Novel one pot synthesis of azolo[1,5-a]pyridines from Viehe's salts

Article abstract of DOI:10.1016/j.tetlet.2005.12.103

We have developed a practical procedure for the synthesis of polyfunctional azolo[1,5-a]pyridines via the reactive species generated in situ from N-substituted lactams and Viehe's salt. The reaction is regioselective with respect to the nucleophilic addit

Full text of DOI:10.1016/j.tetlet.2005.12.103

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1395–1398
Novel one pot synthesis of azolo[1,5-a]pyridines from Viehe’s salts
Alexander S. Kiselyov*
Small Molecule Drug Discovery, Chemical Diversity, 11558 Sorrento Valley Road, San Diego, CA 92121, USA
Received 12 December 2005; revised 14 December 2005; accepted 19 December 2005
Abstract—We have developed a practical procedure for the synthesis of polyfunctional azolo[1,5-a]pyridines via the reactive species
generated in situ from N-substituted lactams and Viehe’s salt. The reaction is regioselective with respect to the nucleophilic addition
of bis-anions derived from methyl azolyl acetates. The described protocol allowed for the introduction of three elements of diversity
into the targeted molecules, including substituents originating from the (i) nucleophile input, (ii) lactam ring, and (iii) nucleophilic
aromatic displacement (SNAr) of the NMe2 group with amines. A short reaction sequence, good yields of title compounds (44–69%),
as well as their ready isolation, and purification are the distinct advantages of the reported protocol.
Ó 2006 Elsevier Ltd. All rights reserved.
Chemistries of Viehe’s salt offer a facile access to a
diverse array of products. These include the derivatives
of 4-pyrone,1 2-pyrone,2 pyrimidine,3 1,3-oxadiazin-6-
one,4 thiazole,5 pyrazole,6 various fused heterocycles,7
and non-aromatic species.8 Recently, a series of poly-
substituted pyrimidines were synthesized using the reac-
tion of bis-electrophilic species 2 generated from Viehe’s
salts and lactams 1 with amidines and guanidines
(Scheme 1).9 This reaction sequence allowed for the
introduction of three elements of diversity into the resul-
tant molecules, including substituents originating from
the (i) nucleophile input, (ii) lactam ring, and (iii) nucleo-
philic aromatic displacement (SNAr) of the NMe2
group.10 In this letter, we further extended this protocol
to access a series of azolo[1,5-a]pyridines via a novel
one-pot reaction sequence (Scheme 1).
In the initial study, we synthesized a set of the targeted
heterocycles with varying R1 and fused azolyl sub-
stituents. Three commercially available N-substituted
2-pyrrolidinones 1a–c (R1 = Me, cyclohexyl, and Ph)
were selected for the preparation of 2. These were sub-
sequently reacted with bis-anions derived from methyl
azolyl acetates. The results of these experiments are
summarized below (Scheme 2).11 Targeted molecules
were conveniently isolated in analytically pure form by
trituration of the concentrated reaction mixtures with
cold Et2O followed by recrystallization of the resulting
solid residue from EtOH. Analysis of the reaction mix-
tures (LC MS and 1H NMR) suggested that the nucleo-
philic addition of bis-anions proceeds regioselectively as
only single regioisomer 3 was detected and isolated.12
The described transformations one likely to proceed
HN
N
R
H2N
N
N
N
n
N
R1
Cl
Cl
R
N
N
Cl
Cl
Viehe's salt
O
n
N
N
N
n
EWG
N
R1
N
R1
N
n
1
N
2
R1
EWG
Scheme 1.
Keywords: Azolo[1,5-a]pyridines; Iminium salts; Viehe’s salt; Lactams; Azolyl acetates; Condensations.
