Synthesis and characterization of 4′-bromomethyl-2-(N-trityl-1H- tetrazol-5-yl) biphenyl

Article abstract of DOI:10.1080/00397910802228495

Biphenyl tetrazole ring is an important component of the Sartan family of novel drugs. 4′-Bromomethyl-2-(N-trityl-1H-tetrazol-5-yl)biphenyl was synthesized in this article from 4′-methyl-2-cyano-biphenyl through three steps. 4′-Methyl-2-cyano-biphenyl was reacted with azide ions with the help of ammonium chloride as catalyst in an autoclave with high conversion to afford the tetrazole compounds in 70.6% yield. After being protected by the trityl group with 92.6% yield, 4′-methyl-2-(N-trityl-1H-tetrazol-5-yl) biphenyl was brominated with N-bromosuccinimide (NBS) in cyclohexane with 2,2′-azo-isobutyronitrile (AIBN) acting as an initiator to provide the title compound in 83.8% yield. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802228495

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Synthesis and Characterization
of 4′-Bromomethyl-2-(N-
trityl-1H-tetrazol-5-yl)
Biphenyl
Guo-xi Wang a , Bao-ping Sun a & Zong-ling Ru a
a Department of Chemical Engineering , Anyang
Institute of Technology , Anyang, China
Published online: 29 Sep 2008.
To cite this article: Guo-xi Wang , Bao-ping Sun & Zong-ling Ru (2008) Synthesis and
Characterization of 4′-Bromomethyl-2-(N-trityl-1H-tetrazol-5-yl) Biphenyl, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 38:20, 3577-3581, DOI: 10.1080/00397910802228495
To link to this article: http://dx.doi.org/10.1080/00397910802228495
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Synthetic Communications1, 38: 3577–3581, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802228495
Synthesis and Characterization of
40-Bromomethyl-2-(N-trityl-1H-tetrazol-5-yl)
Biphenyl
Guo-xi Wang, Bao-ping Sun, and Zong-ling Ru
Department of Chemical Engineering, Anyang Institute of Technology,
Anyang, China
Abstract: Biphenyl tetrazole ring is an important component of the Sartan family
of novel drugs. 40-Bromomethyl-2-(N-trityl-1H-tetrazol-5-yl)biphenyl was synthe-
sized in this article from 40-methyl-2-cyano-biphenyl through three steps.
40-Methyl-2-cyano-biphenyl was reacted with azide ions with the help of ammo-
nium chloride as catalyst in an autoclave with high conversion to afford the tetra-
zole compounds in 70.6% yield. After being protected by the trityl group with
92.6% yield, 40-methyl-2-(N-trityl-1H-tetrazol-5-yl) biphenyl was brominated with
N-bromosuccinimide (NBS) in cyclohexane with 2,20-azo-isobutyronitrile (AIBN)
acting as an initiator to provide the title compound in 83.8% yield.
Keywords: Angiotensin II, free radical bromination, synthesis, tetrazole ring,
trityl protection
People are more interested in heterocyclic compounds containing tetrazole
rings in recent years because of their broad applications in different scien-
tific research fields.[1] As a good ligand, the nitrogen atoms from tetrazole
rings can be coordinated with metallic ions to form various functional
complexes. In medicinal chemistry, the tetrazole ring can act as a meta-
bolically stable surrogate for a carboxylic acid group, and these compounds
have various material science applications, including special explosives.[2]
Received March 4, 2008.
Address correspondence to Guo-xi Wang, Department of Chemical Engineer-
ing, Anyang Institute of Technology, Anyang 455000, China. E-mail: njuwgx@
yahoo.com.cn
3577

