Synthesis of tetrazolo[1,5-a]pyridines utilizing trimethylsilyl azide and tetrabutylammonium fluoride hydrate

Article abstract of DOI:10.1055/s-0028-1083233

A method for the preparation of tetrazolo[1,5-a]pyridines from 2-halopyridines, utilizing trimethylsilyl azide in the presence of tetrabutylammonium fluoride hydrate, is described. In addition, 8-bromotetrazolo[1,5-a]pyridine is further transformed into a variety of novel tetrazolo[1,5-a]pyridine derivatives. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083233

4002
PAPER
Synthesis of Tetrazolo[1,5-a]pyridines Utilizing Trimethylsilyl Azide and
Tetrabutylammonium Fluoride Hydrate
Synthesis
o
of Tetrazolo[
y
1,5-
a
]pyridi
d
Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham & Women’s Hospital
and Harvard Medical School, Cambridge, MA 02139, USA
Fax +1(617)7688606; E-mail: gcuny@rics.bwh.harvard.edu
Received 9 July 2008; revised 22 August 2008
cleophilic displacement and the additional bromide at the
Abstract: A method for the preparation of tetrazolo[1,5-a]py-
ridines from 2-halopyridines, utilizing trimethylsilyl azide in the
presence of tetrabutylammonium fluoride hydrate, is described. In
addition, 8-bromotetrazolo[1,5-a]pyridine is further transformed
into a variety of novel tetrazolo[1,5-a]pyridine derivatives.
3-position could serve as a synthetic handle for further
functionalization of the tetrazolo[1,5-a]pyridine. The re-
action of 1 with either sodium, tetrabutylammonium or
trimethylsilyl azide utilizing various additives, solvents,
temperatures and times was examined.
Key words: tetrazolo[1,5-a]pyridines, 2-halopyridines, trimethyl-
silyl azide, tetrabutylammonium fluoride hydrate, palladium cou-
pling
Table 1 Conversion of 1 into 2 under Various Conditions
Br
Br
RN3, additive
solvent, temp,
time
N
Br
N
Tetrazolo[1,5-a]pyridines are an interesting class of het-
erocycles that have been utilized to synthesize 2-cyanopy-
rroles,1a substituted 1,3-diazepines,1b pyrido-2,3-
furoxanes,1c,d and 2-aminopyridines.1e In some cases the
tetrazolo[1,5-a]pyridines exist in equilibrium with the
corresponding 2-azidopyridines.2 Substituents on the het-
erocyclic ring can influence this equilibrium, but in most
instances the tetrazole is either the predominant or the ex-
clusive species.
N
N
N
1
2
Entry Ra
Additiveb
Solvent
Temp Time Yield
(°C) (h) (%)
1
2
3
4
5
6
7
8
9
Na
–
DMF
DMF
DMF
DMF
MeOH
60
95
95
95
60
24
70
24
24
18
24
24
24
60
24
24
0
Na
–
25c
40c
40c
0
Na
18-crown-6
Tetrazolo[1,5-a]pyridines are prepared either by heating
2-halopyridines with sodium azide in a polar solvent,3 or
by allowing pyridine N-oxides to react with toluenesulfo-
nyl azide,4 or diphenyl phosphoryl azide,5,6 or by treat-
ment of N-(methylsulfonyloxy)pyridinium chlorides
generated in situ with trimethysilyl azide (TMSN3).7 Gen-
erally, high temperatures are required to facilitate the nu-
cleophilic displacement of the halogen by azide ion. The
synthesis of tetrazolo[1,5-a]pyridines from pyridine N-
oxides also suffers from several disadvantages, including
the need for high temperature and a lack of regioselectiv-
ity. Interestingly, during the synthesis of tetrazol-5-yl py-
ridines from N-fluoropyridinium fluorides generated in
situ in the presence of TMSN3 and isonitriles, tetrazo-
lo[1,5-a]pyridines were produced as minor byproducts.8
Herein we report a convenient method for the preparation
of tetrazolo[1,5-a]pyridines from 2-halopyridines. In ad-
dition, one of the tetrazolo[1,5-a]pyridine products is fur-
ther transformed into a variety of novel tetrazolo[1,5-
a]pyridine derivatives.
