A novel approach for the conversion of primary amides into tetrazoles by using tributyltin chloride and sodium azide in the presence of DMF

Article abstract of DOI:10.1055/S-2007-977458

A novel and efficient one-pot synthesis of tetrazole derivatives such as Irbesartan and its analogues has been described from the primary acid amide derivatives. Thus 2-alkyl-3-[p-(o-ami-dophenyl (benzyl]-1.3-diazaspiro[4.4]non- 1-en-4-one derivatives or 4-[α-(acylamino)cyclopentamidomethyl]-2′- carboxamidobiphenyl derivatives were treated with tributyltin chloride and sodium azide in o-xylene in the presence of DMF to afford irbesartan and its analogues without generation of nitriles. The synthesis of these new starting materials is also described, and two of the derivatives have been used as new intermediates in the preparation of irbesartan. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/S-2007-977458

LETTER
1289
A Novel Approach for the Conversion of Primary Amides into Tetrazoles by
Using Tributyltin Chloride and Sodium Azide in the Presence of DMF
Conversionof
P
rim
o
ary
A
mides
r
intoTe
t
r
razoles apati V. V. Prasada Rao,a Ramesh Dandala,*a Vijay K. Handa,a Inti V. Subramanyeswara Rao,a Ananta Rani,a
Sripelly Shivashankar,a Andra Naidub
a
APL Research Center, Aurobindo Pharma Ltd., Bachupally, Hyderabad 500072, India
b
Department of Chemistry, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad 500072, India
Fax +91(40)23042932; E-mail: rdandala@aurobindo.com
Received 20 February 2007
in the presence of DMF in o-xylene, which generates the
corresponding tetrazole derivative, without formation of
nitriles, in good yields (Scheme 1).
Abstract: A novel and efficient one-pot synthesis of tetrazole
derivatives such as Irbesartan and its analogues has been described
from the primary acid amide derivatives. Thus 2-alkyl-3-[p-(o-ami-
dophenyl)benzyl]-1,3-diazaspiro[4.4]non-1-en-4-one derivatives
Our initial investigation was directed towards the con-
version of primary amides into nitriles with p-toluene-
sulfonyl chloride in presence of pyridine. But we failed to
achieve the desired yields and quality due to the formation
of unwanted impurities.
or
4-[a-(acylamino)cyclopentamidomethyl]-2¢-carboxamidobi-
phenyl derivatives were treated with tributyltin chloride and sodium
azide in o-xylene in the presence of DMF to afford irbesartan and
its analogues without generation of nitriles. The synthesis of these
new starting materials is also described, and two of the derivatives
have been used as new intermediates in the preparation of
irbesartan.
Immediately we started the investigation on the direct
conversion of primary amides 4a–e into tetrazoles. The
new compounds 3a–e and 4a–e were prepared and used
for the study. Compound 1a–e were synthesized accord-
ing to the method described in the literature.9 Compounds
3a–e were synthesized by the coupling of compounds
1a–e with amine 2.10,11 Compounds 3b and 4b were found
to be key intermediates for the synthesis of irbesartan. Ini-
tially we started investigating by using primary amides
4a–e. We examined different reagents such as triazido-
chlorosilane, trimethylsilylazide and a mixture of tributyl-
tin chloride and sodium azide. Tributyltin chloride and
sodium azide were found to be the most effective combi-
nation for this tetrazole formation. A significant solvent
effect was found in the cyclization. When the reaction was
carried out in o-xylene, the yield was 30–40%, the reac-
tions did not go to completion on large scale, and two
molar equivalents each of tributyltin chloride and sodium
azide were required. However, o-xylene was suitable for
the preparation of small samples of tetrazole compounds
by using this technique. The yields were increased by
about 30–40% by introducing one molar equivalent of
DMF in the reaction (Table 1, entries 1–5).
