A mild and general one-pot preparation of cyanoethyl-protected tetrazoles

Article abstract of DOI:10.1016/j.tetlet.2010.02.034

Described herein is a mild and general one-pot procedure for the conversion of cyanoethyl amides to cyanoethyl-protected tetrazoles with azidotrimethylsilane via the intermediacy of imidoyl chlorides generated in situ with phosphorus pentachloride. This s

Full text of DOI:10.1016/j.tetlet.2010.02.034

Tetrahedron Letters 51 (2010) 2010–2013
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A mild and general one-pot preparation of cyanoethyl-protected tetrazoles
*
Lawrence J. Kennedy
Metabolic Diseases Chemistry, Research and Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Described herein is a mild and general one-pot procedure for the conversion of cyanoethyl amides to cya-
noethyl-protected tetrazoles with azidotrimethylsilane via the intermediacy of imidoyl chlorides gener-
ated in situ with phosphorus pentachloride. This synthetic sequence works well with sterically hindered
amides and is compatible with acid sensitive functionality.
Received 13 November 2009
Revised 3 February 2010
Accepted 5 February 2010
Available online 11 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Dedicated to Professor John E. Sheats on the
occasion of his retirement from Rider
University
The employment of tetrazoles as isosteres of the carboxylic acid
functionality has long been of interest to the medicinal chemistry
community.1 Tetrazoles have similar physicochemical properties
to carboxylates, such as pKa (Fig. 1) and aqueous solubility, yet
are larger and tend to have greater lipophilicity.1c Tetrazoles can
exhibit enhanced receptor binding compared to carboxylates,
which has been attributed to their ability to form two hydrogen
bonds.1a,d–g The successful replacement of carboxylates with tetra-
zoles in marketed drugs1a has driven the search for new methods
for their synthesis.
Tetrazoles are commonly formed from nitriles and an azide
source via a 1,3-dipolar cycloaddition.1a,b Amines, amides and
aldehydes have also been employed, though to a lesser extent. Pro-
gress has been made in synthesizing tetrazoles without the use of
toxic and/or explosive reagents such as azidotrimethylstannane or
hydrazoic acid through the utilization of safer alternatives such as
azidotrimethylsilane (TMS-N3).1a
N
N
O
~
N
=
N
R
R
OH
H
For R = alkyl and aryl, pKa ~4-5
Figure 1.
R2
R2
NH
R2
N
PCl5
X-N3
R1
N
R1
R1
N
N
O
2
Cl
3
N
4
Scheme 1. Tetrazole synthesis via imidoyl chlorides.
hydrogen chloride as a by-product during imidoyl chloride forma-
tion. The hydrogen chloride can have obvious deleterious effects on
acid sensitive functionality. For example, attempts to convert cya-
noethyl amide 2a to tetrazole 4a using phosphorous pentachloride
(1.5 equiv) and azidotrimethylsilane (4 equiv) successively at re-
duced or elevated temperature (40 °C) produced no desired prod-
uct (Scheme 2).4 At reduced temperature (À5 °C) amide 5 and
tetrazole 6 were isolated in 65% and 23%, respectively (Table 1).
At elevated temperature (40 °C), only amide 5 was produced in
71% yield. When the experiment at elevated temperature was re-
peated with excess pyridine present, the desired tetrazole 4a was
provided in good yield (83%).5
To determine the general applicability of this one-pot synthetic
sequence, a series of aliphatic, aromatic, and hetero-aromatic cya-
noethyl amides were prepared and subjected to the same tetra-
zole-forming reaction conditions.6 The prerequisite cyanoethyl
amides 2 were synthesized from the corresponding carboxylic
acids 1.7,8 Treatment of the carboxylic acids with Vilsmeier reagent
A general and efficient route to protected tetrazoles was re-
quired as part of a structure–activity relationship survey in a
medicinal chemistry program. Tetrazoles protected by a cyano-
ethyl group were determined to be essential due to the mild con-
ditions allowed for deprotection (aqueous hydroxide, rt).2 One of
the earliest methods for tetrazole formation involved the conver-
sion of a secondary amide 2 to the corresponding imidoyl chloride
3 followed by treatment with sodium azide (Scheme 1, X = Na)3a,b
or hydrazoic acid (Scheme 1, X = H)3c,d to afford the desired tetra-
zole 4. More recently, the employment of azidotrimethylsilane in
conjunction with imidoyl chlorides has been reported for the gen-
eration of N-alkyl and N-aryl tetrazoles.4
One of the major drawbacks of accessing tetrazoles from amides
via the intermediacy of imidoyl chlorides is the generation of
* Corresponding author. Tel.: +1 609 818 4864.
