Halogen dance in pyrazole 1-oxides: Synthesis of pyrazolo[3,4-c]quinoline 1-oxides

Article abstract of DOI:10.1016/S0040-4020(02)00858-X

The synthesis of a new series of 3-substituted pyrazolo[3,4-c]quinoline 1-oxides is presented. Regioselective bromine-magnesium exchange of 2-benzylated 3,4,5-tribromopyrazole 1-oxides and subsequent halogen dance of the resulting monometalated intermediates was used to synthesize fused pyrazoloquinoline 1-oxides.

Full text of DOI:10.1016/S0040-4020(02)00858-X

Tetrahedron 58 (2002) 7635–7644
Halogen dance in pyrazole 1-oxides: synthesis
of pyrazolo[3,4-c]quinoline 1-oxides
†
Jørgen Eskildsen,a Niels Østergaard,a,b Per Vedsøa and Mikael Begtrupa
,
,
*
aDepartment of Medicinal Chemistry, The Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100 Copenhagen, Denmark
bACADIA Pharmaceuticals A/S, Fabriksparken 58, DK-2600 Glostrup, Denmark
Received 2 June 2002; revised 16 July 2002; accepted 17 July 2002
Abstract—The synthesis of a new series of 3-substituted pyrazolo[3,4-c ]quinoline 1-oxides is presented. Regioselective bromine–
magnesium exchange of 2-benzylated 3,4,5-tribromopyrazole 1-oxides and subsequent halogen dance of the resulting monometalated
intermediates was used to synthesize fused pyrazoloquinoline 1-oxides. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Recently, we reported the access to the 3-position in N-1
oxidized pyrazoles via regioselective mono bromination of
2-alkylpyrazole 1-oxides.9 Subsequent bromine–mag-
nesium exchange with i-PrMgCl at 2788C afforded C-3
magnesiated pyrazole 1-oxides which could be either
acylated upon addition of an acid chloride10 or arylated11
via transmetalation with ZnCl2 and Pd(0) catalyzed cross-
coupling to afford C-3 functionalized pyrazole 1-oxides.
N-debenzylation gave access to C-3 functionalized
1-hydroxypyrazoles.
Recent reports have shown that pyrazolo[3,4-c ]quinoline
ring systems display significant biological activities, such as
good affinity and selectivity for adenosine A3 receptors,1a,b
benzodiazepine receptor activity,1c,d and NMDA receptor
inhibition.1e
In these ring systems, the pyrazole moiety is typically
constructed at a late stage in the sequence making the
synthetic route lengthy and non-flexible. For example
rearrangement of phenylhydrazones of 3-acylindoles,1f
thermal cyclization of 4-diazomethylquinolinones,1h
addition of diazomethane to cinnamates followed by
reduction and condensation,1g and especially hydrazine
condensations1b,d,e have afforded pyrazolo[3,4-c ]quinoline
ring systems. In order to make the synthesis more flexible,
a methodology based on diversification at a late stage of the
pyrazoloquinoline ring system synthesis would be desirable.
This prompted us to develop a synthetic methodology for
the synthesis of pyrazolo[3,4-c ]quinoline 1-oxides (1,
Scheme 1).
The introduction of substituents at the 4-position of
1-benzyloxypyrazole via iodination followed by mag-
nesium iodine exchange2 and at C-5 via directed ortho
metalation has previously been reported.3,4 These methods
were extended to furnish quinoline- and iso-quinoline-1-
alkoxypyrazoles fused across the C-4–C-5 bond of the
1-benzyloxypyrazole moiety.5,6 These methodologies,
however, failed to provide access to pyrazoloquinolines or
isoquinolines fused across the C-3–C-4 bond, since direct
metalation at the 3-position of 1-alkylpyrazoles is hampered
by the adjacent lone pair effect.7,8
Scheme 1.
2. Results and discussion
Herein, we wish to report the extension of C-3 functiona-
lization of 2-alkylpyrazole 1-oxides to the facile synthesis of
3-substituted 2-benzylpyrazolo[3,4-c ]quinoline 1-oxides.
2.1. Functionalization of pyrazole 1-oxide
Keywords: pyrazole 1-oxides; metalation; halogen dance; pyrazolo[3,4-
c]quinolines.
We speculated that the access to the 3-position in pyrazole
1-oxides could be utilized to prepare pyrazoloquinoline 1-
oxides fused across the C-3–C-4 bond (1) of the starting
pyrazole 1-oxide as outlined in Scheme 2.
*
Corresponding author. Tel.: þ45-35-30-60-00; fax: þ45-35-30-60-40;
e-mail: mb@dfh.dk
Present address: Novo Nordisk A/S, Medicinal Chemistry Research,
˚
DK-2760 Maløv, Denmark.
†
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00858-X

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J. Eskildsen et al. / Tetrahedron 58 (2002) 7635–7644
Scheme 2. Retrosynthetical analysis.
Scheme 4. Synthesis of 3-formyl-2-PMB-pyrazole 1-oxide 11.
This strategy would require a 3-formyl- or acyl 4-halo-
pyrazole 1-oxide of type 2 and a suitably protected ortho
amino phenylboronic acid building block 3.12 Thus two
issues had to be addressed with respect to 2 and later
combined: (1) introduction of aryl groups at C-4 and (2)
introduction of formyl- and acyl-groups at C-3.
2.1.2. Synthesis of 3-formyl-2-(4-methoxybenzyl)pyra-
zole 1-oxide. The 3-magnesiated intermediate formed by
bromine–magnesium exchange in 3-bromo-2-PMB-pyra-
zole 1-oxide (10)11 reacted sluggishly with DMF giving
complex mixtures. However, N-methyl-N-(2-pyridyl)form-
amide (Meyers formylating agent)18 smoothly produced
the formylated 1-oxide 11 (Scheme 4) which was slightly
unstable on silica thus reducing the isolated yield of
analytically pure material to 74%.
2.1.1. Synthesis of 4-arylated 2-(4-methoxybenzyl)pyra-
zole 1-oxides. 2-PMB‡-pyrazole 1-oxide11 (4) was readily
tribrominated using NBS in acetonitrile13 affording the
tribrominated pyrazole 1-oxide 5a in 87% yield. Subsequent
treatment with aqueous Na2SO314 caused ready debromina-
tion at C-3 and C-5 whereas the C-4 bromine was totally
inert towards reduction during these conditions.
In general, the 3-acylated pyrazole 1-oxides were easily
de-para-methoxybenzylated upon treatment with acids at
rt.10
A combination of the two basic protocols thus established
was anticipated to provide access to building blocks of type
2. However, attempts to brominate 11 with NBS in CH3CN
or with bromine in CHCl3 failed. Therefore, an alternative
approach to 2 using 5a as precursor was investigated.
While iodine magnesium exchange provided a route for
C–C bond formation at C-4 in 4-iodo-1-benzyloxypyra-
zoles2 attempted bromine–magnesium exchange in com-
pound 6 was unsuccessful, since treatment of 6 with
1.2 equiv. i-PrMgCl in THF at 08C for 1 h resulted in C-5
deprotonation. Subsequent quenching with MeOD produced
4-bromo-5-deutero-2-PMB-pyrazole 1-oxide in quantitative
yield. Instead, C-4 arylation16 was accomplished by
treatment of 6 with aryl boronic acids under classical
Suzuki–Miyaura17 conditions (Scheme 3).
