2-Benzyloxymethyl-5-(tributylstannyl)tetrazole. A reagent for the preparation of 5-aryl- and 5-heteroaryl-1H-tetrazoles via the Stille reaction

Article abstract of DOI:10.1016/S0040-4039(00)00268-9

2-Benzyloxymethyl-5-(tributylstannyl)tetrazole (2) is a useful reagent for the conversion of aryl- and heteroarylhalides (bromides and iodides) to 5-aryl- and 5-heteroaryl-1H-tetrazoles. The conversion entails a copper(I) iodide co-catalyzed Stille palladium-catalyzed cross-coupling reaction and a N-benzyloxymethyl deprotection step. Coupling was possible with electron neutral and electron poor substrates in yields ranging from 35-93%. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00268-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2805–2809
2-Benzyloxymethyl-5-(tributylstannyl)tetrazole. A reagent for the
preparation of 5-aryl- and 5-heteroaryl-1H-tetrazoles via the
Stille reaction†
Brett C. Bookser ∗
Metabasis Therapeutics Inc., 9390 Towne Centre Drive, San Diego, CA 92121, USA
Received 20 January 2000; accepted 26 January 2000
Abstract
2-Benzyloxymethyl-5-(tributylstannyl)tetrazole (2) is a useful reagent for the conversion of aryl- and heteroaryl-
halides (bromides and iodides) to 5-aryl- and 5-heteroaryl-1H-tetrazoles. The conversion entails a copper(I)
iodide co-catalyzed Stille palladium-catalyzed cross-coupling reaction and a N-benzyloxymethyl deprotection step.
Coupling was possible with electron neutral and electron poor substrates in yields ranging from 35–93%. © 2000
Elsevier Science Ltd. All rights reserved.
Keywords: tetrazoles; palladium and compounds; biaryls; coupling reactions.
The tetrazole functionality is an increasingly popular replacement or isostere for the carboxylic acid
group in drug discovery research.1 The tetrazole group, which is metabolically stable, has a similar pKa
to CO2H and as part of a drug molecule it offers the potential of a longer in vivo half life. Its negative
charge can be delocalized over all four nitrogens which translates into derivatives with a higher log P
and thus better oral bioavailablity and cell penetration. Additionally, the four nitrogen atoms offer a
greater opportunity for H-bond donor/acceptor interactions and the π-electron system of the aromatic
ring can have additional hydrophobic interactions, both of which can provide strong receptor binding.
One example where some of these effects resulted in tetrazole being the preferred CO2H mimetic is the
angiotensin II receptor antagonist Losartan (1).2–4
∗
†
Corresponding author. Tel: 858-622-5512; fax: 858-622-5573; e-mail: bookser@mbasis.com (B. C. Bookser)
Dedicated to Professor Ernest Wenkert on the occasion of his 75th birthday.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00268-9
tetl 16548

2806
Standard methods for 1H-tetrazole synthesis require the use of a toxic azide reagent and a cyano or
carboxamide precursor.1,5 A few methods have been published which allow the preparation of 5-alkyl-
or 5-acyl-1H-tetrazole derivatives from simple N-protected tetrazole precursors using organolithium or
organomagnesium techniques.6 This report focuses on defining a method for the synthesis of 5-aryl-
and 5-heteroaryl-1H-tetrazoles which does not involve azide-based reagents or highly reactive carbanion
chemistry and can be used at virtually any point in a synthetic protocol.
Palladium-catalyzed biaryl synthesis methods meet these requirements.7,8 Prior work by Yi and Yoo
demonstrated that 1-benzyl-5-bromotetrazole was a useful coupling partner in the Suzuki reaction with
various phenyl boronic acids.9 However, this method does not produce free 1H-compounds and it is
limited in scope by the availability of arylboronic acids. Herein is reported the preparation and successful
use of stannane 2 as a reagent for the preparation of 5-aryl-1H-tetrazoles. Use of this reagent with the
neutral reaction conditions of the Stille reaction7 should provide for a high degree of flexibility in the
structure of the aryl coupling partner.
The required stannane 2 can be prepared in two steps from tetrazole (3) (Scheme 1). Alkylation of
tetrazole (3) with benzyl chloromethyl ether (BOM-Cl) produced a separable 1:1 mixture of N2- and
N1-isomers 4 and 5, respectively.10 The 5-lithio species of 4, generated by treatment with n-BuLi and
TMEDA in ether at −78°C, was trapped with Bu3SnCl using inverse addition to produce the desired
stannane 2 (67%).11
Scheme 1.
In contrast, addition of n-BuLi to the N1-isomer (5) under the same reaction conditions resulted in
instantaneous gas evolution (N2) from the reaction mixture, a result of ring-opening fragmentation,
even at temperatures as low as −100°C.12 Examination of prior literature seems to indicate a trend in
this fragmentation process of 5-lithio-1-substituted tetrazoles which is dependent on the N1-substituent.
Electron withdrawing N1-substituents (Ph,12 BOM) lower the thermal barrier to fragmentation while
neutral substituents (CH3,12 Bn,9,6b p-methoxybenzyl6b) appear to stabilize the 5-lithio species.
Scheme 2 shows the process adopted for converting aryl- and heteroarylhalides (bromides and iodides)
to 5-aryl- and 5-heteroaryl-1H-tetrazoles by way of the 5-stannyltetrazole 2.13 When 10 mol% CuI and
5 mol% tetrakis(triphenylphosphine)palladium(0) were combined with the stannane 2 and an arylhalide
in refluxing toluene, the desired coupled products 6 were obtained in good to excellent yield as shown
in Table 1.14 The reaction was effective with a range of electron neutral and electron poor aryl halides

