A regioselective and high-yielding method for formaldehyde inclusion in the 3CC Groebke-Blackburn-Bienaymé reaction: One-step access to 3-aminoimidazoazines

Article abstract of DOI:10.1055/s-0030-1260568

A regioselective, mild, convenient, and effective condition is developed for the inclusion of glyoxylic acid as formaldehyde equivalent in the 3CC reaction towards synthesis of 3-aminoalkyl imidazo-azines. In general, formaldehydes do not perform well wit

Full text of DOI:10.1055/s-0030-1260568

LETTER
1407
A Regioselective and High-Yielding Method for Formaldehyde Inclusion in
the 3CC Groebke–Blackburn–Bienaymé Reaction: One-Step Access to
3-Aminoimidazoazines
O
ne-Ste
p
Access
t
n
o
3-Aminoim
u
idazoazinesj Sharma, Hong-yu Li*
College of Pharmacy, Department of Pharmacoloy/Toxicology, The University of Arizona, Tucson, AZ 85721, USA
Fax +1(520)6260794; E-mail: hongyuli@pharmacy.arizona.edu
Received 27 January 2011
PTSA/N-hydroxysuccinamide,2e montmorillonite K-10,2a
Abstract: A regioselective, mild, convenient, and effective condi-
tion is developed for the inclusion of glyoxylic acid as formalde-
hyde equivalent in the 3CC reaction towards synthesis of 3-
aminoalkyl imidazo-azines. In general, formaldehydes do not per-
silica sulfuric acid,2i in addition to Lewis acids as
Sc(OTf)3,1 MgCl2,2j InCl3,2l ZnCl2.2m The reaction has
also been reported under solid-phase,2b catalyst-free,2n
form well with Ugi-type multicomponent sequences, and the meth- and fluorous liquid-phase conditions.2c
od reported here is a regioselective and high-yielding one for the
Our interest in this scaffold emanated from our continued
HCHO variant of Groebke–Blackburn–Bienaymé reaction.
interest5 in developing kinase inhibitors for cancer thera-
peutics, and recent reports of 2-unsubstituted 3-arylazine
or 3-aminoazines used as putative kinase inhibitors or en-
zyme modulators (Figure 1).6 Synthesis of such 2-unsub-
stituted 3-amino imidazoazine through Groebke–
Blackburn–Bienaymé methodology would require form-
aldehyde as the aldehyde component. However, Ugi-type
multicomponent reactions (MCR) have limited success
with formaldehyde due to formation of unstable imines,
thus resulting in poor yield of the final products.7 Produc-
tion of 2-unsubstituted-3-aminoimidazoazines through
any other route typically results low yields and limited di-
versity.9
Key words: Groebke–Blackburn–Bienaymé,
reaction, aminoimidazoazines, formaldehyde, glyoxylic acid
multicomponent
In 1998, a new 3CC reaction involving isocyanide, alde-
hyde, and aminoazine was discovered by Groebke,
Bienaymé, and Blackburn for the synthesis of imidazo-
pyridines.1 The reaction became immensely popular and
in the last decade, countless reports have appeared cover-
ing wide scope of the reaction.2 The reaction involves
nonconcerted [4+1] cycloaddition between the iminium
species and the isocyanide (Scheme 1) and gives direct
access to various imidazoazines such as imidazo-
pyridines, imidazopyrimidines, and imidazodiazines.
MeO
MeO
Schiff's base
N
N
N
N
[4+1]
RCHO
H+
N
N
N
N
cycloaddition
N
N
Ph
Ph
N
NH2
HN
R'
R
Ph
N
N
O
R'N+ C–
N
N
N
H
Ar
N
Ph
Scheme 1 Groebke–Blackburn–Bienaymé reaction
Figure 1
These compounds are of profound interest due to their
functions as anxiolytics, calcium channel blockers, cyto-
protective, and HIF-1a-prolyl hydroxylase inhibitors.3
Well-known anxiolytic drugs such as alpidem, zolpidem,
and saripidem are examples from this class of com-
pounds.4 The Groebke–Blackburn–Bienaymé reaction is
compatible with a wide range of aryl/alkyl aldehydes,
isonitriles, solvents like MeOH, toluene,2f,k water,2n
PEG,2o and catalysts ranging from Brønsted acids as
NH4Cl,2f acetic acid,1 perchloric acid,1 tosylic acid,2h
Alternatively, two excellent papers have utilized glyoxyl-
ic acid as a source of formaldehyde in Ugi-type MCR.8
One of them by Kercher et al. exhibited successful appli-
cation of either resin-bound or free glyoxylic acid, as a
source of formaldehyde in Groebke–Blackburn–
Bienaymé reaction.8b This protocol developed by Kercher
was directly related to our intended studies and we, hence,
sought to optimize the methodology and extend it to the
synthesis of our target compounds. In this context, we dis-
close a mild and fairly general condition for the reaction
of glyoxylic acid, 2-aminoazines, isocyanides, and HClO4
used as catalyst to produce 2-unsubstituted imidazo[1,2-
a]-annulated heterocycles in a single step.
SYNLETT 2011, No. 10, pp 1407–1412
x
x
.x
x
.2
0
1
1
Advanced online publication: 16.05.2011
DOI: 10.1055/s-0030-1260568; Art ID: S00811ST
© Georg Thieme Verlag Stuttgart · New York

