1-alkyl-5-((di)alkylamino) tetrazoles: Building blocks for peptide surrogates

Article abstract of DOI:10.1021/jo2022235

An approach to the synthesis of 1-alkyl-5-((di)alkylamino)tetrazoles by nucleophilic substitution in 1-alkyl-5-sulfonyltetrazoles with anions generated from the primary or secondary amines was developed. Tolerance of the method to the presence of some fun

Full text of DOI:10.1021/jo2022235

Note
pubs.acs.org/joc
1-Alkyl-5-((di)alkylamino) Tetrazoles: Building Blocks for Peptide
Surrogates
Andriy V. Tymtsunik,†,‡ Vitaliy A. Bilenko,‡ Serhiy O. Kokhan,†,‡ Oleksandr O. Grygorenko,*,†,‡
Dmitriy M. Volochnyuk,‡ and Igor V. Komarov†,‡
†Kyiv National Taras Shevchenko University, Volodymyrska Street 64, Kyiv 01601, Ukraine
‡Enamine Ltd., Alexandra Matrosova Street 23, Kyiv 01103, Ukraine
S
* Supporting Information
ABSTRACT: An approach to the synthesis of 1-alkyl-5-((di)-
alkylamino)tetrazoles by nucleophilic substitution in 1-alkyl-5-sulfonyl-
tetrazoles with anions generated from the primary or secondary amines
was developed. Tolerance of the method to the presence of some
functional groups (i.e., protected amine) in both components of the
reaction was demonstrated. Obtained tetrazoles are promising building blocks for the design of peptide surrogates, in particular,
for replacement approaches of alkyl urea derivatives.
ol 2 and Landiolol 3), and HIV-1 protease inhibitors (Ritonavir
4) (Figure 2). This suggestion is supported by the fact that
etrazole derivatives have attracted close attention in
1
Tbioorganic and medicinal chemistry in recent years. The
tetrazole moiety is a well-known nonclassical bioisostere for the
carboxylate,2 whereas 1,5-disubstituted tetrazoles are consid-
ered as a replacement for the cis-peptide bonds (Figure 1).3
Figure 2. Marketed drugs having an alkyl urea fragment.
Figure 1. Tetrazoles as potential surrogates of functional groups.
some other aminoheterocycles were already considered as urea
surrogates.8
Tetrazole derivatives were used in the discovery of cepha-
losporin antibiotics (e.g., Cefoperazone). Recently, the 1,5-
disubstituted tetrazole moiety was incorporated into the
molecule of Smac peptidomimetic, a potential anticancer
agent.4
Most of the known methods for the preparation of 1-alkyl-5-
((di)alkylamino)tetrazoles rely on the cyclization or cyclo-
addition of the properly substituted precursor.9 Functionaliza-
tion of the synthetic intermediates that already contain the
tetrazole fragment is an alternative and powerful approach that
has been scarcely exploited to date. Alkylation of 5-((di)-
alkylamino)tetrazoles at the N-1 atom is one of the methods to
achieve this; however, this reaction often leads to the mixtures
of products.10 Another approach includes functionalization of
1-alkyl tetrazoles bearing a leaving group (e.g., halo or sulfonyl)
at the C-5 atom. Unlike their more reactive 1-aryl counter-
parts,11 these tetrazoles have been only scarcely used in
nucleophilic substitution reactions to date. The known isolated
1-Alkyl-5-((di)alkylamino)tetrazoles 1 represent a promising
chemotype for the design of the peptide surrogates and other
molecules of potential interest to bioorganic and medicinal
chemistry. Favorable physicochemical properties of these
tetrazole derivatives, their remarkable metabolic stability, and
multiple possibilities for the interaction with the biological
targets provide unique means for that. In particular, the 1-alkyl-
5-(alkylamino)tetrazole moiety might be considered as a
potential replacement of an alkyl urea derivatives, which
themselves are peptide isosteres used in the discovery of human
soluble epoxide inhibitors hydrolase,5 calcitonin mimetics,6
cathepsin inhibitors,7 β1 adrenergic receptor ligands (Xamoter-
Received: October 29, 2011
Published: December 15, 2011
© 2011 American Chemical Society
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Table 1. Amination of Tetrazoles 5a−d
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Table 1. continued
examples of using amines as nucleophiles in the reaction with 1-
alkyl tetrazoles bearing a leaving group differ significantly in the
reaction conditions and hence lack generality.12 In particular,
reaction of 1-benzyl-5-bromotetrazole with benzylamine gave
the substitution product in good yield.13 Nucleophilic
substitution in 1-methyl-5-(methylsulfonyl)tetrazole (5a)
using azole anions as the N-nucleophiles has been described.14
Amination of 5a with a primary amine was also reported;
however, the corresponding product was obtained in 22%
yield.15 An interesting transformation of the properly
functionalized 1-alkyl-5-(alkylsulfonyl)tetrazoles to 1 through
intramolecular nucleophilic substitution can also be men-
tioned.15
tosyl cyanide.17 Apart from the simplest representatives 5a and
5b, a fluorine-containing tetrazole 5c and a proline-derived
tetrazole 5d were included in this study (Table 1), keeping in
mind the potential use of the final products as the building
blocks for the peptide surrogates. Compounds 5a−d were
prepared using the general methods mentioned above
(Schemes 1−3).
