Tetrachlorosilane-sodium azide system in the synthesis of tetrazole-containing amino acid derivatives

Article abstract of DOI:10.1023/A:1021624401405

Treatment of N-acetyl-(RS)-phenylalanine and N-acetyl-(RS)-leucine methyl esters with the system tetrachlorosilane-sodium azide leads to formation of tetrazole-containing amino acid derivatives. The latter can be converted into α-substituted 5-methyl-1-te

Full text of DOI:10.1023/A:1021624401405

Russian Journal of Organic Chemistry, Vol. 38, No. 9, 2002, pp. 1370 1373. Translated from Zhurnal Organicheskoi Khimii, Vol. 38, No. 9, 2002,
pp. 1422 1425.
Original Russian Text Copyright
2002 by Esikov, Morozova, Malin, Ostrovskii.
Dedicated to Full Member of the Russian Academy of Sciences
V.A. Tartakovskii on the 70th Anniversary of His Birth
Tetrachlorosilane Sodium Azide System in the Synthesis
of Tetrazole-Containing Amino Acid Derivatives
K. A. Esikov, S. E. Morozova, A. A. Malin, and V. A. Ostrovskii
St. Petersburg State Institute of Technology, Moskovskii pr. 26, St. Petersburg, 198013 Russia
e-mail: kirill_esikov@mail.ru
Received May 29, 2002
Abstract Treatment of N-acetyl-(RS)-phenylalanine and N-acetyl-(RS)-leucine methyl esters with the system
tetrachlorosilane sodium azide leads to formation of tetrazole-containing amino acid derivatives. The latter
can be converted into -substituted 5-methyl-1-tetrazolylacetic acids and the corresponding bis-tetrazoles.
Structural modification of amino acids and peptides
is a conventional method for synthesizing new con-
jugates as potential biologically active compounds.
A promising fragment for such modification is a tetra-
zole ring which can be regarded as an analog and
stable (from the viewpoint of metabolism) substitute
for carboxy or carboxamide group. The first amino
acid analogs having a 5-tetrazolyl substituent instead
of the carboxy group were reported in 1959 by
McManus and Herbst [1]. Nevertheless, the problem
of molecular design and synthesis of tetrazole-contain-
ing amino acids and peptides remains important. For
example, Constantino et al. [2] recently synthesized
a potential mGlu1 receptor antagonist (S-TBPG)
whose molecule combines a tetrazole ring and bi-
cyclo[1.1.1]pentane skeleton:
poorly. As a rule, tetrazole fragment is incorporated
into peptide chain by the action of PCl5 on a mono-
substituted amide group and subsequent treatment
with HN3 [4]. Taking into account the high toxicity
of hydrazoic acid and risk of explosion, as well as
the fact that unsubstituted amides cannot be invloved
in analogous reactions, the necessity of developing
alternative procedures for synthesis of tetrazole-con-
taining peptidomimetics seems to be obvious.
We recently showed that the azidating system tetra-
chlorosilane sodium azide is a convenient and rela-
tively safe reagent for the synthesis of tetrazoles from
carboxylic acid amides. It is important that this
system allows preparation of both 1,5-disubstituted
[10] and NH-tetrazoles [10, 11] from monosubstituted
or unsubstituted amides, respectively. In the present
work we made an attempt to apply the above system
to structural modification of amino acids.
By heating N-acetyl-(RS)-phenylalanine and
N-acetyl-(RS)-leucine methyl esters IIa and IIb with
tetrachlorosilane and sodium azide in boiling aceto-
nitrile we obtained the corresponding -substituted
5-methyl-1-tetrazolylacetic acid esters IIIa and IIIb.
Their hydrolysis gave carboxylic acids IVa and IVb
(Scheme 1). Esters IIIa and IIIb reacted with
ammonia to give amides Va and Vb, and treatment
of the latter with tetrachlorosilane sodium azide led
to formation of bis-tetrazoles VIa and VIb.
Biological activity of tetrazole-containing analogs
of various biologically active peptides was studied,
specifically of Leu-enkephalin [3], bradykinin [4],
tyroliberin [5], neuropharmacologically active tri-
peptide Pro-Leu-Gly-NH2 [6], and -casomorphin-7-
amide [7]. Also, tetrazol-containing peptidomimetics
II, which inhibit HIV protease, were prepared [8, 9].
We previously showed that N-monosubstituted and
unsubstituted amides exhibit different reactivities
toward the system tetrachlorosilane sodium azide
Despite increased interest in such compounds,
methods for their preparation have been explored
1070-4280/02/3809-1370$27.00 2002 MAIK Nauka/Interperiodica

