Preparation of 5-acyl- and 5-aryl-substituted 1-(benzyloxy)pyrazoles via directed ortho-lithiation/transmetalation and palladium catalyzed cross- coupling

Article abstract of DOI:10.1055/s-1998-2201

Palladium(0) catalyzed cross-coupling of 1-(benzyloxy)pyrazol-5-ylzinc halides 3a,b, prepared by transmetalation of 1-(benzyloxy)-5-lithiopyrazole (2), with acyl chlorides produced 5 acyl-1-(benzyloxy)pyrazoles 4a-d in high yields. Similar coupling of the

Full text of DOI:10.1055/s-1998-2201

SYNTHESIS
Papers
1604
Preparation of 5-Acyl- and 5-Aryl-Substituted 1-(Benzyloxy)pyrazoles via Directed
Ortho-Lithiation/Transmetalation and Palladium Catalyzed Cross-Coupling
Jesper Kristensen, Mikael Begtrup, Per Vedsø*
Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100 Copenhagen, Denmark
Fax +45(35)372209, E-mail: perv@medchem.dfh.dk
Received 17 January 1998; revised 30 March 1998
Abstract: Palladium(0) catalyzed cross-coupling of 1-(benzyl-
oxy)pyrazol-5-ylzinc halides 3a,b, prepared by transmetalation of
1-(benzyloxy)-5-lithiopyrazole (2), with acyl chlorides produced 5-
oxy)pyrazoles by combining DoM/transmetalation and
palladium catalyzed cross-coupling.
acyl-1-(benzyloxy)pyrazoles 4a–d in high yields. Similar coupling
of the pyrazol-5-ylzinc halide with amino-, hydroxy-, methoxy-,
by transmetalation of 1-(benzyloxy)-5-lithiopyrazole (2)
fluoro-, nitro-, or formyl-substituted iodobenzene gave the corre-
1-Benzyloxypyrazol-5-ylzinc chloride (3a) was prepared
using 3 equivalents of zinc chloride. Subsequent treat-
sponding 5-aryl-1-(benzyloxy)pyrazoles 5a–f, while coupling with
ment with acyl chlorides in the presence of 2 mol% tet-
rakis(triphenylphosphine)palladium(0) (Pd(PPh3)4)32 in
THF at room temperature furnished aliphatic and aromat-
ic pyrazolyl ketones 4a–d in good to excellent yields
(Scheme). It was crucial to use an excess of zinc chloride,
since a decrease from 3 to 1.5 equivalents of zinc chloride
decreased the conversion33 to ketone 4a from >95% to
50%. Increasing the amount of the palladium catalyst had
no effect on the reaction yield, but when the reaction was
performed in absence of Pd(PPh3)4 no pyrazolyl ketone
was observed. Replacing zinc chloride with zinc iodide
led to slightly decreased yields. Use of excess acetyl chlor-
ide did not raise the yield, instead large quantities of 1-
acetoxy-4-chlorobutane34 were formed via reaction of
THF and acetyl chloride. Attempts to acylate 1-(benzyl-
oxy)-5-(tributylstannyl)pyrazole11 under similar condi-
tions as above failed.
iodothiophene, iodopyrazole or bromopyridine provided the corre-
sponding 1-(benzyloxy)-5-heteroarylpyrazoles 6a–c.
Key words: pyrazoles, Negishi cross-coupling, metalation, acyla-
tion/arylation, zinc
Directed ortho-metalation (DoM) followed by reaction
with an electrophile is a powerful synthetic method for the
regiospecific introduction of electrophiles into aromatic
and heteroaromatic compounds. Yields are usually high
and a wide range of electrophiles can be introduced.1 The
scope is greatly extended if DoM can be combined with
transmetalation followed by palladium catalyzed cross-
coupling with aryl or acyl halides providing easy access to
numerous biaryls or aryl ketones.2–10 In contrast, acyla-
tion of organolithium reagents with acyl halides is prob-
lematic due to competitive addition of the organolithium
reagent to the newly formed aryl ketone and/or enoliza-
tion of the aryl ketone. DoM has been used for the intro-
duction of substituents in the ortho position of 1-(benz-
yloxy)pyrazoles11 -imidazoles12 and -1,2,3-triazoles.13
Subsequent debenzylation gave rise to the corresponding
substituted 1-hydroxyazoles which are useful in applica-
tions as catalysts in peptide synthesis.14 Organozinc com-
pounds, formed via transmetalation of the corresponding
organolithium compounds have been used for direct intro-
duction of aryl and acyl groups into aromatic9, 15 and
heteroaromatic3, 5, 16–19 compounds. Organozinc reagents
are particularly useful owing to their weakly basic and nu-
cleophilic character and their inherent tolerance of a broad
range of sensitive functional groups.20
1-(Benzyloxy)pyrazol-5-ylzinc halides 3a,b were aryl-
ated by heating with an aryl iodide in the presence of
2 mol% Pd(PPh3)4 in a 1:2 mixture of THF and DMF at
80°C. A range of ortho-substituted iodobenzenes possess-
ing either electron-releasing groups (amino, methoxy) or
electron-withdrawing groups (nitro, formyl, fluoro), were
employed to give 5-arylpyrazoles 5a–f in good to excel-
lent yields (Scheme). Cross-coupling of 3a with 2-io-
dophenol failed, however 4-iodophenol gave the coupled
product 5e in 66% yield demonstrating the weak basicity
of the pyrazolylzinc halides 3a,b.
