A facile IL-DMSO assisted synthesis of 5-, 6-, and 7-membered benzo-annelated cyclic guanidines

Article abstract of DOI:10.1016/j.tetlet.2012.03.060

A new and facile IL-DMSO assisted method has been developed for the synthesis of biologically important cyclic guanidines like 2-aminobenzimidazole, 2-imino-4-quinazolinone, and 2-imino-5-benzotriazepinones at ambient temperatures. The desired products could be obtained by microwave irradiation³² also, but at elevated temperatures. A plausible mechanism for catalysis has been proposed.

Full text of DOI:10.1016/j.tetlet.2012.03.060

Tetrahedron Letters 53 (2012) 2954–2958
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A facile IL–DMSO assisted synthesis of 5-, 6-, and 7-membered
benzo-annelated cyclic guanidines
⇑
⇑
Amit Verma, Rajani Giridhar , Pratik Modh, Mange Ram Yadav
Pharmacy Department, Faculty of Technology & Engineering, Kalabhavan, The M. S. University of Baroda, Vadodara, 390 001 Gujarat, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new and facile IL–DMSO assisted method has been developed for the synthesis of biologically impor-
tant cyclic guanidines like 2-aminobenzimidazole, 2-imino-4-quinazolinone, and 2-imino-5-benzotriaz-
epinones at ambient temperatures. The desired products could be obtained by microwave irradiation32
also, but at elevated temperatures. A plausible mechanism for catalysis has been proposed.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 26 January 2012
Revised 16 March 2012
Accepted 20 March 2012
Available online 29 March 2012
Keywords:
Ionic liquids
DMSO
Cyclic guanidine
Cyanogen bromide
2-Imino-4-quinazolinone
Cyclic guanidines are encountered frequently in biologically ac-
tive natural products such as marine alkaloids.1 Some of the poly-
cyclic guanidine derivatives show biological activities like anti-
tumor,2 broncholytic,3 antihypertensive,4 and immunosuppres-
sive.5 Among the most important cyclic guanidines, compounds
with 2-amino-4-quinazolinone core structure have a wide range
of biological activities.6 Interestingly, despite having an identical
2-amino-4-quinazolinone structural motif, these compounds
exhibit diverse biological activities like anti-cancer,7 anti-viral,8
anti-microbial,9 anti-convulsant,10 and anti-inflammatory.11 This
diversity arises mainly due to the pharmacophoric contributions
of a variety of substituents attached to the ring fused heterocyclic
systems. Similarly 2-aminoimidazoles12 and 2-aminotriazepines13
are also of considerable importance from the medicinal chemistry
point of view.
Methods are available for the synthesis of cyclic guanidines
from aliphatic and aromatic diamines. Thus 2-aminobenzimidaz-
ole, 2-imino-4-quinazolinone, and 2-amino-5-benzotriazepinone
can be obtained as salts by the action of cyanogen bromide on aro-
matic diamine,14 amine,15 and amide16 derivatives, respectively. A
second approach to cyclic guanidines involves the reaction of
amines with 2-methylthio-1,3-diazine (available in two steps from
diamines); this procedure has been used to prepare N-alkylguani-
dines of a wide variety. Two other routes for cyclic guanidine
system, which have limited applicability, are hydrogenation of
2-aminopyrimidine to obtain 2-amino-3,4,5,6-tetrahydropyrimi-
dine, and fusion of guanidine with 4,5-diamino-6-hydroxypyrimi-
dine to afford 8-amino-6-hydroxypurine. Here, we report
a
comparative account of different synthetic protocols as an
improvement to one of the above reported methods.
The use of room temperature ionic liquids (RTILs) as solvents or
catalysts for chemical reactions offers several advantages from the
environmental perspective. Therefore, RTILs17 are attracting aca-
demic and industrial attention world wide,18 as these can be used
to replace the organic solvents in catalysis,19 synthesis,20,21 and
separations.22 The unique properties of RTILs enable their use as
alternative solvents and may speed up the introduction of poten-
tially ‘green’ solvents in the sustainable industrial processes. One
of the synthetic protocols reported in this Letter involves the use
of RTILs in DMSO as solvent at room temperature. The method is
appealing especially for the synthesis of cyclic guanidines as it in-
volves very mild conditions in contrast to the reported methods.
This laboratory has been actively engaged in the synthesis of
4-quinazolinones23 from the medicinal chemistry point. It was of
interest to synthesize 2-imino-4-quinazolinones 3, the cyclic gua-
nidine derivatives. For the preparation of the target structure 3,
substituted isatoic anhydride 1 was reacted with primary amines
to afford 2-aminobenzamides 2. It was planned to react intermedi-
ate 2 with cyanogen bromide to obtain the desired compound 3
(Scheme 1). Classical methods for the synthesis of cyclic guani-
dines typically require an excess of cyanogen bromide in protic
polar solvent like EtOH and activated diamines at higher tempera-
tures.16 When the reaction of compound 2 was carried out in EtOH,
it took 6–8 h for the reaction to complete, offering medium to good
⇑
Corresponding authors. Tel.: +91 265 2434187; fax: +91 265 2418927 (M.R.Y.)
E-mail addresses: rajanimsu@rediffmail.com (R. Giridhar), mryadav11@yahoo.-
co.in (M.R. Yadav).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.060