TETRACHLOROSILANE SODIUM AZIDE SYSTEM
1371
Scheme 1.
R = Ph (a), i-Pr (b).
[10]. In fact, the rate of formation of NH-tetrazoles
is several times higher than the rate of formation of
1,5-disubstituted derivatives. An analogous pattern
was observed by us with phenylalanine derivatives.
By the action of tetrachlorosilane sodium azide,
unsubstituted amide Va was converted into the corre-
sponding tetrazole (VIa) in 12 h, i.e., much faster
than substituted amide IIa (30 h). However, the azida-
tion of both monosubstituted (Vb) and unsubstituted
leucine derivatives (IIb) takes about 10 h.
It should be noted that an additional amount of the
azidating reagent (tetrachlorosilane and sodium azide)
should be added after a certain time to complete the
conversion of amide into tetrazole. Presumably, inter-
mediate silicon azides are unstable, and they decom-
pose on heating [12].
for alkylation with various reagent. An analogous
approach was applied in [6, 13] to the synthesis of
peptidomimetics containing both tetrazole-1,5-diyl
and tetrazole-2,5-diyl fragments.
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on
a Bruker DPX-300 instrument at 300 and 75 MHz,
respectively; the solvent signals (CDCl3 or DMSO-d6)
were used as reference. The mass spectra (70 eV)
were run on a Varian MAT-311 mass spectrometer.
The progress of reactions was monitored, and the
1
purity of products was checked, by H NMR spectros-
copy (compounds IIIb, IVb, Vb, and VIb) or thin-
layer chromatography (IIIa, IVa, Va, and VIa) on
Kieselgel 60 F254 plates (Merck) using CHCl3 MeOH
(9:1) as eluent; spots were visualized with UV light.
CAUTION! Reactions with the system SiCl4 NaN3
can be accompanied by evolution of small amounts
of hydrazoic acid.
Methyl (RS)-2-(5-methyl-1-tetrazolyl)-3-phenyl-
propionate (IIIa). A solution of 7.7 g (0.045 mol) of
tetrachlorosilane in 25 ml of acetonitrile was added
with stirring to a mixture of 5 g (0.023 mol) of ester
IIa and 2.95 g (0.045 mol) of sodium azide in 25 ml
of acetonitrile. The mixture was refluxed for 6 h with
protection from moisture and was analyzed for initial
ester IIa. If necessary, an additional amount of the
azidating reagent was added [0.5 g (0.008 mol) of
NaN3 and 1.7 g (0.01 mol) of SiCl4]. This procedure
was repeated every 6 h until the conversion of ester
IIa was complete. The overall reaction time was 30 h.
Some limitations intrinsic to the azidating system
under study must be noted. Unlike N-acetyl deriva-
tives of amino acids, N-benzoyl derivatives, e.g.,
compound VII, almost do not react with tetrachloro-
silane sodium azide. A propable reason is steric effect
of the benzoyl substituent.
Carboxylic acids IVa and IVb can be used as
terminal amino acids in the synthesis of tetrazole-con-
taining peptidomimetics. In addition, bis-tetrazoles
VIa and VIb may be regarded as substrates suitable
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 9 2002