The arylation of pyrazol-5-ylzinc halide 3a,b was extend-
ed to heteroaryl halides derived from both π-excessive
and π-deficient heterocycles. Thus, Pd(0) catalyzed cross-
coupling of 3a or 3b with 2-iodothiophene, 1-(benzyl-
oxy)-5-iodopyrazole11 or 2-bromopyridine afforded the 5-
heteroaryl-substituted 1-(benzyloxy)pyrazoles 6a–c in
excellent yields (Scheme). For unknown reasons 2-iodo-
1-methylimidazole35 failed to react under similar condi-
tions.
DoM/transmetalation and Pd(0) catalyzed cross-coupling
with acyl or aryl halides could provide easy access to acyl
and arylpyrazoles, which are usually prepared in multi-
step sequences by introducing the aryl21–23 or acyl24 sub-
stituent prior to cyclization. Only a few reports describe
introduction of acyl and aryl substituents after cyclization.
Thus, 1,4-dilithiopyrazole has been acylated with
aromatic25 and heteroaromatic26 alkyl carboxylates, while
pyrazol-3-yl- and pyrazol-4-ylstannanes have been
acylated27 and arylated27, 28 under Pd(0) catalysis. Recent-
ly 5-pyrazolylzinc halides29 were arylated under Pd(0) ca-
talysis. We now report a novel and general approach to 5-
acyl-, 5-aryl-, and 5-heteroaryl-substituted 1-(benzyl-
In contrast to the acylation of 3a, the arylation/heteroaryl-
ation gave nearly complete conversion using 1.5 equiva-
lents of the zinc halide although heating to 80°C for
2 hours was required in order to obtain nearly complete
conversion (93%) of 3a to 5b.39 Initially zinc iodide was

SYNTHESIS
November 1998
1605
Scheme
unless otherwise stated. THF and Et2O were distilled from Na/ben-
zophenone ketyl under N2. DMF was stored over 3Å molecular sieves.
All acid chlorides were distilled prior to use. 1 M solutions of ZnCl2 and
ZnI2 were prepared by flame-drying the zinc salts in vacuo before dis-
solving them in THF (ZnI2) or Et2O (ZnCl2). BuLi was titrated prior to
use.42 Pd(PPh3)4 was prepared as previously described.32
preferred instead of zinc chloride, since it had given nota-
bly better yields in the Pd(0) catalyzed cross-coupling of
aryl/heteroaryl iodides and 1-(benzyloxy)-1,2,3-triazol-5-
ylzinc iodide.38 However, the halide ion did not seem to
play a vital role in the cross-coupling of 1-(benzyl-
oxy)pyrazol-5-ylzinc halides 3a,b, since the conversion
yield in the cross-coupling of 3b or 3a and 1-fluoro-2-io-
dobenzene or 2-iodothiophene increased from 87% to
90% and from 86% to 94%, respectively.
Palladium Catalyzed Cross-Coupling of 1-(Benzyloxy)pyrazol-5-
ylzinc Chloride (3a) with Acyl Chlorides; General Procedure:
To a stirred solution of 1-(benzyloxy)pyrazole (1) (174 mg, 1 mmol)
in THF (8 mL) was added dropwise 1.6 M BuLi in hexanes (0.75 mL,
1.2 mmol) at –78°C over 2 min. Stirring was continued for 5 min,
whereupon 1 M ZnCl2 in Et2O (3 mL, 3 mmol), was added. The solu-
tion was allowed to warm to r.t., and the acid chloride (1.2 mmol) and
Pd(PPh3)4 (2 mol%) were added. Stirring was continued at r.t. for 2 h
before quenching with sat. aq NH4Cl (10 mL). Water (5 mL) was add-
ed to dissolve the formed precipitate and the mixture was extracted
with CH2Cl2 (3 × 15 mL). Drying of the organic phase (MgSO4), fil-
tration and evaporation in vacuo at max 40°C gave the crude product,
which was purified by flash chromatography (silica gel).
