Unusual ring closure reaction of amides with pyrimidines: Novel stereoselective synthesis of hexahydroimidazo[1,2-c]pyrimidines

Article abstract of DOI:10.1055/s-1999-3640

Hexahydromidazo[1,2-c]pyrimidines 6 were prepared by the reaction of tosylpyrimidines 2 with bromoacetamides 3 in one step. The stereoselectivity of the reaction has been confirmed by X-ray analysis. Imidazo[1,2- a]pyrimidines 5 were obtained on heating h

Full text of DOI:10.1055/s-1999-3640

2124
PAPER
Unusual Ring Closure Reaction of Amides with Pyrimidines: Novel
Stereoselective Synthesis of Hexahydroimidazo[1,2-c]pyrimidines
Alberto Acero-Alarcón,a Trinidad Armero-Alarte,a Joan M. Jorda-Gregori,a Cristina Rojas-Argudo,a Elena Zaballos-
García,a Juan Server-Carrió,b Fatima Z. Ahjyaje,a José Sepulveda-Arques*a
a Departamento de Química Orgánica, Facultad de Farmacia, Universidad Valencia, Burjassot, Valencia, Spain
Fax +34(96)3864939; E-mail jose.sepulveda@uv.es
b Departamento de Química Inorgánica, Facultad de Farmacia, Universidad de Valencia, Burjassot, Valencia, Spain
Received 7 April 1999; revised 21 June 1999
similar to the reaction of the alkylated products 4.
Abstract: Hexahydromidazo[1,2-c]pyrimidines 6 were prepared by
(Scheme).
the reaction of tosylpyrimidines 2 with bromoacetamides 3 in one
step. The stereoselectivity of the reaction has been confirmed by X-
ray analysis. Imidazo[1,2-a]pyrimidines 5 were obtained on heating
hexahydroimidazo[1,2-c]pyrimidines 6 with trifluoroacetic anhy-
dride.
The procedure used for the preparation of the imidazo
[1,2-a]pyrimidines 5 was based on the literature using 2-
aminopyridines as starting material.2 In the first step the
tosylation of the 2-aminopyrimidines 1A,B afforded the
sulfonamidopyrimidines 2A,B as solid compounds in
Key words: imidazopyrimidines, Michael addition, unsaturated
imines, stereoselective conjugated addition, ring closure, heterocy-
cles, amides
1
very high yields. The H NMR and 13C NMR data are
shown in Tables 1 and 2. The tosylation of 1C was a slow-
er reaction and when it was heated to completion, the di-
tosylated derivative 7C was obtained (14%) along with
2C (76%).
During the preparation of a series of imidazo[1,2-a]pyri-
midines 5 for a study of pharmacological activity, we
found that the reaction of 2-aminopyrimidine (1A) with p-
toluenesulfonyl chloride and further alkylation of the sul-
fonamidopyrimidine 2A formed with the bromoaceta-
mides 3a–f1 afforded the alkylated products 4Aa–f.
Heating 4Aa–f with trifluoroacetic anhydride afforded the
expected imidazo[1,2-a]pyrimidines 5Aa–c,f. Similar re-
sults occur with the 5-substituted 2-aminopyrimidines
1B,C as starting materials when the bromoacetamide 3a
was used for alkylation. However, when the 2-aminopyri-
midines 1B,C, were tosylated and the derivatives 2B,C
were alkylated with 3b–f, the hexahydroimidazo[1,2-c]
pyrimidines 6, (R1 = B,C; R2 = b–f) were isolated as the
major products along with minor amounts of the corre-
sponding alkylated derivatives 4. Hexahydroimidazo[1,2-
c]pyrimidines 6 were converted to the imidazo[1,2-a]py-
rimidines 5 by refluxing with trifluoroacetic anhydride
The tosylation of 2-aminopyrimidines having electron-
withdrawing substituents at C-5 was not successful. 2-
Amino-5-formylpyrimidine did not react even under
forced conditions and 2-amino-5-ethoxycarbonylpyrimi-
dine gave only small amounts (8%) of the corresponding
tosylated derivative.
In the reaction of 2A with bromoacetamides 3a–f and
2B,C, alkylation occurred on the endocyclic nitrogen in
the reaction with the bromoacetamide (3a) affording the
1
derivatives 4. The products 4, showed in the H NMR
spectra typical AMX patterns (three doublets of doublets)
where R1 = H (4Aa–f) and an AB pattern where R1 π H
(4Ba, 4Ca) for pyrimidine ring hydrogen atoms, because
of the asymmetry of the molecule. The chemical shift of
H-4 was always at lower field than H-6 (Tables 3 and 4).