Na
Bu4NBr
Na
Bu4NBr
Na
–
DMF–H2O (4:1) 95
DMF–H2O (4:1) 95
50d
75d
40c
48c
90d
Na
Bu4NBr
Bu4Nb
TMS
–
–
DMF
DMF
95
95
85
85
10 TMS TBAF·xH2O DMF (1.5 M)
11 TMS TBAF·xH2O
–
90c
100d
a 2 equiv.
b 1 equiv.
c Isolated yield.
d Conversion determined by reverse-phase HPLC analysis.
Heating a mixture of 1 and sodium azide at 60 °C in DMF
for 24 hours did not produce any product (Table 1, entry
1). However, elevating the temperature to 95 °C and pro-
longing the reaction time to 70 hours gave 29 in 25% yield
(entry 2). Addition of the phase-transfer reagents 18-
crown-6 or tetrabutylammonium bromide (TBAB) in-
creased the yield to 40% (entries 3 and 4). Utilizing meth-
anol as solvent was detrimental (entry 5), but using a
2,3-Dibromopyridine (1) was chosen as the starting mate-
rial for the initial optimization reaction because a bromide
at the 2-position of the pyridine ring could facilitate nu-
SYNTHESIS 2008, No. 24, pp 4002–4006
x
x.
x
x
.
2
0
0
8
Advanced online publication: 14.11.2008
DOI: 10.1055/s-0028-1083233; Art ID: M03508SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Tetrazolo[1,5-a]pyridines
4003
mixture of DMF–H2O (4:1) without an additive (entry 6) The scope of the reaction under the optimized conditions
or in the presence of TBAB (entry 7) resulted in 50% and was then examined by employing an array of 2-halopy-
75% conversion of 1 into 2, respectively. Tetrabutylam- ridines, as well as 2-chloroquinoline and 1-chloroisoquin-
monium azide (entry 8) resulted in a conversion yield sim- oline, to give a variety of substituted tetrazolo[1,5-
ilar to that obtained using a combination of TBAB and a]pyridines, tetrazolo[1,5-a]quinoline and tetrazolo[5,1-
sodium azide. TMSN3 proved to be better as an azide a]isoquinoline, respectively. For example, 2-bromopyri-
source (entry 9). Furthermore, TMSN3 in the presence of dine readily underwent cyclization to give 31d in 91%
tetrabutylammonium fluoride hydrate (TBAF·xH2O) in yield (Table 2, entry 2). Interestingly, 2-bromopyridines
DMF at 85 °C for 24 hours gave a 90% conversion of 1 with an additional bromide in the 4- or 6-positions were
into 2 (entry 10). Parenthetically, heating 1 in the presence poor substrates. In the case of 2,4-dibromopyridine (entry
of TBAF·xH2O (1 equiv) in DMF at 95 °C for 24 hours 3), tetrazole 4 was isolated in only 12% yield along with
did not result in exchange of the 2-bromo substituent with 7-azidotetrazolo[1,5-a]pyridine (5), in 37% yield, which
fluoride, although such a reaction has been reported for a was produced by addition of a second equivalent of azide.
different 2-bromopyridine derivative at higher tempera- In the case of 2,6-dibromopyridine, no tetrazole product
ture and in the presence of 20 equivalents of anhydrous was isolated (entry 5). Similarly, a 2-bromo-6-piperi-
TBAF.10 Also, heating a solution of 2-fluoro-3-bromopy- zinepyridine derivative also did not afford any tetrazole
ridine in TMSN3 at 95 °C for 24 hours did not yield 2. (entry 6). However, 2-bromo-6-methylpyridine gave the
These two observations suggest that the 2-fluoropyridine corresponding tetrazole 71a in 76% (entry 7). On the other
derivative is not participating as an intermediate in the hand, 2,5-dibromopyridine was an excellent substrate,
transformation of 1 into 2 in the presence of TMSN3 and giving 62c in 85% yield (entry 4). 2-Chloropyridine deriv-
TBAF·xH2O. Finally, utilizing TMSN3 (2.0 equiv) in the atives could also be utilized as substrates. For example, 3-
presence of TBAF·xH2O (1.0 equiv) without solvent, at bromo-2-chloropyridine gave 2 in 83% yield (entry 8).
85 °C for 24 hours, gave a 100% conversion and a 90% Pyridine substrates containing a fused ring, such as 2-
isolated yield of 2 (entry 11).11 Two equivalents of chloroquinoline and 2-cholorisoquinoline, formed fused
TMSN3 was necessary; one equivalent resulted in a signif- tetrazolo[1,5-a]pyridines12,13 in excellent yields (entries 9
icant amount of unreacted 1 remaining after 24 hours.
and 10). Finally, the optimized reaction conditions were
also found to be compatible with other functional groups.
