Organocatalytic domino Kn?evenagel-Michael reaction in water for the regioselective synthesis of benzo[4,5]imidazo[1,2-: A] pyrimidines and pyrido[2,3- d] pyrimidin-2-amines

Article abstract of DOI:10.1039/c6ra21376f

An organocatalyzed simple and general route towards the regioselective synthesis of benzo[4,5]imidazo[1,2-a]pyrimidines and pyrido[2,3-d]pyrimidin-2-amines is developed vial-proline catalyzed domino reaction of 2-aminobenzimidazole or 2,6-diaminopyrimidin

Full text of DOI:10.1039/c6ra21376f

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Organocatalytic domino Knöevenagel-Michael reaction in water
for the regioselective synthesis of benzo[4,5]imidazo[1,2-
a]pyrimidines and pyrido[2,3-d]pyrimidin-2-amines
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Subarna Jyoti Kalita, Dibakar Chandra Deka* and Hormi Mecadon*
www.rsc.org/
An organocatalyzed simple and general route towards the regioselective synthesis of benzo[4,5]imidazo[1,2-a]pyrimidines
and pyrido[2,3-d]pyrimidin-2-amines is developed via
L-proline catalyzed domino reaction of 2-aminobenzimidazole or 2,6-
diaminopyrimidin-4-one with aldehydes and -ketoesters in water. High yields within shorter reaction time, simple
β
purification, and environmentally benign mild reaction conditions are the key features that make the protocol significantly
applicable.
are relatively very new synthetic concepts and are often highly
efficient and follow, in some way, different biomimetic
pathways, with the same principles that are found in
Introduction
Development of simple, cost effective and environment friendly
procedure, especially in aqueous medium, is a central theme of
green synthetic technology programs. Taking into account that
water is the solvent of choice for nature’s biological chemistry,
the application of water in organic synthesis is of high priority
nowadays. The use of water as the reaction solvent is highly
advantageous because of its abundance, nonꢀtoxicity and nonꢀ
7
f
biosynthesis in nature. It is, therefore, noteworthy to mention
that such design of synthetic routes to privileged heterocyclic
scaffolds of medicinal relevance (Fig 1) by combining the
synthetic efficiency of domino reactions with organocatalysis is
a very important challenge that has received relatively little
7
,8
attention.
1
flammability. In addition, water facilitates novel solvation and
Cl
molecular assembly processes leading to remarkable modes of
reactivity and selectivity.
N
1
,2
N
HN
N
N
O
Cl
The significance of aqueous media reaction has been further
enhanced by the advent of organocatalysis, in 2000 marked by
HN
O
N
N
O
O
CH
3
O
F
3
4
N
NH
the pioneering works of List and McMillan, where small
organic molecules are used in substochiometric amount to
catalyze organic transformations which, in overall, has brought
N
N
2
CO Me
N
N
N(C
2 5 2
H )
H
N
H
N
N
Tyrosine kinase inhibitor
KSP inhibitor
5
H
a new synthetic outlook, especially in asymmetric synthesis.
Cdk4 inhibitor
Calcium antagonist
Not only their requirement in substochiometric amount, but Fig. 1 Some examples of bioactive fused pyrimidines.
organocatalysts offer many advantages in synthesis because
they are air and water stable, easily handled experimentally,
Benzo[4,5]imidazo[1,2ꢀ
a]pyrimidines
and
pyrido[2,3ꢀ
relatively nontoxic, costꢀeffective and readily separated from
the crude reaction mixture. More significantly, the ability of derivatives of the classical Biginelli products which have been
organocatalysts to promote a wide range of reactions by well known for their significant therapeutic and biological
different activation modes makes it ideal for application in properties. The former is known for potential antineoplastic,
domino reactions, which proceed in a oneꢀpot procedure to calcium antagonist, Tꢀcell activities , and also as inhibitors of
d]pyrimidines are biologically relevant fused pyrimidine
6
9
1
0
1
1
12
1
3
14
build complex frameworks from simple starting compounds in Kinesin spindle protein (KSP) and DNAꢀtopoisomerase I.
6
b,7
a single operation.
These organocatalyzed domino reactions The latter also has been proven to act as CC chemokine
1
5
receptor 4 (CCR4) antagonist, and also as potential inhibitors
1
6
17
of tyrosine kinase (TK), cyclinꢀdependent kinaseꢀ4 (Cdk4),
1
8
and dihydrofolate reductase.
benzo[4,5]imidazo[1,2ꢀ
Due to their importance,
Department of Chemistry, University of Gauhati, G. B. Nagar, Guwahati 781014,
Assam, India. E-mails: hmecadon@gmail.com; Fax +91 0361 2700311; Tel:
a
]pyrimidines have been synthesized by
+91(0)9436175136 (HM)/9864075111 (DCD).