Furthermore it was found that nearly complete conversion
(93%) was obtained when a 1:2 mixture of THF/DMF was
used as solvent for the cross-coupling of 3a and 1-iodo-2-
nitrobenzene.40 Using THF/DMF (2:1) gave 74% conver-
sion whereas neat DMF resulted in 87% conversion.
In conclusion, we have developed a new and general one-
pot synthesis of functionalized 5-acyl-, 5-aryl-, and 5-het-
eroaryl-substituted 1-(benzyloxy)pyrazoles using a com-
bination of directed ortho-lithiation/transmetalation and
Pd(0) catalyzed cross-coupling with acyl chlorides or
aryl/heteroaryl halides.
5-Acetyl-1-(benzyloxy)pyrazole (4a):
FC (heptane/EtOAc 1:0 → 4:1) gave 184 mg (85%) of 4a as a slightly
yellow oil; Rf 0.29 (heptane/EtOAc 4:1).
1H NMR (CDCl3): δ = 2.40 (s, 3H, CH3), 5.35 (s, 2H, OCH2Ph), 6.67
(d, 1H, J = 2.4 Hz, H-4), 7.28 (d, 1H, J = 2.4 Hz, H-3), 7.35–7.40 (m,
3H), 7.43–7.48 (m, 2H).
All reactions involving air-sensitive reagents were performed under
N2 using syringe-septum cap technique. All glassware was flame-
dried prior to use. Flash chromatography (FC) was performed using
silica gel Merck 60 (230–400 mesh). Mps are uncorrected. NMR
spectra were recorded on a 200 MHz Bruker or a 300 MHz Varian
instrument with TMS as internal standard. 13C NMR signals were as-
signed via C–H correlations and/or gated spectra. Aromatic 13C NMR
signals from the benzyloxy group are referred to as C-1', C-2', C-3'
and C-4'. The 1H and 13C NMR signals in the 5-aryl substituents are
referred to as arom H and arom C. Solvents and reagents were ob-
tained from Fluka or Aldrich and used without further purification
13C NMR (CDCl3): δ = 28.4 (q), 81.0 (t), 108.7 (d), 128.5 (d), 129.3
(d), 130.0 (d), 132.1 (d), 132.9 (s), 133.4 (s), 186.6 (s).
Anal. calcd for C12H12N2O2: C, 66.65; H, 5.59; N, 12.95. Found: C,
66.42; H, 5.73; N, 12.73.
1-(Benzyloxy)-5-pivaloylpyrazole (4b):
FC (heptane/EtOAc 1:0 → 4:1) gave 198 mg (77%) of 4b as an oil;
Rf 0.39 (heptane/EtOAc 4:1).

SYNTHESIS
Papers
1606
1H NMR (CDCl3): δ = 1.25 (s, 9H, CH3), 5.39 (s, 2H, OCH2Ph), 6.59
(d, 1H, J = 2.4 Hz, H-4), 7.28 (d, 1H, J = 2.4 Hz, H-3), 7.36–7.40 (m,
3H), 7.49–7.53 (m, 2H).
yellow crystals; mp 101–102°C (heptane/EtOAc); Rf 0.36 (heptane/
EtOAc 7:3).
1H NMR (CDCl3): δ = 5.14 (s, 2H, OCH2Ph), 6.20 (d, 1H, J = 2.4 Hz,
H-4), 6.88 (m, 2H, H-2'), 6.93 (dd, 1H, J = 7.2, 1.8 Hz, arom H-6),
7.07 (t, 2H, J = 7.5 Hz, H-3'), 7.20 (t, 1H, J = 7.5 Hz, arom H-4), 7.39
(d, 1H, J = 2.4 Hz, H-3), 7.42 (td, 1H, J = 7.2, 1.5 Hz, arom H-5), 7.48
(td, 1H, J = 7.2, 1.8 Hz, H-4'), 7.95 (dd, 1H, J = 7.2, 1.5 Hz, arom H-
3).
13C NMR (CDCl3): δ = 26.9 (q), 44.3 (s), 81.1 (t), 106.8 (d), 128.5 (d),
129.1 (d), 130.0 (d), 131.4 (s), 131.6 (d), 133.4 (s), 197.0 (s).
Anal. calcd for C15H18N2O2: C, 69.74; H, 7.02; N, 10.84. Found: C,
69.88; H, 6.97; N, 10.88.
