Synthesis of 1-tetrazolylalkan-2-amines and -carbamates

Article abstract of DOI:10.1080/00397911.2013.868490

A novel method for the synthesis of 1-tetrazolylalkan-2-amines and -carbamates via tert-butyl aziridine-1-carboxylates is described.

Full text of DOI:10.1080/00397911.2013.868490

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Synthesis of 1-Tetrazolylalkan-2-amines
and -carbamates
Tom Sundermann a & Matthias Lehr a
a Institute of Pharmaceutical and Medicinal Chemistry , University of
Münster , Münster , Germany
Accepted author version posted online: 19 Mar 2014.Published
online: 14 May 2014.
To cite this article: Tom Sundermann & Matthias Lehr (2014) Synthesis of 1-Tetrazolylalkan-2-amines
and -carbamates, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 44:11, 1641-1648, DOI: 10.1080/00397911.2013.868490
To link to this article: http://dx.doi.org/10.1080/00397911.2013.868490
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Synthetic Communications1, 44: 1641–1648, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.868490
SYNTHESIS OF 1-TETRAZOLYLALKAN-2-AMINES AND
-CARBAMATES
Tom Sundermann and Matthias Lehr
Institute of Pharmaceutical and Medicinal Chemistry, University of Mu¨nster,
Mu¨nster, Germany
GRAPHICAL ABSTRACT
Abstract A novel method for the synthesis of 1-tetrazolylalkan-2-amines and -carbamates
via tert-butyl aziridine-1-carboxylates is described.
Keywords 1-(1H-tetrazol-1-yl)alkan-2-amine; 1-(2H-tetrazol-2-yl)alkan-2-amine;
carbamate derivative; prop-1-en-1-yl-1H-tetrazole; prop-1-en-1-yl-2H-tetrazole; tert-
butyl aziridine-1-carboxylate
INTRODUCTION
Inhibition of cytosolic phospholipase A2a (cPLA2a) is assumed to provide a
novel therapeutic option for the treatment of many inflammatory diseases, such as
rheumatoid arthritis, atopic dermatitis, and Alzheimer’s disease. Recently we have
found that certain 1-(5-carboxyindol-1-yl)- and 1-(5-carboxyindazol-1-yl)propan-2-
ylcarbamates (Fig. 1) are inhibitors of this enzyme.[1,2] In course of our structure–
activity relationship studies we wanted to replace the aryl heterocycle of these
compounds with a tetrazole residue. Surprisingly, the route established for the syn-
thesis of the indole and indazole derivatives (Scheme 1) did not lead to the desired
tetrazole target compound. Thus, a new synthetic approach had to be developed.
RESULTS AND DISCUSSION
The central synthetic sequence for the successful preparation of 1-(5-
carboxyindol-1-yl)- and 1-(5-carboxyindazol-1-yl)propan-2-ylcarbamates[1,2] is
Received October 2, 2013.
Address correspondence to Matthias Lehr, Institute of Pharmaceutical and Medicinal Chemistry,
University of Munster, Corrensstrasse 48, D-48149 Munster, Germany. E-mail: lehrm@uni-muenster.de
¨
¨
1641

1642
T. SUNDERMANN AND M. LEHR
Figure 1. 1-(5-Carboxyindol-1-yl)- and 1-(5-carboxyindazol-1-yl)propan-2-ylcarbamate inhibitors of cPLA2a.
exemplified for the indole derivative 6 in Scheme 1. First, the secondary alcohol of the
intermediate 1 was reacted with methanesulfonyl chloride. The obtained mesylate
group was converted to an azide by reaction with trimethylsilyl azide and tetrabuty-
lammonium fluoride in tetrahydrofuran (THF). Catalytic hydrogenation with Pd on
charcoal led to the amine-substituted compound 4. Reaction of this intermediate with
phenyl chloroformate in the presence of an amine base followed by hydrolysis of the
tert-butyl ester with trifluoroacetic acid gave the desired target compound 6.
