Multi-component reactions between 2-aminopyrimidine, aldehydes and isonitriles: The use of a nonpolar solvent suppresses formation of multiple products

Article abstract of DOI:10.1016/j.tetlet.2005.11.152

A reliable and convenient protocol for MCRs between 2-aminopyrimidine, aldehydes and isonitriles is described. Toluene was chosen as the reaction solvent based on mechanistic reasoning. The product mixtures were found to contain a single imidazo[1,2-a]pyr

Full text of DOI:10.1016/j.tetlet.2005.11.152

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 947–951
Multi-component reactions between 2-aminopyrimidine,
aldehydes and isonitriles: the use of a nonpolar solvent
suppresses formation of multiple products
Vladislav Z. Parchinsky, Olga Shuvalova, Olga Ushakova, Dmitry V. Kravchenko and
Mikhail Krasavin*
Chemical Diversity Research Institute, 2a Rabochaya St., Khimki, Moscow Reg., 114401, Russia
Received 20 October 2005; revised 17 November 2005; accepted 29 November 2005
Available online 20 December 2005
Abstract—A reliable and convenient protocol for MCRs between 2-aminopyrimidine, aldehydes and isonitriles is described. Toluene
was chosen as the reaction solvent based on mechanistic reasoning. The product mixtures were found to contain a single imi-
dazo[1,2-a]pyrimidine product in each case, which were isolated and purified by precipitation and crystallization. Chromatographic
recovery from filtrates raised the total yields to 49–66%. The procedure provides a practical alternative to hitherto reported methods
in which formation of multiple products was observed.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Multi-component reactions (MCRs) have become a sig-
nificant part of todayÕs arsenal of methods in combina-
torial chemistry due to their valued features such as
atom economy, straightforward reaction design, and
the opportunity to construct target compounds by the
introduction of several diversity elements in a single
chemical event.1 Typically, purification of products
resulting from MCRs is also simple since all the organic
reagents employed are consumed and are incorporated
into the target compound.
(Sc(OTf)3,2 perchloric acid,3 or glacial acetic acid4).
After consumption of the starting materials, the prod-
ucts were isolated by chromatography. The moderate
yields observed in some cases were attributed to incom-
plete conversions.
However, after Bradley5 carefully examined these low-
yielding reactions, it became evident that they follow a
more complicated course leading to the formation of
almost equal amounts of isomeric imidazo[1,2-a]pyrimi-
dine products 5. These products are thought to arise
from formation of alternative iminium intermediate I-2
involving the ring nitrogen of 1 (pathway B, Scheme
2), as opposed to the anticipated exclusive formation
of the protonated imine I-1 (pathway A, Scheme 2).
Additionally, nucleophilic solvents (like methanol) were
found to promote interaction of I-1 with the second
molecule of 2-aminopyrimidine as well as the solvent
itself to give products like 6, albeit in low yields (5%).5
2
3
4
´
In 1998, Blackburn, Bienayme, and Groebke reported
an elegant variant of the Ugi MCR involving 2-amino-
azines (in particular, 2-aminopyrimidine, 1)—the
reagents played a dual role by (i) forming a Schiff base
with the aldehyde, and (ii) providing a nucleophilic ring
nitrogen to intercept the intermediate formed after inser-
tion of the isonitrile. In the case of 1, the products were
imidazo[1,2-a]pyrimidines (4, Scheme 1). The reactions
were performed at room temperature by combining all
three reagents in methanolic solution with a catalyst
Being aware of these complications and faced with the
challenge of producing combinatorial arrays of medici-
nally important6 3-alkylamino-2-substituted imidazo-
[1,2-a]pyrimidines 4 for biological screening, we sought
to develop a synthetic protocol that would disfavor the
formation of the unwanted adduct I-2 and thus allow
exclusive formation and straightforward purification of
the target compounds.
Keywords: Imidazo[1,2-a]pyrimidine; Ugi reaction; Combinatorial
chemistry; Toluene; Ammonium chloride.
*
Corresponding author. Tel.: +7 095 995 4942; fax: +7 095 926
9780; e-mail: myk@chemdiv.com
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.152