Scheme 1
In this work, we wish to report a convenient approach to the
synthesis of 1-alkyl-5-((di)alkylamino)tetrazoles by nucleo-
philic substitution in 1-alkyl-5-sulfonyltetrazoles. We have
turned our attention to these compounds as they are readily
available in a few steps from common starting materials, either
through sulfur alkylation−oxidation of 1-alkyltetrazole-5-
thiols15,16 or by [3 + 2] cycloaddition of alkyl azides and
As it turned out soon, tetrazoles 5 are not sufficiently reactive
toward amine nucleophiles at reasonable reaction conditions. In
particular, no product 1ab was detected by LC−MS and NMR
in the reaction of the compound 5b and cyclopropylamine 6a
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Note
nevertheless, they did not contain any trace signals of the
corresponding diastereomers.
Scheme 2
In conclusion, a simple and effective procedure was
developed for the amination of 5-sulfonyltetrazoles. The 1-
alkyl-5-((di)alkylamino)tetrazoles obtained by this reaction are
promising building blocks for the design of peptidomimetics
and other molecules of potential interest to drug discovery and,
in particular, as a potential replacement for the alkyl urea
derivatives.
Scheme 3
EXPERIMENTAL SECTION
■
General Methods. Solvents were purified according to the
standard procedures. 1-Methyl-1H-tetrazole-5-thiol,19 1-isopropyl-
1H-tetrazole-5-thiol,20 1-(bromomethyl)-4-(trifluoromethoxy)-
benzene,21 and tert-butyl (2S)-2-{[(methylsulfonyl)oxy]methyl}-
pyrrolidine-1-carboxylate22 were prepared using the procedures
reported in the literature. All other starting materials were purchased
from the commercial sources. Melting points were measured on an
automated melting point system. Column chromatography was
performed using silica gel (230−400 mesh) as the stationary phase.
1H and 13C NMR spectra were recorded on a 500 MHz NMR
spectrometer (at 499.9 MHz for protons, 124.9 MHz for carbon-13
and 470.3 for fluorine-19) and 400 MHz NMR spectrometer (at 400.4
MHz for protons, 100.7 MHz for carbon-13). Chemical shifts are
reported in ppm downfield from TMS (1H, 13C) or CFCl3 (19F) as an
internal standard. HPLC−MS analyses were done on a LC−MS
instrument (chemical ionization (CI) and electrospray ionization
(ESI)) or a GC−MS instrument (electron impact ionization (EI)).
Flash chromatography was performed on an automated flash
chromatography system.
even upon heating of the starting materials without solvent in a
sealed tube at 100 °C for 48 h. We have found that
deprotonation of 6a by action of the methyl magnesium
chloride in THF solves the reactivity problem: the correspond-
ing anion and 5b smoothly reacted at −40 °C to rt overnight.18
To demonstrate the utility of this procedure, tetrazoles 5a−d
were tested in the reaction with 6a, as well as N-Boc-piperazine
6b containing an additional protected amino function (Table
1). It was found that tetrazoles 5a−d showed similar reactivity
toward anions generated from 6a and 6b; the corresponding
products 1aa−1bd were obtained in 73−92% yields.
In addition to 6a and 6b, amines 6c−6h containing aromatic
substituents, a hidden aldehyde moiety, or a basic tertiary amine
center were also tested in the reaction with tetrazoles 5b and
5d. It was found that the anions formed from the amines 6a−
6c, 6e, and 6f smoothly reacted with the tetrazoles 5 to give the
corresponding products 1cb−1fd in good yields (58−92%).
Under the same reaction conditions, yields of the tetrazoles 1eb
and 1ed were diminished due to incomplete conversion.
Nevertheless, 1eb and 1ed were obtained in 58−62% yields
after a prolonged reaction time. We attribute this fact to lower
nucleophilicity of the anion formed from 6e, which is related to
its relatively tight chelation with the magnesium ion. Moreover,
the anion generated from the amine 6d also showed low
reactivity in these transformations. In particular, less than 10%
yield of the corresponding tetrazole was detected in the crude
product only when 10-fold excess of the reagent was used in the
reaction with 5b. It should be noted that the products
presumably arising from the deprotonation of 5b at the
methylsulfonyl moiety were detected by LC−MS and NMR in
this case. The reaction with 5d was also slower, although the
corresponding product 1bd still was obtained in 80% yield. As
in the case of 6e, we attribute lowered reactivity of the anion of
6d to its chelation with the magnesium ion. These results allow
the assumption that the tosyl-substituted tetrazoles are a better
choice as the substrates for the preparation of 1 if reactivity
problems are expected.
