Sequential functionalization of pyrazole 1-oxides via regioselective metalation: Synthesis of 3,4,5-trisubstituted 1-hydroxypyrazoles

Article abstract of DOI:10.1021/jo015997i

A range of 3,5-diarylated and 3,4,5-triarylated 2-(4-methoxybenzyl)pyrazole 1-oxides have been prepared by regioselective deprotonation at C-5 or bromine-magnesium exchange at C-3 or C-4 followed by transmetalation with ZnCl₂ and palladium(0)-catalyzed cross-coupling. Furthermore, the metalated pyrazole 1-oxides could be trapped with electrophiles. The sequential metalation/functionalization of the pyrazole 1-oxides may follow the order C-5, C-3, C-4, or alternatively the order C-3, C-5, C-4. The 4-methoxybenzyl group of the functionalized 2-(4-methoxybenzyl)pyrazole 1-oxides could be removed by treatment with TFA and i-Pr₃SiH in CH₂Cl₂, providing the corresponding functionalized 1-hydroxypyrazoles.

Full text of DOI:10.1021/jo015997i

3904
J . Org. Chem. 2002, 67, 3904-3907
protocols for regioselective and sequential arylation of the
pyrazole nucleus in a flexible manner and at a late stage
of the reaction sequence would be desirable.
Sequ en tia l F u n ction a liza tion of P yr a zole
1-Oxid es via Regioselective Meta la tion :
Syn th esis of 3,4,5-Tr isu bstitu ted
1-Hyd r oxyp yr a zoles
Previously we reported the preparation of C-4-13 and
C-5-substituted14 1-(benzyloxy)pyrazoles using metalated
intermediates generated from 1-(benzyloxy)pyrazole by
C-4 iodination and subsequent iodine-magnesium ex-
change or by direct C-5 lithiation. However, these meth-
odologies were incapable of providing access to C-3-
substituted derivatives, as metalation at the C-3 position
of 1-substituted pyrazoles is hampered by the adjacent
lone-pair effect15 and, moreover, no direct approach to
C-3 halogenated pyrazoles exists. Recently we reported
a methodology for the introduction of aryl substituents
at the C-3 position based on the transformation of 1 to
the pyrazole 1-oxide 2, which underwent selective mono-
bromination at C-3 followed by smooth bromine-mag-
nesium exchange, transmetalation with ZnCl2, and Pd(0)-
catalyzed cross-coupling.16
Anna Sif Paulson, J ørgen Eskildsen, Per Vedsø,* and
Mikael Begtrup
Department of Medicinal Chemistry, The Royal Danish
School of Pharmacy, Universitetsparken 2, DK-2100
Copenhagen, Denmark
pv@dfh.dk
Received August 2, 2001
Abstr a ct: A range of 3,5-diarylated and 3,4,5-triarylated
2-(4-methoxybenzyl)pyrazole 1-oxides have been prepared
by regioselective deprotonation at C-5 or bromine-magne-
sium exchange at C-3 or C-4 followed by transmetalation
with ZnCl2 and palladium(0)-catalyzed cross-coupling. Fur-
thermore, the metalated pyrazole 1-oxides could be trapped
with electrophiles. The sequential metalation/functionaliza-
tion of the pyrazole 1-oxides may follow the order C-5, C-3,
C-4, or alternatively the order C-3, C-5, C-4. The 4-meth-
oxybenzyl group of the functionalized 2-(4-methoxybenzyl)-
pyrazole 1-oxides could be removed by treatment with TFA
and i-Pr3SiH in CH2Cl2, providing the corresponding func-
tionalized 1-hydroxypyrazoles.
We now wish to report how 2-(4-methoxybenzyl)-
pyrazole 1-oxides can undergo C-4 and C-5 arylation,
which in combination with the protocol for C-3 arylation
led to the synthesis of 3,5-diarylated and 3,4,5-triarylated
1-hydroxypyrazoles via sequential and regioselective
metalation/arylation of the appropriate 2-(4-methoxy-
benzyl)pyrazole 1-oxides.