For the synthesis of analogous tetrazole derivatives, the epoxy derivative 7 was
reacted with tetrazole (Scheme 2). As product, a mixture of 2H- and 1H-tetrazolyl-
substituted propan-2-ols (8a and 8b) was obtained. After chromatographic
separation, 8a was converted to the mesylate 9. Surprisingly, reaction of 9 with
trimethylsilyl azide here did not result in substitution but in elimination, yielding
E- as well as Z-configured propenyl-2H-tetrazoles. Analogous reaction of the
Scheme 1. Reagents and conditions: (a) Methanesulfonyl chloride, pyridine, rt, 4 h, 85%; (b) trimethylsilyl
azide, tetrabutylammonium fluoride, THF, reflux, 3 h, 69%; (c) H2, Pd=C, methanol, THF, rt, 2 h, 99%;
(d) phenyl chloroformate, ethyl(diisopropyl)amine, CH2Cl2, DMF, rt, 16 h, 57%; (e) trifluoroacetic acid,
CH2Cl2, rt, 6 h, 69%.

SYNTHESIS OF 1-TETRAZOLYLALKAN-2-AMINES AND –CARBAMATES
1643
Scheme 2. Reagents and conditions: (a) Tetrazole, solvent-free heating, 23%; (b) methanesulfonyl
chloride, pyridine, 0 ꢀC, 95%; (c) trimethylsilyl azide, tetrabutylammonium fluoride, THF, rt, 24 h; 10a,
32%; 10b, 16%.
1H-tetrazole derivative 8b also only led to elimination products. Variation of the
reaction conditions did not bring out the desired azides.
In literature only a few 1-tetrazolylalkan-2-amines with simple structures
are described. These compounds were synthesized from tetrazole with N-tert-
butoxycarbonyl (BOC)- or N-phthaloyl-protected 2-aminoethanol derivatives under
Scheme 3. Reagents and conditions: (a) Triphenylphosphine, acetonitrile, reflux, overnight, 88%;
(b) di-tert-butyl dicarbonate, triethylamine, diethyl ether, 0 ꢀC, 2 h, 98%; (c) tosyl chloride, 4-dimethylami-
nopyridine, triethylamine, CH2Cl2, rt, 12 h, 78%; (d) powdered KOH, tetrabutylammonium hydrogensul-
fate, CH2Cl2, rt, 12 h, 99%; (e) tetrazole, acetonitrile, BF3-etherate, CH2Cl2, rt, 3 h (16a, 31%; 16b, 41%);
(f) trifluoroacetic acid, CH2Cl2, rt, 2 h (17a, 92%; 17b, 95%); (g) phenyl chloroformate, triethylamine,
THF, rt, 2 h (18a, 95%; 18b, 97%).

1644
T. SUNDERMANN AND M. LEHR
Mitsunobu conditions[3–5] or they were obtained biosynthetically.[6,7] We used a
synthetic route via the BOC-protected aziridine 15, which was obtained starting from
1-azidopropan-2-ol[8] 11 (Scheme 3). The azido group of 11 was converted to an
amine with triphenylphosphine. After protection of the amine moiety of obtained
compound 12 with BOC, the alcohol group of resulting compound 13 was reacted
with tosyl chloride in presence of 4-dimethylaminopyridine to yield the tosylate
14. Formation of the aziridine ring system of 15 was accomplished by treatment
of 14 with powdered KOH=tetrabutylammonium hydrogensulfate in CH2Cl2. Ring
opening of BOC-protected aziridines have been performed with the aromatic hetero-
cycles indole, pyrazole, and imidazole.[9–11] Either basic (KOH, NaH), acid (BF3-
etherate), or neutral conditions were used. In our case, reaction of 15 with tetrazole
could be achieved with BF3-etherate in methylene chloride, yielding the 1H- and 2H-
tetrazolyl-substitued BOC-protected amines 16a and 16b. After chromatographic
separation each isomer was transformed into the amines 17a and 17b, respectively,
by cleavage of the BOC protecting group. Reaction with phenyl chloroformate
finally led to the desired carbamates 18a and 18b.
In conclusion, we have described
a general method to synthesize
1-tetrazolylalkan-2-amines and -carbamates. Up to now only few compounds with
such a structural element have been published in the literature.