2.2. Halogen dance in pyrazole 1-oxides
An intriguing selectivity was observed when the bromine–
magnesium exchange reactions were performed with the
tribrominated pyrazole 5a at different temperatures (Table 1).
Compound 5a first underwent bromine–magnesium
exchange at C-3 (Table 1, entry 1) to give 12 despite that
exchange at C-5 would give a less basic, thermodynamically
favored 1319 and despite that C-3 is more congested than
C-5. This regioselectivity may be due to the low solubility
of 12 which precipitated at 2788C. By heating to rt,
compound 12 was converted to 13, stable at rt and readily
soluble in THF even at 2788C. The halogen dance21,22
12!13 may involve remaining tribromo compound 5a. It
entails halogen–metal exchange and is thus distinct from
most reported halogen dance reactions which involve
proton–metal exchange.23a–c
Treatment of 5a with 2.1 equiv. i-PrMgCl afforded the
3,5-dimagnesio pyrazole dianion intermediate 14, a white
solid stable in THF at rt.24 The 3-position of this dimagnesio
complex reacted more rapidly with electrophiles like Me2S2
to give 15 in 60% isolated yield25 along with 16 and 6.
The formation of 16 is probably the result of higher
solubility of the 3-methylsulfanyl 5-magnesio intermediate.
This approach provides a route for 3,5-disubstituted
Scheme 3. Synthesis of 4-aryl-2-PMB-pyrazole 1-oxides via 4-bromo-2-
PMB-pyrazole 1-oxide (6). (a) The neopentylglycol ester of 2-fluoro
benzeneboronic acid15 was used.
‡
4-Methoxybenzyl.

J. Eskildsen et al. / Tetrahedron 58 (2002) 7635–7644
7637
1
Table 1. Halogen dance in pyrazole 1-oxides. The distribution of 5a, 12–14 was determined by H NMR of aliquots quenched with HCl in diethyl ether
Entry
T (8C)
i-PrMgCl (equiv.)
T (min)
5a
12a
13
14
1
2
3
4
5
278
278–rt
Rt
Rt
Rt
1.1
1.2
1.0
1.0
2.1
10
At rtb
10
–
–
3
–
–
71
–
2
–
–
21
88
89
100
–
8
12
6
–
100
5c
10
a
A 2% NOE was observed between the CH2 on PMB and H-3 on pyrazole after quenching.
Quenched with MeOH.
Quenched with excess TMS-Cl.20
b
c
pyrazole 1-oxides exemplified by the syntheses of 16 and 17
(Scheme 5).
2.3.1. 3-Acylated 4-bromopyrazole 1-oxides. Direct
addition of acid chlorides at 2788C to 3-magnesio pyrazole
1-oxide successfully gave rise to 3-acylated pyrazole
1-oxides.10 Therefore, the same sequence as for the
synthesis of 3-formylated pyrazole 1-oxides of type 2 was
adopted to access 3-acylated derivatives. However, initial
tests following the sequence outlined in Scheme 6 replacing
Meyers reagent with an acid chloride gave low yields, when
tribromide 5a was used. This may be due to readily de-para-
methoxybenzylation of 3-acylated 4-bromo-2-PMB-pyra-
zole 1-oxide, as substantial amounts of p-anisaldehyde were
formed. The 3-acylated 2-benzylpyrazole 1-oxides, synthe-
sized from 5b, were less sensitive than the corresponding
2-PMB compounds. The NMR yield was at least 70%
depending on which acid chloride was used. Unfortunately,
these compounds were unstable on silica gel, as was the
case for the formylated compounds 19a,b. Therefore, the
crude 3-acylated 2-benzyl-4-bromopyrazole 1-oxides were
used directly in the synthesis of pyrazolo[3,4,-c ]quinoline
1-oxides.
2.3. 4-Bromo-3-formylpyrazole 1-oxides
In order to access the desired pyrazole 1-oxides such as 2,
the halogen dance sequence observed when reacting 5a with
1 equiv. of i-PrMgCl in THF (Table 1, entry 4) was
exploited to in situ protect the 5-position with a trimethyl-
silyl group. A subsequent bromine–magnesium exchange at
C-3 followed by reaction with Meyers formylating reagent
gave 4-bromo-3-formyl-2-PMB-pyrazole 1-oxide (19a) in
one pot from 5a (Scheme 6).
The 5-TMS protected intermediates were not purified, as
the only byproduct was MgCl2(2THF).20 Aqueous work-up
followed by treatment with K2CO3 in MeOH–water
smoothly removed the TMS group. In contrast, the use of
TBAF resulted in lower isolated yields.
Unfortunately, the 3-formylated pyrazole 1-oxide 19a was
unstable during the work-up conditions, especially towards
silica, hence the lower isolated yield. Performing the
halogen dance sequence using 3,4,5-tribromo-2-benzyl-
pyrazole 1-oxide (5b)14 instead did not improve the
stability.
2.4. ortho-Aminophenylboronic acid building block 3
N-Boc-2-aminophenylboronic acids have previously been
prepared in moderate yields as pinacol boronates by Pd
catalyzed borylation of 2-halo N-Boc-aniline26 or by
Scheme 6. Synthesis of 4-bromo-3-formylpyrazole 1-oxides via halogen
dance in tribrominated pyrazole 1-oxides 5a or 5b. (a) Isolated yield based
starting tribromides 5a or 5b.
Scheme 5. Reaction of intermediate 14 with electrophiles.

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J. Eskildsen et al. / Tetrahedron 58 (2002) 7635–7644
developed a facile synthetic route to multigram quantities
of the N-Boc-2-aminophenylboronic acid ester 22 (Scheme 7).
Since t-BuLi is significantly more stable in diethyl ether
than in THF29 it was essential to carry out dilithiation of 20
to 21 and the subsequent reaction with B(O-i-Pr)3 in diethyl
ether. The isolation as the neopentylglycol ester 22 was
crucial as well to achieve a close to quantitative yield.
Previous procedures by other groups to isolate the free ortho
boronic acids of the related N-pivaloyl-aniline failed to give
yields higher than about 60%. This was probably due to
inevitable proto-deboronation occurring during the acidic
conditions required for boronic ester hydrolysis.30 The
crude boronic acids are likely to form boroxines upon
drying and to be contaminated with boronic salts.27
However, cyclic boronic esters like 22 are stable white
solids that are easily recrystallized from heptane. They do
not form boroxines and they react readily in ordinary
Suzuki–Miyaura cross-coupling reactions.15
Scheme 7. Synthesis of [2-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-
phenyl]carbamic acid tert-butyl ester (22).
stepwise double lithiation/bromine–lithium exchange of 2-
bromo-N-Boc-aniline.27 In a different study, Stanetty et al.
studied directed ortho lithiation of N-Boc-aniline (20) to
dilithio intermediates.28 Using this methodology, we
2.5. Synthesis of pyrazolo[3,4-c]quinoline 1-oxides
The C–C bond formation to C-4 combined with the
introduction of formyl- and acyl groups in pyrazole 1-oxides
via the observed halogen dance presented the desired
components for the synthesis of pyrazolo[3,4-c ]quinoline
1-oxides.
