6800
N. Ji et al. / Tetrahedron Letters 51 (2010) 6799–6801
acidorthe corresponding trifluoroboratesaltwereunsuccessful(en-
try 1h). In order to address this problem, we decided to access these
compounds via a more conventional approach. Pyrrolopyrazole (4)
was first deprotonated with sodium hydride and the resulting mix-
ture was treated with iodomethane (Table 2). This procedure gener-
ally provided 1:1 mixtures of both regioisomers, which could be
separated by silica gel chromatography or HPLC. Interestingly, for
a substrate containing the electron-withdrawing CF3 group at R1
(4f), the corresponding 1-methyl-5-aminopyrazole (6f) was the ma-
jor product.
Bicyclic compounds such as 14 (Scheme 2) represent another
class of 1-substituted 3-aminopyrazoles. The synthesis of 14
started with the reaction of lactone 11 with acetonitrile under ba-
sic conditions at ꢀ78 °C to provide the b-ketonitrile 12. The crude
product (12) was heated in a solution of hydrazine in methanol at
elevated temperature to produce the 1H-3-aminopyrazole 13. This
was then treated with thionyl chloride in tetrahydrofuran at room
temperature to provide the bicyclic pyrazole 14 in decent to good
yields.
Despite our success at functionalizing at the N1 position of 1H-
3-aminopyrazoles, the developed conditions could not be utilized
to access the 1-tert-butyl analogs.
O
O
N
LDA, CH3CN,—78 ºC
NH2NH2
O
Fortunately, tert-butylhydrazine hydrochloride is readily avail-
able from commercial sources, and its reaction with 2-chloroacry-
lonitrile in aqueous media provided a simple and direct method to
access 3-amino-1-tert-butylpyrazole (Table 3).8 Interestingly, the
regioselectivity of the cyclization process was influenced by the
ratio of additives.9 Under the optimal conditions (K2CO3/NaHCO3 =
1:2), a 5.9:1 mixture of 9 and 10 was obtained (50% isolated yield
for 9). The improvement in regioselectivity proved significant be-
cause it not only led to higher yield of the desired isomer, but also
made the separation of isomers with silica gel chromatography on
larger scales more straightforward.
MeOH, 80 ºC
n
n
HO
11a, n=1
11b, n=2
12a, n=1
12b, n=2
H
n
N
N
N
SOCl2, THF, rt
N
H2N
n
H2N
OH
14a, n=1, 48%
14b, n=2, 77%
13a, n=1, 20-40%
13b, n=2, 38%
(2 steps)
Scheme 2. Syntheses of 1,5-disubstituted-3-aminopyrazoles.
Table 2
N-Methylation of pyrrolylpyrazoles by alkyation
H
In summary, we have developed efficient syntheses of 1-substi-
tuted 3-aminopyrazoles from readily available starting materials.10
The variety of methods described here should provide for easier ac-
cess to these useful building blocks.
N
N
N
R1
R1
R1
N
N
N
MeI
NaH, THF
N
N
N
4
5
6
References and notes
Entry
a
R1
Ratio (5:6)
Combined yield (5)
85
1. (a) Velcicky, J.; Feifel, R.; Hawtin, S. Bioorg. Med. Chem. Lett. 2010, 20, 1293; (b)
Yamada, H.; Kawanishi, H.; Ando, A. JP2003231633.; (c) Le-Brun, A.; Thompson,
F.; Tiraboschi, G.; Mailliet, P.; Salvino, J. M.; WO 2004078732 A1.; (d) Trends in
Heterocyclic Chem. 1991, 2, 97 and references therein.; (e) Artman III, G. D.;
Elliott, J. M.; Ji, N.; Liu, D.; Ma, F.; Mainolfi, N.; Meredith, E.; Miranda, K.;
Powers, J. J.; Rao, C. WO 2010066684 A2.
1:1
b
2:1
92
2. (a) Vasilevskii, S. F.; Shvartsberg, M. S. Izv. Akad. Nauk SSSR, Ser. Khim. 1980, 5,
1071; (b) Torres, J.; Lavandera, J. L.; Cabildo, P.; Claramunt, R. M.; Elguero, J. J.
Heterocycl. Chem. 1988, 25, 771; (c) Tironi, C.; Fruttero, R.; Garrone, A. Farmaco
1990, 45, 473; (d) Di Fabio, R.; St-Denis, Y.; Sabbatini, F. M.; Andreotti, D.;
Arban, R.; Bernasconi, G.; Braggio, S.; Blaney, F. E.; Capelli, A. M.; Castiglioni, E.;
Di Modugno, E.; Donati, D.; Fazzolari, E.; Ratti, E.; Feriani, A.; Contini, S.;
Gentile, G.; Ghirlanda, D.; Provera, S.; Marchioro, C.; Roberts, K. L.; Mingardi, A.;
Mattioli, M.; Nalin, A.; Pavone, F.; Spada, S.; Trist, D. G.; Worby, A. J. Med. Chem.
2008, 51, 7370; (e) Guillemont, J.; Benjahad, A.; Oumouch, S.; Decrane, L.;
Palandjian, P.; Vernier, D.; Queguiner, L.; Andries, K.; de Bethune, M.-P.;
Hertogs, K.; Grierson, D. S.; Nguyen, C. H. J. Med. Chem. 2009, 52, 7473.
3. Breukelman, S. P.; Meakins, G. D.; Tirel, M. D. J. Chem. Soc., Chem. Commun.
1982, 800.
c
1:1
1:1
80
66
d
CF3
e
f
1:1
84
87
CF3
1:3.6
4. (a) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett.
1998, 39, 2933–2936; (b) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.;
Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941–2949.
5. Bénard, S.; Neuville, L.; Zhu, J. J. Org. Chem. 2008, 73, 6441.
Table 3
Synthesis of 1-tert-butyl-3-aminopyrazole
6. Molander, G. A.; Figueroa, R. Aldrichim. Acta 2005, 38, 49.
7. Chenard, B. L. J. Org. Chem. 1984, 49, 1224.
8. McKerrecher, D.; Pike, K. G.; Waring, M. J. WO07007041 A1.
Cl
N
N
H2O, 23 ºC
N
+
N
+
CN
9. The regioselectivity was determined 1H NMR analysis: a sample of reaction
mixture was concentrated and the residue was dissolved in CDCl3. An NMR
analysis of this solution was performed. Peaks from the regioisomers were
identified and ratio of regioisomers was calculated based on integration values.
10. Experimental procedure:
NHNH2•HCl
additives
H2N
H2N
7
8
9
10
Additives (K2CO3:NaHCO3)
Ratio (9:10)
Preparation of 2a: A suspension of Cu(OAc)2 (1.13 g, 6.20 mmol) and 2,20-
bipyridine (0.97 g, 6.20 mmol) in dichloroethane (20 mL) was heated at 70 °C
1:0
4:1
2:1
1:1
1:2
0:1
None
2.5:1
2.9:1
3.3:1
4.3:1
5.9:1
3.2:1
No reaction
for 15 min, then transferred to
a suspension of potassium cyclopropyl-
trifluoroborate (1.84 g, 12.4 mmol), 1a (1.00 g, 6.20 mmol), and Na2CO3
(1.32 g, 12.4 mmol) in dichloroethane (10 mL). The resulting dark-green
mixture was stirred at 70 °C for 4 h, then partitioned between EtOAc and 1 N
HCl. The aqueous layer was extracted with EtOAc. The combined organic layers
were washed with brine, dried (Na2SO4), and concentrated. The residue was
purified by silica gel chromatography (0–100% EtOAc–heptane) to provide 2a