3578
G.-x. Wang, B.-p. Sun, and Z.-l. Ru
In 1994, the first member of Sartan’s family, Losartan, was synthe-
sized and applied to clinical treatments. After that, scientists have been
decorating its molecular structure with chemical reactions on the mother
nucleus to improve its curative effects of lowering blood pressure,
prolonging its process, and decreasing its side effects. Losartan’s out-
standing performance accelerated the emergence of other members of
Sartan’s family and meanwhile promoted the development of medicinal
chemistry. These novel medicines can be used for the treatment of hyper-
tension, heart failure, and kidney diseases.[3]
Until now, the angiotensin II acceptor depressant family has
many members, such as Losartan, Irbesartan, Candesartan, Tasosartan,
Valsartan, and Olmesartan. In these medicinal molecules, there is a
normal 2-substituted biphenyl tetrazole unit, which is the important
intermediate for preparing Sartan. We report here a novel synthetic
method for 40-bromomethyl-2-(N-trityl-1H-tetrazol-5-yl) biphenyl.
With zinc chloride or zinc bromide as a Lewis acid, the azide ion is
reacted with the cyano group to furnish 5-substituted-1H-tetrazole in
the normal synthetic method.[4–8] Demko and Sharpless[2] used water as
solvent and zinc bromide as Lewis acid in a green process that yields
67%. However, a large amount of zinc salts used as Lewis acid may pol-
lute the environment and increase the cost of medicinal production. In
this article, we synthesized 5-substituted-1H-tetrazole biphenyl with
dimethyl formamide (DMF) as solvent and ammonium chloride as cata-
lyst in an autoclave; this yields 70.6% and has a 91.0% conversion rate.
1H- in tetrazole has good activity, with a pKa ca. 4.89, which is
slightly higher than that of acetic acid (pKa ¼ 4.76). It must be protected
before the latter reaction begins.[5,6] In this article, the 1H- was protected
with a trityl group with 92.6% yield, and then the methyl group in the side
chain of the biphenyl ring was brominated via free radical reaction with
N-bromosuccinimide (NBS) to afford the title compound in 83.8% yield.
The synthetic route described in this article is shown in Scheme 1.
Scheme 1. a) NaN3, NH4Cl, DMF=H2O; b) Ph3CCl, NaOH, toluene; and
c) NBS, ABIN, cyclohexane.

40-Bromomethyl-2-(N-trityl-1H-tetrazol-5-yl) Biphenyl
3579
EXPERIMENTAL
Melting points were determined with an X-4 microscope melting-point
testing apparatus (Shanghai) and are uncorrected. IR spectra were
1
recorded on a Bruker spectrum Vector22 (FT) instrument. H NMR
spectra were obtained (CDCl3, d ¼ 7.27 ppm) from a Bruker RX-500
spectrometer (s, d, and m indicate singlet, double, and multiplet res-
pectively). Mass spectrum was measured on a Finnigan LCQTM
spectrometer.
40-Methyl-2-(1H-tetrazol-5-yl) Biphenyl (3)
40-Methyl-2-cyano-biphenyl (2) (89.1 g, 0.461 mol), sodium azide (45.3 g,
0.696 mol), ammonium chloride (27.2 g, 0.506 mol), DMF (600 mL), and
water (100 mL) were mixed in an autoclave and gradually heated to
168 ꢀC. The mixture was stirred and kept at 168 ꢁ 2 ꢀC, 3.6 MPa for
30 h. The reaction mixture was allowed to cool to 50 ꢀC and then poured
into water (7000 mL) carefully, accompanied by precipitates. After stand-
ing still for 30 min, the precipitate was collected, washed with water
(500 mL) sufficiently until the filtrate became neutral (pH ¼ 6–7), and
dried at 60 ꢀC in an oven for 10 h to furnish a yellowish solid (20.0 g).
Analysis showed that the solid was the starting material 40-methyl-2-
cyano-biphenyl (2) and can be recycled. The filtrate and washing solution
were combined, acidified with 1:1 (v=v) aqueous hydrochloric acid to pH
2, and stirred for another 20 min. The resulting solution stood still for 1 h
and then was filtered with suction. The precipitate was washed with
plenty of water and then dried at 60 ꢀC in an oven for 12 h. After recrys-
tallization from ethyl acetate=hexane, 3 was obtained as a white crystal-
line solid (76.8 g) in 70.6% yield based on compound 2. Thin-layer
chromatography (TLC) shows that the product is pure. The developing
agent is ethyl acetate=hexane, and the ratio is 1:3 (v=v). Mp 149–151 ꢀC
(lit.[2]: mp 150 ꢀC, yield 91%). The conversion rate of 2 in this procedure
is 91.0%.
1
MS (ESI, MeOH, -p): 235.02, 236.03. H NMR (CDCl3, 500 MHz)
d: 10.76 (s, br, 1H, NH), 8.37 (d, J ¼ 6.1, 1H, ArH), 7.60 – 7.20 (m, 7H,
ArH), 2.47 (s, 3H, CH3). IR (KBr, cmꢂ1): 3446 (m), 2979 (m), 2902
(m), 2863 (m), 2830 (m), 2748 (m), 2717 (m), 2606 (m), 2553 (m),
2472 (m), 1601 (m), 1567 (s), 1516 (w), 1483 (m), 1447 (m), 1396
(m), 1364 (w), 1257 (w), 1244 (m), 1186 (w), 1159 (m), 1111 (w),
1078 (m), 1049 (m), 1008 (m), 985 (m), 942 (w), 907 (m), 843 (w),
824 (s), 774 (m), 756 (s), 739 (w), 732 (w), 660 (w), 639(w), 555 (w),
523 (w), 520 (m).

