Synthesis of 4-substituted 1-(benzyloxy)pyrazoles via iodine-magnesium exchange of 1-(benzyloxy)-4-iodopyrazole

Full text of DOI:10.1021/jo982160n

4196
J . Org. Chem. 1999, 64, 4196-4198
Ta ble 1. In tr od u ction of Electr op h iles
Syn th esis of 4-Su bstitu ted
1-(Ben zyloxy)p yr a zoles via
Iod in e-Ma gn esiu m Exch a n ge of
1-(Ben zyloxy)-4-iod op yr a zole
J akob Felding, J esper Kristensen, Trine Bjerregaard,
Lone Sander, Per Vedsø,* and Mikael Begtrup
Department of Medicinal Chemistry, The Royal Danish
School of Pharmacy, Universitetsparken 2,
DK-2100 Copenhagen, Denmark
Received October 27, 1998
In tr od u ction
Pyrazole anions are readily generated via direct meta-
lation at C-5.1 Halogen-metal exchange is an attractive
route to enter ring positions of heteroaromatic systems
not accessible by direct metalation. Thus, 4-lithiopyra-
zoles have been prepared by halogen-lithium exchange
of 4-halopyrazoles,2,3 but in some cases the reaction
proceeds with low chemoselectivity due to competing
deprotonation at C-54,5 or isomerization of the 4-lithiopy-
razole to the corresponding 5-lithiopyrazole.6 These prob-
lems have been solved by introducing protection groups
at C-5.7 Recently, iodine-magnesium exchange with
ethyl- or isopropylmagnesium bromide has been de-
scribed as a mild and efficient method for the generation
of positionally stable aryl8 and heteroaryl magnesium
halides.9-14 We have used this approach and report
herein a protocol for the preparation of 4-substituted
1-(benzyloxy)pyrazoles without protection groups at C-5.
Regiospecific monoiodination of 1-(benzyloxy)pyrazole
followed by iodine-magnesium exchange and reaction
with electrophiles produced the corresponding 4-substi-
tuted 1-(benzyloxy)pyrazoles. The method was extended
to the synthesis of 4-aryl- and 4-heteroaryl-substituted
1-benzyloxypyrazoles by combining iodine-magnesium
exchange, transmetalation with zinc chloride, and pal-
ladium-catalyzed cross-coupling.
Resu lts a n d Discu ssion
In tr od u ction of Electr op h iles. 1-(Benzyloxy)-4-iodo-
pyrazole (2)15 was prepared in 81% overall yield by
benzylation of 1-hydroxypyrazole (1) followed by iodina-
tion of the crude 1-(benzyloxy)pyrazole using 3 equiv of
iodine monochloride. Treatment of 2 with 1.2 equiv of
i-PrMgBr in THF at 0 °C for 1 h17 produced positionally
stable 1-(benzyloxy)pyrazol-4-ylmagnesium bromide (3)
in virtually quantitative yield.18,19 1-(Benzyloxy)pyrazol-
4-ylmagnesium bromide (3) reacted with several electro-
philes affording 4-substituted 1-(benzyloxy)pyrazoles in
good yields (Table 1). When benzaldehyde was used as
electrophile, a mixture of 1-(benzyloxy)-4-(phenylhydroxy-
methyl)pyrazole (4b) (33%) and 4-benzoyl-1-(benzyloxy)-
pyrazole (4c) (59%), along with benzyl alcohol, was
isolated. Repeating the experiment and including treat-
ment of the crude reaction mixture with NaBH4 produced
4b as the only product in 87% isolated yield (Table 1,
entry 2). Most likely, 4c is formed via hydride transfer
from the initially generated magnesium alcoholate of 4b
* Tel. +45 35 37 08 50. Fax: +45 35 37 22 09. E-mail: perv@
medchem.dfh.dk.
(1) Vedsø, P.; Begtrup, M. J . Org. Chem. 1995, 60, 4995.
(2) Elguero, J .; J aramillo, C.; Pardo, C. Synthesis 1997, 563.
(3) Hahn, M.; Heinisch, G.; Holzer, W.; Schartz, H. J . Heterocycl.
Chem. 1991, 28, 1189.
(4) Hu¨ttel, R.; Scho¨n, M. E. Liebigs Ann. Chem. 1959, 625, 55.
(5) Treatment of 1-(benzyloxy)-4-bromopyrazole with n-BuLi at -78
°C for 5 min followed by addition of MeOD produced a 1:1:1 mixture
of 1-(benzyloxy)-5-[2H]-pyrazole, 1-(benzyloxy)-4-[2H]-pyrazole, and
1-(benzyloxy)-4-bromo-5-[2H]-pyrazole, according to 1H NMR.
