Regioselective, solvent-free synthesis of 3-aminoimidazo[1,2-a]pyrimidines under microwave irradiation promoted by zeolite HY

Article abstract of DOI:10.1055/s-0028-1087274

Microwave-assisted, solvent-free condensation of 2-aminopyrimidine with aldehydes and isonitriles gave the desired 3-aminoimidazo[1,2-a]pyrimidine products with good to excellent regioselectivity. A hydrogen zeolite ('zeolite HY') was found to be a novel

Full text of DOI:10.1055/s-0028-1087274

LETTER
3183
Regioselective, Solvent-Free Synthesis of 3-Aminoimidazo[1,2-a]pyrimidines
Under Microwave Irradiation Promoted by Zeolite HY
R
egioselective Synthes
a
is of 3-A
m
r
inoimida
k
zo[1,2-
a
]pyrimidin
J
es . Thompson, Jenny M. Hurst, Beining Chen*
Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, S3 7HF, UK
Fax +44(114)2229346; E-mail: b.chen@sheffield.ac.uk
Received 2 July 2008
of products.5 In addition to the expected 3-aminoimida-
zo[1,2-a]pyrimidines, corresponding 2-amino products
are also formed, this mixture arising via the possibility of
initial imine formation through either the exocyclic amino
Abstract: Microwave-assisted, solvent-free condensation of 2-
aminopyrimidine with aldehydes and isonitriles gave the desired 3-
aminoimidazo[1,2-a]pyrimidine products with good to excellent re-
gioselectivity. A hydrogen zeolite (‘zeolite HY’) was found to be a
novel and effective promoter for the reaction, generally leading to group, or one of the ring nitrogen atoms (Scheme 2). Un-
clean conversion and also permitting use of the normally unreactive
4,6-dimethyl-2-aminopyrimidine.
der typical reaction conditions [MeOH–CH2Cl2 (25:75),
Sc(OTf)3 (5 mol%), 50 °C, 48 h], Mandair et al. showed
Key words: multicomponent reactions, heterocycles, zeolites,
regioselectivity, bicyclic compounds
that the two isomeric products are formed in an approxi-
mately 1:1 ratio in the reaction involving 2-aminopyrimi-
dine and a range of aldehydes, particularly substituted
benzaldehydes.5
It is now some ten years since Groebke,1 Bienaymé2 and
Blackburn3 independently reported the multicomponent
synthesis of fused imidazoles from an aldehyde, an isocy-
anide and a 2-aminoazine (Scheme 1). The reaction has
been widely studied with a range of 2-aminoazines, but
works most efficiently with 2-aminopyridine or aminopy-
razine, such that many reports have focused chiefly or ex-
clusively upon the use of these two building blocks.3a,4
Based on mechanistic rationale, Parchinsky and co-work-
ers later demonstrated that formation of the unwanted 2-
aminoimidazo[1,2-a]pyrimidine 1b is suppressed in tolu-
ene, a much less polar solvent, but extended reflux times
are still necessary under these conditions.6 If the 2-amino-
imidazo[1,2-a]pyrimidine product 1b is required, it may
be accessed selectively via a Dimroth rearrangement of
the mixed products.7
Of particular interest is the case of 2-aminopyrimidine,
which has been shown to lead to a regioisomeric mixture
We wished to develop a protocol which would not only be
selective for the 3-amino products 1a, but also be consid-
erably quicker to perform and more amenable to high-
throughput synthesis. Varma and Kumar have reported a
rapid, solvent-free, microwave-assisted procedure pro-
moted by montmorillonite K-10 clay,8 but only two exam-
ples using 2-aminopyrimidine were listed, and no
comment on regioselectivity was made, though the forma-
tion of product mixtures from this 2-aminoazine had not
R2
HN
N
Het
R1CHO
R2NC
+
+
N
R1
Het
NH2
N
Scheme 1 Three-component synthesis of fused aminoimidazoles
R1
R1
H
R2NC
+
N
R1
NH
N
N
C
N+
NH
R2
R2
N
N
N
N
NH
N
1b
+
R1CHO
N
NH2
R2
R2
N+
HN
N
H
R2NC
N
C
N
R1
N
N
R1
R1
N
N
N
N
H
1a
Scheme 2 Mechanistic rationale for the formation of mixed products arising from 2-aminopyrimidine
SYNLETT 2008, No. 20, pp 3183–3187
1
6
.1
2
.2
0
0
8
Advanced online publication: 26.11.2008
DOI: 10.1055/s-0028-1087274; Art ID: D25108ST
© Georg Thieme Verlag Stuttgart · New York