2.5.1. Condensation into pyrazolo[3,4-c]quinoline
1-oxides. When the crude reaction mixture from the cross-
coupling between 19a and the boronic acid ester 22 was
quenched with aqueous HCl condensation into the desired
pyrazolo[3,4-c ]quinoline systems took place (Scheme 8) to
give 23a in 78% isolated yield.
Because of the sensitivity of 3-formyl- and 3-acyl
4-bromopyrazole 1-oxides, the construction of the
fused ring systems was conveniently carried out using
the crude reaction mixtures from the acylation reactions
(Table 2).
Thus the pyrazolo[3,4-c ]quinoline 1-oxides 23a and 23b
were obtained in 38 and 40% isolated yield, respectively,
Scheme 8. Synthesis of 2-PMB-pyrazolo[3,4-c ]quinoline 1-oxide (23a).
Table 2. Synthesis of pyrazolo[3,4-c ]quinoline 1-oxides
Entry
R1
R2
Conditions
Product
Yield (%)c
1
2
3
4
5
6
PMB
Bn
Bn
Bn
Bn
H
H
Me
A
A
A
B
B
B
23a
23b
24
25
26
38
40
48
52
43
26
Et
Cyclopropyl
Ph
Bn
27
(a) (i) 1.05 equiv. i-PrMgCl, THF, 08C, 20 min, then 2.0 equiv. TMS-Cl, 08C to rt, 1.5 h; (ii) 1.2 equiv. i-PrMgCl, THF, 08C, 15 min, then Meyers reagent or an
acid chloride, 2788C to rt; (iii) 2.0 equiv. 2 M K2CO3(aq.), MeOH, rt, 10 min. (b) (i) 1.5 equiv. 22, 0.06 equiv. Pd(PPh3)4, 3 equiv. 2 M K2CO3(aq.), EtOH,
toluene, 908C, 4 h; (ii) Method A: aq. HCl, rt, 50 min, Method B: TFA, DCM, 30 min. (c) Isolated yields over 5 steps based on starting tribromides 5a or 5b.

J. Eskildsen et al. / Tetrahedron 58 (2002) 7635–7644
7639
been prepared under mild conditions from tribrominated
2-alkylpyrazole 1-oxide via a controlled halogen dance
sequence. The approach is flexible and gives access to an
array substituted derivatives.
4. Experimental
4.1. General
All reactions involving air- or moisture-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). Melting points are uncorrected.
NMR spectra were recorded on a 300 MHz Varian
instrument with TMS as internal standard and were run at
208C in CDCl3 unless otherwise stated. For clarity, the
coupling patterns are reported as they appear (Japp). Thus
the AA0XX0 coupling pattern observed in e.g. 4-methoxy-
Figure 1. X-Ray structure of 25.31
and the 3-substituted pyrazolo[3,4-c ]quinoline 1-oxides
24–27 were obtained in 26–52% isolated yield over 5 steps
(76–88% average). In case of derivative 26, 4-chlorobutyryl
chloride was used in the acylation step.
The entire five-step sequence could be carried out within
one working day, providing access to the pyrazolo[3,4-c ]-
quinoline 1-oxide ring systems in a time efficient and
flexible approach, in which further ring-functionalizations
can be envisaged.
0
benzyl groups are reported as Japp¼JAXþJAX . Solvents and
reagents were obtained from Fluka or Aldrich and used
without further purification. THF was distilled from
Na/benzophenone ketyl under N2. i-PrMgCl was titrated
prior to use.33 Pd(PPh3)4 was prepared as previously
described.34
After obtaining suitable crystals of the 3-ethyl derivative 25,
an X-ray structure unambiguously confirmed the structural
assignment. In the crystal structure the two ethyl carbons
and the benzylic carbon are all in the plane of the planar
tricyclic system within the accuracy of the experiment
(Fig. 1).
4.1.1. 3,4,5-Tribromo-2-(4-methoxybenzyl)pyrazole
1-oxide (5a). 2-(4-Methoxybenzyl)pyrazole 1-oxide (4)11
(2.11 g, 10.4 mmol) was dissolved in CH3CN (25 mL). NBS
(5.72 g, 31.1 mmol) was added in small portions over 5 min
keeping the internal temperature below 408C. After stirring
at rt for 1.5 h, the light orange suspension was poured into
water (150 mL), stirred vigorously for 10 min and then
filtered. The crystals were washed with cold diethyl ether to
obtain white crystals. After drying in a dessicator over P2O5
at 1 mbar overnight the title compound was obtained as
colorless crystals (3.96 g, 87%): mp 125–1268C; Rf¼0.53
(heptane/EtOAc 1:1); 1H NMR d 3.78 (s, 3H), 5.42 (s, 2H),
6.84 (d, Japp¼8.4 Hz, 2H), 7.40 (d, Japp¼8.4 Hz, 2H); 13C
NMR d 49.3, 55.2, 95.9, 101.6, 108.4, 114.3, 125.7, 130.3,
160.0. Anal. calcd for C11H9Br3N2O2: C, 29.96; H, 2.06; N,
6.35. Found C, 30.21; H, 2.20; N, 6.32.
2.6. Derivatization of 23a
The pyrazolo[3,4-c ]quinoline 1-oxides described above
could be further functionalized to produce free C- and
N-hydroxy compounds (Scheme 9). By way of example,
exposure of 23a to light caused rearrangement to the
9-hydroxycompound 28 in 44% isolated yield.32 Acidic
cleavage of the PMB group quantitatively afforded the free
N-hydroxy compound 29.
3. Conclusion
4.1.2. 4-Bromo-2-(4-methoxybenzyl)pyrazole 1-oxide (6).
Compound 5a (6.58 g, 14.9 mmol) was refluxed for 5 h in a
suspension of Na2SO3·7H2O (25.2 g, 99.9 mmol) in water/
methanol (300 mLþ300 mL). After cooling to rt the MeOH
was removed by rotary evaporation and the aqueous layer
was extracted with CH2Cl2 (100þ3£50 mL). The combined
organic layers were dried over MgSO4. Evaporation to
dryness gave the title compound as colorless crystals
(3.62 g, 86%). This crude product was .95% pure
according to 1H NMR and used without further purification.
An analytical sample was obtained by recrystallization from
toluene: mp 98–98.58C; Rf¼0.37 (EtOAc); 1H NMR d
3.82 (s, 3H), 5.21 (s, 2H), 6.76 (d, J¼1.4 Hz, 1H), 6.92 (d,
Japp¼8.8 Hz, 2H), 7.21 (d, J¼1.4 Hz, 1H), 7.27 (d, Japp¼8.8
Hz, 2H); 13C NMR d 48.6, 55.3, 88.6, 114.6, 118.3, 120.0,
125.2, 130.4, 160.1; Anal. calcd for C11H11BrN2O2: C,
46.67; H, 3.92; N, 9.89. Found: C, 46.70; H, 3.84; N,
9.58.