1-Methyl-5-(methylsulfonyl)-1H-tetrazole 5a. To a solution of
1-methyl-1H-tetrazole-5-thiol (11.6 g, 0.1 mol) in THF (300 mL) was
added tBuOK (33.7 g, 0.3 mol) at rt. The resulting mixture was stirred
for 10 min, and MeI (18.4 g, 0.130 mol) was added dropwise. The
mixture was stirred for 36 h, evaporated to dryness, diluted with 10%
aq citric acid (300 mL) and extracted with CH2Cl2 (3 × 150 mL). The
combined organic extracts were dried over Na2SO4 and evaporated to
dryness under reduced pressure. The residue was dissolved in CH2Cl2
(500 mL), and MCPBA (51.8 g, 0.3 mol) was added. The reaction
mixture was refluxed for 10 h, then cooled to rt and washed with 1 M
aq K2CO3 (150 mL). The organic phase was separated, dried over
Na2SO4, and evaporated to dryness under reduced pressure to give the
crude compound 5a, which was purified by column chromatography.
Yield 52%. Rf = 0.82 (hexanes−EtOAc (2:1)). White crystals. Mp 70−
72 °C (lit. 72−73 °C).23 MS (m/z, EI): 162 (M+), 119, 79
+
(CH3SO2 ). Anal. Calcd for C3H6N4O2S: C 22.22, H 3.73, N 34.55, S
19.77. Found: C 22.54, H 4.01, N 34.51, S 19.80. 1H NMR (CDCl3) δ
4.35 (s, 3H), 3.28 (s, 3H). 13C NMR (CDCl3) δ 154.1 (C), 43.7
(CH3), 36.1 (CH3).
1-Isopropyl-5-(methylsulfonyl)-1H-tetrazole 5b. Prepared
from 1-isopropyl-1H-tetrazole-5-thiol analogously to 5a. Yield 11 g
(59%). Rf = 0.55 (hexanes−EtOAc (2:1)). White crystals. Mp 69−70
+
°C. MS (m/z, EI): 190 (M+), 147, 121, 79 (CH3SO2 ). Anal. Calcd for
C5H10N4O2S: C 31.57, H 5.30, N 29.45, S 16.86. Found: C 31.79, H
1
5.16, N 29.48, S 17.10. H NMR (CDCl3) δ 5.28 (sept, J = 6.6 Hz,
1H), 3.60 (s, 3H), 1.68 (d, J = 6.6 Hz, 6H). 13C NMR (CDCl3) 153.4
(C), 54.5 (CH), 43.8 (CH3), 22.6 (CH3).
5-[(4-Methylphenyl)sulfonyl]-1-[4-(trifluoromethoxy)-
benzyl]-1H-tetrazole 5c. 1-(Bromomethyl)-4-(trifluoromethoxy)-
benzene (0.10 mol) was dissolved in DMF (250 mL). NaN3 (19.5
g, 0.30 mol) and Bu4N+ I− (3.7 g, 0.01 mol) were added subsequently,
and the resulting mixture was stirred at 80 °C for at 24 h, then cooled,
evaporated under reduced pressure, diluted with water (250 mL), and
extracted with EtOAc (3 × 100 mL). The combined organic extracts
were dried over Na2SO4 and evaporated to dryness under reduced
pressure to give the corresponding azide (16 g) pure enough for the
further use. A mixture of this compound and toluenesulfonyl cyanide
(0.074 mol) was heated in a sealed tube at 80 °C for 48 h. The crude
The sterically hindered anion generated from the amine 6h
was unreactive toward nucleophilic substitution in the tetrazole
5b; in this case, no traces of the corresponding product were
detected in the crude product.
To prove that in the case of the optically active tetrazole 5d
the final products were obtained as single stereoisomers,
1
reaction with both enantiomers 6f and 6g was performed. H
NMR spectra of 1fd and 1gd were remarkably similar;
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Note
mixture was subjected to column chromatography to give 5c. Yield
12.9 g (39%). Yellowish crystals. Rf = 0.70 (hexanes−EtOAc (2:1)).