3580
G.-x. Wang, B.-p. Sun, and Z.-l. Ru
40-Methyl-2-(N-trityl-1H-tetrazol-5-yl) Biphenyl (4)
Compound 4 was prepared following the reported procedure[5] with a
slight modification. Under stirring at ambient temperature, 3 (18.9 g,
0.080 mol) was mixed with toluene (100 mL) and 30% NaOH (10.7 g,
aq.) in a 500- mL, three-neck flask. After stirring for another 10 min, tri-
tyl chloride (22.3 g, 0.080 mol) was added to the system in portions. The
resulting solution was vigorous stirred for another 4 h at rt. Then the sys-
tem was cooled to 0 ꢀC, and water (40 mL) and petroleum ether (120 mL)
were added. It was stirred overnight. The reaction solution was cooled to
less than 0 ꢀC in a refrigerator for over 5 h, then filtered with a suction
pump. The filter cake was washed with cold water until neutral and dried
at 60 ꢀC in an oven. Recrystallization from ethyl acetate gave 4 as white
crystalline particles (35.5 g) in 92.6% yield based on 3. TLC result showed
that the product was a pure compound. The developing agent was ethyl
acetate=hexane, and the ratio was 1:4 (v=v). Mp 165–167 ꢀC (lit.[5,6]
mp163–166 ꢀC, yield 91%).
:
1H NMR (CDCl3, 500 MHz) d: 7.92 (d, J ¼ 7.75 Hz, 1H, ArH),
7.59–6.92 (m, 22H, ArH), 2.47 (s, 3H, CH3). IR (KBr, cmꢂ1): 3416 (br,
s), 1609 (s), 1543 (s), 1490 (w), 1461 (m), 1440 (m), 1414 (m), 1374 (s),
1291 (w), 1220 (m), 1103 (w), 1070 (w), 1046 (w), 1008 (w), 936 (w),
814 (m), 775 (m), 726 (m), 703 (m), 632 (m), 573 (w).
40-Bromomethyl-2-(N-trityl-1H-tetrazol-5-yl) Biphenyl (1)
40-Methyl-2-(N-trityl-1H-tetrazol-5-yl) biphenyl (4) (19.12 g, 0.040 mol)
was mixed with cyclohexane (150 mL) in a 250-mL flask under stirring
at 50 ꢀC. NBS (7.51 g, 0.042 mol) and AIBN (0.40 g) were added, and
the mixture was stirred under reflux for ca. 12 h until the starting material
disappeared. (It was monitored by TLC analysis; the developing agents
were ethyl acetate=hexane, and the ratio was 1:4, v=v.) The resulting solu-
tion was filtered while hot. The filter cake was washed with a small
amount of cyclohexane. The solvent was removed from the filtrate under
reduced pressure. The residue was dispersed with diethyl ether (150 mL)
to precipitate a white solid, which was then cooled in a refrigerator for
4 h. The precipitate was collected, washed with cold diethyl ether, and
then dried in an oven at 70 ꢀC. After recrystallization from ethyl acetate=
petroleum (1:8, v=v), the title compound 1 was afforded (18.7 g) as white
needle crystals in 83.8% yield, mp 135–138ꢀC (lit.[5]: mp 135–137 ꢀC,
crude yield 91.7%).
1H NMR (CDCl3, 500 MHz) d: 7.95 (m, 1H, ArH), 7.64 – 6.91 (m,
22H, ArH), 4.56 (s, 1H, CH2), 4.40 (s, 1H, CH2). IR (KBr, cmꢂ1): 3056

40-Bromomethyl-2-(N-trityl-1H-tetrazol-5-yl) Biphenyl
3581
(w), 3027 (w), 1601 (w), 1491 (m), 1472 (m), 1444 (s), 1428 (m), 1407 (w),
1355 (w), 1326 (w), 1283 (w), 1224 (m), 1187 (w), 1156 (w), 1098 (w), 1083
(w), 1030 (m), 1004 (m), 931 (w), 904 (w), 877 (m), 843 (m), 821 (w), 786
(w), 760 (s), 748 (s), 700 (s), 676 (m), 637 (m), 612 (m), 586 (w), 548 (w),
497 (w).
ACKNOWLEDGMENT
We are grateful to Professors Z. H. He and H. J. Lu from Zhengzhou
University for their help.
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