Homologation of 1-(benzyloxymethyl)-1H-tetrazole via lithiation

Article abstract of DOI:10.1055/s-1998-1708

Lithiation of 1-(Benzyloxymethyl)-1H-tetrazoIe, prepared by alkylation of 1H-tetrazole with benzyl chloromethyl ether, followed by treatement with a variety of electrophiles afforded its homologation products. Hydrogenation or acid hydrolysis gave the corresponding free tetrazoles.

Full text of DOI:10.1055/s-1998-1708

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LETTERS
SYNLETT
Homologation of 1-(Benzyloxymethyl)-1H-tetrazole via Lithiation
Yoshitaka Satoh,* and John Moliterni
Metabolic and Cardiovascular Diseases Research, Novartis Pharmaceuticals Corporation, 556 Morris Avenue, Summit, New Jersey 07901, U.S.A.
Received 15 October 1997
Abstract: Lithiation of 1-(Benzyloxymethyl)-1H-tetrazole, prepared by
alkylation of 1H-tetrazole with benzyl chloromethyl ether, followed by
treatement with a variety of electrophiles afforded its homologation
products. Hydrogenation or acid hydrolysis gave the corresponding free
tetrazoles.
Attention was then focussed on the deprotection step. Under acidic
conditions, warm aqueous hydrochloric acid in dioxane (55 °C, 2 h:
Method A) was sufficient to effect deprotection of the BOM moiety
(entries a, b, d-e, and g) while prolonged treatment with neat TFA was
2
necessary for PMB. The BOM deprotection, albeit in lower yields,
took place with 20 eq. TFA in CH Cl or with TMS-Br. It is interesting
2
2
to note that, in the TMS-Br cleavage reaction, we observed partial
regioisomerization of the BOM group from the N-1 position to N-2.
Preparation of 7d represents a pivotal case to demonstrate the
superiority of the BOM derivatives. The corresponding PMB derivative
could not be cleaved without decomposition. This method is only partly
successful with the highly acid-sensitive substrate 6e where we
observed partial dehydration under the standard conditions (entry e). An
acyltetrazole 6h underwent extensive decomposition under the Method
A (HCl) because of the concomitant Cbz cleavage. With the Bn and
PMB groups, hydrogenolysis required the use of a full equivalent of
During the course of our studies on inhibitors of endothelin converting
enzyme (ECE) based on the 5-aminomethyltetrazole template, we
developed a new method for the synthesis of N-protected 5-(1-
1
hydroxylalkyl)-1H-tetrazoles by the reaction of 5-lithio-1-benzyl- or 1-
2
p-methoxybenzyltetrazole with carbonyl compounds. However, we
encountered a number of cases where significant decomposition of the
products was observed during the deprotection step. Identification of
more versatile and easily removable protective groups of the tetrazole
moiety for this application was therefore urgently needed to expand the
scope of the methodology. In this Letter, we would like to disclose a
successful lithiation and subsequent homologation of 1-
benzyloxymethyl (BOM) protected tetrazole. The BOM group was
removed under much milder conditions than the ones required for
benzyl (Bn) or p-methoxybenzyl (PMB) groups.
2
palladium chloride in EtOH. As expected, however, the BOM
deprotection was performed under standard conditions (10% Pd/C, 1
atm. H , EtOH: Method B), affording the desired tetrazole in reasonable
2
to good yields (entries c and h).
The requisite BOM tetrazole 3 was prepared by condensation of
tetrazole with BOM chloride. The use of NaHMDS in THF greatly
3
improved the yield of 3.
Lithiation of 3 was successfully effected at -78 °C in THF, yielding a
deep-purple solution typical of 5-lithiotetrazole. This is in a good
contrast with 5-lithio derivatives of the Bn and PMB protected
tetrazoles, which are stable only at -100 °C. We believe that improved
stability of the lithiotetrazole in the current study is due to a decreased
steric demand of the BOM group as compared to the corresponding
In summary, we have demonstrated facile deprotonation of N-1 BOM
1H-tetrazole by n-butyllithium, and subsequent reaction with a wide
range of electrophiles. The BOM protective group was removed under
mild conditions, allowing an easy entry to highly functionalized
4
benzylic counterparts. Subsequent in situ condensation with
6
tetrazoles , which are otherwise inaccessible.
electrophiles resulted in the formation of a variety of 1,5-substituted
tetrazoles. As shown in the Table, the reaction proceeded well with
aliphatic, aromatic, and unsaturated aldehydes and ketones (entries a -
e). It should be noted that a good yield of the hydroxyalkyltetrazole (6c)
was obtained even with cyclopentanone (5c), which often shows
tendency for competitive enolization under basic conditions. The amino
acid-based aldehyde required two full equivalents of the base (entry g)
due to the presence of acidic NH. Little diastereoselection was observed
in the reaction with 5g. When a Weinreb amide was used, the most
consistent results were obtained when three equivalents of the
lithiotetrazole was utilized (entry h). Iodination afforded highly
interesting iodide 6f, which may be a good substrate for transition-metal
1-(Benzyloxymethyl)-1H-tetrazole (3) and 2-(Benzyloxymethyl)-2H-
tetrazole (4): Sodium hexamethyldisilazide (360 mL, 1.0M in THF,
0.36 mol) was added to a stirred solution of tetrazole (Aldrich, 25.6 g,
0.36 mol) in 700 mL of dry THF over a period of 30 min at 0 °C. After
30 min, benzyl chloromethyl ether (Tokyo Kasei, 90% pure, 62 g, 0.36
mol) was added and the mixture was stirred for 2 h at room temperature.
The mixture was partitioned between ethyl acetate and water. The
organic layer was separated and the aqueous phase was extracted with
ethyl acetate (x2). The combined organic layer was washed with brine,
dried over magnesium sulfate and evaporated. The oily residue was
chromatographed on silica gel (4.0 kg, 43-60 µM) using 20% ether/
5
catalyzed coupling reactions with organometallics. In contrast,
attempted lithiation of the N-2 regioisomer 4 and subsequent treatment
with benzaldehyde afforded benzyl alcohol, a Cannizzaro product. The
starting material 4 was also recovered unchanged; indicating that no
lithiation took place under similar reaction conditions.
hexane as the eluent. The N-1 regioisomer 3 was obtained as a mobile,
1
colorless oil (27.5 g, 40%): H NMR (500 MHz, CDCl ) δ 4.67 (s, 2 H),
3
13
5.96 (s, 2 H), 7.3 - 4 (m, 5 H), 8.59 (s, 1 H) ppm. C NMR (125.8 MHz,
CDCl ) δ 153.35, 135.51, 128.62, 128.45, 128.25, 79.37, 71.98 ppm. IR
3
-1
(film) 1496, 1325, 1283, 1110, 1023, 764, 702 cm . MS (DCI/NH )
3