(6) Tertov, B. A.; Morkovnik, A. S. Chem. Heterocycl. Comp. Eng.
Transl. 1975, 11, 343.
(15) The position of the iodine of 2 was assigned by comparison of
the 13C NMR signals with those of 1-(benzyloxy)pyrazole.1 In 2 and
1-(benzyloxy)pyrazole, C-4 resonates at 53.0 and 102.9 ppm, respec-
tively, C-3 resonates at 138.6 and 133.2 ppm, and C-5 resonates at
126.8 and 122.4 ppm, respectively. The 49.9 ppm upfield shift of C-4
in 2 agrees with the shift displacement induced by iodine. Furthermore,
3
1J C-5,H-5
,
1J C-3,H-3
,
3J C-5,H-3, and J C-3,H-5 in 2 (199.2, 195.8, 3.2, and
(7) Balle, T.; Vedsø, P.; Begtrup, M., in press.
8.2 Hz) resemble those observed in 1-(benzyloxy)pyrazole (192.7, 188.6,
3.8, and 9.1 Hz) and agree with the values found in other 1-substituted
pyrazoles.16 See also ref 18.
(16) Begtrup, M.; Boyer, G.; Cabildo, P.; Cativiela, C.; Claramunt,
R. M.; Elguero, J .; Garcia, J . I.; Toiron, C.; Vedsø, P. Magn. Reson.
Chem. 1993, 31, 107.
(8) Boymond, L.; Rottla¨nder, M.; Cahiez, G.; Knochel, P. Angew.
Chem., Int. Ed. Engl. 1998, 37, 1701 and references therein.
(9) El Borai, M.; Hassanein, M. Org. Prep. Proced. Int. 1982, 14,
409.
(10) Carver, D. S.; Lindell, S. D.; Saville-Stones, E. A. Tetrahedron
1997, 53, 14481.
(11) Kondo, Y.; Yoshida, A.; Sato, S.; Sakamoto, T. Heterocycles 1996,
42, 105.
(12) J etter, M. C.; Reitz, A. B. Synthesis 1998, 829.
(13) Turner, R. M.; Lindell, S. D. J . Org. Chem. 1991, 56, 5739.
(14) Be´rillon, L.; Lepreˆtre, A.; Turck, A.; Ple´, N.; Que´guiner, G.;
Cahiez, G.; Knochel, P. Synlett 1998, 1359.
(17) Attempts to generate 3 via oxidative addition of magnesium to
2 in THF failed.
(18) Quenching with D2O gave 1-(benzyloxy)-4-[2H]-pyrazole with
>98% deuterium incorporation according to 1H NMR.
(19) Attempts to perform the iodine-lithium exchange with n-BuLi
or t-BuLi (-78 °C in THF) under conditions of reverse addition gave
poor isolated yields (20-25%).
10.1021/jo982160n CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/07/1999

Notes
J . Org. Chem., Vol. 64, No. 11, 1999 4197
Ta ble 2. In tr od u ction of Ar yl a n d Heter oa r yl Gr ou p s
to benzaldehyde, as previously reported for other sys-
tems.20 Accordingly, 4b gave 4c and benzyl alcohol upon
sequential treatment with 0.9 equiv of i-PrMgBr and
benzaldehyde.21 When Ph2PCl was used as the electro-
phile, the initially formed trivalent phosphorus product
was partially oxidized to the corresponding phosphine
oxide 4f upon workup. 1-(Benzyloxy)-4-(diphenylphos-
phinoyl)pyrazole (4f) could be obtained as the only
product in 72% yield if the crude product was treated
with oxygen (Table 1, entry 6).
In tr od u ction of Ar yl a n d Heter oa r yl Su bstitu -
en ts. To extend the scope of this methodology, the
preparation of 4-aryl and 4-heteroaryl-1-(benzyloxy)-
pyrazoles via transmetalation and palladium-catalyzed
cross-coupling was investigated. A comparison between
the Corriu-Kumada22,23 (using 3), Stille24 (using 4g), and
Negishi25 (using 5) cross-couplings26 revealed the latter
to be the method of choice. 1-(Benzyloxy)pyrazol-4-
ylmagnesium bromide (3) failed to react with 4-iodotolu-
ene and 4-iodoaniline under Pd(0) catalysis.27 Similar
treatment of 1-(benzyloxy)-4-tributylstannylpyrazole (4g)
resulted in partial destannylation producing 1-(benzyl-
oxy)pyrazole, whereas 1-(benzyloxy)-pyrazole-4-ylzinc chlo-
ride28 (5) produced the desired products in 92% and 62%
yield (Table 2, entries 1 and 3), respectively. Therefore,
5 was coupled with a range of aryl iodides possessing
either electron-donating or -withdrawing groups, afford-
ing the cross-coupled products 6a -g in 62-92% yield
(Table 2, entries 1-7). Furthermore, cross-coupling of 5
with π-excessive 2 or 2-iodothiophene or with π-deficient
2-bromopyridine produced the 4-heteroaryl-substituted
1-(benzyloxy)pyrazoles 6h -j in 57-89% yield (Table 2,
entries 8-10).