An NOE effect (26%) on the H-6 signal appeared for 4Aa
Scheme
Synthesis 1999, No. 12, 2124–2130 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Unusual Ring Closure Reaction of Amides with Pyrimidines
2125
Table 1 1H NMR (DMSO-d6/TMS) Data of Sulfonamidopyrim-
idines 2a, d, J (Hz)
when NCH2CONH2 was irradiated. Chemical shifts for
quaternary carbons (C-9 and C-12) of the toluenesulfonyl
groups were closer than for the original tosylated deriva-
tives 2A–C as a result of a different electronic effect of
the =NSO2 substituent.
Prod- H4(6) H5
uct
H10
H11
J5,4(6) J10,11 H13
NH
2Ab
2B
2C
8.64 6.95 7.98 7.26 4.75 8.03 2.38
9.85
In the reaction of 2A and 2C with bromoacetamide (3a),
in addition to compounds 4Aa and 4Ca, a small amount
of compounds 8Aa (7%) and 8Ca (8%) derived from
alkylation on the exocyclic nitrogen were obtained.The 1H
NMR agreed with the symmetry of the molecule and only
one doublet for H-4 and H-6 of the pyrimidine ring ap-
peared in spectra. (Tables 5 and 6). Here again the chem-
ical shifts of the quaternary carbons of the p-
toluenesulfonyl group had quite different values.
8.50
8.63
7.87 7.35
7.87 7.33
8.03 2.34
7.95 2.29 11.95
a
b Recorded in CDCl3/TMS.
On the other hand the reaction of 2B,C with bromoaceta-
mides 3b–f, afforded the hexahydroimidazo[1,2-c]pyrim-
idines 6 instead of the expected alkylated products 4, as a
result of an intramolecular Michael addition of the amide
group to the a-b unsaturated imino system. Structures of
compounds 6 were elucidated by 1H and 13C NMR (Tables
7 and 8). A singlet for H-8a at d = 6.2 is in agreement with
a low coupling constant because of the dihedral angle be-
tween hydrogens at C-8a and C-7 (79.3º). On the other
hand the olefinic hydrogen H-7 appeared as a doublet cou-
pled with the NH which exchanges slowly on the NMR
time-scale due to hydrogen bonding with the SO2 group
Table 2 13C NMR (DMSO-d6/TMS) Data of Sulfonamidopyrim-
idines 2a, d
Prod- C2
uct
C4(6) C5
C9
C10
C11
C12
C13
2Ab
2B
2C
156.9 158.6 115.7 136.7 128.4 129.2 144.1 21.6
155.2 154.3 124.3 135.2 125.8 127.3 141.5 20.6
155.8 159.0 112.9 137.2 127.9 129.7 143.9 21.3
a For numbering of the structure, see Table 1.
b Recorded in CDCl3/TMS.
Table 3 1H NMR (DMSO-d6/TMS) Data of 2-[2-(4-Methylphenylsulfonylimino)-1,2-dihydro-1-pyrimidinyl]acetamides 4a, d, J (Hz)
Product H4
H5
H6
H10
H11
H14
J4,5
J4,6
J5,6
J10,11
H13
NH2
4Aa
4Ab
4Ac
4Ad
4Ae
4Af
4Ba
4Ca
8.60
6.83
6.70
6.70
6.68
6.71
6.72
8.35
7.42
7.80
7.48
7.79
7.96
8.44
8.93
7.69
7.77
7.77
7.76
7.78
7.74
7.69
7.86
7.24
7.28
7.27
7.28
7.27
7.28
7.24
7.42
4.74
6.75
6.67
6.90
6.69
6.95
4.78
4.86
4.39
4.38
4.38
4.38
4.40
4.02
2.19
2.20
2.19
2.19
2.20
2.19
2.56
6.58
6.58
6.94
6.58
6.60
6.58
8.23
7.68
8.04
8.05
8.03
8.05
8.23
7.33
2.33
2.34
2.34
2.33
2.33
2.33
2.33
2.34
7.84, 7.45
8.19, 7.77
8.19, 7.84
8.34, 7.93
8.19, 7.79
8.31, 7.96
7.84, 7.44
7.87, 7.66
8.56
8.56
8.57
8.56
8.59
8.60
8.93
a
Table 4 13C NMR (DMSO-d6/TMS) Data of 2-[2-(4-methylphenylsulfonylimino)-1,2-dihydro-1-pyrimidinyl]acetamides 4,a d
Product
C1
C4
C5
C6
C9
C10
C11
C12
C13
C14
C15
4Aa
4Ab
4Ac
4Ad
4Ae
4Af
4Ba
4Ca
154.6
154.4
154.4
154.2
154.5
154.0
154.4
152.9
164.5
164.0
164.1
164.2
164.1
164.5
162.4
164.7
108.0
108.1
108.2
108.3
108.2
108.3
118.8
100.6
151.8
148.5
148.6
147.9
148.5
148.6
149.7
151.6
141.2
141.0
141.0
140.9
141.1
140.8
140.9
140.7
126.7
127.0
127.1
127.0
127.1
127.0
127.0
126.9
128.8
128.9
128.9
128.9
129.0
128.9
128.8
128.9
141.2
141.2
141.3
141.3
141.3
141.4
141.2
141.4
21.1
21.1
21.2
21.1
21.2
21.1
21.1
21.1
54.6
65.1
64.7
63.4
64.7
59.2
54.7
54.8
167.2
167.9
167.7
167.4
168.0
166.7
167.2
166.8
a For numbering of the structure, see Table 3.
