Reactions of 2-[lithio(trimethylsilyl)methyl]-2 H -tetrazoles: Synthesis of 2-[1-(trimethylsilyl)alkyl]-2 H -tetrazoles and (2 H -tetrazol-2-yl)acetates

Article abstract of DOI:10.1055/s-0034-1378933

The reaction of 2-[(trimethylsilyl)methyl]-2H-tetrazoles with various alkyl halides and carbonates using n-butyllithium or lithium diisopropylamide (LDA) gave 2-[1-(trimethylsilyl)alkyl]-2H-tetrazoles and (2H-tetrazol-2-yl)acetates as useful synthons of m

Full text of DOI:10.1055/s-0034-1378933

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 205–208
letter
205
H. Umemoto et al.
Letter
Synlett
Reactions of 2-[Lithio(trimethylsilyl)methyl]-2H-tetrazoles: Syn-
thesis of 2-[1-(Trimethylsilyl)alkyl]-2H-tetrazoles and (2H-Tetra-
zol-2-yl)acetates
Hideaki Umemoto*a
Takuya Onakaa
Ph
R3COX
Yasuyoshi Mikib
Akira Nakamurab
Tomohiro Maegawa*b
N
N
Ph
(R1 = H, Me)
Ph
N
N
COR3
R2X
N
N
N
N
R1
R2
R1
TMS
Li
R1
TMS
(R1 = H, Me)
N
N
N
N
Ph
a Fujimoto Chemicals Co., Ltd., 1-2-38 Kinrakuji-cho,
Amagasaki 660-0806, Japan
h-umemoto@fujimoto-chem.co.jp
b School of Pharmaceutical Sciences, Kinki University,
1) (MeO)2CO
2) R4COX
+
8
1
6
(6
)
4
8
2
3
1
1
5
N
N
N
N
COOMe
(R1 = H)
3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan
+
8
1
6
(6
)
7
2
1
2
5
0
5
COR4
maegawa@phar.kindai.ac.jp
Received: 07.09.2014
Accepted after revision: 16.10.2014
Published online: 27.11.2014
reaction of 2-[(trimethylsilyl)methyl]-2H-tetrazole with
various alkyl halides and carbonates afforded 2-substituted
tetrazoles.
DOI: 10.1055/s-0034-1378933; Art ID: st-2014-u0742-l
We first examined the lithiation of 5-phenyl-2-
[(trimethylsilyl)methyl]-2H-tetrazole (1) followed by al-
kylation with alkyl halides. The lithiation of 1 with n-BuLi
was conducted in THF at –78 °C. Subsequent reaction with
iodomethane successfully afforded 5-phenyl-2-[1-(trimeth-
ylsilyl)ethyl]-2H-tetrazole (2a) with 90% yield (Table 1, en-
try 1). 2-[1-(Trimethylsilyl)butyl]-2H-tetrazole (2b) and 2-
[1-(trimethylsilyl)methyl]-2-phenylethyl-2H-tetrazole (2c)
were also obtained in high yields (87–94%; entries 2 and 3).
Similarly, 2-[1-methyl-1-(trimethylsilyl)ethyl]-2H-tetrazole
(2d) and 2-[1-methyl-1-(trimethylsilyl)butyl]-2H-tetrazole
(2e) were obtained in good yields (70–72%; entries 4 and 5).
The TMS group could be removed by treatment in MeOH
under basic conditions.
Abstract The reaction of 2-[(trimethylsilyl)methyl]-2H-tetrazoles with
various alkyl halides and carbonates using n-butyllithium or lithium di-
isopropylamide (LDA) gave 2-[1-(trimethylsilyl)alkyl]-2H-tetrazoles and
(2H-tetrazol-2-yl)acetates as useful synthons of modified tetrazoles.
Key words tetrazoles, synthetic methods, lithiation, synthons
Tetrazoles are heterocyclic compounds used in agro-
chemicals, materials science, and biochemistry.1 In addi-
tion, some tetrazole derivatives, such as losartan,2 cande-
sartan,2c,d zolarsartan,2c,d and varsartan,2b play an important
role in medicinal chemistry as blockers of the angiotensin II
receptor. Other tetrazole derivatives are used as chemo-
therapeutic agents against certain types of cancer3 and in
the treatment of AIDS.4 Recently, 2-substituted 2H-tetra-
zoles have been shown to exhibit remarkable biological
properties, including hepatitis C serine protease inhibition,5
metabotropic glutamate receptor antagonism,6 inhibition
of stearoyl-coenzyme A δ-9 desaturase,7 G-protein coupled
receptor agonism,8 squalene synthase inhibition,9 and anti-
microbial and anticonvulsant activities.10 These properties
directed our research toward the development of a synthet-
ic method for creating functionalized tetrazole derivatives.