column chromatography (FC) was performed using silica gel
(Merck, 40-63 mesh). TLC was performed using Merck silica
gel 60 F254 aluminum sheets. The sheets were visualized under
UV light (254 nm) and by spraying with ammonium cerium
molybdate.29 Melting points are uncorrected. All new compounds
were colorless, unless otherwise stated. NMR spectra were
recorded in CDCl3 on a 300 MHz Varian spectrometer with
tetramethylsilane/CDCl3 as internal standards. The multiplicity
of 13C NMR signals were assigned from APT spectra.
Ma ter ia ls. All solvents and reagents were obtained from
Fluka or Aldrich and used without further purification except
THF, which was distilled from Na/benzophenone under nitrogen,
and DMF, which was sequentially dried with and stored over 3
Å molecular sieves.30 A 1.0 M solution of ZnCl2 in THF was
prepared by flame-drying ZnCl2 in vacuo and dissolving it in
dry THF. A 1.3 M solution of isopropylmagnesium bromide (i-
PrMgBr) in THF was prepared as previously described31 and
titrated prior to use.32 Pd(PPh3)4 was prepared as previously
described.33
P r ep a r a tion of 1-(Ben zyloxy)-4-iod op yr a zole (2). 1-Hy-
droxypyrazole (1)34 (2.74 g, 32.6 mmol) and N-ethyldiisopropyl-
amine (4.23 g, 32.7 mmol) were dissolved in CH2Cl2 (35 mL) and
cooled to 0 °C. Benzyl bromide (5.63 g, 32.8 mmol) was added,
and the reaction mixture was stirred at room temperature for
16 h. NaOH (1 M, 50 mL) was added, and the reaction mixture
was extracted with CH2Cl2 (3 × 50 mL). The organic phase was
washed with NaOH (1 M) and water, dried over MgSO4, and
concentrated in vacuo. The crude product was dissolved in CHCl3
(100 mL), K2CO3 (13.5 g, 97.8 mmol) was added, and the reaction
mixture was treated with iodine monochloride (15.9 g, 97.8
mmol) dissolved in CHCl3 (15 mL). After 12 h of stirring at room
temperature, the reaction was quenched with Na2SO3 (1 M, 75
mL) and extracted with CH2Cl2 (3 × 75 mL). The organic phase
was dried over MgSO4 and evaporated. Two sequential low
temperature (-78 °C) recrystallizations from EtOAc/heptane (1:
In conclusion, we have developed a method that
permits regiospecific introduction of electrophiles in the
4-position of 1-(benzyloxy)pyrazole via iodine-magne-
sium exchange of 1-(benzyloxy)-4-iodopyrazole. The meth-
odology was extended to include the introduction of aryl-
and heteroarylsubstituents by combining iodine-mag-
nesium exchange, transmetalation with ZnCl2 and pal-
ladium-catalyzed Negishi cross-coupling.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions involving air-sensitive re-
agents were performed under N2 using syringe-septum cap
techniques. All glassware was flame-dried prior to use. Flash
(20) Marshall, J . J . Chem. Soc. 1915, 107, 509.
(21) 1H NMR of the crude product showed a 3:1 mixture of 4-benzoyl-
1-(benzyloxy)pyrazole (4c) and 1-(benzyloxy)-4-(phenylhydroxymeth-
yl)pyrazole (4b), as well as benzyl alcohol.
(22) Corriu, R. J . P.; Masse, J . P. J . Chem. Soc., Chem. Commun.
1972, 144.
(23) Tamao, K.; Sumitani, K.; Kumada, M. J . Am. Chem. Soc. 1972,
94, 4374.
(24) Milstein, D.; Stille, J . K. J . Am. Chem. Soc. 1979, 101, 4992.
(25) Negishi, E. I.; King, A. O.; Okukado, N. J . Org. Chem. 1977,
42, 1821.
(26) For a review on cross-coupling reactions, see: Stanforth, S. P.
Tetrahedron 1998, 54, 263.
(27) The reaction mixture was quenched with MeOD in both
experiments. The crude products were analyzed by 1H NMR and
showed 91% deuterium incorporation in the 4-position of 1-(benzyloxy)-
pyrazole when 4-iodotoluene was used, whereas 1-(benzyloxy)pyrazole
was the only observed product with 4-iodoaniline, indicating high
basicity of 3.
