A novel three-component reaction of N-fluoropyridinium salts: A facile approach to imidazo[1,2-a]pyridines

Article abstract of DOI:10.1016/j.tetlet.2005.04.124

The reaction of N-fluoropyridinium triflate with isonitriles in acetonitrile and propionitrile in the presence of NaBH(OAc)₃ led to the formation of the corresponding imidazo[1,2-a]pyridines in 44-73% yields. The proposed reaction mechanism involves the intermediate formation of a highly reactive carbene species and apparent reduction of the pyridinium intermediate with NaBH(OAc)₃ to yield the targeted heterocycles.

Full text of DOI:10.1016/j.tetlet.2005.04.124

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4487–4490
A novel three-component reaction of N-fluoropyridinium salts:
a facile approach to imidazo[1,2-a]pyridines
Alexander S. Kiselyov*
Small Molecule Drug Discovery, Chemical Diversity, 11558 Sorrento Valley Road, Suite 5, San Diego, CA 92121, USA
Received 26 March 2005; revised 17 April 2005; accepted 20 April 2005
Abstract—The reaction of N-fluoropyridinium triflate with isonitriles in acetonitrile and propionitrile in the presence ofNaB-
H(OAc)3 led to the formation of the corresponding imidazo[1,2-a]pyridines in 44–73% yields. The proposed reaction mechanism
involves the intermediate formation ofa highly reactive carbene species and apparent reduction ofthe pyridinium intermediate with
NaBH(OAc)3 to yield the targeted heterocycles.
Ó 2005 Elsevier Ltd. All rights reserved.
The synthetic potential of N-fluoropyridinium salts con-
veniently generated from pyridines and elemental
fluorine has been the subject ofongoing interest. 1 Reac-
tions ofthese highly reactive substrates have been used
F
F
NO2
HN
COOEt
N
COOEt
N
O
F
2
in the synthesis of2-halogeno pyridines, and for the
3
introduction ofhydroxy, amido,4 phosphonio,5 hetero-
aryl, arylthio, and aryloxy groups at position 2 ofpyr-
idine rings.6 Additional examples ofthe synthetic utility
ofthe N-fluoropyridinium cation include the prepara-
N
F
N
Cl
N
N
PPh3
X
7
NO2
tions ofpyridine-2-yl acetates
and 2-acetamidopyr-
idines.8 Representative examples ofthese chemistries
are summarized in Scheme 1.
N
N
N
NHAc
N
S
Scheme 1.
In our attempt to further expand the synthetic potential
9
ofthese useufl substrates,
we studied the reaction of
N-fluoropyridinium triflates 1 with isonitriles in acetoni-
trile and propionitrile in the presence ofNaBH(OAc) 3.10
This one-pot reaction yielded imidazo[1,2-a]pyridin-3-
amines 2a–p in good yields (Table 1).11,12 Varying
amounts of2-acetylamidopyridines 3 were also isolated
from the reaction mixtures.2,8 Notably, products 2a–p
are not accessible by a previously reported three-compo-
nent condensation of2-aminopyridines with isonitriles
and aldehydes.13
In general, the reaction outcome did not depend on the
nature ofthe isonitrile component ( Table 1, entries a–i).
With the notable exception ofbenzyl isonitrile (entry g),
yields ofthe desired compounds 2 exceeded 50%. We
also studied the effect ofpyridine substitution on the
reaction outcome (entries f–i and m–p). Both weak elec-
tron donating and withdrawing groups afforded good
yields of 2. The strong electron donating group (MeO,
entry n) led to a notably lower yield of 2n (45%) and
significant formation of side products, including the
respective 2-acetamidopyridine 3n (26%). Under similar
reaction conditions, N-fluoropyridinium salts 1 contain-
ing strong electron-withdrawing groups (3,5-chloro,
2-carbmethoxy) afforded very low yields ofthe
desired products 2 (10–22%) along with the respective
2-acetamidopyridines 3 (35–40%) and high-molecular
weight products (LC–MS analysis).1–3,8 3-Substituted
Keywords: N-Fluoropyridinium; Three-component condensation;
Imidazo[1,2-a]pyridine; Isonitrile; Carbene.
*
Tel.: +1 858 794 4860; fax: +1 858 794 4931; e-mail:
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0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.124