EXPERIMENTAL
Column chromatography was performed on silica gel 60, particle size
0.040–0.063 mm (from Macherey & Nagel). Melting points were determined on a
1
Buchi B-540 apparatus and are uncorrected. H NMR spectra were recorded on a
¨
Varian Mercury Plus 400 spectrometer (400 MHz), a Varian Unity Plus 600 spec-
trometer (600 MHz), or an Agilent VNMRS-600 spectrometer (600 MHz). 13C
NMR spectra were measured on a Varian Mercury Plus 400 spectrometer
(101 MHz) or an Agilent VNMRS-600 spectrometer (151 MHz). Electron ionization
(EI) mass spectra were obtained on a Finnigan GCQ apparatus. The high-resolution
mass spectra (HRMS) were recorded on a Bruker micrOTOF-Q II spectrometer
applying electrospray chemical ionization (ESI) or atmospheric pressure chemical
ionization (APCI).
1-Amino-3-(4-phenoxyphenoxy)propan-2-ol Hydrochloride (12)
A
solution of 1-azido-3-(4-phenoxyphenoxy)propan-2-ol[8] (11) (2.00 g,
7.01 mmol) in acetonitrile (25 mL) was treated with triphenylphosphine (1.84 g,
7.02 mmol) and stirred at rt for about 30 min until the development of nitrogen could
be observed. Then the mixture was heated under reflux overnight. The solvent was
distilled off and the residue was dissolved in 1.0 M HCl. The solution was washed with
ethyl acetate=hexane (7:3, v=v) and then treated with hexane. The solid precipitating
at the phase boundary was filtered and dried to yield 12 (1.83 g, 88%). Mp 183 ꢀC; 1H
NMR (600 MHz, DMSO-d6): d 2.81 (ddd, J ¼ 12.7 Hz, 8.7 Hz and 5.8 Hz, 1H), 3.00
(ddd, J ¼ 12.8 Hz, 6.0 Hz and 3.4 Hz, 1H), 3.48 (s broad, 1H), 3.89–3.97 (m, 2H), 4.06
(dtd, J ¼ 8.8 Hz, 5.4 Hz and 3.4 Hz, 1H), 6.89 (dd, J ¼ 8.7 Hz and 1.1 Hz, 1H), 6.96 (s,
4H), 7.04 (tt, J ¼ 7.3 Hz and 1.1 Hz, 1H), 7.32 (dd, J ¼ 8.7 Hz and 7.4 Hz, 2H), 8.10

SYNTHESIS OF 1-TETRAZOLYLALKAN-2-AMINES AND –CARBAMATES
1645
(t broad, J ¼ 6.3 Hz, 3H). 13C NMR (151 MHz, DMSO-d6): d 41.7, 65.6, 70.0, 115.8,
117.3, 120.6, 122.6, 129.9, 149.6, 154.6, 157.9. HRMS (APCI, direct probe) m=z
[MþH]þ calculated: 260.1281; found: 260.1290.
tert-ButylN-[2-Hydroxy-3-(4-phenoxyphenoxy)propyl]carbamate(13)
A suspension of 12 (1.61 g, 5.44 mmol) in diethyl ether (30 mL) was treated at
0 ꢀC with triethylamine (2.26 mL, 16 mmol) followed by di-tert-butyl dicarbonate
(1.19 g, 5.45 mmol). The mixture was stirred for 2 h, concentrated, and chromato-
graphed on silica gel (hexane=ethyl acetate, 6:4) to yield 13 as an oil (1.91 g, 98%).
