An approach to the synthesis of 2-Acylchromeno[3,4- c ]pyrrol-4(2 H)-one derivatives via a sequential three-component reaction

Article abstract of DOI:10.1055/s-0033-1339521

An efficient synthesis of 2-acylchromeno[3,4-c]pyrrol-4(2H)-one derivatives by a three-component reaction of salicylaldehydes, β-keto esters, and p-toluenesulfonylmethyl isocyanide is reported. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1339521

2124▌
LETTER
lAettner Approach to the Synthesis of 2-Acylchromeno[3,4-c]pyrrol-4(2H)-one
Derivatives via a Sequential Three-Component Reaction
2-Acylchromeno[3,4-c]pyrrol-4(2H)-one Derivatives
Abdolali Alizadeh,*a Rashid Ghanbaripour,a Long-Guan Zhub
a
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
Fax +98(21)88006544; E-mail: abdol_alizad@yahoo.com; E-mail: aalizadeh@modares.ac.ir
b
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
Received: 16.06.2013; Accepted after revision: 17.07.2013
4(2H)-one derivatives 3, generated through an [1,3]-acyl
Abstract: An efficient synthesis of 2-acylchromeno[3,4-c]pyrrol-
shift17 in 62–95% yields (Table 1).
4(2H)-one derivatives by a three-component reaction of salicylalde-
hydes, β-keto esters, and p-toluenesulfonylmethyl isocyanide is re-
ported.
Key words: 2-acylchromeno[3,4-c]pyrrol-4(2H)-one, p-toluene- used at room temperature;18 whereas at higher tempera-
sulfonylmethyl isocyanide, salicylaldehyde, [1,3]-acyl shift
Optimization of the reaction conditions showed that the
reaction proceeds with excellent yields when DMF was
tures complex mixtures were obtained. When we used tri-
ethylamine instead of piperidine for the synthesis of 3-
acetylcoumarin, the Knoevenagel condensation did not
occur, thus we used piperidine as a catalyst in this step.
However, as large amounts of piperidine may lead to side
reactions such as Michael addition, we used triethylamine
in the second step. We also examined malonic esters in-
stead of β-keto esters, but this failed to afford the desired
2-alkylcarboxylatechromeno[3,4-c]pyrrol-4(2H)-ones,
probably because of the lower electrophilicity of esters in
comparison to ketones. Having established the optimal
conditions, we then examined the scope of the reaction for
the construction of various 2-acylchromeno[3,4-c]pyrrol-
4(2H)-ones, and the results are summarized in Table 1.
Coumarins play important roles in natural products and
are widely present in animal and microbial metabolites
and also in higher plants such as Rutaceae, Apiaceae,
Asteraceae, Leguminosae, and Thymelaeaceae.1 They ex-
hibit a broad pharmacological profile2 including antican-
cer activity,3 inhibition of platelet aggregation,4 steroid
5α-reductase,5 and HIV-1 protease.6 Coumarins have also
been used as insecticides7 and optical brighteners.8 Conse-
quently, chromenes and coumarins have attracted consid-
erable attention9 and a range of methods has been reported
for their synthesis including cyclization of salicylalde-
hydes with enamines,10 Petasis reaction of salicylalde-
hydes,11 palladium-catalyzed oxidative cyclization of
aryl-3-butenyl ethers,12 Baylis–Hillman reactions of sali-
cylaldehyde,13 and reaction of α,β-unsaturated Fischer
carbene complexes of chromium with propargyl ethers.14
The molecular structures of all products 3a–j were eluci-
dated from their spectroscopic analyses as described here-
in for 3a. In the IR spectrum of 3a, two sharp absorption
bands at 1730 and 1713 cm–1, three bands at 1598, 1524,
and 1462 cm–1, and two absorption bands at 1234 and
1182 cm–1 could be related to NCO and CO2, C=C, and
C–O stretching frequencies,. The mass spectrum of 3a
displayed the molecular ion peak at m/z = 227, and also a
base peak at m/z = 185, which is in good agreement with
the proposed structure and deacylation of the proposed
molecule, respectively. The 1H NMR spectrum of 3a ex-
hibited a sharp singlet signal at δ = 2.71 ppm (CH3) and
Toluenesulfonyl methyl isocyanide (TosMIC) is a useful
synthon, adding to various unsaturated functional group,
such as electron-deficient carbon–carbon double bonds as
well as imino, formyl, and thiocarbonyl groups to give
pyrroles, imidazoles, 1,3-oxazoles, and 1,3-thiazoles, re-
spectively.15 Accordingly, and in continuation of our stud-
ies on the synthesis of new polycyclic heterocyclic
compounds,16 we decided to investigate the reaction of
salicylaldehydes, β-keto esters, and TosMIC in the syn-
thesis of new coumarin derivatives.
To test this new process, we initially explored the reaction
of a range of salicylaldehydes 1 and β-keto esters 2 in
DMF at room temperature in the presence of piperidine
(0.1 mmol) to afforded the expected 3-acetylcoumarins.
Then, a solution of TosMIC (1 mmol) and triethylamine
(1 mmol) was added to this mixture, and we unexpectedly
observed the formation of 2-acylchromeno[3,4-c]pyrrol-
SYNLETT 2013, 24, 2124–2126
Advanced online publication: 02.09.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339521; Art ID: ST-2013-D0554-L
© Georg Thieme Verlag Stuttgart · New York
Figure 1 ORTEP diagram of 3d

