Microwave assisted synthesis of 2,3-diaryl-6,7-dihydro-5H-pyrrolo[1,2 a]imidazoles through direct condensation of aryl 1,2-diketones and l-proline under solvent-free condition

Article abstract of DOI:10.1016/j.tetlet.2013.03.017

Microwave irradiation of a solid mixture of aryl 1,2-diketones, l-proline, and ammonium acetate (excess) for 15 min produces 2,3-diaryl-6,7-dihydro-5H- pyrrolo[1,2-a]imidazoles in moderate yields. Mechanistically this one-pot three-component reaction generates pyrroloimidazoles through the intramolecular cyclization of 1,2-diimine intermediates derived from the condensation of aryl 1,2-diketones, l-proline, and ammonia in 1:1:1 molar proportion. The significant advantages of this methodology are cost-effectiveness, operational simplicity, and reduced reaction time.

Full text of DOI:10.1016/j.tetlet.2013.03.017

Tetrahedron Letters 54 (2013) 2528–2532
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave assisted synthesis of 2,3-diaryl-6,7-dihydro-5H-pyrrolo[1,2-a]imi-
dazoles through direct condensation of aryl 1,2-diketones and L-proline under
solvent-free condition
⇑
Subhendu Maity, Sudipta Pathak, Animesh Pramanik
Department of Chemistry, University of Calcutta, 92, A.P.C. Road, Kolkata 700 009, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Microwave irradiation of a solid mixture of aryl 1,2-diketones, L-proline, and ammonium acetate (excess)
Received 17 December 2012
Revised 5 March 2013
Accepted 6 March 2013
Available online 13 March 2013
for 15 min produces 2,3-diaryl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazoles in moderate yields. Mechanisti-
cally this one-pot three-component reaction generates pyrroloimidazoles through the intramolecular
cyclization of 1,2-diimine intermediates derived from the condensation of aryl 1,2-diketones, L-proline,
and ammonia in 1:1:1 molar proportion. The significant advantages of this methodology are cost-effec-
tiveness, operational simplicity, and reduced reaction time.
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Solvent-free condition
Microwave irradiation
2,3-Diaryl-6,7-dihydro-5H-pyrrolo[1,2-
a]imidazoles
Aryl 1,2-diketones
L-Proline
Ammonium acetate
Derivatives of imidazole are very important for their diverse
biological activities in pharmaceuticals as well as agrochemical
field.1 Moreover imidazole moieties are present in a vast number
of naturally occurring molecules, like essential amino acids histi-
dine, histamine, and pilocarpine alkaloids.2 Imidazole based mole-
cules also act as inhibitors of p38 MAP kinase,3a B-Raf kinase,3b
transforming growth factor b1 (TGF-b1) type 1 active in recep-
tor-like kinase (ALK5),3c cyclooxygenase-2 (COX-2),3d and biosyn-
thesis of interleukin-1 (IL-1).3e Substituted imidazoles are also
used as glucagon receptors4a and CB1 cannabinoid receptor antag-
onists,4b modulators of P-glycoprotein (P-gp)-mediated multidrug
resistance (MDR),4c antibacterial,4d and antitumor.4e Several meth-
odologies have been reported in the literature for synthesis of
imidazole derivatives, such as hetero-Cope rearrangement,5 con-
densation of aryl glyoxals, primaryamines, carboxylic acids, and
isocyanides on Wang resin,6 reaction of N-(2-oxo)amides with
ammonium trifluroacetate,7 1,2-aminoalcohols in the presence of
PCl5,8 condensation of diketones, aldehydes, amine, and ammo-
possesses anti-inflammatory, analgesic, antihypertensive, spasmo-
lytic, tranquilizing, and antitussive properties,15a and are also use-
ful sedative and hypotensive agents.15b,c Some methods have been
reported in the literature for the synthesis of fused imidazole
derivatives such as 6,7-dihydro-5H-pyrroloimidazoles.16 Still all
these methods have some significant drawbacks such as most of
them are multistep processes causing longer reaction time and
inconvenience in work-up procedure and also employing unusual
starting materials.16 Therefore, efficient, cost-effective, and eco-
friendly methodologies are required for the synthesis of these
potentially bio-active pyrroloimidazoles within the frame of Green
Chemistry principles.17
Microwave-assisted organic synthesis (MAOS) under solvent-
free condition has a significant impact on synthetic chemistry be-
cause of its intrinsic advantages, like it reduces the reaction time,
X
X
Ar
O
O
Ar
HN
NH4OAc
nium acetate,9 from
a
-aminonitriles,10 and palladium-catalyzed
N
N
+
cyclization of o-pentafluorobenzoylamidoximes,11,12 from keto
oxime, aldehydes, and ammonium acetate.13 Moreover, fused
imidazoles are found to exhibit interesting biological properties.14
For example, 1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-one
Microwave
Irradiation
15 min.
HO
Ar'
H
Ar'
O
2
1
3
Ar, Ar' = Aryl group, 2a (X = H)
2b (X= OH)
⇑
Corresponding author. Tel.: +91 33 2484 1647; fax: +91 33 2351 9755.
E-mail address: animesh_in2001@yahoo.co.in (A. Pramanik).
Scheme 1. Synthesis of 2,3-diaryl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazoles 3.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.017