For example, ethyl 2-chloronicotinate and 2,3-dichloro-5-
trifluoromethylpyridine afforded 101c and 112a in 81% and
78% yields, respectively (entries 11 and 12).
Table 2 Synthesis of Tetrazolo[1,5-a]pyridines
R2
R1
8
TMSN3 (2 equiv)
3
Reactions of tetrazolo[1,5-a]pyridines have been limited
to a few examples, such as reduction of the pyridine ring
to give aliphatic tetrazoles,14 and alkylation15 or
arylation16 of the tetrazole to give N-substituted bicyclic
tetrazoles. Therefore, the reactivity of 8-bromotetrazo-
lo[1,5-a]pyridine was studied in order to further explore
the chemistry of this interesting heterocycle (Scheme 1).
For example, arylation of 2 with phenylboronic acid or 2-
chlorophenylboronic acid under Suzuki reaction
conditions15 gave 12 or 13 in 100% and 43% yields, re-
spectively. Arylamination of 2 with aniline utilizing a pal-
ladium-mediated reaction gave 14 in 52% yield.18
Functional group transformation of the aryl bromide to an
acetyl group was achieved utilizing a Stille coupling with
tributyl(1-ethoxyvinyl)tin, followed by hydrolysis in situ
to afford 15 in 49% yield.19 Finally, anion generation with
n-BuLi or LDA at –78 °C, followed by addition of methyl
iodide, gave 16 in 41% isolated yield (based on recovered
starting material).20 Hydrogenation of 16 using 10% Pd/C
gave 7 in 54% yield, providing further structural confir-
mation of 16.
TBAF•xH2O (1 equiv)
6
5
N
N
X
N
neat, 85 °C, 24 h
N
N
Entry
X
R1
Product
(% yield)
R2
1
2
3
Br
Br
Br
3-Br
–
2 (90)
3 (91)
8-Br
–
4-Br
4 (12)
7-Br
7-N3
5 (37)a
4
5
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
5-Br
6-Br
6 (85)
–
6-Br
–
6
6-N-Boc-Pipb
6-Me
–
–
7
7 (76)
2 (83)
8 (88)
9 (95)
10 (81)
11 (78)c
5-Me
8
3-Br
8-Br
9
5,6-benzo
3,4-benzo
3-CO2Et
3-Cl-5-CF3
5,6-benzo
7,8-benzo
8-CO2Et
8-Cl-6-CF3
10
11
12
All of the products synthesized herein existed exclusively
in the tetrazole form in the solid state. IR spectra on KBr
plates for all the products, with the exception of 5 which
incorporates a second equivalent of azide, lacked absorp-
tion in the azide diagnostic region (2120–2160 cm–1).
a 94% pure as determined by reverse-phase HPLC analysis.
b Pip = piperazinyl.
c Tetrazole–azide (3:1) in CDCl3 as determined by 1H NMR.
1
Similarly, H NMR spectra of the products recorded in
two different solvents (CDCl3 and DMSO-d6) indicated
Synthesis 2008, No. 24, 4002–4006 © Thieme Stuttgart · New York

4004
J. K. Laha, G. D. Cuny
PAPER
ArB(OH)2, Na2CO3,
R
N
Pd(PPh3)4, DMF
Unless otherwise noted, all reagents and solvents were purchased
from commercial sources and used without further purification. De-
gassed solvents were used in all of the palladium-coupling reactions
and performed under positive pressure of argon. NMR spectra were
obtained using a Varian 500 MHz spectrometer. All 1H NMR spec-
tra are reported in d units (ppm) and referenced to tetramethylsilane
(TMS). All 13C NMR spectra are reported in d units (ppm) and ref-
erenced to the central line of the CDCl3 triplet at d = 77.23 ppm.
Column chromatography was performed on a CombiFlash Sg 100c
separation system (ISCO) with disposable silica gel columns
(Luknova). IR spectra were recorded on a Perkin-Elmer System
2000 FT-IR spectrophotometer. High-resolution mass spectra were
carried out on an Agilent 6210 Time-of-Flight LC/MS with ESI+
mode using direct flow injection. Elemental analyses were per-
formed by Perkin-Elmer 2400 CHN analyzer. Melting points were
recorded on a Mel-Temp® melting point apparatus and are uncor-
rected.