3184
M. J. Thompson et al.
LETTER
yet been deduced at that time. We thus sought to investi-
gate microwave synthesis of 3-aminoimidazo[1,2-a]pyri-
midines further, paying attention to the regioselectivity
and scope of the reaction under such conditions.
N
PhCHO
+
+
NC
Ph
N
NH2
Since we ultimately required the free 3-amino com-
pounds, Walborsky’s reagent (1,1,3,3-tetramethylbutyl
isocyanide) was employed as a cleavable isonitrile com-
ponent since it has found successful application as such in
previous syntheses of 3-aminoimidazo[1,2-a]pyridines3c
and some other heterocycles.9 Thus, we set out to evaluate
a model reaction between 2-aminopyrimidine, benzalde-
hyde and Walborsky’s reagent (Scheme 3).
HN
+
N
N
NH
Ph
N
N
N
N
2a
2b
Scheme 3 Model three-component condensation used for optimisa-
tion of reaction conditions
This reaction was first carried out under conventional
heating with Sc(OTf)3 catalysis, and the isomers were
separated by careful column chromatography. Gradient
NOE experiments identified the lower-running product on
TLC as 3-amino compound 2a (25% yield), since an inter-
action was observed between the amino NH and H-5
(0.7% enhancement), the latter also showing some inter-
action with the alkyl group but not the phenyl ring pro-
tons. Conversely, the faster-eluting spot showed
interaction of H-5 with the phenyl ring (0.8% enhance-
ment to o-CH) but not the 1,1,3,3-tetramethylbutyl group,
thus identifying it as the 2-amino isomer 2b (23% yield;
Figure 1). Strong interaction of H-5 with H-6 was seen in
both cases, with enhancements of 2.3% and 3.0% for 2a
and 2b, respectively. The above observations contradict
an earlier report,5 which stated that 2b was the more polar
according to TLC analysis.
Following assignment of the products, our model reaction
was then carried out under microwave irradiation in the
presence of montmorillonite K-10.8 Preformation of the
imine, prior to addition of the isonitrile, was found advan-
Table 1 Isolated Yields of 2- and 3-Aminoimidazo[1,2-a]pyrimidines from Various Aldehydes and Isonitriles under Different Heating Pro-
tocolsa
R1CHO
R2NC
Product
Method Ab
a (%)e
40
Method Bc
a (%)
Conventional heatingd
b (%)f
b (%)
a (%)
b (%)
Ph
2
3
1.0
36
1.9
25
23
NC
NC
CHO
49
37
0.9
2.3
44
40
2.4
3.7
24
16
MeO
CHO
g
g
4
–
–
NC
MeO2C
O2N
CHO
5h
6
38
22
1.1
0
32
–
2.9
–
33
22
19
–
NC
NC
S
CHO
CF3
Ph
Ph
7
8
49
45
1.6
2.8
–
–
19
27
15
11
NC
S
40
7.2
NC
a All reactions were carried out on a 10-mmol scale.
b Reaction conditions: zeolite (50 mg/mmol), 3 × 30 s heating intervals for imine preformation, 4 × 30 s after addition of R2NC.
c Reaction conditions: zeolite (75 mg/mmol), 3 × 30 s heating intervals for imine preformation, 8 × 30 s (at 50% power) after addition of R2NC.
d MeOH–CH2Cl2 (1:3, 100 mL), Sc(OTf)3 (5 mol%), 50 °C, 48 h.
e 3-Amino product.
f 2-Amino product.
g ‘–’ denotes value not determined.
h Heating time was reduced in final stage due to strong microwave absorption (4 × 15 s for method A; 6 × 30 s for method B).