Mp 76−77 °C. MS (m/z, EI): 370 (M+ − N2), 217, 175
1.48 (s, 9H), 0.79−0.85 (m, 2H), 0.62−0.64 (m, 2H). 13C NMR
(CDCl3) δ 156.5 (C), 155.7 (C), 80.9 (C), 56.6 (CH), 48.2 (CH2),
47.0 (CH2), 29.5 (CH2), 28.5 (CH3), 25.6 (CH), 23.5 (CH2), 7.3
(CH2), 7.1 (CH2).
+
+
(CF3OC6H4CH2 ), 155, 91 (C7H7 ). MS (m/z, ESI): 399 (MH+).
Anal. Calcd for C16H13F3N4O3S: C 48.24, H 3.29, N 14.06, S 8.05.
Found: C 47.94, H 3.63, N 13.74, S 8.41. 1H NMR (CDCl3) δ 7.79 (d,
J = 8.2 Hz, 2H), 7.43 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H),
7.22 (d, J = 8.2 Hz, 2H), 5.93 (s, 2H), 2.45 (s, 3H). 13C NMR
(CDCl3) δ 155.0 (C), 150.1 (C), 149.8 (C), 134.4 (C), 131.5 (C),
130.49 (CH), 130.46 (CH), 129.3 (CH), 121.6 (CH), 120.4 (q, J =
257 Hz, CF3), 52.1 (CH2), 22.0 (CH3). 19F NMR (CDCl3) δ −58.4.
tert-Butyl (2S)-2-({5-[(4-Methylphenyl)sulfonyl]-1H-tetrazol-
1-yl}methyl)pyrrolidine-1-carboxylate 5d. Prepared from tert-
butyl (2S)-2-{[(methylsulfonyl)oxy]methyl}pyrrolidine-1-carboxylate
analogously to 5c. Yield 13.3 g (43%). Yellowish crystals. Rf = 0.43
(hexanes−EtOAc (2:1)). Mp 201−202 °C (dec). Anal. Calcd for
C18H25N5O4S: C 53.06, H 6.18, N 17.19, S 7.87. Found: C 53.37, H
tert-Butyl 4-(1-Methyl-1H-tetrazol-5-yl)piperazine-1-carbox-
ylate, 1ba. Yield 1.21 g (73%). White crystals. Rf = 0.64 (EtOAc). Mp
89−90 °C. MS (m/z, EI): 268 (M+), 212, 195, 168, 112, 69, 57
+
(C(CH3)3 ). Anal. Calcd for C11H20N6O2: C 49.24, H 7.51, N 31.32.
1
Found: C 49.51, H 7.83, N 31.07. H NMR (CDCl3) δ 3.88 (s, 3H),
3.58 (t, J = 4.9 Hz, 4H), 3.25 (t, J = 4.9 Hz, 4H), 1.46 (s, 9H). 13C
NMR (CDCl3) 159.0 (C), 154.7 (C), 80.6 (C), 49.6 (CH2), 43.1
(CH2), 33.8 (CH3), 28.49 (CH3).
tert-Butyl 4-(1-Isopropyl-1H-tetrazol-5-yl)piperazine-1-car-
boxylate, 1bb. Yield 1.22 g (78%). White crystals. Rf = 0.82
(EtOAc). Mp 160−162 °C. MS (m/z, EI): 296 (M+), 223, 140, 57
((CH3)3C+). Anal. Calcd for C13H24N6O2: C 52.68, H 8.16, N 28.36.
Found: C 52.95, H 7.05, N 28.03. 1H NMR (CDCl3) δ 4.47 (sept, J =
6.7 Hz, 1H), 3.60 (t, J = 4.8 Hz, 4H), 3.19 (t, J = 4.8 Hz, 4H), 1.59 (d,
J = 6.7 Hz, 6H), 1.48 (s, 9H). 13C NMR (CDCl3) 158.4 (C), 154.7
(C), 80.6 (C), 50.7 (CH2), 50.2 (CH), 43.2 (CH2), 28.5 (CH3), 22.6
(CH3).
tert-Butyl 4-{1-[4-(Trifluoromethoxy)benzyl]-1H-tetrazol-5-
yl}piperazine-1-carboxylate, 1bc. Yield 0.82 g (77%). White
crystals. Rf = 0.75 (hexanes−EtOAc (5:1)). Mp 133−134 °C. MS (m/
z, ESI): 429 (MH+), 373 (MH+−(CH3)2C=CH2). Anal. Calcd for
C18H23F3N6O3: C 50.46, H 5.41, N 19.62. Found: C 50.29, H 5.37, N
19.66. 1H NMR (CDCl3) δ 7.24−7.29 (m, 4H), 5.42 (s, 2H), 3.50 (t, J
= 4.7 Hz, 4H), 3.19 (t, J = 4.7 Hz, 4H), 1.47 (s, 9H). 13C NMR
(CDCl3) δ 158.7 (C), 154.5 (C), 149.5 (C), 132.2 (C), 128.8 (CH),
121.6 (CH), 120.4 (q, J = 258 Hz, CF3), 80.5 (C), 50.01 (CH2), 49.97
(CH2), 42.8 (CH2), 28.4 (CH3). 19F NMR (CDCl3) δ −58.4.
tert-Butyl 4-(1-{[(2S)-1-(tert-Butoxycarbonyl)pyrrolidin-2-yl]-
methyl}-1H-tetrazol-5-yl)piperazine-1-carboxylate, 1bd. Yield
0.85 g (80%). Yellowish crystals. Rf = 0.78 (EtOAc). Mp 107−109 °C.
