Reaction of N-fluoropyridinium fluoride with isonitriles and diazo compounds: A one-pot synthesis of (pyridin-2-yl)-1H-1,2,3-triazoles

Article abstract of DOI:10.1016/j.tetlet.2006.02.030

Reaction of N-fluoropyridinium fluoride generated in situ with a series of isonitriles and diazo compounds led to the formation of the corresponding (pyridine-2-yl)-1H-1,2,3-triazoles in good yields (37-59%). Best outcome was consistently achieved with bo

Full text of DOI:10.1016/j.tetlet.2006.02.030

Tetrahedron Letters 47 (2006) 2631–2634
Reaction of N-fluoropyridinium fluoride with isonitriles
and diazo compounds: a one-pot synthesis of
(pyridin-2-yl)-1H-1,2,3-triazoles
Alexander S. Kiselyov*
Small Molecule Drug Discovery, Chemical Diversity, 11558 Sorrento Valley Road, San Diego, CA 92121, USA
Received 2 September 2005; revised 2 February 2006; accepted 6 February 2006
Available online 21 February 2006
Abstract—Reaction of N-fluoropyridinium fluoride generated in situ with a series of isonitriles and diazo compounds led to the for-
mation of the corresponding (pyridine-2-yl)-1H-1,2,3-triazoles in good yields (37–59%). Best outcome was consistently achieved
with both aromatic isonitriles and stabilized diazo derivatives. The proposed reaction mechanism involves the intermediate forma-
tion of a highly reactive carbene species.
ꢀ 2006 Elsevier Ltd. All rights reserved.
R
R
N
O
The synthetic potential of N-fluoropyridinium salts con-
veniently generated in situ 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 Pyridine-2-yl acetates,7 2-acetamido-
pyridines,8 and picolinamides9 were successfully pre-
pared in a one-pot procedures from in situ generated
N-fluoropyridinium salts. A three-component cycliza-
tion protocols based on this chemistry to yield
pyrido[1,2-a][1,3,5]triazin-4-ones (A),10 tetrazol-5-yl pyr-
idines (B),11 and imidazo[1,2-a]pyridines (C)12 have been
described (Scheme 1). In our attempt to further expand
the synthetic utility of these useful substrates, we studied
the reaction of N-fluoropyridinium fluorides with iso-
nitriles in the presence of diazo compounds. The reac-
tion with diazo ethylacetate in absolute EtOH was
reported by us earlier to yield the respective fluorinated
species D (Scheme 1).13
R'
N
N
N
N
N
N
N
B
A
N
F
X
R3
HN
N
COOR
R2
R1
N
N
F
D
C
Scheme 1.
dine-2-yl)-1H-1,2,3-triazoles 3a–p (Scheme 2, 32–59%
isolated yields). Varying amounts of 2-picolinamides 4
(15–34% yields) were also isolated from the reaction
mixtures, along with a respective ethyl 2-fluoro-2-(pyri-
din-2-yl)acetates 5 (10–16% yields).2,7 The reaction out-
come was relatively independent of the nature of the
isonitrile component (Scheme 2, entries a–h).14,15
Initially, we found that one-pot reaction of diazo ethyl-
acetate with 2 and a series of isonitriles furnished (pyri-
Reactions with p-trifluoromethylphenyl isocyanide
(Scheme 2, entries e, i–p) were most practical as they
both (i) afforded the highest yields and (ii) allowed for
the easy isolation of the desired products 3 by trituration
of the concentrated reaction mixtures with EtOAc/Et2O
(1:1 mixture) followed by recrystallization of the solid
residue from EtOH. Regiochemistry of the reaction
has been confirmed by NOE experiments.14,15
Keywords: N-Fluoropyridinium; (Pyridine-2-yl)-1H-1,2,3-triazoles;
Isonitriles; Carbene; Three-component reaction.
*
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0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.030