P r ep a r a tion of 5-Ar yla ted P yr a zole 1-Oxid es. To
investigate the C-5 arylation of 2-(4-methoxybenzyl)-
pyrazole 1-oxide (2), prepared from 1 as previously
reported,16 2 was deprotonated with various bases fol-
lowed by transmetalation with ZnCl2 and finally cross
coupling17 with 4-iodoanisole in the presence of 3 mol %
Pd(PPh3)4. When the initial deprotonation of 2 was
performed with i-PrMgCl, 3 was obtained in 95% yield.
In contrast, deprotonation performed with the lithium
bases LDA or n-BuLi produced significantly lower iso-
lated yields of 3: 57% and 56%, respectively (Scheme 1).
Pyrazoles possessing aryl substituents appear fre-
quently in molecules of pharmaceutical interest. A large
number of drugs incorporating C-arylated pyrazole moi-
eties have been reported to have a wide range of impor-
tant biological activities, such as hypocholesterolemic ac-
tivity,1 selective inhibition of cyclooxygenase-2 (COX-2),2,3
HIV-1 protease inhibition,4 selective ligands for human
dopamine D4 receptor in treatment of schizophrenia,5,6
anti-diabetic activity,7 and high-affinity selectivity for the
estrogen receptor.8-10 Typically these C-arylated pyra-
zoles were prepared in condensation reactions between
hydrazines and R,â-unsaturated carbonyl compounds or
1,3-dicarbonyl compounds. However, these reaction types
almost inevitably produce mixtures of regioisomers.11,12
Subtle variations and combinations of the arylation
pattern on the pyrazole motif often have a profound effect
on the biological activities.2,3,9 Accordingly, efficient
1
The H NMR spectra of the crude products showed full
conversion of 2, suggesting that the putative 5-lithio
intermediate is unstable even at -78 °C. In comparison,
the corresponding 5-lithio-1-(benzyloxy)pyrazole18 is stable
at -78 °C. However, H-5 in 1-(benzyloxy)pyrazole is
considerably less acidic than H-5 of 2, as attempted C-5
magnesiation of 1-(benzyloxy)pyrazole using i-PrMgCl
failed and consequently the N-oxide 2 undergoes C-5
arylation under milder conditions than 1-(benzyloxy)-
pyrazole.
* To whom correspondence should be addressed. Tel: +45 35 30 60
00. Fax: +45 35 30 60 40.
(1) Tanaka, A.; Teresawa, T.; Hagihara, H.; Sakuma, Y.; Ishibe, N.;
Sawada, M.; Takasugi, H.; Tanaka, H. J . Med. Chem. 1998, 41, 2390.
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Collins, P. W.; Docter, S.; Graneto, M. J .; Lee, L. F.; Malecha, J . W.;
Miyashiro, J . M.; Rogers, R. S.; Rogier, D. J .; Yu, S. S.; Anderson, G.
D.; Burton, E. G.; Cogburn, J . N.; Gregory, S. A.; Koboldt, C. M.;
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D.; Patel, S.; Patel, S.; Emms, F.; Marwood, R.; Chapman, K. L.;
Fletcher, A. E.; Showell, G. A. Bioorg. Med. Chem. 1998, 6, 1731.
(7) Soliman, R.; Faid-Allah, H. M.; El Sadany, S. K. J . Pharm. Sci.
1987, 76, 626.
(8) Huang, Y. R.; Katzenellenbogen, J . A. Org. Lett. 2000, 2, 2833.
(9) Stauffer, S. R.; Coletta, C. J .; Tedesco, R.; Nishiguchi, G.; Carlson,
K.; Sun, J .; Katzenellenbogen, B. S.; Katzenellenbogen, J . A. J . Med.
Chem. 2000, 43, 4943.
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(11) Elguero, J . In Comprehensive Heterocyclic Chemistry II; Katritz-
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p 1.
(12) J oule, J . A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell
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(13) Felding, J .; Kristensen, J .; Bjerregaard, T.; Sander, L.; Vedsø,
P.; Begtrup, M. J . Org. Chem. 1999, 64, 4196.
(14) Kristensen, J .; Begtrup, M.; Vedsø, P. Synthesis 1998, 1604.
(15) Takeuchi, Y.; Yeh, H. J . C.; Kirk, L.; Cohen, L. A. J . Org. Chem.