Footnotes relating to the title and/or authors should appear here.
condensation of 2ꢀaminobenzimidazole, aldehydes and
ketoesters using a number of catalysts such as AcONa,
sulfamic acid, silica sulfuric acid, [bmim]BF , N,N´ꢀ
4
βꢀ
†
1
1,19
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
2
0
21
22
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Scheme 1 One-pot regioselective synthesis of benzo[4,5]imidazo[1,2-a]pyrimidines and pyrido[2,3-d]pyrimidin-2-amines.
2
3
dichlorobis(2,4,6ꢀtrichlorophenyl)urea,
αꢀzirconium
2
4
25
sulfophenylphosphonate,
thiamine hydrochloride (VB
,1,3,3ꢀ ′, ′ꢀtetramethylguanidium
TMGT) , Zn(ClO .6H O[30] and also by microwave
melaminetrisulfonic acid,
2
6
27
Results and Discussion
1
), MgO,
H
3
PO
4 2 3
ꢀAl O [28],
1
(
N,N,N N
trifluoroacetate
Initially, a mixture of 2ꢀaminobenzimidazole (1, 1mmol),
benzaldehyde (2a, 1mmol) and ethylacetoacetate (3a, 1 mmol)
2
9
4
)
2
2
3
1
irradiation. On the other hand, to the best of our knowledge,
there are only four known synthetic methods for methyl 2ꢀ
aminoꢀ7ꢀmethyl/ethylꢀ4ꢀoxoꢀ5ꢀalkyl/arylꢀ3,4,5,8ꢀ
in 5 mL of water was refluxed in the presence of 10 mol%
Lꢀ
proline for 6 h. Much to our delight the reaction yielded ethylꢀ
2
a
1
ꢀmethylꢀ4ꢀphenylꢀ1,4ꢀdihydrobenzo[4,5]imidazo[1,2ꢀ
]pyrimidineꢀ3ꢀcarboxylate (4aa) in 65% yield (Table 1, entry
). Inspired by this result, when the reaction was then set for
tetrahydropyrido[2,3ꢀ
reaction of 2,6ꢀdiaminopyrimidinꢀ4ꢀone, aldehydes and
ketoester: two by NaOAc and ZnBr [33] catalyzed thermal
2
heating and the other two by microwave irradiation. While the
efficiency of the modified synthetic procedures are not
d]pyrimidineꢀ6ꢀcarboxylates from the
β
ꢀ
3
2
optimization it was found that 20 mol% of Lꢀproline gave the
3
4
best result with 91% yield in 3 h (Table 1, entry 3). Next, some
potential nonꢀtoxic Lewis catalysts and other organocatalysts
were also tested to find the best effect of the reaction but none
of the reactions showed any satisfactory result (Table 1, entries
understated, such as the VB
1
catalyzed method which is
generally unstable to heat, however, a number of them suffer
from one or more drawbacks, such as unsatisfactory yields,
high temperature, long reaction times, multistep sequences, and
limited substrate scope. Moreover, the use of toxic organic
solvents, ionic liquids, metals, acids and salts as catalyst
increases the waste generation and cost of the synthesis. In
addition, while the classical Biginelli reaction has received
intensive inputs for procedural improvements, on the other
hand, efforts for competent synthetic procedures for the
5
ꢀ9) than compared to
Lꢀproline catalysis. Further, when the
effect of solvents such as EtOH, MeOH and toluene in the
reaction, with
L
ꢀproline as the catalyst, was studied the desired
a
Table 1 Optimization of the reaction
biologically
benzo[4,5]imidazo[1,2ꢀ
potential
fused
Biginelli
and
pyrimidines:
pyrido[2,3ꢀ
a]pyrimidines
d]pyrimidinꢀ2ꢀamines, are relatively underexplored which,
therefore, requires significant attention.
With these backgrounds and our continued efforts on
developing synthetic procedures relevant to green chemistry,
we wish to present herein a simple, general and straightforward
organocatalytic procedure by for the regioselective synthesis of
c
b
Temp.