Synlett 2008, No. 20, 3183–3187 © Thieme Stuttgart · New York

LETTER
Regioselective Synthesis of 3-Aminoimidazo[1,2-a]pyrimidines
3185
Figure 1 NOE spectra showing key interactions observed in the
NMR of 2a and 2b, permitting assignment of regioisomeric structures
Figure 2 X-ray structures of 7a and 8a confirmed their identity as
3-aminoimidazo[1,2-a]pyrimidines
tageous in terms of cleaner reactions giving fewer side
products, and an optimal quantity of the clay support of 25
mg/mmol was used.10 Further heating for 4 × 30 s inter-
vals at full power gave optimum conversion, and after
chromatography, the desired 3-aminoimidazo[1,2-a]pyri-
midine 2a was found to be by far the major product, iso-
lated in 50% yield compared to 2% of 2b. Though
encouraging as an initial result, noticeable contaminants
and strong coloration were seen in the products from reac-
tions utilising the montmorillonite clay, leading us to in-
vestigate a hydrogen zeolite11 as an alternative, mildly
acidic support.
ferent substrates, good to excellent selectivity for the 3-
aminoimidazo[1,2-a]pyrimidines was always seen. The
structures of 7a and 8a were confirmed by X-ray
crystallography12 (Figure 2), and it became apparent that
the 3-amino isomer is always the more polar (lower run-
ning on TLC) of the two products.
To further expedite the synthesis of the 3-aminoimida-
zo[1,2-a]pyrimidines, it was established that sufficiently
crystalline products may be isolated without the need for
chromatography. For example, 7a was accessed by direct
crystallisation from the reaction mixture in 33% yield and
good purity. Such cases were aided by employing a small
excess of aldehyde and isonitrile, to ensure complete con-
version of the 2-aminopyrimidine.
Cleaner reactions were indeed observed in the presence of
an optimal amount (50 mg/mmol) of zeolite HY, with
only a little lower conversion (40% yield of 2a) and equiv-
alent regioselectivity (‘Method A’). When the second
phase of the reaction was carried out under irradiation at
50% power (for 8 × 30 s intervals), similarly to Varma and
Kumar’s method, the cleanest model reactions of all were
observed, and in similar yields, provided the amount of
zeolite HY was raised to 75 mg/mmol (‘Method B’).
Montmorillonite K-10 again gave less satisfactory results
in combination with this heating protocol.
Our microwave-assisted method was also extended to the
more hindered 4,6-dimethyl-2-aminopyrimidine. In the
conventionally heated reaction, most of this starting mate-
rial was recovered unchanged, and the desired product
seemed not to be present in the complex mixture which re-
sulted. Pleasingly, under microwave heating (Method A),
two novel compounds derived from this more demanding
2-aminoazine were isolated successfully (Scheme 4), al-
beit in low yield. Exclusive formation of the 5,7-dimethyl-
3-aminoimidazo[1,2-a]pyrimidines was seen in these
examples, and the structure of 10 was confirmed by X-ray
crystallography.12
Having established the two plausible methods above for
the reaction, we set out to investigate their use with a va-
riety of aldehydes and isonitriles. Our intention was both
to find which conditions were better suited to parallel li-
brary synthesis, and to confirm whether or not the regiose-
lectivity observed in the model reaction was general.
After carrying out a range of examples (Table 1), it soon
became apparent that this was in fact the case. Though the
exact ratio of isomeric products varied somewhat with dif-
In conclusion, we have achieved rapid, regioselective syn-
thesis of 3-aminoimidazo[1,2-a]pyrimidines13 under mi-
crowave irradiation in the presence of a hydrogen zeolite,
Synlett 2008, No. 20, 3183–3187 © Thieme Stuttgart · New York

3186
M. J. Thompson et al.
LETTER
(10) The amount of montmorillonite K-10 added proved
important; too little gave low conversion, whereas too much
resulted in more side reactions and lower isolated yields.
