Synthesis of Boc-amino tetrazoles derived from α-amino acids

Article abstract of DOI:10.1080/00397910802374133

A simple route for the synthesis of Boc-protected tetrazole analogs of amino acids starting from Nα-Boc amino acids has been described. The [2 + 3] cycloaddition of Boc-α-amino nitrile and sodium azide in the presence of a catalytic amount of zinc bromide yielded the desired tetrazoles in good yields and purity. All the compounds obtained have been characterized by 1H and 13C-NMR and mass spectral studies. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802374133

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Synthesis of Boc-Amino
Tetrazoles Derived from α-
Amino Acids
Vommina V. Sureshbabu a , Shankar A. Naik a & G.
Nagendra a
a Peptide Research Laboratory, Department of
Studies in Chemistry, Central College Campus,
Bangalore University, Bangalore, India
Published online: 08 Jan 2009.
To cite this article: Vommina V. Sureshbabu , Shankar A. Naik & G. Nagendra
(2009): Synthesis of Boc-Amino Tetrazoles Derived from α-Amino Acids, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 39:3, 395-406
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Synthetic Communications1, 39: 395–406, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802374133
Synthesis of Boc-Amino Tetrazoles Derived
from a-Amino Acids
Vommina V. Sureshbabu, Shankar A. Naik, and G. Nagendra
Peptide Research Laboratory, Department of Studies in Chemistry,
Central College Campus, Bangalore University, Bangalore, India
Abstract: A simple route for the synthesis of Boc-protected tetrazole analogs of
amino acids starting from Na-Boc amino acids has been described. The [2 þ 3]
cycloaddition of Boc-a-amino nitrile and sodium azide in the presence of a
catalytic amount of zinc bromide yielded the desired tetrazoles in good yields
and purity. All the compounds obtained have been characterized by 1H and
13C-NMR and mass spectral studies.
Keywords: Boc-Amino acids, [2 þ 3], cycloaddition, nitriles, tetrazoles
INTRODUCTION
Tetrazoles are a versatile class of compounds frequently used as meta-
bolically stable surrogates for carboxylic acid group[1] and have shown
valuable properties as precursors of a variety of nitrogen-containing
heterocycles.[2]
The tetrazolic acid fragment ꢀCN4H (Fig. 1) has acidity similar to
the carboxylic acid group and is isosteric with it. The interest in the
ability of tetrazoles to mimic the carboxylic acid group has motivated
the incorporation of tetrazoles into biologically active compounds. The
tetrazolic ring has also featured in the structure of many efficient drugs.[3]
Organocatalysis has experienced a renaissance in asymmetric synthesis.
In this context, proline-derived tetrazoles have proved to be versatile
Received April 24, 2008.
Address correspondence to Vommina V. Sureshbabu, Department of Studies in
Chemistry, Central College Campus, Bangalore University, Dr. B. R. Ambedkar
Veedhi, Bangalore 560 001, India. E-mail: hariccb@rediffmail.com
395

396
V. V. Sureshbabu, S. A. Naik, and G. Nagendra
Figure 1. Tetrazolic acids: bioisosters of carboxylic acids.
catalysts for the asymmetric Mannich, nitro-Micheal, and aldol
reactions.[4]
The cycloaddition of an azide and a nitrile has been the conventional
route for the synthesis of 5-substituted tetrazoles. However, the azide
source, hydrazoic acid (HN3),[5] was of major concern on account of its
high toxicity in solution, explosive nature, and low boiling point (37 ꢁC).
Even addition of azide salts to nitriles was a commonly employed method
for the synthesis of tetrazoles involving the use of sodium azide in the
presence of ammonium chloride or tertiary ammonium chloride.[6] Tri-
methylsilyl and trialkyl tin azides[7] are also important alternatives but
the use of expensive reagents, harsh reaction conditions and difficulty
in removal of highly toxic organotin compounds cannot be ignored.