1408
A. Sharma, H.-y. Li
LETTER
A panel of potential formaldehyde equivalents and acid
catalysts were screened in a reaction of 2-amino-5-bro-
mopyridine (1a), and 1,1,3,3-tetramethylbutylisocyanide
(2a) to form the product 3a (Table 1). In a standard condi-
tion involving aqueous solution of formaldehyde and
Sc(OTf)3 as catalyst, the product was obtained in low
yield (entry 1, Table 1). The side product, N,N’-bis(5-bro-
mopyridin-2-yl)methanediamine was formed using silica
gel (entry 2, Table 1).7i However, there was a moderate
enhancement in the yield when acid catalysts were used,
especially HClO4 (entry 5, Table 1). Further, an attempt to
replace MeOH with H2O or toluene did not yield the de-
sired result (entries 6 and 7, Table 1). After identification
of the optimal catalyst and solvent, the goal was to find a
suitable formaldehyde source. Three formaldehyde equiv-
alents were tested (entries 8–10, Table 1) and glyoxylic
acid provided a significant enhancement in the yield up to
88%. However, the yield dropped to 71% in the absence
of HClO4 (entry 11, Table 1) thus clearly underlying the
importance of HClO4 in this method. AcOH as an organo-
catalyst proved comparable to HClO4 in terms of yield of
3a (entry 12, Table 1).
Table 1 Optimization of a Formaldehyde-Based Groebke–
Blackburn–Bienaymé Reactiona
Br
NC
Br
formaldehyde source
N
N
+
acid catalyst
12 h
N
NH2
HN
1a
2a
3a
Entry Formaldehyde source Acid catalyst Solvent
Yield (%)b
1
2
HCHO aq (37%)
HCHO aq (37%)
HCHO aq (37%)
HCHO aq (37%)
HCHO aq (37%)
HCHO aq (37%)
HCHO aq (37%)
paraformaldehyde
Sc(OTf)3
silica gel
AcOH
MeOH
MeOH
MeOH
MeOH
MeOH
H2O
56
0c
3
67
59
68
32
38
52d
0
4
PTSA
5
HClO4
HClO4
HClO4
HClO4
6
7
toluene
MeOH
MeOH
MeOH
MeOH
MeOH
8
After optimizing the conditions for this 3CC sequence, the
scope and limitations of this protocol were tested with a
series of aminoazines and isonitriles.10As delineated in
Table 2, the method is high-yielding in most cases. In gen-
eral, substitutions at the 4- or 5-position of the hetero-
cyclic ring provided better yields than the unsubstituted
ones. Similarly, all the isocyanides employed for this re-
action demonstrated good to excellent reactivity. Unfortu-
nately, 3-bromopyridine 1e (entry 10, Table 2) and
thiazole 1i (entry 17, Table 2) resulted in poor yield of
their respective products, and a majority of the starting
material was recovered. There was no observable reaction
with the use of oxazole 1j (entry 18, Table 2). In the above
three cases, poor imine formation likely resulted in low
yield or failure to complete the reaction. Overall, the
method worked well on the heterocyclic skeletons tested
(pyridines, pyrimidines, pyrazines, and diazines) and a
range of aryl/alkyl isocyanides.
9
trimethyl orthoformate HClO4
CHOCOOH aq (50%) HClO4
10
11
12
88.2
71
85
CHOCOOH aq (50%)
–
CHOCOOH aq (50%) AcOH
a Reactions were run on a 1.05 mmol scale of 1a, 1.7 mmol of alde-
hyde, 10 mol% of catalyst followed by 1.05 mmol of 2a in 1.5 mL of
solvent and stirred at r.t. for 12 h.
b Yield after column purification.
c Some unresolved side product was formed.
d 17% of the regioisomer were isolated.
R2N+ C–
[4+1]
CHOCOOH
N
N
cycloaddition
– CO2
N
N
HN
R2
3
COOH
It is worthwhile to mention that we did not find the regio-
isomeric product 2-aminoimidazoazine in any of the prod-
ucts,11 which is otherwise a common occurrence to
Groebke reaction, especially in polar protic solvents like
MeOH.2f,o,7,12 The regioselectivity was established
more reactive imine
4
N
NH2
N
N
HN
R2
R1
R2N+ C–
[4+1]
R1CHO
+
cycloaddition
N
N
N+
NH
R1
R1
N
N
less reactive imine
6
5
R1
NH
R2
Scheme 2
Figure 2 Compound 3b crystallized as [ClO4]– salt
Synlett 2011, No. 10, 1407–1412 © Thieme Stuttgart · New York