Key words: primary acid amides, tributyltin chloride, sodium
azide, o-xylene, DMF, irbesartan
Tetrazole compounds have been used as anticancer1 and
antimicrobial2 agents. Recently tetrazole compounds
were found to be very useful drugs in the treatment of car-
diovascular complaints. Irbesartan is one of the important
drugs in this class of tetrazole compounds.3–6 Very few
synthetic approaches have been reported for the conver-
sion of amides into tetrazoles. In 1990, Duncia et al. dis-
covered that the protected primary amides were
selectively converted into 5-substituted tetrazole deriva-
tives by reacting with azidotrimethylsilane in presence of
triphenylphosphine and diethyl azidocarboxylate
(DEAD). Thus cyanoethyl group has been used as protect-
ing group to facilitate the formation of tetrazole without
the conversion of the primary amide back into its corre-
sponding nitrile.7 In 1997, Elmorsy et al., for the first time,
found that the primary acid amides can be converted into
the corresponding 5-substituted tetrazole derivatives by
treating them with triazidochlorosilane, which was
prepared in situ from tetrachlorosilane and sodium azide
in acetonitrile.8 Based on the available literature, it is the
only method which can be used for the conversion of
primary amides into tetrazole derivatives. To the best of
our knowledge, there is no report for the conversion of
primary acid amides into tetrazoles by using tributyltin
chloride and sodium azide.
Thereafter, we started investigating the direct conversion
of amides 3a–e into the corresponding tetrazoles without
formation of nitriles. However, the reactions proceeded
through the formation of amides 4a–e and the overall
yields went up by about 10% (Table 1).
The selective formation of tetrazoles (entries 1–5) is con-
sidered to proceed as follows: (i) formation of iminotribu-
tyltin ether 6 from amide, (ii) greater tendency of
formation of oxonium salt 7 to prevent the formation of
nitrile, (iii) elimination of tributyltin hydroxide enhances
the intermolecular cyclization to form the tetrazole 5 in
the presence of DMF. The reaction mechanism is depicted
in Scheme 2.
In the present contribution, we report the reaction of
primary amides with tributyltin chloride and sodium azide
SYNLETT 2007, No. 8, pp 1289–1293
1
6.
0
5.
2
0
0
7
Advanced online publication: 08.05.2007
DOI: 10.1055/s-2007-977458; Art ID: G06207ST
© Georg Thieme Verlag Stuttgart · New York

1290
K. V. V. P. Rao et al.
LETTER
CONH2
COOH
DCC, HOBT
+
CH2NH2·HCl
NH
(i-Pr)2NEt
ROC
1
2
H2NOC
O
N
TFA
H2NOC
O
N
H
R
N
xylene
CH2
NH
ROC
3
4
Bu3SnCl
NaN3, DMF
Bu3SnCl
For compounds 1, 3, 4 and 5
N
NaN3, DMF
N
N
N
NH
a R = (CH2)4CH3
b R = n-Bu
c R = n-Pr
d R = Et
O
R
N
CH2
e R = H
5
Scheme 1
Table 1 Preparation of Primary Acid Amides 3a–e12 and 4a–e13 and
Their Conversion into Tetrazoles 5a–e14 with Tributyltin Chloride
and Sodium Azide in the Presence of DMF
SnBu3
O
O
H
N N N
NaN3
H
+
H
Bu3SnCl
R
N
H
R
N
– HCl
– HN3
Entry
R
Starting
Product
Time
(h)
Yield
(%)a
compound
6
1
2
(CH2)4CH3
n-Bu
n-Pr
1a
1b
1c
1d
1e
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
3a
3b
3c
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
5a
5b
5c
6
4.5
3
85
90
80
72
60
60
65
40
33
55
53
60
50
42
35
56
65
60
SnBu3
N
N
N
N
N
N
O
R
NH
H
– Bu3SnOH
N
3
R
R
N
N
H
H
N
N
4
Et
3
5
7
Scheme 2
5
H
1
6
(CH2)4CH3
n-Bu
n-Pr
24
17
15
15
15
40
40
40
40
18
60
50
40
The chemistry reported above permits the direct forma-
tion of tetrazoles from primary acid amides. The reaction
proceeds at higher temperature and in good to excellent
yields without catalyst. It is regioselective for preparing 5-
substituted tetrazole derivatives. The method outlined will
be of high interest not only for the conversion of simple
primary amides, it is also useful for the synthesis of
tetrazoles from compounds containing multiple amide
linkages.
7
8
9
Et
10
11
12
13
14
15
16
17
18
H
(CH2)4CH3
n-Bu
n-Pr
Acknowledgment
Et
We thank the management of Aurobindo Pharma Limited for
allowing us to carry out the present work. The authors are also
thankful to colleagues at the Analytical Research Department and
Chemical Research Department of APL Research Center for their
cooperation.
H
(CH2)4CH3
n-Bu
n-Pr
19
20
Et
H
3d
3e
5d
5e
40
25
52
40
a Isolated yield. With the exception of compounds 3b, 4b and 5b the
yields were not optimized; the reaction was generally run once.