A new series of pyrazolo[3,4-c ]quinoline 1-oxides have
Scheme 9. Further functionalization of 23a.

7640
J. Eskildsen et al. / Tetrahedron 58 (2002) 7635–7644
4.2. 4-Arylation of 4-bromo-2-(4-methoxybenzyl)-
pyrazole 1-oxide (6)
cooling bath was removed. After stirring for an additional
1.5 h the reaction mixture was quenched by addition of
4 M aqueous HCl (25 mL) and extracted with EtOAc
(6£50 mL). The combined organic layers were washed with
2 M aqueous HCl (30 mL), brine and dried over Na2SO4
before evaporation to dryness. This gave almost pure title
compound (757 mg, 90%) as judged by 1H NMR, however
the compound slowly decomposed on silica requiring fast
purification. After purification by FC (heptane/EtOAc
1:1!EtOAc) the title compound was obtained as colorless
crystals (629 mg, 74%): mp 116–1188C; Rf¼0.37 (EtOAc);
1H NMR d 3.76 (s, 3H), 5.70 (s, 2H), 6.81 (d, Japp¼8.6 Hz,
2H), 6.87 (d, J¼2.7 Hz, 1H), 7.25 (d, J¼2.7 Hz, 1H), 7.45
(d, Japp¼8.6 Hz, 2H), 9.44 (s, 1H); 13C NMR d 47.1, 55.1,
113.8, 114.0, 120.3, 126.7, 127.1, 130.4, 159.7, 176.4. Anal.
calcd for C12H12N2O3: C, 62.06; H, 5.21; N, 12.06. Found:
C, 61.52; H, 5.03; N, 11.91.
4.2.1. 4-(2-Formylphenyl)-2-(4-methoxybenzyl)pyrazole
1-oxide (7). Compound 6 (229 mg, 0.809 mmol) and
2-formylbenzeneboronic acid (209 mg, 1.39 mmol) were
dissolved in toluene (10 mL) and EtOH (1.0 mL) and to this
mixture was added 2.0 M aqueous K2CO3 (1.0 mL,
2.0 mmol). The mixture was degassed with N2 for 10 min
prior to addition of Pd(PPh3)4 (25 mg, 0.046 mmol) and
stirred under N2 at 908C for 8 h. The mixture was poured
into CH2Cl2 (80 mL) and washed with saturated aqueous
NaHCO3 solution (10 mL) and brine (20 mL). Drying over
Na2SO4 and evaporation yielded 305 mg of an orange wax.
This was purified by FC (EtOAc) to give the title compound
(216 mg, 87%) as yellow crystals: mp 105–1088C; Rf¼0.19
(EtOAc); 1H NMR (200 MHz) d 3.85 (s, 3H), 5.35 (s, 2H),
6.85 (d, J¼1.5 Hz, 1H), 6.93 (d, Japp¼9.4 Hz, 2H), 7.31–
7.38 (m, 3H), 7.43 (d, J¼1.5 Hz, 1H), 7.46–7.52 (m, 1H),
7.57–7.66 (m, 1H), 7.94–7.98 (m, 1H), 10.15 (d, J¼0.8 Hz,
1H); 13C NMR (75 MHz) d 48.6, 55.2, 113.3, 114.4, 117.7,
119.0, 125.2, 128.0, 128.4, 130.1, 130.3, 133.3, 133.8,
133.9, 159.6, 191.0. Anal. calcd for C18H16N2O3: C, 70.11;
H, 5.23; N, 9.09. Found: C, 70.00; H, 5.32; N, 8.94.
4.2.5. 4-Bromo-3-methylsulfanyl-(4-methoxybenzyl)-
pyrazole 1-oxide (15). To a solution of compound 5a
(385 mg, 0.87 mmol) in THF (10 mL) at rt was added
dropwise i-PrMgCl (1.89 M in THF, 0.97 mL, 1.83 mmol).
The resulting suspension was stirred for further 10 min at rt
and then cooled to 2788C. Me2S2 (90 mg, 0.96 mmol in
1 mL THF) was added dropwise and the mixture was stirred
for 10 min before removal of the cooling bath. After stirring
for an additional hour without cooling the mixture was
quenched by addition of a saturated aqueous solution of
NH4Cl (10 mL). The aqueous layer was extracted with
CH2Cl2 (5£10 mL) and the combined organic layers were
washed with H2O (10 mL), dried over MgSO4 and
evaporated to dryness. Purification by FC (heptane/EtOAc
1:1!1:2) gave the title compound as a hygroscopic
4.2.2. 4-(2-Fluorophenyl)-2-(4-methoxybenzyl)pyrazole
1-oxide (8). Compound 8 was prepared from 6 and
2-(2-fluorophenyl)-5,5-dimethyl-[1,3,2]dioxaborinane15 in
a manner similar to that described for the preparation of 7.
Compound 8 was obtained as colorless crystals (80%): mp
104–1068C; Rf¼0.27 (EtOAc); 1H NMR (200 MHz) d 3.81
(s, 3H), 5.31 (s, 2H), 6.93 (d, Japp¼9.4 Hz, 2H), 7.05–7.19
(m, 3H), 7.22 (dd, J¼1.5, 1.6 Hz, 1H), 7.32–7.43 (m, 3H),
7.64 (dd, J¼1.5, 1.6 Hz, 1H); 13C NMR (50 MHz) d 48.1,
55.0, 111.5, 114.5, 116.4, 116.0 (d, J¼24 Hz), 116.6, 116.8
(d, J¼10 Hz), 117.7, 117.8 (d, J¼10 Hz), 118.3, 118.5
(d, J¼14 Hz), 124.6, 124.5 (d, J¼3 Hz), 125.9, 127.0, 127.1
(d, J¼4 Hz), 128.5, 128.6 (d, J¼9 Hz), 130.2, 157.1, 162.1
(d, J¼268 Hz), 160.0. Anal. calcd for C17H15FN2O2: C,
68.45; H, 5.07; N, 9.39. Found: C, 68.52; H, 5.05; N, 9.22.
1
colorless oil (173 mg, 60%): H NMR d 2.11 (s, 3H), 3.77
(s, 3H), 5.48 (s, 2H), 6.85 (d, Japp¼8.8 Hz, 2H), 7.26 (s, 1H),
7.36 (d, Japp¼8.8 Hz, 2H); 13C NMR d 19.1, 46.6, 55.2,
98.7, 114.2, 120.5, 122.9, 127.2, 129.8, 159.6. Anal. calcd
for C12H13BrN2O2S·1.5H2O: C, 42.24; H, 4.23; N, 8.21.
Found: C, 42.04; H, 3.91; N, 8.00.
4.2.6. 4-Bromo-3,5-dimethylsulfanyl-2-(4-methoxy-
benzyl)pyrazole 1-oxide (16). To a solution of compound
5a (310 mg, 0.70 mmol) in THF (10 mL) at rt was added
dropwise i-PrMgCl (1.89 M in THF, 0.78 mL, 1.47 mmol).