S. Maity et al. / Tetrahedron Letters 54 (2013) 2528–2532
2529
Table 1
Synthesis of 2,3-diaryl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazoles 3 under conventional and microwave heating
Entry
1,2-Diketone (1)
Product (3)
Conventional heatinga
Time (h)
Yieldc (%)
Microwave heatingb
Time (min)
Yieldc (%)
Mp (°C)
L-Proline (2)
O
O
N
1
2a
7
42
15
60
150–15216a
N
1a
3a
O
N
2
2a
7
41
15
53
182–184
N
O
3b
1b
F
F
O
N
16d
3
2a
7
40
15
51
128–130
N
O
F
F
Br
1c
3c16d
Br
O
N
4
2a
7
38
15
50
166–168
N
O
Br
Br
1d
3d
O
N
O
O
O
O
5
2a
7
41
15
52
96–98
N
O
1e
3e
Cl
Cl
O
O
N
N
6
2a
7
45
15
57
82–84
O
O
O
O
3f
1f
O
O
O
N
7
8
2a
2b
7
7
35
15
15
43
41
130–132
O
N
O
O
3g
1g
1a
OH
O
N
N
0
76–78
O
3h
(continued on next page)

2530
S. Maity et al. / Tetrahedron Letters 54 (2013) 2528–2532
Table 1 (continued)
Entry
1,2-Diketone (1)
Product (3)
Conventional heatinga
Time (h)
Yieldc (%)
Microwave heatingb
Time (min)
Yieldc (%)
Mp (°C)
L-Proline (2)
OH
O
O
N
9
2b
7
0
15
42
95–97
N
3i
1b
F
F
F
OH
O
N
10
2b
7
0
15
43
70–72
N
O
1c
F
3j
OH
O
O
N
O
O
O
O
11
2b
N
7
0
15
41
69–71
1e
3k
a
b
c
Conventional heating in an oil bath at 120 °C temperature.
Microwave heating at 150 W (at 123 °C temperature).
Isolated yield.
energy, and manpower, increases the reaction yields, and sup-
presses the side products.18 In the present Letter, we wish to report
a microwave assisted synthesis of a series of 2,3-diaryl-6,7-dihy-
dro-5H-pyrrolo[1,2-a]imidazoles from easily available starting
materials under solvent-free condition. It has been observed that
the microwave irradiation of a solid mixture of aryl 1,2 diketones
A plausible mechanism of the formation of pyrroloimidazoles 3
is depicted in Scheme 2. The initial nucleophilic attack of -proline
L
2 to one of the carbonyl groups of aryl 1,2-diketones 1 affords pos-
itively charged imine intermediate 4. Subsequently the imine 4 can
either undergo decarboxylation to produce dipolar intermediate 5
(Pathway A) or can react with ammonia, generated from NH4OAc
on heating, to produce 1,2-diimine intermediate 6 (Pathway B).
Then both the possible intermediates 5 and 6 can generate the
common dipolar 1,2-diimine intermediate 7 either through the
condensation with ammonia or decarboxylation, respectively. Fi-
nally the intermediate 7 undergoes intramolecular cyclization
1, L-proline 2, and excess amount of ammonium acetate produces
2,3-diaryl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazoles 3 in moderate
to good yields within a short period of time (Scheme 1, Table 1).19
To the best of our knowledge, this is the first report of formation of
6,7-dihydro-5H-pyrroloimidazoles through the direct condensa-
tion of aryl 1,2-diketones and
L-proline.
involving six-p electrons, followed by aerial oxidation to produce
At the beginning of our investigation we focus on the systematic
evaluation of 2,3-diaryl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazoles
3 from aryl 1,2-diketones 1 and L-proline (2a) in the presence of
2,3-diaryl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazoles 3. All the com-
pounds have been fully characterized by 1H and 13C NMR. The X-
ray crystal structure of 2,3-diphenyl-6,7-dihydro-5H-pyrrolo[1,2-
a]imidazole (3a) shown in Figure 1 further confirms the product
formation.20 Interestingly the formation of regioselective product
2-(20-chlorophenyl)-3-(30,40-dimethoxyphenyl)-6,7-dihydro-5H-
pyrrolo[1,2-a]imidazole (3f) is also confirmed by X-ray crystal
structure analysis (Fig. 2).20 The regioselective formation of 3f
an excess amount of ammonium acetate under conventional heat-
ing at 120 °C, without using any solvent.19 It has been observed
that the reactions take longer time and also the yields of the prod-
ucts 3a–g are less (Table 1). Also, under conventional heating at
120 °C the condensation of aryl 1,2 diketones 1, 4-hydroxy proline
(2b), and ammonium acetate does not occur at all (Table 1, entry
8–11). Therefore MAOS is conducive for the improvement of prod-
uct yields and shortening of reaction time for the above thermal
reactions. The results show that the reactions time and the product
yields in the formation of 2,3-diaryl-6,7-dihydro-5H-pyrrolo[1,2-
a]imidazoles 3a–k have been improved significantly under micro-
wave irradiation at 123 °C temperature (Table 1). Most interest-
ingly, the condensation between 4-hydroxyproline (2b) and aryl
1,2-diketones 1, which was not possible under conventional heat-
ing, now takes place substantially under microwave irradiation at
123 °C temperature to from product 2,3-diaryl-6,7-dihydro-5H-
pyrrolo[1,2-a]imidazol-6-ols, 3h–k (Table 1, entry 8–11). Further
we observe that the reaction tolerates various electron-donating
and withdrawing aryl groups in 1,2-diketones and also substituted
can be rationalized by the initial nucleophilic attack of L-proline
to the more reactive carbonyl carbon attached to 2-chlorophenyl
group of the unsymmetrical 1-(20-chlorophenyl)-2-(30,40-dime-
thoxyphenyl)ethane-1,2-dione (1f).
In conclusion, we have successfully developed a microwave as-
sisted new green methodology for the synthesis of biologically
important
2,3-diaryl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazoles
from easily available starting materials under solvent-free condi-
tion. The significant advantages of this methodology are cost-effec-
tiveness, operational simplicity, and reduced reaction time. To the
best of our knowledge this is the first report of formation of fused
pyrroloimidazoles through the direct condensation of aryl 1,2-
diketones and L-proline. The mechanism of this thermal condensa-
tion reaction is interesting, which may provide important insights
for designing new reactions.
L
-proline. The results are summarized in Table 1.

