Halogenation of pyrazoloquinolines and pyrazoloisoquinolines. Theoretical analysis of the regioreactivity and cross-coupling of 3-halogen derivatives

Article abstract of DOI:10.1039/b006435l

The halogenation of pyrazoloquinolines and pyrazoloisoquinolines was discussed. The theoretical analysis of the regioreactivity and cross-coupling of 3-halogen derivatives was also performed. The utility of the prepared halides was demonstrated by a serie

Full text of DOI:10.1039/b006435l

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Halogenation of pyrazoloquinolines and pyrazoloisoquinolines.
Theoretical analysis of the regioreactivity and cross-coupling of
3-halogen derivatives†
1
Jan Pawlas,a Jeremy Greenwood,a Per Vedsø,a Tommy Liljefors,a Palle Jakobsen,b
Per Olaf Huusfeldtb and Mikael Begtrup*a
a Department of Medicinal Chemistry, The Royal Danish School of Pharmacy,
Universitetsparken 2, DK-2100 Copenhagen, Denmark. E-mail: begtrup@dfh.dk;
fax: (45) 35306040
b Medicinal Chemistry Research, Novo Nordisk Park, DK-2760 Måløv, Denmark
Received (in Cambridge, UK) 7th August 2000, Accepted 16th November 2000
First published as an Advance Article on the web 26th January 2001
Selective C*‡ halogenation (I and Br) of pyrazoles 1a, 3a and 4a gave halopyrazoles 5, 7–9, 11, 12. Reactivity
differences between 1a, 3a and 4a, and the failure of 2a to give the expected halopyrazoles 6, 10 were explained
using calculated relative energies of bromination, and inspection of frontier molecular orbitals. Utility of the
prepared halides was demonstrated by a series of palladium-catalysed cross-coupling reactions.
Introduction
Haloheteroaromatics are valuable synthetic intermediates in the
course of drug discovery, not least because of the ease of func-
tionalisation. Recently, we developed annelation protocols to
access the family of tricyclic N-hydroxypyrazoles 1b–4b from
C-4 and C-5 aryl substituted 1-benzyloxypyrazoles (Fig. 1).1
Activities as benzodiazepine antagonists,2 acetylcholinesterase
inhibitors,3 interleukin-1 antagonists,4 and anti-inflammatory
agents4–7 have been reported for derivatives of the parent ring
systems of 1b–4b. Direct functionalisation of C* is previously
unexplored. The only reported C* derivatives have been
obtained by late assembly of the pyrazole ring, using precursors
with the C* substituent already in place.§ A general means
of derivatising the C* position would allow structure–activity
relationship (SAR) studies of previously inaccessible analogues
of 1–4. C* derivatives of 3b are particularly attractive due to
their close resemblance to the potent peptide coupling reagent
Fig. 1 Hydroxypyrazolo(iso)quinolines 1b–4b prepared from C-4 and
C-5 aryl substituted 1-benzyloxypyrazoles via the corresponding Bn
protected 1a–4a. See ref. 1 for the synthetic details. N-Methoxy
analogues 1c–4c were used in the theoretical study. See text and
supporting information for further details.
1-hydroxy-7-azabenzotriazole (HOAt).8
Results and discussion
Halogenation of pyrazoloquinolines and pyrazoloisoquinolines
1a–4a
entry 8) under identical conditions, a new thermodynamically
unstable compound arose.|| This could be due to a single-
electron transfer induced by light and Cl2 in ICl. Therefore, the
iodination was re-attempted with the exclusion of light, only to
give recovery of starting material after 16 h at rt. However, on
raising the temperature to reflux, 4a was consumed after ca.
24 h, and 8 was isolated as the sole product (Table 1, entry 9).
These conditions were then used to attempt iodination of 1a–
3a. The summary in Table 1 reveals striking trends in the regio-
reactivity of 1a–4a towards ICl. Compound 1a required 93 h
for conversion to 5 (entry 2) whereas 3a was converted to 7 in
only 6 h (entry 6). Finally, 2a did not give 6 at all (entry 4).
Instead, a complex mixture of iodinated products resulted,
including iodination of the Bn ring. This contrasts with the
clean mono-iodinations of 1a, 3a and 4a.** Thus the suscepti-
bility of 1a–4a to C* iodination is as follows: 3a > 4a ӷ 1a,
with failure for 2a.
Our goal was to regioselectively halogenate the Bn protected
1a–4a at C*, and examine the utility of the resulting halo-
pyrazoles in a series of test reactions. However, attempted
iodination of 1a with ICl at rt led to no conversion (Table 1,
entry 1), similar to the findings regarding the unreactive C-3 of
1-benzyloxypyrazole.9,10 Trying the recently reported “super-
active” reagent “Iϩ” (ICl–Ag2SO4 in H2SO4)11 resulted in
non-selective overiodination§¶ together with substantial BnO
cleavage. The deprotected N-hydroxypyrazole 1b exhibited
much greater reactivity towards ICl, as shown by the quantita-
tive iodination of 1b at C-1 after 3 h, though the OH group was
lost. By contrast with 1a, when 4a was treated with ICl (Table 1,
† Spectral and theoretical data are available as supplementary data.
For direct electronic access see http://www.rsc.org/suppdata/p1/b0/
b006435l/
‡ C* indicates C-3 for pyrazoles 2 and 4 and C-1 for pyrazoles 1 and 3.
§ See ref. 1 for typical syntheses of these ring systems.
¶ At least 3 I were incorporated into the substrate according to LC/MS.
|| Converted back to 4a upon standing in CDCl3 solution.
** No further iodination of 5, 7 or 8 occurred even when ICl treatment
was prolonged.
DOI: 10.1039/b006435l
J. Chem. Soc., Perkin Trans. 1, 2001, 861–866
This journal is © The Royal Society of Chemistry 2001
861