5-Benzoyl-1-(benzyloxy)pyrazole (4c):
13C NMR (CDCl3): δ = 80.0 (t, OCH2Ph), 103.5 (dd, 1J = 190.4, 2JH-3
= 9.4 Hz, C-4), 122.8 (arom C-1), 124.3 (d, arom C-3), 128.2 (d, C-
3'), 129.0 (d, C-4'), 129.3 (d, arom C-4), 129.7 (d, C-2'), 132.1 (d,
arom C-6), 132.2 (s), 132.5 (d, arom C-5), 132.8 (s), 133.2 (dd, 1J =
190.4, 2JH-4 = 4.3 Hz, C-3), 139.7 (s, arom C-2).
FC (heptane/EtOAc 1:0 → 2:1) gave 193 mg (69%) of 4c; mp 59–
60°C (heptane/EtOAc); Rf 0.25 (heptane/EtOAc 4:1).
1H NMR (CDCl3): δ = 5.44 (s, 2H, OCH2Ph), 6.46 (d, 1H, J = 2.4 Hz,
H-4), 7.25–7.32 (m, 3H), 7.34 (d, 1H, J = 2.4 Hz, H-3), 7.39–7.49 (m,
4H), 7.54–7.65 (m, 1H), 7.71–7.77 (m, 2H).
Anal. calcd for C16H13N3O3: C, 65.08; H, 4.44; N, 14.23. Found: C,
65.20; H, 4.50; N, 14.25.
13C NMR (CDCl3): δ = 81.3 (t, OCH2Ph), 109.7 (dd, 1J = 180.4, 2JH-3
= 9.5 Hz, C-4), 128.2 (d), 128.4 (d), 129.1 (d), 129.4 (d), 129.9 (d),
131.9 (d), 132.9 (s), 133.0 (dd, 2JH-4 = 8.7, 3JH-3 = 3.8 Hz, C-5), 133.1
(dd, 1J = 191.6, 2JH-4 = 4.1 Hz, C-3), 137.0 (d), 183.4 (s, C=O).
Anal. calcd for C17H14N2O2: C, 73.37; H, 5.07; N, 10.07. Found: C,
73.08; H, 5.12; N, 10.28.
5-(2-Aminophenyl)-1-(benzyloxy)pyrazole (5c):
Following the general procedure using ZnI2 and 2-iodoaniline,
quenching with aq 5% NaHCO3 (15 mL), extraction with CH2Cl2 (5
× 30 mL), drying of the organic phase (MgSO4), filtration, evapora-
tion and FC (heptane/EtOAc 2:1 → 1:2) gave 233 mg (88%) of 5c;
mp 70–71°C (EtOAc/heptane); Rf 0.36 (heptane/EtOAc 2:1).
1H NMR (CDCl3): δ = 3.6 (br s, 2H, NH2), 5.14 (s, 2H, OCH2Ph),
6.23 (d, 1H, J = 2.4 Hz, H-4), 6.70 (dd, 1H, J = 8.4, 1.2 Hz, arom H-
3), 6.75 (td, 1H, J = 7.5, 1.2 Hz, arom H-5), 7.02–7.08 (m, 3H, H-2' +
arom H-6), 7.15–7.22 (m, 3H, H-3' and arom H-4), 7.28 (t, 1H, J =
7.2 Hz, H-4'), 7.38 (d, 1H, J = 2.4 Hz, H-3).
5-Acryloyl-1-(benzyloxy)pyrazole (4d):
FC (heptane/EtOAc 1:0 → 4:1) gave 193 mg (90%) of 4d as a white
foam. The compound is unstable and therefore a correct microanaly-
sis could not be obtained; Rf 0.31 (heptane/EtOAc 4:1).
1H NMR (CDCl3): δ = 5.38 (s, 2H, OCH2Ph), 5.88 (dd, 1H, J = 10.4,
1.5 Hz, H-3'cis), 6.41 (dd, 1H, J = 17.1, 1.5 Hz, H-3'trans), 6.69 (d, 1H,
J = 2.4 Hz, H-4), 6.88 (dd, 1H, J = 17.1, 10.4 Hz, H-2'), 7.33 (d, 1H,
J = 2.4 Hz, H-3), 7.34–7.50 (m, 5H, Ph).
13C NMR (CDCl3): δ = 80.4 (t, OCH2Ph), 103.9 (d, C-4), 113.5 (s,
arom C-2), 115.6 (d, arom C-6), 118.0 (d, C-4'), 128.3 (d, C-3'), 128.9
(d, C-4'), 129.7 (d, C-2'), 129.9 (d, arom C-5), 131.0 (d, arom C-3),
133.1 (d, C-3), 133.2 (s), 133.5 (s), 144.6 (s, arom C-1).
13C NMR (CDCl3): δ = 81.3, 108.7, 128.5, 129.3, 130.0, 130.4, 132.3,
132.9, 133.2, 133.3, 179.1.