*
Tel.: +1 858 794 4860; fax: +1 858 794 4931; e-mail: ask@chemdiv.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.103

1396
A. S. Kiselyov / Tetrahedron Letters 47 (2006) 1395–1398
N
N
N
N
EWG
N
Cl
Cl
N
Cl
Cl
N
n
O
n
toluene/THF,
N
N
toluene,
reflux, 1 h
n
-78oC to reflux, 4 hrs
N
R1
R1
EWG
R1
n = 1,2
1
3a-r
2
Yieldsa of pyrimidines 3a-r
Compound, 3
Compound, 3
N
N
N
EWG
Yield, %
n
R1
Yield, %
n
R1
EWG
N
N
N
N
N
a
b
1
1
44
51
COOMe
COOMe
j
2
Me
Me
Me
Me
COOMe
46
58
N
N
N
N
Me
k
l
2
2
CN
N
N
N
N
N
COOMe
Me
COOMe
53
57
c
d
1
1
N
N
N
Me
56
62
CN
m
n
2
1
Ph
COOMe
COOMe
69
68
N
N
N
Me
COOMe
N
e
f
1
1
Ph
Me
o
p
2
2
CN
Me
Ph
47
54
N
N
COOMe
CN
44
63
N
N
N
N
g
1
COOMe
N
h
i
1
2
Ph
66
49
COOMe
COOMe
N
N
q
r
1
1
61
55
Me
Me
COOMe
COOMe
N
N
Me
N
N
aYields refer to isolated analytically pure compounds.
Scheme 2.
via the initial formation of the respective dichloro imin-
ium species 2 that undergo nucleophilic attack by the
C-atom of 1,3-dianions. This event is followed by cycli-
zation and aromatization steps to yield the observed
polysubstituted azolo[1,5-a]pyridines 3a–r.
(Scheme 2), presumably due to the hydrolytic instability
of the respective iminium intermediate 2 under the reac-
tion conditions. Optimized reaction conditions include
application of dry THF/toluene or dioxane/toluene as
solvents. Use of alternative solvent step including freshly
distilled dry DMF, dimethoxyethane, or N-methylpyr-
rolidone (NMP) afforded somewhat lower yields of the
targeted products (by ca. 10–15%). The nature of base
used for deprotonation did not affect the outcome of
the condensation. For example, LDA, Li(morpholide),
NaHMDS, and KHMDS resulted in comparable yields
The nature of neither azolyl acetates nor lactams 1 sig-
nificantly affected the outcome of the reaction (for
example, compare yields for 3a and 3i, 3h and 3m,
Scheme 2). N-Methyl substituted lactams furnished
somewhat lower yields of the targeted heterocycles 3

A. S. Kiselyov / Tetrahedron Letters 47 (2006) 1395–1398
1397
Product
RR'NH
Yield, %a
4
5
52
47
NH2
NH2
R
N
R'
N
N
Cl
Cl
RR'NH
NMP, uwave, 180 sec
N
N
N
N
6
68
N
NH2
CN
CN
3d
4-8
7
8
71
65
N
H
H2N
N
aYields refer to isolated, analytically pure compounds.
Scheme 3.
3. (a) Neidlein, R.; Wang, Z. Synth. Commun. 1997, 27,
1223–1235; (b) Wang, Z.; Neidlein, R. Heterocycles 1998,
48, 1923–1930; (c) Lockhart, C. C.; Sowell, J. W., Sr. J.
Heterocycl. Chem. 1996, 33, 659–661.
4. (a) Decock-Plancquaert, M.-A.; Evariste, F.; Guillot, N.;
Janousek, Z.; Maliverney, C.; Merenyi, R.; Viehe, H. G.
Bull. Soc. Chim. Belg. 1992, 101, 313–321; (b) Neidlein, R.;
Meffert, P.; Sui, Z. Synthesis 1992, 443–446; (c) Neidlein,
R.; Sui, Z. Synthesis 1990, 959–961.
of 3, as evidenced by the LC MS analysis of the crude
reaction mixtures. In addition to the targeted molecules
3a–r the reaction mixtures also contained products of
self-condensation of bis-anions (ca. 25–30%) and high
molecular weight products. Additional quantities of
3a–r (ca. 5–10%) could be isolated from the reaction
mixtures by flash chromatography (Silicagel, eluent:
hexanes/EtOAc, 2:1).
5. Maliverney, C.; Merenyi, R.; Viehe, H. G. Bull. Soc. Chim.
Belg. 1990, 99, 941–949.
