Four-component tandem reaction to synthesize dihydrotetrazolopyrimidinyl carbamides

Article abstract of DOI:10.1002/jhet.698

Four-component tandem procedure to prepare a series of dihydrotetrazolopyrimidinyl carbamides starting from diketene, amine, 5-aminotetrazole, and aldehyde was newly developed in the presence of iodine. Most of the products were obtained in moderate to good yield after simple workup of the final reaction mixture, the scope and limitation was also probed into..

Full text of DOI:10.1002/jhet.698

January 2012
Four-Component Tandem Reaction to Synthesize
Dihydrotetrazolopyrimidinyl Carbamides
237
Li-Yan Zeng, Fei Ji, and Chun Cai*
Chemical Engineering College, Nanjing University of Science & Technology,
Nanjing, Jiangsu 210094, China
*E-mail: c.cai@mail.njust.edu.cn
Received June 6, 2010
DOI 10.1002/jhet.698
Published online 13 October 2011 in Wiley Online Library (wileyonlinelibrary.com).
Four-component tandem procedure to prepare a series of dihydrotetrazolopyrimidinyl carbamides
starting from diketene, amine, 5-aminotetrazole, and aldehyde was newly developed in the presence of
iodine. Most of the products were obtained in moderate to good yield after simple workup of the final
reaction mixture, the scope and limitation was also probed into.
J. Heterocyclic Chem., 49, 237 (2012).
INTRODUCTION
terest for both chemists and biologists. Accordingly,
adding the amine to the classical Biginelli MCR directly
is extremely costly leading to dihydropyrimidinyl carba-
mides. To complete the one-pot reaction, the usual 1,3-
dicarbonyl compound used in classical Biginelli reaction
was replaced by diketene which could be readily ring-
opened to afford acetoacetic derivatives [6] for the fur-
nishment of target structure in a tandem manner.
Over the years, considerable attention has been
focused on the synthesis and selective multifunctionali-
zation of dihydropyrimidines owing to the pharmacolog-
ical properties associated with many derivatives of this
privileged heterocyclic core [1]. Based on the Biginelli
scaffold, dihydropyrimidines were largely extended by
varying the aldehydes and 1,3-dicarbonyl compounds
including b-ketoesters and cyclic b-diketones [2]. How-
ever, we noted that the dihydropyrimidinyl carbamides
evaluated as a1A-adrenergic receptor antagonists for the
treatment of benign prostatis hyperplasia [3] were rarely
investigated because of a paucity of efficient synthetic
route. According to the literature survey, the construc-
tion of the amide bond encountered either the prerequi-
site of initial b-ketoamides formation to participate the
following Biginelli reaction [3,4], or the stepwise syn-
thetic route [5] involving the synthesis of dihydropyri-
midinyl ester firstly, deallylation of ester to dihydropyri-
midinyl carboxylic acid secondly, and condensation the
carboxylic acid with selected amine lastly (Scheme 1).
These reported methods obviously complicated the gen-
eration of library diversity needed for the drug discov-
ery. Therefore, a valuable and facile approach is
desired.
RESULTS AND DISCUSSION
As part of our on going interests in tetrazolopyrimi-
dines [7], 5-aminotetrazole (5-AT) bearing both endocy-
clic nitrogen and exocyclic amino group which could
participate the construction of pyrimidine-ring simulta-
neously was initially chosen as the 1,3-binucleophile
synthon. Our study commenced with the model reaction
of N-benzyl-3-oxobutanamide M, which was generated
from benzyl amine and diketene in situ at room temper-
ature, with 4-chlorobenzaldehyde and 5-AT in AcOEt as
depicted in Scheme 2. Fortunately, the anticipated prod-
uct A1 was obtained after refluxing the materials in
AcOEt for 24 hours, the structure was proved by means
of Ms and NMR, wherein a molecular ion peak dis-
played at m/z 379 in the mass spectrum, the sharp sin-
glet signals at d ¼ 2.2, 6.75 ppm arising from 5-Me, 7-
CH, and the two doublet signals at d ¼ 4.09–4.14,
4.30–4.35 (J ¼ 15 Hz) arising from NACH2 exhibited
distinctly in 1H NMR. However, the yield was poor
(16%). Meanwhile, iodine, as a mild, cheap, less toxic
In times where a premium is always put on speed, di-
versity and efficiency, simultaneous molecular interac-
tion of three or more component namely multicompo-
nent reactions (MCRs) offering significant advantages
over conventional linear-type syntheses are of great in-
C
V
2011 HeteroCorporation

238
L.-Y. Zeng, F. Ji, and C. Cai
Vol 49
Scheme 1. Traditional methods to dihydropyrimidinyl carbamides.