Synthesis 1999, No. 12, 2124–2130 ISSN 0039-7881 © Thieme Stuttgart · New York

2126
A. Acero-Alarcón et al.
PAPER
Table 5 1H NMR (DMSO-d6/TMS) Data of 2-[4-Methylphenyl-(2-
pyrimidinyl)sulfonamido]acetamides 8a, d, J (Hz)
(as it can be deduced from an X-Ray study on 6Ac which
shows a distance of 1.76 Aº between H (61) and O (11).
Heterocosy spectra on 6Bd and 6Be showed a correlation
between H-8a (d = 6.19 and 6.02) and the aliphatic carbon
signal at d = 66.6 and 65.8, in agreement with the pro-
posed structure. The hexahydroimidazo[1,2-c]pyrim-
idines 6 with the =NSO2C6H4Me substituent at C-5,
presented very close values for the chemical shifts of the
quaternary carbons of the toluenesulfonyl group.
Prod- H4(6) H5 H10 H11 H14 J4(6),5 J10,11 H13 NH2
uct
8Aa 8.49 7.06 8.00 7.35 4.76 4.73 8.40 2.36 7,59, 7.11
8Ca 8.68
7.98 7.36 4.74
8.05 2.37 7.60, 7.14
a
The imidazo[1,2-a]pyrimidines 5 were obtained when ei-
ther the alkylated products 4, or the hexahydroimid-
azo[1,2-c]pyrimidines 6, were heated at reflux with triflu-
oroacetic anhydride in dichloromethane as a solvent. The
yields were lower when R2 = H and also when R1 = 5,5-
dimethyl-1,3-dioxan-2-yl. In this latter case the low yield
Table 6 13C NMR (DMSO-d6/TMS) Data of 2-[4-Methylphenyl(2-pyrimidinyl)sulfonamidoacetamides 8a, d
Product
C2
C4(6)
C5
C9
C10
C11
C12
C13
C14
C15
8Aa
8Ca
157.7
156.2
158.0
158.2
116.2
112.9
137.8
137.2
128.8
128.8
129.2
129.2
143.8
144.0
21.3
21.2
48.1
48.4
169.5
169.0
a For numbering of the structure, see Table 5.
Table 7 1H NMR (DMSO-d6/TMS) Data of Hexahydroimidazo[1,2-c]pyrimidines 6a, d, J (Hz)
Product
H3
H7
H8
H8a
H12
H13
J12,13
H15
2 NH
6Ac
6Bb
6Bc
6Bd
6Be
6Cb
6Cc
6Cd
5.03
5.16
5.16
5.50
5.17
5.23
5.23
5.59
6.40
6.49
6.48
6.49
6.48
6.72
6.70
6.71
5.07
6.04
6.02
6.03
6.19
6.02
6.18
6.16
6.29
7.60
7.60
7.61
7.52
7.62
7.58
7.56
7.50
7.27
7.28
7.28
7.26
7.28
7.26
7.27
7.25
8.02
8.03
8.03
8.05
8.03
8.05
8.03
8.03
2.35
2.34
2.34
2.34
2.34
2.33
2.35
2.34
9.28, 9.17
9.44, 9.23
9.45, 9.30
9.43, 9.37
9.43, 9.25
9.53
9.53, 9.51
9.62, 9,52
a
Table 8 13C NMR (DMSO-d6/TMS) Data of Hexahydroimidazo[1,2-c]pyrimidines 6a, d
Product
C2
C3
C5
C7
C8
C8a
C11
C12
C13
C14
C15
6Ac
6Bb
6Bc
6Bd
6Be
6Cb
6Cc
6Cd
169.1
170.2
169.8
169.2
170.2
170.1
169.6
169.1
61.8
62.2
61.7
60.6
61.6
63.6
63.0
61.7
148.5
148.0
148.0
148.2
148.1
147.7
147.7
147.8
125.1
122.2
122.1
122.0
122.2
125.4
125.4
125.3
100.1
108.9
109.1
109.8
109.0
94.6
65.6
65.8
65.9
66.6
65.8
68.5
68.3
68.8
140.7
140.7
140.6
140.8
140.7
140.6
140.5
140.7
125.9
125.8
125.9
125.7
125.9
126.0
125.9
125.7
129.4
129.4
129.4
129.3
129.5
129.6
129.5
129.4
142.1
142.1
142.2
142.1
142.2
142.4
142.3
142.2
21.1
21.1
21.2
21.1
21.1
21.2
21.2
21.2
94.6
95.1
a For numbering of the structure, see Table 7.
