Reaction of N-fluoropyridinium fluoride with isonitriles: A convenient route to picolinamides

Article abstract of DOI:10.1016/j.tetlet.2005.02.010

Reaction of N-fluoropyridinium fluoride generated in situ with a series of isonitriles led to the formation of the corresponding picolinamides in good yields. A similar reaction sequence for quinoline yielded the respective derivatives of 2-quinoline carboxylic acid. The proposed reaction mechanism involves the intermediate formation of a highly reactive carbene species.

Full text of DOI:10.1016/j.tetlet.2005.02.010

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2279–2282
Reaction of N-fluoropyridinium fluoride with isonitriles:
a convenient route to picolinamides
Alexander S. Kiselyov*
Small Molecule Drug Discovery, Chemical Diversity, 11558 Sorrento Valley Road, San Diego, CA 92121, USA
Received 16 January 2005; revised 31 January 2005; accepted 1 February 2005
Abstract—Reaction of N-fluoropyridinium fluoride generated in situ with a series of isonitriles led to the formation of the corre-
sponding picolinamides in good yields. A similar reaction sequence for quinoline yielded the respective derivatives of 2-quinoline
carboxylic acid. The proposed reaction mechanism involves the intermediate formation of a highly reactive carbene species.
Ó 2005 Elsevier Ltd. All rights reserved.
2-Substituted pyridines continue to attract considerable
interest as ligands for metals,1 building blocks in organic
synthesis,2 and physiologically active compounds.3
However, methods for the introduction of a substituent
at position 2 of the pyridine ring are quite limited. In
addition to the Chichibabin amination methodologies,4
the more general approaches involve displacement of a
nucleophugal group (usually a halogen),5 diazotation
strategies (for example, Ullman reaction),6 Reissert–
Henze and related conversions,7 Abramovitch and Saha
reaction,8 and transformations of a functionality already
present at position 2 of the pyridine.9 In this respect, we
were interested in the synthetic potential of N-fluoro-
pyridinium salts conveniently generated from pyridines
and elemental fluorine.10 Reactions of these highly reac-
tive substrates have been used in the synthesis of 2-halo-
geno pyridines,11 and for the introduction of hydroxy,12
amido,13 phosphonio,14 heteroaryl, arylthio, and aryl-
oxy groups at position 2 of pyridine ring.15 Additional
examples of the synthetic utility of N-fluoropyridinium
cation include preparations of pyridine-2-yl acetates16
and 2-acetamidopyridines.17 Representative examples
of these chemistries are summarized in Scheme 1.18
N
OR
N
O
NHCOR
N
F
X
N
N
COOR
N
N
R
F
Scheme 1.
(Scheme 2).19,20 Varying amounts of 2-chloropyridines
4 were also isolated from the reaction mixtures.11
In general, the reaction outcome did not depend on the
nature of the isonitrile component (Scheme 2, entries a–h).
With the notable exception of benzyl isonitrile and
ethyl isocyanoacetate (entries f and g), yields of the de-
sired compounds 3 exceeded 50%. Furthermore, reac-
tions with cyclohexyl- and p-nitrophenyl isocyanides
were most practical as they both (i) afforded the highest
yields and (ii) allowed for the easy isolation of the de-
sired products 3 via straightforward recrystallization of
reaction concentrate from EtOH.19 We also studied
the effect of pyridine substitution on the reaction out-
come (entries i–p). 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
In our attempt to further expand the synthetic potential
of these useful substrates, we studied the reaction of N-
fluoropyridinium fluoride with isonitriles. This one-pot
reaction yielded 2-pyridilcarboxamides 3 in good yields
Keywords: N-Fluoropyridinium; Picolinamide; Isonitrile; Carbene.
*
Tel.: +1 858 794 4860; fax: +1 858 794 4931; e-mail: ask@
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0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.010