Synlett 2007, No. 8, 1289–1293 © Thieme Stuttgart · New York

LETTER
Conversion of Primary Amides into Tetrazoles
1291
Thereafter, N-hydroxybenzotriazole (11.85g, 0.087 mol)
was added followed by diisopropylethylamine (62.70 g,
0.482 mol) and heated to reflux for 6 h. The reaction mixture
was cooled to 25 °C and the salts were filtered. The filtrate
was washed with H2O (230 mL) followed by sat. Na2CO3
solution (575 mL) and concentrated to a 1200-mL volume.
The slurry obtained was cooled to 10–15 °C and stirred for 1
h. The solid was filtered and washed with precooled CH2Cl2
(230 mL) and dried to afford compound 3b as a white
powder; mp 100–101 °C. 1H NMR (300 MHz, DMSO-d6):
d = 0.83–0.88 (t, J = 7.41 Hz, 3 H), 1.22–1.29 (m, 2 H), 1.45–
1.50 (m, 2 H), 1.60–2.00 (m, 4 H), 1.87–2.07 (m, 4 H), 2.11–
2.16 (t, J = 7.41 Hz, 2 H), 4.28–4.30 (d, J = 6.04 Hz, 2 H),
7.22–7.48 (m, 8 H), 7.27, 7.62 (2 × br s, 2 H), 7.89 (s, 1 H),
8.02–8.06 (t, J = 6.04 Hz, 1 H). 13C NMR (75 MHz,
DMSO-d6): d = 14.7, 22.7, 24.8, 28.2, 36.1, 37.1, 42.9, 67.1,
127.3, 127.7, 128.9, 130, 130.7, 138.2, 139.4, 139.6, 139.8,
171.1, 173.4, 174.7. MS: m/z = 422.2 [M+]. Anal. Calcd for
C25H31N3O3: C, 71.23; H, 7.41; N, 9.97. Found: C, 71.01; H,
7.41; N, 9.99.
4-[a-(n-Hexanoylamino)cyclopentamidomethyl]-2¢-
carboxamidobiphenyl (3a): mp 137–138 °C. 1H NMR (300
MHz, DMSO-d6): d = 0.82–0.86 (t, J = 7.41 Hz, 3 H), 1.24–
1.28 (m, 2 H), 1.47–1.52 (m, 2 H), 1.61–1.63 (m, 4 H), 1.88–
2.07 (m, 8 H), 2.10–2.15 (t, J = 7.41 Hz, 2 H), 4.29–4.30 (d,
J = 6.04 Hz, 2 H), 7.22–7.48 (m, 8 H), 7.27, 7.62 (2 × br s, 2
H), 7.89 (s, 1 H), 8.02–8.06 (t, J = 6.04 Hz, 1 H). 13C NMR
(75 MHz, DMSO-d6): d = 14.8, 22.8, 24.8, 25.7, 31.8, 36.3,
37.1, 42.8, 67.1, 127.3, 127.7, 128.3, 128.9, 130.0, 130.6,
138.2, 139.4, 139.5, 139.8, 172.1, 173.4, 174.7. MS: m/z =
434.2 [M–]. Anal. Calcd for C26H33N3O3: C, 71.70; H, 7.64;
N, 9.65. Found: C, 71.44; H, 7.65; N, 9.67.
4-[a-(n-Butanoylamino)cyclopentamidomethyl]-2¢-
carboxamidobiphenyl (3c): mp 108–109 °C. 1H NMR (300
MHz, DMSO-d6): d = 0.82–0.85 (t, J = 7.41 Hz, 3 H), 1.47–
1.52 (m, 2 H), 1.60–1.62 (m, 4 H), 1.88–2.03 (m, 4 H), 2.08–
2.13 (t, J = 7.41 Hz, 2 H), 4.28–4.30 (d, J = 6.04 Hz, 2 H),
7.22–7.46 (m, 8 H), 7.25, 7.45 (2 × br s, 2 H), 7.88 (s, 1 H),
8.01–8.05 (t, J = 6.04 Hz, 1 H). 13C NMR (75 MHz, DMSO-
d6): d = 14.5, 19.4, 24.8, 37.1, 38.3, 39.5, 42.8, 67.1, 127.3,
127.7, 128.3, 128.9, 130.0, 138.2, 139.4, 139.5, 139.8,
172.1, 173.2, 174.7. MS: m/z = 406.3 [M–]. Anal. Calcd for
C24H29N3O3: C, 70.74; H, 7.17; N, 10.31. Found: C, 71.00;
H, 7.16; N, 10.31.
