as a component for the MCR,
substrates of this type have poor reactivity due to conjugation
of double bond with the carbonyl group (Table 3). It was
observed that furan-2(5H)-one 5a underwent addition with
salicylaldehyde 1a and malononitriles to give 6a in 60% yield
with 3.8:1 dr (Table 3). Furan-2(5H)-one 5a was also reacted
with electron-deficient 1c and electron-rich 1k aldehydes, and
afforded 6b and 6c in good yield with lower dr (Table 3). The 4-
methyl furan-2(5H)-one 5b was also reacted with
salicylaldehyde 1a, 1c and 1k, and afforded desired products
6d, 6e and 6f respectively, with moderate yield and selectivity.
Further, 4-phenylfuran-2(5H)-one 5c also gave the desired
product 6g with moderate yield and poor dr.
4t
, 60%, (dr = 4:1)
4u
, 65%, (dr = 7.3:1)
4v,
4w
, 0%
65%, (dr = 2.3:1)
aReaction Conditions: Salicylaldehyde 1 (0.2 mmol), malononitrile 2 (0.2 mmol),
β,γ-butenolide 3 (0.3 mmol) and NaOtBu (0.2 mmol) were taken in 1 ml 1,4-
Dioxane for 16 h at room temerature. bReactions were performed in DCM (1 ml).
cReaction performed with 50 mol% NaOtBu in 1,4-Dioxane. dReaction was
performed in THF (1 ml). eReaction run for 24 h. Isolated yield. gDiastereomeric
ratio (syn:anti) was determined by crude 1H NMR spectroscopy.
f
butenolides 3d gave 4v in 65% yield with lower dr 2.3:1.
Unfortunately, 5-phenyl substituted β,γ-butenolides 3e did not
afford the desired product. To unambiguously determine the
relative configuration of MCR products, we obtained a crystal
structure of 4a (See supporting Information). The relative
salicylaldehyde afforded 4k and 4l respectively in high yield
and excellent dr (9:1 and 11.5:1). We also investigated the
effect of simultaneous presence of both electron-withdrawing
and electron-donating groups on salicylaldehydes.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Next, the carbanion has two possibilities to approach the
In order to establish the mechanism of the developed reaction,
control experiments were performed (Scheme 3). The reaction
of salicyaldehyde with malononitrile in the absence of base
afforded iminochromene 4a’ in 15% yield but in the presence
of a base provided 4a’ in 84% yield (Scheme 3a) suggesting
that the base is important for the formation of iminochromene
4a’. This iminochromene 4a’ may react with butenolide 3a
under optimized reaction condition to afford desired product
4a in 65% yield with dr 1.6:1 (Scheme 3b). However, the
reaction of 1a with 3a in the presence of base afforded
product 7a which was further subjected to react with
malononitrile, did not lead to the desired product 4a (Scheme
3c). This implied that 4a’ is the intermediate for the reaction.
Thus, the base is required for the formation of intermediate
4a’ as well as for final product 4a.
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substrate: i) from the syn side, and ii) from the anti side (TS-I
DOI: 10.1039/C9OB01345H
and TS-II respectively), which lead to the formation of two
intermediates, Int-I and Int-II respectively. Calculations suggest
that the syn-intermediate (Int-I) is more favorable than the
anti-intermediate (Int-II), both thermodynamically and
kinetically. The barrier (ΔG#) for the formation of the syn-
intermediate was found to be 4.2 kcal/mol whereas for the
formation of the anti-intermediate, it was 4.6 kcal/mol. While
the difference in barriers is somewhat small, since the ratio of
the products formed as a function of the barriers is an
exponential function, even a small difference in barrier would
still translate to diastereoselectivity. Hence, the computational
studies corroborate the experimental findings
.