The resulting suspension was stirred for further 10 min at rt
and then cooled to 2788C. Me2S2 (0.20 mL, 2.25 mmol)
was added dropwise and the mixture was stirred for 70 min
and then allowed to reach rt overnight. The solution was
finally heated to 508C for 4 h before quenched by addition of
a saturated aqueous solution of NH4Cl (10 mL). The
aqueous layer was extracted with CH2Cl2 (4£10 mL). The
combined organic layers were washed with H2O (10 mL),
dried over MgSO4 and evaporated to dryness. Purification
by FC (heptane!heptane/EtOAc 1:1) gave the title
compound as a colorless oil that very slowly solidified
(177 mg, 67%): mp 64.5–658C; Rf¼0.31 (heptane/EtOAc
1:1); 1H NMR d 2.15 (s, 3H), 2.48 (s, 3H), 3.79 (s, 3H), 5.51
(s, 2H), 6.89 (d, Japp¼8.8 Hz, 2H), 7.41 (d, Japp¼8.8 Hz,
2H); 13C NMR d 15.3, 19.0, 47.3, 55.2, 104.7, 114.1, 121.9,
125.5, 127.1, 130.0, 159.6. Anal. calcd for C13H15N2BrO2-
S2: C, 41.60; H, 4.03; N, 7.46. Found: C, 41.71; H, 3.99; N,
7.47.
4.2.3. 4-(4-Tolyl)-2-(4-methoxybenzyl)pyrazole 1-oxide
(9). Compound 9 was prepared from 6 and in a manner
similar to that described for the preparation of 7. Compound
9 was obtained as colorless crystals (65%): mp 150–
1
150.58C; Rf¼0.21 (EtOAc); H NMR (200 MHz) d 2.34
(s, 3H), 3.81 (s, 3H), 5.28 (s, 2H), 6.93 (d, Japp¼9.4 Hz, 2H),
6.97 (d, J¼1.5 Hz, 1H), 7.16 (d, Japp¼8.7 Hz, 2H), 7.25
(d, Japp¼8.7 Hz, 2H), 7.32 (d, Japp¼9.4 Hz, 2H), 7.50
(d, J¼1.5 Hz, 1H); 13C NMR (50 MHz) d 20.7, 48.2, 55.1,
114.0, 114.5, 117.0, 118.0, 125.1, 126.0, 127.7, 129.7,
130.3, 137.3, 160.1. Anal. calcd for C18H18N2O2: C, 73.45;
H, 6.16; N, 9.52. Found: C, 73.42; H, 6.00; N, 9.47.
4.2.4. 3-Formyl-2-(4-methoxybenzyl)pyrazole 1-oxide
(11). A solution of 3-bromo-2-PMB-pyrazole 1-oxide
(10)11 (1.03 g, 3.64 mmol) in THF (40 mL) was cooled to
2788C. (If left for more than 10 min crystals may form.) A
solution of i-PrMgCl in THF (2.1 M, 2.0 mL, 4.2 mmol)
was added dropwise and the solution containing a white
precipitate was stirred for 15 min. Meyers reagent
(N-methyl-N-(2-pyridyl)-formamide, 647 mg, 4.75 mmol
in 10 mL THF) was added dropwise and after 20 min the

J. Eskildsen et al. / Tetrahedron 58 (2002) 7635–7644
7641
4.2.7. 4-Bromo-3,5-dichloro-2-(4-methoxybenzyl)pyra-
zole 1-oxide (17). Prepared as described for compound
16, except adding C2Cl6 (931 mg, 3.93 mmol) at rt to the
dimagnesio intermediate (14) derived from 5a (493 mg,
1.12 mmol) in 16 mL THF. After FC (heptane/EtOAc
4:1!2:1) the title compound was obtained as colorless
crystals (247 mg, 63%); mp 113.5–1148C; Rf¼0.58 (heptane/
EtOAc 1:1); 1H NMR d 3.79 (s, 3H), 5.39 (s, 2H), 6.87 (d,
Japp¼8.8 Hz, 2H), 7.41 (d, Japp¼8.8 Hz, 2H); 13C NMR d
47.9, 55.3, 89.3, 114.2, 115.1, 120.1, 125.4, 130.2, 159.9.
Anal. calcd for C11H9N2O4BrCl2: C, 37.53; H, 2.58; N,
7.96. Found: C, 37.80; H, 2.59; N, 7.68.
lithium (57 mL, 96.3 mmol) was added dropwise keeping
the temperature between 220 and 2108C. The mixture was
stirred at an internal temperature between 215 and 2108C
for 3 h and was then cooled to 2788C. Tri-i-propylborate
(25 mL, 108 mmol) was added slowly and the mixture was
left overnight. Saturated aqueous NH4Cl solution (85 mL)
was added and the mixture stirred vigorously for 20 min
before extraction of the aqueous layer with EtOAc
(2£400 mL). The combined organic layers were washed
with water and evaporated to almost dryness. Toluene
(500 mL) was added and the mixture was stirred with
neopentylglycol (11.3 g, 0.109 mol) at rt overnight to give a
two phase mixture. Dilution with diethyl ether (500 mL),
washing with water (4£100 mL) and evaporation to dryness
yielded the title compound quantitatively as colorless
crystals: mp 85–888C. This compound was used as well
as a recrystallized sample without any difference in the
reaction outcome. Recrystallization from heptane gave the
title compound as colorless crystals (11.6 g, 86%): mp
90–918C; Rf¼0.36 (heptane/EtOAc, 10:3, with substantial
tailing); 1H NMR d 1.04 (s, 6H), 1.52 (s, 9H), 3.82 (s, 4H),
6.97 (ddd, J¼7.4, 7.3, 1.1 Hz, 1H), 7.39 (ddd, J¼8.4, 7.3,
1.7 Hz, 1H), 7.77 (dd, J¼7.4, 1.7 Hz, 1H), 8.20 (br d,
J¼8.4 Hz, 1H), 8.92 (br s, 1H); 13C NMR (the B ipso carbon
was not observed) d 21.7, 28.3, 31.7, 72.4, 79.7, 117.6,
121.4, 132.1, 135.6, 145.2, 153.3. Anal. calcd for
C16H24BNO4: C, 62.97; H, 7.93; N, 4.59. Found: C,
62.95; H, 7.99; N, 4.86.
4.2.8. 4-Bromo-3-formyl-2-benzylpyrazole 1-oxide (19b).