2807
(entries a–c and f–j) as well as sterically hindered substrates (entries b and c). Entries d and e failed to
produce coupled products which may be related to the electron rich character of these aryl halides.
Scheme 2.
Table 1
Deprotection was conducted in acidic media or by hydrogenolysis. The latter was a useful alternative
when other acid labile groups were present in the molecule (entries h and j). For example, hydrogenolysis
was necessary to convert 6j to 8-(tetrazol-5-yl)adenosine (7j) since 8-substituted purine nucleosides are
susceptible to deglycosylation in acid.15

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This two-step method for the installation of tetrazole rings onto aryl and heteroaryl halides should be
useful to medicinal and other areas of chemistry desiring to explore the utility of this nitrogen-dense,
carboxylate-mimicking aromatic-ring.
References
1. (a) Butler, R. N. In Comprehensive Heterocyclic Chemistry; Potts, K. T., Ed. Tetrazoles. Pergamon Press: Oxford, 1984; Vol.
5, pp. 791–838. (b) Butler, R. N. In Comprehensive Heterocyclic Chemistry II; Storr, R. C., Ed. Tetrazoles. Pergamon Press:
Oxford, 1996; Vol. 4, pp. 621–678.
2. (a) Carini, D. J.; Duncia, J. V.; Aldrich, P. E.; Chiu, A. T.; Johnson, A. L.; Pierce, M. E.; Price, W. A.; Santella III, J. B.;
Wells, G. J.; Wexler, R. R.; Wong, P. C.; Yoo, S.-E.; Timmermans, P. B. M. W. M. J. Med. Chem. 1991, 34, 2525–2547. (b)
Ribadeneira, M. D.; Aungst, B. J.; Eyermann, C. J.; Huang, S.-M. Pharm. Res. 1996, 13, 227–233.
3. The total 1998 annual sales worldwide of Losartan-based products COZAAR® and HYZARR® was >US$1 billion. Private
comm. from Paul Chusid, Executive Consultant, Public Affairs, Human Health, Merck & Co., Inc, One Merck Drive, PO
Box 100, WS1A-10A, Whitehouse Station, NJ 08889-0100, USA.
4. A survey of the MDL Comprehensive Medicinal Chemistry database (CMC) reveals 33 FDA approved drugs incorporate
the 1H-tetrazole functionality. MDL Information Systems, Inc, 14600 Catalina Street, San Leandro, CA 94577, USA. Tel:
510-352-2870.
5. (a) Duncia, J. V.; Pierce, M. E.; Santella III, J. B. J. Org. Chem. 1991, 56, 2395–2400. (b) Wittenberger, S. J.; Donner, B. G.
Ibid. 1993, 58, 4139–4141.
6. (a) Andrus, A; Heck, J. V.; Christensen, B. G.; Partridge, B. J. Am. Chem. Soc. 1984, 106, 1808–1811. (b) Satoh, Y.;
Marcopulos, N. Tetrahedron Lett. 1995, 36, 1759–1762. (c) Huff, B. E.; LeTourneau, M. E.; Staszak, M. A.; Ward, J. A.
Ibid. 1996, 37, 3655–3658. (d) Bookser, B. C.; Kasibhatla, S. R.; Appleman, J. R.; Erion, M. D. J. Med. Chem. 2000, 43,
1495–1507.
7. Farina, V; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1.
8. (a) Suzuki, A. In Metal Catalyzed Cross-Coupling Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley VCH, 1998; pp 49–97.
(b) Miyaura, N; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
9. Yi, K. Y.; Yoo, S.-e. Tetrahedron Lett. 1995, 36, 1679–1682.
10. Yokoyama, M.; Hirano, S.; Matsushita, M.; Hachiya, T.; Kobayashi, N.; Kubo, M.; Togo, H.; Seki, H. J. Chem. Soc., Perkin
Trans. 1 1995, 1747–1753.
11. 2-Benzyloxymethyl-5-(tributylstannyl)tetrazole (2): To a mixture of tetrazole (3) (2.00 g, 28.5 mmol) and powdered K2CO3
(5.90 g, 42.7 mmol) in 30 mL DMF cooled to 0°C was added benzyl chloromethyl ether (5.36 g, 34.2 mmol) and the resulting
mixture stirred for 30 min at 0°C and then for 16 h at rt. Dilution with water and extraction with ether (2×), drying (MgSO4)
and evaporating the combined ether extracts followed by chromatography of the residue eluting with 2.5:1 hexane:EtOAc
provided 2.22 g (41%) of compound 410 as a colorless oil: 1H NMR (DMSO-d6) δ 4.64 (s, 2), 6.13 (s, 2), 7.2–7.4 (m, 5),
9.10 (s, 1). Anal. Calcd for C9H10N4O: C, 56.83; H, 5.30; N, 29.46. Found: C, 56.92; H, 5.31; N, 29.74. To a solution of
compound 4 (2.00 g, 10.5 mmol) and TMEDA (3.2 mL, 21 mmol) in 30 mL diethyl ether at −78°C was added 4.2 mL of a
2.5 M solution of n-BuLi in hexanes (10.5 mmol) and a dark red solution resulted. This was left to stir for 5 min at −78°C
and then added via cannula needle to a precooled (−78°C) solution of (n-Bu)3SnCl (3.42 g, 10.5 mmol) in 20 mL of diethyl
ether. The resulting pale yellow solution was stirred at −78°C for 30 min and then diluted with water and diethyl ether. The
ether layer was separated, washed with brine, dried (MgSO4) and evaporated. The residue was subjected to chromatography
on SiO2 eluting with hexane:EtOAc mixtures of 100:1, 50:1 and 25:1 which provided 3.35 g (67%) of the stannane 2 as a
colorless oil: 1H NMR (DMSO-d6) δ 0.83 (t, 9, J=7 Hz), 1.0–1.8 (m, 18), 4.61 (s, 2), 6.11 (s, 2), 7.2–7.4 (m, 5). Anal. calcd
for C21H36N4OSn: C, 52.63; H, 7.57; N, 11.69. Found: C, 52.74; H, 7.65; N, 11.82.
12. Early work by Raap identified N1-substituted C5-anions as being susceptible to decomposition by an N2-elimination,
electrocyclic ring-opening fragmentation: Raap, R. Can. J. Chem. 1971, 49, 2139–2142. This fragmentation route was
confirmed when 5 was treated with t-BuLi in THF/DMPU at −78°C followed by benzyl bromide to produce N-
benzyloxymethyl-N-benzylcyanamide (67%): mp 51–53°C; 1H NMR (CDCl3) δ 4.29 (s, 2), 4.58 (s, 2), 4.65 (s, 2), 7.2–7.5
(m, 10). Anal. calcd for C16H16N2O: C, 76.16; H, 6.39; N, 11.10. Found: C, 75.93; H, 6.35; N, 11.03.
13. A typical procedure: 5-Phenyltetrazole (7a): A mixture of bromobenzene (8) (63 mg, 0.4 mmol), stannane 2 (230 mg, 0.48
mmol), tetrakis(triphenylphosphine)palladium(0) (24 mg, 0.02 mmol) and copper(I) iodide (8 mg, 0.04 mmol) in 2 mL of
toluene was refluxed at 110°C for 2 h. The resulting mixture was filtered over Celite and the filtrate evaporated. The residue