Demko and Sharpless have coined the term ‘‘click chemistry’’[8] for one
of the most practical and reliable transformations. His group employed
Z-protected amino acids as key synthons for the synthesis of Z-protected
amino acid derived tetrazoles.[9] Sureshbabu et al.[10] have reported the
synthesis of tetrazoles employing Fmoc-chemistry. Grzonka et al.[11] have
reported the synthesis of tetrazole analogs of amino acids using sodium
azide and aluminum chloride. There is one report on the synthesis of
Boc-Asn and Boc-Gln tetrazoles using n-Bu3SnN3 at reflux.[12] As the
Boc group is regularly employed in peptide chemistry, we believe Boc-
protected tetrazole analoges of amino acids will find utility in solution-
phase synthesis, and hence, we describe here the synthesis of these
compounds.
RESULTS AND DISCUSSION
The key problem encountered in amide synthesis is the development of an
adequate method for carboxyl group activation, which determines the
method’s efficiency, occurrence of side reactions, and formation of by-
products. Z=Boc-amino acid amides are generally prepared using a di-
tert-butyl pyrocarbonate[13] [(Boc)2]-pyridine system. We chose to
synthesize Boc-amino acid amides by an alternate cost-effective procedure
involving addition of aq. ammonia to the in situ generated mixed

Boc-Amino Tetrazoles
397
anhydride.[14] Initially, Boc-protected alanine was treated with N-methyl-
morpholine and ethyl chloroformate at ꢀ10 ꢁC, resulting in its mixed
anhydride generation, to which aqueous ammonia solution was added.
The reaction mixture was stirred for 4 h during which the entire starting
material was consumed. Boc-Ala-NH2 was obtained as solid in excellent
purity. Similarly, all amides were synthesized and isolated as stable solids
in 90–96% yield (Scheme 1).
Nitriles are valuable intermediates in organic synthesis and can be trans-
formed to yield a broad spectrum of functionalities (e.g., tetrazoles, triazoles,
thiazoles, and oxazolidones). The conversion of amides to nitriles is brought
about by various dehydrating agents such as trifluroacetic anhydride
(TFAA), cyanuric chloride, Burgess reagent, and dicyclohexylcarbodiimide
(DCC)–pyridine system.[15] Upon careful study of these reagents, TFAA
was found to be ideally suited for our protocol as it could be used with milder
reaction conditions and it avoids the formation of by-products, thus simplify-
ing the isolation of the product and furnishing better yields. The use of pyri-
dine enhances the rate of reaction and neutralizes the subsequently formed
trifluoroacetic acid. In a typical experiment, Boc-Ala-NH2 was stirred with
TFAA inthe presence of pyridine in tetrahydrofuran (THF) at0ꢁC. Thereac-
tion was complete in 2 h (as monitored by thin-layer chromatography, TLC,
and infrared, IR). Further, the conversion of amide to nitrile was confirmed
by a characteristic peak around 2240 cmꢀ1 in the IR spectrum. After evapor-
ating the solvent and a simple workup, Boc-protected alanine nitrile was
obtained as a pure solid in 90% yield. Employing TFAA and pyridine system,
the Boc-amino acid amides 2a–k were converted into the corresponding
nitriles 3a–k with excellent yields (Scheme 2).
The methodology introduced by Sharpless et al., which involves
simple heating of the N-protected a-amino nitrile in water=2-propanol
Scheme 1. Synthesis of Boc-amino acid amides: (i) NMM, ECF, aq. NH3,
ꢀ10 ꢁC, 4 h.

398
V. V. Sureshbabu, S. A. Naik, and G. Nagendra
Scheme 2. Synthesis of Boc-amino nitriles: (i) TFAA, pyridine, THF, 0 ꢀC, 2 h.
mixture at reflux (80 ꢀC) in the presence of sodium azide and zinc bromide
for the synthesis of 5-substituted tetrazoles was found to be applicable in
the case of Boc-a-amino nitriles also. In a typical experiment, Boc-Ala-CN
was dissolved in a water=2-propanol (2:1) mixture to which sodium azide
and a stoichiometric amount of zinc bromide were added and refluxed for
nearly 16 h. When the nitrile was completely consumed, the reaction mix-
ture was acidified with citric acid and the product was extracted into ethyl
acetate. A simple work-up followed by recrystallization using ethyl
acetate–hexane (2:8) yielded Boc-AlaT as pure solid in 80% yield. The
procedure was applied to other Boc-a-amino nitriles and all the Boc-
amino tetrazoles were obtained as obtained as solids in good yields
1
(Scheme 3, Table 1). The compounds were characterized by H and 13C
NMR and mass spectral data. The reaction sequence was found to be free
from racemization as determined by chiral high-performance liquid
Scheme 3. Synthesis of Boc-protected tetrazole analogs of amino acids: (i) NaN3,
ZnBr2, water=2-propanol, 80 ꢀC, 16 h.