1978, 43, 3565.
(16) Eskildsen, J .; Kristensen, J .; Vedsø, P.; Begtrup, M. J . Org.
Chem. 2001, 66, 8654.
(17) Stanforth, S. P. Tetrahedron 1998, 54, 263 and references cited
herein.
10.1021/jo015997i CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/27/2002

Notes
J . Org. Chem., Vol. 67, No. 11, 2002 3905
Ta ble 1. Syn th esis of 3,5-Disu bstitu ted P yr a zole
1-Oxid es: Ar yla tion a t C-5 F ollow ed by Ar yla tion a t C-3
Sch em e 1
P r ep a r a tion of 3,5-Dia r yla ted P yr a zole 1-Oxid es
via Step w ise Meta la tion /Ar yla tion . To access 3,5-
diarylated pyrazole 1-oxides such as 6a -e, we investi-
gated two strategies. First, C-3 arylation of 5-arylated
pyrazole 1-oxides was investigated, and second, C-5 aryl-
ation of 3-arylated pyrazole 1-oxides such as 7a ,b16 was
examined. For the first approach a 5-arylated pyrazole
1-oxide metalated at C-3 was required. In a test experi-
ment, 3 was treated with 2 equiv of i-PrMgCl at -78 °C
for 15 min. Subsequent quench with MeOD resulted in
complete recovery of 3. Performing the reaction at 0 °C
for 1 h gave 25% deuterium incorporation at C-3 along
with extensive decomposition. Fortunately, 3-magnesiat-
ed pyrazole 1-oxides can be obtained via bromine-mag-
nesium exchange from the corresponding 3-bromo deriv-
atives.16 In contrast to the bromination of 2, which takes
place exclusively at C-3,19 attempted monobromination
of 3 proceeded with poor regioselectivity. Thus, treatment
of 3 with 1.1 equiv of NBS produced a 8:23:46:23 mixture
of unchanged 3 along with the 3-bromo (5a ), 4-bromo,
and 3,4-dibromo (8) derivatives, as determined by 1H
NMR. Using Br2 instead of NBS gave the four compounds
in a 52:5:38:5 mixture. As monobromination of 3 proved
unsuccessful, we could obtain the 5-arylated 3-bromopy-
razoles 5a ,b from the 3-bromopyrazole 4 via C-5 lithia-
tion/transmetalation and subsequent arylation. It was
crucial to use the hard base LDA for C-5 metalation, as
i-PrMgCl and n-BuLi resulted in bromine-metal ex-
change at C-3. Moreover, the C-5 lithiation/transmeta-
lation was advantageously performed at -100 °C instead
of -78 °C, as the isolated yields of 5a and 5b increased
from 53% to 76% (Table 1, entries 1 and 2) and from 55%
to 79% (Table 1, entries 3 and 4), respectively. This
observation supports the fact that 5-lithiated pyrazole
1-oxides are unstable intermediates even at low temper-
ature. Using our recently reported protocol for C-3
arylation16 based on bromine-magnesium exchange,
transmetalation with ZnCl2, and Pd(0) catalyzed cross
coupling, 5a ,b were cross-coupled with a range of aryl
halides possessing either electron-donating (Table 1,
entry 5), or -withdrawing groups (Table 1, entries 6-8),
affording 3,5-diarylated pyrazoles 6a -d in 70-77% yield.
Preparation of the 3,5-diarylated pyrazoles 6a ,e (Table
2, entries 1 and 2) via C-3 arylation and subsequent C-5
arylation was accomplished by using first the protocol
for C-3 arylation16 followed by C-5 arylation using the
i-PrMgCl-based protocol developed above for conversion
of 2 to 3.
arylation at C-3
arylation at C-5
entry
R
R
R′
product yield (%)
1a
2
OMe
OMe
Me
5a
5a
5b
5b
6a
6b
6c
6d
53
76
55
79
76
74
70
77
3a
4
Me
5
6
7
8
4-OMe 4-OMe
4-OMe 2-NO2
4-Me
4-Me
2-CHO
2-CN
a
C-5 lithiation was performed at -78 °C.