E-mail address: lawrence.kennedy@bms.com
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.034

L. J. Kennedy / Tetrahedron Letters 51 (2010) 2010–2013
2011
CN
CN
CN
CN
i) PCl5, CH2Cl2
Additive,
SEMO
Cl
SEMO
Cl
Temperature
NH
N
NH
N
N
ii) TMS-N3, r.t
N
N
N
N
O
O
N
2a
4a
5
6
Scheme 2. Effect of pyridine on formation of tetrazole 4a.
Table 1
Effect of pyridine on formation of tetrazole 4a
Conversion of amides 2a–h to the corresponding tetrazoles 4a–
h using the previously described conditions proceeded efficiently
(Table 2, entries 1–8).10,11 The yield of the tetrazoles was reason-
ably consistent (73–86%) and the nature of the R-group appeared
to have little impact. Sterically hindered aliphatic amides 2e–h
were converted as efficiently as their aromatic counterparts
(2a–d). Functional groups such as methoxy and nitro, as well as
SEM, Boc, and acetal protecting groups were unaffected by the
transformation.
Temperature (°C)
Additive
% Yield 4a
% Yield 5
% Yield 6
À5
40
40
None
None
Pyridine
0
0
83
65
71
0
23
0
0
7 resulted in clean and efficient acid chloride formation.9 Addition
of excess 3-aminopropanenitrile provided the desired amides 2a–
h in good to excellent yield (Table 2).
To further explore the ability of pyridine to protect acid sensi-
tive functionality in this transformation, the reactions of amides
Table 2
Synthesis of cyanoethyl amides 2 and tetrazoles 4
i) PCl5, pyridine
CN
CN
i) CH2Cl2, r.t.
CH2Cl2, reflux
R
N
R
OH
R
NH
N
N
ii) 0 oC to r.t.
CN
N
N
ii) TMS-N3, r.t.
O
1
O
2
Cl
7
H2N
4
Entry
1
R
% Yield 2
Tetrazole 4
Method
% Yield 4
4a
Aa
Bb
83
0
86
(2a)
SEMO
F
F
F
4b
A
B
73
26
92
(2b)
2
N
4c
A
B
76
0
98
(2c)
3
4
O
O
4d
A
B
86
21
95
(2d)
Boc NH
4e
4f
A
A
85
73
95
(2e)
5
6
Cl
98
(2f)
O
Ar
4g
4h
A
81
99
(2g)
7
8
Ar = 4-NO2-phenyl
A
77
0
99
(2h)
Cc
Cl
a
b
c
Method A: (i) PCl5, pyridine, CH2Cl2, reflux; (ii) TMS-N3, rt.
Method B: (i) PCl5, CH2Cl2, reflux; (ii) TMS-N3, rt.