A solution of 5b14 (410 mg, 1.00 mmol) in THF (10 mL)
was cooled to 08C. A 1.90 M i-PrMgCl solution in THF
(0.55 mL, 1.05 mmol) was added dropwise and the initially
formed white suspension was left with stirring for 20 min
at 08C to give a clear, yellow solution. After addition of
TMS-Cl (0.25 mL, 1.98 mmol) the cooling bath was
removed and the mixture was left at rt for 1.5 h and then
evaporated to dryness. The resulting orange foam of 3,4-di-
bromo-5-TMS-2-benzylpyrazole 1-oxide was redissolved in
THF (10 mL), cooled to 08C and slowly added i-PrMgCl
solution in THF (0.63 mL, 1.20 mmol). After stirring for
15 min the solution was cooled to 2788C and Meyers
reagent (0.16 mL, 1.34 mmol) was added dropwise. After
stirring at 2788C for 20 min the cooling bath was removed
and the mixture left for 2.5 h before addition of 2 M aqueous
HCl (10 mL). The mixture was extracted with CH2Cl2
(4£25 mL) and after washing of the combined organic
layers with brine the organic layer was evaporated to
dryness. The semicrystalline mass was dissolved in MeOH
(30 mL), 2.0 M aqueous K2CO3 (2.00 mL, 4.0 mmol) was
added and after stirring for 1.5 h at rt brine (30 mL) was
added. The MeOH was removed by rotary evaporation and
the aqueous layer was extracted with CH2Cl2 (4£25 mL).
The combined organic layers were washed with brine
(10 mL), dried over MgSO4 and evaporated to dryness.
After purification by FC (heptane/EtOAc 1:1) the title
compound was obtained as colorless crystals (123 mg,
4.3. Synthesis of pyrazolo[3,4-c]quinoline 1-oxides
4.3.1. 2-(4-Methoxybenzyl)pyrazolo[3,4-c]quinoline
1-oxide (23a). Compound 22 (1.37 g, 4.50 mmol) and
compound 19a (940 mg, 3.02 mmol) were dissolved in a
mixture of toluene (40 mL), EtOH (4 mL) and 2.0 M K2CO3
(4.5 mL, 9.0 mmol). After passing N2 through the solution
for 15 min Pd(PPh3)4 (212 mg, 0.18 mmol, 6 mol%) was
added and the mixture was refluxed under N2 for 4 h.
Aqueous 4 M HCl (30 mL) was added with vigorous stirring
and after 50 min the mixture was neutralized by addition of
a saturated aqueous solution of NaHCO3 (approx. 70 mL).
The aqueous layer was extracted with CH2Cl2 (150þ
2£50 mL). The combined organic layers were washed with
NaHCO3 (sat. aq, 50 mL), H2O (3£50 mL) and then dried
over MgSO4. The crude product was adsorbed onto silica
gel (about 2 g) and purified by FC (heptane/EtOAc
1:1!1:3) to yield the title compound as light yellow
crystals (717 mg, 78%): mp 196–1988C; Rf¼0.48 (EtOAc);
1H NMR d 3.76 (s, 3H), 5.67 (s, 2H), 6.86 (d, Japp¼8.8 Hz,
2H), 7.34 (d, Japp¼8.8 Hz, 2H), 7.61–7.74 (m, 2H), 7.97–
8.00 (m, 1H), 8.06 (s, 1H), 8.12–8.15 (m, 1H), 8.77 (s, 1H);
13C NMR d 46.2 (t), 55.2 (q), 111.8 (d), 114.6 (d), 119.5 (s),
119.7 (s), 123.0 (d), 124.6 (s), 126.1 (s), 127.81 (d), 127.83
(d), 129.6 (d), 130.2 (d), 133.2 (d), 143.3 (s), 159.9 (s). Anal.
calcd for C18H15N3O2: C, 70.51; H, 4.95; N, 13.76. Found:
C, 70.54; H, 4.97; N, 13.34.
1
44%): mp 99.5–1008C; Rf¼0.35 (heptane/EtOAc 1:1); H
NMR d 5.67 (s, 2H), 7.20–7.25 (m, 4H), 7.33–7.37 (m,
2H), 9.47 (s, 1H); 13C NMR d 47.3, 103.2, 121.1, 123.5,
128.5, 128.71, 128.73, 134.4, 175.6. Anal. calcd for
C11H9N2O2Br: C, 47.00; H, 3.23; N, 9.97; Found: C,
47.25; H, 3.35; N, 9.85.
4.2.9. 4-Bromo-3-formyl-2-(4-methoxybenzyl)pyrazole
1-oxide (19a). In a procedure similar to the preparation of
19b, compound 19a was obtained as colorless crystals
1
(51%): mp 118–1198C; Rf¼0.4 (heptane/EtOAc 1:1); H
NMR d 3.77 (s, 3H), 5.70 (s, 2H), 6.83 (d, Japp¼8.8 Hz, 2H),
7.25 (s, 1H), 7.43 (d, Japp¼8.8 Hz, 2H), 9.56 (s, 1H); 13C
NMR d 47.12, 55.17, 103.27, 114.03, 121.25, 123.48,
126.68, 130.62, 159.85, 175.75. Anal. calcd for
C12H11N2O3Br: C, 46.32; H, 3.56; N, 9.00. Found: C,
46.45; H, 3.41; N, 8.78.
When the same procedure was carried out using crude 19a
(worked up but not chromatographed), compound 23a was
obtained in 38% overall yield based on the tribromide 5a.
4.2.10. [2-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)phenyl]-
carbamic acid tert-butyl ester (22). A solution of phenyl-
carbamic acid tert-butyl ester 2035 (8.52 g, 44.1 mmol) in
diethyl ether (90 mL) was cooled to 2208C. tert-Butyl-
4.3.2. 2-Benzylpyrazolo[3,4-c]quinoline 1-oxide (23b).
Compound 23b was obtained as described for 23a using

7642
J. Eskildsen et al. / Tetrahedron 58 (2002) 7635–7644
the crude 19b (worked up but not chromatographed) in 40%
overall yield based on 5b: mp 206–2098C (decomp.); Rf¼
0.49 (EtOAc); 1H NMR d 5.73 (s, 2H), 7.31–7.36 (m, 5H),
7.62–7.67 (m, 2H), 7.96–7.99 (m, 1H), 8.01 (s, 1H), 8.08–
8.14 (m, 1H), 8.76 (s, 1H); 13C NMR d 46.4, 111.9, 119.5,
119.6, 123.0, 124.7, 127.84, 127.85, 127.9, 128.7, 129.3,
130.3, 133.2, 134.2, 143.4; Anal. calcd for C17H13N3O: C,
74.17; H, 4.76; N, 15.26. HRMS (EI): calcd for C17H13N3O:
275.1059. Found: 275.1053
4.3.4. 2-Benzyl-3-ethylpyrazolo[3,4-c]quinoline 1-oxide
(25). Compound 25 was obtained as described for 24 in
1 mmol scale using propionyl chloride (111 mg, 1.2 mmol)
as acid chloride. After the Suzuki cross-coupling step the
following procedure was used for ring closure.