and easily accessible metal-free catalyst, has entered
into widespread use for promoting the MCR-heterocycli-
zation in recent years [8]. We have effectively validated
the high activity in our previous work [7,8c,h,i]. There-
upon, 25 mol % of iodine as a Lewis acid catalyst was
added into the model reaction (Scheme 2). To our
delight, the yield was increased up to 56%, and the reac-
tion time was shortened to 8 hours. The catalyst concen-
tration was ultimately fixed on 30 mol %, because the
anticipated product could be yielded in 63% in the pres-
ence of 30 mol % of iodine and further increasing the
amount of iodine didn’t improve the yield.
catalyzed system to aliphatic aldehyde such as butyral-
dehyde and 4-chloroaniline respectively. Similar results
were obtained when 5-AT was replaced by urea or thio-
urea, and the data has been reported while our research
was in progress [9]. On the other hand, the steric factor
made limited impact on the reaction, inasmuch as the 2-
chlorobenzaldeheyde and 2-fluorobenzyl amine (Entries
4 and 8, Table 1) were converted to the corresponding
products successfully in slightly lower yield of 46 and
49%, respectively.
In summary, we have successfully designed a tandem
reaction involving an initial addition of amine to dike-
tene followed by a Biginelli-like condensation with 5-
AT and aldehyde in one-pot in the presence of iodine
for the first time. The dihydrotetrazolopyrimidinyl car-
bamide and derivatives were produced in moderate to
good yield, and the limitation was disclosed when the
system was applied to electron-rich aldehydes and elec-
tro-deficient amines. The simplicity and efficiency of the
present procedure make it an interesting alternative to
the complex multistep approach.
Since there were limited publications devoted to the
synthesis of dihydrotetrazolopyrimidinyl carbamides,
especially in one-pot tandem fashion starting from
amine directly, the success of the preliminary experi-
mentation encouraged us to further explore the scope
and limitation of this four-compound condensation via
varying aldehydes and amines. The results were col-
lected in Table 1. All of the representative aromatic
aldehydes bearing either electron-withdrawing group
(such as chloro, nitro) or electron-donating group and
amines including aromatic and aliphatic amines were
smoothly transformed into the target products in moder-
ate to good yields after refluxing no more than 12 hours.
Impressively, electron-deficient aldehydes and electro-
rich amines were favorable for the transformation, the
4-methoxybenzaldehyde delivered lower yields (Entry 2,
Table 1), while the expected product was not detected
in the final mixture in the case of aniline (Entry 9, Table
1), moreover, we failed completely to apply this iodine-
EXPERIMENTAL
Starting material 5-AT was prepared according to literature
procedure [10], others were obtained from commercial suppli-
ers and used without further purification. All melting points
were uncorrected. The purity was analyzed qualitatively by
high performance liquid chromatography (HPLC) on Waters
600E chromatograph, 2487 detector. Mass spectra were taken
on an Finnigan TSQ Quantum-LC/MS/MS instrument in the
Scheme 2. Iodine catalyzed four-component tandem reaction to synthesize N-benzyl-7-(4-chlorophenyl)-5-methyl-4,7-dihydrotetrazolo[1,5-a]pyrimi-
dine-6-carboxamide A1.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2012 Four-Component Tandem Reaction to Synthesize Dihydrotetrazolopyrimidinyl Carbamides
239
Table 1
Iodine catalyzed four-component tandem reaction to synthesize the N,7-disubstituted-5-methyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-
carboxamides A.a
.