Ta ble 2. Syn th esis of 3,5-Disu bstitu ted P yr a zole
1-Oxid es: C-5 Ar yla tion of 3-Ar yla ted P yr a zole 1-Oxid es
entry
R
R′
product
yield (%)
1
2
4-OMe
2-F
4-OMe
2-CN
6a
6e
82
69
Thus, 3,5-diarylated pyrazoles can be accessed via step-
wise metalation/arylation at C-5 and C-3 or alternatively
in the opposite order. This flexibility in the cross-coupling
protocol allows the presence of base-sensitive groups in
the aryl substituent to be introduced in the final cross-
coupling step: e.g., nitro (compound 6b), formyl (com-
pound 6c), and cyano groups (compounds 6d ,e).
P r ep a r a tion of 3,4,5-Tr ia r yla ted P yr a zole 1-Ox-
id es. While monobromination of 3 was not possible,
treatment of 3 with excess NBS in acetonitrile afforded
the 3,4-dibrominated pyrazole 8 in 98% yield (Table 3).
As expected, treatment of 8 with i-PrMgCl resulted in
bromine-magnesium exchange exclusively at the C-3
position.20 Transmetalation with ZnCl2 and cross coupling
with 4-iodotoluene produced 9 in 72% yield.
Preparation of the highly functionalized triarylated
pyrazole 10a was achieved either via a Suzuki-Miyaura
type cross-coupling21 between 4-fluorobenzeneboronic
acid and 9 (Table 3, entries 1 and 2) or via bromine-
magnesium exchange, using i-PrMgCl, followed by trans-
metalation with ZnCl2 and Pd(0)-catalyzed cross-coupling
with 4-fluoroiodobenzene (Table 3, entry 4). Attempts to
(18) Vedsø, P.; Begtrup, M. J . Org. Chem. 1995, 60, 4995.
(19) (a) Ferguson, I. J .; Grimmet, M. R.; Schofield, K. Tetrahedron
Lett. 1972, 27, 2771. (b) Ferguson, I. J .; Schofield, K.; Barnett, J . W.;
Grimmet, M. R. J . Chem. Soc., Perkin Trans. 1 1977, 672. (c) Begtrup,
M.; Larsen, P.; Vedsø, P. Acta Chem. Scand. 1992, 46, 972.

3906 J . Org. Chem., Vol. 67, No. 11, 2002
Notes
Ta ble 3. Syn th esis of 3,4,5-Tr isu bstitu ted P yr a zole
1-Oxid es
Ta ble 4. De-p-m eth oxyben zyla tion of Ar yla ted P yr a zole
1-Oxid es
entry
R
R′
product
yield (%)
1
2
3
4
4-OMe
2-NO2
4-Me
H
H
11a
11b
11c
11d
84
82
68
79
4-F-Ph
4-NO2-Ph
4-Me
Sch em e 2
use n-BuLi instead of i-PrMgCl led to the total decom-
position of 9 (Table 3, entry 3).
Suzuki-Miyaura type cross-coupling in EtOH/toluene
with K2CO3 as base21 (Table 3, entry 1) was hampered
by considerable C-4 debromination. However, performing
the coupling in dioxane with K3PO4 as base21 led to a
notable increase in the yield of 10a (Table 3, entry 2).
By reversing the polarity of the cross-coupling, pyra-
zoles 10a ,b were prepared via bromine-magnesium
exchange followed by transmetalation with ZnCl2 and
Pd(0)-catalyzed cross-coupling (Table 3, entries 4 and 5).
De-p -m et h oxyb en zyla t ion of Ar yla t ed P yr a zole
1-Oxid es. The PMB group of 6a ,b and 10a ,b was readily
removed by treatment with TFA in the presence of
triisopropylsilane,16 providing the corresponding 1-hy-
droxypyrazoles 11a -d in 68-84% yield (Table 4, entries
1-4). Thus, the procedure described herein represents a
convergent approach for the conversion of 1-hydroxy-
pyrazole (1) to 3,5-diarylated or 3,4,5-triarylated 1-hy-
droxypyrazoles such as 11a -d via pyrazole 1-oxides.