4-[a-(n-Propylamino)cyclopentamidomethyl]-2¢-
carboxamidobiphenyl (3d): mp 189–190 °C. 1H NMR (300
MHz, DMSO-d6): d = 0.96–1.00 (t, J = 7.41 Hz, 3 H), 1.62–
1.64 (m, 4 H), 1.86–2.10 (m, 4 H), 2.13–2.18 (t, J = 7.41, 2
H), 4.28–4.30 (d, J = 6.04 Hz, 2 H), 7.22–7.49 (m, 8 H), 7.32,
7.61 (2 × br s, 2 H), 7.86 (s, 1 H), 8.03–8.07 (t, J = 6.04 Hz,
1 H). 13C NMR (75 MHz, DMSO-d6): d = 10.5, 24.9, 29.4,
37.2, 42.8, 67, 127.3, 127.7, 128.3, 130, 130.7, 138.2, 139.4,
139.5, 139.9, 172.1, 174, 174.7. MS: m/z = 392.2 [M–]. Anal.
Calcd for C23H27N3O3: C, 70.21; H, 6.92; N, 10.68. Found:
C, 70.50; H, 6.91; N, 10.70.
References and Notes
(1) Eiichi, K.; Masayawa, F.; Yoshito, N.; Takashi, H.;
Masataka, F. Jpn. Patent JP60130572, 1985; Chem. Abstr.
1986, 104, 88553.
(2) Butler, R. N. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R.; Rees, C. W., Eds.; Pergamon Press:
Oxford, 1984, 791–838.
(3) Bernhart, C. A.; Perreaut, P. M.; Ferrari, B. P.; Muneaux, Y.
A.; Assens, J. L. A.; Clement, J.; Haudricourt, F.; Muneaux,
C. F.; Taillades, J. E.; Vignal, M.-A.; Gougat, J.; Guiraudou,
P. R.; Lacour, C. A.; Roccon, A.; Cazaubon, C. F.; Brelière,
J.-C.; Le Fur, G.; Nisato, D. J. Med. Chem. 1993, 36, 3371.
(4) Mann, J. J. Dtsch. Med. Wochenschr. 1996, 121, 568.
(5) Sun, L. L.; Pan, Q. C. Zhongguo Linchuang Yalolixue Zazh.
2000, 16, 228.
(6) Satyanarayana, B.; Sumalatha, Y.; Venkataraman, S.;
Mahesh Reddy, G.; Pratap Reddy, P. Synth. Commun. 2005,
35, 1979.
(7) Duncia, J. V.; Pierce, M. E.; Santella, J. B. III J. Org. Chem.
1991, 56, 2395.
(8) El-Ahl, A.-A. S.; Elmorsy, S. S.; Elbheery, A. H.; Amer, F.
A. Tetrahedron Lett. 1997, 38, 1257.
(9) Buchi Reddy, R.; Sudhakar, S.; Sridhar, C.; Narender Rao,
S.; Venkataraman, S. WO Patent, 113518A1, 2005; Chem.
Abstr. 2006, 144, 22926.
(10) Ashton, W. T.; Chang, L. L.; Maccoss, M.; Chakravarty, P.
K.; Greenlee, W. J.; Patchett, A. A.; Flanagan, K. US Patent,
US5411980, 1995; Chem. Abstr. 1991, 114, 207268.
(11) Solvents and reagents were obtained from commercial
sources and used without purification. Melting points were
determined on a Polmon melting point apparatus. All
melting points are uncorrected. The 1H NMR and 13C NMR
spectra were recorded on a Bruker 300 spectrometer at 300
MHz and 75 MHz, respectively. The chemical shifts are
reported in d (ppm) relative to TMS. The mass spectra were
recorded on a API 2000 Perkin Elmer PE-SCIEX mass
spectrometer.
Synthesis of 2-(4-Aminomethylphenyl)benzamide
Hydrochloride (2): 2-(4-Aminomethylphenyl)benzonitrile
hydrochloride (150 g, 0.614 mol) was neutralized in a
mixture of CH2Cl2 (750 mL) and H2O (300 mL) at 15–20 °C
by the addition of NaOH (25.90 g, 0.647 mol). The organic
layer was separated and washed with H2O and concentrated.