Method C: diethylazodicarboxylate, triphenylphosphine, azidotrimethylsilane, THF, rt 16 h, then reflux 8 h.2

2012
L. J. Kennedy / Tetrahedron Letters 51 (2010) 2010–2013
7. (a) All starting acids employed in this study were commercially available with
the exception of 1a. 3-Aminopropanenitrile was purchased stabilized over
potassium carbonate. The Vilsmeier reagent 7 was purchased from Sigma–
2b–d were repeated without pyridine. When the conversion of the
nicotinamide 2b to tetrazole 4b was attempted without pyridine,
product was isolated but the yield was dramatically reduced
(26%, Table 2, entry 2, method B) compared to the identical reac-
tion with pyridine (73%, Table 2, entry 2, method A).12 Attempted
conversion of amide 3c to tetrazole 4c without pyridine produced
no desired product and completely decomposed starting amide 3c
(Table 2, entry 3, method B).12 When amide 2d was subjected to
the reaction without pyridine, unreacted 2d was recovered (11%)
and product tetrazole 4d was isolated in significantly reduced yield
(21%, Table 2, entry 4, method B).12 The presence of pyridine pre-
sumably had a protective effect for acid sensitive functionality by
sequestering hydrogen chloride generated during imidoyl chloride
formation.
The synthesis of cyanoethyl tetrazoles possessing acid sensitive
functionality (Boc-protected amines)13 has been reported under
Mitsunobu-like conditions (diethylazodicarboxylate, triphenyl-
phosphine, azidotrimethylsilane).2 However, this methodology
can fail in sterically demanding systems. For example, when this
synthetic sequence was applied to cyanoethyl amide 2h, no desired
product was detected at ambient or elevated temperature as ana-
lyzed by HPLC and LC–MS (Table 2, entry 8, method C).
In summary, a mild and general method for the conversion of
cyanoethyl amides to the corresponding cyanoethyl-protected tet-
razoles has been described. This procedure differs from other
methods in that it employs pyridine to mitigate the negative ef-
fects of hydrogen chloride generated during imidoyl chloride for-
mation with phosphorous pentachloride. This transformation is
tolerated by a variety of functional groups, is amenable to use with
acid-sensitive functionality, and efficiently converts sterically hin-
dered amides. Furthermore, the reaction does not require hydra-
zoic acid or azide salts, and has the added advantage of being
performed in a one-pot manner.
Aldrich; (b) Preparation of acid 1a: To
(hydroxymethyl)benzoate (332 mg, 2.0 mmol), tetrabutylammonium iodide
(148 mg,0.40 mmol), and triethylamine (558 L, 4.0 mmol) in THF (4.0 mL) was
added (2-(chloromethoxy)ethyl)trimethylsilane (706 L, 4.0 mmol) dropwise
a
solution of methyl 4-
l
l
over 2 min and the resulting mixture heated to 40 °C. After 6 h methanol (2 mL)
was added. After 10 min aqueous lithium hydroxide (3.0 mL, 12.0 mmol, 4 M)
was added and the resulting mixture stirred vigorously. After 20 min the
reaction was cooled to room temperature and the pH adjusted to 2–3 with
concentrated hydrochloric acid, then ethyl acetate/diethyl ether (1:1, 20 mL)
was added. After 20 min the organic layer was separated, dried over sodium
sulfate, and concentrated in vacuo. The resulting residue was purified via flash
chromatography (SiO2, 0–100% ethyl acetate/hexanes) to afford 1a (348 mg,
62%) as a white solid. 1H NMR (400 MHz, CDCl3): d = 8.10 (d, J = 8.2 Hz, 2H),
7.46 (d, J = 8.2 Hz, 2H), 4.79 (s, 2H), 4.69 (s, 2H), 3.68 (t, J = 8.6 Hz, 2H), 0.95 (t,
J = 8.5 Hz, 2H), 0.03 (s, 9H). 13C NMR (100 MHz, CDCl3): d = 171.82, 144.42,
130.35, 128.51, 127.39, 94.41, 68.68, 65.46, 18.08, À1.43. LC–MS: m/z calcd for
C14H21O4Si [MÀH]À 281.1; found: 281.3.