We recently reported the regioselective 2-arylation of 5-
substituted tetrazoles in the preparation of 2-aryl-2H-tetra-
zoles.11 This report details the functionalization of 2-alkyl-
2H-tetrazoles by alkylation of the α-carbon on the 2-alkyl
group as a useful preparation of 2-functional tetrazoles. To
our knowledge, only the analogous reactions with alde-
hydes and ketones have been reported.12 We focused on
commercially available 2-[(trimethylsilyl)methyl]-2H-
tetrazole, which was expected to have a higher acidity than
the non-TMS-substituted derivative,13 and found that the
Table 1 Reaction of 2-[2-(Trimethylsilyl)alkyl]-2H-tetrazoles with Alkyl
Halide
1) n-BuLi (1.1 equiv)
2) R2X (1.1 equiv)
Ph
Ph
1) THF, –78 °C
N
N
N
N
R1
R2
TMS
N
N
R1
TMS
N N
1, 2a
2
Entry
1, 2a
R1
R2X
Time (h)
2
Yield (%)a
1
2
3
4
5
1
H
MeI
2
4
2
2
4
2a
2b
2c
2d
2e
90
87
94
70
72
1
H
n-PrI
BnBr
MeI
1
H
2a
2a
Me
Me
n-PrI
a Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 205–208

206
H. Umemoto et al.
Letter
Synlett
The introduction of a carbonyl function group into a 2-
[(trimethylsilyl)methyl]-2H-tetrazole derivative was also
evaluated. Reactions of 2-[1-(trimethylsilyl)ethyl]-2H-
tetrazole (2a) with several acylating reagents did not yield
satisfactory results. Dimethyl carbonate, however, was a
successful acylating reagent and yielded methyl 2-(5-phe-
nyl-2H-tetrazol-2-yl)propionate (3a) with 77% yield (Table
2, entry 1). The analogous reaction with 2-[(trimethylsi-
lyl)methyl]-2H-tetrazole (1) gave the desired product (3b)14
with only a 34% yield and 1 was recovered with 45% yield
(entry 2). Although the reaction of 1 using 1.1 equiv of lith-
ium N,N-diisopropyl amide (LDA) resulted in 47% yield and
the recovery of 1 with 34% yield (entry 3), the use of 2.1
equiv of LDA led to complete reaction, and 3b was obtained
with 88% yield (entry 4). S,S′-Dimethyl dithiocarbonate was
also effective and provided thioester 3c with 79% yield (en-
try 5). The reaction of 1 with N,N-dimethylbenzamide gave
ketone 3d15 with 64% yield (entry 6), but the same reaction
with N,N-dimethylacetamide gave poor results due to the
acidic α-proton of N,N-dimethylacetamide. No reaction was
observed with acetic anhydride (entry 8).
yield the intermediate c. ROLi (R = Me or TMS) is eliminated
from intermediate c to form ketene acetal d, which reacts
again with LDA to give a lithiated ketene acetal g.