(28) Prepared by transmetalation of 1-(benzyloxy)pyrazol-4-ylmag-
nesium bromide (3) with ZnCl2; see the Experimental Section for
details. Attempts to generate 5 via direct insertion of zinc (as described
by Bhanu Prasad, A. S.; Stevenson, T. M.; Citineni, J . R.; Nyzam, V.;
Knochel, P. Tetrahedron 1997, 53, 7237) failed.
(29) Ammonium cerium molybdate: Ce(SO4)2‚4H2O (0.4 g) and
(NH4)6Mo7O24 (20 g) dissolved in 10% H2SO4 (400 mL).
(30) Burfield, D. R.; Smithers, R. H. J . Org. Chem. 1978, 43, 3966.
(31) Drake, N. L.; Cooke, G. B. Org. Synth. Coll. Vol II 1943, 406.
(32) Lin, H.-S.; Paquette, L. Synth. Commun. 1994, 24, 2503.
(33) Coulson, D. R. Inorg. Synth. 1972, 13, 121.
(34) Begtrup, M.; Vedsø, P. J . Chem. Soc., Perkin Trans. 1 1995,
243.

4198 J . Org. Chem., Vol. 64, No. 11, 1999
Notes
20, 20 mL and 7 mL) gave 7.92 g (81%) of 1-(benzyloxy)-4-
iodopyrazole (2), mp 40-41 °C (EtOAc/heptane). Rf (EtOAc/
heptane, 1:4) 0.44. δΗ (CDCl3): 7.40-7.28 (m, 5H), 7.32 (d, J )
0.9 Hz, 1H), 7.04 (d, J ) 0.9 Hz, 1H), 5.27 (s, 2H). δC (CDCl3):
zyloxy)-4-iodopyrazole (2) (300 mg, 1.0 mmol) in THF (1 mL) at
0 °C was added 1.3 M i-PrMgBr in THF (0.92 mL, 1.2 mmol)
over 2 min. Stirring was continued for 1 h at 0 °C before 1 M
ZnCl2 in THF (1.5 mL, 1.5 mmol) was added. After 1 h of stirring
at room temperature, the aryl halide (1.5 mmol) and Pd(PPh3)4
(0.02 mmol) in DMF (2.5 mL) were added. The mixture was
heated to 80 °C (oil bath) for 1 h and quenched with saturated
aqueous NH4Cl (5 mL). Water (5 mL) was added to dissolve the
formed precipitate before extracting with Et2O (3 × 15 mL).
Drying of the combined organic phases (MgSO4), filtration, and
concentration in vacuo gave the crude products which were
purified by flash coloumn chromatography using EtOAc/heptane
as the eluent.
1
3
138.6 (dd, J C-3,H-3 ) 195.8, J C-3,H-5 ) 8.2 Hz, C-3), 133.3 (s),
1
129.6 (d), 129.4 (d), 128.7 (d), 126.8 (dd, J C-5,H-5 ) 199.2,
2
3J C-5,H-3 ) 3.2 Hz, C-5), 80.8 (t), 53.0 (dd, 2J C-4,H-5 and J C-4,H-3
7.9 and 6.7 Hz, C-4). Anal. Calcd for C10H9IN2O: C, 40.02; H,
3.02; N, 9.33. Found: C, 40.14; H, 2.84; N, 9.24.
Iod in e-Ma gn esiu m Exch a n ge of 2 F ollow ed by Rea c-
tion w ith a n Electr op h ile. Gen er a l P r oced u r e. To a stirred
solution of 1-(benzyloxy)-4-iodopyrazole (2) (300 mg, 1.0 mmol)
in dry THF (1 mL) at 0 °C was added 1.3 M i-PrMgBr in THF
(0.92 mL, 1.2 mmol) over 2 min. Stirring was continued for 1 h
at 0 °C before the electrophile (1.5 equiv) was added. After 1 h
at room temperature, the mixture was quenched with saturated
aqueous NH4Cl (5 mL). Water (5 mL) was added to dissolve the
formed precipitate before extraction with CH2Cl2 (3 × 10 mL)
and drying of the combined organic phases (MgSO4). Filtration
and concentration in vacuo gave the crude products, which were
purified by flash column chromatography, using EtOAc/heptane
as eluent.
Ack n ow led gm en t. This work was supported by the
Danish Council for Technical and Scientific Research
and the Lundbeck Foundation.
Su p p or tin g In for m a tion Ava ila ble: Full experimental
details for the synthesis and characterization of compound
4a -g and 6a -j. This material is available free of charge via
the Internet at http://pubs.acs.org.
P a lla d iu m -Ca ta lyzed Cr oss-Cou p lin g of 5 w ith Ar yl
Ha lid es. Gen er a l P r oced u r e. To a stirred solution of 1-(ben-
J O982160N