The reaction mixture was poured into CH2Cl2 (50 mL) and
washed with saturated aqueous NaHCO3 solution (10 mL)
and brine (20 mL). The aqueous phase was extracted
CH2Cl2 (2£50 mL) and the combined organic layers were
then dried over Na2SO4 and evaporated to dryness. The
crude intermediate was dissolved in CH2Cl2 (5 mL) and
TFA (5 mL) was added. After stirring for 1 h at rt, the
reaction mixture was evaporated to dryness. The crude
mixture was redissolved in CH2Cl2, adsorbed onto silica gel
and purified by FC (heptane/EtOAc 3:1!1:2) to yield the
title compound as colorless crystals (157 mg, 52%, 5 steps
from 5b): mp 160–1618C (EtOAc/heptane); Rf¼0.36
4.3.3. 2-Benzyl-3-methylpyrazolo[3,4-c]quinoline
1-oxide (24). Preparation of building block 2. A solution
of tribromide 5b14 (511 mg, 1.24 mmol) in THF (13 mL)
was cooled to 08C. A solution of i-PrMgCl in THF (1.91 M,
0.68 mL, 1.30 mmol) was added dropwise and the mixture
was stirred at 08C for 20 min to produce a light orange
solution. TMS-Cl (0.31 mL, 2.45 mmol) was added, cooling
was removed and the mixture was stirred at rt for 1 h before
evaporation to dryness to remove excess TMS-Cl. The
mixture was redissolved in THF (13 mL) and cooled to
08C. A solution of i-PrMgCl in THF (1.91 M, 0.72 mL,
1.38 mmol) was added dropwise and after stirring the
solution for 15 min at 08C it was cooled to 2788C. Acetyl
chloride (0.11 mL, 1.52 mmol) was added dropwise and the
mixture was stirred for 1 h and then allowed to slowly reach
rt. After 30 min, a solution of saturated aqueous NH4Cl
(10 mL) was added and the mixture extracted with CH2Cl2
(4£25 mL). The combined organic layers were evaporated
to almost dryness and the semicrystalline residue was
dissolved in MeOH (30 mL). A solution of 2.0 M
aqueous K2CO3 (0.62 mL, 1.24 mmol) was added and
after stirring for 30 min at rt brine (30 mL) was added. The
MeOH was removed by rotary evaporation and the
aqueous layer was extracted with CH2Cl2 (5£25 mL). The
combined organic layers were washed with brine (20 mL),
dried over MgSO4 and evaporated to dryness to give the
crude 2.
1
(heptane/EtOAc 1:1); H NMR d 1.34 (t, J¼ 7.5 Hz, 3H),
3.11 (q, J¼7.5 Hz, 2H), 5.94 (s, 2H), 7.02–7.07 (m, 2H),
7.24–7.33 (m, 3H), 7.55–7.68 (m, 2H), 7.97 (br d,
J¼7.8 Hz, 1H), 8.07 (br d, J¼7.8 Hz, 1H), 8.16 (s, 1H);
13C NMR d 12.9, 28.6, 47.4, 112.3, 118.9, 120.4, 122.8,
124.5, 126.1, 127.1, 128.0, 128.4, 129.3, 129.7, 135.9,
143.0, 147.2. HRMS (ESI): calcd for C19H18N3O (MþH)þ:
304.1450. Found: 304.1449.
4.3.5. 2-Benzyl-3-cyclopropylpyrazolo[3,4-c]quinoline
1-oxide (26). Compound 26 was obtained as described for
25 in 1 mmol scale using 4-chlorobutyryl chloride (169 mg,
1.2 mmol) as acid chloride. Purification by FC (heptane/E-
tOAc 3:1!1:2) gave the title compound as colorless
crystals (135 mg, 43%, 5 steps from 5b): mp 158–1598C
(EtOAc/ heptane); Rf¼0.48 (heptane/EtOAc 1:1); 1H NMR
d 0.97–0.99 (m, 2H), 1.31–1.37 (m, 2H), 2.26–2.36 (m,
1H), 6.10 (s, 2H), 7.10–7.14 (m, 2H), 7.26–7.33 (m, 5H),
7.53–7.65 (m, 2H), 7.94–8.02 (m, 2H), 8.14 (s, 1H); 13C
NMR d 8.7, 14.8, 47.7, 112.2, 119.9, 122.7, 125.6, 126.2,
126.9, 127.9, 128.2, 129.3, 129.7, 136.0, 143.0, 146.2.
HRMS (ESI): calcd for C20H18N3O (MþH)þ: 316.1450.
Found: 316.1443.
Suzuki cross-coupling with building block 22. The crude
intermediate 2 and 22 (502 mg, 1.64 mmol) were dissolved
in a mixture of toluene (40 mL), EtOH (4 mL) and 2.0 M
K2CO3 (4.5 mL, 9.0 mmol). After passing N2 through the
solution for 15 min Pd(PPh3)4 (80 mg, 0.069 mmol,
6 mol%) was added and the mixture was heated to 908C
under N2 for 3 h.
4.3.6. 2-Benzyl-3-phenylpyrazolo[3,4-c]quinoline
1-oxide (27). Compound 27 was obtained as described for
25 in 1 mmol scale using benzoyl chloride (169 mg,
1.2 mmol) as acid chloride. Purification by FC (heptane/
EtOAc 3:1!1:2) gave the title compound as colorless
crystals (91 mg, 26%, 5 steps from 5b): mp 194–1958C
(EtOAc/ heptane); Rf¼0.36 (heptane/EtOAc 1:1); 1H NMR
d 5.94 (s, 2H), 6.51–6.54 (m, 2H), 7.03–7.15 (m, 3H),
7.44–7.56 (m, 5H), 7.61–7.72 (m, 2H), 8.04 (br d,
J¼7.6 Hz, 1H), 8.07 (br d, J¼7.6 Hz, 1H), 8.23 (s, 1H);
13C NMR d 47.5, 112.8, 119.1, 121.8, 122.9, 124.2, 126.8,
127.7, 127.9, 128.4, 128.7, 128.9, 129.3, 129.8, 130.4,
135.2, 137.9, 143.1, 145.0. HRMS (ESI): calcd for
C23H18N3O (MþH)þ: 352.1450. Found: 352.1434.
Ring closure. Aqueous 4 M HCl (30 mL) was added with
vigorous stirring and after 50 min the mixture was
neutralized by addition of a saturated aqueous solution of
NaHCO3 (approx. 70 mL). The aqueous layer was extracted
with CH2Cl2 (150þ2£50 mL). The combined organic
layers were washed with NaHCO3 (sat. aq., 50 mL), H2O
(3£50 mL) and then dried over MgSO4. The crude product
was adsorbed onto silica gel (about 2 g) and purified by FC
(heptane/EtOAc 3:2!2:3) to yield the title compound as
colorless crystals (174 mg, 48%, 5 steps from 5b): mp 167–
1
1688C; Rf¼0.23 (heptane/EtOAc 1:1); H NMR d 2.84 (s,
4.3.7. 9-Hydroxypyrazolo[3,4-c]quinoline (28). Com-
pound 23a (62 mg, 0.203 mmol) was dissolved in CH2Cl2
(15 mL) and the solution was degassed with N2 for 10 min.