Ph
Tz
TMS
Tz =
Li
N
N
N
N
a
R
R = Me, TMS
(MeO)2CO
Tz
TMS
OLi
MeO
OMe
b
path A
path B
MeOLi
TMS
Tz
Li
Tz
MeO
OTMS
MeO
O
OMe
c
Table 2 Reaction of 2-[1-(Trimethyl)alkyl]-2H-tetrazoles with Carbon-
ates
e
ROLi
Ph
Ph
LDA
1) electrophile (1.1 equiv)
base (1.1 equiv)
THF, –78 °C, 2 h
N
N
N
N
Tz
Tz
TMS
OLi
N
N
R1
N
N
R1
2) H+
TMS
1, 2a
R2
MeO
OR
MeO
3
d
f
Entry 1, 2a R1
Electrophile Base (equiv) R2
3
Yield
(%)a
LDA
1
2
3
4
5
6
7
8
2a
1
Me
H
(MeO)2CO
(MeO)2CO
(MeO)2CO
(MeO)2CO
(MeS)2CO
n-BuLi (1.1)
n-BuLi (1.1)
LDA (1.1)
LDA (2.1)
LDA (2.1)
CO2Me
CO2Me
CO2Me
CO2Me
3a
3b
3b
3b
77
34b
47c
88
Tz
Li
Tz
H+
1
H
1
H
MeO
OR
MeO
O
1
H
COSMe 3c
79
g
3b
1
H
PhCONMe2 LDA (2.1)
COPh
COMe
COMe
3d
3e
3e
64
Scheme 1 Proposed mechanisms of esterification
1
H
AcNMe2
Ac2O
LDA (2.1)
LDA (2.1)
14d
n.r.e
1
H
The second proposed pathway proceeds via the ester
(path B). Adduct b eliminates MeOLi to form ester e and a
further reaction with LDA affords ketene acetal f. Finally, a
Brook rearrangement of f leads to g. Because the acidity of
both intermediates d and e is stronger than that of 1, start-
ing material remained with the use of 1.1 equiv of LDA.
A multicomponent reaction was evaluated to confirm
the possible reaction mechanisms described above (Table
3). The reaction of lithiated ketene acetal, generated from 2-
[(trimethylsilyl)methyl]-2H-tetrazole (1) and dimethyl car-
bonate, was treated with ClCO2Me at 10 °C to give dimethyl
malonate (4a) with 51% yield. Methyl benzyl malonate (4b)
and methyl tert-butyl malonate (4c) were also obtained
a Isolated yield.
b Starting material was recovered with 45% yield.
c Starting material was recovered with 34% yield.
d Starting material was recovered with 47% yield.
e No reaction.
Two different paths for this series of reactions may be
hypothesized (Scheme 1). One is a Peterson type reaction
(path A). The reaction of 2-(lithiomethyl)tetrazole (a),
which is generated from 2-[(trimethylsilyl)methyl]tetrazole
(1) and LDA, with dimethyl carbonate gives the adduct b,
which immediately undergoes a Brook rearrangement to
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 205–208

207
H. Umemoto et al.
Letter
Synlett
yields of 46–74% by reactions with ClCO2Bn and (Boc)2O, re-
spectively. Reaction with Ac2O also provided the acetylated
product 4d with 75% yield (entry 4).
(5) (a) Sun, Y.; Liu, D.; Or, Y. S.; Wang, Z. WO 2008 019 289, 2008;
Chem. Abstr. 2008, 148, 262901 (b) Sun, Y.; Liu, D.; Or, Y. S.;
Wang, Z. WO 2008 021 733, 2008; Chem. Abstr. 2008, 148,
308635 (c) Sun, Y.; Liu, D.; Or, Y. S.; Wang, Z. WO 2009 064 955,
2009; Chem. Abstr. 2009, 150, 555797.
(6) (a) Tehrani, L. R.; Smith, N. D.; Huang, D.; Poon, S. F.; Roppe, J. R.;
Seiders, T. J.; Chapman, D. F.; Chung, J.; Cramer, M.; Cosford, N.
D. P. Bioorg. Med. Chem. Lett. 2005, 15, 5061. (b) Arora, J.;
Edwards, L.; Isaac, M.; Kers, A.; Staaf, K.; Slassi, A.; Stefanac, T.;
Wensbo, D.; Xin, T.; Holm, B. WO 2005 080 386, 2005; Chem.
Abstr. 2005, 143, 266955 (c) Arzel, E.; Edwards, L.; Isaac, M.;
Mcleod, D. A.; Slassi, A.; Xin, T. WO 2009 051 556, 2009; Chem.
Abstr. 2009, 150, 447953
Table 3 Multicomponent Reaction of 2-[1-(Trimethyl)methyl]-
2H-tetrazole
Ph
Ph
1) (MeO)2CO (1.1 equiv)
LDA (2.1 equiv)
THF, –78 °C
N
N
N
N
N
N
N
N
R
2) electrophile (2.1 equiv)
3) H+
TMS
COOMe
(7) Lachance, N.; Li, C. S.; Leclerc, J.-P.; Ramtohul, Y. K. WO 2008
128 335, 2008; Chem. Abstr. 2008, 149, 513832
1
4
(8) Wood, H. B.; Szewczyk, J. W.; Huang, Y.; Adams, A. D. WO 2009
129 036, 2009; Chem. Abstr. 2008, 151, 491142
Entry Electrophile
Temp (°C) Time (h)
R
Yield (%)a
1
2
3
4
ClCO2Me
ClCO2Bn
(Boc)2O
Ac2O
10
10
10
r.t.