2280
A. S. Kiselyov / Tetrahedron Letters 46 (2005) 2279–2282
R
R
R
R
R
F2, CH2Cl2
-60 oC
R'-NC
-60 oCto RT
O
+
N
F
+
NHR'
N
F
N
N
NHR'
N
Cl
O
O
2
5a
4a, i-p
1
3a-p
Entry, 1
R
R'
Yields, %
Entry, 1
R
R'
Yields, %
3
4
3
4
-
a
b
c
d
e
f
H
H
H
H
H
H
H
H
n-Bu
t-Bu
64 12
60 11
62 15
55 24
i
2-Me
3-Me
p-NO2-C6H4
68 10
j
p-NO2-C6H4-
69b 12c
71 15
68 22
66 25
k
l
4-Me p-NO2-C6H4-
Ph
2-Cl
4-Cl
p-NO2-C6H4-
p-NO2-C6H4-
m-CF3-C6H4- 61 21
m
n
o
p
CH2COOEt 46 15
2-OMe p-NO2-C6H4-
2-Ph p-NO2-C6H4-
2-COOMe p-NO2-C6H4-
52
26
g
CH2Ph
39 20
33d 11
h
p-NO2-C6H4- 69 11
31
40
aYields of 5 did not exceed 5-8% (isolated yields, 7-10% LC MS yields), small amounts of 2-
fluoropyridines (2-5%, LC MS yields) were also detected in reaction mixtures; bMixture of 2- and 6-
substituted derivatives, ca.1.5:1 isolated ratio, respectively; cMixture of 2- and 6-substituted derivatives,
ca. 1.5:1 isolated ratio, respectively; dMixture contained products of fluorination of the Ph ring (ca.
25%, LC MS)
Scheme 2.
3 and significant formation of side products, including
the respective 2-chloropyridines 4. Possible reasons for
this outcome are (a) partial fluorination of pyridine ring
for 1n or phenyl ring for 1o under the reaction condi-
tions and (b) relative instability of the intermediate N-
fluoropyridinium fluoride species for 2p.10–13 3-Substi-
tuted pyridine yielded mixture of the respective 2- and
6-regioisomers in ca. 1.5:1 ratio and 69% overall isolated
yield (Scheme 2, 1j). Similar regioselectivity was ob-
served by us earlier.18 Ratio 1:2, pyridine to isonitrile,
was found to furnish the best yields of the desired prod-
ucts 3, larger molar excess of pyridines afforded in-
creased amounts of the respective 2-chloro derivatives
4. Dichloromethane was found to be the optimal solvent
for this reaction, similar procedures conducted in
CHCl3, dichloroethane or CH3CN resulted in consider-
ably lower yields of the desired materials and significant
formation of side products.18 Thorough temperature
control was found to be critical for securing good yields
of the desired materials. Specifically, both the generation
of 2 as well as the addition of isonitriles to the reaction
mixtures have to be conducted at temperatures less than
À50 °C.18
6 (Scheme 3).10–15 We suggest that this resulting carbene
undergoes a subsequent reaction with isonitrile to afford
the respective isonitrilium ylide, the postulated precur-
sor to 2-carboxamidopyridines 3. Product 5 is likely to
originate from the addition of 2 equiv of isonitrile to
the carbene species as shown below. In addition, the
strong electron-deficient nature of 6 allows for its reac-
tion with CH2Cl2 and formation of 4, as described
earlier.11
The postulated intermediacy of the carbene 6 in the ami-
dation reactions of pyridine is in agreement with the
lack of formation of the respective acetamido derivative
in an attempted reaction of 2,6-dimethylpyridine 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 and isonitrile as described above (8, 12; 47%
and 41% yields, respectively, Scheme 4).19 Yields of
the desired materials were lower than observed for the
similar reaction protocols with pyridines 1. In addition,
significant amounts of high molecular weight products
were detected in the reaction mixtures (LC–MS).
Mechanistically, the outcome of this reaction could be
explained by an initial formation of N-fluoropyridinium
species 2 followed by proton abstraction from the
strongly activated position 2 of the N-fluoropyridinium
cation by fluoride to yield the highly reactive carbene
In summary, we described the reaction of in situ gener-
ated N-fluoropyridinium fluorides with isonitriles to
yield the respective picolinamides in good yields. A