Synthesis 1999, No. 12, 2124–2130 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Unusual Ring Closure Reaction of Amides with Pyrimidines
2127
Table 9 1H NMR (DMSO-d6/TMS) Data of Imidazo[1,2-a]pyrim-
idines 5a, d, J (Hz)
was stored in THF at room temperature for a week in the
presence of catalytic amounts of diisopropylethylamine
(DIPEA), the corresponding product 6Ac was obtained
(20%). On the other hand when 6Be was stirred with cat-
alytic amounts of p-toluenesulfonic acid, the correspond-
ing open ring alkylated product 4Be was detected by 13C
NMR spectroscopy (partial hydrolysis of the ketal func-
tion was observed). These experiments and the reported
fact that imidazo[1,2-a]pyrimidines 5 can be obtained ei-
ther from alkylated pyrimidines 4 or from imidazo[1,2-
c]pyrimidines 6, indicate that both compounds can be in-
terconverted and that the proportion in which they are ob-
tained from the sulfonamidopyrimidines 2 depends on the
substituents of the reactants and also on the reaction con-
ditions.
Prod- H3
uct
H5
H6
H7
J5,6
J5,7
J6,7
NH
5Aa 8.21 9.01 7.11 8.54 6.94 1.83 4.38 10.48
5Ab
5Ac
5Af
8.44 6.76 8.28 6.95 1.83 4.03 10.74
8.41 6.72 8.22 6.95 1.83 4.38 10.63
8.75 7.19 8.68 7.04 2.20 5.13 11.11
5Ba 8.13 8.51
8.86
8.70
8.73
8.58
1.83
5Bb
5Bd
8.70
8.37
9.48
11.99
10.14
2.42
2.19
5Ca 8.16 9.34
a
Compounds 6Bb–e and 6Cb–d, where R2 π H, can exist
in diastereoisomeric forms due to the stereogenic centres
1
at C-3 and C-8a. However, the H and 13C NMR spectra
of compounds 6 show only one set of signals indicating
that the ring closure reaction is diastereoselective. In ex-
Table 10 13C NMR (DMSO-d6/TMS) Data of Imidazo[1,2-a]pyrimidines 5a, d, J (Hz)
Product
C2
C3
C5
C6
C7
C8a
C10
2JC,F
C12
1JC,F
5Aa
5Ab
5Ac
5Af
5Ba
5Bb
5Bd
5Ca
140.7
126.8
126.3
137.8
144.2
126.6
126.1
141.4
100.5
117.2
116.0
118.2
97.8
117.7
113.8
101.6
133.5
133.0
133.2
133.9
132.8
130.3
130.7
135.1
108.7
110.2
110.3
110.2
120.2
121.3
121.1
104.1
149.5
151.3
151.6
151.8
148.3
149.8
149.7
150.6
144.8
145.4
145.6
145.9
145.0
145.1
145.3
143.4
154.6
155.0
156.0
155.1
155.6
156.0
155.0
154.6
37.8
37.8
37.8
37.8
37.8
37.8
37.8
37.8
115.2
115.5
116.1
116.0
116.0
116.0
115.9
115.8
283.5
283.5
289.8
283.5
289.8
289.8
289.8
289.8
a For numbering of the structure, see Table 9.
is due to partial hydrolysis of the ketal group. Table 9 and
10 show the NMR data of some examples of compounds
5, prepared from 4 or 6 as starting materials.
periments with 6Be and 6Bd an NOE effect was not ob-
served on the H-8a signal when H-3 was irradiated in
agreement with a trans-disposition of both hydrogens.
The formation of the hexahydroimidazo[1,2-c]pyrim-
idines 6 appears to be the first example of a Michael addi-
tion of a carboxamide on an a,b-unsaturated imino system
and it constitutes a novel method of synthesis of these
compounds.
The X-ray crystallographic analysis of a single crystal of
6Ac (from ethyl acetate/dichloromethane) confirmed un-
equivocally the structure and also the stereochemistry.