948
V. Z. Parchinsky et al. / Tetrahedron Letters 47 (2006) 947–951
N
N
N
O
R2 N+
C
NH2
R1
+
N
+
N
H
R1
3
2
1
4
HN
R2
acid catalyst
N
N
H
N
N
H
N+
H
H
C
N
N
N+
N+
H
R1
R1
H
N
R2
R1
N+
R2
N
R2
Scheme 1. Imidazo[1,2-a]pyrimidine synthesis using MCR.
N
H
N
R1
N
Nu
6
R2 N+
C
N
N
3
N
N
H
N+
N
R1
R1
Pathway A
Pathway B
I-1
4
HN
R2
N
N
O
H
R1
NH2
+
R2 N+
C
N
N
3
2
1
NH
H
N+
R1
N
NH
R2
R1
5
I-2
Scheme 2. Mechanistic considerations justifying possible formation of multiple products in the multicomponent reaction under investigation.
We reasoned that while formation of the charged I-2 is
plausible in a polar protic solvent like methanol, in a
nonpolar solvent the stability of I-1 (probably in its
non-protonated form) would be far greater than that
of I-2. Additionally, a non-nucleophilic aprotic solvent
is also unlikely to give rise to adducts like 6. Since
the publication of the first report7 on an Ugi reac-
tion promoted by ammonium chloride in toluene, there
have been a number of examples8,9 in the literature of
the successful use of this set of conditions. Therefore,
we tested its applicability to the MCR-based synthesis
of 4.
dark-brown solutions containing an ammonium chlo-
ride precipitate. These mixtures were washed with hot
water, without cooling to room temperature, and diluted
with hexane to provide thick precipitates, which were fil-
tered off and their identity as imidazo[1,2-a]pyrimidines
4 was confirmed by LCMS analysis (in some cases, the
precipitated products were at least 90% pure) and, sub-
sequently, by the X-ray structure of a representative
product (4j, Fig. 1). Further crystallization from ether
provided analytically pure material. The yields after
crystallization were moderate to good (Table 1). The fil-
trates were analyzed by LCMS and, to our delight, were
also found to contain mostly the same imidazo[1,2-a]-
pyrimidines 4, which were recovered by column chroma-
tography thereby raising the total yield of 4 by
6–23% (Table 1). Notably, neither isomeric products 5
nor adducts like 6 were detected in these processes.
While the yields in these reactions are still modest, the
method described offers a very practical alternative to
the hitherto reported protocols2–4 in which formation
of multiple products is possible5 and is likely to compli-
cate product purification. Furthermore, this method was
In all cases studied (Table 1), an imine intermediate (a
non-protonated form of I-1, Scheme 2) was pre-formed
by heating equimolar amounts 2-aminopyrimidine 1 and
an aldehyde 2 at 50 ꢁC for 30 min10 prior to the addition
of 2 equiv of solid ammonium chloride and 1 equiv of
isonitrile 3. After the reaction mixture was brought to
reflux, the progress of the reaction was monitored by
the disappearance of 1 according to TLC analysis. All
reactions went to completion within 30 h to provide

V. Z. Parchinsky et al. / Tetrahedron Letters 47 (2006) 947–951
Table 1. 3-Alkylamino-2-substituted imidazo[1,2-a]pyrimidines 4 prepared in this study
949
N
1) toluene, 50 oC, 30 min
N
N
N
O
H
N
R1
NH2
+
R1
2) NH4Cl, R2-NC (3),
toluene, reflux, 30 h
HN
R2
4
1
2
Compound
R1
R2
Yield (%) after trituration
or crystallization
Yield (%) after recovery
from filtrate
4a
52
45
43
43
47
49
47
60
N
4b
4c
4d
4e
4f
64
66
49
62
61
66
OMe
Br
O
F
F
F
F
O
4g
Cl
OMe
4h
48
65
OMe
OMe
OMe
4i
45
51
45
28
37
65
61
58
52
52
4j
F
F
4k
4l
Cl
F
MeO
4m
4n
4o
24
25
55
60
Br
BnO
found applicable for 2-aminopyridine and 2-aminopyr-
methoxybenzaldehyde and benzylisonitrile (the reagents
azine: a similar MCR of these 2-aminoazines with p-
used for preparation of 4b) provided good yields of