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SYNLETT
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191 (M+1), 208 (M + NH ). Anal. Calcd for C H N O: C, 56.83; H,
magnesium sulfate and concentrated. Flash chromatography (silica gel,
4
9 10 4
5.30; N, 29.46. Found: C, 57.05; H, 5.19; N, 29.66. Further elution with
30% ethyl acetate/hexane) gave 330 mg (71%) of the alcohol 6a as an
1
30% ether/hexane afforded, after a small amount of impurity, 4 (19.6 g,
oil. H NMR (500 MHz, CDCl ) δ 3.32 (d, J = 5.6 Hz, 1 H), 4.65 (s, 2
3
1
29%) as a colorless oil: H NMR (500 MHz, CDCl ) δ 4.60 (s, 2 H),
H), 5.89 (s, 2 H), 6.18 (d, J = 5.6 Hz, 1 H), 7.28 - 7.52 (m, 10 H) ppm.
3
13
5.82 (s, 2 H), 7.30 (d, J = 8.0 Hz, 2 H), 7.34 - 7.38 (m, 3 H), 8.76 (s, 1
C NMR (125.8 MHz, CDCl ) δ 168.56, 140.02, 135.52, 128.71,
3
13
H) ppm. C NMR (125.8 MHz, CDCl ) δ 142.68, 135.10, 128.77,
128.57, 128.51, 128.38, 128.18, 126.61, 79.67, 72.10, 69.03 ppm. IR
3
-1
128.72, 128.30, 75.66, 71.92 ppm. IR (film) 1480, 1159, 1094, 750, 700
(film) 3420, 1602, 1494, 1454, 1110, 752, 698 cm . MS (ES +) 297
-1
cm . MS (DCI/NH ) 191 (M+1), 208 (M + NH ). Anal. Calcd for
(M+1). Anal. Calcd for C H N O : C, 64.85; H, 5.44; N, 18.91.
16 16 4 2
3
4
C H N O: C, 56.83; H, 5.30; N, 29.46. Found: C, 56.62; H, 5.19; N,
Found: C, 64.88; H, 5.51; N, 18.78.
9
10 4
29.74.
5-(1-Hydroxy-2-benzyloxyethyl)-1H-tetrazole (7b),
a
Typical
1-Benzyloxymethyl-5-(1-hydroxy-1-phenylmethyl)-1H-tetrazole
(6a), Typical Procedure for the Synthesis of 6: To a stirred solution of
3 (300 mg, 1.58 mmol) in 10 mL of THF was added n-butyllithium
(0.986 mL, 1.6 M in hexanes, 1.58 mmol) dropwise at -78 °C. After 5
min, benzaldehyde (152 mg, 1.43 mmol) was added and the mixture was
stirred for 15 min. The mixture was then slowly allowed to reach room
temperature over a period of 30min, quenched by addition of saturated
aqueous ammonium chloride solution, and extracted with ethyl acetate
(x2). The combined organic extracts were washed with brine, dried over
Procedure for BOM Cleavage by Aqueous HCl (Method A): To a
solution of 6b (310 mg, 0.91 mmol) in dioxane (4 mL) was added 6 M
HCl (2.0 mL, 13.2 mmol) and the mixture was heated at 55 °C for 2 h.
The mixture was cooled, poured into diethyl ether (25 mL) and
extracted with 1 M NaOH (x3). The combined basic extracts were
washed with diethyl ether (x1), then made acidic with 1 M HCl, and
extracted with ethyl acetate (x3). The combined organic extracts were
washed with brine, dried over magnesium sulfate, and concentrated to
give 180 mg (90%) of the title compound (6d) as a white solid: mp 98.5