1H NMR (600 MHz, CDCl3): d 1.46 (s, 9H), 3.05 (s broad, 1H), 3.30 (dd, J ¼ 14.3 Hz
Hz and 6.5 Hz, 1H), 3.47 (dd, J ¼ 14.2 Hz and 3.6 Hz, 1H), 3.93 (dd, J ¼ 9.4 Hz and
6.3 Hz, 1H), 3.97 (dd, J ¼ 9.4 Hz and 4.9 Hz, 1H), 4.10 (tdd, J ¼ 6.4 Hz, 4.8 Hz and
3.6 Hz, 1H), 5.04 (s broad, 1H), 6.88 (d, J ¼ 9.0 Hz, 2H), 6.94 (dd, J ¼ 8.7 Hz and
1.1 Hz, 2H), 6.97 (d, J ¼ 9.0 Hz, 2H), 7.05 (tt, J ¼ 7.4 Hz and 1.1 Hz, 1H), 7.30
(dd, J ¼ 8.7 Hz and 7.4 Hz, 2H). 13C NMR (151 MHz, CDCl3): d 28.3, 43.5, 69.9,
70.0, 79.9, 115.6, 117.7, 120.7, 122.6, 129.6, 150.6, 154.6, 157.1, 158.3. HRMS
(APCI, direct probe) m=z [MþH]þ calculated: 360.1805; found: 360.1806.
1-[(tert-Butoxycarbonyl)amino]-3-(4-phenoxyphenoxy)propan-2-yl
4-Methylbenzenesulfonate (14)
A solution of 13 (1.95 g, 5.43 mmol) in CH2Cl2 (10 mL) was added dropwise to a
solution of tosyl chloride (1.55 g, 8.13 mmol) and 4-dimethylaminopyridine (0.33 g,
2.70 mmol) in CH2Cl2 (30 mL). The mixture was treated with triethylamine
(1.13 mL, 8.11 mmol) and stirred at rt for 12 h. After extractive workup with water
and ethyl acetate, the organic phase was washed three times with 1.0 M aqueous
KHSO4 and brine, dried over NaSO4, concentrated, and chromatographed on silica
gel (hexane=ethyl acetate, 9:1 to 8:2) to yield 14 as a white solid (2.18 g, 78%). Mp
1
105–106 ꢀC; H NMR (600 MHz, CDCl3): d 1.42 (s, 9H), 2.43 (s, 3H), 3.46 (dt,
J ¼ 14.9 Hz and 6.2 Hz, 1H), 3.59 (dt, J ¼ 15.4 Hz and 5.6 Hz, 1H), 3.98–4.07 (m,
2H), 4.79–4.89 (m, 2H), 6.66 (d, J ¼ 8.5 Hz, 2H), 6.87–6.95 (m, 4H), 7.04 (tt, J ¼ 7.4 Hz
and 1.1 Hz, 1H), 7.29 (dd, J ¼ 8.7 Hz and 7.4 Hz, 2H), 7.32 (d, J ¼ 8.0 Hz, 2H), 7.81 (d,
J ¼ 8.2 Hz, 2H). 13C NMR (151 MHz, CDCl3): d 21.6, 28.3, 41.7, 67.5, 79.3, 79.9,
115.5, 117.7, 120.6, 122.6, 128.0, 129.6, 129.8, 133.5, 144.9, 150.8, 154.1, 155.8,
158.2. HRMS (ESIþ) m=z [MþH]þ calculated: 514.1894; found: 514.1899.
tert-Butyl 2-[(4-Phenoxyphenoxy)methyl]aziridine-1-carboxylate (15)
Tetrabutylammonium hydrogensulfate (0.15 g, 0.44 mmol) and freshly
powdered KOH (85%) (0.56 g, 8.5 mmol) were added to a solution of 14 (2.05 g,
3.99 mmol) in CH2Cl2 (40 mL). The mixture was stirred at rt for 12 h. After addition
of water (30 mL), the reaction mixture was extracted with CH2Cl2. The organic phase
was dried with NaSO4, concentrated, and chromatographed on silica gel (hexane=
ethyl acetate, 8:2) to yield 15 as an oil (1.36 g, 99.8%). 1H NMR (600 MHz, CDCl3):
d 1.45 (s, 9H), 2.25 (d, J ¼ 3.7 Hz, 1H), 2.38 (d, J ¼ 6.1 Hz, 1H), 2.83 (dtd, J ¼ 6.1 Hz,
4.9 Hz and 3.7 Hz, 1H), 4.00 (dd, J ¼ 10.5 Hz and 4.8 Hz, 1H), 4.13 (dd, J ¼ 10.5 Hz

1646
T. SUNDERMANN AND M. LEHR
and 4.9 Hz, 1H), 6.89 (d, J ¼ 9.0 Hz, 2H), 6.94 (dd, J ¼ 8.8 Hz and 1.1 Hz, 2H), 6.97
(d, J ¼ 9.0 Hz, 2H), 7.04 (tt, J ¼ 7.4 Hz and 1.1 Hz, 1H), 7.30 (dd, J ¼ 8.7 Hz and
7.4 Hz, 2H).13C NMR (151 MHz, CDCl3): d 28.0, 29.6, 35.9, 68.3, 81.6, 115.9,
117.8, 120.8, 122.7, 129.8, 150.7, 154.7, 158.5, 161.9. HRMS (APCI, direct probe)
m=z [MþH]þ calculated: 342.1700; found: 342.1690.