A. Verma et al. / Tetrahedron Letters 53 (2012) 2954–2958
2955
O
O
O
R2
R2
R2
NH2
CNBr
N
N
O
H
K2CO3, DMF
Methods 1-19
NH
N
R1
3 a-m
NH
450, 45 min
R1
N
R1
1 a-d
O
2 a-m
Scheme 1. Synthesis of six-membered cyclic guanidines.
Table 1
Synthesis of 1,3-disubstituted-2,3-dihydro-2-imino-4-quinazolinones31
Compd
Substituents
(R2)
Yield (%)
(R1)
EtOH, 70 °C, 6–8 h
EtOH M.W. 150 W
RTIL/DMSO (1:10),
90 °C, 8–10 min
90 °C, 5–8 min
3a
3b
78
80
94
90
95
92
3c
3d
3e
3f
74
72
56
85
90
89
85
95
92
90
82
94
3g
3h
72
78
92
89
95
90
Me
Me
3i
74
90
92
3j
73
65
90
85
94
88
3k
3l
82
76
90
88
94
92
3m
yields (Table 1). To further enhance the yield of the products (3), it
was thought to carry out the reaction in polar aprotic solvents like
DMSO or in ILs like dibutylimidazolium bromide ([bbim]+[Br]À).
Surprisingly in pure DMSO or in pure IL, the desired product could
not be obtained even after heating of the reaction mixture for 12 h
at 90 °C. There are some reports24–26 of catalyzing effects of IL in
DMSO on some reactions. Srinivasan et al. have reported a facile
esterification reaction using sodium carboxylates and alkyl halides
in 1:10 ratio of RTIL and DMSO.27,28 Thinking that this ratio might
work with our reactants, the reaction was repeated using the same
ratio of IL and DMSO at 90 °C. To our astonishment the ratio of 1:10
of IL and DMSO offered the desired products in high yields in a
short span of time (5–8 min). Cyclization was also tried under
microwave irradiation. Exposure of the reaction mixture for a brief
period to microwaves offered the desired products in high yields.
Results depicted in Table 1 are quite evident to show that these
protocols could be adopted for the synthesis of various aromatic
motifs. In order to expand the intended diversity profile of the
resulting cyclic guanidines, synthesis of 5 and 7 membered ben-
zo-annelated systems like 2-aminoimidazole and 2-amino-5-
benzo[1,2,4]triazepinone were also investigated. Further results
of RTIL–DMSO protocol and microwave irradiation methods are
shown in Tables 2 and 3. Synthesis of 2-aminoimidazole (6) was
started with methyl 4-fluoro-2-nitrobenzoate and was carried
out in three steps, nucleophilic substitution with suitable amines
followed by reduction of nitro group and finally cyclization with

