Regioselective introduction of electrophiles in the 4-position of 1- hydroxypyrazole via bromine-lithium exchange

Article abstract of DOI:10.1021/jo981970w

Two protocols for introduction of electrophiles at the 4-position of 1- hydroxypyrazoles have been developed. The first is deprotonation of 4-bromo- 1-[(tert-butyldiphenylsilyl)oxy]pyrazole (6) with LDA to produce the 5-lithio derivative in which the silyl group migrates spontaneously from oxygen to C-5 affording 4-bromo-5-(tert-butyldiphenylsilyl)-1-lithoxypyrazole (8). Subsequent treatment with t-BuLi causes bromine-lithium exchange to give 5- tert-butyldiphenylsilyl-4-lithio-1-lithoxypyrazole which is trapped with electrophiles affording 4-substituted 5-(tert-butyldiphenylsilyl)-1- hydroxypyrazoles 9a-e in a one-pot sequence. The second is treatment of 4- bromo-1-hydroxypyrazole (5) with excess LDA and trimethylsilyl chloride to produce 3,5-bis(trimethylsilyl)-4-bromo-1-hydroxypyrazole (12), which upon sequential metalation with n-BuLi and reaction with electrophiles affords 4- substituted 3,5-bis(trimethylsilyl)-1-hydroxypyrazoles 13a-e. The tert- butyldiphenylsilyl group of 9a and the trimethylsilyl groups of 12 can be removed selectively by treatment with tetrabutylammonium fluoride in THF in the presence of trifluoroacetic acid.

Full text of DOI:10.1021/jo981970w

5366
J . Org. Chem. 1999, 64, 5366-5370
Regioselective In tr od u ction of Electr op h iles in th e 4-P osition of
1-Hyd r oxyp yr a zole via Br om in e-Lith iu m Exch a n ge
Thomas Balle,†,‡ Per Vedsø,† and Mikael Begtrup*,†,§
Department of Medicinal Chemistry, Royal Danish School of Pharmacy, Universitetsparken 2,
DK-2100 Copenhagen, Denmark, and Department of Organic Chemistry, Technical University of
Denmark, DK-2800 Lyngby, Denmark
Received September 29, 1998
Two protocols for introduction of electrophiles at the 4-position of 1-hydroxypyrazoles have been
developed. The first is deprotonation of 4-bromo-1-[(tert-butyldiphenylsilyl)oxy]pyrazole (6) with
LDA to produce the 5-lithio derivative in which the silyl group migrates spontaneously from oxygen
to C-5 affording 4-bromo-5-(tert-butyldiphenylsilyl)-1-lithoxypyrazole (8). Subsequent treatment with
t-BuLi causes bromine-lithium exchange to give 5-tert-butyldiphenylsilyl-4-lithio-1-lithoxypyrazole
which is trapped with electrophiles affording 4-substituted 5-(tert-butyldiphenylsilyl)-1-hydroxy-
pyrazoles 9a -e in a one-pot sequence. The second is treatment of 4-bromo-1-hydroxypyrazole (5)
with excess LDA and trimethylsilyl chloride to produce 3,5-bis(trimethylsilyl)-4-bromo-1-hydroxy-
pyrazole (12), which upon sequential metalation with n-BuLi and reaction with electrophiles affords
4-substituted 3,5-bis(trimethylsilyl)-1-hydroxypyrazoles 13a -e. The tert-butyldiphenylsilyl group
of 9a and the trimethylsilyl groups of 12 can be removed selectively by treatment with
tetrabutylammonium fluoride in THF in the presence of trifluoroacetic acid.
In tr od u ction
to 5-lithiopyrazole.15 Obviously, these problems can be
avoided by introducing a protection group at C-5. We
selected silyl protecting groups for this purpose since they
could be easily introduced by metalation-silylation and
removed again after the crucial metalation at C-4. This
allowed for a one-pot sequence.
1-Substituted pyrazoles can be lithiated at the 5-posi-
tion by treatment with organolithium reagents, and the
5-lithiopyrazoles formed react with a series of different
electrophiles to give 1,5-disubstituted pyrazoles.1,2 Sub-
sequent N-deprotection gives access to 3(5)-substituted
pyrazoles.1,3,4 1-Substituted pyrazoles readily undergo
electrophilic halogenation5,6 and nitration7 at the 4-posi-
tion giving access to only halo- and nitro-substituted
pyrazoles. An alternative approach to 4-substituted pyra-
zoles would be reaction of 4-lithiopyrazoles with electro-
philes. However, there are only a few examples of
pyrazole C-4 lithiation,8-13 all based on bromine-lithium
exchange. This reaction sometimes proceeds with low
chemoselectivity due to competing deprotonation at
C-58,14 or isomerization of initially formed 4-lithiopyrazole
Resu lts a n d Discu ssion
Attem p ted Meta la tion a t C-4. We first attempted
direct lithiation of the 4-position in 1-benzyloxy-5-tri-
methylsilylpyrazole (1c)2 using n-BuLi. However, 1c was
lithiated at the benzylic CH2 group, affording the anion
2 which underwent N-O bond cleavage producing 1-lithio-
5-trimethylsilylpyrazole and benzaldehyde. The latter
compound reacted with n-BuLi, and aqueous workup
gave 3(5)-trimethylsilylpyrazole (3) and 1-phenyl-1-pen-
tanol (Scheme 1).16 To avoid lateral deprotonation we
attempted lithiation of 1-(9-phenylfluoren-9-yloxy)-5-
(trimethylsilyl)pyrazole (1a ) or 1-hydroxy-5-(tert-butyl-
diphenylsilyl)pyrazole (1b)2 which are devoid of benzylic
protons. However, these compounds remained unchanged
upon treatment with n-, sec-, or t-BuLi (Scheme 1).