80 °C, 18 h
N
N
N
12 R = Ph (100%)
13 R = 2-ClC6H4 (43%)
PhNH2, Cs2CO3,
Pd(OAc)2, BINAP,
NHPh
toluene, 110 °C, 18 h
52%
N
N
N
N
14
2
SnBu3
OEt
Me
O
Cs2CO3, Pd(PPh3)2Cl2
toluene, 110 °C, 24 h,
then aq HCl
Tetrazolo[1,5-a]pyridines; Typical Procedure for 8-Bromo-
tetrazolo[1,5-a]pyridine (2)9
N
N
N
N
Into a screw-capped vial equipped with a magnetic stirring bar were
added 1 (237 mg, 1.00 mmol) and TBAF·xH2O (262 mg, 1.00
mmol). TMSN3 (230 mg, 2.00 mmol) was then added slowly to the
solid mixture (CAUTION: exothermic reaction). After the vigor-
ous reaction subsided, the vial was sealed and heated under vigor-
ous stirring at 85 °C for 24 h. The heterogeneous mixture was
transferred to a flask using a mixture of 2 N NH3 in MeOH–CH2Cl2
(2:98) and then concentrated under reduced pressure. EtOAc (40
mL) was added to the residue and the solution was washed sequen-
tially with H2O (2 × 10 mL) and brine (1 × 10 mL), dried with anhyd
Na2SO4, filtered and concentrated to give a crude product that was
purified by column chromatography (silica gel; 0–2% 2 N NH3 in
MeOH–CH2Cl2, 2:98) to give 2.9
49%
15
n-BuLi or LDA,
THF, –78 °C, 1 h
Br
then MeI
–78 °C to –20 °C, 1 h
41%
Me
N
N
N
N
16
Scheme 1 Tetrazolo[1,5-a]pyridines prepared from 2
Yield: 180 mg (90%); pale-yellow solid; mp 217–219 °C.
IR (KBr): 939, 1101, 1406, 1480, 3024–3110 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.14 (t, J = 7.0 Hz, 1 H), 7.89 (d,
J = 7.0 Hz, 1 H), 8.81 (d, J = 7.0 Hz, 1 H).
the presence of only one form in solution, except in the
case of 11,2a which was in equilibrium with the azide form
(tetrazole/azide = 3:1 in CDCl3; Table 2, entry 12). At-
tempts to trap the azido form of 12 in solution through the
reaction with triphenylphosphine, via a Staudinger reac-
tion, were unsuccessful and only resulted in recovered
starting material. These results are consistent with pre-
dominance of the tetrazole form. In addition, compound
12 demonstrated remarkable stability in strong acid,
which is again indicative of the tetrazole form and is in ac-
cordance with the literature.2d In the case of compound 11,
treatment with triphenylphosphine gave 3-chloro-5-tri-
fluoromethyl-N-(triphenylphosphoranylidene)-2-pyridin-
amine (17) in 98% yield, which confirms the presence of
the azide form in solution.
Anal. Calcd for C5H3BrN4: C, 30.18; H, 1.52; N, 28.15. Found: C,
30.39; H, 1.47; N, 27.95.
Tetrazolo[1,5-a]pyridine (3)1d
Yield: 91%; pale-yellow solid; mp 161–163 °C.
IR (KBr): 1492, 3033–3127 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.24–7.26 (m, 1 H), 7.67–7.71 (m,
1 H), 8.07 (d, J = 9.0 Hz, 1 H), 8.85 (d, J = 9.0 Hz, 1 H).
Anal. Calcd for C5H4N4: C, 50.00; H, 3.36; N, 46.65. Found: C,
49.88; H, 3.09; N, 46.33.
7-Bromotetrazolo[1,5-a]pyridine (4)
Yield: 12%; pale-yellow solid; mp 152–154 °C.
IR (KBr): 1099, 1471, 1621, 3018–3111 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.33 (d, J = 9.0 Hz, 1 H), 8.25 (s,
In summary, a method for the preparation of tetrazolo[1,5-
a]pyridines from 2-halopyridines, utilizing trimethylsilyl
azide in the presence of tetrabutylammonium fluoride hy-
drate, has been developed. One derivative, 8-bromotetra- 1 H), 8.71 (d, J = 9.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 118.5, 121.0, 125.7, 126.7.
zolo[1,5-a]pyridine (2), was further transformed into a
variety of novel tetrazolo[1,5-a]pyridine derivatives.