[α]D = −8.8 (c 0.5, MeOH). MS (m/z, ESI): 460 (MNa+), 438
(MH+). Anal. Calcd for C20H35N7O4: C 54.90, H 8.06, N 22.41.
Found: C 55.17, H 7.93, N 22.40. 1H NMR (CDCl3) δ 4.47 (br d, J =
11.7 Hz, 0.8H), 4.33 (br s, 0.4H), 4.08−4.18 (m, 1.8H), 3.60 (s, 4H),
3.22−3.47 (m, 6H), 1.73−2.04 (m, 4H), 1.48 (s, 9H), 1.45 (s, 9H).
13C NMR (CDCl3) 159.1 (C), 154.9 (C), 154.7 (C), 80.3 (C), 80.2
1
5.90, N 16.89, S 8.06. H NMR (CDCl3) δ 8.00 (d, J = 8.3 Hz, 2H),
7.42 (br s, 2H), 4.84 (br s, 1.5H), 4.7 (br s, 0.5H), 4.49 (br m, 1H),
3.32−3.52 (m, 2H), 2.48 (s, 3H), 1.79−2.03 (m, 4H), 1.39 (s, 4.5H),
1.32 (s, 4.5H). 13C NMR (CDCl3) δ 155.5 (C), 154.8 and 154.4 (C),
147.5 (C), 134.7 (C), 130.4 (CH), 129.5 (CH), 80.7 and 80.2 (C),
57.0 and 56.2 (CH), 52.0 (CH2), 46.8 and 46.6 (CH2), 29.1 and 28.2
(CH2), 28.4 (CH3), 22.7 and 22.8 (CH2), 22.0 (CH3).
General Procedure for the Preparation of 1. A solution of the
amine 6 (10 mmol) in dry THF (100 mL) was cooled to −10 °C, and
MeMgCl (3 M in THF, 4 mL) was added dropwise under argon
atmosphere. The obtained mixture was stirred at −10 °C for 1 h, and
then cooled to −40 °C. The solution of the compound 5 (5 mmol) in
THF (50 mL) was added dropwise at this temperature. The resulting
mixture was stirred at −40 °C for 2 h, then slowly warmed to rt, and
left for 18−72 h. Silica gel (15 g) was added, and the mixture was
stirred at rt for 2 h. SiO2 was filtered off and washed with MeOH (3 ×
30 mL). The combined filtrates were evaporated to give the crude
compound 1, which was purified by column, preparative thin-layer, or
flash chromatography.
N-Cyclopropyl-1-methyl-1H-tetrazol-5-amine, 1aa. Yield 0.65
g (76%). White crystals. Rf = 0.57 (EtOAc). Mp 138−140 °C. MS (m/
z, ESI): 140 (M+). Anal. Calcd for C5H9N5: C 43.16, H 6.52, N 50.33.
1
Found: C 43.47, H 6.46, N 50.03. H NMR (CDCl3) δ 4.76 (br s,
(C), 55.8 (CH), 49.8 (CH2), 48.6 (CH2), 47.0 (CH2), 43.2 (CH2),
28.57 (CH3), 28.51 (CH3), 28.3 (CH2), 23.5 (CH2).
N-Benzyl-1-isopropyl-1H-tetrazol-5-amine, 1cb. Yield 0.94 g
1H), 3.78 (s, 3H), 2.81−2.86 (m, 1H), 0.86 (dd, J = 11.9 and 6.5 Hz,
2H), 0.65−0.68 (m, 2H). 13C NMR (CDCl3) δ 156.2 (C), 32.1
(CH3), 26.0 (CH), 7.8 (CH2).
(82%). White crystals. Rf = 0.77 (EtOAc). Mp 138−140 °C. MS (m/z,
N-Cyclopropyl-1-isopropyl-1H-tetrazol-5-amine, 1ab. Yield
+
CI): 218 (MH+), 176, 91 (C7H7 ). Anal. Calcd for C11H15N5: C 60.81,
0.75 g (85%). White crystals. Rf = 0.53 (EtOAc). Mp 82−83 °C.