2956
A. Verma et al. / Tetrahedron Letters 53 (2012) 2954–2958
Table 2
Synthesis of 1-substituted-2-aminoimidazoles
Compd
Substituent (R)
Yield (%)
EtOH, 70 °C, 6–8 h
EtOH, M.W. 150 W,
RTIL/DMSO (1:10),
90 °C, 8–10 min
90 °C, 5–8 min
Cl
6a
70
92
94
6b
6c
84
72
94
88
95
89
O
Table 3
Synthesis of 1,4-disubstituted-1,2,3,4-tetrahydro-2-amino-5-benzo[1,2,4]triazepinone
Compd
Substituents
Yield (%)
(R1)
(R3)
EtOH, 70 °C, 6–8 h
EtOH M.W.
150 W 90 °C,
8–10 min
RTIL/DMSO (1:10)
90 °C, 5–8 min
9a
9b
68
54
90
82
90
90
O
O
O
NH2
N
CNBr
O
NH2
R
NO2
O
NH2
O
N
1. DIPEA, DMF
RT, 8 Hr
2. Pd-C, MeOH
Method 8
NH
R
F
R
5 a-c
6 a-c
4
Scheme 2. Synthesis of five-membered cyclic guanidines.
O
O
O
R3
R3
N
R3
NHNH2
N
CNBr
NH2
O
N
Method 8
K2CO3,DMF
900, 3Hr
NH
R1
N
R1
9 a-b
N
R1
7 a-b
O
NH2
8 a-b
Scheme 3. Synthesis of seven-membered cyclic guanidines.
CNBr in RTIL and separately by microwave irradiation, offering 6 in
excellent yields (Scheme 2). Consequently, the synthesis of 2-ami-
no-5-triazepinone was also achieved, starting with N-substituted
isatoic anhydride and using the same protocol as described above
(Scheme 3).
After improving the yields of the desired benzo-annelated cyclic
guanidines it was thought of reducing the reaction temperature so
that the developed experimental protocol could be applied to tem-
perature-sensitive starting materials. Replacing EtOH with easily
available MeOH proved to be disastrous as the reaction mixture
did not proceed even after refluxing the reaction mixture for
18 h. Here also the IL/DMSO mixture in 1:10 ratio provided another
pleasant surprise when the reaction got completed in just 25 min
at room temperature to afford a high quality product (3a) in high
yields (Table 4). The quality of the product was so good that simple
dilution of the reaction mixture with ice-water, filtration and
water washing of the precipitate yielded the analytical grade
sample. Thinking that a simple mixture of both these solvents
would yield same results, different ratios of IL–DMSO were used
as solvents. Different concentrations of IL like 5%, 10%, 20%, 30%,
and 50% in DMSO were used to observe the results. Among all
these ratios an optimum 10–20% IL in DMSO gave the best results

A. Verma et al. / Tetrahedron Letters 53 (2012) 2954–2958
2957
Table 4
Formation of compound 3a, using different synthetic methods
R
δ(−)
H
Br
N
Method
Solvent/reaction cond.
Temp (°C)
Compd (3a)
Time Yield (%)
δ(−)
N
C
S
δ(+)
B
R1
δ(−)
N
1
EtOH
Reflux
8 h
70
60
No rean.
No rean.
58
52
94
88
85
86
82
84
82
88
62
No rean.
No rean.
53
A
N
H
H
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
EtOH
MeOH
Toluene
DMSO
rt
18 h
18 h
12 h
28 h
18 h
25 min
8 min
5 h
45 min
4 h
6 h
12 h
1 h
δ(−)
R
rt/Reflux
Reflux
rt/Reflux
rt/90
rt
90
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
Reflux
δ(+)
O
Me
IL
Me
IL/DMSO::1:10
IL/DMSO::1:10
IL/DMSO:: 1:1
KBr + DMSO
CsBr + DMSO
NaBr + DMSO
LiBr + DMSO
KCl + DMSO
KI + DMSO
Cs2CO3 + DMSO
Cu2I2 + DMSO
KBr + IL
Figure 1. Formation of 6- and 7-membered pseudo-ring structures during the
stabilization of transition state in Step 1.
Me
R2
O
R2
δ(−
)
δ(+
O
)
16 h
18 h
18 h
18 h
5 min
S
O
H
δ(−)
δ(−)
δ(−)
N
H
N
C
O
OR
Me
Me
R
δ(+)
δ(+)
δ(+)
C
N
δ(−)
S
δ(−)
EtOH + M.W.
92
N
N
R1
H
N
Me
R1
N
and the reaction was completed in 25–30 min at room tempera-
ture. Bydecreasing or increasing the ratio of IL in DMSO took more
time (2–8 h) to complete the reaction. Use of 10% IL in DMSO at
room temperature condition was of special interest to us as this
protocol could be adopted for temperature sensitive compounds
with low concentrations of costly ILs.
N
R
Figure 2. Formation of 6-membered pseudo-ring system with DMSO or by H-bond
formation with DMSO and [bbim]+ in the stabilization of the transition state in Step
2.
The above described observations needed a plausible explana-
tion. During the course of reactions using various solvents under
different temperature conditions, it was observed that the reaction
proceeds in two steps (Scheme 4) as inferred from the TLC analysis
of the reaction mixtures, when analyzed at different time intervals.
It became evident that step 1 is a slower one than step 2. That
means IL–DMSO mixture (1:10) might be catalyzing both the steps
but definitely does catalyze step 1. Step 1 can be considered to be a
nucleophilic substitution reaction while step 2 is essentially an
addition step. Transition state of step 1 is expected to be much
more highly polarized than the starting reactants. Factors leading
to stabilization of the transition would enhance the rate of reaction
in Step 1.
A high level of stabilization of the transition state can be ex-
plained by a mixture of DMSO and IL as shown in Figure 1. IL
and DMSO make two pseudo ring structures with both of the react-
ing species thereby stabilizing the partial charges on the atoms as
shown in Figure 1.
Formation of ring A increases the nucleophilicity of amino
nitrogen by increasing the partial negative charge through hydro-
gen bonding with oxygen of DMSO and stabilizing the developing
negative charge on nitrogen of cyano group through the electro-
static interaction with sulfur of DMSO. Formation of ring B is much
more important as it would stabilize the developing negative
charge on bromine and nitrogen atoms through hydrogen bonding
with the two planar hydrogens of [bbim]+.29,30 As carbon and nitro-
gen atoms of cyanogen bromide would be in a state similar to sp2
hybridization state, formation of a planar pseudo seven-membered
ring (B) would be stable in the transition state. Once the cyanamide
intermediate is formed, step 2 is expected to be quite fast as an in-
tra-molecular addition reaction takes place. There could be some
degree of stabilization of the transition state by DMSO in step 2
also, as seen in Figure 2. This stabilization could be facilitated by
DMSO either all alone or in conjugation with IL. Either of the acidic
protons29,30 of C-2, C-4, or C-5 can participate in the stabilization of
this transition state. But the overriding factor seems to be the
internal attack of the nucleophile in step 2. As the reaction rate
is slower in other proportions of IL and DMSO than 10–20%, it is
hypothesized that higher or lower concentrations of IL in DMSO
disrupts the matrix as shown in Figure 1 in the transition state of
step 1 rather than affecting the transition state of step 2.
Since the developing negative charges on bromide and nitrogen
atoms in the transition stage (Step 2) could be stabilized by a cat-
ion through electrostatic interaction, it was considered worthwhile
to perform the reaction in the presence of salts with varying sizes
of cations in the reaction medium having DMSO as the solvent. As
solvation factor of the cation and/or the anion could be an impor-
tant criterion in catalytic reactions, anions of varying sizes were
employed in the salts. To compare and establish the facts, a repre-
sentative derivative of six-membered cyclic guanidine compound
3a was synthesized using different salts maintaining the reaction
conditions as mentioned above. The results are summarized in Ta-
ble 4. These results show that the use of potassium bromide in
DMSO afforded the product fastest while iodide was the least effec-
tive among the potassium salts of halides. Being a much bigger
R2
N
O
O
R2
O
R2
Step 1
N
Step 2
N
H
H
N
N
NH
N
R1
C
N
N
C Br
R1
R1
H
Scheme 4. Mechanism for the formation of 1,3-disubstituted-2,3-dihydro-2-imino-4-quinazolinones.