LETTER
One-Step Access to 3-Aminoimidazoazines
1409
through crystal structure confirmation of the product 3b and may get isomerized (intermediates 5 and 6) resulting
(Figure 2).13
in a mixture of regioisomers (Scheme 2).
It is possible that the glyoxylic acid derived imine 4 We did not observe the cycloaddition product without de-
(Scheme 2) is more reactive and undergoes cycloaddition carboxylation and assume that removal of CO2 from the
before isomerization resulting in a single regioisomer 3. intermediate 1 was concurrent during cycloaddition.
Imines derived from other aldehydes are not as reactive
Table 2 Scope and Limitations of the Formaldehyde-Based Groebke–Blackburn–Bienaymé Reactiona
formaldehyde source
N
NC
R
N
+
acid catalyst
12 h
NH2
HN
HN
1
2
R
3
Entry
Aminoazine
Isonitrile
Product
Yield (%)b
NC
N
N
1
77
N
NH2
N
H
1b
2b
3b
Br
NC
Br
N
N
2
3
85
61
N
NH2
N
H
1a
2b
3c
N
NC
N
N
NH2
N
2c
1b
1b
H
3d
CN
N
N
4
71
N
N
NH2
H
2d
3e
CN
N
N
5
6
61
61
MeO
N
NH2
N
1b
1c
OMe
H
2e
3f
N
NC
N
N
N
N
NH2
N
H
2b
3g
Synlett 2011, No. 10, 1407–1412 © Thieme Stuttgart · New York

1410
A. Sharma, H.-y. Li
LETTER
Table 2 Scope and Limitations of the Formaldehyde-Based Groebke–Blackburn–Bienaymé Reactiona (continued)
formaldehyde source
N
NC
R
N
+
acid catalyst
12 h
NH2
HN
HN
1
2
R
3
Entry
7
Aminoazine
Isonitrile
Product
Yield (%)b
Br
Br
CN
N
N
71
N
NH2
HN
2f
1a
1c
3h
3i
N
N
N
N
NC
8
9
57
66
N
NH2
HN
2c
Cl
N
Cl
N
NC
N
NH2
N
H
2b
1d
1e
1c
3j
Br
Br
NC
N
N
10
11
39
80
N
NH2
N
H
2g
2h
3k
N
N
N
N
NC
N
NH2
N
H
3l
Cl
N
Cl
N
NC
12
13
93
92
N
NH2
2g
N
H
1d
3m
Cl
NC
Cl
N
N
N
NH2
HN
1f
2l
3n
Synlett 2011, No. 10, 1407–1412 © Thieme Stuttgart · New York