(11) Zeolite Y, hydrogen form, also known as zeolite HY;
purchased from Zeolyst International (product ref.
CBV400).
N
ArCHO
+
+
NC
N
NH2
(12) CCDC-693378 (7a), CCDC-693379 (8a) and CCDC-
693380 (10) contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request_cif.
HN
N
9
Ar = Ph (14%)
10 Ar = thiophen-2-yl (11%)
N
Ar
N
(13) 2-(Trifluoromethyl)benzyl isocyanide and 2-(thiophen-2-
yl)ethyl isocyanide were prepared from the requisite amines
using a known procedure.14 Representative experimental
procedures for each of the two methods described (Table 1)
are detailed below.
Scheme 4 Successful application of the less reactive 4,6-dimethyl-
2-aminopyrimidine using the microwave-assisted method
which gave more satisfactory results than the previously
studied montmorillonite K-10 clay support. The attrac-
tiveness of the procedure lies in its operational simplicity
and the fact that it is quick to carry out, both of which ren-
der it ideal for application in the synthesis of chemical li-
braries.
2-(4-Methoxyphenyl)-N-(2,4,4-trimethylpentan-2-yl)-
imidazo[1,2-a]pyrimidin-3-amine (3a): Method A:
2-Aminopyrimidine (951 mg, 10 mmol), zeolite HY11 (500
mg) and p-anisaldehyde (1.22 mL, 1.36 g, 10 mmol) were
mixed in a 100-mL round-bottomed flask, which was
supported in a sand bath and placed inside a household
microwave oven (800 W power rating). The mixture was
irradiated at full power for 3 × 30 s intervals with a 30 s
cooling period between heating, during which the flask was
swirled gently to allow good mixing of the reagents. Once
preformation of the imine was complete, Walborsky’s
reagent (1.75 mL, 1.39 g, 10 mmol) was added and
irradiation was continued for an additional 4 × 30 s intervals,
again allowing a brief cooling period between each and
ensuring efficient mixing. After the reaction, the material
was cooled to r.t. and taken up in CH2Cl2. The suspension
was filtered to remove the zeolite, washed with sat. aq
NaHCO3, dried over MgSO4 and evaporated. Purification
was carried out by flash column chromatography on basic
alumina,15 eluted with ethyl acetate–toluene mixture (20:80
→ 33:67 → 50:50 → 33:67 → 0:100) then 1% MeOH–
CH2Cl2, to provide firstly 3b (orange oil; 33 mg, 0.9%),16
followed by 3a (thick brown gum, crystallised on standing;
1.71 g, 49%).17 An analytically pure sample was obtained by
recrystallisation from CHCl3–cyclohexane, as was also the
case for other examples.
Method B: Carried out as for method A, with the exception
that after addition of Walborsky’s reagent (1.75 mL, 1.39 g,
10 mmol), heating was continued for 8 × 30 s intervals at
50% of full power, still allowing a brief cooling period
between each and ensuring efficient mixing. After workup
and purification as above, 3b (85 mg, 2.4%) and 3a (1.55 g,
44%) were obtained.
2-Phenyl-N-[2-(trifluoromethyl)benzyl]imidazo[1,2-
a]pyrimidin-3-amine (7a) by Direct Crystallisation:
Imine preformation using 2-aminopyrimidine (792 mg, 8.33
mmol), zeolite HY (420 mg) and benzaldehyde (1.02 mL,
1.06 g, 10 mmol) was carried out as per method A above. 2-
(Trifluoromethyl)benzyl isocyanide (1.85 g, 10 mmol) was
added, and heating was continued as detailed in method A.