These methods will facilitate the synthesis of additional
tetrazolo[1,5-a]pyridine derivatives that can be used for
various applications, including screening for biological
activities.
Anal. Calcd for C5H3BrN4: C, 30.18; H, 1.52; N, 28.15. Found: C,
30.04; H, 1.59; N, 27.86.
7-Azidotetrazolo[1,5-a]pyridine (5)
Yield: 37%; yellow solid; mp 175 °C (dec.).
IR (KBr): 1232, 1450, 1642, 2142, 3037–3116 cm–1.
Synthesis 2008, No. 24, 4002–4006 © Thieme Stuttgart · New York

PAPER
Synthesis of Tetrazolo[1,5-a]pyridines
4005
1H NMR (500 MHz, DMSO-d6): d = 7.23 (d, J = 7.5 Hz, 1 H), 7.98
(s, 1 H), 9.31 (d, J = 7.5 Hz, 1 H).
HRMS: m/z [M + H]+ calcd for C6H2ClF3N4: 222.9992; found:
222.9996.
13C NMR (125 MHz, CDCl3): d = 102.8, 112.5, 128.1, 146.0, 149.7.
8-Phenyltetrazolo[1,5-a]pyridine (12)
Bulk material was 94% pure as determined by reverse-phase HPLC
analysis (column: Zorbax SB-C8, 4.6 x 30 mm, 3.5 micron; injec-
tion volume: 5 mL; sample concentration: 1 mg/mL in MeCN; l =
254 nm; gradient: 5% MeCN in H2O to 95% MeCN in H2O over 2.5
min; total run time: 2.5 min; elution rate: 3 mL/min). An analytical-
ly pure sample was prepared after several purifications using silica
gel chromatography.
A mixture of 2 (70 mg, 0.35 mmol), phenylboronic acid (52 mg,
0.42 mmol), Pd(PPh3)4 (29 mg, 0.025 mmol), and Na2CO3 (56 mg,
0.53 mmol, dissolved in minimum amount of H2O) in DMF (3.5
mL) was heated at 80 °C for 18 h under an argon atmosphere. The
solvent was removed under reduced pressure and excess EtOAc (30
mL) was added to the solid residue. The organic layer was washed
sequentially with H2O (2 × 5 mL) and brine (1 × 5 mL), dried over
anhyd Na2SO4, filtered and concentrated. The residue was purified
by column chromatography (silica gel; 0–2% 2 N NH3 in MeOH–
CH2Cl2, 1:99) to give 12.
Anal. Calcd for C5H3N7: C, 37.27; H, 1.88; N, 60.85. Found: C,
37.55; H, 2.08; N, 60.58.
6-Bromotetrazolo[1,5-a]pyridine (6)2c
Yield: 85%; white solid; mp 156–158 °C.
IR (KBr): 1480, 3069–3114 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.75 (d, J = 9.0 Hz, 1 H), 7.97 (d,
J = 9.0 Hz, 1 H), 9.00 (br s, 1 H).
Yield: 68 mg (100%); white solid; mp 118–120 °C.
IR (KBr): 762, 3056–3114 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.32 (t, J = 6.0 Hz, 1 H), 7.51–
7.53 (m, 1 H), 7.57 (t, J = 7.0 Hz, 2 H), 7.83 (d, J = 6.0 Hz, 1 H),
8.14 (d, J = 7.0 Hz, 2 H), 8.81 (d, J = 6.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 117.2, 124.0, 128.7, 128.8, 129.3,
130.0, 130.1, 133.7, 148.2.
Anal. Calcd for C5H3BrN4: C, 30.18; H, 1.52; N, 28.15. Found: C,
30.50; H, 1.59; N, 28.00.
Anal. Calcd for C11H8N4: C, 67.34; H, 4.11; N, 28.55. Found: C,
67.03; H, 4.06; N, 28.55.
5-Methyltetrazolo[1,5-a]pyridine (7)1a
Yield: 76%; white solid; mp 157–159 °C.
IR (KBr): 803, 1509, 1639, 3066–3101 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.96 (s, 3 H), 7.01 (d, J = 7.0 Hz,
1 H), 7.61 (dd, J = 9.0, 7.0 Hz, 1 H), 7.92 (d, J = 7.0 Hz, 1 H).
8-(2-Chlorophenyl)tetrazolo[1,5-a]pyridine (13)
Prepared in the same manner as 12, except using 2-chlorophenylbo-
ronic acid.