Time Yield
Entry Catalyst (mol%)
Solvent
o
(
C)
(h)
(%)
3
5
1
2
3
4
5
6
7
8
9
L
L
L
L
ꢀProline (10)
ꢀProline (15)
ꢀProline (20)
ꢀProline (25)
H
H
H
H
H
H
H
H
H
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
6
65
3
80
91
91
20
30
17
15
15
75
73
65
20
10
3
benzo[4,5]imidazo[1,2ꢀ
]pyrimidinꢀ2ꢀamines through
KnöevenagelꢀMichael reaction of 2ꢀaminobenzimidazol or 2,6ꢀ
diaminopyrimidinꢀ4ꢀone with aldehydes and ꢀketoesters in
water under mild reaction conditions (Scheme 1). It may noted
that, ꢀproline is well known cost effective and
a]pyrimidines
and
pyrido[2,3ꢀ
3
d
L
ꢀproline catalyzed domino
FeCl
InCl
NiSO
3
.6H
(20)
.6H
2
O (20)
3
β
3
3
4
2
O (20)
3
L
a
Glycine (20)
3
environmentally benign catalyst with remarkable efficacy in
promoting diversity of synthetic transformations involving
Aldol, Mannich, Michael and analogous reactions, which
overcomes major drawbacks of heterogeneous catalysts like
long reaction time, metalꢀleaching and structural stability. The
present synthesis has been proved to be operationally simple
and cost effective with mild reaction conditions in water,
affording high to excelling yields within short reaction time
with simple purification process.
Thioureadioxide (20)
3
1
0
L
L
L
ꢀproline (20)
ꢀproline (20)
ꢀproline (20)
EtOH
3
11
12
MeOH
3
3
6
Toluene
H O
3
ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
ꢀProline (20)
2
12
24
1
3
4
d
1
L
H
2
O
RT
a
b
c
Reaction scale: 1 (1 mmol), 2a (1 mmol) and 3a (1 mmol). 5 mL. Isolated
d
o
yield. RT ≈ 25 C.
2
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product could be isolated but relatively in low yields (Table 1, methyl acetoacetate (3b), used instead of ethyl acetoacetate
entries 10ꢀ12). On the other hand, an attempt to obtain the 3a), with 2ꢀaminobenzimidazole ( ) and various aldehydes (
desired product under catalystꢀfree condition and at room efficiently produced the methyl analogs
temperature failed (Table 1, entries 13ꢀ14). Thus, based on benzo[4,5]imidazo[1,2ꢀ ]pyrimidines (Table 2, 4bk-4bn).
(
1
2)
of
a
these results, 20 mol%
is regarded as the optimum reaction conditions for this method.
L
ꢀproline in water under reflux condition
Furthermore, the scope of the method was also extended by
exploring towards regioselective synthesis of pyrido[2,3ꢀ
d
]pyrimidinꢀ2ꢀamines, under the same optimized reaction
conditions. The synthesis was carried out by reacting 2,6ꢀ
diaminopyrimidinꢀ4ꢀone ( ) with various aldehydes ( ) and
ketoesters ( ) (Table 3). Various benzaldehydes reacted
smoothly with and ethyl acetoacetate (3a) to furnish the
a
Table 2 Synthesis of benzo[4,5]imidazo[1,2-a]pyrimidines
5
2
βꢀ
3
5
desired product in good to high yields, without any substantial
electronic and steric hindrances from the substitutents of the
benzene ring. With similar effect, the reaction involving
heteroaromatic aldehyde such as furanꢀ3ꢀcarbaldehyde also
gave its resultant product 6bh in good yield of 80%. In
addition, aliphatic aldehydes like phenylacetaldehyde also
reacted efficiently and gave its resultant pyrido[2,3ꢀ
1
2
b
Entry
R
R
Product
Time
h)
3
Yield
(%)
91
(
1
2
3
4
5
6
7
8
9
C
6
H
5
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OMe
OMe
OMe
4aa
4ab
4ac
4ad
4ae
4af
2ꢀClC
3ꢀFC
4ꢀOMeC
6
H
4
3
92
90
88
85
80
93
80
80
75
87
80
81
85
6
H
4
3
d
]pyrimidinꢀ2amine 6ae in 80% yield. Moreover, the use of
6
H
4
2.5
3
methyl acetoacetate (3b), by replacing ethyl acetoacetate (3a),
also showed equal competency and produced their
3,5ꢀ(OMe)
2ꢀFuryl
2
C
6 3
H
3.5
3.5
4
corresponding methyl derivatives of pyrido[2,3ꢀ
amines (Table 3, 6bf bh).
d
]pyrimidinꢀ2ꢀ
2ꢀPyridyl
2ꢀNapthyl
4ag
4ah
4ai
ꢀ
a
Table 3 Synthesis of pyrido[2,3-d]pyrimidin-2-amines
C
6
H
5
CH
Butyl
2ꢀFC
3ꢀBrC
4ꢀClC
4ꢀNO
2
4
1
1
1
1
1
0
1
2
3
4
4aj
4
6
H
4
4bk
4bl
3
6
H
4
3.5
3.5
3.5
H
6 4
4bm
4bn
2
C
6
H
4
1
2
b
Entry
R
R
Product
Time
h)
3
Yield
(%)
82
(
a
b
Reaction Scale: 1 (1mmol), 2 (1mmol), 3 (1 mmol) and H
yield.