H 6.96, N 32.23. Found: C 60.99, H 7.15, N 32.36. 1H NMR (CDCl3)
δ 7.31−7.39 (m, 5H), 4.65 (d, J = 5.4 Hz, 2H), 4.25 (br s, 1H), 4.25
(sept, J = 6.6 Hz, 1H), 1.54 (d, J = 6.6 Hz, 6H). 13C NMR (CDCl3)
154.5 (C), 137.9 (C), 129.0 (CH), 128.2 (CH), 128.2 (CH), 49.1
(CH), 48.9 (CH2), 21.8 (CH3).
+
MS (m/z, EI): 167 (M+), 138, 124 (c-C3H5NHCN4 ), 69, 43
((CH3)2CH+). Anal. Calcd for C7H13N5: C 50.28, H 7.84, N 41.88.
1
Found: C 50.05, H 8.11, N 42.17. H NMR (CDCl3) δ 4.93 (br s,
1H), 3.22 (sept, J = 6.6 Hz, 1H), 2.81−2.85 (m, 1H), 1.52 (d, J = 6.6
Hz, 6H), 0.82 (dd, J = 13.1 and 5.5 Hz, 2H), 0.62−0.65 (m, 2H). 13C
NMR (CDCl3) δ 155.1 (C), 49.0 (CH), 26.0 (CH), 21.8 (CH3), 7.6
(CH2).
tert-Butyl (2S)-2-{[5-(Benzylamino)-1H-tetrazol-1-yl]methyl}-
pyrrolidine-1-carboxylate, 1cd. Yield 0.74 g (85%). White crystals.
Rf = 0.82 (EtOAc). Mp 166−168 °C. [α]D = −8.4 (c 0.5, MeOH). MS
(m/z, ESI): 359 (MH+). Anal. Calcd for C18H26N6O2: C 60.32, H
7.31, N 23.45. Found: C 60.12, H 7.70, N 23.58. 1H NMR (CDCl3) δ
7.42 (d, J = 6.0 Hz, 2H), 7.33 (t, J = 7.2 Hz, 2H), 7.27 (t, J = 7.2 Hz,
1H), 6.64 (br s, 1H), 4.61−4.70 (m, 2H), 4.26−4.32 (m, 1H), 4.12 (d,
J = 14.7 Hz, 1H), 3.80 (br s, 1H), 3.32 (br s, 1H), 3.23 (br s, 1H),
2.03−2.10 (m, 1H), 1.93−2.01 (m, 1H), 1.79−1.91 (m, 2H), 1.40 (s,
9H). 13C NMR (CDCl3) 156.1 (C), 155.5 (C), 138.1 (C), 128.7
(CH), 128.0 (CH), 127.6 (CH), 80.9 (C), 56.8 (CH), 48.3 (CH2),
46.9 (CH2), 29.6 (CH2), 28.4 (CH3), 23.7 (CH2).
N-Cyclopropyl-1-[4-(trifluoromethoxy)benzyl]-1H-tetrazol-
5-amine, 1ac. Yield 0.61 g (82%). White crystals. Rf = 0.54 (EtOAc).
Mp 130−131 °C. MS (m/z, EI): 299 (M+), 270, 175
+
+
(CF3OC6H4CH2 ), 124 (c-C3H5NHCN4 ), 69. Anal. Calcd for
C12H12F3N5O: C 48.16, H 4.04, N 23.40. Found: C 48.47, H 3.87,
1
N 23.25. H NMR (CDCl3) δ 7.22 (s, 4H), 5.33 (s, 2H), 4.76 (br s,
1H), 2.72−2.76 (m, 1H), 0.78 (dd, J = 12.8 and 6.4 Hz, 2H), 0.53−
0.56 (m, 2H). 13C NMR (CDCl3) δ 156.0 (C), 149.6 (C), 132.0 (C),
129.0 (CH), 121.8 (CH), 120.5 (q, J = 258 Hz, CF3), 48.6 (CH2),
26.0 (CH3), 7.7 (CH2). 19F NMR (CDCl3) δ −58.4.
tert-Butyl (2S)-2-({5-[(2,2-Dimethoxyethyl)amino]-1H-tetra-
zol-1-yl}methyl)pyrrolidine-1-carboxylate, 1dd. Yield 0.67 g
(77%). Yellowish crystals. Rf = 0.61 (EtOAc). Mp 135−136 °C.
[α]D = −26.0 (c 0.5, MeOH). MS (m/z, ESI): 357 (MH+). Anal.