The analysis revealed the presence of four molecules in
the cell: two of the (R,R)-enantiomer that are chemically
In the literature there are examples of conjugated addi- equivalent, and two molecules of the (S,S)-enantiomer
tions of organomagnesium compounds to a,b-unsaturated generated by the inversion centre. The Figure shows one
imines.3 In our reaction the nucleophile is probably the of these molecules with the numbering scheme used in the
CONH- formed in basic solution of diisopropylethyl- crystal study. Table 11 gives the selected bond lengths,
amine
in
dimethylformamide.
The
electron- angles and torsion angles. The trans-disposition of the hy-
withdrawing =NSO2C6H4Me substituent at C-2 favours drogen atoms attached to C(91) and C(31) confirms that
the nucleophilic attack.
the conjugated Michael addition is diastereoselective with
the nucleophilic attack of the amido nitrogen occurring
preferentially on the opposite face to the aryl substituent
(R2) at C-3.
The formation of the hexahydroimidazo[1,2-c]pyrim-
idines 6 as major products only in the case of pyrimidines
with substituents at C-5 and R2 different from H can be
due to steric factors that induce a favourable conformation
for the ring closure. However, they can be also obtained
from C-5 unsubstituted sulfonamidopyrimidines 2A. In
fact when the alkylated product 4Ac, obtained from 2Ac,
In summary we have presented a new synthesis of
hexahydroimidazo[1,2-c]pyrimidines 6 in good yields
Synthesis 1999, No. 12, 2124–2130 ISSN 0039-7881 © Thieme Stuttgart · New York

2128
A. Acero-Alarcón et al.
PAPER
Table 11 Selected X-Ray Bond Lengths, Bond Angles and Torsional Angles for 6Ac
S(1)-O(11)
S(1)-N(71)
1.920(9)
1.594(8)
1.214(8)
1.330(9)
1.446(8)
1.454(9)
1.345(7)
1.472(9)
1.356(9)
1.398(8)
1.314(9)
1.541(9)
1.312(8)
1.492(8)
C(21)–N(11)–C(91)
C(31)–N(41)–C(91)
C(51)–N(41)–C(91)
C(51)–N(61)–C(71)
N(11)–C(21)-C(31)
N(41)–C(31)-C(21)
N(41)–C(51)-N(61)
N(61)–C(71)-C(81)
C(71)–C(81)-C(91)
N(11)–C(91)-N(41)
N(41)–C(91)-C(81)
N(41)–C(31)-H(31)
C(21)–C(31)-H(31)
C(101)–C(31)-H(31)
N(11)–C(91)-H(91)
N(41)–C(91)-H(91)
C(81)–C(91)-H(91)
115.4(7)
112.9(6)
121.7(6)
119.4(6)
108.1(7)
101.3(6)
116.6(6)
121.9(8)
116.9(8)
100.7(6)
109.4(6)
110.0
O(21)-C(21)-N(11)-C(91)
C(21)-N(11)-C(91)-C/(81)
C(21)-C(31)-C(101)-C(111)
C(21)-C(31)-C(101)-C(151)
C(31)-C(21)-N(11)-C(91)
C(51)-N(41)-C(91)-C(81)
C(51)-N(61)-C(71)-C(81)
N(11)-C(21)-C(31)-N(41)
N(11)-C(21)-C(31)-C(101)
N(11)-C(91)-N(41)-C(31)
N(11)-C(91)-N(41)-C(51)
N(11)-C(91)-C(81)-C(71)
N(41)-C(31)-C(101)-C(111)
N(41)-C(31)-C(101)-C(151)
N(41)-C(51)-N(61)-C(71)
N(41)-C(91)-N(11)-C(21)
N(61)-C(51)-N(41)-C(31)
N(61)-C(51)-N(41)-C(91)
N(61)-C(71)-C(81)-C(91)
N(71)-C(51)-N(41)-C(31)
N(71)-C(51)-N(41)-C(91)
N(71)-C(51)-N(61)-C(71)
173.6(8)
129.5(8)
92.0(9)
–88.1(9)
–5.9(9)
35.8(9)
O(21)-C(21)
N(11)-C(21)
N(11)-C(91)
N(41)-C(31)
N(41)-C(51)
N(41)-C(91)
N(61)-C(51)
N(61)-C(71)
N(71)-C(51)
C(21)-C(31)
C(71)-C(81)
C(81)-C(91)
23.8(12)
–2.3(8)
122.9(7)
–12.5(8)
159.5(6)
–146.8(8)
151.4(8)
28.6(10)
–21.9(10)
11.2(9)
161.8(6)
–9.3(10)
6.4(12)
–18.5(10)
170.4(7)
158.5(8)
115.8
100.9
111.4
117.6
101.6
was heated at reflux temperature for 16 h in a Dean–Stark apparatus.