Based on the above control experiments, it was proposed that
the base abstracts a proton from malononitrile to form
carbanion, which attacks on carbonyl group of salicylaldehyde
followed by pinner cyclization to give iminochromene
intermediate, which further undergoes vinylogous Michael
addition with butenolide to give 2-amino-4-(2-furanone)-4H-
chromene-3-carbonitrile product. The observed syn selectivity
in these MCRs can probably be due to an acyclic transition
state model as illustrated in Fig 2. The TS-II is disfavoured due
to strong electronic repulsion between the lone pair of
electron on the furan oxygen atom of 2-furoxy anion and the
circulating л-electron cloud of the nitrile group. The reaction
was also found to be practically viable as scaling up (5 mmol)
did not show any loss in selectivity (7.3:1) although it had
slightly lower yield (60%) (Scheme 3d).
Also, the observed diasteroselectivity was supported by
quantum chemical calculations, performed with density
functional theory (DFT) at the PBE/TZVP level of theory. The
approach of carbanion (3a’) to the substrate (4a’) leads to the
formation of a reactant complex (RC), which is favorable by 8.2
kcal/mol (Figure 1).
CHO
CN
NH
CN
CN
NaOtBu (0.2 mmol)
(a)
1,4-Dioxane ( 1ml),
r.t.
OH
O
t
2
(0.2 mmol)
4a',
4a',
1a
15% yield (without NaO Bu)
(0.2 mmol)
t
84% yield (with NaO Bu)
NaOtBu
O
O
NC
NH2
CN
NH
(0.2 mmol)
O
(b)
O
O
1,4-Dioxane, r.t.
O
H
3a
4a'
(0.2 mmol)
t
O
4a
, 0% (without NaO Bu)
(0.3 mmol)
O
65% yield, dr = 2.1:1
(with NaOtBu)
O
4a,
O
H
H
O
O
Me
H
CHO
OH
N
N
NaOtBu
C
O
O
C
CN
(c)
(d)
(0.2 mmol)
+
O
Me
O
Me
O
O
O
NH
1,4-Dioxane, r.t.
NH
O
NH2
3a
(0.3 mmol)
1a
(0.2 mmol)
7a
, 80% yield
TS-I
TS-II
disfavored
favored
syn-product (major)
4a
NC
NH2
O
CHO
O
H
NaOtBu
CN
O
O
O
1,4-Dioxane
16h, r.t.
CN
OH
Figure 2. Plausible transition state for the stereochemical outcome
2,
3a,
(7.5 mmol)
1a,
(5 mmol)
(5 mmol)
4a,
yield 60% (dr = 7.3:1)
Scheme 3. Controlled experiments for mechanistic studies and scale
up version of the reaction
For chiral one-pot MCR reaction with salicylaldehyde 1c (1.0
equiv), malononitrile 2 (1.0 equiv) and α-Angelica lactone 3a
(1.5 equiv) in presence of quinine catalyst (20 mol%) afforded
MCR adduct 8a in 42% yield with low diastereoselectivity and
enantioselectivity (Scheme 4).
O
O
O
O
Ts II
-3.6
-4.0
Me
CN
0.0
O
H
Me
CN
H
O
O
O
Ts1
O
NH
H
O
O
NH
O
O
4.2
3a'
Ts I
Me
CN
CN
NH
O
4.6
O
O
NH
Quinine
*
O
-8.2
RC
O
4a'
H
Br
CHO
O
-9.4
CN
CN
Br
(20 mol%)
CN
O
O
Me
Int II
H
*
CN
NH
1,4-Dioxane
16h, r.t.
CN
OH
O
-9.8
O
NH2
O
NH
Int I
O
Me
1c,
2,
3a,
(0.3 mmol)
(0.2 mmol)
(0.2 mmol)
8a,
yield 42%
er 73:27; dr = 1.9:1
Scheme 4. Chiral one-pot MCR reaction of Salicylaldehyde 1c
Figure 1. The free energy profile for the diastereoselective synthesis
of 2-amino-4-(2-furanone)-4H-chromene-3-carbonitrile. All the
energy values have been given in kcal/mol.
4 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
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with moderate to high diastereomeric ratio (upto 11.5:1)
under mild conditions. The reaction could be scaled up to gram
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9
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Conflicts of interest
There are no conflicts to declare”.
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Acknowledgements
We are grateful for generous financial support from the DAE
(2018043702RP04978-BRNS), the Council of Scientific and
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