4488
A. S. Kiselyov / Tetrahedron Letters 46 (2005) 4487–4490
Table 1.
R3
HN
R2CN (solvent)
R1
R1
R1
R3NC, NaBH(OAc)3
N
+
+
R2
R1
NHR3
N
N
F
- 40oC to RT
N
NHCOR2
N
OTf
O
4a
2a-p
3
1
Entry 1
R1
R2
R3
Yields (%)
2
3
a
b
c
d
e
f
H
Me
Me
Me
Me
Me
Me
Me
Me
i-Pr
t-Bu
Ph
57
62
67
58
68
61
44
65
18
14
11
16
12
15
21
12
H
H
H
CH2COOEt
m-CH3–C6H4–
Ph
H
2-Me
4-Me
4-i-Pr
g
h
CH2Ph
p-NO2–C6H4–
i
2-Ph
Me
55
18
j
H
Et
Et
Ph
69
72
67
73
45
57b
69b
12
9
k
l
H
m-Me–C6H4–
p-Me–C6H4–
p-NO2–C6H4–
p-NO2–C6H4–
Ph
H
Et
Et
12
11
26
21c
15c
m
n
o
p
2-Me
2-OMe
3-Cl
3-Me
Et
Me
Me
Ph
aYields of 4 did not exceed 5–8% (isolated yields, 7–10% LC–MS yields).
b Mixture of2- and 6-substituted derivatives, ca. 2:1 isolated ratio, respectively.
c Mixture of2- and 6-substituted derivatives, ca. 2:1 isolated ratio, respectively.
2
pyridinium salts 1o,p yielded a mixture ofthe expected
2- and 6-regioisomers in ca. 2:1 ratio, respectively, and
57% (3-Cl, 1o) and 69% (3Me, 1p) overall isolated yields
(Table 1). A similar regioselectivity was observed by us
earlier.8 A ratio of1:2, N-fluoropyridinium salt 1 to iso-
nitrile, was found to furnish the best yields of 2. A larger
molar excess of 1 afforded increased amounts of 3. Pre-
cise temperature control, as well as reagent addition
order was found to be critical for securing good yields
ofthe desired materials. For example, addition ofNaB-
H(OAc)3 (suspension in MeCN) to the mixture of 1
and isonitrile resulted in higher yields ofthe respective
2-acetamidopyridines 3 (35–40%, LC–MS analysis). At
the same time, mixing 1 and NaBH(OAc)3 resulted in
the extensive formation of 2-fluoropyridines along with
a number ofunidentified products. Addition of 1 to a
vigorously stirred mixture ofreagents at temperatures
not exceeding À35 °C was found to be optimal for the
yields of 2.11
Mechanistically, the outcome ofthis reaction could be
explained by proton abstraction from the strongly acti-
vated position 2 ofthe N-fluoropyridinium cation 1 by
the base (NaBH(OAc)3) to yield the highly reactive car-
bene C (Scheme 2).1–5 We suggest that this resulting car-
bene undergoes a subsequent reaction with nitrile
(solvent) to afford the respective nitrilium ylid, the pos-
tulated precursor to 2.8 This intermediate undergoes
addition ofisonitrile of llowed by a subsequent cycliza-
tion ofthe resulting cation into a respective bicyclic
B:
R1-CN
R2-NC
N
N
:
N
F
N
N
F
-BH
N
F
H
N
F
N
C
- F
C
R1
N
R2
R1
R1
C
X
P
R2-NC
hydrolysis
H:
hydrolysis
R1
F
2
3
N
N
F
4
N
N
- F
N
N
F
N
N
R
R
HN
R1
R2
Scheme 2.