LETTER
2-Acylchromeno[3,4-c]pyrrol-4(2H)-one Derivatives
2125
Table 1 One-Pot, Three-Component Synthesis of 2-Acylchromeno[3,4-c]pyrrol-4(2H)-one Derivatives 3a–j
O
R
N
O
O
S
NC
one-pot
O
O
CHO
OH
+
+
R
OMe
Me
r.t., 8 h
DMF
O
O
1
2
3
Entry
Products
Compound 1
R
Yield (%)
1
2
3a
3b
3c
3d
3e
3f
salicylaldehyde
Me
Me
Me
Me
Me
Me
Me
Me
n-Pr
n-Pr
75
80
90
85
65
95
87
70
65
62
3-methoxysalicylaldehyde
4-methoxysalicylaldehyde
5-methoxysalicylaldehyde
5-nitrosalicylaldehyde
3,5-dichlorosalicylaldehyde
5-chlorosalicylaldehyde
3
4
5
6
7
3g
3h
3i
8
2-hydroxynaphthalene-1-carbaldehyde
salicylaldehyde
9
10
3j
3-methoxysalicylaldehyde
four aromatic protons of the coumarin as two triple dou- ed structure. The most important peak is related to the
blets at δ = 7.26 and 7.36 ppm and two double doublets at NCO group which appeared at δ = 169.1 ppm (see Sup-
δ = 7.28 and 7.98 ppm. Two protons of the pyrrole ring ap- porting Information). Final confirmation for the formation
peared as two mutually coupled doublets at δ = 8.26 and of the reaction products was obtained by X-ray crystal
1
8.41 ppm. The H-decoupled 13C NMR spectrum of 3a structure analysis of compound 3d. The ORTEP diagram
showed 13 distinct signals in agreement with the suggest- for compound 3d is shown in Figure 1.
O
O
O
CHO
OH
R2
piperidine
+
R2
OMe
– H2O, – MeOH
R1
R1
O
O
1
2
4
Et3+NH
–
Et3N
N+
Ts
N+
Ts
C–
C–
5
Et3N
Ts
N
N
H
O
O
desulfonylation
[3+2] cycloaddition
4 + 5
R2
R2
R1
R1
O
O
O
O
7
6
O
N
R2
[1,3]-acyl shift
O
O
3
Scheme 1 Proposed mechanism for the formation of 3
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2124–2126

2126
A. Alizadeh et al.
LETTER
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A plausible mechanism for the sequential three-compo-
nent reaction is proposed in Scheme 1. The formation of
the 2-acylchromeno[3,4-c]pyrrol-4(2H)-one 3 can be
explained by initial Knoevenagel condensation between
salicylaldehydes 1 and β-keto esters 2 in the presence of
piperidine leading to 3-acetylcoumarins 4.19 Then, [3+2]
cycloaddition of the TosMIC ion pair 5 leads to interme-
diate 6. Desulfonylation of 6 under the basic conditons of
the reaction leads to intermediate 7 which is converted
into 2-acylchromeno[3,4-c]pyrrol-4(2H)-one 3 by [1,3]-
acyl shift. To evaluate this proposed mechanism, 3-acetyl-
coumarin was synthesized separately and added to the
TosMIC ion-pair solution with the same result being ob-
served.
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Although acyl shifts are more difficult than hydrogen
shifts and usually require forcing conditions, in this case
full aromatization of the pyrrole ring and full conjugation
of the π-electron system and steric effects led to [1,3]-acyl
shift at room temperature.
In summary, we have disclosed a concise approach to the
synthesis of N-acylchromeno[3,4-c]pyrrol-4(2H)-one de-
rivatives by the reaction between salicylaldehyde, β-keto
esters, and TosMIC through an unexpected acyl shift. A
simple workup procedure, mild reaction conditions, lack
of side products, and good yields are the main aspects of
this method.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
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Synlett 2013, 24, 2124–2126
© Georg Thieme Verlag Stuttgart · New York