Calcd for C15H28N6O4: C 50.55, H 7.92, N 23.58. Found: C 50.29, H
7.67, N 23.40. H NMR (CDCl3) δ 6.20 (br s, 1H), 4.59 (br s, 1H),
4.19−4.26 (br s, 1H), 4.10 (d, J = 14.5 Hz, 1H), 3.80 (br s, 1H), 3.53−
3.64 (m, 2H), 3.39 (s, 6H), 3.32−3.41 (m, 1H), 3.22 (br s, 1H), 1.79−
tert-Butyl (2S)-2-{[5-(Cyclopropylamino)-1H-tetrazol-1-yl]-
methyl}pyrrolidine-1-carboxylate, 1ad. Yield 0.70 g (92%).
White crystals. Rf = 0.54 (EtOAc). Mp 158−160 °C. [α]D = −19.3
(c 0.5, MeOH). MS (m/z, ESI): 309 (MH+). Anal. Calcd for
C14H24N6O2: C 54.53, H 7.84, N 27.25. Found: C 54.28, H 7.99, N
27.45. 1H NMR (CDCl3) δ 6.46 (br s, 1H), 4.25−4.29 (m, 1H), 4.05
(d, J = 14.2 Hz, 1H), 3.78 (br s, 1H), 3.21−3.32 (m, 2H), 2.81−2.86
(m, 1H), 2.07 (br s, 1H), 1.93−2.01 (m, 1H), 1.76−1.89 (m, 2H),
1
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Note
2.04 (m, 4H), 1.46 (s, 9H). 13C NMR (CDCl3) 156.1 (C), 155.5 (C),
102.1 (CH), 80.8 (C), 56.6 (CH), 54.1 (CH3), 53.8 (CH3), 48.3
(CH2), 46.9 (CH2), 45.6 (CH2), 29.4 (CH2), 28.5 (CH3), 23.6 (CH2).
1-(1-Isopropyl-1H-tetrazol-5-yl)-4-methylpiperazine, 1eb.
Yield 0.68 g (62%). Yellowish crystals. Rf = 0.46 (MeOH). Mp
149−151 °C (dec). MS (m/z, EI): 210 (M+), 140, 98, 83, 71, 56, 43.
Anal. Calcd for C91H18N6: C 51.41, H 8.63, N 39.97. Found: C 51.50,
H 8.86, N 40.09. H NMR (CDCl3) δ 4.45 (sept, J = 6.6 Hz, 1H),
3.30−3.34 (m, 4H), 2.64−2.68 (m, 4H), 2.40 (s, 3H), 1.57 (d, J = 6.6
Hz, 6H). 13C NMR (CDCl3) 158.3 (C), 54.1 (CH2), 50.4 (CH2), 50.2
(CH), 46.0 (CH3), 22.6 (CH3).
tert-Butyl (2S)-2-{[5-(4-Methylpiperazin-1-yl)-1H-tetrazol-1-
yl]methyl}pyrrolidine-1-carboxylate, 1ed. Yield 0.50 g (58%).
White crystals. Rf = 0.42 (MeOH). Mp 235−237 °C. [α]D = +12.0 (c
0.42, MeOH). Anal. Calcd for C16H29N7O2: C 54.68, H 8.32, N 27.90.
Found: C 54.86, H 8.24, N 28.13. 1H NMR (CDCl3) δ 4.04−4.44 (br
m, 3H), 3.25−3.54 (br m, 6H), 2.60 (br s, 4H), 2.34 (s, 3H), 1.72−
1.98 (br m, 4H), 1.42 (s, 9H). 13C NMR (CDCl3) 158.8 (C), 154.8
(C), 80.0 and 80.6 (C), 56.1 and 55.6 (CH), 54.2 (CH2), 49.9 and
49.3 (CH2), 48.6 (CH2), 47.0 and 46.6 (CH2), 46.0 (CH3), 29.7 and
29.0 (CH2), 28.5 (CH3), 23.4 and 22.7 (CH2).
REFERENCES
■
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tert-Butyl (2S)-2-[(5-{[(1R)-1-Phenylethyl]amino}-1H-tetrazol-
1-yl)methyl]pyrrolidine-1-carboxylate, 1fd. Yield 0.76 g (83%).
White crystals. Rf = 0.82 (EtOAc). Mp 187−188 °C. [α]D = +32.5 (c
0.26, MeOH). MS (m/z, ESI): 373 (M+). Anal. Calcd for
C19H28N6O2: C 61.27, H 7.58, N 22.56. Found: C 61.14, H 7.90, N
́
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1
22.51. H NMR (CDCl3) δ 7.46 (d, J = 7.5 Hz, 2H), 7.31 (t, J = 7.5
Hz, 2H), 7.23 (t, J = 7.5 Hz, 1H), 6.99 (br s, 1H), 5.02 (quint, J = 7.2
Hz, 1H), 4.22 (dd, J = 14.3 and 8.4 Hz, 1H), 4.11 (d, J = 14.3 Hz, 1H),
3.70 (br s, 1H), 3.40 (br s, 1H), 3.22 (br s, 1H), 1.96−2.02 (m, 1H),
1.90 (br s, 3H), 1.62 (d, J = 7.5 Hz, 3H), 1.49 (s, 9H). 13C NMR
(CDCl3) 155.6 (C), 155.3 (C), 144.0 (C), 128.7 (CH), 127.4 (CH),
126.4 (CH), 81.0 (C), 57.0 (CH), 54.3 (CH), 48.8 (CH2), 46.8
(CH2), 29.8 (CH2), 28.6 (CH3), 23.8 (CH2), 23.6 (CH3).