Obviously the 4-proton in these pyrazole derivatives is
not sufficiently acidic to be abstracted by butyllithium
bases. Therefore, halogen-lithium exchange was inves-
tigated. However, when 4-bromo-1-hydroxypyrazole (5)
was treated with t-BuLi followed by reaction with MeOD,
a 15:30:40:15 mixture of 1-hydroxypyrazole (4) together
with its 4-bromo-5-deuterio, 4-deuterio, and 5-deuterio
derivatives was obtained indicating poor chemoselectivity
and thermodynamically instability of initially formed
4-lithio-1-lithoxypyrazole. These experiments show that
selective lithiation at C-4 requires a 4-bromopyrazole
† Royal Danish School of Pharmacy.
‡ Technical University of Denmark.
§ Tel.: +45 35 37 08 50. FAX: +45 35 37 22 09. E-mail: begtrup@
medchem.dfh.dk.
(1) For a recent review on lithiated pyrazoles, see: Grimmett, M.
R.; Iddon, B. Heterocycles 1994, 37, 2087.
(2) Vedsø, P.; Begtrup, M. J . Org. Chem. 1995, 60, 4995.
(3) Fugina, N.; Holzer, W.; Wasicky, M. Heterocycles 1992, 34, 303.
(4) Katritzky, A. R.; Lue, P.; Akutagawa, K. Tetrahedron 1989, 45,
4253.
(5) Hu¨ttel, R.; Scha¨fer, O.; J ochum, P. Liebigs Ann. Chem. 1955,
593, 200.
(6) Lipp, M.; Dallacker, F.; Munnes, S. Liebigs Ann. Chem. 1958,
618, 110.
(7) Hu¨ttel, R.; Bu¨chele, F.; J ochum, P. Chem. Ber. 1955, 88, 1577.
(8) Hu¨ttel, R.; Scho¨n, M. E. Liebigs Ann. Chem. 1959, 625, 55.
(9) Hahn, M.; Heinisch, G.; Holzer, W.; Schwarz, H. J . Heterocycl.
Chem. 1991, 28, 1189.
(10) Iwata, S.; Qian, C.-P.; Tanaka, K. Chem. Lett. 1992, 357.
(11) Sakamoto, T.; Shiga, F.; Uchiyama, D.; Kondo, Y.; Yamanaka,
H. Heterocycles 1992, 33, 813.
(12) Elguero, J .; J aramillo, C.; Pardo, C. Synthesis 1997, 563.
(13) J eon, D. J .; Yu, D. W.; Yun, K. Y.; Ryu, E. K. Synth. Commun.
1998, 28, 2159.
(14) 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-ben-
zyloxy-4-bromo-5-[2H]-pyrazole according to 1H NMR.
(15) Tertov, B. A.; Morkovnik, A. S. Chem. Heterocycl. Compd. (Engl.
Transl.) 1975, 11, 343.
(16) Uhlmann, P.; Felding, J .; Vedsø, P.; Begtrup, M. J . Org. Chem.
1997, 62, 9177.
10.1021/jo981970w CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/02/1999

Introduction of Electrophiles in 1-Hydroxypyrazole
J . Org. Chem., Vol. 64, No. 15, 1999 5367
Sch em e 1
Sch em e 3
Sch em e 2
the role of the TFA may be that it protonates the
N-oxygen so that formation of an unfavorable O,C-
dianion is avoided. This hypothesis was supported by the
fact that desilylation of the O-protected 1-benzyloxy-5-
(tert-butyldiphenylsilyl)pyrazole could be achieved by
TBAF in THF at 0 °C in the absence of TFA.
P r ep a r a tion of 4-Su bstitu ted 3,5-Bis(tr im eth yl-
silyl)-1-h yd r oxyp yr a zoles. To find a more labile and
less sterically demanding silyl protecting group, use of
the trimethylsilyl group was investigated. Attempts to
isolate 4-bromo-1-(trimethylsilyloxy)pyrazole (10) failed
due to its ready desilylation. However 10 could be
generated in situ by reaction of 4-bromo-1-hydroxypyra-
zole (5) with LDA in the presence of 1 equiv of trimeth-
ylsilyl chloride. Subsequent treatment with excess LDA
produced 4-bromo-1-hydroxy-5-(trimethylsilyl)pyrazole
together with 6-8% of 3,5-bis(trimethylsilyl)-4-bromo-
1-hydroxypyrazole (12) and 15-20% of 4-bromo-1-hy-
droxypyrazole (5). Even in the presence of only 0.9 equiv
of trimethylsilyl chloride, formation of 12 could not be
avoided. Neither regioselectivity between C-3 and C-5 or
monoselectivity could be achieved; therefore C-3 and C-5
disilylation was attempted using an excess of LDA and
trimethylsilyl chloride for in situ trapping18,19 of the
pyrazole anions. This afforded 3,5-bis(trimethylsilyl)-4-
bromo-1-hydroxypyrazole (12) in 99% yield (Scheme 3).
Presumably, O-silylation of 5 is followed by deprotonation
and silylation at C-5 and then deprotonation and silyla-
tion at C-3. To the best of our best knowledge, this is the
first example of deprotonation at the 3-position of 1-sub-
stituted pyrazoles.20 Most likely, the bromine at C-4
enhances the acidity of H-3 since similar treatment of
1-hydroxypyrazole (4) produced 1-hydroxy-5-(trimethyl-
silyl)pyrazole as the only product. The extended reaction
time (3.5 h) and elevated temperature (-40 °C instead
of -78 °C) indicate that the 3-lithiopyrazole is formed
sluggishly.
protected at the 5-position and two successful strategies
were then developed as described below.
