Reaction of N-fluoropyridinium fluoride with isonitriles and TMSN 3: A convenient one-pot synthesis of tetrazol-5-yl pyridines

Article abstract of DOI:10.1016/j.tetlet.2005.05.066

Reaction of N-fluoropyridinium fluoride generated in situ with a series of isonitriles and TMSN₃ led to the formation of the corresponding tetrazol-5-yl pyridines in good yields (37-84%). A similar reaction sequence for quinoline yielded the respective derivatives of 2-quinoline. The proposed reaction mechanism involves the intermediate formation of a highly reactive carbene species.

Full text of DOI:10.1016/j.tetlet.2005.05.066

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4851–4854
Reaction of N-fluoropyridinium fluoride with isonitriles and
TMSN3: a convenient one-pot synthesis of tetrazol-5-yl pyridines
Alexander S. Kiselyov*
Small Molecule Drug Discovery, Chemical Diversity, 11558 Sorrento Valley Road, San Diego, CA 92121, USA
Received 4 May 2005; revised 15 May 2005; accepted 16 May 2005
Abstract—Reaction of N-fluoropyridinium fluoride generated in situ with a series of isonitriles and TMSN3 led to the formation of
the corresponding tetrazol-5-yl pyridines in good yields (37–84%). A similar reaction sequence for quinoline yielded the respective
derivatives of 2-quinoline. The proposed reaction mechanism involves the intermediate formation of a highly reactive carbene
species.
ꢀ 2005 Elsevier Ltd. All rights reserved.
The synthetic potential of N-fluoropyridinium salts
conveniently generated from pyridines and elemental
fluorine has been the subject of ongoing interest.1 Reac-
tions of these highly reactive substrates have been used
in the synthesis of 2-halogeno pyridines,2 and for the
introduction of hydroxy,3 amido,4 phosphonio,5 hetero-
aryl, arylthio, and aryloxy groups at position 2 of
pyridine rings.6 Additional examples of the synthetic
utility of the N-fluoropyridinium cation include the
preparations of pyridine-2-yl acetates7 and 2-
acetamidopyridines.8
ation of the concentrated reaction mixtures with
EtOAc–Et2O (1:2 mixture) followed by recrystallization
of the solid residue from EtOH.11
We also studied the effect of pyridine substitution on the
reaction outcome (entries i–p). Consistent with our ear-
lier observations,10 both weak electron donating- and
withdrawing groups enhanced the overall yields of the
desired products 3 (entries i–m). Strong electron donat-
ing- and withdrawing groups (entries n and p) as well as
aromatic substituents (entry o) on the pyridine ring led
to considerably lower yields of the targeted compounds
3 and significant formation of side products, including
the respective picolinamides 4.10 Possible reasons for
this outcome are (a) electrophilic fluorination of pyr-
idine ring for 1n or phenyl ring for 1o under the reaction
conditions (ca. 15–25% of fluorinated materials by
LC–MS) and (b) relative instability of the intermediate
N-fluoropyridinium fluoride species for 2p.1,2 3-Substi-
tuted pyridine yielded mixture of the respective 2-and
6-regioisomers in ca. 2:1 ratio and 76% overall iso-
lated yield (Scheme 1, 1j). Similar regioselectivity was
observed by us earlier.8 Ratio 1:2, pyridine to isonitrile,
and pyridine to TMSN3 furnished the best yields of the
desired products 3. TMSN3 afforded significantly higher
yields (by ca. 35–40%) than NaN3 or a Bu4NF/NaN3
system, presumably due Àto the mild and quantitative
in situ generation of N3 anion. Larger molar excess
of pyridines led to increased amounts of the respective
picolinamides 4 and tetrazolo[1,5-a]pyridines 5. In
addition, significant amounts of 2-chloro- and 2-fluoro-
pyridines were detected in the reaction mixtures
In our attempt to further expand the synthetic potential
of these useful substrates,9 we studied the reaction of
N-fluoropyridinium fluorides 1 generated in situ with
isonitriles in the presence of TMSN3.10 This one-pot
reaction yielded tetrazol-5-yl pyridines 3a–p in good
yields (Scheme 1).11,12 Varying amounts of 2-picolin-
amides 4 were also isolated from the reaction mixtures
along with tetrazolo[1,5-a]pyridines.2,7,10 The reaction
outcome was independent of the nature of the isonitrile
component (Scheme 2, entries a–h). In general, yields of
the desired compounds 3 exceeded 50%. Reactions with
p-trifloromethylphenyl isocyanide were most practical as
they both (i) afforded the highest yields and (ii) allowed
for the easy isolation of the desired products 3 by tritur-
Keywords: N-Fluoropyridinium; Tetrazol-5-yl pyridine; Isonitriles;
Carbene; Three-component reaction.
*
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doi:10.1016/j.tetlet.2005.05.066