The solvent was removed and the residue extracted with EtOAc,
then washed with aq NaOH solution and the solvent was evaporat-
ed. Addition of Et2O afforded the crystalline product 1B (4.6 g,
68%, mp 186–187 ºC.
HRMS: m/z found M+, 209.1163. C10H15N3O3 requires M,
209.1164.
1H NMR: d = 0.81 (s, 3 H), 1.28 (s, 3 H), 3.62 (d, J = 11 Hz, 2 H),
3.75 (d, J = 11 Hz, 2 H), 5.30 (br, 2 H), 5.33 (s, 1 H), 8.41 (s, 2 H).
13C NMR: d = 21.8, 22.9, 30.1, 77.5, 98.9, 122.3, 156.8, 163.2.
Sulfonamidopyrimidines 2 A,B; General Procedure
p-Toluenesulfonyl chloride (30 mmol) in pyridine (6 m L) was
slowly added to the corresponding 2-aminopyrimidine 1A,B (20
mmol) in pyridine (8 mL) at 0 ºC. The mixture was stirred for 2 h
and allowed to reach r.t., then it was poured into H2O (100 mL) and
the solid was filtered off and recrystallized from CHCl3.
Figure X-Ray Crystallographic Structure of 6Ac
2A
(70–80%) by alkylation of sulfonamidopyrimidines 2
with α-arylbromoacetamides. This reaction is the first ex-
ample of an intramolecular conjugated Michael addition
of an amide to an α,β-unsaturated imino system and con-
stitutes a novel and stereoselective procedure for the prep-
aration of these compounds.
Yield: 88%; mp 204–206 ºC.
HRMS: m/z found M+, 249.0568. C11H11N3O2S requires M,
249.0571.
2B
Yield: 75%; mp 274–276 ºC.
HRMS: m/z found (M + 1)+, 364.1336 (FAB). C17H22N3O4S re-
quires M + 1, 364.1331 (M + 1).
Melting points were determined with a Kofler hot-stage apparatus
1
and are uncorrected. H and 13C NMR spectra were recorded on a
Sulfonamidopyrimidine 2C
Bruker AC-250 in DMSO-d6, unless otherwise indicated. HRMS
were obtained for all compounds using a VG Autospec TRIO 1000
intrument. The ionization mode used in mass spectra was electron
impact (EI) at 70 eV or fast atom bombardment (FAB). All new
p-Toluenesulfonyl chloride (60 mmol) in pyridine (20 mL) was
slowly added to 1C (20 mmol) in pyridine (20 mL). The mixture
was heated at 80 ºC for 16 h and then was poured into H2O (100
mL). The solid was washed with H2O, hexane and CH2Cl2 and re-
crystallized from EtOH affording 2C (76%); mp 254–256 ºC. The
CH2Cl2 filtrate contained the product 7C.
1
compounds were characterized spectroscopically by H and 13C
NMR spectra and HRMS.
HRMS: m/z found 327.9758 (M + 1)+, (FAB). C11H10BrN3O2S re-
quires (M + 1), 327.9755.
5-(5,5-Dimethyl-1,3-dioxan-2-yl)-2-pyrimidinamine (1B)
2,2-Dimethylpropane-1,3-diol (3.75 g, 36 mmol) was added to 2-
amino-5-pyrimidinecarboxaldehyde4 (4 g, 32 mmol) and p-toluene-
sulfonic acid (1,15 g, 6 mmol) in toluene (130 mL). The mixture
7C
Yield. 18%; mp 243–245 ºC.
Synthesis 1999, No. 12, 2124–2130 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Unusual Ring Closure Reaction of Amides with Pyrimidines
2129
HRMS: m/z found (M + 1)+, 481.9836 (FAB). C18H17 Br N3O4S2 re-
HRMS: m/z found (M – 1)+, 513.1621. C25H26FN4O5S requires (M
quires (M + 1), 481.9844 (M + 1).
– 1), 513.1608.
1H NMR: δ = 3.3 (s, 6 H), 7.50 (d, J = 8 Hz, 4 H), 7.95 (d, J = 8 Hz,
4Ca
4 H), 9.20 (s, 2 H).
Yield: 87%; mp 215–217 ºC.
13C NMR: d = 21.4, 121.0, 128.9, 129.9, 136.2, 145.9, 154.1, 161.0.
HRMS: m/z found M+:383.9874. C13H13BrN4O3S requires M
383.9892),
Alkylation of Sulfonamidoyrimidines 2 A–C with Bromoaceta-
mides 3 a–f; General Procedure
8Ca
Yield: 8%.