Entry
R1
R2
T (h)b
Product
Yield (%)c
1
2
3
C6H5CH2
C6H5CH2
C6H5CH2
4-ClC6H4
4-MeOC6H4
4-NO2C6H4
2-ClC6H4
C6H5
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
8
9
8
A1
A2
A3
A4
A5
A6
A7
A8
A9
A10
63
31
73
46
54
54
61
49
–
4
C6H5CH2
C6H5CH2
4-FC6H4CH2
4-MeOC6H4CH2
2-FC6H4CH2
C6H5
12
10
8
5
6
7
8
8
10
24
6
9
10
CH3(CH2)3
61
a Reaction conditions: after 2 mmol of diketene and amine were stirred in 3 mL of AcOEt at room temperature for 2 hours, 2 mmol of aldehyde
and 5-AT, 0.6 mmol of iodine were then added and the reaction finally proceeded at 78ꢀC.
b The time since 5-AT was added.
c Isolated yield.
electrospray ionization (negative) mode. The IR spectra were
recorded on KBr pellets on Shimadzu IR Prestige-21 spectro-
165.67; Ms (ESI) m/z 379 [M – H]; Anal. Calcd for
C19H17ClN6O: C, 59.92; H, 4.50; N, 22.07. Found: C, 60.07;
H, 4.65; N, 22.00.
1
photometer. H and 13C NMR spectra were recorded at 300 or
500 MHz and 75 or 125 MHz, respectively, in DMSO-d6, and
chemical shifts were reported in ppm from internal TMS (d).
N-benzyl-7-(4-methoxyphenyl)-5-methyl-4,7-dihydrotetra-
zolo[1,5-a]pyrimidine-6-carboxamide (A2). (Table 1, Entry
2): Yield 0.23g (31%) of light yellow powder, 98% pure by
HPLC. Mp 238-240ꢀC; IR (KBr): 3352, 3204, 3062, 2951,
Elemental analyses were performed on
MT3CHN recorder.
a
Yanagimoto
1
The typical procedure for the synthesis of N,7-disubsti-
tuted-5-methyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-
carboxamides A. A solution of amine (2 mmol) and diketene
(2 mmol) was stirred in 3 mL of AcOEt at room temperature
for 2 hours. Then, the aldehyde (2 mmol), 5-AT (2 mmol) and
iodine (0.6 mmol) were added, and the temperature was
increased to 78ꢀC. The precipitate appeared gradually after 2
hours, the reaction was terminated till the mixture was solidi-
fied after several hours (Table 1). After the reaction mixture
was cooled to room temperature, 3 mL of AcOEt was added,
and then the solid precipitated was filtrated, washed with a so-
lution of sodium thiosulfate followed by water and EtOH.
White powder was obtained after drying, the further purifica-
tion was needless as the purity of the corresponding product
was high up to 98% based on the analysis of HPLC.
2836, 1676, 1625, 1518, 1447, 1412, 1311, 996, 846; H NMR
(500 MHz DMSO-d6): d ¼ 2.18 (3H, s, CH3), 3.74 (3H, s,
CH3O), 4.14-4.18 (1H, m, BnCH2), 4.29-4.33 (1H, m,
BnCH2), 6.70 (1H, s, CH), 6.76-6.83 (2H, m, Ar-H), 6.91-7.00
(2H, m, Ar-H), 7.12-7.17 (3H, m, Ar-H), 7.24-7.30 (2H, m,
Ar-H), 8.39-8.41 (1H, m, NH), 10.54 (1H, s, NH); 13C NMR
(125 MHz DMSO-d6): d ¼ 17.74, 42.42, 55.66, 59.52, 104.14,
114.49, 126.96, 127.21, 128.42, 128.62, 129.20, 129.40,
131.95, 135.27, 139.56,159.99, 149.36, 165.98; Ms (ESI) m/z
375 [M – H]; Anal. Calcd for C20H20N6O2: C, 63.82; H, 5.36;
N, 22.33. Found: C, 63.17; H, 5.69; N, 22.13.