14
14
14
2
CO2Me
4a
4b
4c
4d
51
46
74
75
(9) Ichikawa, M.; Ohtsuka, M.; Ohki, H.; Haginoya, N.; Itoh, M.;
Sugita, K.; Usui, H.; Suzuki, M.; Terayama, K.; Kanda, A. Bioorg.
Med. Chem. 2012, 20, 3072.
(10) (a) Chul, L. S.; Yong, U. M.; Ryune, C. N.; Won, L. D.; Young, L. J.;
Ho, K. H.; Ho, L. D. US Patent 8 501 436, 2010; Chem. Abstr. 2010,
154, 86383 (b) Rostom, S. A. F.; Ashour, H. M. A.; Razik, H. A. A.
E.; Fattah, A. E. F. H. A. E.; El-Din, N. N. Bioorg. Med. Chem. 2009,
17, 2410.
CO2Bn
CO2t-Bu
=C(OH)Me
a Isolated yield.
(11) Onaka, T.; Umemoto, H.; Miki, Y.; Nakamura, A.; Maegawa, T. J.
Org. Chem. 2014, 79, 6703.
(12) (a) Thomas, E. W.; Cudahy, M. M. J. Org. Chem. 1993, 58, 1623.
(b) Moody, C. J.; Rees, C. W.; Young, R. G. J. Chem. Soc., Perkin
Trans. 1 1991, 323. (c) Moody, C. J.; Rees, C. W.; Young, R. G.
Synlett 1990, 413.
In conclusion, this study demonstrates the reactivity of
2-[lithio(trimethylsilyl)methyl]-2H-tetrazoles and the syn-
thesis of 2-[1-(trimethylsilyl)alkyl]-2H-tetrazoles or (2H-
tetrazol-2-yl)acetates, which may be used as synthons of
modified tetrazoles.16–18
(13) Zhang, S.; Zhang, X.-M.; Bordwell, F. G. J. Am. Chem. Soc. 1995,
117, 602.
(14) Einberg, F. J. Org. Chem. 1970, 35, 3978.
Supporting Information
(15) Krylov, A. S.; Dogadina, A. V.; Trifonov, R. E. Russ. J. Org. Chem.
2014, 50, 892.
(16) Reaction of 2-[2-(Trimethylsilyl)alkyl]-2H-tetrazoles with
Alkyl Halides; Typical Procedure for 5-Phenyl-2-[1-(trimeth-
ylsilyl)ethyl]-2H-tetrazole (2a):
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378933.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
References and Notes
A solution of 1 (0.50 mmol) in anhydrous THF (1 mL) was
cooled to –78 °C under an argon atmosphere. n-BuLi (1.6 M in
n-hexane, 0.55 mmol) was added to the suspension dropwise
over 30 min, and the mixture was stirred further for 1 h.
Iodomethane (0.55 mmol) was added to the mixture, which was
stirred at –78 °C for 2 h. After quenching with HCl, the reaction
mixture was extracted with EtOAc. The organic layer was
washed with H2O, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chroma-
tography on silica gel to afford 2a (90%) as a colorless oil.
1H NMR (CDCl3): δ = 0.15 [s, 9 H, (CH3)3Si], 1.71 (d, J = 7.6 Hz,
3 H, CH3), 4.52 (q, J = 5.6 Hz, 1 H, CH), 7.42–7.53 (m, 3 H, ArH),
8.12–8.20 (m, 2 H, ArH); 13C NMR (CDCl3): δ = –3.50, 16.23,
51.86, 126.73, 127.90, 128.82, 130.00, 164.49; HRMS (ESI): m/z
[M + H]+ calcd for C12H19N4Si: 247.1379; found: 247.1353.