4852
A. S. Kiselyov / Tetrahedron Letters 46 (2005) 4851–4854
Scheme 1.
B:
- BH
R
N
2a
N
:
N
N
R
N
F
6
N
F
N
N
R
F
R
F
Hydrolysis
N3
N3
5a
3a
4a
Scheme 2.
(LC–MS).1,2 Chloroform was the optimal solvent for
this reaction. Similar procedures conducted in CH3CN
(À42 ꢁC) resulted in considerably lower yields of the de-
sired materials 3 and formation of side products.8 Thor-
ough temperature control was found to be critical for
securing good yields of the desired materials. Specifi-
cally, it was important for both the generation of 2 as
well as for the addition of isonitriles to maintain the
reaction temperature at less than À50 ꢁC. At higher
reaction temperatures (>À40 ꢁC), the white suspension
of 2 generated in situ rapidly changed color to dark
yellow/brown. Significant amounts of the respective
2-chloro- and 2-fluoropyridines were observed in the
mixtures.1,7,10
The outcome of the reported reaction could be explained
by an initial formation of N-fluoropyridinium species 2
followed by proton abstraction from the strongly acti-
vated position 2 of the N-fluoropyridinium cation by
fluoride to yield the electrophilic carbene 6 (Scheme
2).1,2 We suggest that 6 undergoes a subsequent reaction
with isonitrile to afford the respective isonitrilium ylide.
This ylide undergoes subsequent reaction with in situ
generated azide anion to yield the observed product 3.
Product 5 is likely to originate from the addition of
azide anion to either carbene species or to N-fluoropyr-
idinium fluoride 2 followed by the elimination of HF
(cine-substitution step).10 Apparently, the reaction of 6
with isonitrile to yield the ylide intermediate seems to