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Table 1 Iodination and bromination of pyrazoles 1a–4a
Reaction
Reaction
time/h
Yield
(%)
Entry
Substrate
Product
conditionsa
1
2
A
C
168
93
0b
72
3
4
5
6
7
B
C
B
C
B
6
16
0.5
6
84
0c
0c
91
96
1
8
9
A
C
16
24
0d
78
10
B
1
85
a Iodinations and brominations were conducted using ICI or Br2 in CHCl3. Reaction conditions (A) room temperature; (B) room temperature,
exclusion of light; (C) 62 ЊC, exclusion of light. b No conversion. c Complex mixture. d See text.
As bromoheteroaromatic compounds are also desirable, 1a–
4a were treated with bromine at rt. Compounds 3a and 4a were
brominated at roughly the same rate (Table 1, entries 7 and 10)
whereas 1a reacted more sluggishly (entry 3) and bromination
of 2a resulted in a complex mixture of products (entry 5), all in
keeping with the iodination results. The reactivity towards Br2
at C* of 1a–4a is then 3a ≈ 4a ӷ 1a, with failure for 2a.
Preferred attack at the pyrazole nucleus can first be under-
stood by comparison of the classical valence bond structures of
the σ-intermediates. For reasons which will become apparent,
we introduce model 1-methoxy analogues of 1a–4a, denoted
1c–4c (Fig. 1). The σ-intermediates are denoted 1cn to 4cn where
n indicates the position of Brϩ addition. Some examples are
given in Fig. 2. Only the most “stable” classical resonance form,
that in which all atoms possess an octet structure, is drawn here
in each case. By comparing 1c1, 1c4–1c9 we can easily see that
only 1c1 possesses two aromatic rings, while 1c4–1c9 are essen-
tially non-aromatic. The same is apparent for 2c3, 3c1 and 4c3,
which can likewise be drawn with preserved aromaticity where-
as 2c4–2c9, 3c5–3c9, and 4c5–4c9 respectively cannot. Classically
then, we would expect electrophilic attack at C*, but this does
not explain the observed reactivity differences, and in particular
the failure to obtain 6.
However, such clear reactivity differences should be amen-
able to investigation by ab initio molecular orbital theory,
including frontier orbital analysis. Two parallel approaches
were pursued: quantitative comparison of the relative energies
of regional bromination, and qualitative inspection of the
HOMOs of the substrates. Frontier orbital analysis provides
an indication of the transition state, which relates to reaction
862
J. Chem. Soc., Perkin Trans. 1, 2001, 861–866