After the reaction, and cooling to r.t., the material was taken
up in a small volume (ca. 10 mL) of CH2Cl2 and the
suspension was filtered to remove the zeolite. After washing
through the sinter with a little extra CH2Cl2, hexane was
added slowly until precipitation commenced. Once
crystallisation was complete, the product was collected by
filtration and dried to afford 7a as golden brown needles
(1.01 g, 33%).18
Acknowledgment
The authors gratefully acknowledge Mr Harry Adams for X-ray
crystallography work and Ms Sue Bradshaw for assistance with
NMR studies. This work was funded by a grant from BBSRC
(Grant No. BB/E014119/1).
References and Notes
(1) Groebke, K.; Weber, L.; Mehlin, F. Synlett 1998, 661.
(2) Bienaymé, H.; Bouzid, K. Angew. Chem. Int. Ed. 1998, 37,
2234.
(3) (a) Blackburn, C.; Guan, B.; Fleming, P.; Shiosaki, K.; Tsai,
S. Tetrahedron Lett. 1998, 39, 3635. (b) Blackburn, C.
Tetrahedron Lett. 1998, 39, 5469. (c) Blackburn, C.; Guan,
B. Tetrahedron Lett. 2000, 41, 1495.
(4) (a) Kercher, T.; Rao, C.; Bencsik, J. R.; Josey, J. A. J. Comb.
Chem. 2007, 9, 1177. (b) Adib, M.; Mahdavi, M.; Noghani,
M. A.; Mirzaei, P. Tetrahedron Lett. 2007, 48, 7263.
(c) Shaabani, A.; Soleimani, E.; Maleki, A. Tetrahedron
Lett. 2006, 47, 3031. (d) Masquelin, T.; Bui, H.; Brickley,
B.; Stephenson, G.; Schwerkoske, J.; Hulme, C.
Tetrahedron Lett. 2006, 47, 2989. (e) Ireland, S. M.; Tye,
H.; Whittaker, M. Tetrahedron Lett. 2003, 44, 4369.
(f) Schwerkoske, J.; Masquelin, T.; Perun, T.; Hulme, C.
Tetrahedron Lett. 2005, 46, 8355. (g) Rousseau, A. L.;
Matlaba, P.; Parkinson, C. J. Tetrahedron Lett. 2007, 48,
4079.
(5) Mandair, G. S.; Light, M.; Russell, A.; Hursthouse, M.;
Bradley, M. Tetrahedron Lett. 2002, 43, 4267.
(6) Parchinksy, V. Z.; Shuvalova, O.; Ushakova, O.;
Kravchenko, D. V.; Krasavin, M. Tetrahedron Lett. 2006,
47, 947.
(7) Carballares, S.; Cifuentes, M. M.; Stephenson, G. A.
Tetrahedron Lett. 2007, 48, 2041.
(8) Varma, R. S.; Kumar, D. Tetrahedron Lett. 1999, 40, 7665.
(9) (a) Veljkovic, I.; Zimmer, R.; Reissig, H.-U.; Brüdgam, I.;
Hartl, H. Synthesis 2006, 2677. (b) Dömling, A.; Beck, B.;
Magnin-Lachaux, M. Tetrahedron Lett. 2006, 47, 4289.
(c) Thompson, M. J.; Chen, B. Tetrahedron Lett. 2008, 49,
5324.
(14) Jacobsen, E. J.; Stelzer, L. S.; Belonga, K. L.; Carter, D. B.;
Im, W. B.; Sethy, V. H.; Tang, A. H.; von Voigtlander,
P. F.; Petke, J. D. J. Med. Chem. 1996, 39, 3820.
Synlett 2008, No. 20, 3183–3187 © Thieme Stuttgart · New York

LETTER
Regioselective Synthesis of 3-Aminoimidazo[1,2-a]pyrimidines
3187
(15) Due to their acid sensitivity, compounds containing the
1,1,3,3-tetramethylbutyl group were best columned on basic
(2, 3, 5, 6, 9, 10) or neutral (4) alumina, rather than silica,
which was suitable for the other examples (7, 8).