In tr od u ction of Electr op h iles. To demonstrate the
general utility of the metalated pyrazole 1-oxides de-
scribed herein, the metalation was succeeded by reaction
with an electrophile. By way of example, introduction of
electrophiles was carried out on selected arylated pyra-
zole 1-oxides. Thus, pyrazole 7a was lithiated at C-5
using LDA at -100 °C, and subsequent reaction with
methyl iodide afforded the 5-methylated pyrazole 12 in
87% yield. The sterically highly congested pyrazole 13
was prepared in 35% yield by bromine-magnesium
exchange of pyrazole 9 using i-PrMgCl followed by
reaction with benzaldehyde. Finally, the 3-thiomethyl-
substituted pyrazole 14 was prepared in 79% yield by
bromine-magnesium exchange of pyrazole 5a followed
by reaction with dimethyl disulfide (Scheme 2).
The procedures described herein represent convergent
approaches for conversion of 1-hydroxypyrazole (1) to 3,5-
diarylated or 3,4,5-triarylated pyrazole 1-oxides and the
corresponding arylated 1-hydroxypyrazoles via selectively
metalated pyrazole 1-oxides. The metalation/arylation
can be effected in the order C-5, C-3, C-4 or in the orderC-
3, C-5, C-4. The flexibility in the cross-coupling protocols
allows the presence of base-sensitive groups in the aryl
substituent being introduced in the final step. Further-
more, it was shown that the magnesiated and lithiated
pyrazole 1-oxides could be trapped with electrophiles to
give the corresponding functionalized pyrazole 1-oxides.
(20) When the bromine-magnesium exchange was followed by
quenching with MeOH, 4-bromo-2-(4-methoxybenzyl)-5-(4-methoxy-
phenyl) pyrazole 1-oxide with δH(CH2) at 5.27 ppm and δH(H-3) at 6.87
ppm was isolated as the sole product. A NOE difference spectrum with
irradiation at 5.27 ppm resulted in a 5% NOE on H-3.
(21) Suzuki, A. J . J . Organomet. Chem. 1999, 576, 147 and refer-
ences cited therein.
Exp er im en ta l Section
Gen er a l Meth od s a n d Ma ter ia ls. See the Supporting
Information.
Rep r esen ta tive P r oced u r es for Ar yla tion a t th e C-5
P osition : 2-(4-Meth oxyben zyl)-5-(4-m eth oxyp h en yl)p yr a -

Notes
J . Org. Chem., Vol. 67, No. 11, 2002 3907
for preparation of 6d in 1.02 mmol scale using 8 and
4-iodotoluene gave after FC (CH2Cl2 f CH2Cl2/EtOAc, 4:1) 347
mg (72%) of 9 as beige crystals. Recrystallization gave off-white
crystals, mp 149-150 °C (EtOAc). Rf (CH2Cl2/EtOAc, 4:1): 0.41.
δH (CDCl3): 2.45 (s, 3H), 3.77 (s, 3H), 3.86 (s, 3H), 5.34 (s, 2H),
6.77 (d, J app ) 8.8 Hz, 2H), 7.02 (d, J app ) 9.0 Hz, 2H), 7.08 (d,
zole 1-Oxid e (3). Pyrazole 216 (409 mg, 2.0 mmol) was dissolved
in THF (16 mL) at room temperature. i-PrMgCl (1.1 mL, 2.1 M,
2.4 mmol) was added dropwise over 3 min, and the mixture was
stirred for 30 min. A solution of ZnCl2 in THF (6.0 mL, 1.0 M, 6
mmol) was added dropwise over 5 min, followed by stirring for
30 min. 4-Iodoanisole (3.0 mmol) and Pd(PPh3)4 (69 mg, 3 mol
%) were added, and the mixture was stirred at 60 °C for 3 h
before standard workup. FC (CH2Cl2 f EtOAc) gave 590 mg
(95%) of 3 as beige crystals: mp 136-137 °C (EtOAc). Rf
(EtOAc): 0.51. δH (CDCl3): 3.81 (s, 3H), 3.85 (s, 3H), 5.29 (s,
a
J app ) 8.8 Hz, 2H), 7.26 (d, J app ) 8.4 Hz, 2H), 7.31 (d, J app
)
8.1 Hz, 2H), 7.95 (d, J app ) 9.0 Hz, 2H). δC (CDCl3): 21.6, 47.3,
55.3, 55.4, 89.5, 113.9, 114.1, 119.4, 124.8, 127.8, 129.8, 129.9,
130.3, 130.9, 131.88, 131.90, 140.2, 159.6, 160.3. Anal. Calcd for
C25H23BrN2O3: C, 62.64; H, 4.84; N, 5.84. Found: C, 62.70; H,
4.74; N, 5.73.