2958
A. Verma et al. / Tetrahedron Letters 53 (2012) 2954–2958
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but it catalyzed the reaction slower than the potassium ions.
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The authors thank the Director, SAIF-Division of the Punjab Uni-
versity for their help. Also, Amit Verma thanks AICTE, New Delhi
for his NDF-fellowship.
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Supplementary data (experimental procedures and character-
ization data of all the compounds) associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2012.03.060.
31. General procedure for the synthesis of 1,3-disubstituted-2,3-dihydro-2-
iminoquinazolin-4(1H)-ones: In
a 50 ml round-bottom flask, substituted
isatoic anhydride (1a–d) (1 mmol), amine (1 mmol) and K2CO3 (1.5 mmol)
were stirred in DMF (2 ml) at 45 °C for 45 min. The progress of the reaction was
monitored by TLC. After completion of the reaction, the reaction mixture was
allowed to cool at room temperature and diluted with small amount of water.
The solid (2a–m) that separated out, was filtered, washed with water, dried
and used for next step without purification. A mixture of 2a–m (1 mmol), in
10% mixture (2 ml) of IL in DMSO and CNBr (2.5 mmol) was stirred at 90 °C for
about 8–10 min and the reaction was monitored by TLC. After completion of
reaction, the reaction mixture was diluted with ice cold water (10 ml). The
solid quinazolinone products (3a–m), which separated out, were filtered,
washed with water and dried. The crude products, thus isolated, were pure
enough (single spot on TLC) and obtained in excellent yields of 90–95%, and
were fully characterized.
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32. Microwave method: Microwave reactions were carried out using CEM-Discover
Mono-mode Micro-reactor. Reaction mixtures were irradiated at 90 °C with
150 W micropower for 5 min. The progress of the reactions was monitored by
TLC.