P r ep a r a tion of 4-Su bstitu ted 5-(ter t-Bu tyld ip h en -
ylsilyl)-1-h yd r oxyp yr a zoles. 4-Bromo-1-[(tert-butyl-
diphenylsilyl)oxy]pyrazole (6) was obtained by bromina-
tion of 1-hydroxypyrazole (4) to give 4-bromo-1-hydroxy-
pyrazole (5) which was O-silylated under standard condi-
tions producing 6 in quantitative yield. Treatment of 6
with the soft base n-BuLi gave rise to a complicated
mixture, probably due to competing bromine-lithium
exchange and deprotonation. In contrast, the hard base
LDA afforded exclusively C-5 deprotonation which was
followed by the previously observed2 spontaneous migra-
tion of the tert-butyldiphenylsilyl group from the N-
oxygen to C-5 affording the 4-bromo-5-silyl-protected
pyrazole 9a (91% yield) upon aqueous workup. If the
aqueous workup was omitted, subsequent selective and
quantitative bromine-lithium exchange of the interme-
diate 8 by adding excess t-BuLi could be accomplished
in the same pot. Quenching of the putative intermediate
5-tert-butyldiphenylsilyl-1-lithoxypyrazol-4-yllithium with
deuterio, carbon, or sulfur electrophiles produced 4-sub-
stituted 5-(tert-butyldiphenylsilyl)-1-hydroxypyrazoles
9b-e in good to excellent yields (Scheme 2). By way of
example, the tert-butyldiphenylsilyl protecting group of
9a was removed by heating the solution to reflux in THF
containing tetrabutylammonium fluoride (TBAF) and 1
equiv of trifluoroacetic acid (TFA) to give 5 in 91% yield
(Scheme 4). The presence of TFA was essential for
obtaining high yields. Fluoride ion-catalyzed protiodesi-
lylation proceeds via an intermediate anion;17 therefore
As shown in Scheme 3, pyrazole 12 underwent bro-
mine-lithium exchange when treated with 5 equiv of
n-BuLi. Deprotonation of the N-hydroxy group took place
prior to bromine-lithium exchange since complete re-
generation of the starting material was observed when
(18) Krizan, T. D.; Martin, J . C. J . Am. Chem. Soc. 1983, 105, 6155.
(19) Caron, S.; Hawkins, J . M. J . Org. Chem. 1998, 63, 2054.
(20) We have previously reported the 3,5-bistrimethylsilylation of
2-benzylpyrazole 1-oxide via repeated deprotonation and C-silylation.21
Pavlik et al.22 have reported the preparation of 3-lithio-1-methylpyra-
zole via bromine-lithium exchange.
(17) Eaborn, C.; Seconi, G. J . Chem. Soc., Perkin Trans. 2 1976, 925.

5368 J . Org. Chem., Vol. 64, No. 15, 1999
Balle et al.
Sch em e 4
otherwise difficultly accessible C-4 funtionalized 1-hy-
droxypyrazoles. The silyl protecting groups could be
removed readily as exemplified by the desilylation of 9a
and 12 by treatment with TBAF in THF and in the
presence of TFA.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions involving air-sensitive
reagents were performed under nitrogen using syringe-
septum cap techniques. All glassware was flame-dried prior
to use. Unless otherwise indicated, the reaction mixtures were
worked up by addition of saturated aqueous NH4Cl and CH2-
Cl2, isolation of the organic layer, extraction of the aqueous
phase with CH2Cl2, drying of the combined organic phases
(MgSO4), filtration, and evaporation of the filtrate in vacuo.
Flash chromatography (FC) was performed using silica gel
(Merck 60, 70-230 mesh). Melting points are uncorrected. All
new compounds were colorless, unless otherwise stated. NMR
spectra were recorded on a 200 or a 300 MHz instrument.27
Ma ter ia ls. All solvents and reagents were obtained from
Fluka or Aldrich and used without further purification except
TMEDA which was distilled from CaH2, THF which was
distilled from Na/benzophenone under nitrogen, and DMF
which was sequentially dried with and stored over 3 Å
molecular sieves. n-, sec-, and tert-Butyllithium were titrated
prior to use.28
only 1 equiv of n-BuLi was used. After addition of the
first equivalent of n-BuLi, the reaction mixture turns
dark yellow indicating the start of formation of the
putative dianion 4-lithio-3,5-bis(trimethylsilyl)-1-lithoxy-
pyrazole. Performing the bromine-lithium exchange at
-78 °C for 1 h resulted in only 92% exchange. However
complete bromine-lithium exchange was achieved in 30
min at -50 °C. The relatively long reaction time as
compared to other halogen-metal exchange reactions23
most likely is due to the slow formation of dianions in
solution and to the bulkiness of the adjacent trimethyl-
silyl groups. Quenching 4-lithio-3,5-bis(trimethylsilyl)-
1-lithoxypyrazole with deuterio, carbon, or sulfur elec-
trophiles produced 4-substituted 3,5-bis(trimethylsilyl)-
1-hydroxypyrazoles 13a -e in good to excellent yields
(Scheme 3). Attempts to use more bulky electrophiles
such as trimethylsilyl chloride or benzaldehyde failed.