S. Maity et al. / Tetrahedron Letters 54 (2013) 2528–2532
2531
X
O
O
HN
+
H
OH
O
1
2
- H2O
X
+
N
H
OH
O
NH4OAc
Pathway B
O
-CO2
4
X
X
Pathway A
+
N
O
+
-
N
H
OH
NH
O
NH4OAc
X
-CO2
5
6
+
N
-
NH
7
Cyclization
X
X
Aerial
N
N
N
oxidation
N
H
3
8
Scheme 2. Plausible mechanism for the formation of pyrroloimidazoles 3.
Acknowledgments
C4
N2
C3
S.M. and S.P. thank CSIR, New Delhi, India, for offering SRF. The
financial assistance of CSIR, New Delhi is gratefully acknowledged
[Major Research Project, No. 02(0007)/11/EMR-II]. Crystallography
was performed at the DST-FIST, India-funded single crystal diffrac-
tometer facility at the Department of Chemistry, University of
Calcutta.
C5
C18
C17
C16
C2
C13
N1
C6
C15
C1
C7
Supplementary data
C14
Supplementary data (IR, 1H, 13C data of compounds 3a–k) asso-
ciated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2013.03.017.
C12
C8
References and notes
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2532
S. Maity et al. / Tetrahedron Letters 54 (2013) 2528–2532
Figure 2. ORTEP diagram of X-ray crystal structure of compound 3f with atom numbering scheme. Thermal ellipsoids are shown at 50% probability.
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19. (a) Typical procedure for synthesis of 2,3-diphenyl-6,7-dihydro-5H-pyrrolo[1,2-
a]imidazole (3a) under conventional heating: A solid mixture of benzil (210 mg,
1.0 mmol), L-proline (230 mg, 2.0 mmol), and ammonium acetate (730 mg,
10 mmol) was placed in a 100 ml round bottomed flask fitted with a reflux
condenser and heated in an oil-bath at 120 °C for 3 h. Then excess amount of
ammonium acetate (730 mg, 10 mmol) was added to the same reaction
mixture and heated further at 120 °C for another 4 h. After the reaction, the
reaction mass was poured into water, extracted with ethyl acetate and
concentrated. Crude mass was purified through column chromatography (60%
EtOAc in hexane) to isolate white solid 3a (yield ꢀ110 mg, 42%).
(b) Typical procedure for synthesis of 2,3-diphenyl-6,7-dihydro-5H-pyrrolo[1,2-
a]imidazole (3a) under microwave condition: A solid mixture of benzil (210 mg,
1.0 mmol), L-proline (230 mg, 2.0 mmol), and ammonium acetate (730 mg,
10 mmol) was irradiated under MW at 150 watt (temp 123 °C) for 8 min in an
open vial (a BPL oven, Model No. BMO 800 TS was used). Then excess amount
of ammonium acetate (730 mg, 10 mmol) was added to the same reaction
mixture and further heated under MW irradiation for another 7 min. After the
reaction, the cooled reaction mixture was poured into water, extracted with
ethyl acetate and concentrated. Crude mass was purified through column
chromatography (60% EtOAc in hexane) to isolate white solid 3a (yield
ꢀ156 mg, 60%).