N-benzyl-5-methyl-7-(4-nitrophenyl)-4,7-dihydrotetrazolo
[1,5-a]pyrimidine-6-carboxamide (A3). (Table 1, Entry 3):
Yield 0.57g (73%) of yellow powder, 99% pure by HPLC. Mp
231-233ꢀC; IR (KBr): 3460, 3076, 2953, 2860, 1670, 1622,
1597, 1525, 1435, 1352, 999, 831; 1H NMR (500 MHz DMSO-
d6): d ¼ 2.19 (3H, s, CH3), 4.09-4.13 (1H, m, BnCH2), 4.28-4.32
(1H, m, BnCH2), 6.90 (1H, s, CH), 6.84-6.86 (2H, d, Ar-H),
7.05-7.17 (3H, m, Ar-H), 7.56-7.57 (2H, d, Ar-H), 8.18-8.19
(2H, d, Ar-H), 8.44-8.46 (1H, m, NH), 10.81 (1H, s, NH); 13C
NMR (125 MHz DMSO-d6):d ¼ 17.74, 42.42, 55.66, 59.52,
104.14, 114.49, 126.96, 127.21, 128.42, 128.62, 129.20, 129.40,
131.95, 135.27, 139.56, 159.99, 149.36, 165.98; Ms (ESI) m/z
390 [M – H]; Anal. Calcd for C19H17N7O3: C, 58.31; H, 4.38; N,
25.05. Found: C, 58.49; H, 4.24; N, 25.96.
All of the products were new, and have been fully character-
1
ized by H NMR, 13C NMR, IR, Mass and elemental analysis.
N-benzyl-7-(4-chlorophenyl)-5-methyl-4,7-dihydrotetrazolo
[1,5-a]pyrimidine-6-carboxamide (A1). (Table 1, Entry 1):
Yield 0.48g (63%) of white powder, 99% pure by HPLC. Mp
254-256ꢀC; IR (KBr): 3343, 3065, 2944, 1670, 1625, 1600,
1
1555, 1521, 1489, 1420, 1318, 1011, 840; H NMR (300 MHz
DMSO-d6): d ¼ 2.17 (3H, s, CH3), 4.09-4.14 (1H, m, BnCH2),
4.30-4.35 (1H, m, BnCH2) 6.74 (1H, s, CH), 6.77-7.79 (2H,
m, Ar-H), 7.14-7.17 (3H, m, Ar-H), 7.32-7.35 (2H, d, Ar-H),
7.42-7.45 (2H, d, Ar-H), 8.35 (1H, s, NH); 13C NMR (75 MHz
DMSO-d6):d ¼ 17.64, 42.32, 59.28, 103.50, 126.92, 127.08,
128.32, 129.16, 130.04, 133.84, 135.37, 138.54, 139.402,
N-benzyl-7-(2-chlorophenyl)-5-methyl-4,7-dihydrotetrazolo
[1,5-a]pyrimidine-6-carboxamide (A4). (Table 1, Entry 4):
Yield 0.35g (46%) of white powder, 99% pure by HPLC. Mp
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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L.-Y. Zeng, F. Ji, and C. Cai
Vol 49
218-221ꢀC; IR (KBr): 3313, 3059, 2943, 1666, 1625, 1600,
4.28-4.32 (1H, m, BnCH2), 6.76 (1H, s, CH), 6.54-6.57 (1H, m, Ar-
H), 6.89-6.92 (1H, m, Ar-H), 7.09-9.11 (1H, m, Ar-H), 7.16-7.26
(1H, m, Ar-H), 7.32-7.37 (2H, m, Ar-H), 7.42-7.48 (2H, m, Ar-H),
8.41-8.44 (1H, m, NH), 10.66 (1H, s, NH); 13C NMR (125 MHz
DMSO-d6): d ¼ 17.77, 59.32, 103.38, 115.24, 124.26, 126.02,
129.06, 129.12, 129.28, 130.04, 133.94, 136.06, 138.67, 159.31,
161.25, 149.37, 165.89; Ms (ESI) m/z 397 [M – H]; Anal. Calcd for
C19H16ClFN6O: C, 57.22; H, 4.04; N, 21.07. Found: C, 57.91; H,
4.15; N, 21.32.