In the preparation of 13d , better results were obtained
when only 2.2 equiv of t-BuLi and 1.2 equiv of DMF were
used. Increasing the amount of DMF gave rise to com-
plicated mixtures. The facile removal of the silyl protect-
ing groups was illustrated by the monoselective desily-
lation of 3,5-bis(trimethylsilyl)-4-bromo-1-hydroxypyrazole
(12) using TBAF in THF in the presence of equivalent
amounts of TFA. The trimethylsilyl group at the 5-posi-
tion24 was readily removed at room temperature whereas
removal of the trimethylsilyl group at C-3 required
heating to 70 °C for 14 h (Scheme 4). The observed
regioselectivity in this fluoride ion-catalyzed protiodesi-
lylation reflects that in pyrazoles the 5-anion is more
stable than the 3-anion.26
1-(9-P h e n ylflu or e n -9-yloxy)-5-(t r im e t h ylsilyl)p yr a -
zole (1a ). To a solution of 1-(9-phenylfluoren-9-yloxy)pyrazole2
(1.04 g 3.22 mmol) and TMEDA (0.63 mL, 4.2 mmol) in 20
mL of dry THF was added dropwise 1.4 M n-BuLi in hexanes
(3.0 mL, 4.20 mmol) at -78 °C. After 20 min, trimethylsilyl
chloride (0.82 mL, 6.5 mmol) was added. Stirring was contin-
ued for 1 h, and the solution was allowed to warm to room
temperature over 1 h and stirred for further 1 h. Standard
workup and FC (heptane f CH2Cl2-Et2O-heptane 1:1:8)
provided 1.25 g (98%) of 1-(9-phenylfluoren-9-yloxy)-5-(tri-
methylsilyl)pyrazole (1a ), mp 108 °C (heptane): Rf(CH2Cl2-
1
Et2O-heptane 1:1:8) 0.51; H NMR (CDCl3) δ 7.68-7.57 (m,
4 H), 7.40-7.30 (m, 5 H), 7.16 (d, J ) 2.1 Hz, 1 H), 7.11 (d, J
) 7.5 Hz, 2 H), 6.92 (d, J ) 7.5 Hz, 2 H), 6.04 (d, J ) 2.2 Hz,
1 H), -0.26 (s, 9 H); 13C NMR (CDCl3) δ 144.2 (s), 141.3 (s),
140.6 (s), 137.5 (s), 132.4 (d), 129.6 (d), 128.0 (d), 127.9 (d),
127.7 (d), 126.3 (d), 126.1 (d), 119.9 (d), 110.0 (d), 97.1 (s), -1.85
(q). Anal. Calcd for C25H24N2OSi: C, 75.72; H, 6.10; N, 7.06.
Found: C, 75.95; H, 6.31; N, 6.89.
3(5)-Tr im eth ylsilylp yr a zole (3). To a solution of 1-ben-
zyloxy-5-(trimethylsilyl)pyrazole (1c) (246 mg, 1 mmol) and
TMEDA (0.30 mL, 2.0 mmol) in dry THF (10 mL) was added
dropwise 1.6 M n-BuLi in hexanes (1.25 mL, 2.0 mmol)29 at
-78 °C. After 10 min, D2O (0.30 mL) was added and stirring
was continued for 5 min before the solution was allowed to
warm to 0 °C. Standard workup and FC (CH2Cl2-Et2O-
pentane 1:1:20 f 1:1:0) provided 144 mg (88%) of 1-phenyl-
1-pentanol, Rf(CH2Cl2-Et2O-pentane 1:1:8) 0.33 and 119 mg
(84%) of 3(5)-trimethylsilylpyrazole (3), mp 76 °C (pentane)
(lit.30 mp 79-80 °C): Rf(CH2Cl2-Et2O 1:1) 0.45; 1H NMR
(CDCl3) δ 7.67 (d, J ) 1.7 Hz, 1 H), 6.44 (d, J ) 1.7 Hz, 1 H),
0.32 (s, 9 H); 13C NMR (CDCl3) δ 142.4 (s), 138.6 (d), 112.1
(d), -1.23 (q).
4-Br om o-1-h yd r oxyp yr a zole (5). Bromine (1.55 mL, 30
mmol) was added dropwise to a mixture of 1-hydroxypyrazole
(4)27 (2.49 g, 29.6 mmol) and 48% aqueous HBr (1.7 mL) in 60
mL of CH2Cl2 at -78 °C. Stirring was continued for 1 h, and
the solution was allowed to warm to room temperature over 1
h and stirred for further 12 h resulting in a brown inhomo-
geneous solution. Addition of Na2SO3‚7H2O (3 g) dissolved in
Con clu sion s
In conclusion, we have demonstrated that 4-lithio-1-
lithoxypyrazoles can be generated by bromine-lithium
exchange in the presence of silyl protecting groups at C-5
or at C-3 and C-5. These species can be used to obtain
(21) Begtrup, M.; Vedsø, P. J . Chem. Soc., Perkin Trans. 1 1993,
625.
(22) Pavlik, J . W.; Kurzweil, E. M. J . Heterocycl. Chem. 1992, 29,
1357.
(23) Narasimhan, N. S.; Sunder, N. M.; Ammanamanchi, R.; Bonde,
B. D. J . Am. Chem. Soc. 1990, 112, 4431.
(24) The position of the trimethylsilyl group of 14 was assigned by
comparison of the 13C NMR signals with those of 4-bromo-1-hydroxy-
pyrazole (5). In 14 and 5 C-5 resonate at 123.1 and 121.8 ppm,
respectively, while C-3 resonate at 144.7 and 131.6 ppm, respectively.
The 13.1 ppm downfield shift of C-3 in 14 agrees with the shift
displacement induced by a trimethylsilyl group. Furthermore, 1J C-5,H-5
3
and J C-3,H-5 in 14 (199.3 and 7.8 Hz) resemble those observed in 5
(199.1 and 7.7 Hz). This agrees with the values found in other
(27) Begtrup, M.; Vedsø, P. J . Chem. Soc., Perkin Trans. 1 1995,
243.