The solution was irradiated at 254 nm for 40 h with an UV
lamp (Vilber Lourmat VL-4LC 4 W) used for TLC plate
visualization. After purification by FC (CH2Cl2!CH2Cl2/
3H), 5.95 (s, 2H), 7.06–7.08 (m, 2H), 7.26–7.33 (m, 3H),
7.57–7.68 (m, 2H), 7.96–7.99 (m, 1H), 8.03–8.06 (m, 1H),
8.14 (s, 1H); 13C NMR d 23.1, 47.1, 112.0, 118.8, 120.0,
122.6, 124.9, 126.0, 127.1, 127.9, 128.1, 129.2, 129.3,
135.8, 142.3, 142.8. HRMS (ESI): calcd for C18H16N3O
(MþH)þ: 290.1293. Found: 290.1297.

J. Eskildsen et al. / Tetrahedron 58 (2002) 7635–7644
7643
316–321. (h) Ito, K.; Maruyama, J. J. Heterocycl. Chem.
1988, 1681–1687.
EtOAc 6:4) the title compound was obtained as light yellow
crystals (27 mg, 44%): mp 219–2208C; Rf¼0.69 (EtOAc);
1H NMR (dmso-d6) d 3.70 (s, 3H), 5.57 (s, 2H), 6.87 (d,
Japp¼8.3 Hz, 2H), 7.26 (d, Japp¼8.3 Hz, 2H), 7.56–7.69 (m,
2H), 8.07–8.09 (m, 1H), 8.31–8.34 (m, 1H), 9.38 (s, 1H),
11.40 (br s, the signal only integrates to approx. 0.5H).
Carrying out a NOE difference experiment with irradiation
of the benzylic protons at d 5.57 ppm, a 20% NOE was
observed on the d 9.38 ppm singlet along with a 8% NOE on
the d 7.26 doublet. 13C NMR (dmso-d6) d 51.4, 55.0, 107.9,
114.0, 122.2, 122.6, 125.7, 127.8, 129.1, 129.3, 129.4,
134.8, 137.8, 141.4, 155.7, 158.9. Anal. calcd for
C18H15N3O2: C, 70.81; H, 4.95; N, 13.76. Found: C,
70.60; H, 5.02; N, 13.52.
2. Felding, J.; Kristensen, J.; Bjerregaard, T.; Sander, L.; Vedsø,
P.; Begtrup, M. J. Org. Chem. 1999, 64, 4196–4198.
3. Vedsø, P.; Begtrup, M. J. Org. Chem. 1995, 60, 4995–4998.
4. Kristensen, J.; Begtrup, M.; Vedsø, P. Synthesis 1998,
1604–1608.
5. Pawlas, J.; Vedsø, P.; Jakobsen, P.; Huusfeldt, P.-O.; Begtrup,
M. J. Org. Chem. 2000, 65, 9001–9006.
6. Pawlas, J.; Vedsø, P.; Jakobsen, P.; Huusfeldt, P.-O.; Begtrup,
M. J. Org. Chem. 2001, 66, 4214–4219.
7. Takeuchi, Y.; Yeh, H. J. C.; Kirk, K. L.; Cohen, L. A. J. Org.
Chem. 1978, 43, 3565–3569.
8. Takeuchi, Y.; Yeh, H. J. C.; Kirk, K. L.; Cohen, L. A. J. Org.
Chem. 1978, 43, 3570–3578.
9. For the synthesis of 2-alkylpyrazole 1-oxides from 1-hydroxy-
pyrazole see: Eskildsen, J.; Vedsø, P.; Begtrup, M. Synthesis
2001, 1053–1056, or Ref. 11.
4.3.8. 1-Hydroxypyrazolo[3,4-c]quinoline (29). Com-
pound 23a (23 mg, 0.075 mmol) was stirred at rt in conc.
aqueous HCl (10 mL) overnight. The solution was diluted
with conc. aqueous HCl (10 mL) and washed with toluene
(2 mL) before evaporation to dryness. Addition of toluene
(30 mL) and evaporation was subsequently carried out twice
and the mixture was dried at rt at 1 mbar overnight to give
the HCl salt of the title compound as white crystals (17 mg,
10. Østergaard, N.; Skjærbæk, N.; Begtrup, M.; Vedsø, P. J. Chem.
Soc., Perkin Trans. 1 2002, 428–433.
11. Eskildsen, J.; Kristensen, J.; Vedsø, P.; Begtrup, M. J. Org.
Chem. 2001, 66, 8654–8656.
12. Condensation of 2-acylated 20-N-Boc substituted biphenyls
prepared using Suzuki–Miyaura cross coupling conditions has
been successfully utilized in the synthesis of alkylated
phenanthridines, see: Lamba, J. J. S.; Tour, J. M. J. Am.
Chem. Soc. 1994, 116, 11723–11736.
1
100%): mp 235–2378C; H NMR (dmso-d6) d 7.84–7.92
(m, 2H), 8.30–8.36 (m, 1H), 8.48–8.53 (m, 1H), 9.11 (s,
1H), 9.84 (s, 1H); 13C NMR (dmso-d6) 117.9, 121.0, 121.8,
123.3, 124.9, 129.27, 129.34, 132.1, 133.6, 139.8. HRMS
(EI): calcd for C10H7N3O: 185.0589. Found: 185.0589.
13. N-Bromosuccinimide in CH3CN has been used as a mild and
regiospecific nuclear brominating reagent for methoxy-
benzenes and naphthalenes, see: Carreno, M. C.; Ruano, J. L.
G.; Sanz, G. S.; Toledo, M. A.; Urbano, A. J. Org. Chem.
1995, 60, 5328–5331.
Acknowledgments
14. Begtrup, M.; Larsen, P.; Vedsø, P. Acta Chem. Scand. 1992,
46, 972–980.
This work was supported by the Corporate Research Affairs
at Novo Nordisk A/S and The Graduate School of Drug
Research at The Royal Danish School of Pharmacy by a
graduate fellowship to J. E. The work was also supported by
ACADIA Pharmaceuticals A/S and The Danish Academy of
Technical Sciences by a graduate fellowship to N. Ø. We
wish to thank Dr John E. Davies (Cambridge University,
UK) for determining the crystal structure of compound 25.
The 300 MHz NMR instrument was provided by The
Danish National Science Research Council.
´
15. Kristensen, J.; Lysen, M.; Vedsø, P.; Begtrup, M. Org. Lett.
2001, 3, 1435–1437.
16. Aryl substituents can be introduced at C-4 in sterically
congested 3,5-diaryl-4-bromopyrazole 1-oxides, see: Paulson,
A. S.; Eskildsen, J.; Vedsø, P.; Begtrup, M. J. Org. Chem.
2002, 67, 3904–3907.
17. For a recent review see: Suzuki, A. J. Organomet. Chem. 1999,
576, 147–168, and references cited herein.
18. Comins, D.; Meyers, A. I. Synthesis 1978, 403–404.
19. We anticipate that the order of basicity in 5a follows the same
order observed in 2-PMB-pyrazole 1-oxide (4): treatment of 4
with i-PrMgCl in THF at rt for 30 min exclusively afforded the
5-magnesio intermediate, see Ref. 16.
20. 1H NMR of the crude mixture showed exclusively 3,4-di-
bromo-5-TMS-2-PMB-pyrazole 1-oxide along with 1 equiv.
of MgCl2(2THF).
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