2
O (5 mL). Isolated
1
2
3
4
5
6
7
8
C
6
H
5
OEt
6aa
6ab
6ac
6ad
6ae
6bf
6bg
6bh
3ꢀNO
4ꢀCH
2,5ꢀ(OMe)
C H CH
2
C
6
H
5
OEt
2.5
3
88
81
80
82
83
76
80
C
6
H
4
OEt
Subsequently, with this optimized reaction condition the
scope of the reaction was studied by reacting 2ꢀ
aminobenzimidazole (
ketoesters ( ) for the synthesis of benzo[4,5]imidazo[1,2ꢀ
]pyrimidines. As shown in Table 2, various aromatic
aldehydes participated well in the reaction to generate the
desired product in good to excellent yields. The presence of
electron withdrawing or donating group in orthoꢀ, metaꢀ and
paraꢀ position of benzene ring of benzaldehyde has no
significant impact on the reaction and their corresponding
3
2
C
6
H
3
OEt
3
1
) with various aldehydes (
2
) and
β
ꢀ
OEt
3.5
3
6
5
2
3
2ꢀBrC
3ꢀClC
3ꢀFuryl
6
H
5
OMe
OMe
OMe
a
6
H
4
3.5
3.5
a
b
Reaction Scale: 5 (1 mmol), 2 (1 mmol), 3 (1 mmol) and H
yield.
2
O (5 mL). Isolated
1
products were obtained successfully (Table 2, 4aa
bk bn). Heteroaromatic aldehydes like furanꢀ2ꢀcarbaldehyde
ꢀ
4ae and
All the synthesized compounds were characterized by H,
C NMR, IR, mass spectral and elemental analysis. The known
1
3
4
ꢀ
and 2ꢀpyridinecarboxyldehyde also participated well in the compounds were further authenticated from literature reports.
reaction to give their corresponding products 4af and 4ag in The products (Table 2, 4aa 4bn) were purified by simple
0% and 93% yields respectively (Table 2, entries 6 and 7). filtration process and (Table 3, 6aa 6bh) were purified by
Gratifyingly, aliphatic aldehydes like valeraldehyde and column chromatography.
phenylacetaldehyde also reacted efficiently to generate their
In order to establish the probable reaction mechanism,
resultant products 4aj and 4ai with respective yields of 75% initially we refluxed benzaldehyde (2a) and ethyl acetoacetate
and 80%. The synthesis was also extended towards
3a) in the presence of 20 mol% of ꢀproline for 1 h which
polyaromatic aldehyde like 2ꢀnaphthaldehyde and its resulted in the formation of ethyl 2ꢀbenzylideneꢀ3ꢀoxobutanoate
corresponding product 4ah was obtained in 81% yield. Further
7a) in 45% yield. However in the absence of any catalyst, 7a
generality of the scope was also observed when the reactions of was formed only in trace amount. Next we investigated the
ꢀ
8
ꢀ
(
L
(
L
ꢀ
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Experimental
All reagents were purchased from commercial suppliers and
were used without further purification. IR spectra were
recorded on a SHIMADZU infrared spectrometer as KBr
ꢀ1
1
13
pellets with absorption in cm . H and C NMR spectra were
recorded in DMSOꢀ on 300 MHz or 400 MHz or 600 MHz
Bruker NMR spectrometer at 25 C and resonances (
given in ppm relative to tetramethylsilane. Data are reported as
follows: chemical shift ( ), multiplicity (s = singlet, d =
d
6
o
δ) are
δ
doublet, t = triplet, m = multiplet), coupling constants in Hz
with integration. LCMS were obtained on Waters ZQ 4000 and
equipped with ESI source. Melting points were determined
using Veego VMPꢀD and not corrected. Elemental analysis was
done on Perkin Elmer Series II Analyzer 2400. Column
chromatography was performed on silica gel (200ꢀ300 mesh)
using ethyl acetate: hexane (1:1) as the eluent. Thin Layer
Chromatography (TLC) was performed using Merck preꢀcoated
silica gel or silica gel G and the components were visualized
under a UV or an iodine chamber.