8. Representative experimental procedure for cyanoethyl amides 2a–h: (a) Amide 2a:
To a solution of 1a (282 mg, 1.0 mmol) in dichloromethane (5 mL) was added
1-chloro-N,N,2-trimethylprop-1-en-1-amine (7) (159
over 1 min. After 1 h the reaction mixture was cooled to 0 °C then 3-
aminopropanenitrile (295 L, 4.0 mmol) was added dropwise over 1 min,
lL, 1.2 mmol) dropwise
l
producing a white suspension. After 30 min the cooling bath was removed.
After 1 h a 5% aqueous solution of citric acid (5 mL) was added and the resulting
mixture stirred vigorously for 30 min. The organic phase was separated, dried
over sodium sulfate, and concentrated in vacuo. The resulting residue was
purified via flash chromatography (SiO2, 0–100% ethyl acetate/hexanes) to afford
2a (288 mg, 86%) as a white solid. 1H NMR (400 MHz, CDCl3): d = 7.74 (d,
J = 8.2 Hz, 2H), 7.42 (d, J = 8.3 Hz, 2H), 6.52 (br s, 1H), 4.74 (s, 2H), 4.63 (s, 2H),
3.70 (q, J = 6.2 Hz, 2H), 3.64 (t, J = 8.2 Hz, 2H), 2.73 (t, J = 6.2 Hz, 2H), 0.93 (t,
J = 8.6 Hz, 2H), 0.04 (s, 9H). 13C NMR (100 MHz, CDCl3): d = 167.64, 142.55,
132.63, 127.72, 127.12, 118.26, 94.33, 68.53, 65.41, 36.10, 18.54, 18.11, À1.40.
LC–MS: m/z calcd for C17H25N2O3Si [MÀH]À: 333.2; found: 333.3; (b) Amide 2b
(white solid): 1H NMR (400 MHz, CDCl3): d = 7.85 (d, J = 7.7 Hz, 1H), 7.56 (d,
J = 8.3 Hz, 1H), 6.58 (br s, 1H), 3.71 (q, J = 6.1 Hz, 2H), 2.79 (t, J = 6.1 Hz, 2H), 2.73
(s, 3H). 13C NMR (100 MHz, CDCl3): d = 167.93, 157.48, 148.73 (q, J = 35 Hz),
136.16, 133.40, 121.06 (q, J = 275 Hz), 117.89, 117.61, 36.13, 22.97, 18.39. LC–
MS: m/z calcd for C11H11N3OF3 [M+H]+: 258.1; found: 258.1; (c) Amide 2c (white
solid): 1H NMR (400 MHz, CDCl3): d = 7.72 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.3 Hz,
2H), 6.54 (br s, 1H), 5.09 (t, J = 4.7 Hz, 1H), 3.93–3.88 (m, 2H), 3.87–3.82 (m, 2H),
3.72 (t, J = 6.1 Hz, 2H), 3.03 (d, J = 4.4 Hz, 2H), 2.75 (t, J = 6.3 Hz, 2H). 13C NMR
(100 MHz, CDCl3): d = 167.82, 140.50, 131.77, 130.10, 126.96, 118.34, 103.99,
65.01, 40.52, 36.12, 18.46. LC–MS: m/z calcd for C14H17N2O3 [M+H]+: 261.1;
found: 261.1. (d) Amide 2d (white solid): 1H NMR (400 MHz, DMSO-d6): d = 8.79
(t, J = 5.5 Hz, 1H), 7.80 (d, J = 7.7 Hz, 2H), 7.46 (t, J = 6.1 Hz, 1H), 7.32 (d, J = 8.3 Hz,
2H), 4.17 (d, J = 6.1 Hz, 2H), 3.48 (q, J = 6.1 Hz, 2H), 2.77 (t, J = 6.6 Hz, 2H), 1.40 (s,
9H). 13C NMR (100 MHz, DMSO-d6): d = 166.24, 155.70, 143.68, 132.22, 127.11,