Boc-Amino Tetrazoles
399
Table 1. Boc-protected tetrazole analogs of amino acids
Sl. no.
Amino acid
Yield (%)
Mp (ꢁC)
Mass (obs.=calc.)a
4a
4b
4c
4d
4e
4f
4g
4h
4i
Gly
Ala
Val
Leu
Ile
Phe
Pro
72
75
75
71
78
80
65
70
68
69
74
112–114
135–137
104–106
96–98
119–121
142–144
81–83
126–128
133–135
142–144
145–147
184.3=184.0
198.3=198.1
226.4=226.1
240.3=240.1
240.2=240.1
274.5=274.1
239.3=239.0
304.5=304.1
332.4=332.2
346.2=346.1
260.4=260.2
Ser(OBzl)
Asp(OBzl)
Glu(OBzl)
L-Phg
4j
4k
aES-MS.
chromatography (HPLC) of the methylated derivatives of the correspond-
ing tetrazoles. An attempt to prepare side chain–derived tetrazoles in the
case of Boc-Asn and Gln was made using a similar protocol but was not
satisfactory even after extended hours of reflux.
CONCLUSION
1,3-Dipolar nitrile-azide cycloaddition reaction has been used successfully
to obtain the tetrazole analogs of Boc-amino acids. The Boc-a-amino
nitrile reactants have been prepared via an efficient TFAA-mediated
dehydration of the corresponding amide. Treatment of the nitriles with
NaN3 in the presence of ZnBr2 has resulted in tetrazoles, which have been
isolated as stable solids and fully characterized.
EXPERIMENTAL
All solvents were freshly distilled before use. Amino acids were used as
received from Sigma-Aldrich Company. Melting points were determined
on a Buchi model 150-melting point apparatus in open capillaries and are
uncorrected. IR spectra were recorded on a Nicolet model impact 400D
1
FT-IR spectrometer (KBr pellets, 3 cmꢀ1 resolution). H NMR spectra
were recorded on a Bruker AMX 400-MHz spectrometer. Mass spectra
were recorded on Maldi-TOF (Kratos) mass spectrometer. Unless other-
wise mentioned, all amino acids used have an L-configuration. TLC
analysis was carried out using the precoated silica-gel G254 plates.

400
V. V. Sureshbabu, S. A. Naik, and G. Nagendra
General Procedure for the Synthesis of Boc-Amino Acid Amides, 2
A solution of Boc-protected amino acid (1 mmol), N-methylmorpholine
(1.1 mmol), and ethyl chloroformate (1.1 mmol) in THF (5 mL) was
cooled to ꢀ10 ꢁC (ice=salt bath). After stirring for 20 min at the same
temperature, NH3 solution (0.4 mL) was added, and stirring was contin-
ued for another 4 h. The solvent was removed in vacuo and the residue
was dissolved in ethyl acetate. The organic layer was washed with 1N
KHSO4, water, and brine and dried over anhydrous Na2SO4. After
evaporation of the solvent, the crude product was recrystallized from
ethyl acetate–hexane (3:8). The amide was obtained as pure solid.
General Procedure for the Synthesis of Boc-Amino Nitriles, 3
TFAA (1.5 mmol) and pyridine (3 mmol) were added to an ice-cold sol-
ution of Na-Boc-amino amide (1 mmol) in dry THF (5 mL) at ꢀ10 ꢁC.
The resulting reaction mixture was stirred for 2 h. The solvent was
removed in vacuo, and the residue was dissolved in ethyl acetate. The
organic layer was washed with 1N KHSO4, water, and brine and dried
over anhydrous Na2SO4. After evaporation of the solvent, the crude
product was recrystallized using ethyl acetate–hexane (2:8). The resulting
nitrile was obtained as a solid.