A. S. Kiselyov / Tetrahedron Letters 46 (2005) 4851–4854
1. F2, CHCl3, - 60oC
4853
2. R-NC, TMSN3,
- 60oC to RT
R
N
+
+
N
NHR
N
N
N
N
R = p-CF3-C6H4
N
N
N
N
O
N
7
8 (36%)
9 (21%)
10 (19%)
1. F2, CHCl3, - 60oC
2. R-NC, TMSN3,
- 60oC to RT
N
N
+
+
N
N
N
R = p-CF3-C6H4
R
N
N
N
N
O
NHR
11
N
N
14 (14%)
13 (32%)
12 (33%)
Scheme 3.
8563; (b) Umemoto, T.; Tomita, K.; Kawada, K. In
Organic Synthesis; John Wiley and Sons: New York, NY,
1990; Vol. 69, p 129; (c) Umemoto, T.; Harasawa, K.;
Tomizawa, G.; Kawada, K.; Tomita, K. Bull. Chem. Soc.
Jpn. 1991, 64, 1081; (d) Hebel, D.; Rozen, S. J. Org. Chem.
1991, 56, 6298; (e) Stavber, S.; Zupan, M. Tetrahedron
Lett. 1990, 31, 775.
be the main route for this conversion. The yields of tet-
razolo[1,5-a]pyridines, products of the side reaction of 6
with azide anion did not exceed 15%. Picolinamides are
likely to result from the hydrolysis of the isonitrilium
ylide species.10 Formation of 2-chloro- and 2-fluoropyr-
idines at elevated temperatures can be rationalized in
terms of the reaction of highly reactive species 6 with
the solvent (CHCl3) or fluoride anion.1,2
2. (a) Umemoto, T.; Tomizawa, G. J. Org. Chem. 1989, 54,
1726; (b) Hebel, D.; Rozen, S. J. Org. Chem. 1991, 56,
6298; (c) Hebel, D.; Rozen, S. J. Org. Chem. 1988, 53,
1123.
3. Van Der Puy, M.; Nalewajek, D.; Wicks, G. E. Tetra-
hedron Lett. 1988, 29, 4389.
4. Umemoto, T.; Tomizawa, G. Tetrahedron Lett. 1987, 28,
2705.
5. Kiselyov, A. S.; Gakh, A. A.; Kagramanov, N. D.;
Semenov, V. V. Mendeleev Commun. 1992, 128.
6. Kiselyov, A. S.; Strekowski, L. J. Heterocycl. Chem. 1993,
30, 1361.
7. Kiselyov, A. S.; Strekowski, L. J. Org. Chem. 1993, 58,
4476.
8. Kiselyov, A. S.; Strekowski, L. Synth. Commun. 1994, 24,
2387.
9. (a) Kiselyov, A. S. Tetrahedron Lett. 1994, 35, 8951; (b)
Kiselyov, A. S.; Strekowski, L. Tetrahedron 1993, 49,
2151.
10. (a) Kiselyov, A. S. Tetrahedron Lett. 2005, 46, 2279–2282;
(b) Kiselyov, A. S.; Strekowski, L. Trends Heterocycl.
Chem. 1993, 3, 57–72.
11. In a typical reaction sequence, an excess of fluorine gas (15–
20 mmol) was bubbled through a solution of pyridine
(0.79 g, 10 mmol) in CHCl3 (50 mL), at such a rate that
the initial temperature of À78 ꢁC (acetone/dry ice bath)
did not raise above À50 ꢁC (critical!). The resultant white
suspension of 2 was thoroughly flushed with nitrogen
(critical!) to remove molecular fluorine and then treated
dropwise (À50 ꢁC) with a solution of isonitrile (20 mmol
in 50 mL of CHCl3) followed by a solution of TMSN3
(20 mmol in 50 mL of CHCl3). The resultant pale yellow
mixture was stirred at À50 ꢁC for 1 h, allowed to reach
0 ꢁC within the next 4 h, and finally stirred for additional
4 h at 0 ꢁC, after which time the KI/starch test showed the
absence of 2. The mixture was concentrated (efficient N2
trap to contain excess of isonitrile!), passed through a thin
layer of silica gel, and the gel was washed with CHCl3. The
solutions were combined, washed with water, dried
(MgSO4), and concentrated. Elution with hexanes/EtOAc
(1:2) furnished 2-tetrazol-5-yl pyridines 3 as main products
along with varying quantities of 4 (6–33%) and 5 (7–10%
isolated yields). Alternatively, for p-trifluoromethylphenyl
isocyanide reaction mixtures, the resulting concentrate
was washed with EtOAc–Et2O, 1:2 (2 · 15 mL), the
The postulated intermediacy of the carbene 6 is in agree-
ment with the lack of formation of the respective
derivatives 3 in an attempted reaction of 2,6-dimethyl-
pyridine and 2,6-dichloropyridine under the described
conditions.
Consistent with this reactivity pattern is the formation
of the respective 2-quinoline and 1-isoquinoline deriva-
tives upon treatment of quinoline and isoquinoline with
fluorine followed by the reaction of the intermediary
cationic species with isonitrile and TMSN3 as described
above (8 and 12; 36% and 33% yields, respectively,
Scheme 3).11,12 However, the yields of the desired mate-
rials were lower than for 3. In addition, significant
amounts of chlorinated species along with the high
molecular weight products were detected in the reaction
mixtures (LC–MS). Notably, pyrimidine, pyridazine,
and pyrazine failed to produce the expected tetrazole
derivatives under a variety of reaction conditions, pre-
sumably due to the liability of the intermediate N-fluori-
nated species. Instead, a complex mixture of fluorinated
products (19F NMR), none of them major was observed
in each case.
In summary, we described the reaction of in situ gener-
ated N-fluoropyridinium fluorides with isonitriles and
TMSN3 to yield the respective tetrazol-5-yl pyridines
in good yields. A similar reaction was observed for both
quinoline and isoquinoline (isoquinoline was functional-
ized at position 1). Intermediate formation of a highly
reactive carbene intermediate is proposed to explain
the outcome of this reaction.
References and notes
1. (a) Umemoto, T.; Fukami, S.; Tomizawa, G.; Harasawa,
K.; Kawada, K.; Tomita, K. J. Am. Chem. Soc. 1990, 112,