126.63, 119.19, 77.80, 43.04, 35.33, 28.12, 17.41. LC–MS: m/z calcd for
C16H21N3O3 [MÀH]À: 302.2; found: 302.4; (e) Amide 2e (white solid): 1H NMR
(400 MHz, CDCl3): d = 7.32–7.25 (m, 4H), 5.96 (br s, 1H), 3.58–3.50 (m, 1H), 3.42–
3.34 (m, 1H), 2.82 (d, J = 10.1 Hz, 1H), 2.69–2.61 (m, 1H), 2.56–2.49 (m, 1H), 2.41–
2.32 (m, 1H), 1.04 (d, J = 6.6 Hz, 3H), 0.71 (d, J = 7.2 Hz, 3H) . 13C NMR (100 MHz,
CDCl3): d = 173.69, 137.29, 133.11, 129.52, 128.68, 118.11, 60.91, 35.69, 31.61,
21.42, 20.21, 18.36. LC–MS: m/z calcd for C14H18N2OCl [M+H]+: 265.1; found:
265.3; (f) Amide 2f (white solid): 1H NMR (400 MHz, CDCl3): d = 7.32 (d,
J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 5.63 (br s, 1H), 3.81 (s, 3H), 3.36 (q,
J = 6.2 Hz, 2H), 2.54 (t, J = 6.3 Hz, 2H), 2.24–2.18 (m, 2H), 2.07–1.99 (m, 2H), 1.64–
1.55 (m, 2H), 1.53–1.42 (m, 4H), . 13C NMR (100 MHz, CDCl3): d = 177.23, 158.41,
134.40, 127.82, 117.96, 114.32, 55.27, 55.17, 50.23, 35.79, 34.22, 25.72, 22.61,
18.08. LC–MS: m/z calcd for C17H23N2O2 [M+H]+: 287.2; found: 287.5; (g) Amide
2g (white solid): 1H NMR (400 MHz, CDCl3): d = 8.18 (d, J = 8.8 Hz, 2H), 7.52 (d,
J = 9.3 Hz, 2H), 6.09 (br s, 1H), 3.52 (q, J = 6.4 Hz, 2H), 2.65 (t, J = 6.1 Hz, 2H), 2.37–
2.30 (m, 2H), 2.05–2.01 (m, 2H), 1.98–1.87 (m, 8H), 1.81–1.75 (m, 2H). 13C NMR
(100 MHz, CDCl3): d = 177.69, 157.09, 146.12, 125.88, 123.50, 118.16, 43.93,
41.66, 38.22, 37.33, 35.54, 35.28, 28.53, 18.31. LC–MS: m/z calcd for C20H24N3O3
[M+H]+: 354.2; found: 354.3; (h) Amide 2h (white solid): 1H NMR (400 MHz,
CDCl3): d = 7.36–7.29 (m, 4H), 5.65 (br s, 1H), 3.40 (q, J = 6.1 Hz, 2H), 2.59 (t,
J = 6.3 Hz, 2H), 1.56 (s, 6H). 13C NMR (100 MHz, CDCl3): d = 177.59, 124.95,
133.16, 128.94, 127.80, 117.88, 46.67, 35.86, 26.91, 18.00. LC–MS: m/z calcd for
C13H16N2OCl [M+H]+: 251.1; found: 251.1; (i) Amide 5: (white solid): 1H NMR
(400 MHz, CDCl3): d = 7.78 (d, J = 8.2 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H), 6.56 (br s,
1H), 4.62 (s, 2H), 3.73 (q, J = 6.4 Hz, 2H), 2.76 (t, J = 6.1 Hz, 2H). 13C NMR
(100 MHz, CDCl3): d = 167.37, 141.36, 133.39, 128.79, 127.47, 118.29, 45.25,
36.17, 18.46. LC–MS: m/z calcd for C11H12N2OCl [M+H]+: 223.1; found: 223.1.
9. Devos, A.; Remion, J.; Frisque-Hesbain, A.-M.; Colens, A.; Ghosez, L. J. Chem. Soc.,
Chem. Commun. 1979, 24, 1180.
Acknowledgments
I would like to thank Scott A. Shaw, Bruce A. Ellsworth, Jeffrey A.