General Procedure for the Synthesis of Boc-Amino Tetrazoles, 4
Na-Boc-amino nitrile (1 mmol), sodium azide (2 mmol), and zinc bromide
(0.5 mmol) were dissolved in a mixture of 2-propanol (15 mL) and water
(30 mL) and stirred at reflux for 16 h. After completion of the reaction [as
monitored by TLC, using chloroform–methanol (9:1) as eluant], 5 mL of
10% citric acid and 30 mL of ethyl acetate were added and stirring was
continued until no solid remained. The aqueous layer was extracted twice
with ethyl acetate. The combined organic layer was washed with water
and dried over anhydrous Na2SO4. The solvent was removed in vacuo,
and the residue was recrystallized from EtOAc–hexane (1:4).
Data
N-tert-Butyloxycarbonyl Glycine Nitrile, 3a
IR (KBr) 2243, 1705, 1532 cmꢀ1; 1H NMR (CDCl3, 400 MHz): d 1.40 (m,
9H), 4.08 (d, 2H), 4.60 (t, J ¼ 7.9 Hz, 1H); 13C NMR (CDCl3,100 MHz): d
28.5, 32.6, 80.2, 118.3, 154.5.

Boc-Amino Tetrazoles
401
N-tert-Butyloxycarbonyl Alanine Nitrile, 3b
IR (KBr) 2241, 1705, 1532 cmꢀ1; 1H NMR (CDCl3, 400 MHz): d 1.39 (m,
9H), 1.65 (d, J ¼ 5.9 Hz, 3H), 4.72 (d, 1H), 4.77 (m, 1H); 13C NMR
(CDCl3, 100 MHz): d 21.2, 28.2, 42.0, 80.6, 118.5, 155.2.
N-tert-Butyloxycarbonyl Valine Nitrile, 3c
IR (KBr) 2240, 1706, 1534 cmꢀ1; 1H NMR (CDCl3, 400 MHz): d 0.96 (d,
J ¼ 5.2 Hz, 6H), 1.40 (s, 9H), 1.90 (m, 1H), 4.58 (br, 1H), 4.82 (br, 1H);
13C NMR (CDCl3, 100 MHz): d 17.8, 28.1, 28.5, 46.6, 81.2, 118.8,
155.6.
N-tert-Butyloxycarbonyl Leucine Nitrile, 3d
IR (KBr) 2242, 1705, 1532 cmꢀ1; 1H NMR (CDCl3, 400 MHz): d 0.98 (d,
6H), 1.47 (s, 9H), 1.56–1.85 (m, br., 3H), 4.60 (m, 1H), 4.74 (d,
J ¼ 8.1 Hz); 13C NMR (CDCl3, 100 MHz): d 21.8, 22.1, 24.7, 28.2, 40.9,
41.8, 42.0, 81.0, 119.0, 154.1.
N-tert-Butyloxycarbonyl Isoleucine Nitrile, 3e
IR (KBr) 2240, 1705, 1534 cmꢀ1; 1H NMR (CDCl3, 400 MHz): d 0.83 (d,
J ¼ 4.8 Hz, 3H), 0.93 (d, J ¼ 5.9 Hz, 3H), 1.41 (s, 9H), 1.60 (m, 2H), 1.92
(m, 1H), 4.31 (t, J ¼ 5.9 Hz, 1H), 5.3 (br, 1H); 13C NMR (CDCl3,
100 MHz): d 18.2, 21.5, 26.4, 28.3, 32.8, 57.9, 80.8, 119.2, 155.1.
N-tert-Butyloxycarbonyl Phenylalanine Nitrile, 3f
IR (KBr) 2240, 1705, 1534 cmꢀ1; 1H NMR (CDCl3, 400 MHz): d 1.44 (s,
9H), 3.12 (m, 2H), 4.84 (m, 1H), 4.94 (d, J ¼ 8.1 Hz, 1H), 7.25–7.38 (m,
5H); 13C NMR (CDCl3, 100 MHz): d 28.1, 39.3, 43.2, 81.0, 118.5,
127.7, 128.9, 129.3, 134.0.