Anal. calcd for C16H15N3O: C, 72.43; H, 5.70; N, 15.84. Found: C,
72.39; H, 5.82; N, 15.73.
Palladium Catalyzed Cross-Coupling of 1-(Benzyloxy)pyrazol-5-
ylzinc Halide 3a,b with Aryl Halides; General Procedure:
To a stirred solution of 1-(benzyloxy)pyrazole (1) (174 mg, 1 mmol)
in THF (8 mL) was added dropwise 1.6 M BuLi in hexanes (0.75 mL,
1.2 mmol) at –78°C over 2 min. Stirring was continued for 5 min,
whereupon 1 M ZnI2 in THF (1.5 mL, 1.5 mmol) or 1 M ZnCl2 in
Et2O (1.5 mL, 1.5 mmol), was added. The solution was allowed to
warm to r.t., and the aryl halide (1.50 mmol) and Pd(PPh3)4 (2 mol%)
in DMF (16 mL) were added. The mixture was heated to 80°C for 2 h
before quenching with sat. aq NH4Cl (10 mL). Water (5 mL) was add-
ed and the mixture was extracted with CH2Cl2 (3 × 15 mL).43 Drying
of the organic phase (MgSO4), filtration and evaporation in vacuo at
max 40°C gave the crude product, which was purified by flash chro-
matography (silica gel).
1-(Benzyloxy)-5-(2-methoxyphenyl)pyrazole (5d):
Following the general procedure using ZnCl2 and 2-iodoanisole, FC
(heptane/EtOAc 1:0 → 4:1) gave 255 mg (91%) of 5d; mp 54°C; Rf
0.35 (heptane/EtOAc 4:1).
1H NMR (CDCl3): δ = 3.75 (s, 3H, CH3), 5.14 (s, 2H, OCH2Ph), 6.32
(d, 1H, J = 2.4 Hz, H-4), 6.91 (d, 1H, J = 8.7 Hz, H-6'), 6.95 (t, 1H, J
= 7.5, H-4'), 7.08 (m, 2H, H-2'), 7.16–7.27 (m, 3H), 7.30–7.37 (m,
3H).
13C NMR (CDCl3): δ = 55.2 (q, CH3), 80.0 (t), 105.0 (d), 110.8 (d),
117.3 (s), 120.1 (d), 128.2 (d), 128.7 (d), 129.5 (d), 129.9 (d), 131.0
(d), 132.2 (s), 132.5 (d), 133.4 (s), 156.7 (s).
Anal. calcd for C17H16N2O2: C, 72.84; H, 5.75; N, 9.99. Found: C,
72.60; H, 5.80; N, 9.97.
1-(Benzyloxy)-5-(2-fluorophenyl)pyrazole (5a):
Following the general procedure using ZnCl2 and 2-iodofluoroben-
zene, FC (heptane/EtOAc 1:0 → 4:1) gave 228 mg (85%) of 5a as an
oil; Rf 0.42 (heptane/EtOAc 4:1).
1-(Benzyloxy)-5-(4-hydroxyphenyl)pyrazole (5e):
Following the general procedure using ZnI2 and 4-iodophenol, FC
(heptane/EtOAc 4:1 → 1:1) gave 176 mg (66%) of 5e; mp 127–
129°C (heptane/EtOAc); Rf 0.31 (heptane/EtOAc 7:3).
1H NMR (CDCl3): δ = 5.14 (s, 2H, OCH2Ph), 6.24 (d, 1H, J = 2.4 Hz,
H-4), 6.94 (d, 2H, J = 9.0 Hz, H-2'), 7.14–7.28 (m, 5H), 7.36 (d, 1H,
J = 2.4 Hz, H-3), 7.47 (d, 2H, J = 9.0 Hz, H-3')
1H NMR (CDCl3): δ = 5.16 (s, 2H, OCH2Ph), 6.14 (t, 1H, J = 2.4 Hz,
H-4), 7.00–7.30 (m, 8H), 7.36 (d, 1H, J = 2.4 Hz, H-3), 7.44 (td, 1H,
J = 7.8, 1.8 Hz, arom H-4).