1
1537, 1442, 1333, 1001, 754; H NMR (500 MHz DMSO-d6):
d ¼ 2.18 (3H, s, CH3), 4.08-4.12 (1H, m, BnCH2), 4.32-4.37
(1H, m, BnCH2), 7.07 (1H, s, CH), 6.77-6.80 (2H, d, Ar-H),
7.14-7.15 (3H, m, Ar-H), 7.31-7.36 (1H, m, Ar-H), 7.41-7.44
(2H, m, Ar-H), 7.48-7.50 (1H, m, Ar-H), 8.42-8.44 (1H, m,
NH), 10.64 (1H, s, NH); 13C NMR (125 MHz DMSO-d6): d ¼
17.69, 42.46, 58.10, 102.91, 126.96, 127.10, 128.14, 128.52,
130.55, 131.06, 131.50, 133.17, 135.51, 136.22, 139.47,
149.63, 165.79; Ms (ESI) m/z 379 [M – H]; Anal. Calcd for
C19H17ClN6O: C, 59.92; H, 4.50; N, 22.07. Found: C, 59.21;
H, 4.03; N, 22.91.
N-butyl-7-(4-chlorophenyl)-5-methyl-4,7-dihydrotetrazolo-
[1,5-a]pyrimidine-6-carboxamide (A10). (Table 1, Entry 10):
Yield 0.42g (61%) of white powder, 99% pure by HPLC. Mp
230-232ꢀC; IR (KBr): 3293, 3080, 2957, 2865, 1676, 1605,
N-benzyl-5-methyl-7-phenyl-4,7-dihydrotetrazolo[1,5-a]py-
rimidine-6-carboxamide (A5). (Table 1, Entry 5): Yield
0.38g (54%) of white powder, 99% pure by HPLC. Mp 232-
234ꢀC; IR (KBr): 3282, 3062, 2945, 2839, 1674, 1604, 1585,
1
1540, 1490, 1432, 1383, 1325, 1001, 829; H NMR (500 MHz
DMSO-d6): d ¼ 0.70-0.75 (3H, m, CH3), 0.94-1.02 (2H, m,
CH2), 1.14-1.21 (2H, m, CH2), 2.13 (3H, s, CH3), 2.94-3.00
(2H, m, CH2), 6.71 (1H, s, CH), 7.30-7.31 (2H, d, Ar-H),
7.41-7.43 (2H, d, Ar-H), 7.85 (1H, d, NH), 10.57 (1H, s, NH);
13C NMR (125 MHz DMSO-d6):d ¼ 14.02, 17.66, 19.77,
31.44, 38.64, 59.33, 103.91, 129.09, 129.84, 133.81, 135.08,
138.61, 149.48, 165.52; Ms (ESI) m/z 345 [M – H]; Anal.
Calcd for C16H19ClN6O: C, 55.41; H, 5.52; N, 24.23. Found:
C, 55.14; H, 5.78, N, 24.39.
1
1496, 1388, 1323, 999, 746, 698; H NMR (500 MHz DMSO-
d6): d ¼ 2.10 (3H, s, CH3), 4.14-4.18 (1H, m, BnCH2), 4.29-
4.33 (1H, m, BnCH2), 6.76 (1H, s, CH), 6.82-6.83 (2H, d,
Ar-H), 7.12-7.15 (3H, m, Ar-H), 7.30-7.31 (2H, m, Ar-H),
7.34-7.39 (3H, m, Ar-H), 8.42-8.44 (1H, m, NH), 10.59 (1H,
s, NH); 13C NMR (125 MHz DMSO-d6): d ¼ 17.76, 42.48,
60.62, 103.97, 126.95, 127.20, 128.05, 128.51, 128.62, 129.20,
129.40, 135,51, 135.52, 139.80, 149.50, 165.91; Ms (ESI) m/z
345 [M – H]; Anal. Calcd for C19H17N6O: C, 65.88; H, 5.24;
N, 24.26. Found: C, 66.06; H, 5.71; N, 24.17.
Acknowledgments. Financial support by Nanjing University of
Science and Technology (2010ZDJH14) is gratefully acknowledged.