N-tert-Butyloxycarbonyl Proline Nitrile, 3g
IR (KBr) 2243, 1704, 1532 cmꢀ1; 1H NMR (CDCl3, 400 MHz): d 1.40 (s,
9H), 1.80–1.94 (m, 4H), 3.42–3.55 (m, 2H), 4.55 (m, 1H); 13C NMR
(CDCl3, 100 MHz): d 24.3, 28.1, 30.1, 46.8, 52.0, 80.7, 118.3, 155.2.

402
V. V. Sureshbabu, S. A. Naik, and G. Nagendra
N-tert-Butyloxycarbonyl-O-Benzyl Serine Nitrile, 3h
IR (KBr) 2240, 1705, 1534 cmꢀ1; 1H NMR (CDCl3, 400 MHz): d 1.45 (s,
9H), 3.60–3.76 (m, br., 2H), 4.62 (s, 2H), 4.73 (m, 1H), 5.35 (d, br., 1H),
7.25–7.37 (m, 5H); 13C NMR (CDCl3, 100 MHz): d 28.2, 42.3, 68.9, 73.6,
80.9, 117.7, 127.8, 128.2, 136.7, 154.2.
N-tert-Butyloxycarbonyl-O-Benzoyl Aspartic Nitrile, 3i
IR (KBr) 2243, 1704, 1532 cmꢀ1; 1H NMR (CDCl3, 400 MHz): d 1.40 (s,
9H), 2.80 (m, 2H), 4.52 (m, 1H), 5.34 (s, 2H), 5.51 (t, J ¼ 5.9 Hz, 1H),
7.15–7.25 (m, 5H); 13C NMR (CDCl3, 100 MHz): d 28.3, 39.9, 48.3,
68.5, 79.5, 118.0, 127.2, 127.7, 129.0, 141.2, 156.0, 171.8.
N-tert-Butyloxycarbonyl-O-Benzoyl Glutamic Nitrile, 3j
IR (KBr) 2240, 1705, 1534 cmꢀ1; 1H NMR (CDCl3, 400 MHz): d 1.39 (s,
9H), 1.8–2.35 (m, 4H), 4.91 (s, 1H), 5.34 (s, 2H), 7.12–7.24 (m, 5H); 13C
NMR (CDCl3, 100 MHz): d 28.3, 28.4, 30.6, 50.2, 68.2, 79.8, 118.4, 127.2,
127.8, 129.1, 141.1, 156.5, 172.3.
N-tert-Butyloxycarbonyl Phenylglycine Tetrazole, 3k
1
IR (KBr) 2240, 1704, 1532 cmꢀ1; H NMR (CDCl3, 400 MHz): d 1.40
(s, 9H), 6.18 (d, J ¼ 7.9 Hz, 1H), 7.22–7.40 (m, 5H); 13C NMR
(CDCl3, 100 MHz): d 28.5, 50.32, 80.1, 118.2, 126.8, 127.0, 128.6,
142.2, 156.3.
N-tert-Butyloxycarbonyl Glycine Tetrazole, 4a
IR (KBr) 1705, 1532, 1264 cmꢀ1; 1H NMR (CDCl3, 400 MHz): d 1.39 (s,
9H), 4.12 (t, J ¼ 6.6 Hz, 2H), 5.40 (br d, J ¼ 5.9 Hz, 1H); 13C NMR
(CDCl3, 100 MHz): d 28.3, 43.2, 78.2, 154.5, 158.3.
N-tert-Butyloxyarbonyl Alanine Tetrazole, 4b
1
IR (KBr) 1707, 1530, 1262 cmꢀ1; H NMR (CDCl3, 400 MHz): d 1.40
(s, 9H), 1.49 (d, J ¼ 6.1 Hz, 3H), 4.15 (m, 1H), 5.42 (br d, J ¼ 5.9 Hz,
1H); 13C NMR (CDCl3, 100 MHz): d 21.5, 28.3, 46.6, 78.2, 151.3,
155.0.