Robl, and Jun Li for many helpful discussions.
References and notes
1. (a) Herr, R. J. Bioorg. Med. Chem. 2002, 10, 3379; (b) Butler, R. N.. In
Comprehensive Heterocyclic Chemistry; Katritsky, A. R., Rees, C. W., Eds.;
Pergamon Press: Oxford, 1984; Vol. 5, pp 791–838; (c) Hansch, C.; Leo, L.
Exploring QSAR. Fundamentals and Applications in Chemistry and Biology;
American Chemical Society: Washington, DC, 1995. Chapter 13; (d) Peters, L.;
Frolich, R.; Boyd, A. S. F.; Kraft, A. J.Org. Chem. 2001, 66, 3291; (e) Goldgur, Y.;
Craigie, R.; Cohen, G. H.; Fujiwara, T.; Yoshinaga, T.; Fujishita, T.; Sugimoto, H.;
Endo, T.; Murai, H.; Davies, D. R. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 13040; (f)
Wexler, R. R.; Greenlee, W. J.; Irvin, J. D.; Goldberg, M. R.; Prendergast, K.;
Smith, R. D.; Timmermans, P. B. M. W. M. J. Med. Chem. 1996, 39, 625; (g) Noda,
K.; Saad, Y.; Kinoshita, A.; Boyle, T. P.; Graham, R. M.; Husain, A.; Karnik, S. S. J.
Biol. Chem. 1995, 270, 2284.
2. Duncia, J. V.; Pierce, M. E.; Santella, J. B., III J. Org. Chem. 1991, 56, 2395.
3. (a) Forster, M. O. J. Chem. Soc. 1909, 95, 184; (b) Schroeter, G. Ber. 1909, 42,
2336; (c) von Braun, J.; Rudolph, W. Ber. 1941, 74, 264; (d) Harvill, E. K.; Herbst,
R. M.; Schreiner, E. C.; Roberts, C. W. J. Org. Chem. 1950, 15, 662.
4. For examples of the synthesis of tetrazoles from amides using phosphorous
pentachloride and azidotrimethylsilane, see: (a) Wu, S.; Fluxe, A.; Sheffer, J.;
Janusz, J. M.; Blass, B. E.; White, R.; Jackson, C.; Hedges, R.; Murawsky, M.; Fang,
B.; Fadayel, G. M.; Hare, M.; Djandjighian, L. Biorg. Med. Chem. Lett. 2006, 16,
6213; For examples involving tin(IV) chloride catalysis, see: (b) Boyko, V.;
Rodik, R.; Danylyuk, O.; Tsymbal, L.; Lampeka, Y.; Suwinska, K.; Lipkowski, J.;
Kalchenko, V. Tetrahedron 2005, 61, 12282; (c) Yu, K. L.; Johnson, R. L. J. Org.
Chem. 1987, 52, 2051.
5. (a) Elevated temperature (40 °C) was found to be optimal, compared to reduced
or ambient temperature, for complete conversion of the starting amide to the
corresponding imidoyl chloride; (b) Addition of 1–2 equiv of azidotri-
methylsilane typically resulted in incomplete tetrazole formation.
10. Representative experimental procedure for tetrazoles 4a–h: (a) Tetrazole 4a: To a
solution of amide 2a (167 mg, 0.50 mmol) and pyridine (243 lL, 3.0 mmol) in
dichloromethane (5 mL) was added phosphorous pentachloride (156 mg,
0.75 mmol) and the resulting mixture heated to reflux. After 3 h the reaction
6. All amide-forming reactions were performed on
a 1–2 mmol scale. All
mixture was cooled to room temperature and azidotrimethylsilane (265
2.0 mmol) was added. After 16 h the reaction mixture was carefully quenched
with freshly prepared saturated aqueous sodium bicarbonate (ꢀ200 L), then
lL,
tetrazole-forming reactions were performed on a 0.5 mmol scale. Reaction
conditions are not optimized.