The concentrated mass was dissolved in t-BuOH (450 mL)
and heated to 65 °C. Freshly prepared KOH powder (48.52
g, 85%, 0.736 mol) was added and heated to reflux for 7 h.
The reaction mixture was cooled to r.t. and diluted with
CH2Cl2 (750 mL) followed by H2O (600 mL). The aqueous
layer was separated and extracted with CH2Cl2 (750 mL).
The combined CH2Cl2 extract was washed with H2O (300
mL) and dried over anhyd Na2SO4. The pH was adjusted to
1.2–1.4 with HCl acid at 2–5 °C over a period of 60 min and
stirring was continued for another 60 min. The precipitate
obtained was collected by filtration and dried to afford the
title compound (135 g, 83.8%) as a white crystalline powder;
mp 140–142 °C (Lit.3 182 °C). 1H NMR (300 MHz, DMSO-
d6): d = 4.03 (br s, 2 H), 7.33–7.57 (m, 10 H), 8.66 (br s, 3
H). 13C NMR (75 MHz, DMSO-d6): d = 42.7, 128.1, 128.4,
129.3, 129.7, 130.1, 130.7, 133.8, 138.2, 139.1, 141.4,
171.9. MS: m/z = 227.2 [M+].
4-[a-(n-Formyloxyamino)cyclopentamidomethyl]-2¢-
carboxamidobiphenyl (3e): mp 87–88 °C. 1H NMR (300
MHz, DMSO-d6): d = 1.65–1.67 (m, 4 H), 1.90–2.11 (m, 4
H), 4.29–4.31 (d, J = 6.04 Hz, 2 H), 7.22–7.48 (m, 8 H), 7.26,
7.61 (2 × br s, 2 H), 7.96 (s, 1 H), 8.20–8.24 (t, J = 6.04 Hz,
1 H), 8.27 (s, 1 H). 13C NMR (75 MHz, DMSO-d6): d = 24.8,
38.0, 42.9, 66.7, 127.3, 127.7, 128.3, 129.0, 129.1, 130.0,
130.7, 138.2, 139.4, 139.5, 139.7, 162.1, 165.4, 172.1,
174.1. MS: m/z = 434.2 [M–]. Anal. Calcd for C21H23N3O3:
C, 69.02; H, 6.34; N, 11.50. Found: C, 69.11; H, 6.34; N,
11.51.
(12) Typical Experimental Procedure for the Synthesis of 4-
[a-(n-Acylamino)cyclopentamidomethyl]-2¢-carbox-
amidobiphenyls 3a–e: Compound 2 (115 g, 0.438 mol) was
added to a mixture of dicyclohexylcarbodiimide (DCC;
99.36 g, 0.482 mol) in CH2Cl2 (2300 mL) followed by
compound 1a10 (93.38 g, 0.438 mol) at 25–30 °C.
Synlett 2007, No. 8, 1289–1293 © Thieme Stuttgart · New York

1292
K. V. V. P. Rao et al.
LETTER
(13) Typical Experimental Procedure for the Synthesis
of 2-Alkyl-3-[p-(o-amidophenyl)benzyl]-1,3-diaza-
spiro[4.4]non-1-en-4-ones 4a–e: Trifluoroacetic acid (15.5
g, 0.136 mol) was added to a preheated suspension of 4-[a-
(n-pentanoylamino)cyclopentamidomethyl]-2¢-carbox-
amidobiphenyl (3b; 50 g, 0.124 mol) in o-xylene (500 mL)
over a period of 30 min. Thereafter, the mixture was heated
to reflux for 18 h. Xylene was distilled off and a mixture of
EtOAc (750 mL) and H2O (250 mL) was added at 55 °C and
the reaction mixture was cooled to r.t. The pH was adjusted
to 9.0–9.5 with aq NH3 and stirred for 5 min. The organic
layer was separated and washed with H2O (250 mL). The
organic layer was concentrated to a volume of about 250 mL
and cooled to 0–5 °C. The slurry obtained was stirred for 30
min to complete the crystallization. The solid obtained was
filtered and washed with precooled EtOAc (50 mL) and
dried to afford 2-(n-butyl)-3-[p-(o-amidophenyl)benzyl]-
1,3-diazaspiro[4.4]non-1-en-4-one (4b) as a white crystal-
line powder; mp 146–147 °C. 1H NMR (300 MHz,
DMSO-d6): d = 0.79–0.83 (t, J = 7.41 Hz, 3 H), 1.20–1.29
(m, 2 H), 1.48–1.51 (m, 2 H), 1.67–1.85 (m, 8 H), 2.32–2.37
(t, J = 6.04 Hz, 2 H), 4.71 (s, 2 H), 7.15–7.50 (m, 8 H), 7.30,
7.66 (2 × br s, 2 H). 13C NMR (75 MHz, DMSO-d6): d =
14.5, 22.4, 26.3, 27.5, 28.4, 37.7, 43.2, 76.7, 127.0, 127.9,
128.4, 129.6, 130.1, 130.7, 131.9, 136.8, 138.2, 139.2,
140.5, 162.0, 172.0, 186.6. MS: m/z = 404.5 [M+]. Anal.