Boc-Amino Tetrazoles
403
N-tert-Butyloxycarbonyl Valine Tetrazole, 4c
IR (KBr) 1705, 1532, 1262 cmꢀ1; 1H NMR (CDCl3, 400 MHz): d 0.96 (d,
J ¼ 4.4 Hz , 6H), 1.39 (s, 9H), 1.90 (m, 1H), 4.21 (br, 1H), 5.31 (br, 1H);
13C NMR (CDCl3, 100 MHz): d 18.0, 28.2, 31.7, 61.6, 78.3, 153.4, 155.1.
N-tert-Butyloxycarbonyl Leucine Tetrazole, 4d
1
IR (KBr) 1707, 1530, 1264 cmꢀ1; H NMR (CDCl3, 400 MHz): d 0.87–
0.91 (m, 6H), 1.39 (s, 9H), 1.56–1.65 (m, 1H), 1.70–1.87 (m, 2H), 4.15
(t, J ¼ 6.6 Hz, 1H), 5.05 (m, 3H), 5.37 (br, 1H); 13C NMR (CDCl3,
100 MHz): d 21.5, 22.6, 24.1, 28.1, 41.8, 44.4, 65.6, 78.3, 154.2, 155.3.
N-tert-Butyloxycarbonyl Isoleucine Tetrazole, 4e
IR (KBr) 1705, 1532, 1262 cmꢀ1; 1H NMR (CDCl3, 400 MHz): d 0.82 (d,
J ¼ 4.4 Hz, 3H), 0.91 (d, J ¼ 5.8 Hz, 3H), 1.40 (s, 9H), 1.62 (m, 2H), 1.91
(m, 1H), 4.32 (t, J ¼ 5.9 Hz 1H), 5.4 (br, 1H); 13C NMR (CDCl3,
100 MHz): d 18.1, 21.6, 26.3, 28.2, 32.6, 57.7, 78.2, 153.5, 154.9.
N-tert-Butyloxycarbonyl Phenylalanine Tetrazole, 4f
IR (KBr) 1706, 1531, 1262 cmꢀ1; 1H NMR (CDCl3, 400 MHz): d 1.40 (s,
9H), 3.20 (t, J ¼ 5.9 Hz, 2H), 5.21 (m, 1H), 7.02–7.28 (m, 5H); 13C NMR
(CDCl3, 100 MHz): d 28.2, 38.2, 65.5, 78.2, 126.6, 127.5, 128.3, 129.1,
129.8, 136.6, 154.2, 155.7.
N-tert-Butyloxycarbonyl Proline Tetrazole, 4g
IR (KBr) 1705, 1530, 1264 cmꢀ1; 1H NMR (CDCl3, 400 MHz): d 1.42 (s,
9H), 1.80–1.96 (m, 4H), 3.42–3.55 (m, 2H), 4.94 (t, J ¼ 12.2 Hz, 1H); 13C
NMR (CDCl3, 100 MHz): d 24.1, 28.2, 30.1, 46.8, 52.0, 79.1, 136.7, 155.2.
N-tert-Butyloxycarbonyl-O-benzyl Serine Tetrazole, 4h
IR (KBr) 1705, 1532, 1264 cmꢀ1; 1H NMR (CDCl3, 400 MHz): d 1.40 (s,
9H), 3.80–3.92 (m, 2H), 4.48 (m, 1H), 4.52 (s, 2H), 5.25 (br, 1H), 7.12–
7.34 (m, 5H); 13C NMR (CDCl3, 100 MHz): d 28.1, 46.7, 69.6, 72.3,
79.3, 127.4, 127.5, 127.8, 127.9, 128.2, 137.8, 153.9, 155.1.

404
V. V. Sureshbabu, S. A. Naik, and G. Nagendra
N-tert-Butyloxycarbonyl-O-benzoyl Aspartic Tetrazole, 4i
IR (KBr) 1705, 1530, 1262 cmꢀ1; 1H NMR (CDCl3, 400 MHz): d 1.40 (s,
9H), 2.80 (m, 2H), 4.1 (t, 1H), 5.34 (s, 2H), 5.51 (t, J ¼ 5.9 Hz), 7.15–7.25
(m, 5H); 13C NMR (CDCl3, 100 MHz): d 28.3, 39.9, 48.3, 68.5, 79.5,
127.2, 127.7, 129.0, 141.2, 156.0, 158.2, 171.8.