1-substituted pyrazoles.25
(25) 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.
(28) Suffert, J . J . Org. Chem. 1989, 54, 509.
(29) Using only 1 equiv of n-BuLi/TMEDA resulted in 48% starting
material 1c together with 44% of 1-phenyl-1-pentanol and 41% of 3.
(30) Birkofer, L.; Franz, M. Chem. Ber. 1972, 105, 1759.
(26) Effenberger, F.; Krebs, A. J . Org. Chem. 1984, 49, 4687.

Introduction of Electrophiles in 1-Hydroxypyrazole
J . Org. Chem., Vol. 64, No. 15, 1999 5369
30 mL of H2O gave a clear solution. Addition of Et2O (50 mL),
separation of the organic layer, extraction of the aqueous phase
five times with ether, drying of the combined organic phases
(MgSO4), filtration, and evaporation gave 4.88 g of a mixture
of 4-bromo-1-hydroxypyrazole (5), dibrominated 1-hydroxy-
pyrazole, and unchanged starting material 4 in the ratio 79:
13:8 (1H NMR). A single recrystallization from EtOAc-heptane
(1:6, ca. 35 mL) gave 3.33 g (69%) of 4-bromo-1-hydroxypyra-
zole (5), mp 133 °C: 1H NMR ((CD3)2CO) δ 11.6 (br s, 1H),
7.72 (d, J ) 1.1 Hz, 1H), 7.21 (d, J ) 1.1 Hz, 1H); 13C NMR
(0.73 mL, 11.7 mmol) as the electrophile. After stirring at -78
°C for 30 min, 33% dimethylamine in ethanol (6 mL) was
added in order to destroy excess methyl iodide, and the solution
was allowed to warm to room temperature. Addition of
saturated aqueous NH4Cl (10 mL), adjustment of pH to 2 using
2 M HCl followed by extraction five times with Et2O, drying
of the combined organic phases (MgSO4), filtration, and
evaporation of the filtrate in vacuo followed by FC (HOAc-
EtOAc-heptane 1:10:200 f 1:10:50) gave 234 mg (70%) of
5-(tert-butyldiphenylsilyl)-1-hydroxy-4-methylpyrazole (9c), mp
202-204 °C (EtOAc-heptane 1:4): Rf(HOAc-EtOAc-heptane
1
3
((CD3)2CO) δ 131.6 (dd, J C-3,H-3 ) 194.8, J C-3,H-5 ) 7.7 Hz,
C-3), 121.8 (dd, 1J C-5,H-5 ) 199.1, 3J C-5,H-3 ) 2.9 Hz, C-5), 88.9
1:10:100) 0.09; H NMR (CDCl3) δ 7.70-7.30 (m, 10 H), 6.91
1
2
2
(dd, J C-4,H-5 and J C-4,H-3 5.9 and 6.4 Hz, C-4). Anal. Calcd
for C3H3BrN2O: C, 22.11; H, 1.86; N, 17.19. Found: C, 22.02;
H, 1,84; N, 16.93.
(s, 1 H), 1.28 (s, 3 H), 1.26 (s, 9 H); 13C NMR (CDCl3) δ 135.9,
133.7, 131.8, 129.4, 128.2, 127.8, 123.6, 28.7, 18.9, 11.2. Anal.
Calcd for C20H24N2OSi: C, 71.39; H, 7.19; N, 8.32. Found: C,
71.29; H, 7.28; N, 8.24.
4-Br om o-1-[ter t-(bu tyld ip h en ylsilyl)oxy]p yr a zole (6).
To a solution of 4-bromo-1-hydroxypyrazole (5) (2.59 g, 15.9
mmol) and N-ethyldiisopropylamine (2.80 mL, 16.3 mmol) in
15 mL of CH2Cl2 at -20 °C was added dropwise tert-butyl-
diphenylsilyl chloride (4.20 mL, 16.3 mmol). Stirring was
continued at room temperature for 12 h. Removal of the CH2-
Cl2 afforded a solid that was extracted with ether (4 × 50 mL).
The combined ether phases were filtered and evaporated to
dryness. Extraction with 50 °C heptane (4 × 50 mL), filtration
through activated carbon, and removal of the heptane gave
6.40 g (100%) of 4-bromo-1-[tert-(butyldiphenylsilyl)oxy]pyra-
zole (6),31 mp 66-69 °C (EtOAc-heptane): 1H NMR (CDCl3)
δ 7.73-7.67 (m, 4H), 7.51-7.33 (m, 6H), 6.98 (d, J ) 1.05 Hz,
1H), 6.95 (d, J ) 1.05 Hz, 1H), 1.17 (s, 9H); 13C NMR (CDCl3)
δ 135.6 (d), 132.0 (d), 130.6 (d), 130.1 (s), 127.7 (d), 121.8 (d),
89.9 (s), 26.5 (q), 19.2 (s). Anal. Calcd for C19H21BrN2OSi: C,
56.86; H, 5.27; N, 6.98. Found: C, 57.11; H, 5.40; N, 6.67.