Diisopropylethylamine (0.65 mL, 3.6 mmol) was slowly added to
the corresponding sulfonamidopyrimidines 2 (3 mmol) in DMF (12
mL) under argon over 40 min. The corresponding bromoacetamide
3 (3.6 mmol) was added to the mixture and stirred for 16 h at r.t. The
crude mixture was poured into H2O (200 mL) affording the alkylat-
ed derivatives 4 or the Michael addition products 6 besides small
amounts of 8.
HRMS: m/z found M+, 383.9879. C13H13BrN4O3S requires M,
383.9892.
Isolation of Compounds 4Ba and 6Cb–d
When the reaction product did not precipitate, the aqueous phase
was extracted with EtOAc (3 × 50 mL), the combined extracts were
dried (Na2SO4) and the solvent evaporated. The residue was chro-
matographed on silica using CH2Cl2/THF (9:1) or CH2Cl2/EtOAc
(7:3) to afford compounds 4Ba and 6Cb–d. Compounds 6Cb–d,
were obtained as gums which could not be induced to crystallise.
4Aa
Yield: 85%; mp 213–215 ºC.
HRMS: m/z found (M + 1)+, 307.0865 (FAB). C13H15N4O3S re-
quires (M + 1), 307.0865.
4Ba
Yield: 65%; mp 191–193 ºC.
8Aa
Yield: 7%; mp 220–222 ºC.
HRMS: m/z found M+, 420.1449. C19H24N4O5S requires M,
420.1467.
HRMS: m/z found (M + 1)+, 307.0858 (FAB). C13H15N4O3S re-
quires (M + 1), 307.0865.
6Cb
Yield: 71%.
4Ab
HRMS: m/z found M+, 492.0101. C19H17BrN4O5S requires M,
Yield: 89%; mp 196–198 ºC.
492.0103.
HRMS: m/z found M+, 382.1097. C19H18N4O3S requires M,
382.1100.
6Cc
Yield: 75%.
4Ac
HRMS: m/z found M+, 569.9203. C19H16Br2N4O5S requires M,
Yield: 70%; mp 187–189 ºC.
569.9208.
HRMS: m/z found M+, 460.0201. C19H17BrN4O3S requires M,
460.0205.
6Cd
Yield: 80%.
4Ad
HRMS: m/z found M+, 529.9709. C19H16BrClN4O5S requires M,
Yield: 91%; mp 254–257 ºC.
529.9713.
HRMS: m/z found (M + 1)+, 417.0783 (FAB). C19H18ClN4O3S re-
quires (M + 1), 417.0788.
Conversion of 4Ac to 6Ac
4Ae
When the alkylated product 4Ac was stored in THF solution at room
temperature for a week in the presence of catalytic amounts of di-
isopropylethylamine, the corresponding product 6Ac was obtained;
yield: 20%; mp 196–198 ºC.
Yield: 67%; mp 214–216°C.
HRMS: m/z found M+, 400.1008. C19H17FN4O3S requires M,
400.1005.
4Af
HRMS: m/z found M+, 460.0201. C19H17BrN4O3S requires M,
Yield: 80%; mp 226–228 ºC.
460.0205.
HRMS: m/z found M+, 418.0909. C19H16F2N4O3S requires M,
418.0911.
Imidazo[1,2-a]pyrimidines 5; General Procedure
The alkylated derivatives 4Aa, 4Ab, 4Ac, 4Af, 4Ba, 4Ca and the
hexahydroimidazo[1,2-c]pyrimidines 6Bb, 6Bd (2 mmol) were
heated at reflux with trifluoroacetic acid (15 mL, 50 mmol) in
CH2Cl2 (35 mL) under argon for 4 h.. The solvent was evaporated
and the residue extracted with EtOAc. The organic phase washed
with aq NaHCO3 solution, dried (Na2SO4) and concentrated. The
residue was purified by column chromatography using CH2Cl2/
EtOAc (3:1) affording imidazo[1,2-a]pyrimidines 5.
6Bb
Yield: 69%; mp 228–230 ºC.
HRMS: m/z found M+, 495.1706. C25H27N4O5S requires M,
495.1702.
6Bc
Yield: 74%; mp 248–250 ºC.
HRMS: m/z found M+, 574.0864. C25H27BrN4O5S requires M,
574.0886.
5Aa
Yield: 40%; mp 255–257 ºC.
HRMS: m/z found M+, 230.0413; C8H5F3N4O requires M,
230.0415.
6Bd
Yield: 75%; mp 249–251 ºC.
HRMS: m/z found (M – 1)+, 529.1310. C25H26ClN4O5S requires (M
– 1), 529.1312.