N-tert-Butyloxycarbonyl-O-benzoyl Glutamic Tetrazole, 4j
1
IR (KBr) 1704, 1534, 1262 cmꢀ1; H NMR (CDCl3, 400 MHz): d 1.39
(s, 9H), 1.8–2.35 (m, 4H), 5.15 (s, 1H), 5.34 (s, 2H), 7.12–7.24 (m, 5H);
13C NMR (CDCl3, 100 MHz): d 28.3, 28.4, 30.6, 50.2, 68.2, 79.8, 127.2,
127.8, 129.1, 141.1, 156.5, 157.5, 172.3.
N-tert-Butyloxycarbonyl Phenylglycine Tetrazole, 4k
IR (KBr) 1705, 1532, 1264 cmꢀ1; 1H NMR (CDCl3, 400 MHz): d 1.39 (s,
9H), 6.16 (d, J ¼ 7.9 Hz, 1H), 7.24–7.42 (m, 5H); 13C NMR (CDCl3,
100 MHz): d 28.5, 50.32, 80.1, 126.8, 127.0, 128.6, 142.2, 156.3, 158.1.
ACKNOWLEDGMENT
Authors are grateful to the Council of Scientific and Industrial Research,
Government of India, for financial support.
REFERENCES
1. (a) Singh, H.; Chawla, A. S.; Kapoor, V. K.; Paul, D.; Malhotra, R. K.
Medicinal chemistry of tetrazoles. Prog. Med. Chem. 1980, 17, 151; (b) Juby,
P. F.; Hudyma, T. W.; Brown, M. Preparation and antiinflammatory proper-
ties of some 5-(2-anilinophenyl)tetrazoles. J. Med. Chem. 1968, 11, 111–117.
2. Moderhack, D. Ring transformations in tetrazole chemistry. J. Prakt. Chem.
1998, 340, 687–709.
3. (a) Wittenberger, S. J. Recent development in tetrazole chemistry: A review.
Org. Prep. Proced. Int. 1994, 26, 499–531; (b) Wu, S.; Fluxe, A.; Sheffer, J.;
Janusz, J. M.; Blass, B. E.; White, R.; Jackson, C.; Hedges, R.; Muawsky,
M.; Fang, B.; Fadayel, G. M.; Hare, M.; Djandjighian, L. Discovery and
in vitro=in vivo studies of tetrazole derivatives as Kv1.5 blockers. Bioorg.
Med. Chem. Lett. 2006, 16, 6213–6218; (c) Liljebris, C.; Larsen, S. D.; Ogg,
D.; Palazuk, B. J.; Bleasdale, J. E. Investigation of potential bioisosteric
replacements for the carboxyl groups of peptidomimetic inhibitors of protein

Boc-Amino Tetrazoles
405
tyrosine phosphatase 1B: Identification of a tetrazole-containing inhibitor
with cellular activity. J. Med. Chem. 2002, 45, 1785–1798.
4. (a) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S. V.
Organocatalysis with proline derivatives: improved catalysts for the asym-
metric Mannich, nitro-Michael, and aldol reactions. Org. Biomol. Chem.
2005, 3, 84–96; (b) Chowdari, N. S.; Ahmad, M.; Albertshofer, K.; Tanaka,
F.; Barbas, III. C. F. Expedient synthesis of chiral 1,2- and 1,4-diamines:
Protecting group dependent regioselectivity in direct organocatalytic asym-
metric Mannich reactions. Org. Lett. 2006, 8, 2839–2842.
5. (a) von Braun, J.; Keller, W. Ber. Dtsch. Chem. Ges. 1932, 65, 1677; (b)
Herbst, R. M.; Froberger, C. F. Synthesis of iminotetrazoline deriva-
tives as trichomonacidal and fungicidal agents. J. Org. Chem. 1957, 22,
1050–1053.