2632
A. S. Kiselyov / Tetrahedron Letters 47 (2006) 2631–2634
R
R'-NC
R
R
R'
R
R
N2
COOEt
N
F2, CHCl3
- 60 oC
N
NHR'
+
+
N
N
F
- 60 oC to RT
N
F
N
N
F
N
EtO2C
O
COOEt
5a
Yields, %
1
2
4a, i-p
3a-p
Entry, 1
Entry, 1
R
R'
Yields, %
R
R'
3
4
3
4
-
a
b
c
d
e
f
H
H
H
H
H
H
H
H
n-Bu
t-Bu
38 34
41 26
i
2-Me
3-Me
p-CF3-C6H4
53
20
j
p-CF3-C6H4-
48b 19c3
45
21
k
l
4-Me p-CF3-C6H4-
59
37
39
15
31
25
Ph
52 18
2-Cl
4-Cl
p-CF3-C6H4-
p-CF3-C6H4-
p-CF3-C6H4- 56
16
m
n
o
p
O
32 27
44 21
2-OMe p-CF3-C6H4-
2-Ph p-CF3-C6H4-
2-COOMe p-CF3-C6H4-
47 31
28d 25
37 18
N
g
CH2Ph
h
p-NO2-C6H4- 57 17
aYields of 5 did not exceed 10-16% (isolated yields, 15-20% LC MS yields); bMixture of 2- and 6-
substituted derivatives, ca. 2:1 isolated ratio, respectively; cMixture of 2- and 6-substituted derivatives,
ca. 2:1 isolated ratio, respectively; dMixture contained products of fluorination of the Ph ring (ca.
25%, LC MS).
Scheme 2.
We then studied the effect of pyridine substitution on the
reaction outcome (Scheme 2, entries i–p). Consistent
with our earlier observations,11,12 both weak electron-
donating and withdrawing groups enhanced the overall
yields of the desired products 3 (entries i–m). Strong elec-
tron-donating and withdrawing groups (entries n, p) as
well as aromatic substituent (entry o) on the pyridine ring
led to a considerably lower yields of the targeted com-
pounds 3 and a significant formation of side products,
including the respective picolinamides 4.9 Possible reas-
ons for this outcome are (a) electrophilic fluorination
of pyridine ring for 1n or phenyl ring for 1o under the
reaction conditions (ca. 15–25% of fluorinated materials
by 19F NMR and LC MS) and (b) relative instability of
the intermediate N-fluoropyridinium fluoride species for
2p.1,2 3-Substituted pyridine yielded mixture of the
respective 2- and 6-regioisomers in ca. 2:1 ratio and
48% overall isolated yield (Scheme 1, entry j). Similar
regioselectivity was observed by us earlier.8,9 A ratio of
pyridine:isonitrile:diazo ethylacetate of 1:2:2 furnished
the best yields of the desired products 3. Larger molar
excess of pyridines led to formation of the increased
amounts of the respective picolinamides 4. In addition,
both 2-chloro and 2-fluoropyridines were detected in
the reaction mixtures (ca. 10–15% by LC MS).1,2 Chloro-
form was the optimal solvent for this reaction. Similar
procedures conducted in CH3CN (À42 ꢁC) resulted in
lower yields of the desired materials 3 and formation of
side products (2-acetamidopyridines).8 Thorough tem-
perature control was found to be critical for securing
good yields of the desired materials. Specifically, it was
important for both the generation of 2 as well as for
the addition of isonitriles to maintain the reaction tem-
perature at less than À60 ꢁC. At higher reaction temper-
atures (>À40 ꢁC), the white suspension of 2 generated
in situ rapidly changed color to dark yellow/brown. Sig-
nificant amounts of the respective 2-chloro and 2-fluoro-
pyridines were observed in the mixtures.1,7
We further investigated the effect of a substituent in
diazo reagents on the reaction outcome. Specifically,
we varied the diazo component, while maintaining the
optimized nitrile input (p-CF3–C6H4–NC). The results
of these studies are summarized below (Scheme 3).
In our hands, the best yields of the targeted triazoles 3
were achieved with diazo compounds stabilized with
ArCO-functionality (Scheme 3, entries q, t–v). Reactions