l

L. J. Kennedy / Tetrahedron Letters 51 (2010) 2010–2013
2013
excess saturated aqueous sodium bicarbonate (ꢀ2 mL) was added and the
resulting mixture stirred vigorously for 15 min. The organic layer was
separated, dried over sodium sulfate, and concentrated in vacuo. The
resulting residue was purified via flash chromatography (SiO2, 0–100% ethyl
acetate/hexanes) to furnish tetrazole 4a (149 mg, 83%) as a colorless oil: 1H
NMR (400 MHz, CDCl3): d = 7.68 (d, J = 7.5 Hz, 2H), 7.60 (d, J = 7.6 Hz, 2H), 4.81
(s, 2H), 4.72 (s, 2H), 4.68 (t, J = 6.9 Hz, 2H), 3.69 (t, J = 7.2 Hz, 2H), 3.14 (t,
J = 7.2 Hz, 2H), 0.97 (t, J = 8.3 Hz, 2H), 0.04 (s, 9H) . 13C NMR (100 MHz, CDCl3):
d = 154.72, 142.47, 128.96, 128.48, 121.96, 115.45, 94.43, 68.35, 65.49, 43.25,
18.51, 18.08, À1.43. LC–MS: m/z calcd for C17H26N5O2Si [M+H]+: 360.2; found:
360.5; (b) Tetrazole 4b (colorless oil): 1H NMR (400 MHz, CDCl3): d = 7.98 (d,
J = 7.7 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 4.53 (t, J = 6.3 Hz, 2H), 3.14 (t, 6.3 Hz,
2H), 2.54 (s, 3H). 13C NMR (100 MHz, CDCl3): d = 159.30, 152.63, 150.31 (q,
J = 35 Hz), 139.82, 121.66, 120.93 (q, J = 275 Hz), 118.07, 115.51, 43.18, 22.95,
18.82. LC–MS: m/z calcd for C11H10N6F3 [M+H]+: 283.1; found: 283.2; (c)
Tetrazole 4c (white solid): 1H NMR (400 MHz, CDCl3): d = 7.62 (d, J = 8.3 Hz,
2H), 7.52 (d, 8.3 Hz, 2H), 5.13 (t, J = 4.7 Hz, 1H), 4.68 (t, J = 7.2 Hz, 2H), 3.99–
3.84 (m, 4H), 3.13 (t, J = 7.2 Hz, 2H), 3.08 (d, J = 4.4 Hz, 2H). 13C NMR (100 MHz,
CDCl3): d = 154.82, 140.45, 131.04, 128.74, 121.10, 115.48, 103.84, 65.05,
43.23, 40.52, 18.48. LC–MS: m/z calcd for C14H16N5O2 [M+H]+: 286.1; found:
286.4; (d) Tetrazole 4d (white solid): 1H NMR (400 MHz, CDCl3): d = 7.65 (d,
J = 8.2 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 5.04 (br s, 1H), 4.67 (t, J = 6.9 Hz, 2H),
4.43 (d, J = 6.1 Hz, 2H), 3.14 (t, J = 6.9 Hz, 2H), 1.48 (s, 9H). 13C NMR (100 MHz,
CDCl3): d = 155.96, 154.67, 143.41, 129.09, 128.13, 121.63, 115.55, 79.88,
44.04, 43.23, 28.33, 18.46. LC–MS: m/z calcd for C16H21N6O2 [M+H]+: 329.2;
found: 329.4; (e) Tetrazole 4e (white solid): 1H NMR (400 MHz, CDCl3):
d = 7.34–7.30 (m, 2H), 7.24–7.20 (m, 2H), 4.49–4.33 (m, 2H), 3.74 (d, J = 9.6 Hz,
1H), 2.99–2.91 (m, 1H), 2.81–2.66 (m, 2H), 1.05 (d, J = 6.6 Hz, 3H), 0.88 (d,
J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): d = 156.56, 136.12, 134.06, 129.68,
129.41, 115.62, 48.28, 42.34, 33.08, 21.57, 20.50, 18.40. LC–MS: m/z calcd for