tert-Butyl N-[1-(4-Phenoxyphenoxy)-3-(2H-tetrazol-2-yl)propan-
2-yl]carbamate (16a) and tert-Butyl N-[1-(4-Phenoxyphenoxy)-3-
(1H-tetrazol-1-yl)propan-2-yl]carbamate (16b)
A 0.45 M solution of tetrazole in acetonitrile (13 ml, 5.85 mmol) was added to a
solution of 15 (1.33 g, 3.90 mmol) in CH2Cl2 (30 mL). After addition of seven drops of
BF3-etherate, the mixture was stirred at rt for 3 h, concentrated, and chromato-
graphed on silica gel (hexane=ethyl acetate, 9:1 to 8:2) to yield the isomers 16a
(0.49 g, 31%) and 16b (0.65 g, 41%) as oils.
Compound 16a. 1H NMR (600 MHz, CDCl3): d 1.42 (s, 9H), 3.99 (dd,
J ¼ 9.5 Hz and 5.0 Hz, 1H), 4.04 (dd, J ¼ 9.6 Hz and 3.3 Hz, 1H), 4.54–4.61 (m,
1H), 4.94 (dd, J ¼ 13.7 Hz and 5.3 Hz, 1H), 5.03 (dd, J ¼ 13.8 Hz and 6.9 Hz, 1H),
5.24 (d, J ¼ 9.1 Hz, 1H), 6.86 (d, J ¼ 9.0 Hz, 2H), 6.94 (dd, J ¼ 8.7 Hz and 1.1 Hz,
2H), 6.97 (d, J ¼ 9.0 Hz, 2H), 7.06 (tt, J ¼ 7.4 Hz and 1.1 Hz, 1H), 7.30 (dd, J ¼ 8.7 Hz
and 7.4 Hz, 2H), 8.54 (s, 1H). 13C NMR (151 MHz, CDCl3): d 28.4, 49.7, 53.7, 67.6,
80.6, 115.8, 118.0, 120.9, 122.8, 129.8, 151.3, 153.2, 154.2, 155.0, 158.3. HRMS
(ESIþ) m=z [MþH]þ calculated: 412.1979; found: 412.1979.
Compound 16b. 1H NMR (600 MHz, CDCl3): d 1.49 (s, 9H), 3.95 (dd,
J ¼ 9.7 Hz and 5.5 Hz, 1H), 4.04 (dd, J ¼ 9.6 Hz and 3.8 Hz, 1H), 4.39–4.45 (m,
1H), 4.79 (d, J ¼ 5.9 Hz, 2H), 5.19 (d, J ¼ 8.4 Hz, 1H), 6.86 (d, J ¼ 9.0 Hz, 2H), 6.94
(dd, J ¼ 8.7 Hz and 1.0 Hz, 2H), 6.98 (d, J ¼ 9.0 Hz, 2H), 7.06 (tt, J ¼ 7.4 Hz and
1.1 Hz, 1H), 7.31 (dd, J ¼ 8.6 Hz and 7.3 Hz, 2H), 8.67 (s, 1H). 13C NMR
(151 MHz, CDCl3): d 28.4, 48.8, 49.9, 67.3, 81.0, 115.7, 118.1, 120.9, 122.9, 129.8,
143.5, 151.5, 153.9, 155.2, 158.2. HRMS (ESIþ) m=z [MþH]þ calculated: 412.1979;
found: 412.1970.