LETTER
One-Step Access to 3-Aminoimidazoazines
1411
Table 2 Scope and Limitations of the Formaldehyde-Based Groebke–Blackburn–Bienaymé Reactiona (continued)
formaldehyde source
N
NC
R
N
+
acid catalyst
12 h
NH2
HN
HN
1
2
R
3
Entry
14
Aminoazine
Isonitrile
Product
Yield (%)b
Cl
NC
Cl
N
N
88
N
NH2
MeO
HN
OMe
1f
2e
3o
N
N
N
N
NC
N
15
16
65
NH2
HN
2g
1g
3p
N
N
NC
50c
N
N
N
NH2
HN
2g
1h
3q
O
O
S
EtO
S
EtO
NC
17
18
N
29c
N
N
NH2
2g
N
H
1i
3r
Cl
N
O
NC
NH2
no product
–
2g
1j
a Reactions were run on a 1.05 mmol scale of 1 in MeOH (1.5 mL) containing 1.78 mmol of CHOCOOH, 10 mol% of HClO4 followed by 1.05
mmol of 2 at r.t. for 12 h.
b Isolated yields.
c Yields based on LC-MS.
In conclusion, we have successfully demonstrated a mild,
convenient, and effective method for the use of glyoxylic
acid as a formaldehyde equivalent in the 3CC reaction for
the synthesis of 2-aminoalkyl imidazo-azines. This regi-
oselective methodology is superior to previous methods in
terms of yield and simplicity. The main advantages of the
protocol include complete regioselectivity, use of inex-
pensive formaldehyde source, and an inexpensive cata-
lyst, high yields, and broad applicability. Extension of this
formaldehyde inclusion methodology to other MCR se-
quences is presently under way.
References and Notes
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We would like to thank the University of Arizona for funding. We
also acknowledge Dr. C. Hulme for suggestions and discussions.
Synlett 2011, No. 10, 1407–1412 © Thieme Stuttgart · New York

1412
A. Sharma, H.-y. Li
LETTER
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(10) Representative Procedure for the Synthesis of N-(2,6-
dimethylphenyl)imidazo[1,2-a]pyridin-3-amine (3b,
Table 2)
To a solution of 2-aminopyridine (1b, 1.05 mmol) in MeOH
(1.5 mL), was added glyoxylic acid (1.78 mmol) followed by
HClO4 (0.105 mmol), and the solution was stirred for 10
min. 2-Isocyano-1,3-dimethylbenzene (1.05 mmol) was
added to this mixture, and the solution was stirred for 12 h.
MeOH was evaporated from the reaction mixture, and the
crude was purified through silica gel chromatography to
provide 3b in 77% yield. 1H NMR (400 MHz, DMSO-d6):
d = 8.72 (d, J = 8 Hz, 1 H), 7.81 (d, J = 4 Hz, 2 H), 7.60 (s,
1 H), 7.52–7.48 (m, 1 H), 7.11 (d, J = 8 Hz, 2 H), 7.05–7.02
(m, 3 H), 2.09 (s, 6 H). 13C NMR (400 MHz, DMSO-d6):
d = 138.5, 136.4, 135.8, 133.4, 132.0, 131.7, 129.3, 128.0,
125.8, 125.3, 116.6, 112.9, 106.3, 18.1. HRMS: m/z calcd for
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98.6% (l = 214 nm).
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(11) Formation of regioisomer was observed during optimization
studies using paraformaldehyde as formaldehyde source
(entry 8, Table 1).
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Synlett 2011, No. 10, 1407–1412 © Thieme Stuttgart · New York