1372
ESIKOV et al.
The mixture was then poured in small portions under
stirring to a solution of Na2CO3, maintaining the pH
greater than 7. The product was extracted into ethyl
acetate (2 50 ml), the solvent was removed under
reduced pressure, and the residue was recrystallized
from 50 70% ethanol. Yield 4.52 g (81%). Colorless
crystalline substance, mp 88 89 C. 1H NMR spectrum
(DMSO-d6), , ppm: 2.19 s (3H, 5-CH3), 3.42 d.d
(1H, CH2, J = 11.0, 14.1 Hz), 3.69 d.d (1H, CH2, J =
4.4, 14.1 Hz), 3.74 s (3H, OCH3), 5.92 d.d (1H, CH,
added with stirring to a solution of 0.57 g (14 mmol)
of NaOH in 20 ml of water. When the mixture
became homogeneous, it was stirred for 3 h at room
temperature, 20 ml of water and charcoal were added,
and the mixture was stirred for 0.5 h and filtered from
charcoal. The filtrate was acidified with hydrochloric
acid, evaporated by half under reduced pressure, and
cooled, and the precipitate was filtered off. Yield
0.51 g (55%). Colorless crystalline substance, mp
1
131 132 C; published data [14]: mp 127 C. H NMR
J = 4.8, 11.0 Hz), 7.05 7.27 m (5H, Ph). 13C NMR
spectrum (DMSO-d6), C, ppm: 7.8 (5-CH3); 36.3
(CH2); 53.1 (OCH3); 60.1 (CH); 127.0, 128.4, 128.8,
135.4 (Ph); 152.8 (C5); 167.6 (COOMe). Found, %:
C 58.99; H 5.98; N 22.81. C12H14N4O2. Calculated,
%: C 58.53; H 5.73; N 22.75.
spectrum (CDCl3), , ppm: 0.93 d.d [6H, CH(CH3)2,
J = 4.4, 6.5 Hz], 1.31 1.46 m [1H, CH(CH3)2], 2.12
2.27 m (1H, CH2), 2.33 2.49 m (1H, CH2), 2.59 s
(3H, 5-CH3), 5.20 d.d (1H, 1-CH, J = 4.4, 10.9 Hz),
12.92 br.s (COOH). 13C NMR spectrum (CDCl3), ,
ppm: 9.2 (5-CH3), 21.0 and 22.8 [CH(CH3)2], 24.8
[CH(CH3)2], 38.7 (CH2), 59.1 (1-CH), 152.8 (C5),
170.2 (COOH). Found, %: C 48.91; H 6.80; N 28.20.
C8H14N4O2. Calculated, %: C 48.47; H 7.12; N 28.26.
(RS)-2-(5-Methyl-1-tetrazolyl)-3-phenylpropion-
amide (Va). To a solution of 2 g (8.1 mmol) of ester
IIIa in 10 ml of EtOH we added 15 ml of 25%
aqueous ammonia. The mixture was heated for 2 h
at the boiling point, the solvent was removed under
reduced pressure, and the residue was recrystallized
from a minimal amount of ethanol (3 5 ml). Yield
0.9 g (48%). Colorless crystalline substance. mp 130
132 C. 1H NMR spectrum (DMSO-d6), , ppm: 2.21 s
(3H, 5-CH3), 3.34 d.d (1H, CH2, J = 10.6, 14.1 Hz),
3.61 d.d (1H, CH2, J = 4.8, 14.1 Hz), 5.47 d.d (1H,
CH, J = 4.8, 10.6 Hz), 7.07 7.25 m (5H, Ph),
7.57 br.s and 7.78 br.s (2H, CONH2). 13C NMR spec-
trum (DMSO-d6), , ppm: 8.4 (5-CH3); 36.6 (CH2);
61.4 (CH); 126.9, 128.4, 128.9, 136.3 (Ph); 152.7
(C5); 167.9 (CONH2). Found, %: C 56.84; H 5.77;
N 30.41. C11H13N5O. Calculated, %: C 57.13; H 5.67;
N 30.28.
Methyl (RS)-4-methyl-2-(5-methyl-1-tetrazolyl)-
pentanoate (IIIb) was synthesized in a similar way.
Reaction time 10 h. Yield 90%. Light yellow oily
substance. 1H NMR spectrum (CDCl3), , ppm:
0.89 d.d [6H, CH(CH3)2, J = 2.2, 6.6 Hz], 1.24
1.43 m [1H, CH(CH3)2], 2.03 2.19 m (1H, CH2),
2.26 2.42 m (1H, CH2), 2.53 s (3H, 5-CH3), 3.72 s
(3H, OCH3), 5.14 d.d (1H, 1-CH, J = 4.9, 11.0 Hz).
13C NMR spectrum (CDCl3), C, ppm: 9.4 (5-CH3),
21.0 and 22.7 [CH(CH3)2], 24.6 [CH(CH3)2], 38.9
(CH2), 53.4 (OCH3), 58.6 (1-CH), 152.3 (C5), 168.3