3
3
2H), 6.36 (d, J H-4,H-3 ) 4.0 Hz, 1H, H-4), 6.80 (d, J H-3,H-4
)
4.0 Hz, 1H, H-3), 6.90 (d, J app ) 8.8 Hz, 2H), 6.98 (d, J app ) 9.1
Hz, 2H), 7.31 (d, J app ) 8.8 Hz, 2H), 8.15 (d, J app ) 9.1 Hz, 2H).
δC (CDCl3): 48.3, 55.22, 55.24, 99.1, 113.9, 114.5, 118.0, 121.2,
126.4, 127.7, 129.6, 130.2, 159.7, 159.8. Anal. Calcd for
C18H18N2O3: C, 69.66; H, 5.85; N, 9.03. Found: C, 69.41; H, 5.82;
N, 8.94.
R ep r esen t a t ive P r oced u r e for Ar yla t ion a t t h e C-4
P osit ion : 4-(4-F lu or op h en yl)-2-(4-m et h oxyb en zyl)-5-(4-
m eth oxyph en yl)-3-(4-m eth ylph en yl)pyr azole 1-Oxide (10a)
(Ta ble 3, En tr y 2). Pyrazole 9 (300 mg, 0.63 mmol), 4-fluo-
robenzeneboronic acid (132 mg, 0.95 mmol), aqueous K3PO4 (3.0
mL, 2.0 M, 6.0 mmol), and dioxane were mixed, and N2 was
bubbled through for 15 min. Pd(PPh3)4 (36 mg, 5 mol %) was
added, and the mixture was heated to 90 °C for 5 h and then
poured into CH2Cl2 (60 mL) and washed with saturated aqueous
NaHCO3 (15 mL) and brine (15 mL). The organic layer was dried
over anhydrous Na2SO4 and evaporated to dryness. FC (CH2Cl2
f CH2Cl2/EtOAc, 4:1) gave 207 mg (66%) of 10a as beige
crystals. Recrystallization gave off-white crystals, mp 137-138
°C (EtOAc). Rf (CH2Cl2/EtOAc, 4:1): 0.23. δH (CDCl3): 2.38 (s,
3H), 3.79 (s, 3H), 3.81 (s, 3H), 5.34 (s, 2H), 6.81 (d, J app ) 8.7
Hz, 2H), 6.86 (d, J app ) 8.5 Hz, 4H), 6.95 (d, J app ) 8.7 Hz, 2H),
7.00 (d, J app ) 8.1 Hz, 2H), 7.14 (d, J app ) 7.9 Hz, 2H), 7.18 (d,
J app ) 8.7 Hz, 2H), 7.55 (d, J app ) 9.0, 2H). δC (CDCl3): 21.3 (q),
46.6 (t), 55.1 (q), 55.2 (q), 113.6 (d), 113.7 (s), 113.9 (d), 115.3 (d
(dC,F, J C,F ) 21.5 Hz)), 121.1 (s), 125.3 (s), 127.5 (s (dC,F, J C,F, )
3.5 Hz)), 128.0 (s), 128,3 (s), 129.5 (d), 129.6 (d), 130.1 (s), 130.8
3-Br om o-2-(4-m eth oxyben zyl)-5-(4-m eth oxyph en yl)pyr a-
zole 1-Oxid e (5a ). Pyrazole 416 (283 mg, 1.0 mmol) was
dissolved in THF (8 mL) at room temperature and cooled to -100
°C (Et2O/N2(l)). A freshly prepared solution of LDA in THF (4.26
mL, 0.31 M, 1.3 mmol) was added over 3 min, and immediately
after a solution of ZnCl2 in THF (3.0 mL, 1.0 M, 3 mmol) was
added. The mixture was warmed to room temperature, and then
4-iodoanisole (1.5 mmol) and Pd(PPh3)4 (35 mg, 3 mol %) were
added and the mixture was stirred at 60 °C for 3 h before
standard workup. FC (CH2Cl2 f CH2Cl2/EtOAc, 4:1) provided
296 mg (76%) of 5a as beige crystals. Recrystallization gave off-
white crystals, mp 118-119 °C (EtOAc). Rf (EtOAc): 0.80. δH
(CDCl3): 3.78 (s, 3H), 3.84 (s, 3H), 5.42 (s, 2H), 6.47 (s, 1H, H-4),
6.86 (d, J app ) 8.8 Hz, 2H), 6.96 (d, J app ) 9.1 Hz, 2H), 7.42 (d,
J app ) 8.8 Hz, 2H), 8.07 (d, J app ) 9.1 Hz, 2H). δC (CDCl3): 46.7,
55.17, 55.20, 100.2, 102.2, 114.0, 114.1, 120.3, 126.9, 127.9, 129.8,
130.6, 159.6, 160.0. Anal. Calcd for C18H17BrN2O3: C, 55.54; H,
4.40; N, 7.20. Found: C, 55.45; H, 4.36; N, 7.12.