General procedure for the synthesis of benzo[4,5]imidazo[1,2-
Scheme 2 The possible mechanism for the L-proline catalyzed reaction.
a]pyrimidines (4aa-4bn)
A mixture of 2ꢀaminobenzimidazole (
mmol) and ꢀketoester ( , 1 mmol) in 5 mL of water was
refluxed for appropriate time in the presence of 20 mol% of
proline as catalyst (Table 2). On completion of the reaction as
indicated by TLC, the crude reaction mass was allowed to cool
and the precipitate was filtered and washed with water (10 mL
x 3) to get the pure product.
1, 1 mmol), aldehyde (2,
proline catalyzed stepꢀwise condensation reaction between 7a
,
1
β
3
prepared in situ, and 2ꢀaminobenzimidzole ( ) by refluxing it
1
Lꢀ
for 2 h which resulted the target compound 4aa in 75% yield;
while without catalyst only 20% product formation could be
observed and the reaction was slightly sluggish. This proves
that
Lꢀproline has a catalytic role in both the steps. Thus based
2
6,36f
upon these observations and literature reports
a mechanism
is proposed as shown in Scheme 2. It is believed that the
reaction proceeds by initial Knöevenagel condensation between
General procedure for the synthesis of pyrido[2,3-d]pyrimidin-2-
amines (6aa-6bh)
benzaldehyde
(
2
)
and
β
ꢀketoester
(3) to generate the
A
mixture of 2,6ꢀdiaminopyrimidinꢀ4ꢀone
aldehyde ( , 1 mmol) and ꢀketoester ( , 1 mmol) was refluxed
in 5 mL of water for appropriate time in the presence of 20
mol% of ꢀproline as catalyst (Table 3). On completion of the
(
5
,
1mmol),
Knöevenagel adduct
7
followed by Michael addition of 2ꢀ
2
β
3
aminobenzimidazole (
followed by cyclization and dehydration via the intermediate
and or 10 and 11 to yield the final product or
Scheme 2).
1
) or 2,6ꢀdiaminopyrimidinꢀ4ꢀone (
5
8
)
L
9
4
6 respectively
reaction as indicated by TLC the reaction mass was allowed to
cool and the precipitate was filtered and purified by column
chromatography to afford pure products.
(
Conclusions
In conclusion we have developed a simple, general and
environmentꢀfriendly protocol for regioselective synthesis of
Acknowledgements
H. M. and S. J. K. thank the DSTꢀINSPIRE, DST, Govt. of
India for the financial assistance. The authors also acknowledge
SAIFꢀGU, SAIFꢀNEHU and IITꢀGuwahati for sample analyses.
benzo[4,5]imidazo[1,2ꢀ
]pyrimidinꢀ2ꢀamines through
KnöevenagelꢀMichael reaction of 2ꢀaminobenzimidazole or
,6ꢀdiaminopyrimidinꢀ4ꢀone with aldehydes and ꢀketoesters
under mild reaction conditions. This application of water as
reaction medium along with ꢀproline as an organocatalyst
a]pyrimidines
and
pyrido[2,3ꢀ
d
L
ꢀproline catalysed domino
2
β
Notes and references
L
1
For selected reviews see (a) M. B. Gawande, V. D. B.
Bonifácio, R. Luque, P. S. Branco and R. S. Varma, Chem.
expand the scope of less explored aqueous media domino
reaction. The efficiency of organocatalysis, wide substrate
scope, easy work up procedure and simple purification process
under mild reaction conditions significantly widens the
procedural scopes for the synthesis of a huge library of
Soc. Rev., 2013, 42, 5522ꢀ5551; (b) C.ꢀJ. Li, Chem. Rev.
,
2
005, 105, 3095ꢀ3166; (c) C.ꢀJ. Li and L. Chen, Chem. Soc.
Rev., 2006, 35, 68ꢀ82; (d) R. N. Butler and A. G. Coyne,
Chem. Rev., 2010, 110, 6302ꢀ6337; (e) H. C. Hailes, Org.
Process Res. Dev., 2007, 11, 114ꢀ120; (f) A. Chanda and V.
V. Fokin, Chem. Rev., 2009, 109, 725ꢀ748; (g) P. E. Savage,
Chem. Rev., 1999, 99, 603ꢀ621.
important benzo[4,5]imidazo[1,2ꢀa]pyrimidines and pyrido[2,3ꢀ
d]pyrimidinꢀ2ꢀamines.
4
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ARTICLE
2
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