Yield: 43%; white solid; mp 156–158 °C.
IR (KBr): 753, 3072–3104 cm–1.
Anal. Calcd for C6H6N4: C, 53.72; H, 4.51; N, 41.77. Found: C,
53.51; H, 4.28; N, 42.03.
1H NMR (500 MHz, CDCl3): d = 7.33 (t, J = 6.5 Hz, 1 H), 7.44–
7.46 (m, 2 H), 7.58–7.60 (m, 1 H), 7.64–7.66 (m, 1 H), 7.75 (d,
J = 6.5 Hz, 1 H), 8.86 (d, J = 6.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 116.6, 124.8, 127.3, 128.0, 130.6,
130.8, 131.9, 132.5, 132.7, 133.2, 148.4.
Tetrazolo[1,5-a]quinoline (8)12
Yield: 88%; white solid; mp 157–159 °C.
IR (KBr): 763, 823, 1611 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.74 (t, J = 7.0 Hz, 1 H), 7.88–
7.92 (m, 2 H), 7.96–8.00 (m, 2 H), 8.73 (d, J = 8.0 Hz, 1 H).
Anal. Calcd for C11H7ClN4: C, 57.28; H, 3.06; N, 24.29. Found: C,
57.41; H, 3.17; N, 24.36.
Anal. Calcd for C9H6N4: C, 63.52; H, 3.55; N, 32.92. Found: C,
63.44; H, 3.65; N, 33.06.
8-Phenylaminotetrazolo[1,5-a]pyridine (14)
Tetrazolo[5,1-a]isoquinoline (9)13
Yield: 95%; white solid; mp 146–148 °C.
IR (KBr): 792 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.45 (d, J = 8.5 Hz, 1 H), 7.85–
7.87 (m, 2 H), 7.93–7.95 (m, 1 H), 8.57 (d, J = 7.5 Hz, 1 H), 8.79–
8.81 (m, 1 H).
A mixture of 2 (100 mg, 0.500 mmol), aniline (56.0 mg, 0.600
mmol), Pd(OAc)2 (12.0 mg, 0.0500 mmol), BINAP (63.0 mg, 0.100
mmol), and Cs2CO3 (244 mg, 0.750 mmol) in toluene (5 mL) was
heated at 110 °C for 20 h under an argon atmosphere. The solvent
was removed under reduced pressure and excess EtOAc (30 mL)
was added to the solid residue. The organic layer was washed se-
quentially with H2O (2 × 5 mL) and brine (1 × 5 mL), dried over an-
hyd Na2SO4, filtered and concentrated. The residue was purified by
column chromatography (silica gel; 0–2% 2 N NH3 in MeOH–
CH2Cl2, 2:98) to give 14.
Anal. Calcd for C9H6N4: C, 63.52; H, 3.55; N, 32.92. Found: C,
63.42; H, 3.42; N, 32.67.
Ethyl Tetrazolo[1,5-a]pyridine-8-carboxylate (10)1c
Yield: 81%; white solid; mp 124–126 °C.
IR (KBr): 1713, 3061–3089 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.51 (t, J = 7.0 Hz, 3 H), 4.60 (q,
J = 7.0 Hz, 2 H), 7.35 (t, J = 7.0 Hz, 1 H), 8.44 (d, J = 7.0 Hz, 1 H),
9.01 (d, J = 7.0 Hz, 1 H).
Yield: 55 mg (52%); yellow solid; mp 135–137 °C.
IR (KBr): 1563, 3269 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.04 (t, J = 7.0 Hz, 1 H), 7.12 (d,
J = 7.0 Hz, 1 H), 7.17–7.20 (m, 1 H), 7.33–7.35 (m, 2 H), 7.41–7.45
(m, 2 H), 7.49 (br s, 1 H), 8.28 (d, J = 7.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 105.5, 114.8, 118.3, 121.8, 124.8,
130.0, 133.3, 139.3, 143.8.
Anal. Calcd for C8H8N4O2: C, 50.00; H, 4.20; N, 29.15. Found: C,
49.96; H, 4.15; N, 29.09.
Anal. Calcd for C11H9N5: C, 62.55; H, 4.29; N, 33.16. Found: C,
62.62; H, 4.50; N, 32.84.
8-Chloro-6-trifluoromethyltetrazolo[1,5-a]pyridine (11)2a
Yield: 78%; viscous liquid.