7-(4-chlorophenyl)-N-(4-fluorobenzyl)-5-methyl-4,7-dihy-drote-
trazolo[1,5-a]pyrimidine-6-carboxamide (A6). (Ta-ble 1, Entry
6): Yield 0.43g (54%) of white powder, 99% pure by HPLC.
Mp 254-257ꢀC; IR (KBr): 3294, 3064, 2973, 1672, 1630,
REFERENCES AND NOTES
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1
1539, 1510, 1492, 1413, 1380, 993, 825; H NMR (500 MHz
DMSO-d6): d ¼ 2.176 (3H, s, CH3), 4.11-4.14 (1H, m,
BnCH2), 4.27-4.31 (1H, m, BnCH2), 6.71 (1H, s, CH), 6.79-
6.85 (2H, d, Ar-H), 6.95-6.98 (2H, d, Ar-H), 7.32-7.39 (2H,
m, Ar-H), 7.42-7.44 (2H, m, Ar-H), 8.44 (1H, s, NH), 10.66
(1H, s, NH); 13C NMR (125 MHz DMSO-d6):d ¼ 17.80,
41.77, 59.35, 103.5, 114.98, 115.15, 129.20, 129.24, 130.08,
133.91, 135.77, 138.65, 160.44, 162.39, 149.37, 165.78; Ms
(ESI) m/z 397 [M – H]; Anal. Calcd for C19H16ClFN6O: C,
57.22; H, 4.04; N, 21.07. Found: C, 57.45; H, 4.27; N, 21.53.
7-(4-chlorophenyl)-N-(4-methoxybenzyl)-5-methyl-4,7-dihy-
drotetrazolo[1,5-a]pyrimidine-6-carboxamide (A7). (Table
1, Entry 7): Yield 0.50g (61%) of white powder, 99% pure by
HPLC. Mp 220-224ꢀC; IR (KBr): 3430, 3072, 2956, 2835,
1678, 1620, 1527, 1490, 1460, 1382, 1001, 821; 1H NMR
(500 MHz DMSO-d6): d ¼ 2.15 (3H, s, CH3), 3.75 (3H, s,
CH3), 4.03-4.07 (1H, m, BnCH2), 4.23-4.27 (1H, m, BnCH2),
6.76 (1H, s, CH), 6.68-6.73 (4H, m, Ar-H), 7.31-7.33 (2H, d,
Ar-H), 7.42-7.43 (2H, d, Ar-H), 8.36-8.38 (1H, m, NH), 10.62
(1H, s, NH); 13C NMR (125 MHz DMSO-d6):d ¼ 17.76,
41.86, 55.63, 59.40, 103.69, 109.59, 113.81, 128.52, 129.21,
129.41, 130.08, 131.45, 133.89, 135.45, 138.65, 159.45,149.39,
165.67; Ms (ESI) m/z 409 [M – H]; Anal. Calcd for
C20H19ClN6O2: C, 58.47; H, 4.66; N, 20.45. Found: C, 58.03;
H, 4.56; N, 20.41.
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T. R.; Reddy, V. V. N. Tetrahedron Lett 2002, 43, 2657; (e) Shaabani,
A.; Bazgir, A. Tetrahedron Lett 2004, 45, 2575.
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Shen, Q.; Forray, C.; Ransom, R.; Chang, R. S. L.; Vyas, K. P.;
Zhang, K.; Gluchowski, C. Bioorg Med Chem Lett 2000, 10, 175;
(b) Barrow, J. C.; Nantermet, P. G.; Selnick, H. G.; Glass, K. L.; Rit-
tle, K. E.; Gilbert, K. F.; Steele, T. G.; Homnick, C. F.; Freidinger,T.
W.; Ransom, R. W.; Kling, P.; Reiss, D.; Broten, T. P.; Schorn, T.
W.; Chang, R. S. L.; O’Malley, S. S.; Olah, T. V.; Ellis, J. D.; Barrish,
A.; Kassahun, K.; Leppert, P.; Nagarathnam, D.; Forray, C. J Med
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7-(4-chlorophenyl)-N-(2-fluorobenzyl)-5-methyl-4,7-dihy-
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