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1
- 100 °C. H NMR (300 MHz, DMSO-d ) δ 3.67 - 3.81 (m, 2 H), 4.50
References and Notes
6
(s, 2 H), 5.17 (t, J = 5.3 Hz, 1 H), 6.3 (br s, 1 H), 7.23 - 7.34 (m, 5 H),
(1) De Lombaert, S.; Stamford, L. B.; Blanchard, L.; Tan, J.; Hoyer,
D.; Diefenbacher, C. G.; Wei, D.; Wallace, E. M; Moscal, M.;
Savage, P.; Jeng, A. Y. Bioorg. Med. Chem. Lett. 1997, 7, 1059-
64, and references cited therein.
13
16.3 (br s, 1 H) ppm. C NMR (75.47 MHz, CDCl ) δ 157.36, 138.07,
3
128.24, 127.51, 72.65, 72.33, 63.95 ppm. IR (KBr) 3360, 2880, 1585,
-1
1452, 1253, 1133, 734, 694 cm . MS (ES +) 221 (M+1). Anal. Calcd
for C
H N O : C, 54.53; H, 5.49; N, 25.44. Found: C, 54.39; H, 5.70;
10 12 4 2
(2) Satoh, Y.; Marcopulos, N. Tetrahedron Lett. 1995, 36, 1759-62.
N, 25.21.
(3) Yokoyama, M.; Hirano, S.; Matsushita, M.; Hachiya, T.;
5-(1-Hydroxycyclopentyl)-1H-tetrazole (7c), a Typical Procedure
for BOM Cleavage by Hydrogenation (Method B): To a solution of
6c (240 mg, 0.87 mmol) in EtOH (6 mL) was added 10% Pd/C (240 mg)
Kobayashi, N.; Kubo, M.; Togo, H.; Seki, H. J. Chem. Soc.,
Perkin Trans.
1 1995, 1747-53. In this article, rigorous
regiochemical assignment of 3 and 4 using a variety of NMR
techniques was reported.
at room temperature. The mixture was subjected to H (1 atm) for 4 h.
2
The catalyst was removed by filtration through a wad of celite, and the
residue obtained upon evaporation was diluted with ether and extracted
with 1 M NaOH (x2). The combined aqueous phase was acidified with
conc. HCl to pH 2, and back-extracted with ethyl acetate (x3). The ethyl
acetate layer was dried and evaporated. The solid residue was
crystallized from ethyl acetate/hexane to give 80 mg (60%) of 7c as a
(4) The PMB protected 5-lithiotetrazole undergoes decomposition
with concomitant loss of gaseous nitrogen to afford N-PMB-
cyanamide. The temperature required for this irreversible process
appears to be dependent upon the size of the N-1 substituent. See
ref. 2, footnote 10. See also: Raap, R. Can. J. Chem. 1971, 44,
791-2. It is also possible that the ether oxygen of the BOM group
may be stabilizing the lithiotetrazole through internal
coordination. Studies clarifying these aspects are underway.
1
white crystalline solid: mp 112 - 114 °C. H NMR (300 MHz, DMSO-
13
d ) δ 1.69 - 2.00 (m, 8 H), 5.40 - 6.10 (br s, 1 H) ppm. C NMR (75.47
6
MHz, CDCl ) δ 162.05, 76.42, 40.43, 23.32 ppm. IR (KBr) 1550, 1417,
3
-1
(5) Yi, K. Y.; Yoo, S-e. Tetrahedron Lett. 1995, 36, 1679-82.
1199, 1041, 1016 cm . MS (ES +) 155 (M+1). Anal. Calcd for
C H N O: C, 46.74; H, 6.54; N, 36.35. Found: C, 46.66; H, 6.44; N,
36.36.
(6) For a general review of synthesis and chemistry of tetrazoles, see:
Butler, R. N. Comprehensive Heterocyclic Chemistry II; Storr, R.
C. Ed.; Elsevier: Oxford, 1996, Vol. 4, pp 905-1006.
6
10 4
Acknowledgment: We would like to thank Drs. J. L. Stanton and G.
Ksander for their helpful discussion and support.