Calcd for C25H29N3O2: C, 74.41; H, 7.24; N, 10.41. Found:
C, 74.70; H, 7.25; N, 10.43.
Calcd for C21H21N3O2: C, 72.60; H, 6.09; N, 12.10. Found:
C, 72.70; H, 6.10; N, 12.11.
(14) Typical Experimental Procedure for the Synthesis of 2-
Alkyl-3-[2¢-(1H-tetrazol-5-yl)(1,1¢-biphenyl-4-yl)meth-
yl]-1,3-diazaspiro[4.4]non-1-en-4-ones 5a–e: Sodium
azide (16.20 g, 0.249 mol) was added to tributyltin chloride
(81 g, 0.249 mol) at 25–30 °C under a nitrogen atmosphere
and the contents were stirred for 30 min at the same
temperature. Thereafter, DMF (13 g, 0.18 mol) was added at
25–30 °C and the stirring continued for 30 min at
temperatures below 45 °C. o-Xylene (50 mL) was added
followed by 2-(n-butyl)-3-[p-(o-amidophenyl)benzyl]-1,3-
diazaspiro[4.4]non-1-en-4-one (4b; 50 g, 0.124 mol). The
temperature was raised to 150–155 °C and the stirring was
continued for 60 h at the same temperature under nitrogen
atmosphere. Thereafter, the reaction mixture was cooled to
25 °C and diluted with CH2Cl2 (200 mL), o-xylene (100 mL)
and H2O (100 mL) at the same temperature. HCl acid (13 g,
35%) was added in 15 min at 25 °C and stirring was
continued for 1 h at the same temperature. The precipitated
solid was filtered and washed with a CH2Cl2 and o-xylene
(1:1) mixture. The wet material was dried under reduced
pressure at 65–70 °C to afford the compound 2b (54.5 g). It
was dissolved in EtOH (1090 mL) at reflux temperature to
get a cloudy solution and was cooled to 60 °C. Carbon (5 g)
and hyflo (10 g) were added and the mixture was again
refluxed for 15 min. Thereafter, the temperature was brought
down to 60 °C and the mixture was filtered to remove
carbon. The filtrate was concentrated to 500-mL volume
under reduced pressure at 55–65 °C. The resulting
2-(n-Pentyl)-3-[p-(o-amidophenyl)benzyl]-1,3-diaza-
spiro[4.4]non-1-en-4-one (4a): mp 142–144 °C. 1H NMR
(300 MHz, DMSO-d6): d = 0.78–0.82 (t, J = 7.41 Hz, 3 H),
1.20–1.23 (m, 2 H), 1.25–1.85 (m, 10 H), 2.31–2.36 (t, J =
6.04 Hz, 2 H), 4.71 (s, 2 H), 7.15–7.49 (m, 8 H), 7.30, 7.65
(2 × br s, 2 H). 13C NMR (75 MHz, DMSO-d6): d = 14.7,
22.6, 25.1, 26.3, 28.6, 31.5, 37.7, 43.2, 76.7, 127.0, 127.9,
128.4, 129.6, 130.1, 130.7, 136.8, 138.2, 139.2, 140.4,
162.0, 171.9, 186.6. MS: m/z = 418.0 [M+]. Anal. Calcd for
C26H31N3O2: C, 74.79; H, 7.48; N, 10.06. Found: C, 75.00;
H, 7.48; N, 10.11.