5Ab
Yield: 75%; mp 235–237 ºC.
HRMS: m/z found M+, 306.0734. C14H9F3N4O requires M,
306.0728.
6Be
Yield: 80%; mp 250–252 ºC.
Synthesis 1999, No. 12, 2124–2130 ISSN 0039-7881 © Thieme Stuttgart · New York

2130
5Ac
A. Acero-Alarcón et al.
PAPER
pic temperature factor. In the final stages an empirical weighting
scheme was chosen as to give no trends in <wD2F> vs <Fo> and vs
<sinq/l> using the program PESOS,7 giving final R = 0.069 and
Rw = 0.072 values.
Yield: 80%; mp 233–235 ºC.
HRMS: m/z found M+, 383.9834. C14H8BrF3N4O requires M,
383.9834.
5Af
Yield: 78%; mp 211-213 C.
HRMS: m/z found M+, 342.0545. C14H7F5N4O rrequires M,
342.0540.
Acknowledgement
We are indebted to Lilly SA for support and Dirección General de
Investigación Científico y Técnica, for project PB95-1076. Fatima
Z. Ahjyaje thanks Agencia Española de Cooperación Internacional
for a grant.
5Ba
Yield: 36%; mp 265–267 ºC.
HRMS: m/z found M+, 344.1099. C14H15F3N4O3 requires M,
344.1096.
References
5Bb
(1) Hamdouchi C.; Blas J.; Prado M.; Gruber J.; Heinz B.A.;
Vance L. J. Med. Chem. 1999, 42, 50.
(2) Bochis, R.J.; Olen, L.E.; Fischer, M.H.; Reamer, R.A. J. Med.
Chem. 1981, 24, 1483.
Yield: 32%; mp 270–272 ºC.
HRMS: m/z found M+, 420.1407. C20H19N4O3F3 requires M,
420.1409.
(3) Vo N.H.; Snider B.B. J. Org. Chem. 1994, 59, 5419.
Snider B.B.; Yang K. J. Org. Chem. 1992, 57, 3615.
Paquette L.A.; Macdonald D.; Anderson L.G. J. Am. Chem.
Soc. 1990, 112, 9292.
5Bd
Yield: 40%; mp 172–174 ºC.
HRMS: m/z found (M + 1)+, 455.1093 (FAB). C20H19ClF3N4O3 re-
quires (M + 1), 455.1098.
Tomioka K.; Shindo M.; Koga K. J. Am. Chem. Soc. 1989,
111, 8266.
5Ca
(4) Gupton J.T.; Gall J.E.; Riesinger S.W.; Smith S.Q.; Bevirt
K.M.; Sikorsi J.A.; Dahl L.; Arnold Z. J. Heterocyclic Chem.
1991, 28, 1281.
(5) Altomere A.; Burla M.C.; Camalli M.; Cascarano G.;
Giacovazzo G.; Guagliardi A.; Polidiri G. J Appl. Crystallogr.
1994, 27, 435.
Yield: 42%; mp 299–301 ºC.
HRMS: m/z Found M+, 307.9521. C8H4BrF3N4O requires M,
307.9521.
X-ray Crystal Data
C19H17N4O3SBr (6Ac): M = 461.34, triclinic Pl, a = 9.303(1),
b = 11.962(2), c = 18.417(2) Å, α = 83.30(1), b = 78.44(1),
γ = 78.04(1)°, U = 1958.3(4) Å3, Dc = 1.57 g cm-3, Z = 4, MoKα
(λ = 0.7107 Å), µ = 22.3 cm-1. From the 6861 independent reflec-
tions 3446 were considered observed with the I>2σ(I) criterion. The
structure was solved by direct methods using the program SIR92.5
All non-hydrogen atoms were anisotropically refined by least-
squares on F using the XRAY76 System6 (505 refined parameters).
Hydrogens bonded to C atoms were placed at calculated positions
and Fourier difference maps detected the hydrogens on the N atoms,
all these were included as fixed contributors with a common isotro-
(6) Steward J.M.; Machin P.A.; Dickinson H-L.; Ammon H.L.;
Heck H.; Flak H. The X-ray 76 System, Technical report TR-
446, Computer Science Center. University of Maryland,
Cllege Park, Maryland 1976.
(7) Martínez-Ripoll M.; Cano F.H. PESOS Computer Program,
Instituto Rocasolano, C.S.I.C. Madrid, Spain 1975.
Article Identifier:
1437-210X,E;1999,0,12,2124,2130,ftx,en;P02199SS.pdf
Synthesis 1999, No. 12, 2124–2130 ISSN 0039-7881 © Thieme Stuttgart · New York