Rea r r a n gem en t of 4-Br om o-1-[ter t-(bu tyld ip h en ylsi-
lyl)oxy]p yr a zole (6) in to 4-Br om o-5-(ter t-bu tyld ip h en yl-
silyl)-1-h yd r oxyp yr a zole (9a ). Freshly prepared LDA (2.99
mmol) in 6 mL of THF was added dropwise during 2 min to a
solution of 4-bromo-1-(tert-butyldiphenylsilyloxy)pyrazole (6)
(610 mg, 1.52 mmol) in THF (15 mL) at -78 °C. Stirring was
continued at -78 °C for 10 min, and aquesous HCl (4 M, 10
mL) was added. The solution was allowed to warm to room
temperature and extracted five times with Et2O. Removal of
the solvent in vacuo and FC (HOAc-EtOAc-heptane 1:10:
100 f 1:10:50) gave 560 mg (91%) of 4-bromo-5-(tert-butyl-
diphenylsilyl)-1-hydroxypyrazole (9a ), mp 173-175 °C: Rf-
(HOAc-EtOAc-heptane 1:10:100) 0.13; 1H NMR (CDCl3) δ
7.7-7.3 (m, 10 H), 7.07 (s, 1 H), 1.28 (s, 9 H); 13C NMR (CDCl3)
δ 136.0, 133.9, 132.4, 130.0, 129.6, 127.7, 101.0, 28.5, 19.0.
Anal. Calcd for C19H21BrN2OSi: C, 56.86; H, 5.27; N, 6.98.
Found: C, 57.02; H, 5.38; N, 7.02.
5-(ter t-Bu t yld ip h en ylsilyl)-4-for m yl-1-h yd r oxyp yr a -
zole (9d ). The general method was used with DMF (0.54 mL,
7 mmol) as the electrophile. After stirring at -78 °C for 30
min, the solution was allowed to warm to 0 °C over 1 h and
stirred for a further 1 h. Addition of 2 M HCl (10 mL), stirring
at room temperature for 1 h, separation of the organic phase,
extraction of the aqueous phase with CH2Cl2, drying of the
combined organic phases (MgSO4), filtration, and evaporation
of the filtrate in vacuo followed by FC (EtOAc-heptane 1:4 f
1:1) gave 348 mg (99%) of 5-(tert-butyldiphenylsilyl)-4-formyl-
1-hydroxypyrazole (9d ), mp 190-191 °C (EtOAc-heptane
1:4): Rf(EtOAc-heptane 1:1) 0.34; 1H NMR (CDCl3) δ 8.50 (s,
1 H), 7.71 (s, 1 H), 7.60-7.34 (m, 10 H), 1.31 (s, 9 H); 13C NMR
(CDCl3) δ 186.0, 136.0, 135.7, 134.1, 132.1, 130.3, 128.6, 128.3,
28.7, 18.9. Anal. Calcd for C20H22N2O2Si: C, 68.54; H, 6.33;
N, 7.99. Found: C, 68.46; H, 6.35; N, 7.97.
5-(ter t-Bu tyld ip h en ylsilyl)-1-h yd r oxy-4-(m eth ylth io)-
p yr a zole (9e). Using the general procedure, with dimethyl
disulfide (0.68 mL, 7.6 mmol) as the electrophile and workup
as described for 1-hydroxy-4-methyl-5-(tert-butyldiphenylsilyl)-
pyrazole (9c) gave 364 mg (99%) of 5-(tert-butyldiphenylsilyl)-
1-hydroxy-4-(methylthio)pyrazole (9e), mp 133-135 °C (EtOAc-
heptane 1:4): Rf(HOAc-EtOAc-heptane 1:10:100) 0.11; 1H
NMR (CDCl3) δ 7.80-7.30 (m, 10 H), 6.97 (s, 1 H), 1.85 (s, 3
H), 1.27 (s, 9 H); 13C NMR (CDCl3) δ 136.0, 134.2, 133.1, 131.5,
129.4, 127.5, 121.2, 28.5, 19.5, 18.9. Anal. Calcd for C20H24N2-
OSSi: C, 65.18; H, 6.56; N; 7.60 Found: C, 65.43; H, 6.72; N,
7.65.
3,5-Bis(tr im eth ylsilyl)-4-br om o-1-h ydr oxypyr azole (12).
A freshly prepared solution of LDA (37.4 mmol) in 30 mL of
THF was added at -78 °C during 4 min to a solution of
4-bromo-1-hydroxypyrazole (5) (1.51 g, 9.29 mmol) and tri-
methylsilyl chloride (7.4 mL, 58 mmol) in 20 mL of THF. The
reaction mixture was stirred at -50 to -40 °C for 3.5 h,
quenched with 4 M HCl (20 mL), and allowed to warm to room
temperature. The aqueous phase was extracted five times with
Et2O, and the combined organic phases were washed with
brine and water, dried (MgSO4), filtered, and evaporated in
vacuo to give 2.82 g (99%) of 3,5-bis(trimethylsilyl)-4-bromo-
1-hydroxypyrazole (12), mp 157-159 °C (pentane): 1H NMR
(CDCl3) δ 0.43 (s, 9H), 0.35 (s, 9H); 13C NMR (CDCl3) δ 143.7
Rea r r a n gem en t of 4-Br om o-1-[ter t-(bu tyld ip h en ylsi-
lyl)oxy]p yr a zole (6) in to 4-Br om o-1-lith oxy-5-(ter t-bu -
tyld ip h en ylsilyl)p yr a zole (8) F ollow ed by Br om in e-
Lith iu m Exch a n ge a n d Rea ction w ith a n Electr op h ile.
Gen er a l. Freshly prepared LDA (2 mmol) in 4 mL of THF
was added dropwise during 2 min to a solution of 4-bromo-1-
(tert-butyldiphenylsilyloxy)pyrazole (6) (401 mg, 1.00 mmol)
in THF (8 mL) at -78 °C. Stirring was continued at -78 °C
for 10 min, 1.44 M t-BuLi in pentane (2.78 mL, 4 mmol) was
added over 1 min, and the mixture was stirred at -78 °C for
a further 3 min before addition of the electrophile.
(s), 132.2 (s), 106.2 (s), -0.8 (q), -1.1 (q). Anal. Calcd for C9H19
-
BrN2OSi2: C, 46.84; H, 7.86; N, 10.92. Found: C, 47.07; H,
7.77; N, 10.91.