1-(4-Phenoxyphenoxy)-3-(2H-tetrazol-2-yl)propan-2-amine
Hydrochloride (17a)
A solution of 16a (0.200 g, 0.487 mmol) in CH2Cl2 (12 mL) was treated with sev-
eral drops of trifluoroacetic acid and stirred at rt for 2 h. Then the reaction mixture
was evaporated. The residue was treated with 2.0 M aqueous NaOH solution and
extracted with ethyl acetate. The aqueous layer was extracted three times with ethyl
acetate and the combined organic phases were dried over Na2SO4. The solvent was
distilled off and the residue was treated with dry CH2Cl2 (5 mL) and 1.0 M etheric
HCl (5 mL). The resulting solution was concentrated to yield 17a as a white solid
1
(0.155 g, 92%). Mp 196–197 ꢀC; H NMR (400 MHz, DMSO-d6): d 4.11–4.22 (m,
2H), 4.28 (dd, J ¼ 11.8 Hz and 5.8 Hz, 1H), 5.18 (d, J ¼ 5.6 Hz, 2H), 6.93 (dd,
J ¼ 8.7 Hz and 1.1 Hz, 2H), 6.96–7.06 (m, 4H), 7.04–7.14 (m, 1H), 7.35 (dd, J ¼ 8.7 Hz
and 7.4 Hz, 2H), 8.83 (s broad, 3H), 9.08 (s, 1H).13C NMR (101 MHz, DMSO-d6): d

SYNTHESIS OF 1-TETRAZOLYLALKAN-2-AMINES AND –CARBAMATES
1647
49.0, 51.1, 65.7, 116.1, 117.5, 120.6, 122.8, 129.9, 150.3, 153.7, 153.8, 157.7. HRMS
(APCI, direct probe) m=z [MþH]þ calculated: 312.1455; found: 312.1456.
Phenyl N-[1-(4-Phenoxyphenoxy)-3-(2H-tetrazol-2-yl)propan-2-
yl]carbamate (18a)
Triethylamine (0.084 mL, 0.60 mmol), followed by phenyl chloroformate
(0.036 mL, 0.29 mmol), was added dropwise to a solution of 17a (0.090 g, 0.26 mmol)
in THF (10 mL) at 0 ꢀC. The mixture was stirred at rt for 2 h, concentrated, and
chromatographed on silica gel (hexane=ethyl acetate, 9:1 to 8:2) to yield 18a as an
1
oil (0.106 g, 95%). H NMR (400 MHz, CDCl3): d 4.08 (dd, J ¼ 9.7 Hz and 5.1 Hz,
1H), 4.13 (dd, J ¼ 9.6 Hz and 3.5 Hz, 1H), 4.68 (ddt, J ¼ 7.2 Hz, 5.4 Hz and 3.7 Hz,
1H), 5.03 (dd, J ¼ 13.9 Hz and 5.0 Hz, 1H), 5.14 (dd, J ¼ 13.9 Hz and 6.8 Hz, 1H),
5.83 (d, J ¼ 8.8 Hz, 1H), 6.88 (d, J ¼ 9.1 Hz, 2H), 6.96 (dd, J ¼ 8.8 Hz and 1.1 Hz,
2H), 6.99 (d, J ¼ 9.0 Hz, 2H), 7.04–7.13 (m, 3H), 7.18–7.24 (m, 1H), 7.28–7.39 (m,
4H), 8.57 (s, 1H). 13C NMR (101 MHz, CDCl3): d 50.4, 53.4, 67.3, 115.8, 118.0,
120.9, 121.6, 122.9, 125.8, 129.5, 129.8, 150.8, 151.4, 153.4, 154.0, 154.1, 158.2.
HRMS (ESIþ) m=z [MþH]þ calculated: 432.1666; found: 432.1685.
SUPPORTING INFORMATION
Full experimental details for compounds 8a, 8b, 9, 10a, 10b, 17b, and 18b;
1H and 13C NMR spectra for all new compounds; and HPLC traces for 18a and
18b can be accessed on the publisher’s website.
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