1.60 (s, 2 H), 1.05 (s, 9 H), 0.98 (s, 6 H). 13C NMR (100
MHz, CDCl3): d = 159.5, 149.3, 144.8, 140.9, 131.1, 129.9,
126.8, 121.2, 113.8, 107.9, 60.9, 57.0, 55.3, 31.8, 31.7, 29.0.
IR (solid): 3235, 2924, 2849, 1615, 1504, 1245, 1204, 1030,
786, 764, 498, 485 cm–1. MS (ES): m/z = 353 [M + H]+.
HRMS: m/z [M + H]+ calcd for C21H29N4O: 353.2341;
found: 353.2333.
(16) 3-(4-Methoxyphenyl)-N-(2,4,4-trimethylpentan-2-
yl)imidazo[1,2-a]pyrimidin-2-amine (3b): 1H NMR (400
MHz, CDCl3): d = 8.19–8.25 (m, 2 H), 7.39 (d, 2 H, J = 8.5
Hz), 7.09 (d, 2 H, J = 8.5 Hz), 6.67–6.72 (m, 1 H), 4.19 (s,
1 H), 3.90 (s, 3 H), 1.91 (s, 2 H), 1.58 (s, 6 H), 1.00 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 159.1, 151.1, 146.1, 144.1,
129.8, 126.5, 120.9, 115.3, 107.4, 102.9, 56.1, 55.4, 53.0,
31.8, 31.7, 30.2. IR (solid): 3259, 2946, 2899, 1605, 1564,
1246, 1231, 1189, 1174, 836, 758, 587 cm–1. MS (ES):
m/z = 353 [M + H]+. HRMS: m/z [M + H]+ calcd for
C21H29N4O: 353.2341; found: 353.2348.
(17) 2-(4-Methoxyphenyl)-N-(2,4,4-trimethylpentan-2-
yl)imidazo[1,2-a]pyrimidin-3-amine (3a): 1H NMR (400
MHz, CDCl3): d = 8.58 (dd, 1 H, J = 1.5, 6.5 Hz), 8.48–8.51
(m, 1 H), 7.89 (d, 2 H, J = 8.5 Hz), 6.98 (d, 2 H, J = 8.5 Hz),
6.87 (dd, 1 H, J = 4.5, 6.5 Hz), 3.87 (s, 3 H), 3.40 (s, 1 H),
(18) 2-Phenyl-N-[2-(trifluoromethyl)benzyl]imidazo[1,2-
a]pyrimidin-3-amine (7a): 1H NMR (400 MHz, CDCl3):
d = 8.45 (dd, 1 H, J = 2.0, 4.0 Hz), 8.12 (dd, 1 H, J = 2.0, 6.5
Hz), 8.01–8.06 (m, 2 H), 7.64–7.69 (m, 1 H), 7.40–7.46 (m,
2 H), 7.31–7.39 (m, 3 H), 7.19–7.24 (m, 1 H), 6.75 (dd, 1 H,
J = 4.0, 6.5 Hz), 4.34 (d, 2 H, J = 6.5 Hz), 3.71 (t, 1 H, J =6.5
Hz). 13C NMR (100 MHz, CDCl3): d = 149.4, 144.6, 138.2,
137.0, 133.3, 132.2, 131.1, 129.8, 128.6, 128.3 (q, J = 31.5
Hz), 128.0, 127.9, 127.3, 126.3 (q, J = 5.5 Hz), 124.5 (q, J =
270 Hz), 123.2, 108.2, 49.0. 19F NMR (235 MHz, CDCl3):
d = –58.8 (s). IR (solid): 3248, 1612, 1500, 1309, 1116, 762,
692 cm–1. MS (ES): m/z = 369 [M + H]+. HRMS: m/z [M +
H]+ calcd for C20H16F3N4: 369.1327; found: 369.1331.
Synlett 2008, No. 20, 3183–3187 © Thieme Stuttgart · New York

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