A. S. Kiselyov / Tetrahedron Letters 47 (2006) 2631–2634
2633
CF3
CF3
NH
F3C
NC
R
R
R
R
R
F2, CHCl3
-60 oC
N
N
N2
R'
N
F
+
+
N
-60 oC to RT
N
F
N
N
N
F
R'
R'
O
1
5a
2
4q-v
3q-v
Entry, 1
R
R'
Yields, %
Entry, 1
R
R'
Yields, %
3
4
3
4
q
r
s
H
H
H
COPh
COMe
-
52 12
29b 27
12b 29
t
H
CO-C6H4-pCl 48 14
u
v
4-Me
4-Cl
COPh
COPh
55 11
41 28
aYields of 5 did not exceed 8-13% (isolated yields, 12-15% LC MS yields); bExtensive formation of a
high MW products was observed under a variety of experimental conditions.
Scheme 3.
with both diazoacetone (entry r) and diazomethane
tates 5, products of the side reaction of 6 with carbanion
do not exceed 20% (LC MS data). Picolinamides 4 are
likely to result from the hydrolysis of the isonitrilium
ylid species.9 Formation of 2-chloro and 2-fluoropyri-
dines 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 The postulated
intermediacy of the carbene 6 is in agreement with the
lack of formation of the respective derivatives 3 in an
attempted reaction of 2,6-dimethylpyridine under the
described conditions.
(entry s) resulted in the excessive formation of high-
molecular weight products (>40%) under a variety of
experimental conditions.
The outcome of the reported reaction could be explained
by an initial formation of N-fluoropyridinium species 2.
These undergo proton abstraction from the strongly
activated position 2 of the N-fluoropyridinium cation
by fluoride anion to yield the electrophilic carbene 6
(Scheme 4).1,2 We suggest that 6 undergoes a subsequent
reaction with isonitrile to afford the respective isonitri-
lium ylid. This ylid reacts with diazo molecule to yield
the observed product 3. Product 5 is likely to originate
from the direct addition of diazo compound to either
carbene species 6 or to N-fluoropyridinium fluoride 2
followed by the elimination of HF (cine-substitution
step) and displacement of N2 with nucleophilic FÀ.13
Apparently, the reaction of 6 with isonitrile to yield
the ylid intermediate seems to be the main route for this
conversion as the yields of 2-fluoro-2-(pyridin-2-yl)ace-
In summary, we described a one-pot reaction of in situ
generated N-fluoropyridinium fluorides with isonitriles
and diazo compounds to afford the respective (pyri-
dine-2-yl)-1H-1,2,3-triazoles in a satisfactory yields
(32–59%). Best outcome was consistently achieved with
both aromatic isonitriles and stabilized diazo deriva-
tives. Intermediate formation of a highly reactive car-
bene intermediate is proposed to explain the result of
this reaction.
R
N
2
N
:
N
N
R
N
F
N
F
N
N
R
F
R
F
6
Hydrolysis
R
N2
R
N2
F
N2
5a
3a
N2
4a
N
N
- F
- N2
F
R
R
Scheme 4.