(COOMe). Found, %: C 50.71; H 7.96; N 26.84.
C9H16N4O2. Calculated, %: C 50.93; H 7.60; N 26.40.
(RS)-2-(5-Methyl-1-tetrazolyl)-3-phenylpropionic
acid (IVa). Ester IIIa, 0.45 g (1.8 mmol), was added
in small portions with stirring to a solution of 0.22 g
(5.5 mmol) of NaOH in 10 ml of water. When the
mixture became homogeneous, it was stirred for 3 h at
room temperature, 10 ml of water and charcoal were
added, and the mixture was stirred for 0.5 h. It was
filtered from charcoal, the filtrate was acidified with
hydrochloric acid and cooled, and the precipitate was
filtered off. Yield 0.32 g (75%). Colorless crystalline
substance, mp 182 C; published data [14]: mp 178 C.
1H NMR spectrum (DMSO-d6), , ppm: 2.18 s
(3H, 5-CH3), 3.38 d.d (1H, CH2, J = 11.9, 14.1 Hz),
3.64 d.d (1H, CH2, J = 4.4, 14.1 Hz), 5.81 d.d (1H,
CH, J = 4.6, 11.3 Hz), 7.04 7.21 m (5H, Ph),
13.84 br.s (1H, COOH). 13C NMR spectrum
(DMSO-d6), , ppm: 7.9 (5-CH3); 36.2 (CH2); 60.3
(CH); 126.9, 128.4, 128.8, 135.9 (Ph); 152.8 (C5);
168.7 (COOH). Found, %: C 56.28; H 4.85; N 24.42.
C11H12N4O2. Calculated, %: C 56.89; H 5.21;
N 24.12.
(RS)-4-Methyl-2-(5-methyl-1-tetrazolyl)pentan-
amide (Vb) was synthesized in a similar way from
1
ester IIIb. Yield 43%. mp 113 C. H NMR spectrum
(CDCl3), , ppm: 0.92 d [6H, CH(CH3)2, J = 6.5 Hz],
1.25 1.44 m [1H, CH(CH3)2], 2.04 2.19 m (1H,
CH2), 2.26 2.41 m (1H, CH2), 2.60 s (3H, 5-CH3),
4.98 d.d (1H, 1-CH, J = 5.1, 10.9 Hz), 5.87 br.s and
6.26 br.s (2H, CONH2). 13C NMR spectrum (CDCl3),
, ppm: 9.3 (5-CH3), 21.4 and 22.7 [CH(CH3)2], 24.8
[CH(CH3)2], 40.9 (CH2), 60.9 (1-CH), 152.7 (C5),
169.5 (COOH). Found, %: C 48.25; H 7.20; N 35.01.
C8H15N5O. Calculated, %: C 48.72; H 7.67; N 35.51.
(RS)-1-(5-Methyl-1-tetrazolyl)-1-(5-tetrazolyl)-2-
phenylethane (VIa). The azidation of amide Va
(1.03 g, 4.5 mmol) was carried out as described above
(RS)-4-Methyl-2-(5-methyl-1-tetrazolyl)penta-
noic acid (IVb). Ester IIIb, 1 g (4.7 mmol), was
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 9 2002

TETRACHLOROSILANE SODIUM AZIDE SYSTEM
in the synthesis of ester IIIa (reaction time 12 h). REFERENCES
1373
The mixture was then poured in small portions under
stirring to a solution of Na2CO3, maintaining the pH
above 7. The precipitate of silicic acid was filtered
off, a solution of sodium nitrite was added to the fil-
trate, and the mixture was slowly acidified to pH 2 by
adding hydrochloric acid. The solution was cooled,
and the crystals were filtered off. Yield 0.96 g (84%).
Colorless crystalline substance. An analytical sample
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1
mp 191 193 C. H NMR spectrum (DMSO-d6),
,
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off, a solution of sodium nitrite was added to the
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1
oily substance which crystallizes on storage. H NMR
spectrum (CDCl3), , ppm: 0.96 t [6H, CH(CH3)2,
J = 6.5 Hz], 1.33 1.50 m [1H, CH(CH3)2], 2.37
2.63 m (2H, CH2), 2.66 s (3H, 5-CH3), 6.12 d.d (1H,
1-CH, J = 6.5, 9.5 Hz), 13.66 br.s (1H, NH). 13C
NMR spectrum (CDCl3), , ppm: 9.3 (5-CH3), 21.6
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 9 2002