Lith ia tion of 3,5-Bis(tr im eth ylsilyl)-4-br om o-1-h yd r ox-
yp yr a zole (12) F ollow ed by Rea ction w ith a n Electr o-
p h ile. Gen er a l. To a solution of 3,5-bis(trimethylsilyl)-4-
bromo-1-hydroxypyrazole (12) (307 mg, 1.0 mmol) in THF (10
mL) was added dropwise 1.6 M n-BuLi in hexanes (3.13 mL,
5.0 mmol) at -78 °C over 2 min. The dark yellow solution was
stirred at -78 °C for 5 min and at -50 °C for 30 min and then
cooled to -78 °C whereupon the electrophile was added.
3,5-Bis(tr im eth ylsilyl)-4-[2H]-1-h yd r oxyp yr a zole (13b).
The general method with D2O (1.2 mL, 60 mmol) as the
electrophile was used. After stirring at -78 °C for 5 min, the
reaction mixture was allowed to warm to room temperature
over 30 min. Addition of 2 M HCl (10 mL), separation of the
organic layer, extraction of the aqueous layer with CH2Cl2,
washing of the combined organic phases with water, drying
5-(ter t-Bu t yld ip h en ylsilyl)-4-[2H ]-1-h yd r oxyp yr a zole
(9b). The general method was used with monodeuteriometha-
nol (0.60 mL, 15 mmol) as the electrophile. After stirring at
-78 °C for 30 min, the solution was allowed to warm to 0 °C
over 10 min. Standard workup gave 314 mg (97%) of 5-(tert-
butyldiphenylsilyl)-4-[2H]-1-hydroxypyrazole (9b). The 1H NMR
spectrum was identical with the spectrum of 5-(tert-butyl-
diphenylsilyl)-1-hydroxypyrazole2 except that the signal for
H-4 at 6.18 ppm was absent, indicating quantitative deutera-
tion at the 4-position.
5-(ter t-Bu t yld ip h en ylsilyl)-1-h yd r oxy-4-m et h ylp yr a -
zole (9c). The general method was used with methyl iodide
(31) 6 partially desilylated upon attempted flash chromathography.

5370 J . Org. Chem., Vol. 64, No. 15, 1999
Balle et al.
(MgSO4), filtration, and evaporation in vacuo gave 190 mg
(trimethylsilyl)-[2H]-1-hydroxypyrazole (13b), and FC (HOAc-
EtOAc-heptane 1:10:300 f 1:10:100) gave 261 mg (95%) of
3,5-bis(trimethylsilyl)-1-hydroxy-4-(methylthio)pyrazole (13d ),
mp 145-146 °C (pentane): Rf(HOAc-EtOAc-heptane 1:10:
(83%) of 3,5-bis(trimethylsilyl)-[2H]-1-hydroxypyrazole (13b)
1
as a solid. The H and 13C NMR spectra were similar to those
of 3,5-bis(trimethylsilyl)-1-hydroxypyrazole (13a ) except that
1
1
the H NMR signal at 6.29 ppm was missing, indicating that
100) 0.33; H NMR (CDCl3) δ 2.19 (s, 3H), 0.47 (s, 9H), 0.38
the extent of deuteration was >99%. The 13C NMR signal at
116.5 ppm was a triplet (1J C-4, D-4 ) 28 Hz) with low intensity,
characteristic for a deuterio-substituted carbon atom.
3,5-Bis(tr im eth ylsilyl)-1-h yd r oxyp yr a zole (13a ). Using
the general method, with H2O (1.08 mL, 60 mmol) as the
electrophile and reaction conditions and workup as described
for 3,5-bis(trimethylsilyl)-[2H]-1-hydroxypyrazole (13b) gave
215 mg (94%) of 3,5-bis(trimethylsilyl)-1-hydroxypyrazole
(13a ), mp 146-149 °C (pentane): 1H NMR (CDCl3) δ 6.29 (s,
1H) 0.35 (s, 9H), 0.27 (s, 9H); 13C NMR (CDCl3) δ 143.8 (s),
132.9 (s), 116.5 (d), -1.1 (q), -1.7 (q). Anal. Calcd for C9H20N2-
OSi2: C, 47.32; H, 8.82; N, 12.26. Found: C, 47.71; H, 8.72;
N, 12.24.
(s, 9H); 13C NMR (CDCl3) δ 149.7 (s), 136.8 (s), 124.1 (s), 23.6
(q), -0.43 (q), -0.56 (q). Anal. Calcd for C10H22N2OSSi2: C,
43.75; H, 8.08; N, 10.20. Found: C:, 44.07; H, 8.13; N, 10.14.
Desilyla tion of C-Silyla ted 4-Br om o-1-h yd r oxyp yr a -
zoles. 4-Br om o-1-h ydr oxypyr azole (5). A solution of 4-bromo-
5-(tert-butyldiphenylsilyl)-1-hydroxypyrazole (9a ) (250 mg,
0.62 mmol), TBAF‚3H2O (980 mg, 3.1 mmol), and TFA (0.050
mL, 0.65 mmol) in THF (4 mL) was refluxed for 14 h under a
nitrogen atmosphere. After cooling to room temperature and
addition of 4 M HCl (3 mL), the solution was extracted five
times with Et2O. The combined organic phases were dried
(MgSO4), and the ether was removed in vacuo. FC (HOAc-
EtOAc-heptane 1:10:200 f 1:10:25) gave 92 mg (91%) of
4-bromo-1-hydroxypyrazole (5), identical with the material
described above.