A. S. Kiselyov / Tetrahedron Letters 46 (2005) 4487–4490
4489
MeCN (solvent)
HN
N
t-BuNC, NaBH(OAc)3
N
+
+
- 40oC to RT
N
F
NHt-Bu
N
N
NHCOMe
OTf
O
6 (39%)
5
8 (13%)
7 (25%)
HN
N
MeCN (solvent)
t-BuNC, NaBH(OAc)3
N
- 40oC to RT
+
+
F
N
N
N
OTf
NHCOMe
O
NHt-Bu
9
10(32%)
12 (18%)
11 (21%)
Scheme 3.
pyridinium species P+. Reduction ofthis reactive inter-
mediate with NaBH(OAc)3 followed by aromatization
ofthe resultant zwitterion yields the observed imi-
dazo[1,2-a]pyridines 2. Product 3 is likely to originate
from the hydrolysis of the intermediate nitrilium ylid.
Product 4 probably results from the direct reaction of
C with isonitriles followed by hydrolysis of the interme-
diate isonitrilium ylid. Consistent with the proposed
mechanism, presence ofthe reducing agent (NaB-
H(OAc)3) was found to be critical for the preparation
of 2. Specifically, borohydride is likely to serve as a base
to yield the ylid C. In addition, it reduces the reactive
intermediate P+ into stable aromatic species 2. Applica-
tion ofother bases, including diisopropyl ethyl amine
(HunigÕs base) or Bu4NF, yielded complex mixture of
products, major components (ca. 35–40% by LC–MS
analysis) were found to be 3, 4 in addition to various
amounts ofthe respective 2-chloro- and 2-fluoropyr-
idines.2 We believe that the species P+ are unstable
under nonreducing conditions and undergo hydrolysis
to yield 3. Other reducing agents, namely NaBH4 and
NaBH3CN also afforded 2, although the yields did not
exceed ca. 30–35% presumably due to their poor solubil-
ity in the reaction system. The postulated intermediacy
ofthe carbene C is in agreement with the lack offorma-
tion ofthe respective derivatives 2 and 3 in an attempted
reaction of2,6-dimethylpyridine under the described
conditions.
yields. Similar transformations were observed for both
quinoline and isoquinoline. Formation ofa highly reac-
tive carbene intermediate is proposed to explain the out-
come ofthis reaction.
References and notes
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
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.
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. Tetrahe-
dron 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.
Consistent with this reactivity pattern is the formation
ofthe respective 2-quinoline and 1-isoquinoline deriva-
tives upon treatment of N-fluoroquinolinium- and iso-
quinolinium salts 5, 910 with t-BuNC as described
above (6, 10; 39% and 32% yields, respectively, Scheme
3).11,12 Yields ofthe desired materials were lower than
those observed for the similar reaction protocols with
N-fluoropyridinium salts 1, although the reaction pat-
tern was similar. In addition, significant amounts of
high molecular weight products were detected in the
reaction mixtures (LC–MS analysis).
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. Other bases, including Et3N, HunigÕs base and Bu4NF
afforded a mixture of 3 and 4 exclusively, the targeted
imidazo[1,2-a]pyridines 2 were not detected in the reaction
mixtures. All N-fluoropyridinium-, quinolinium, and iso-
quinolinium salts were synthesized as described earlier.1,2,8
N-Fluoropyridinium salts with BF4À counterion reacted in
a similar fashion, however the yields of imidazo[1,2-
a]pyridines
2 were significantly lower (ca. 15–30%),
presumably due to the poor solubility oftetrafluorobo-
rates in nitriles at lower temperature. Attempted reactions
with other nitriles (i-PrCN and t-BuCN) were not
successful as the mixtures were frozen under the reaction
conditions. Increased temperatures afforded complex
reaction mixtures. Reactions in a binary solvent systems
In summary, we described the reaction of N-fluoropyrid-
inium salts with isonitriles in acetonitrile and propionit-
rile in the presence ofNaBH(OAc)
respective imidazo[1,2-a]pyridine-3-amines in good
to yield the
3