The described protocol was further extended to the syn-
thesis of fused tricyclic systems 3n–r (44–68% yields) by
reaction of the intermediate 2 with dianions derived
from 2-indole- and 2-benzimidazole methyl acetates
(Scheme 2). Further, azolo[1,5-a]pyridine 3d was reacted
with a series of amines (Scheme 3) under microwave
irradiation in dry NMP at 140 °C to furnish products
of formal SNAr of the NMe2 group 4–8 in 47–71% yields
(Scheme 3).13
6. (a) Van Vyve, T.; Viehe, H. G. Angew. Chem., Int. Ed.
Engl. 1974, 13, 79; (b) De Voghel, G. J.; Eggerichs, T. L.;
Janousek, Z.; Viehe, H. G. J. Org. Chem. 1974, 39, 1233;
(c) Van Vyve, T.; Viehe, H. G. Angew. Chem. 1974, 86, 45;
(d) Hervens, F.; Viehe, H. G. Angew. Chem., Int. Ed. Engl.
1973, 12, 405.
7. For the synthesis of fused heterocycles using Viehe’s salt,
see: (a) Quintela, J. M.; Moreira, M. J.; Peinador, C.
Tetrahedron 1996, 52, 3037–3048; (b) Quntela, J. M.;
Veiga, M. C.; Peinador, C.; Gonzalez, L. Heterocycles
1997, 1733–1743; (c) Peinador, C.; Quintela, J. M.;
Moreira, M. J. Tetrahedron 1997, 53, 8269–8272; (d)
Quintela, J. M.; Peinador, C. Tetrahedron 1996, 52,
10497–10506; (e) Player, M. R.; Sowell, J. W., Sr. J.
Heterocycl. Chem. 1995, 32, 1537–1540; (f) Quintela, J.
M.; Peinador, C.; Moreira, M. J. Tetrahedron 1995, 51,
5901–5912; (g) Kokel, B. J. Heterocycl. Chem. 1994, 31,
845–855; (h) Kokel, B. J. Heterocycl. Chem. 1994, 31,
1185–1192.
8. (a) Schlama, T.; Gouverneur, V.; Valleix, A.; Greiner, A.;
Toupet, L.; Mioskowski, C. J. Org. Chem. 1997, 62, 4200–
4202; (b) Bouvy, D.; Janousek, Z.; Viehe, H. G. Bull. Soc.
Chim. Belg. 1993, 102, 129–140; (c) Tinant, B.; Declercq,
J.-P.; Bouvy, D.; Janousek, Z.; Viehe, H. G. J. Chem. Soc.,
Perkin Trans. 2 1993, 911–915; (d) Vovk, M. V.; Bratenko,
M. K.; Samarai, L. I. Ukr. Khim. Z. 1991, 57, 431–432; (e)
Guillot, N.; Janousek, M. B.; Viehe, H. G. Synth.
Commun. 1989, 19, 2825.
In summary, we have developed a practical procedure
for the synthesis of polyfunctional azolo[1,5-a]pyridines
via the reactive species generated in situ from N-substi-
tuted lactams and Viehe’s salt. The reaction is regio-
specific with respect to the nucleophilic addition of
bis-anions derived from methyl azolyl acetates. The
described protocol allowed for the introduction of three
elements of diversity into the targeted molecules, includ-
ing substituents originating from the (i) nucleophile
input, (ii) lactam ring, and (iii) nucleophilic aromatic
displacement (SNAr) of the NMe2 group with amines.
A short reaction sequence, good yields of title com-
pounds (44–69%), as well as their ready isolation, and
purification are the distinct advantages of the reported
protocol.