Rep r esen ta tive P r oced u r e for Ar yla tion a t th e C-3
P osition : 3-(2-Cya n op h en yl)-2-(4-m eth oxyben zyl)-5-(4-m e-
th ylp h en yl)p yr a zole 1-Oxid e (6d ) (Ta ble 1, En tr y 8). 3-Bro-
mo-2-(4-methoxybenzyl)-5-(4-methylphenyl)pyrazole 1-oxide (5b;
0.51 mmol) was dissolved in THF (10 mL) and cooled to -78 °C.
i-PrMgCl (0.52 mL, 1.99 M, 1.03 mmol) was added dropwise over
2 min, and the solution was stirred for 15 min at -78 °C. Then
ZnCl2 (1.54 mL, 1.0 M, 1.54 mmol) was added dropwise over 3
min. The mixture was warmed to room temperature over 45 min.
2-Bromobenzonitrile (1.03 mmol) and Pd(PPh3)4 (18 mg, 3 mol
%) were added, and the mixture was heated to 60 °C for 10 h.
Standard workup followed by FC (CH2Cl2 f CH2Cl2/EtOAc, 17:
3) gave 154 mg (77%) of 6d as slightly brownish crystals.
Recrystallization gave off-white crystals, mp 162-163 °C (EtOAc).
Rf (CH2Cl2/EtOAc, 8:2): 0.68. δH (CDCl3): 2.38 (s, 3H), 3.73 (s,
3H), 5.37 (s, 2H), 6.72 (s, 1H, H-4), 6.74 (d, J app ) 8.9 Hz, 2H),
6.96 (d, J app ) 8.6 Hz, 2H), 7.27 (d, J app ) 8.1 Hz, 2H), 7.33 (d
(br), J ) 7.7 Hz, 1H), 7.51 (dt, J ) 7.7, 1.2 Hz, 1H), 7.60 (dt, J
(d (dC,F, J ) 35.6 Hz)), 132.0 (d), 132.1 (d), 139.3 (s), 159.3 (s),
159.6 (s), 161.9 (s (dC,F, J ) 248.4 Hz)). Anal. Calcd for C31H27
FN2O3: C, 75.29; H, 5.50; N, 5.66. Found: C, 75.00; H, 5.61; N,
5.64.