6. (a) Alterman, M.; Hallberg, A. Fast microwave-assisted preparation of aryl
and vinyl nitriles and the corresponding tetrazoles from organo-halides. J.
Org. Chem. 2000, 65, 7984–7989; (b) Finnegan, W. G.; Henry, R. A.;
Lofquist, R. An improved synthesis of 5-substituted tetrazoles. J. Am. Chem.
Soc. 1958, 80, 3908–3911; (c) Bernstein, P. R.; Vacek, E. P. Improved con-
ditions for the formation of tetrazoles. Synthesis 1987, 1133–1134.
7. (a) Nohara, A.; Kuriki, H.; Saijo, T.; Sugihara, H.; Kanno, M.; Sanno, Y.
Studies on antianaphylactic agents, 5: Synthesis of 3-(1H-tetrazol-5-yl)
chromones, a new series of antiallergic substances. J. Med.Chem. 1977, 20,
141–145; (b) Amantini, D.; Beleggia, R.; Fringuelli, F.; Pizzo, F.; Vaccaro,
L. TBAF-catalyzed synthesis of 5-substituted 1H-tetrazoles under solventless
conditions. J. Org. Chem. 2004, 69, 2896–2898; (c) Athanassopoulos, C. M.;
Garnelis, T.; Vahliotis, D.; Papaioannou, D. Efficient syntheses of
5-aminoalkyl-1H-tetrazoles and of polyamines incorporating tetrazole rings.
Org. Lett. 2005, 7, 561–564.
8. Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Click chemistry: diverse chemical
function from a few good reactions. Angew. Chem. Int. Ed. 2001, 40, 2004–
2021.
9. Demko, Z. P.; Sharpless, K. B. An expedient route to the tetrazole analogues
of a-amino acids. Org. Lett. 2002, 4, 2525–2527.
10. Sureshbabu, V. V.; Venkataramanarao, R.; Naik, S. A.; Chennakrishnareddy,
G. Synthesis of tetrazole analogues of amino acids using Fmoc chemistry:
Isolation of amino free tetrazoles and their incorporation into peptides.
Tetrahedron Lett. 2007, 48, 7038–7041.
11. (a) Grzonka, Z.; Liberek, B. Tetrazole analogues of amino acids and
peptides, part I: Preparation of tetrazole analogues of amino acids from
amino acids. Roczniki Chem. 1971, 45, 967–980; (b) Grzonka, Z.; Rekowska,
E.; Liberek, B. Tetrazole analogues of amino acids and peptides, V: Synthesis
of peptide derivatives containing tetrazoles analogues of amino acids in
C-terminal position. Tetrahedron 1971, 27, 2317–2322.
12. Ornstein, P. L.; Arnold, M. B.; Evrard, D.; Leander, J. D.; Lodge, D.;
Darryle, D. Tetrazole amino acids as competitive NMDA antagonists.
Bioorg. Med. Chem. Lett. 1993, 3, 43–48.

406
V. V. Sureshbabu, S. A. Naik, and G. Nagendra
13. Pozdnev, V. F. Activation of carboxylic acids by pyrocarbonates: Appli-
cation of di-tert-butyl pyrocarbonate as condensing agent in the synthesis
of amides of protected amino acids and peptides. Tetrahedron Lett. 1995,
36, 7115–7118.
14. Kawamoto, I.; Endo, R.; Ishikawa, K.; Kojima, K.; Miyauchi, M.;
Nakayama, E. A convenient synthesis of versatile side-chain intermediates
for carbapenem antibiotics. Synlett 1995, 575–577.
15. (a) Campagna, F.; Carotti, A.; Casini, G. A convenient synthesis of nitriles
from primary amides under mild conditions. Tetrahedron Lett. 1977, 21,
1813–1816; (b) Maetz, P.; Rodriguez, M.
A simple preparation of
N-protected chiral a-aminonitriles from N-protected a-amino acid amides.
Tetrahedron Lett. 1997, 38, 4221–4222; (c) Claremon, D. A.; Phillips, B. T.
An efficient chemoselective synthesis of nitriles from primary amides.
Tetrahedron Lett. 1988, 29, 2155–2158.