2-(n-Propyl)-3-[p-(o-amidophenyl)benzyl]-1,3-diaza-
spiro[4.4]non-1-en-4-one (4c): mp 182–184 °C. 1H NMR
(300 MHz, DMSO-d6): d = 0.85–0.90 (t, J = 7.41 Hz, 3 H),
1.53–1.58 (m, 2 H), 1.60–1.99 (m, 10 H), 2.30–2.35 (t, J =
6.04 Hz, 2 H), 4.78 (s, 2 H), 7.08–7.50 (m, 8 H), 7.30, 7.65
(2 × br s, 2 H). 13C NMR (75 MHz, DMSO-d6): d = 14.3,
18.8, 26.3, 30.5, 37.7, 43.1, 76.7, 127.0, 127.9, 128.4, 129.6,
130.1, 136.8, 138.2, 139.2, 140.4, 161.8, 172.0, 86.6. MS:
m/z = 390.3 [M+]. Anal. Calcd for C24H27N3O2: C, 74.01; H,
6.99; N, 10.79. Found: C, 74.20; H, 7.00; N, 10.80.
2-Ethyl-3-[p-(o-amidophenyl)benzyl]-1,3-diaza-
suspension was cooled to 5–10 °C and stirred for 1 h at the
same temperature. The solid was filtered and washed with
precooled EtOH (100 mL) and dried under reduced pressure
at 65–70 °C to afford the title compound, 2-(n-butyl)-3-[2¢-
(1H-tetrazol-5-yl)(1,1¢-biphenyl-4-yl)methyl]-1,3-diaza-
spiro[4.4]non-1-en-4-one [irbesartan (5b); 42.5 g, 80%)] as
a white crystalline powder; mp 181–182 °C (Lit.3 182 °C).
1H NMR (300 MHz, DMSO-d6): d = 0.70–0.91 (t, J = 7.41
Hz, 3 H), 1.20–1.40 (sext, 2 H), 1.45–1.60 (quint, 2 H),
1.60–2.00 (m, 8 H), 2.20–2.40 (t, J = 6.04 Hz, 2 H), 3.00–
3.60 (br s, 1 H), 4.60–4.80 (s, 2 H), 7.32–7.95 (m, 8 H). 13
C
NMR (75 MHz, DMSO-d6): d = 14.5, 22.4, 26.3, 27.4, 28.3,
37.7, 43.1, 76.7, 124.3, 127.1, 128.7, 130.1, 131.4, 131.9,
137.2, 139.2, 141.9, 155.9, 162.0, 186.5. MS: m/z = 429
[M+].
2-(n-Pentyl)-3-[2¢-(1H-tetrazol-5-yl)(1,1¢-biphenyl-4-
yl)methyl]-1,3-diazaspiro[4.4]non-1-en-4-one (5a): mp
184–185 °C. 1H NMR (300 MHz, DMSO-d6): d = 0.78–0.83
(t, J = 7.41 Hz, 3 H), 1.19–1.21 (m, 4 H), 1.48–1.84 (m, 10
H), 2.25–2.30 (t, J = 6.04 Hz, 2 H), 3.00–3.60 (br s, 1 H),
4.67 (s, 2 H), 7.08–7.70 (m, 8 H). 13C NMR (75 MHz,
DMSO-d6): d = 14.7, 22.6, 25.0, 26.3, 27.4, 28.6, 31.4, 37.7,
43.1, 76.7, 124.3, 127.1, 128.7, 130.1, 131.4, 131.5, 131.9,
137.2, 139.2, 141.9, 155.9, 162.0, 186.5. MS: m/z = 443.2
[M+]. Anal. Calcd for C26H30N6O: C, 70.56; H, 6.83; N,
18.99. Found: C, 70.71; H, 6.84; N, 19.00.
2-(n-Propyl)-3-[2¢-(1H-tetrazol-5-yl)(1,1¢-biphenyl-4-
yl)methyl]-1,3-diazaspiro[4.4]non-1-en-4-one (5c): mp
110–112 °C. 1H NMR (300 MHz, DMSO-d6): d = 0.83–0.89
(t, J = 7.41 Hz, 3 H), 1.55–1.60 (quint, 4 H), 1.85–2.02 (m,
8 H), 2.72–2.77 (t, J = 6.04 Hz, 2 H), 3.20–3.80 (br s, 1 H),
7.10–7.20 (m, 4 H), 7.50–7.70 (m, 4 H). 13C NMR (75 MHz,
DMSO-d6): d = 14.0, 19.0, 26.1, 29.8, 37.6, 44.2, 72.7,
124.4, 127.7, 128.8, 130.2, 131.4, 131.5, 131.9, 134.9,
139.9, 141.8, 155.9, 172.5, 180.4. MS: m/z = 413.2 [M–].