4490
A. S. Kiselyov / Tetrahedron Letters 46 (2005) 4487–4490
(nitrile/CH2Cl2, nitrile/THF, nitrile/acetone, various
ratios) afforded very low yields ofthe desired imi-
dazo[1,2-a]pyridines even at low temperatures
(À50 °C). Instead, products ofsolvent addition to pyridine
(e.g., 2-chloropyridines, 2-pyridones) were detected in the
reaction mixtures.1,8
2-Ethyl-5-methyl-N-(4-nitrophenyl)H-imidazo[1,2-a]pyri-
din-3-amine (2m): mp 212–214 °C, 73% yield, NMR (400
MHz, DMSO-d6): d 1.25 (t, J = 7.6 Hz, 3H, Et), 2.52 (q,
J = 7.6 Hz, 2H, Et), 2.57 (s, 3H, Me), 4.46 (br s, 1H, exch.
D2O, NH), 6.56 (d, J = 8.0 Hz, 1H), 6.76 (d, J = 9.2 Hz,
2H), 7.01 (m, 1H), 7.35 (d, J = 6.8 Hz, 1H), 7.92 (d,
J = 9.2 Hz, 2H); 13C NMR (DMSO-d6): d 14.2, 18.1, 22.9,
117.1, 119.3, 122.1, 124.2, 124.5, 128.2, 135.1, 136.3, 138.8,
144.5, 149.4; ESI MS: (M+1) 297, (MÀ1) 295; HR ESI
MS: Exact mass calcd for C16H16N4O2 296.1273. Found:
296.1264. Elemental analysis calcd for C16H16N4O2: C,
64.85; H, 5.44; N, 18.91. Found: C, 64.72; H, 5.61; N,
18.75.
2-Ethyl-5-methoxy-N-(4-nitrophenyl)H-imidazo[1,2-a]pyri-
din-3-amine (2n): mp > 250 °C, 55% yield, 1H NMR
(400 MHz, DMSO-d6): d 1.26 (t, J = 7.6 Hz, 3H, Et),
2.52 (q, J = 7.6 Hz, 2H, Et), 3.75 (s, 3H, OMe), 4.27 (br s,
1H, exch. D2O, NH), 5.98 (d, J = 8.0 Hz, 1H), 6.52 (d,
J = 6.8 Hz, 1H), 6.74 (d, J = 9.2 Hz, 2H), 7.02 (m, 1H),
7.93 (d, J = 9.2 Hz, 2H); 13C NMR (DMSO-d6): d 14.3,
18.0, 56.5, 108.8, 110.6, 117.3, 122.0, 124.3, 135.2, 138.0,
138.2, 149.2, 144.6, 165.3. ESI MS: (M+1) 313, (MÀ1)
311; HR ESI MS: Exact mass calcd for C16H16N4O3
312.1222. Found: 312.1213. Elemental analysis calcd for
C16H16N4O3: C, 61.53; H, 5.16; N,17.94. Found: C, 61.38;
H, 5.27; N, 17.82.
N-tert-Butyl-2-methyl-H-imidazo[2,1-a]isoquinolin-3-amine
(10): mp > 250 °C, 32% d 1.11 (s, 9H, t-Bu), 2.29 (s, 3H,
Me), 4.52 (br s, 1H, exch. D2O, NH), 7.48–7.52 (m, 2H),
7.58 (m, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 6.8 Hz,
1H), 8.43 (d, J = 8.0 Hz, 1H); 13C NMR (DMSO-d6): d
9.6, 30.2, 53.1, 121.1, 124.3, 124.9, 125.1, 126.7, 127.1,
128.2, 130.1, 133.9, 136.5, 144.3. ESI MS: (M+1) 254,
(MÀ1) 252; HR ESI MS: Exact mass calcd for C16H19N3
253.1579. Found: 253.1575. Elemental analysis calcd for
C16H19N3: C, 75.85; H, 7.56; N, 16.59. Found: C, 75.71;
H, 7.68; N, 16.43.
2
11. In a typical reaction sequence, a solution of N-fluoropy-
ridinium triflate (1, 2 mmol) in a dry degassed nitrile
(25 mL) was added dropwise to a vigorously stirred
mixture ofisonitrile (4 mmol) and NaBH(OAc)
3
(4.5 mmol) in the same solvent (25 mL) under Ar at
À40 °C (water/ethylene glycol bath). The temperature of
the mixture was thoroughly controlled so as not to exceed
À35 °C during the addition of 1. The resultant mixture
was stirred for additional 4 h at this temperature, 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 1. The mixture was concentrated
(efficient N2 trap to contain excess ofisonitrile!), passed
through a thin layer ofsilica gel, and the gel was washed
with CH2Cl2. The solutions were combined, washed with
water, dried (MgSO4), and concentrated. Solid residue was
re-dissolved in EtOAc and purified by column chroma-
tography on silica gel. Elution with hexanes/EtOAc (1:1)
furnished imidazo[1,2-a]pyridine-3-amines 2 as main prod-
ucts along with varying quantities of 3 (9–22% isolated
yields) and 4 (5–8% isolated yields).
12. Representative examples: 7-Isopropyl-2-methyl-N-(4-nitro-
phenyl)H-imidazo[1,2-a]pyridin-3-amine (2h): mp 225–
227 °C, 65% yield, 1H NMR (400 MHz, DMSO-d6): d
1.32 (d, J = 7.6 Hz, 6H, i-Pr), 2.25 (s, 3H, Me), 3.15 (m,
1H, i-Pr), 4.74 (br s, 1H, exch. D2O, NH), 6.61 (d,
J = 8.0 Hz, 1H), 6.76 (d, J = 9.2 Hz, 2H), 7.43 (s, 1H), 7.92
(d, J = 9.2 Hz, 2H), 8.12 (d, J = 8.0 Hz, 1H); 13C NMR
(DMSO-d6): d 10.1, 23.6, 36.5, 114.8, 117.6, 121.6, 122.1,
124.0, 124.8, 134.1, 138.7, 144.2, 149.3, 155.1. ESI MS:
(M+1) 311, (MÀ1) 309; HR ESI MS: Exact mass calcd for
C17H18N4O2 310.1430. Found: 310.1427. Elemental anal-
ysis calcd for C17H18N4O2: C, 65.79; H, 5.85; N, 18.05.
Found: C, 65.66; H, 5.94; N, 18.14.
13. Chen, J. J.; Golebiowski, A.; McClenaghan, J.; Klopfen-
stein, S. R.; West, L. Tetrahedron Lett. 2001, 42, 2269, and
references cited therein.