IR (KBr): 1197, 1335, 3043–3103 cm–1.
1H NMR (500 MHz, CDCl3): dtetrazole = 7.85 (br s, 1 H), 9.13 (br s, 1
H); dazide = 7.88 (br s, 1 H), 8.50 (br s, 1 H).
1-Tetrazolo[1,5-a]pyridin-8-ylethanone (15)
A mixture of 2 (100 mg, 0.500 mmol), tributyl(1-ethoxyvinyl)tin
(362 mg, 1.00 mmol), Pd(PPh3)2Cl2 (35.0 mg, 0.050 mmol), and
Cs2CO3 (325 mg, 1.00 mmol) in toluene (3 mL) was heated at
Synthesis 2008, No. 24, 4002–4006 © Thieme Stuttgart · New York

4006
J. K. Laha, G. D. Cuny
PAPER
110 °C for 24 h under an argon atmosphere. The reaction mixture
was treated with 3 N HCl (2 mL) at r.t. for 4 h. Excess EtOAc (30
mL) was added and the organic layer was separated. The organic
layer was washed sequentially with H2O (2 × 5 mL) and brine (1 ×
5 mL), dried over anhyd Na2SO4, filtered and concentrated. The res-
idue was purified by column chromatography (silica gel; 0–2% 2 N
NH3 in MeOH–CH2Cl2, 2:98) to afford 15.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
The authors appreciate financial support from the Harvard Neuro-
Discovery Center.
Yield: 40 mg (49%); off-white solid; mp 134–136 °C.
IR (KBr): 1682, 3064–3112 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.13 (s, 3 H), 7.39 (t, J = 7.0 Hz,
1 H), 8.37 (d, J = 7.0 Hz, 1 H), 9.02 (d, J = 7.0 Hz, 1 H).
References
(1) (a) Simoni, D.; Rondanin, R.; Furnò, G.; Aiello, E.;
Invidiata, F. P. Tetrahedron Lett. 2000, 41, 2699.
(b) Reisinger, A.; Koch, R.; Wentrup, C. J. Chem. Soc.,
Perkin Trans. 1 1998, 2247. (c) Pollak, A.; Polanc, S.;
Stanovnik, B.; Tišler, M. Monatsh. Chem. 1972, 103, 1591.
(d) Boyer, J. H.; McCane, D. I.; McCarville, W. J.; Tweedie,
A. T. J. Am. Chem. Soc. 1953, 75, 5298. (e) Mekheimer, R.
Pharmazie 1994, 49, 322.
13C NMR (125 MHz, CDCl3): d = 31.3, 116.5, 125.7, 129.2, 134.2,
147.7, 193.8.
Anal. Calcd for C7H6N4O: C, 51.85; H, 3.73; N, 34.55. Found: C,
51.63; H, 3.68; N, 34.25.
7-Bromo-8-methyltetrazolo[1,5-a]pyridine (16)
(2) (a) Cmoch, P.; Korczak, H.; Stefaniak, L.; Webb, G. A.
J. Phys. Org. Chem. 1999, 12, 470. (b) Lowe-Ma, C. K.;
Nissan, R. A.; Wilson, W. S. J. Org. Chem. 1990, 55, 3755.
(c) Sasaki, T.; Kanematsu, K.; Murata, M. Tetrahedron
1971, 27, 5359. (d) Boyer, J. N.; Hyde, H. W. J. Org. Chem.
1960, 25, 458. (e) Kanyalkar, M.; Coutinho, E. C.
Tetrahedron 2000, 56, 8775.
(3) Boyer, J. H.; Schoen, W. J. Am. Chem. Soc. 1956, 78, 423.
(4) Reddy, K. S.; Iyengar, D. S.; Bhalerao, U. T. Chem. Lett.
1983, 1745.
A solution of 2 (100 mg, 0.500 mmol) in THF (4 mL) under an ar-
gon atmosphere was cooled to –78 °C. n-BuLi (0.250 mL, 0.625
mmol, 2.5 M in hexanes) was slowly added and the resulting solu-
tion was stirred at –78 °C for 1 h. MeI (142 mg, 1.00 mmol) was
added and the reaction mixture was allowed to slowly warm to
–20 °C over 1 h. The reaction mixture was quenched with H2O and
then allowed to warm to r.t. Excess EtOAc (30 mL) was added and
the organic layer was separated. The organic layer was washed se-
quentially with H2O (2 × 5 mL) and brine (1 × 5 mL), dried over an-
hyd Na2SO4, filtered and concentrated. The residue was purified by
column chromatography (silica gel; hexanes–EtOAc, 3:2) to give
16.