1
13C NMR (CDCl3): δ = 80.1 (t, OCH2Ph), 104.8 (dd(d), J = 179.7,
2JH-3 = 9.5, 4JC–F = 5.1 Hz, C-4), 115.5 (d(d),2JC–F = 22.1 Hz, arom C-
3), 116.2 (s(d), 2JC–F = 13.4 Hz, arom C-1), 123.6 (d(d),4JC–F = 3.5 Hz,
arom C-5), 128.1 (d, C-3'), 128.8 (d, C-4'), 129.5 (d, C-2'), 129.8
(s(d),3JC–F = 0.5 Hz, C-5), 129.9 (d(d),3JC–F = 8.3 Hz, arom C-4 or
arom C-6), 130.4 (d(d),3JC–F = 2.3 Hz, arom C-6 or arom C-4), 132.7
(dd, 1J = 189.2, 2JH-4 = 4.3 Hz, C-3), 132.8 (s, C-1'), 159.0 (s(d), 1JC–
F = 251.3 Hz, arom C-2).
13C NMR (CDCl3): δ = 80.6 (t), 102.1 (d), 115.6 (d), 120.0 (s), 128.4
(d), 129.2 (d), 129.3 (d), 130.0 (d), 132.80 (d), 132.83 (s), 136.4 (s),
156.9 (s).
Anal. calcd for C16H14N2O2: C, 72.17; H, 5.30; N, 10.52. Found: C,
72.22; H, 5.37; N, 10.46.
Anal. calcd for C16H13FN2O: C, 71.63; H, 4.88; N, 10.44. Found: C,
71.86; H, 5.02; N, 10.43.
1-(Benzyloxy)-5-(2-formylphenyl)pyrazole (5f):
Following the general procedure using ZnCl2 and 2-bromobenzalde-
hyde, FC (heptane/EtOAc 1:0 → 4:1) gave 231 mg (83%) of 5f as an
oil. The compound is slightly unstable and a correct microanalysis
could not be obtained; Rf 0.30 (heptane/EtOAc 4:1).
1-(Benzyloxy)-5-(2-nitrophenyl)pyrazole (5b):
Following the general procedure using ZnI2 and 1-iodo-2-nitroben-
zene, FC (heptane/EtOAc 1:0 → 4:1) gave 236 mg (80%) of 5b as

SYNTHESIS
November 1998
1607
1H NMR (CDCl3): δ = 5.14 (s, 2H, OCH2Ph), 6.15 (d, 1H, J = 2.4 Hz,
H-4), 6.81 (d, 2H, J = 7.5 Hz, H-2'), 7.03 (t, 2H, J = 7.5 Hz, H-3'),
7.14–7.20 (m, 2H, arom H-6 and H-4'), 7.41 (d, 1H, J = 2.4 Hz, H-3),
7.46 (t, 1H, J = 7.5, 1.8 Hz, arom H-5), 7.51 (td, 1H, J = 7.5, 1.8 Hz,
arom H-4), 7.89 (dd, 1H, J = 7.5, 1.8 Hz, arom H-3), 9.57 (s, 1H,
CHO).
(4) Gray, G. W.; Hird, M.; Lacey, D.; Toyne, K. J. J. Chem. Soc.,
Perkin Trans. 2 1989, 2041.
(5) Ennis, D. S.; Gilchrist, T. L. Tetrahedron 1990, 46, 2623.
(6) Alo, B. I.; Patil, P. A.; Sharp, M. J.; Siddiqui, M. A.; Snieckus,
V. J. Org. Chem. 1991, 56, 3763.
(7) Brandão, M. A. F.; de Oliveira, A. B.; Snieckus, V. Tetrahedron
Lett. 1993, 34, 2437.
13C NMR (CDCl3): δ = 80.0 (t, OCH2Ph), 106.0 (dd, 1J = 178.6, 2JH-3
= 9.6 Hz, C-4), 127.1 (d), 128.1 (d), 128.8 (d), 129.1 (d), 129.7 (d),
(8) Larsen, R. D.; King, A. O.; Chen, C. Y.; Corley, E. G.; Foster,
B. S.; Roberts, F. E.; Yang, C.; Lieberman, D. R.; Reamer, R.
A.; Tschaen, D. M.; Verhoeven, T. R.; Reider, P. J.; Lo, Y. S.;
Rossano, L. T.; Brookes, A. S.; Meloni, D.; Moore, J. R.; Ar-
nett, J. F. J. Org. Chem. 1994, 59, 6391.
1
130.9 (s), 131.0 (d), 132.5 (s), 132.7 (s), 133.0 (d), 133.1 (dd, J =
190.1, 2JH-4 = 4.3 Hz, C-3), 133.6 (s), 191.0 (d, CHO).
1-(Benzyloxy)-5-(2-thienyl)pyrazole (6a):
Following the general procedure using ZnCl2 and 2-iodothiophene,
FC (heptane/EtOAc 1:0 → 4:1) gave 223 mg of a 18:1 mixture of 6a
and starting material corresponding to an isolated yield of 6a of
215 mg (84%). Recrystallisation from heptane/EtOAc gave pure 6a;
mp 73–74°C; Rf 0.54 (heptane/EtOAc 7:3).