950
V. Z. Parchinsky et al. / Tetrahedron Letters 47 (2006) 947–951
Figure 1. X-ray structure of the compound 4j.
X
N
1) toluene, 50 oC, 30 min
X
N
O
NH2
+
2) NH4Cl, PhCH2NC
toluene, reflux, 30 h
Ph
O
N
NH
O
7, X = CH, 56%
8, X = N, 62%
Scheme 3. Other 2-aminoazines employed in the MCR under investigation.
imidazo[1,2-a]pyridine 7 and imidazo[1,2-a]pyrazine 8,
quantity of 4 with analytical data11 identical to those
of the material obtained by crystallization.
respectively11 (Scheme 3).
In conclusion, we have demonstrated that judicious
choice of a nonpolar reaction medium for multi-compo-
nent reactions between 2-aminopyrimidine, aldehydes
and isonitriles results in the formation of the target imi-
dazo[1,2-a]pyrimidines 4 as sole products. This new pro-
tocol can be extended to other 2-aminoazines and is
suitable for the convenient production of combinatorial
compound libraries.
References and notes
1. Doemling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39,
3168–3210.
2. Blackburn, C. Tetrahedron Lett. 1998, 39, 5469–5472.
´
3. Bienayme, H.; Bouzid, K. Angew. Chem., Int. Ed. 1998,
37, 2234–2237.
4. Groebke, K.; Weber, L.; Mehlin, F. Synlett 1998, 661–
663.
General procedure for MCR of 2-aminopyrimidine,
aldehydes and isonitriles: A solution of 2-aminopyrimi-
dine (1, 1 mmol) and an aldehyde (2, 1 mmol) in toluene
(15 mL) was heated at 50 ꢁC for 30 min. Solid ammo-
nium chloride (2 mmol) and an isonitrile (3, 1 mmol)
were added and the reaction mixture was brought to
reflux. After 30 h, the resulting dark brown solution, while
still hot, was washed with water (50 ꢁC, 25–50 mL),
cooled down to rt, and diluted with hexane (50 mL).
The resulting precipitate was collected by filtration,
washed with hexane (2 · 25 mL), air dried and recrystal-
lized from ether to provide imidazo[1,2-a]pyrimidines 4.
The filtrate and crystallization liquor were combined,
concentrated in vacuo, and subjected to column chro-
matography on silica gel using 2.5–10% methanol in
dichloromethane as the eluent to provide an additional
5. Mandair, G. S.; Light, M.; Russell, A.; Hursthouse, M.;
Bradley, M. Tetrahedron Lett. 2002, 43, 4267–
4269.
6. (a) Rival, Y.; Grassy, G.; Michel, G. Chem. Pharm. Bull.
1992, 40, 1170–1176; (b) Rival, Y.; Taudou, A.; Ecalle, R.
Farmaco 1993, 48, 857–869; (c) Tully, R. W.; Gardner, C.
R.; Gillespie, R. J.; Westwood, R. J. Med. Chem. 1991, 34,
2060–2067; (d) Barlin, G. B.; Davies, L. P.; Ireland, S. J.;
Ngu, M. M. L.; Zhang, J. Aust. J. Chem. 1992, 45, 877–
888.
7. Cristau, P.; Vors, J.-P.; Zhu, J. Org. Lett. 2001, 3, 4079–
4082.
´
8. Janvier, P.; Sun, X.; Bienayme, H.; Zhu, J. J. Am. Chem.
Soc. 2002, 124, 2560–2567.
9. Fayol, A.; Zhu, J. Org. Lett. 2004, 6, 115–118.
10. Omitting the imine formation step resulted in significant
reduction the yields of 4. Longer reaction times prior to