9. Kiselyov, A. S. Tetrahedron Lett. 2005, 46, 1177.
10. Vorbruggen, H. Adv. Heterocycl. Chem. 1990, 49, 117.
11. Experimental procedure: 1.5 mmol of Viehe’s salt (Aldrich)
was added to a vigorously stirred solution of 1 mmol of
lactam in dry degassed toluene (15 mL) at room temper-
ature under Ar. The heterogeneous dark yellow mixture
was slowly warmed up to 80 °C (30 min), and the resulting
mixture was stirred at this temperature for an additional
1.5 h. The dark-red mixture was quickly filtered under
References and notes
1. (a) Morris, J.; Wishka, D. G.; Luke, G. P.; Judge, T. M.;
Gammill, R. B. Tetrahedron 1997, 53, 11211–11222; (b)
Morris, J.; Luke, G. P.; Wishka, D. G. J. Org. Chem.
1996, 61, 3218–3220.
2. Bouvy, D.; Janousek, Z.; Viehe, H. G. Bull. Soc. Chim.
Belg. 1993, 102, 129–140.

1398
A. S. Kiselyov / Tetrahedron Letters 47 (2006) 1395–1398
argon blanket and cooled down to À70 °C. Separately, a
(s, 3H, COOMe), 7.54 (d, J = 4.8 Hz, 1H), 7.81 (d,
J = 4.8 Hz, 1H). 13C NMR (100 MHz, DMSO-d6): d
20.8, 21.1, 38.2, 40.4, 50.1, 51.2, 99.6, 100.1, 116.2, 125.4,
144.9, 155.3, 162.0, 168.5. ESI MS: (M+1) 289, (MÀ1)
287; HR ESI MS: Exact mass calcd for C15H20N4O2:
288.1586, found: 288.1581. Elemental analysis, calcd for
C15H20N4O2: C, 62.48; H, 6.99; N, 19.43. Found: C, 62.23;
H, 7.11; N, 19.21.
solution of the respective methyl azolyl acetate (1 mM) in
dry THF or dioxane (5 mL) was treated with freshly
prepared LDA (2.5 mM) in the same solvent (5 mL) at
À78 °C under Ar. The resulting pale yellow mixture was
slowly (5–10 min) added via cannula to the toluene
solution of 2 at 0 °C. The reaction mixture was slowly
brought to rt (20 min) and, subsequently to reflux
(20 min). Further, it was refluxed for additional 3–4 h.
The mixture was then concentrated to ca. 10 mL on
rotavap, diluted with EtOAc (50 mL), the organic extract
was washed twice with brine (30 mL), dried over Na2SO4,
concentrated to ca. 15 mL, cooled down in the freezer, and
triturated with cold ether. The resulting crystals were
collected, washed with ether, recrystallized from EtOH,
and dried in vacuo to yield analytically pure azolo[1,5-a]-
pyridines in a 44–69% yields. Additional quantities of 3a–r
(ca. 5–10%) could be isolated from the reaction mixtures
by flash chromatography (Silicagel, eluent: hexanes/
EtOAc, 2:1).
Compound 3n: 68% yield, mp >250 °C. 1H NMR
(400 MHz, DMSO-d6): d 2.44 (s, 3H, N–Me), 2.55 (s,
6H, NMe2), 2.72 (m, 2H), 3.25 (m, 2H), 3.92 (s, 3H,
COOMe), 6.35 (s, 1H), 7.05 (m, 1H), 7.12 (m, 1H), 7.38 (d,
J = 7.2 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H). 13C NMR
(100 MHz, DMSO-d6): d 19.2, 36.4, 39.9, 51.3, 55.8, 94.5,
96.2, 98.8, 110.7, 113.5, 119.4, 119.8, 120.5, 122.3, 128.6,
137.5, 139.7, 165.7. ESI MS: (M+1) 324, (MÀ1) 322; HR
ESI MS: Exact mass calcd for C19H21N3O2: 323.1634,
found: 323.1625. Elemental analysis, calcd for
C19H21N3O2: C, 70.57; H, 6.55; N, 12.99. Found: C,
70.36; H, 6.38; N, 12.81.