(9) Evans, P. A.; Nelson, J. D.; Stanley, A. L. J. Org. Chem. 1995,
60, 2298.
(10) Mohri, S.; Stefinovic, M.; Snieckus, V. J. Org. Chem. 1997, 62,
7072.
(11) Vedsø, P.; Begtrup, M. J. Org. Chem. 1995, 60, 4995.
(12) Eriksen, B. L.; Vedsø, P.; Morel, S.; Begtrup, M. J. Org. Chem.
1998, 63, 12.
(13) Uhlmann, P.; Felding, J.; Vedsø, P.; Begtrup, M. J. Org. Chem.
1997, 62, 9177.
(14) Spetzler, J. C.; Meldal, M.; Felding, J.; Vedsø, P.; Begtrup, M.
J. Chem. Soc., Perkin Trans. 1 1998, 1727.
(15) Negishi, E.; King, A. O.; Okukado, N. J. Org. Chem. 1977, 42,
1821.
(16) Sakamoto, T.; Kondo, Y.; Takazawa, N.; Yamanaka, H.
J. Chem. Soc., Perkin Trans. 1 1996, 1927.
1H NMR (CDCl3): δ = 5.30 (s, 2H, OCH2Ph), 6.34 (d, 1H, J = 2.4 Hz,
H-4), 7.05 (dd, 1H, J = 5.1, 3.6 Hz, thiophene H-4), 7.30 (d, 1H, J =
2.4 Hz, H-3), 7.31–7.40 (m, 7H).
13C NMR (CDCl3): δ = 80.3 (t, OCH2Ph), 101.9 (dd, 1J = 178.4, 2JH-3
= 9.4 Hz, C-4), 126.10 (d), 126.13 (d), 127.3 (d), 128.5 (d), 129.1 (s),
129.2 (d), 129.9 (d), 130.3 (s), 133.07 (s), 133.1 (dd, 1J = 189.5, 2JH-
4 = 4.3 Hz, C-3).
Anal. calcd for C14H12N2OS: C, 65.60; H, 4.72; N, 10.93. Found: C,
65.78; H, 4.82; N, 10.99.
1,1'-Bis(benzyloxy)-5,5'-bipyrazole (6b):
(17) Trécourt, F.; Gervais, B.; Mallet, M.; Quéguiner, G. J. Org.
Chem. 1996, 61, 1673.
(18) Anderson, B. A.; Harn, N. K. Synthesis 1996, 583.
(19) Amat, M.; Hadida, S.; Pshenichnyi, G.; Bosch, J. J. Org. Chem.
1997, 62, 3158.
(20) For a review on transition-metal-catalyzed reactions of organo-
zinc reagents, see: Erdik, E. In Organozinc Reagents in Organic
Synthesis; CRC: Boca Raton, FL, 1996; pp 271–343.
(21) Takano, S.; Imamura, Y.; Ogasawara, K. Heterocycles 1982, 7,
1223.
Following the general procedure using ZnI2 and 1-(benzyloxy)-5-
iodopyrazole11 (1.0 mmol), FC (heptane/EtOAc 1:0 → 2:1) gave 298
mg (86%) of 6b; mp 117°C; Rf 0.50 (heptane/EtOAc 7:3).
1H NMR (CDCl3): δ = 5.09 (s, 4H, OCH2Ph), 6.49 (d, 2H, J = 2.4 Hz,
H-4), 7.25–7.34 (m, 12H).
13C NMR (CDCl3): δ = 80.3 (t, OCH2Ph), 103.9 (dd, 1J = 181.2, 2JH-3
= 9.7 Hz, C-4), 124.0 (ddd, 2JH-4 = 8.0, 3JH-3 = 4.3, 3JH-4' = 0.8 Hz, C-
5), 128.5 (d), 129.3 (d), 129.9 (d), 132.9 (s), 133.0 (dd, 1J = 190.4, 2JH-
4 = 4.6 Hz, C-3).
Anal. calcd for C20H18N4O2: C, 69.35; H, 5.24; N, 16.17. Found: C,
69.26; H, 4.99; N, 16.15.
(22) Cativiela, C.; de Villegas, M. D. D.; Gainza, M. P. Synth. Com-
mun. 1987, 17, 165.
(23) Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.;
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.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.;
Zhang, Y. Y.; Isakson, P. C. J. Med. Chem. 1997, 40, 1347.
(24) Gelin, S.; Gelin, R.; Hartmann, D. J. Org. Chem. 1978, 43, 2665.
(25) Heinisch, G.; Holzer, W.; Huber, T. Arch. Pharm. 1987, 320,
1267.