V. Z. Parchinsky et al. / Tetrahedron Letters 47 (2006) 947–951
951
addition of ammonium chloride and isonitrile 3 did not
improve the yields. The unstable imine intermediate
could not be detected by TLC due to hydrolysis on silica
gel.
8.20 (dd, J = 5.6, 8.7 Hz, 2H), 7.26 (t, J = 8.9 Hz, 2H),
7.19 (d, J = 7.6 Hz, 2H), 6.94 (dd, J = 4.0, 6.6 Hz, 1H),
6.88 (d, J = 8.1Hz, 1H), 6.80 (t, J = 7.4 Hz, 1H), 5.23 (t,
J = 6.0 Hz, 1H), 4.08 (d, J = 6.0 Hz, 2H), 3.65 (s, 3H); dC
(75 MHz, DMSO-d6) 161.4 (d, JC–F = 243.3 Hz), 157.1,
149.2, 143.5, 134.4, 131.2, 130.5 (d, JC–F = 2.9 Hz), 128.7,
128.6 (d, JC–F = 7.4 Hz), 127.1, 124.9, 120.0, 115.1 (d,
JC–F = 21.1 Hz), 110.5, 107.7, 55.1, 46.1; LCMS m/z 349
(M+1); HRMS m/z (EI) found: 348.3829; C20H17FN4O
requires 348.3831.7—beige solid; mp = 126–128 ꢁC; dH
(300 MHz, DMSO-d6) 8.70 (m, 1H), 8.06 (m, 2H), 7.86
(m, 2H), 7.10–7.37 (m, 9H), 6.22 (br s, 1H), 4.13 (s, 2H),
3.83 (s, 3H); dC (75 MHz, DMSO-d6) 159.5, 139.2, 138.4,
137.0, 133.8, 130.6, 128.8, 128.2, 127.7, 127.1, 125.0, 123.5,
116.8, 114.0, 55.2, 49.5, 39.5; LCMS m/z 330 (M+1);
HRMS m/z (EI) found: 329.4055; C21H19N3O requires
329.4051. 8—yellow solid; mp = 133–136 ꢁC (decomp.);
11. Analytical data for selected compounds: 4a—yellowish
solid, mp = 134–138 ꢁC; dH (300 MHz, DMSO-d6) 8.46
(unresolved dd, J = 6.8 Hz, 1H), 8.34 (m, 1H), 8.06 (d,
J = 8.6 Hz, 2H), 7.20–7.30 (m, 5H), 6.87 (dd, J = 4.1,
6.8 Hz, 1H), 6.82 (d, J = 8.6 Hz, 2H), 5.32 (t, J = 5.9 Hz,
1H), 4.08 (d, J = 5.9 Hz, 2H), 2.96 (s, 6H); dC (75 MHz,
DMSO-d6) 149.7, 148.2, 143.3, 139.8, 136.2, 130.6, 128.2,
127.8, 127.0, 123.1, 121.5, 112.0, 107.5, 51.1, 40.0; LCMS
m/z 344 (M+1); HRMS m/z (EI) found: 343.4348;
C21H21N5 requires 343.4350. 4b—pale solid, mp = 146–
148 ꢁC (decomp.); dH (300 MHz, DMSO-d6) 8.57 (dd,
J = 1.9, 6.8 Hz, 1H), 8.43 (dd, J = 4.1, 1.9 Hz, 1H), 8.10
(d, J = 8.9 Hz, 2H), 7.18–7.26 (m, 5H), 7.04 (d,
J = 8.9 Hz, 2H), 6.97 (dd, J = 4.1, 6.8 Hz, 1H), 5.47
(unresolved t, 1H), 4.08 (d, J = 4.5 Hz, 2H), 3.82 (s, 3H);
dC (75 MHz, DMSO-d6) 158.9, 149.5, 143.0, 139.6, 134.3,
131.3, 128.3, 128.2, 127.1, 125.6, 124.0, 113.9, 108.3, 95.4,
55.1, 51.0; LCMS m/z 331 (M+1); HRMS m/z (EI) found:
330.3923; C20H18N4O requires 330.3927. 4j—yellowish
solid, mp = 156–158 ꢁC; dH (300 MHz, DMSO-d6) 8.49
(dd, J = 1.9, 6.8 Hz, 1H), 8.42 (dd, J = 1.9, 4.0 Hz, 1H),
dH (300 MHz, DMSO-d6) 9.04 (s, 1H), 8.63 (d, J = 4.5 Hz,
1H), 7.95 (d, J = 7.9 Hz, 2H), 7.83 (d, J = 4.5 Hz, 1H),
7.16 (s, 5H), 7.03 (d, J = 7.9 Hz, 2H), 6.76 (br s, 1H), 4.21
(s, 2H), 3.80 (s, 3H); dC (75 MHz, DMSO-d6) 160.0, 138.9,
136.1, 132.2, 128.7, 128.2, 127.2, 126.3, 125.1, 119.2, 116.1,
114.4, 111.6, 55.3, 50.4, 39.5; LCMS m/z 331 (M+1);
HRMS m/z (EI) found: 330.3931; C20H18N4O requires
330.3927.