(17) Preparation of Acetates and Ketones; Typical Procedure for
Methyl (5-Phenyl-2H-tetrazol-2-yl)acetate (3b): A mixture of
1 (0.50 mmol) and dimethyl carbonate (0.55 mmol) in anhy-
drous THF (1 mL) was cooled to –78 °C under an argon atmo-
sphere. LDA (1.1 M in n-hexane–THF, 1.05 mmol) was added to
the suspension dropwise over 60 min. After stirring for 2 h at –
78 °C, HCl (1.0 M, 3 mL) was added to the mixture. The mixture
was allowed to reach r.t., and stirred for 30 min. The reaction
mixture was extracted with EtOAc and the organic layer was
(1) (a) Butler, R. N. In Comprehensive Heterocyclic Chemistry; Vol. 4;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.; Pergammon:
Oxford, 1996. (b) Koldobskii, G. I.; Kharbash, R. B. Russ. J. Org.
Chem. 2003, 39, 453. (c) Roh, J.; Vávrová, K.; Hrabálek, A. Eur. J.
Org. Chem. 2012, 6101.
(2) (a) Herr, R. J. Bioorg. Med. Chem. 2002, 10, 3379. (b) Aureggi, V.;
Sedelmeier, G. Angew. Chem. Int. Ed. 2007, 46, 8440. (c) Alonen,
A.; Finel, M.; Kostiainen, R. Biochem. Pharmacol. 2008, 76, 763.
(d) Alonen, A.; Jansson, J.; Kallonen, S.; Kiriazis, A.; Aitio, O.;
Finel, M.; Kostiainen, R. Bioorg. Chem. 2008, 36, 148.
(3) (a) Bavetsias, V.; Jackman, A. L.; Kimbell, R.; Boyle, F. T.; Bisset,
G. M. F. Bioorg. Med. Chem. Lett. 1996, 6, 631. (b) Tamura, Y.;
Watanabe, F.; Nakatani, T.; Yasui, K.; Fuji, M.; Komurasaki, T.;
Tsuzuki, H.; Maekawa, R.; Yoshioka, T.; Kawada, K.; Sugita, K.;
Ohtani, M. J. Med. Chem. 1998, 41, 640.
(4) (a) May, B. C. H.; Abell, A. D. J. Chem. Soc., Perkin Trans. 1 2002,
172. (b) Gagnon, A.; Landry, S.; Coulombe, R.; Guse, I.;
Thavonekham, B.; Bonneau, P. R.; Yoakim, C.; Simoneau, B.
Bioorg. Med. Chem. Lett. 2009, 19, 1199.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 205–208

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H. Umemoto et al.
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washed with H2O, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chroma-
tography on silica gel to afford 3b (88%) as a white solid.
n-hexane–THF, 1.05 mmol) was added to the suspension drop-
wise over 30 min. After stirring for 30 min, methyl chlorofor-
mate (1.05 mmol) was added to the mixture. The mixture
allowed to reach 10 °C slowly, and stirred overnight. After
quenching with HCl, the reaction mixture was extracted with
EtOAc and the organic layer was washed with H2O, dried over
Na2SO4, and concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel to afford
4a (51%) as a colorless oil.
Mp 97–98 °C (n-hexane–CHCl3) (Lit.14 93–94 °C); IR (ATR):
1756 cm–1 1H NMR (CDCl3): δ = 3.83 (s, 3 H, COOCH3), 5.48 (s,
;
2 H, CH2), 7.47–7.53 (m, 3 H, ArH), 8.13–8.20 (m, 2 H, ArH); 13
C
NMR (CDCl3): δ = 53.23, 53.31, 127.01, 127.04, 128.93, 130.56,
165.53, 165.71; HRMS (ESI): m/z [M + H]+ calcd for C10H11N4O2:
219.0882; found: 219.0872.
(18) Multicomponent Reaction of 2-[1-(Trimethylsilyl)methyl]-
2H-tetrazole; Typical Procedure for Dimethyl 2-(5-Phenyl-
2H-tetrazol-2-yl)malonate (4a): A mixture of 1 (0.50 mmol)
and dimethyl carbonate (0.55 mmol) in anhydrous THF (1 mL)
was cooled to –78 °C under an argon atmosphere. LDA (1.1 M in
IR (ATR): 1752 cm–1; 1H NMR (CDCl3): δ = 3.91 (s, 6 H, COOCH3),
6.37 (s, 1 H, CH), 7.47–7.51 (m, 3 H, ArH), 8.16–8.22 (m, 2 H,
ArH); 13C NMR (CDCl3): δ = 54.13, 66.61, 126.73, 127.14, 128.87,
130.70, 162.51, 165.69; HRMS (ESI): m/z [M + H]+ calcd for
C
12H13N4O2: 277.0937; found: 277.0927.
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