4854
A. S. Kiselyov / Tetrahedron Letters 46 (2005) 4851–4854
resultant solid residue was recrystallized from EtOH to
afford analytically pure 3i–p.
analysis, calcd for C13H7ClF3N5: C, 47.94; H, 2.17; N,
21.50. Found: C, 47.69; H, 2.35; N, 21.23.
12. Regiochemistry of substitution was confirmed by NOE
experiments:
2-(1-(4-(Trifluoromethyl)phenyl)-1H-tetrazol-5-yl)quino-
line (8): mp >250 ꢁC, 36% yield; 1H NMR (400 MHz,
DMSO-d6): d 7.24 (d, J = 7.6 Hz, 2H), 7.41 (d, J = 7.6 Hz,
2H), 7.48 (m, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.63 (m, 1H),
7.70 (d, J = 8.4 Hz, 1H), 8.02–8.06 (m, 2H); 13C NMR
(DMSO-d6): d 119.1, 124.4, 125.0, 125.5, 126.8, 128.2,
128.9, 129.8, 130.5, 131.3, 132.4, 137.2, 147.2, 155.4, 157.8.
ESI MS: (M+1) 342, (MÀ1) 340; HR ESI MS: Exact mass
calcd for C17H10F3N5 341.0888. Found: 341.0881. Ele-
mental analysis, calcd for C17H10F3N5: C, 59.83; H, 2.95;
N, 20.54. Found: C, 59.66; H, 3.08; N, 20.37.
CF3
Cl
N
H
H
N
N
N
N
observed significant
nOe's for 3m
2-(1-(4-(Trifluoromethyl)phenyl)-1H-tetrazol-5-yl)quino-
line (12): mp >250 ꢁC, 33% yield; 1H NMR (400 MHz,
DMSO-d6): d 7.21 (d, J = 7.6 Hz, 2H), 7.46–7.53 (m, 5H),
7.73 (d, J = 7.2 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 8.44 (d,
J = 7.2 Hz, 1H); 13C NMR (DMSO-d6): d 116.5, 124.1,
124.8, 126.8, 127.1, 127.3, 128.2, 129.9, 130.4, 130.9, 132.1,
137.2, 141.6, 150.8, 160.5. ESI MS: (M+1) 342, (MÀ1)
340; HR ESI MS: Exact mass calcd for C17H10F3N5
341.0888. Found: 341.0876. Elemental analysis, calcd for
C17H10F3N5: C, 59.83; H, 2.95; N, 20.54. Found: C, 59.58;
H, 3.11; N, 20.33.
Representative examples: 4-Chloro-2-(1-(4-(trifluoro-
methyl)phenyl)-1H-tetrazol-5-yl)pyridine (3m): mp 203–
205 ꢁC, 84% yield; 1H NMR (400 MHz, DMSO-d6): d 7.21
(d, J = 7.6 Hz, 2H), 7.29 (d, J = 8.0 Hz, 1H), 7.52
(d, J = 7.6 Hz, 2H), 7.66 (s, 1H), 8.72 (d, J = 8.0 Hz,
1H); 13C NMR (DMSO-d6): d 122.9, 123.8, 124.3, 126.0,
129.5, 131.1, 132.2, 142.4, 150.4, 152.3, 156.7. ESI MS:
(M+1) 327, (MÀ1) 325; HR ESI MS: Exact mass calcd for
C13H7ClF3N5: 325.0342. Found: 325.0333. Elemental