Anal. Calcd for C24H26N6O: C, 69.54; H, 6.32; N, 20.27.
Found: C, 69.23; H, 6.32; N, 20.29.
spiro[4.4]non-1-en-4-one (4d): mp 102–104 °C. 1H NMR
(300 MHz, DMSO-d6): d = 0.95–0.99 (t, J = 7.41 Hz, 3 H),
1.60–1.63 (m, 8 H), 2.20–2.25 (t, J = 6.04 Hz, 2 H), 4.78 (s,
2 H), 7.18–7.40 (m, 8 H), 7.30, 7.65 (2 × br s, 2 H). 13C NMR
(MHz, DMSO-d6): d = 14.3, 19.8, 24.3, 37.2, 38.5, 39.4,
42.1, 76.7, 127.4, 127.9, 128.4, 129.6, 130.1, 138.2, 139.2,
139.9, 161.7, 172.0, 186.5. MS: m/z = 376.1 [M+]. Anal.
Calcd for C23H25N3O2: C, 73.57; H, 6.71; N, 11.90. Found:
C, 73.61; H, 6.70; N, 11.91.
3-[p-(o-Amidophenyl)benzyl]-1,3-diazaspiro[4.4]non-1-
en-4-one (4e): mp 152–154 °C. 1H NMR (300 MHz,
DMSO-d6): d = 1.67–1.84 (m, 8 H), 4.67 (s, 2 H), 7.23–7.50
(m, 8 H), 7.29, 7.66 (2 × br s, 2 H), 8.03 (s, 1 H). 13C NMR
(75 MHz, DMSO-d6): d = 26.2, 37.5, 44.2, 77.7, 127.7,
127.9, 128.0, 129.6, 130.1, 130.7, 136.6, 138.2, 139.2,
140.6, 153.3, 171.9, 185.6. MS: m/z = 390.3 [M+]. Anal.
Synlett 2007, No. 8, 1289–1293 © Thieme Stuttgart · New York

LETTER
2-Ethyl-3-[2¢-(1H-tetrazol-5-yl)(1,1¢-biphenyl-4-
Conversion of Primary Amides into Tetrazoles
1293
3-[2¢-(1H-Tetrazol-5-yl)(1,1¢-biphenyl-4-yl)methyl]-1,3-
diazaspiro[4.4]non-1-en-4-one (5e): mp 190–191 °C. 1H
NMR (300 MHz, DMSO-d6): d = 1.65–1.86 (m, 8 H), 4.65
(s, 2 H), 7.08–7.19 (m, 4 H), 7.54–7.71 (m, 4 H), 8.0 (s, 1 H),
16.37 (br s, 1 H). 13C NMR (75 MHz, DMSO-d6): d = 26.2,
37.4, 44.1, 77.7, 124.3, 127.8, 128.7, 130.1, 131.5, 132.0,
137, 139.4, 141.9, 153.3, 155.9, 185.5. MS: m/z = 371.1
[M–]. Anal. Calcd for C21H20N6O: C, 67.73; H, 5.41; N,
22.57. Found: C, 67.91; H, 5.41; N, 22.60.
yl)methyl]-1,3-diazaspiro[4.4]non-1-en-4-one (5d): mp
104–106 °C. 1H NMR (300 MHz, DMSO-d6): d = 1.19–1.24
(t, J = 7.41 Hz, 3 H), 1.94–2.03 (m, 8 H), 2.76–2.78 (q, 2 H),
3.50 (br s, 1 H), 4.86 (s, 2 H), 7.20–7.30 (m, 4 H), 7.60–7.78
(m, 4 H). 13C NMR (75 MHz, DMSO-d6): d = 9.8, 22.3, 26.2,
37.5, 44.0, 73.5, 124.3, 127.7, 128.7, 130.2, 131.4, 131.5,
131.9, 135.3, 139.7, 141.8, 155.9, 171.6, 181.5. MS: m/z =
399.1 [M–]. Anal. Calcd for C23H24N6O: C, 68.98; H, 6.04;
N, 20.99. Found: C, 69.11; H, 6.03; N, 21.00.
Synlett 2007, No. 8, 1289–1293 © Thieme Stuttgart · New York

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