3,5-Bis(t r im et h ylsilyl)-1-h yd r oxy-4-m et h ylp yr a zole
(13c). The general method was used with methyl iodide (0.19
mL, 3 mmol) as the electrophile. Stirring at -78 °C for 10 min
and at -40 °C for 1 h, addition of aqueous 2 M HCl (10 mL),
workup as described for 3,5-bis(trimethylsilyl)-[2H]-1-hydroxy-
pyrazole (13b), and FC (HOAc-EtOAc-heptane 1:10:300 f
1:10:100) gave 222 mg (92%) of 3,5-bis(trimethylsilyl)-1-
hydroxy-4-methylpyrazole (13c), mp 144-147 °C (pentane): Rf-
(HOAc-EtOAc-heptane 1:10:100) 0.39; 1H NMR (CDCl3) δ
2.15 (s, 3H), 0.37 (s, 9H), 0.30 (s, 9H); 13C NMR (CDCl3) δ 141.3
(s), 130.4 (s), 127.2 (s), 11.5 (q), -0.85 (q), -0.87 (q). Anal.
Calcd for C10H22N2OSi2: C, 49.54; H, 9.15; N, 11.55. Found:
C, 49.43; H, 9.10; N, 11.78.
4-Br om o-1-h yd r oxy-3-(tr im eth ylsilyl)p yr a zole (14). 3,5-
Bis(trimethylsilyl)-4-bromo-1-hydroxypyrazole (12) (123 mg,
0.40 mmol), TBAF‚3H2O (500 mg, 1.58 mmol), and TFA (0.030
mL, 0.40 mmol) were mixed in THF (8 mL) at 0 °C. The
solution was stirred at room temperature for 3.5 h, 4 M HCl
(4 mL) was added, and the reaction mixture was worked up
as above. FC (HOAc-EtOAc-heptane 1:10:200 f 1:10:50)
gave 89 mg (95%) of 4-bromo-1-hydroxy-3-(trimethylsilyl)-
pyrazole (14) as a pale yellow oil:24 Rf(HOAc-EtOAc-heptane
1
1:10:100) 0.10; H NMR (CDCl3) δ 7.40 (s, 1H), 0.33 (s, 9H);
13C NMR (CDCl3) δ 144.7 (ddec, 3J C-3,H-5 ) 7.8, 3J C-3,SiMe3 ) 2
3,5-Bis(t r im e t h ylsilyl)-4-for m yl-1-h yd r oxyp yr a zole
Hz, C-3), 123.1 (d, 1J C-5,H-5 ) 199.3 Hz, C-5), 98.2 (d, 2J C-4,H-5
(13d ). To
a solution of 3,5-bis(trimethylsilyl)-4-bromo-1-
1
3
) 5.7 Hz, C-4), -1.64 (qhep, J ) 120.4, J ) 2.0 Hz). Anal.
Calcd for C6H11BrN2OSi: C, 30.65; H, 4.72; N, 11.91. Found:
C, 30.93; H, 4.52; N, 11.64.
hydroxypyrazole (12) (324 mg, 1.05 mmol) in THF (10 mL) at
-78 °C was added t-BuLi (1.53 mL, 2.31 mmol) over 2 min.
The reaction mixture was stirred at -78 °C for 5 min and at
-50 °C for 30 min. After cooling to -78 °C, DMF (0.096 mL,
1.26 mmol) was added. The mixture was stirred at -78 °C for
1 h, quenched with 4 M HCl (10 mL), and allowed to warm to
room temperature followed by workup as described for 3,5-
bis(trimethylsilyl)-[2H]-1-hydroxypyrazole (13b). FC (HOAc-
EtOAc-heptane 1:10:200 f 1:10:75) gave 183 mg (68%) of 3,5-
bis(trimethylsilyl)-4-formyl-1-hydroxypyrazole (13d ), mp 183-
184 °C (pentane-EtOAc 10:1): Rf(HOAc-EtOAc-heptane
4-Br om o-1-h yd r oxyp yr a zole (5). 3,5-Bis(trimethylsilyl)-
4-bromo-1-hydroxypyrazole (12) (144 mg, 0.47 mmol), TBAF‚
3H2O (0.60 g, 1.90 mmol), and TFA (0.096 mL, 1.28 mmol)
were mixed in THF (10 mL) at 0 °C. The solution was refluxed
for 14 h under an argon atmosphere. Addition of 4 M HCl (5
mL) and standard workup as above followed by FC (HOAc-
EtOAc-heptane 1:10:200 f 1:10:25) gave 74 mg (97%) of
4-bromo-1-hydroxypyrazole (5), identical with the material
described above.
1
1:10:100) 0.33; H NMR (CDCl3) δ 10.01 (s, 1H), 0.48 (s, 9H),
0.36 (s, 9H); 13C NMR (CDCl3) δ 185.3 (d), 150.9 (s), 138.5 (s),
133.0 (s), -0.70 (q), -1.33 (q). Anal. Calcd for C10H20N2O2Si2:
C, 46.84; H, 7.86; N, 10.92. Found: C, 47.07; H, 7.77; N, 10.91.
3,5-Bis(tr im eth ylsilyl)-1-h yd r oxy-4-(m eth ylth io)p yr a -
zole (13e). The general method was used with dimethyl
disulfide (0.90 mL, 10 mmol) as the electrophile. Stirring at
-78 °C for 1 h and at room temperature for 3 h, addition of
aqueous 2 M HCl (10 mL), workup as described for 3,5-bis-
Ack n ow led gm en t. This work was supported by the
Danish Council for Technical and Scientific Research
and the Lundbeck Foundation. Dr. Ebbe Kelstrup, The
Technical University of Denmark, is gratefully acknowl-
edged for fruitful discussions and comments.
J O981970W