Representative spectral data of compounds: 2,3-di-p-tolyl-6,7-dihydro-5H-
pyrrolo[1,2-a]imidazole (3b): White solid (155 mg, 53% yield); mp 182–
184 °C; 1H NMR (300 MHz, CDCl3): d 7.38 (d, J = 8.1 Hz, 2H), 7.30–7.11 (m,
4H), 6.99 (d, J = 7.5 Hz, 2H), 3.86 (t, J = 6.9 Hz, 2H), 2.93 (t, J = 6.9 Hz, 2H), 2.56
(t, J = 6.9 Hz, 2H), 2.32(s, 3H), 2.24(s, 3H); 13C NMR (75 MHz, CDCl3): d 153.2,
141.2, 137.3, 135.8, 132.3, 129.4, 128.7, 128.7, 128.3, 126.8, 124.9, 44.3, 26.0,
23.5, 21.2, 21.0; IR (KBr): 1496, 1433 cmꢁ1. Anal. Calcd for C20H20N2: C, 83.30;
H, 6.99; N, 9.71%. Found C, 83.22; H, 6.90; N, 9.62.
11. (a) D’Souza, D. M.; Müller, T. J. J. Chem. Soc. Rev. 2007, 36, 1095; (b) Müller, T. J.
J. Chim. Oggi/Chem. Today 2007, 25, 70; (c) Müller, T. J. J. In Targets in
Heterocyclic Systems; Attanasi, O. A., Spinelli, D., Eds.; Royal Society of
Chemistry, Thomas Graham House, Science Park, Milton Road: Cambridge
CB4 0WF, UK, 2006; Vol. 10, p 54.
12. Zaman, S.; Mitsuru, K.; Abell, A. D. Org. Lett. 2005, 7, 609.
13. Sparks, R. B.; Combs, A. P. Org. Lett. 2004, 6, 2473.
14. Jamalian, A.; Shafiee, A.; Hemmateenejad, B.; Khoshneviszadeh, M.; Miri, R.;
Madadkar-Sobhani, A.; Bathaie, S. Z.; Moosavi-Movahedi, A. A. J. Iran. Chem. Soc.
2011, 8, 1098.
2-(20-Chlorophenyl)-3-(30,40-dimethoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-
a]imidazole (3f): White solid (200 mg, 57% yield); mp 82–84 °C; 1H NMR
(300 MHz, CDCl3): d 7.56 (d, J = 7.8 Hz, 1H), 7.42–7.32 (m, 3H), 7.08 (s, 1H),
6.97–6.94 (dd, J1 = 8.4 Hz, J2 = 2.1 Hz, 1H), 6.74–6.70 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz,
1H), 3.98 (t, J = 8.1 Hz, 2H), 3.84 (s, 3H), 3.71 (s, 3H), 3.07 (t, J = 7.8 Hz, 2H),
2.69–2.62 (m, 2H); 13C NMR (75 MHz, CDCl3): d 153.3, 148.5, 147.6, 142.3,
135.0, 133.0, 130.8, 130.0, 129.9, 127.8, 127.1, 121.4, 118.4, 111.0, 109.5, 55.7,
55.4, 44.1, 25.9, 23.6; IR (KBr): 1498, 1443 cmꢁ1; Anal. Calcd for C20H19ClN2O2:
C, 67.70; H, 5.40; N, 7.89%. Found C, 67.61; H, 5.33; N, 7.81.
15. (a) Geigy, J. R. Neth. Appl. 6,613,264, 1967; Chem. Abstr. 1967, 67, 82204q; (b)
Graf, W. Swiss 481,123, 1969; Chem. Abstr. 1970, 72, 100709t; (c) Graf, W.
Swiss 481,124, 1969; Chem. Abstr. 1970, 72, 100710m.
16. (a) Hill, J. H. M.; Fogg, T. R.; Guttmann, H. J. Org. Chem. 1975, 40, 2562; (b)
McClure, J. R.; Custer, J. H.; Schwarz, H. D.; Lill, D. A. Synlett 2000, 710; (c)
20. Crystallographic data for the structures 3a and 3f in this Letter have been
deposited with Cambridge Crystallographic Data Center as supplementary
publication No. CCDC 912957, 912958, respectively. Copies of the data can be
obtained, free of charge on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK, (fax: +44 01223 336033 or e-mail: deposit@ccdc.cam.ac.uk).