(5) Hwang, S. H.; Tsai, H.-J.; Liu, J.-Y.; Morisseau, C.; Hammock, B.
D. J. Med. Chem. 2007, 50, 3825−3840.
(6) Petrie, C.; Mckernan, P. A.; Moore, E. E.; Ostrech, J. M.; Meyer,
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(7) Frizler, M.; Lohr, F.; Furtmann, N.; Klas, J.; Gutschow, M. J. Med.
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tert-Butyl (2S)-2-[(5-{[(1S)-1-Phenylethyl]amino}-1H-tetrazol-
1-yl)methyl]pyrrolidine-1-carboxylate, 1gd. Yield 0.73 g (80%).
White crystals. Rf = 0.81 (EtOAc). Mp 173−175 °C. [α]D = −21.3 (c
0.08, MeOH). MS (m/z, ESI): 373 (M+). Anal. Calcd for
C19H28N6O2: C 61.27, H 7.58, N 22.56. Found: C 61.46, H 7.25, N
̈
̈
(8) (a) Lippa, B.; Morris, J.; Corbett, M.; Kwan, T. A.; Noe, M. C.;
Snow, S. L.; Gant, T. G.; Mangiaracina, M.; Coffey, H. A.; Foster, B.;
Knauth, E. A.; Wessel, M. D. Bioorg. Med. Chem. Lett. 2006, 16, 3444−
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2009, 19, 5716−5721. (c) Brands, M.; Grande, Y. C.; Endermann, R.;
1
22.49. H NMR (CDCl3) δ 7.46 (d, J = 7.3 Hz, 2H), 7.32 (t, J = 7.3
Hz, 2H), 7.24 (t, J = 7.3 Hz, 1H), 6.95 (br s, 1H), 5.05 (quint, J = 6.8
Hz, 1H), 4.22 (dd, J = 14.6 and 8.4 Hz, 1H), 4.07 (d, J = 14.6 Hz, 1H),
3.82 (br s, 1H), 3.40 (br s, 1H), 3.20−3.26 (m, 1H), 1.85−2.07 (m,
4H), 1.62 (d, J = 6.8 Hz, 3H), 1.49 (s, 9H). It is interesting to note
Gahlmann, R.; Kruger, J.; Raddatz, S. Bioorg. Med. Chem. Lett. 2003,
̈
1
that H NMR spectra of 1fd and 1gd differ significantly by a single
13, 2641−2645.
signal (at 3.70 and 3.82 ppm, respectively). This is clearly seen in a
spectrum of their mixture. 13C NMR (CDCl3) 155.6 (C), 155.4 (C),
144.0 (C), 128.7 (CH), 127.4 (CH), 126.3 (CH), 81.1 (C), 57.0 (C),
54.4 (CH), 48.9 (CH), 46.8 (CH2), 29.8 (CH2), 28.5 (CH3), 23.8
(CH2), 23.4 (CH3).
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ASSOCIATED CONTENT
■
(11) For selected examples, see: (a) Kharbash, R. V.; Alam, L. V.;
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S
* Supporting Information
Copies of NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: gregor@univ.kiev.ua.
ACKNOWLEDGMENTS
■
(12) Almost all known examples have been disclosed in patents:
(a) Li, L.; Wang, X.; Harran, P. G.; De Brabander, J. K.; Thomas, R.
M.; Suzuki, H. U.S. Patent 2005/197403, 2005. (b) Ohmoto, K.;
Tanaka, M.; Miyuazaki, T.; Ohno, H. U.S. Patent 5710153, 1998.
(c) Bays, D.; Hayes, R.; Blatcher, P. U.S. Patent 4585781, 1986.
The authors thank Olga V. Manoylenko for the chromato-
graphic separations, Vitaly Polovinko for NMR spectra
measurements, and Valentin Tkachenko for LC−MS measure-
ments.
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Note
(d) Bays; D. E.; Carey; L.; Hayes; R.; Mackinnon; J. W. M. U.S. Patent
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Thorarensen, A.; Trujillo, J. I.; Turner, S. R. U.S. Patent 2008/146569,
2008.
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(18) A single example of an analogous transformation was described
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́
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