1
-
Rep r esen ta tive P r oced u r e for De-p-m eth oxyben zyla -
tion of th e Ar yla ted 2-(4-m eth oxyben zyl)p yr a zole 1-Ox-
id es: 3,5-Bis(4-m eth oxyp h en yl)-1-h yd r oxyp yr a zole (11a )
(Ta ble 4, En tr y 1). To a solution of pyrazole 6a (0.24 mmol)
in CH2Cl2 (5 mL) was added triisopropylsilane (0.10 mL,
0.48 mmol). After slow addition of trifluoroacetic acid (TFA; 5
mL) the mixture was gently heated to reflux for 24 h. The
mixture was evaporated to dryness. Addition of water (5 mL)
was followed by extraction with EtOAc (3 × 10 mL), drying
over anhydrous MgSO4, and evaporation. The crude product
was purified by FC (CH2Cl2 f CH2Cl2/EtOAc, 5:1) to give 60
mg (84%) of 11a as slightly brownish crystals. Recrystalli-
zation gave off-white crystals, mp 184-186 °C (EtOAc). Rf (CH2-
Cl2:EtOAc, 4:1): 0.42. δH (DMSO-d6): 3.75 (s, 3H), 3.78 (s, 3H),
6.84 (s, 1H, H-4), 6.96 (d, J app ) 8.9 Hz, 2H), 7.03 (d, J app ) 9.0
Hz, 2H), 7.70 (d, J app ) 8.9 Hz, 2H), 7.74 (d, J app ) 9.0 Hz, 2H).
δC (DMSO-d6): 55.5, 55.6, 98.4, 114.5, 114.6, 121.5, 126.29,
126.32, 129.1, 136.1, 142.6, 159.2, 159.6. Anal. Calcd for
C17H16N2O3: C, 68.91; H, 5.44; N, 9.45. Found: C, 68.77; H, 5.49;
N, 9.18.
) 7.7, 1.3 Hz, 1H), 7.76 (dd, J ) 7.7, 1.1 Hz, 1H), 8.12 (d, J app
)
8.3 Hz, 2H). δC (CDCl3): 22.4 (q), 47.8 (t), 56.3 (q), 103.3 (d),
113.9 (s), 115.3 (d), 118.4 (s), 126.3 (s), 127.6 (d), 128.6 (s), 129.6
(s), 129.9 (d), 130.5 (d), 130.7 (d), 131.1 (s), 131.8 (d), 133.7 (s),
134.1 (d), 135.2 (d), 140.0 (s), 160.5 (s). Anal. Calcd for
C25H21N3O2: C, 75.93; H, 5.35; N, 10.63. Found: C, 75.97; H,
5.46; N, 10.65.
3,4-Dibr om o-2-(4-m eth oxyben zyl)-5-(4-m eth oxyp h en yl)-
p yr a zole 1-Oxid e (8). Pyrazole 3 (3.14 g, 10.7 mmol) was
dissolved in CH3CN (200 mL) and cooled to 0 °C. NBS (3.96 g,
22.2 mmol) was added in small portions. The mixture was stirred
for 2 h at 0 °C and 2 h at room temperature. Addition of water
(900 mL) caused precipitation. The precipitate was isolated by
filtration, washed with water (30 mL) and cold Et2O (30 mL),
and dried at 0.1 mmHg to give 4.71 g (98%) of 8 as colorless
crystals, mp 115-117 °C (EtOAc). Rf (EtOAc/PE, 2:1): 0.62. δH
Ack n ow led gm en t. This work was supported by the
Corporate Research Affairs at Novo Nordisk A/S and
The Graduate School of Drug Research at The Roy-
alDanish School of Pharmacy by a graduate fellowship
fellowship to J .E. The mass spectrometer was a gift from
The Velux Foundation of 1981 and The Ib Henriksen
Foundation.
(CDCl3): 3.78 (s, 3H), 3.84 (s, 3H), 5.46 (s, 2H), 6.86 (d, J app
)
8.8 Hz, 2H), 6.99 (d, J app ) 9.1 Hz, 2H), 7.47 (d, J app ) 8.8 Hz,
2H), 7.87 (d, J app ) 9.1 Hz, 2H). δC (CDCl3): 48.0, 55.2, 55.3,
92.8, 102.4, 113.8, 114.2, 118.6, 126.4, 129.4, 130.3, 130.6, 159.8,
160.3. Anal. Calcd for C18H16Br2N2O3: C, 46.18; H, 3.44; N, 5.98.
Found: C, 46.47; H, 3.32; N, 5.92.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and spectral data for the compounds mentioned above.
This material is available free of charge via the Internet at
http://pubs.acs.org.
4-Br om o-2-(4-m eth oxyben zyl)-5-(4-m eth oxyp h en yl)-3-(4-
m eth ylp h en yl)p yr a zole 1-Oxid e (9). Following the procedure
J O015997I