2634
A. S. Kiselyov / Tetrahedron Letters 47 (2006) 2631–2634
of 4 (11–34%) and 5 (8–16%). Alternatively, for p-
References and notes
trifluoromethylphenyl isocyanide reaction mixtures, the
resulting concentrate was washed with EtOAc/Et2O, 1:1
(2 · 15 mL), the resultant solid residue was recrystallized
from EtOH to afford analytically pure 3e, i–q, t–v.
15. Regiochemistry of substitution in 3 was confirmed by
NOE experiments:
1. (a) Umemoto, T.; Fukami, S.; Tomizawa, G.; Harasawa,
K.; Kawada, K.; Tomita, K. J. Am. Chem. Soc. 1990, 112,
8563; (b) Umemoto, T.; Tomita, K.; Kawada, K. In Org.
Synth.; 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; (f) Kiselyov, A. S.; Strekowski, L. Trends
Heterocycl. Chem. 1993, 3, 57–72.
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.
CF3
nOe
H
H
N
N
N
N
EtO2C
3e
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.
Analytical data for a representative (pyridine-2-yl)-1H-
1,2,3-triazoles 3:
Ethyl 5-(pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-
1,2,3-triazole-4-carboxylate (3e), mp 226–228 ꢁC, 56%
yield, 1H NMR (400 MHz, DMSO-d6):
d 1.36 (t,
J = 8.4 Hz, 3H), 4.11 (q, J = 8.4 Hz, 2H), 7.13 (d,
J = 8.8 Hz, 2H), 7.33 (dd, J1 = 7.6 Hz, J2 = 3.6 Hz, 1H),
7.38 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 6.8 Hz, 1H), 7.75
(dd, J1 = 6.8 Hz, J2 = 7.6 Hz, 1H), 8.71 (d, J = 3.6 Hz,
1H); 13C NMR (DMSO-d6): d 15.0, 58.9, 119.5, 123.2,
124.7, 125.6, 127.5, 129.8, 130.7, 131.3, 137.3, 138.5, 150.1,
156.2, 168.2. ESI MS: (M+1) 363, (MÀ1) 361; Elemental
analysis, calcd for C17H13F3N4O2: C, 56.36; H, 3.62; N,
15.46. Found: C, 56.31; H, 3.49; N, 15.27.
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; (c) Kiselyov, A. S. Tetrahedron Lett. 2005, 46, 2279.
10. Kiselyov, A. S.; Strekowski, L. Tetrahedron Lett. 1994, 35,
207.
11. Kiselyov, A. S. Tetrahedron Lett. 2005, 46, 4851.
12. Kiselyov, A. S. Tetrahedron Lett. 2005, 46, 4487.
13. Kiselyov, A. S.; Strekowski, L. Heterocycles 1994, 38, 259.
14. 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 À60 ꢁC (critical!). The resultant white
suspension of 2 was thoroughly flushed with nitrogen
(critical!) to remove molecular fluorine and then treated
dropwise (À60 ꢁC) with a solution of isonitrile (20 mmol
in 50 mL of CHCl3) followed by a solution of diazo
compound (20 mmol in 50 mL of CHCl3). The resultant
pale yellow mixture was stirred at À60 ꢁC for 1 h, allowed
to reach 0 ꢁC within the next 2 h, and finally stirred for
additional 2 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 (Na2SO4), and concentrated. Elution with
hexanes/EtOAc (1:1) furnished (pyridine-2-yl)-1H-1,2,3-
triazoles 3 as main products along with varying quantities
Ethyl
5-(4-methylpyridin-2-yl)-1-(4-(trifluoromethyl)-
phenyl)-1H-1,2,3-triazole-4-carboxylate (3k), mp >244–
246 ꢁC, 36% yield; 1H NMR (400 MHz, DMSO-d6): d
1.31 (t, J = 8.4 Hz, 3H), 2.24 (s, 3H), 4.07 (q, J = 8.4 Hz,
2H), 7.16 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 4.0 Hz, 1H),
7.41 (d, J = 8.8 Hz, 2H), 7.48 (s, 1H), 8.64 (d, J = 3.6 Hz,
1H); 13C NMR (DMSO-d6): d 14.3, 25.0, 58.6, 124.1,
124.6, 125.1, 125.3, 127.7, 129.9, 131.5, 132.2, 137.6, 147.8,
149.7, 156.1, 168.1. ESI MS: (M+1) 377, (MÀ1) 375;
Elemental analysis, calcd for C18H15F3N4O2: C, 57.45; H,
4.02; N, 14.89. Found: C, 57.22; H, 3.87; N, 14.66.
Phenyl(5-(pyridin-2-yl)-1-(4-(trifluoromethyl)phenyl)-
1H-1,2,3-triazol-4-yl)methanone (3q); mp >250 ꢁC, 52%
yield; 1H NMR (400 MHz, DMSO-d6):
d 7.21 (d,
J = 8.4 Hz, 2H), 7.35 (dd, J1 = 8.0 Hz, J2 = 3.6 Hz, 1H),
7.43–7.47 (m, 4H), 7.51 (m, 1H), 7.58 (d, J = 8.0 Hz, 1H),
7.80–7.83 (m, 3H), 8.66 (d, J = 3.6 Hz, 1H); 13C NMR
(DMSO-d6): d 119.7, 123.8, 124.1, 124.9, 129.0, 129.6,
130.1, 130.7, 131.5, 133.2, 134.6, 137.4, 142.8, 144.7, 149.5,
156.1, 190.3. ESI MS: (M+1) 395, (MÀ1) 393; Elemental
analysis, calcd for C21H13F3N4O: C, 63.96; H, 3.32; N,
14.21. Found: C, 63.77; H, 3.21; N, 14.02.