(5) Andrews, D. M.; Page, T. C. M.; Peach, J. M.; Pratt, A. J.
J. Chem. Soc., Perkin Trans. 1 1995, 1045.
(6) Keith, J. M. J. Org. Chem. 2006, 71, 9540.
(7) Nishiyama, K.; Miyata, I. Bull. Chem. Soc. Jpn. 1985, 58,
2419.
(8) Kiselyov, A. S. Tetrahedron Lett. 2005, 46, 4851.
(9) Azev, Y. u. A.; Mokrushina, G. A.; Postovskii, I. Y. Khim.
Geterotsikl. Soedin. 1974, 792.
(10) Zhang, Y.; Pavlova, O. A.; Chefer, S. I.; Hall, A. W.; Kurian,
V.; Brown, L. L.; Kimes, A. S.; Mukhin, A. G.; Horti, A. G.
J. Med. Chem. 2004, 47, 2453.
Yield: 20 mg (41% based on recovered starting material); white sol-
id; mp 179–181 °C.
IR (KBr): 1505 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.92 (s, 3 H), 6.91 (d, J = 7.0 Hz,
1 H), 7.81 (d, J = 7.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 17.5, 106.3, 116.0, 134.6, 136.3.
Anal. Calcd for C6H5BrN4: C, 33.83; H, 2.37; N, 26.30. Found: C,
34.00; H, 2.12; N, 26.11.
(11) Amantini, D.; Beleggia, R.; Fringuelli, F.; Pizzo, F.;
Vaccaro, L. J. Org. Chem. 2004, 69, 2896.
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1478.
(13) Messmer, A.; Hajos, G.; Tamas, J.; Neszmelyi, A. J. Org.
Chem. 1979, 44, 1823.
Synthesis of 7 via Hydrogenation of 16
A solution of 16 (21 mg, 0.10 mmol) and 10% Pd/C (25 mg) in
EtOH–EtOAc (3:1, 4 mL) was stirred at r.t. under a H2 atmosphere
for 18 h. Filtration followed by concentration of the solvent gave 7.
(14) Boyer, J. H.; Chang, M. S.; Reinisch, R. F. J. Org. Chem.
1960, 25, 286.
Yield: 7 mg (54%).
(15) (a) Cmoch, P.; Wiench, J. W.; Stefaniak, L.; Sitkowski, J.
J. Mol. Struct. 1999, 477, 119. (b) Messmer, A.; Hajos, G.;
Juhasz-Riedl, Z.; Sohar, P. J. Org. Chem. 1988, 53, 973.
(16) Messmer, A.; Hajos, G.; Fleischer, J.; Czugler, M. Monatsh.
Chem. 1985, 116, 1227.
(17) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(18) Wolfe, J. P.; Buchwald, S. L. Tetrahedron Lett. 1997, 38,
6359.
(19) Kosugi, M.; Sumiya, T.; Obara, Y.; Sukuki, M.; Sano, H.;
Migita, T. Bull. Chem. Soc. Jpn. 1987, 60, 767.
(20) Boyer, J. H.; Reinisch, R. F. J. Am. Chem. Soc. 1960, 82,
2218.
3-Chloro-5-trifluoromethyl-N-(triphenylphosphoranylidene)-
2-pyridinamine (17)
A solution of 11 (22 mg, 0.10 mmol) and Ph3P (30 mg, 0.11 mmol)
in anhyd CHCl3 (0.5 mL) was heated at 60 °C for 18 h. The reaction
mixture was purified by column chromatography (silica gel;
hexanes–EtOAc, 3:1) to obtain 17.
Yield: 45 mg (98%); viscous liquid.
1H NMR (500 MHz, CDCl3): d = 7.44–7.47 (m, 6 H), 7.52–7.56 (m,
3 H), 7.64 (s, 1 H), 7.83–7.87 (m, 6 H), 7.93 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 128.6, 128.7, 129.5, 132.1, 132.2,
133.0, 133.3, 133.5, 142.8.
HRMS: m/z [M + H]+ calcd for C24H17ClF3N2P: 457.0842; found:
457.0841.
Synthesis 2008, No. 24, 4002–4006 © Thieme Stuttgart · New York