C14H17N5Cl [M+H]+: 290.1; found: 290.3; (f) Tetrazole 4f (white solid): 1H NMR
(400 MHz, CDCl3): d = 7.12 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 9.3 Hz, 2H), 4.07 (t,
J = 7.4 Hz, 2H), 3.81 (s, 3H), 2.53–2.44 (m, 2H), 2.38 (t, J = 7.4 Hz, 2H), 2.20–2.08
(m, 2H), 1.76–1.61 (m, 5H), 1.50–1.38 (m, 1H). 13C NMR (100 MHz, CDCl3):
d = 159.83, 158.84, 135.01, 127.42, 25.44, 22.48, 17.27. LC–MS: m/z calcd for
C17H22N5O [M+H]+: 312.2; found: 312.2; (g) Tetrazole 4g (white solid): 1H NMR
(400 MHz, DMSO-d6): d = 8.17 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H), 4.88 (t,
J = 6.3 Hz, 2H), 3.22 (t, J = 6.3 Hz, 2H), 2.30–2.24 (m, 2H), 2.23–2.20 (m, 2H),
2.15–2.08 (m, 4H), 2.06–1.98 (m, 2H), 1.95–1.87 (m, 2H), 1.86–1.79 (m. 1H),
1.78–1.71 (m, 1H). 13C NMR (100 MHz, DMSO-d6): d = 160.01, 157.32, 145.66,
126.54, 123.27, 117.94, 44.04, 43.89, 50.40, 38.12, 37.06, 34.27, 28.02, 18.26 .
LC–MS: m/z calcd for C20H23N6O2 [M+H]+: 379.2; found: 379.3; (h) Tetrazole
(white solid) 4h: 1H NMR (400 MHz, CDCl3): d = 7.38 (d, J = 8.8 Hz, 2H), 7.10 (d,
J = 8.3 Hz, 2H), 3.95 (t, J = 7.2 Hz, 2H), 2.78 (t, J = 6.9 Hz, 2H), 1.86 (s, 6H). 13C
NMR (100 MHz, CDCl3): d = 160.66, 142.17, 134.02, 129.72, 126.96, 115.38,
43.45, 38.45, 28.86, 17.45. LC–MS: m/z calcd for C13H15N5Cl [M+H]+: 276.1;
found: 276.1; (i) Tetrazole 6 (colorless oil): 1H NMR (400 MHz, CDCl3): d = 7.70
(d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 4.69 (t, J = 6.5 Hz, 2H), 4.67 (s, 2H),
3.15 (t, J = 6.9 Hz, 2H). 13C NMR (100 MHz, CDCl3): d = 154.46, 141.36, 129.62,
129.34, 122.87, 115.45, 45.05, 43.33, 18.56. LC–MS: m/z calcd for C11H11N5Cl
[M+H]+: 248.1; found: 248.1.
11. In an attempt to limit the potential formation of hydrazoic acid during work-
up, the reactions were quenched with aqueous sodium bicarbonate.
Throughout the course of this study it was found that a freshly prepared
solution of sodium bicarbonate (pH ꢀ8) was optimal to work up the reactions.
Sodium bicarbonate solution becomes more basic over time (to pH ꢀ10),
which can lead to partial cleavage of the cyanoethyl-protecting group (5–10%).
12. Numerous unidentified species were observed via HPLC and LC–MS analysis.
13. Hernandez, A. S.; Cheng, P. T. W.; Musial, C. M.; Swartz, S. G.; George, R. J.;
Grover, G.; Slusarchyk, D.; Seethala, R. K.; Smith, M.; Dickinson, K.; Giupponi,
L.; Longhi, D. A.; Flynn, N.; Murphy, B. J.; Gordon, D. A.; Biller, S. A.; Robl, J. A.;
Tino, J. A. Bioorg. Med. Chem. Lett. 2007, 17, 5928.