(26) Hahn, M.; Heinisch, G.; Holzer, W.; Schwarz, H. J. Heterocycl.
Chem. 1991, 28, 1189.
(27) Sakamoto, T.; Shiga, F.; Uchiyama, D.; Kondo, Y.; Yamanaka,
H. Heterocycles 1992, 33, 813.
1-(Benzyloxy)-5-(2-pyridyl)pyrazole (6c):
Following the general procedure using ZnI2 and 2-bromopyridine, FC
(heptane/EtOAc 2:1 → 1:1) gave 216 mg (86%) of 6c; mp 55–57°C
(EtOAc/heptane); Rf 0.14 (heptane/EtOAc 4:1).
1H NMR (CDCl3): δ = 5.32 (s, 2H, OCH2Ph), 6.66 (d, 1H, J = 2.4 Hz,
H-4), 7.19–7.30 (m, 6H), 7.37 (d, 1H, J = 2.4 Hz, H-3), 7.69 (td, 1H,
J = 8.1, 1.8 Hz, pyridine H-4), 7.74 (dt, 1H, J = 8.1, 1.8 Hz, pyridine
H-3), 8.62 (dd, 1H, J = 4.8, 1.8 Hz, pyridine H-6).
13C NMR (CDCl3): δ = 80.8 (t, OCH2Ph), 104.4 (d, C-4), 122.3 (d,
pyridine C-3), 122.6 (d, pyridine C-5), 128.4 (d), 129.2 (d), 129.9 (d),
133.1 (d, C-3), 135.4 (s), 136.5 (pyridine C-4), 139.5 (s), 147.5 (s,
pyridine C-2), 149.5 (d, pyridine C-6).
Anal. calcd for C15H13N3O: C, 71.70; H, 5.21; N, 16.72. Found: C,
71.49; H, 5.25; N, 16.63.
(28) Elguero, J.; Jaramillo, C.; Pardo, C. Synthesis 1997, 563.
(29) Almost simultaneously with our preliminary communication30 a
palladium-catalyzed arylation of pyrazol-5-ylzinc halides and
pyrazol-5-ylstannanes was reported.31
This work was supported by The Danish Technical Research Council
and The Lundbeck Foundation. J. K. thanks The Novo Nordisk
Research Board for a grant. The NMR spectrometer is a gift from the
Velux Foundation of 1981, The Danish Technical Research Council,
The Ib Henriksen Foundation and the Torkil Steenbeck Foundation.
(30) Kristensen, J.; Begtrup, M.; Vedsø, P. Abstract of the Sixteenth
International Congress of Heterocyclic Chemistry, 1997; Mon-
tana State University: Abstract No. POI-134.
(31) Yagi, K.; Ogura, T.; Numata, A.; Ishii, S.; Arai, K. Heterocycles
1997, 45, 1463.
(32) Coulson, D. R. Inorg. Synth. 1972, 13, 121.
(33) Product 4a relative to starting material 1 according to 1H NMR.
(34) Negishi, E.; Begheri, V.; Chatterjee, S.; Luo, F.; Miller, J. A.;
Stoll, A. T. Tetrahedron Lett. 1983, 24, 5181.
(1) Snieckus, V. Chem. Rev. 1990, 90, 879.
(2) Sharp, M. P.; Snieckus, V. Tetrahedron Lett. 1985, 26, 5997.
(3) Bell, A. S.; Roberts, D. A.; Ruddock, K. S. Tetrahedron Lett.
1988, 29, 5013.
(35) In the cross-coupling of 1-alkyl-2-haloimidazoles the Suzuki
type seems to be favorable.36–38

SYNTHESIS
Papers
1608
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(37) Kaswasaki, I.; Yamashita, M.; Ohta, S. J. Chem. Soc., Chem.
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(38) Felding, J.; Uhlmann, P.; Kristensen, J.; Vedsø, P.; Begtrup, M.
Synthesis 1998, 1181.
(40) Okamoto et al.41 have reported that the cross-coupling of 4-bro-
mobenzaldehyde and butylzinc halide gives maximum yield
using a 1:2 mixture of THF and HMPA as solvent.
(41) Okamoto, Y.; Yoshioka, K.; Yamana, T.; Mori, H. J. Organo-
met. Chem. 1989, 369, 285.
(42) Suffert, J. J. Org. Chem. 1989, 54, 509.
(39) Performing the reaction at 20°C using 1-iodo-2-nitrobenzene as
the aryl iodide gave only 8% conversion to 5b.
(43) When performing the synthesis on a 2–4 mmol scale, extraction
with Et2O is preferred since alternative extraction with CH2Cl2
requires subsequent evaporation of substantial amounts of
DMF.