2809
was subjected to chromatography on SiO2 eluting with hexane:EtOAc mixtures of 100:1, 50:1 and 25:1 which provided 67
mg (63%) of the compound 6a as an oil contaminated with approximately 5 mol% tributyltin iodide by 1H NMR: 1H NMR
(DMSO-d6) δ 4.69 (s, 2), 6.12 (s, 2), 7.3–7.4 (m, 5), 7.5–7.6 (m, 3), 8.0–8.2 (m, 2). A solution of compound 6a (60 mg, 0.23
mmol) in 2 mL of methanol and 0.2 mL of 6 M HCl was refluxed at 65°C for 3 h and then the solvent evaporated. The residue
was dissolved in 1 M NaOH and extracted with EtOAc (2×) and these organic extracts discarded. The aqueous layer pH was
lowered to 1 with 6 M HCl and then extracted with EtOAc (4×). This EtOAc extract was dried (MgSO4) and evaporated to
provide 28 mg (83%) of compound 7a as a white solid. It was recrystallized with water/ethanol: mp 214–216°C (Aldrich
cat. No. 34,774-4 mp 216°C). 1H NMR (DMSO-d6) δ 7.5–7.6 (m, 3), 8.0–8.1 (m, 3). Anal. calcd for C7H6N4·0.1H2O: C,
56.83; H, 4.22; N, 37.87. Found: C, 57.04; H, 3.87; N, 37.54.
14. The coupling was poor or unsuccessful in the absence of CuI. For an initial report on the usefulness of co-catalytic CuI in
the Stille reaction, see: Liebeskind, L. S.; Fengl, R. W. J. Org. Chem. 1990, 55, 5359–5364.
15. (a) Holmes, R. E.; Robins, R. K. J. Am. Chem. Soc. 1965, 87, 1772–1776. (b) Matsuda, A.; Nomoto, Y.; Ueda, T. Chem.
Pharm. Bull. 1979, 27, 183–192.