Y. Hoashi et al. / Tetrahedron Letters 54 (2013) 2199–2202
2201
H
moiety under heating conditions without activation by deprotona-
tion. Acetic acid and mesitylenesulfonate anion is considered to
stabilize the transition state (E). Simultaneous deprotonation and
protonation provide a protonated form of the pyrazolo[1,5-a]pyri-
dine (F). This mechanism is consistent with the improved yield
obtained by using acetic acid (Table 1, entries 6 vs 7). Proton
exchange between acetate anion and mesitylenesulfonic acid
yields the pyrazolo[1,5-a]pyridine as a salt form with mesitylene-
sulfonic acid (G). Since this product would make the reaction mix-
ture acidic, a suitable alternative for acid-sensitive substrates could
be the use of the buffered conditions (Table 1, entry 2).
This reaction was then applied to the synthesis of the melatonin
agonist 1, which has an angularly dihydrofuran-fused pyrazol-
o[1,5-a]pyridine as its core structure (Scheme 4). The reported
synthetic route involves the intermolecular [3+2] cycloaddition of
N-aminopyridine with an alkynoic ester for the construction of
pyrazolo[1,5-a]pyridine ring.3 The reaction afforded the desired
compound in low yield (Scheme 1 and 17%) with the undesirable
regioisomer. The known pyridone 717 was treated with triflic anhy-
dride in pyridine to afford the triflate 8, which was converted into
the alkynylpyridine 9 by the Sonogashira coupling reaction (82%
yield over two steps). The key N-aminopyridine derivative 5h, pre-
pared by the amination of 9 with MesONH2 in acetonitrile (80%
yield), was cyclized under the heating conditions to yield the 8,9-
dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridine 6h (Table 2, entry 7).
The introduction of the amide side chain at the C1 position of the
tricyclic core was achieved by the reported procedure with minor
modification.18 Treatment of 6h with Eschenmoser’s salt yielded
a N,N-dimethylaminomethyl analog, which was converted into
the known intermediate 103 by the formation of quaternary amine
and subsequent nucleophilic substitution with potassium cyanide
(89% yield over three steps). This reaction scheme avoided the pro-
duction of the regioisomer and improved the chemical yield as
compared to the previous one.
AcO
Ph
Ph
N
N
N
N
NH2
OMes
H
OMes
H
A
E
H
AcO
AcOH
AcO
N
N
Ph
N
H
Ph
MesOH
MesO
H
MesO
MesOH
G
F
Scheme 3. Plausible reaction mechanism.
Me
O
O
O
OTf
b
a
O
NH
N
N
7
8
9
Me
MesO
1
O
d
O
c
N
N
N
Me
Me
NH2
5h
6h
O
CN
N
H
e
O
O
N
N
N
Me
N
Me
10
In conclusion, we described the development of thermal
intramolecular cyclization of N-amino-2-alkynylpyridines for the
facile and versatile synthesis of pyrazolo[1,5-a]pyridines. Explora-
tion of the reaction conditions based on mechanistic consideration
revealed that N-amino-2-alkynylpyridines are efficiently converted
into pyrazolo[1,5-a]pyridines by heating at 80 °C in acetic acid.
This reaction method provided different types of substituted pyr-
azolo[1,5-a]pyridines in excellent yield and established a superior
synthetic route to the melatonin receptor agonist 1.
1
Scheme 4. Synthesis of melatonin agonist 1. Reagents and conditions: (a) trifluo-
romethanesulfonic anhydride, pyridine, 0 °C, 95%; (b) 1-butyne, PdCl2 (PPh3)2, CuI,
Et3N, rt, 86%; (c) MesONH2, MeCN, 0 °C, 80%; (d) AcOH, 80 °C, 88%; (e) (1)
Eschenmoser’s salt, MeCN, rt, (2) MeI, AcOEt, rt, (3) KCN, 18-crown-6, MeCN, 80 °C,
89% from 6 h.
under the buffered conditions, we investigated the reaction condi-
tions without deprotonating reagents, to completely avoid the pro-
duction of the 1,3-dipole B. The reaction without additives (entry
3) and under acidic conditions (entries 4 and 5) did not proceed
at room temperature. Surprisingly, however, the cyclization was
accomplished by simply heating 5a in N,N-dimethylformamide at
80 °C (63%, entry 6).15 Moreover, changing the solvent to acetic
acid provided 6a in excellent yield (94%, entry 7).16 This is the first
example of obtaining pyrazolo[1,5-a]pyridines from N-amino-2-
alkynylpyridines without the formation of the 1,3-dipolar species.
We next investigated the scope and limitation of the R1 substit-
uents on the pyridine ring and the R2 substituents at the alkyne
terminus (Table 2). Installation of the electron-withdrawing (Cl)
and -donating (OMe) groups at the C5 position of the pyridine ring
had no effect on the reaction yield (entries 1 and 2), and the
C3- and C6-substitution with methyl group also resulted in good
yield (entries 3 and 4). The substrates with tertiary butyl and phe-
nyl groups at the alkyne terminus were efficiently cyclized (entries
5 and 6). Finally, the fused pyridine 5h was applied as a practical
example to obtain the tricyclic derivative 6h in good yield (entry
7). These results suggest that this reaction could allow for the facile
synthesis of a wide variety of substituted pyrazolo[1,5-a]pyridines.
A plausible reaction mechanism is described in Scheme 3. The
cyclization starts with attack of the amino group on the alkyne
Acknowledgment
The authors thank Dr. Kazuyoshi Aso and Dr. Tetsuji Kawamoto
for helpful discussions.
Supplementary data
Supplementary data (experimental procedures and character-
ization data) associated with this article can be found, in the online
References and notes
1. Nakashima, M.; Kanamaru, M.; Uematsu, T.; Mizuno, A.; Toriumi, C.; Hotta, M.;
Komuro, M.; Ishida, R.; Uchida, H. Arzneim.-Forsch. 1992, 42, 60–64.
2. Akahane, A.; Katayama, H.; Mitsunaga, T.; Kato, T.; Kinoshita, T.; Kita, Y.;
Kusunoki, T.; Terai, T.; Yoshida, K.; Shiokawa, Y. J. Med. Chem. 1999, 42, 779–783.
3. Koike, T.; Takai, T.; Hoashi, Y.; Nakayama, M.; Kosugi, Y.; Nakashima, M.;
Yoshikubo, S.; Hirai, K.; Uchikawa, O. J. Med. Chem. 2011, 54, 4207–4218.
4. (a) Boekelheide, V.; Fedoruk, N. A. J. Org. Chem. 1968, 33, 2062–2064; (b)
Tamura, Y.; Sumida, Y.; Miki, Y.; Ikeda, M. J. Chem. Soc., Perkin Trans. 1 1975,
406–409; (c) Elsner, J.; Boeckler, F.; Davidson, K.; Sugden, D.; Gmeiner, P.
Bioorg. Med. Chem. 2006, 14, 1949–1958; (d) Johnston, K. A.; Allcock, R. W.;
Hoashi, Yasutaka