A. S. Kiselyov / Tetrahedron Letters 46 (2005) 2279–2282
2281
B:
- BH
R
N
2a
N
:
N
N
R
N
F
6
N
F
N
N
R
F
R
F
R
N
Hydrolysis
CH2Cl2
R
N
R
Hydrolysis
N
4a
N
N
5a
3a
O
NH
R
N
R
Scheme 3.
1. F2, CH2Cl2, - 60oC
2. R-NC, - 60oC to RT
O
+
+
NHR’
N
N
Cl
N
N
NHR’
R = p-NO2-C6H4
O
O
7
8 (47%)
10 (4%)
9 (23%)
1. F2, CH2Cl2, - 60oC
2. R-NC, - 60oC to RT
+
+
N
N
N
N
R = p-NO2-C6H4
H
Cl
N
O
NHR
O
O
R
11
12 (41%)
14 (6%)
13 (26%)
Scheme 4.
M.; Huang, Q.; Kim, J.; Smith, L. M.; Stec, M.; Yuan, C.
C.; Kiselyov, A. S. U.S. Patent Appl. 05197, 2003.
similar reaction was observed for both quinoline and
isoquinoline (isoquinoline was functionalized at position
1). Intermediate formation of a highly reactive carbene
intermediate is proposed to explain the outcome of this
reaction.
4. For reviews, see: (a) Pozharskii, A. F.; Simonov, A. M.;
DoronÕkin, V. N. Russ. Chem. Rev. 1978, 47, 1042; (b)
Vorbruggen, H. Adv. Heterocycl. Chem. 1992, 49, 117; (c)
Comins, D. L.; OÕConnor, S. Adv. Heterocycl. Chem.
1988, 44, 199; (d) McGill, C. K.; Rappa, A. Adv.
Heterocycl. Chem. 1988, 44, 1.
References and notes
5. (a) Patel, K. M.; Sparrow, J. T. Synth. Commun. 1979, 9,
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Angew. Chem., Int. Ed. Engl. 1972, 11, 846.
6. Khan, M. A.; Polya, J. B. J. Chem. Soc. 1970, 85.
7. (a) Hebel, D.; Rozen, S. J. Org. Chem. 1991, 56, 6298; (b)
Bauer, L.; Dickerhofe, T. E.; Tserng, K.-Y. J. Heterocycl.
Chem. 1975, 12, 797; (c) Stavber, S.; Zupan, M. Tetrahe-
dron Lett. 1990, 31, 775; (d) Bauer, L.; Gardella, L. A. J.
Org. Chem. 1963, 28, 1320.
1. (a) Sundberg, R. J.; Mente, D. C.; Yilmaz, I.; Gupta, G. J.
Heterocycl. Chem. 1977, 14, 1279; (b) Freitas de Sousa, G.;
Filgueiras, C. A. L. Transition Met. Chem. 1990, 15,
286.
2. (a) Umeno, M.; Takita, S. Japanese Patent 01 75,468,
1989; Chem. Abstr. 1989, 111, 134004y; (b) Marumoto, R.;
Shunsuke, S.; Masao, T. Eur. Pat. Appl. EP 38,161, 1981;
Chem. Abstr. 1982, 104, 85940m.
3. (a) Vercek, B.; Ogorevc, B.; Stanovnik, B.; Tisler, M.
Monatsh. Chem. 1983, 114, 789; (b) Knox, L. I.; Rogers,
R. B. U.S. Patent 4,775,762, 1988; (c) Seidel, M. C.; Von
Meyer, W. C.; Greenfield, S. A. U.S. Patent 4,120,864,
1979; (d) Kiselyov, A.S.; Piatnitski, E.; Doody, J.; Hadari,
Y.; Ouyang, S.; Chen, X. US Patent Appl. 2004 00624; (e)
Piatnitski, E.; Kiselyov A. S. U.S. Patent Appl. 0017248,
2004; (f) Chen, X.; Hadari, Y.; Ouyang, S.; Doody, J.;
Piatnitski, E.; Kiselyov, A. S. U.S. Patent Appl. 052280,
2004; (g) Adams, J.; Geuns-Meyer, S.; Booker, S.;
Elbaum, D.; German, J.; Kim, T.-S.; Ouyang, X.; Patel,
V. F.; Tasker, A.; Xi, N.; Xu, S.; Bemis, J.; Cai, G.; Chen,
G.; Croghan, M.; Dipetro, L.; Dominguez, C.; Handley,
8. Abramovitch, R. A.; Saha, J. G. Adv. Heterocycl. Chem.
1966, 6, 229.
9. (a) Taylor, E. C.; LaMattina, J. L.; Tseng, C. P. J. Org.
Chem. 1982, 47, 2043; (b) Grandberg, I. I.; Krokhina, N.
F.; KondratÕev Khim. Pharm. Zh. 1968, 2, 24; (c) Coppa,
F.; Fontana, F.; Lazzassi, E.; Minisci, F. Heterocycles
1993, 36, 2687.
10. (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. Org.
Synth. 1990, 69, 129; (c) Umemoto, T.; Harasawa, K.;
Tomizawa, G.; Kawada, K.; Tomita, K. Bull. Chem. Soc.
Jpn. 1991, 64, 1081.