Analytical data for representative compounds:
Compound 5: 47% yield, mp >250 °C. 1H NMR
(400 MHz, DMSO-d6): d 2.49 (s, 3H, N–Me), 2.84 (m,
2H), 3.41 (m, 2H), 5.12 (br s, exch D2O, 1H, NH), 6.44 (d,
J = 5.6 Hz, 1H), 6.55 (d, J = 7.8 Hz, 2H), 6.98 (d,
J = 7.8 Hz, 2H), 7.75 (d, J = 5.6 Hz, 1H). 13C NMR
(100 MHz, DMSO-d6): d 18.4, 36.8, 55.6, 87.6, 95.4,
110.9, 117.3, 118.3, 123.7, 129.6, 132.5, 134.0, 141.8, 160.5,
166.7. ESI MS: (M+1) 325, (MÀ1) 323; HR ESI MS:
Exact mass calcd for C17H14ClN5 323.0938, found:
323.0934. Elemental analysis, calcd for C17H14ClN5: C,
63.06; H, 4.36; N, 21.63. Found: C, 62.87; H, 4.19; N,
21.48.
Compound 3a: 44% yield, mp 227–229 °C. 1H NMR
(400 MHz, DMSO-d6): d 2.54 (s, 3H, N–Me), 2.66 (s, 6H,
NMe2), 2.84 (m, 2H), 3.56 (m, 2H), 3.92 (s, 3H, COOMe),
6.54 (d, J = 5.6 Hz, 1H), 7.95 (d, J = 5.6 Hz, 1H). 13C
NMR (100 MHz, DMSO-d6): d 18.8, 36.9, 41.1, 51.4, 54.6,
96.2, 100.4, 109.3, 133.5, 134.8, 155.7, 163.0, 167.1. ESI
MS: (M+1) 275, (MÀ1) 273; HR ESI MS: Exact mass
calcd for C14H13N4O2: 274.1430, found: 274.1422. Ele-
mental analysis, calcd for C14H13N4O2: C, 61.30; H, 6.61;
N, 20.42. Found: C, 61.09; H, 6.47; N, 20.27.
Compound 3h: 66% yield, mp >250 °C. 1H NMR
(400 MHz, DMSO-d6): d 2.69 (s, 6H, NMe2), 2.85 (m,
12. Significant NOE’s for the selected compounds.
N
N
N
N
N
N
N
O
N
Me
N
N
N
N
H
Me
H
O
O
O
O
O
Me
Me
Me
H
3a
3h
3l
2H), 3.64 (m, 2H), 3.92 (s, 3H, COOMe), 6.61 (d,
J = 7.2 Hz, 2H), 6.69 (m, 1H), 7.02 (m, 2H), 7.56 (d,
J = 4.8 Hz, 1H), 7.79 (d, J = 4.8 Hz, 1H). 13C NMR
(100 MHz, DMSO-d6): d 18.9, 40.7, 50.2, 51.7, 98.8, 108.3,
112.7, 115.0, 117.6, 125.7, 128.4, 141.8, 148.2, 157.3, 162.5,
166.5. ESI MS: (M+1) 337, (MÀ1) 335; HR ESI MS:
Exact mass calcd for C19H20N4O2: 336.1586, found:
336.1578. Elemental analysis, calcd for C19H20N4O2: C,
67.84; H, 5.99; N, 16.66. Found: C, 67.58; H, 6.14; N,
16.21.
13. Microwave heating of 3d with amines in NMP for 180 s
was found to yield better yields of the targeted amines 4–8
(by ca. 20–30%, as evidenced by LC MS analyses of the
crude reaction mixtures) when compared to a conventional
heating of the reaction components in i-PrOH, dioxane, or
DMF. However, under these conditions, reactions of
methyl esters 3a–c with amines resulted in significant
formation of the respective amides (ca. 30–50% yields),
along with SNAr of the NMe2 group. The yields of amides
were reduced to ca. 10–15% by prolonged heating of the
reaction components (48–72 h) at 70 °C in NMP. Under
these conditions the conversion of 3a–c was 60–70%,
whereas the yields of the respective amines were 80–90%.
Compound 3l: 53% yield, mp 235–237 °C. 1H NMR
(400 MHz, DMSO-d6): d 1.92 (m, 2H), 2.51 (s, 3H, N–
Me), 2.60 (s, 6H, NMe2), 2.75 (m, 2H), 3.18 (m, 2H), 3.90