2282
A. S. Kiselyov / Tetrahedron Letters 46 (2005) 2279–2282
11. (a) Umemoto, T.; Tomizawa, G. J. Org. Chem. 1989, 54,
1726; (b) See Ref. 7a; (c) Hebel, D.; Rozen, S. J. Org.
Chem. 1988, 53, 1123.
12. Van Der Puy, M.; Nalewajek, D.; Wicks, G. E. Tetrahe-
dron Lett. 1988, 29, 4389.
ether, the resultant solid residue was recrystallized from
EtOH to afford analytically pure 3i–p. Small amounts of
side products (5, 5–8% isolated yields) along with addi-
tional quantities of 3 (10–15%) were isolated from the
resulting mother liquors by column chromatography on
silica gel as described above.
13. Umemoto, T.; Tomizawa, G. Tetrahedron Lett. 1987, 28,
2705.
20. Representative examples: 6-methoxy-N-(4-nitrophenyl)pico-
linamide (3n): mp 235–237 °C, 52% yield, 1H NMR
(400 MHz, DMSO-d6): d 3.75 (s, 3H, Me), 7.14 (d,
J = 7.6 Hz, 1H), 7.45 (m, 1H), 7.93 (d, J = 9.2 Hz, 2H),
8.22 (d, J = 9.2 Hz, 2H), 8.28 (d, J = 7.6 Hz, 1H), 8.64 (br
s, 1H, exch. D2O, NH); 13C NMR (DMSO-d6): d 56.6,
109.5, 113.0, 121.3, 122.3, 139.4, 142.3, 144.3, 149.0,
162.4, 163.8. ESI MS: (M+1) 274, (MÀ1) 272; HR ESI
MS: exact mass calcd for C13H11N3O4: 273.0750, found:
273.0746. Elemental analysis, calcd for C13H11N3O4: C,
57.14; H, 4.06; N, 15.38. Found: C, 57.03; H, 4.08; N,
15.22. N-(4-Nitrophenyl)-6-phenylpicolinamide (3o): mp
>250 °C, 33% yield, 1H NMR (400 MHz, DMSO-d6): d
7.28 (m, 1H), 7.35 (m, 2H), 7.88 (m, 2H), 7.98 (m,
3H), 8.05 (d, J = 7.6 Hz, 1H), 7.92 (m, 1H), 8.20 (d,
J = 9.2 Hz, 2H), 8.48 (br s, 1H, exch. D2O, NH);
13C NMR (DMSO-d6): d 119.2, 121.5, 122.3, 127.0,
127.5, 127.7, 129.5, 136.5, 138.8, 142.2, 144.0, 151.4,
153.5, 162.5; ESI MS: (M+1) 320, (MÀ1) 318; HR ESI
MS: exact mass calcd for C18H13N3O3: 319.0957, found:
319.0952. Elemental analysis, calcd for C18H13N3O3: C,
61.71; H, 4.10; N, 13.16. Found: C, 61.54; H, 4.18; N,
13.02. Methyl 6-((4-nitrophenyl)carbamoyl)picolinate
(3p): mp 212–214 °C, 31% yield, 1H NMR (400 MHz,
DMSO-d6): d 3.86 (s, 3H, Me), 7.92 (d, J = 9.2 Hz, 2H),
8.20 (d, J = 9.2 Hz, 2H), 8.55 (br s, 1H, exch. D2O, NH),
8.67 (m, 1H), 8.78 (d, J = 7.6 Hz, 1H), 8.92 (d,
J = 7.6 Hz, 1H); 13C NMR (DMSO-d6): d 51.8, 121.4,
122.5, 125.8, 127.5, 139.8, 142.2, 144.8, 147.1, 150.2,
162.9, 168.0. ESI MS: (M+1) 302, (MÀ1) 300; HR ESI
MS: exact mass calcd for C14H11N3O5: 301.0700, found:
301.0693. Elemental analysis, calcd for C14H11N3O5: C,
55.82; H, 3.68; N, 13.95. Found: C, 55.70; H, 3.81; N,
13.81.
14. Kiselyov, A. S.; Gakh, A. A.; Kagramanov, N. D.;
Semenov, V. V. Mendeleev Commun. 1992, 128.
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30, 1361.
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2151.
19. 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 CH2Cl2 (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 to
remove molecular fluorine and then treated dropwise
(À50 °C) with a solution of isonitrile (20 mmol in 50 mL
of CH2Cl2). The resultant pale yellow mixture was stirred
at À50 °C for 1 h, allowed to reach 0 °C within the next
1 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 CH2Cl2. The solutions
were combined, washed with water, dried (MgSO4), and
concentrated. Silica gel chromatography (hexanes) affor-
ded 2-chloropyridines 4. Subsequent elution with hexanes/
ether (1:2) furnished 2-pyridylcarboxamides 3 as main
products along with varying quantities of 5 (5–7% isolated
yields). Alternatively, for p-nitrophenyl isocyanide reac-
tion mixtures, the resulting concentrate was washed with