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Table 2 Gas phase (ab initio) energies of model species
E0 (HF/6-31G(d))/
hartree
∆∆E0 a/kcal molϪ1
1c
Ϫ659.73638
Ϫ3229.36761
Ϫ3229.34804
Ϫ3229.35654
Ϫ3229.36284
Ϫ3229.35493
Ϫ3229.36285
1c1
1c4
1c6
1c7
1c8
1c9
2.49
14.78
9.44
5.49
10.45
5.48
2c
Ϫ659.74057
Ϫ3229.36186
Ϫ3229.33478
Ϫ3229.36775
Ϫ3229.35134
Ϫ3229.36715
Ϫ3229.35691
2c3
2c4
2c6
2c7
2c8
2c9
8.73
25.73
5.04
15.33
5.41
Fig. 2 Some examples of cationic bromine adducts of 1c–4c.
11.84
barrier height and kinetics, while the thermodynamic approach
measures the relative energy of a short-lived high energy
minimum on the reaction path. By the Hammond postulate, the
transition state and the high energy intermediate of the rate
limiting step most likely resemble each other, and either may be
used as an indication of the course of the reaction by a perturb-
ative approach. Comparisons can be made between structures,
and also within a single substrate where there are competing
reaction sites. The reason for modelling N-methoxy substrates
(1c–4c, Fig. 1) was to substantially reduce computational
expense, the extra phenyl ring not playing a significant role in
the reaction. It being of interest to compare the relative ease of
bromination at C* with other competing positions, the cationic
complexes formed from all five available aromatic positions on
each substrate were considered, 1cn to 4cn. Geometry optimis-
ation (Gaussian 9812) was performed using the HF/6-31G(d)
method.††13 Allminimawerevalidatedbyfrequencycalculations,
and inclusion of thermodynamic terms found to have negligible
effect (see supporting information for full energies and geom-
etries). The results are shown in Fig. 3 (Spartan 5.114). The
comparisons are presented in Table 2, and for ease of interpret-
ation, the energies (kcal molϪ1) are corrected relative to the
bromination of 4c at C-3 to give 4c3 (Scheme 1). In Fig. 3, the
HOMO is depicted as a map of the orbital co-efficient onto the
van der Waals surface of the substrate—a red to blue spectrum
indicating low to high HOMO density. Relative energies of
bromination at each site are also indicated. Compare in particu-
lar the densities proximal to the C* position (bottom left), and
the associated energies. The least electron density over C* is
observed for 2c, which has a bromination energy 9 kcal higher
than that of 4c. The qualitative orbital picture and the relative
thermodynamics are concordant, and in excellent agreement
with experiment, that the reactivity order is 4c ≈ 3c ӷ 1c, and
that side-reactions (e.g. 2c6, 2c8) are favoured over C* bromin-
ation of 2c. The observed reactivities are thus rationalised in
terms of electronic structure.
3c
Ϫ659.74109
Ϫ3229.37580
Ϫ3229.34121
Ϫ3229.34252
Ϫ3229.36913
Ϫ3229.33404
Ϫ3229.36797
3c1
3c5
3c6
3c7
3c8
3c9
0.31
22.02
21.19
4.50
26.52
5.23
4c
Ϫ659.73625
Ϫ3229.37146
Ϫ3229.36149
Ϫ3229.34500
Ϫ3229.35020
Ϫ3229.34087
Ϫ3229.35252
4c3
4c5
4c6
4c7
4c8
4c9
0.00
6.25
16.60
13.34
19.20
11.88
a E0 = E ϩ ZPE. ∆E0 = E0 Ϫ E0(1c–4c). ∆∆E0 = ∆E0 Ϫ ∆E0(4c3).
C*.§§ Oxidative zinc insertion15 also failed. Next investigated
were cross-coupling reactions—a powerful tool for function-
alisation of heteroaromatics.16 Pd(0)-catalysed cross-coupling
of 4-tolylboronic acid to 9, 11 and 12 (Table 3, entries 1, 4 and
6) revealed that the Suzuki reaction17,18 is successful. Extending
the cross-coupling to boronic acids having bulky (entry 2),
electron-withdrawing (entry 3) and heteroaromatic groups
(entry 5) was straightforward, demonstrating the generality of
the method. In addition, examples of Negishi19 (entry 7) and
Sonogashira20 and their co-workers (entry 8) couplings show
the versatility of the accessed halopyrazoles.
Conclusion
C* iodination and bromination of 1a, 3a and 4a was achieved
by the exclusion of light. The observed differences in regio-
reactivity, including the refractory 2a, were rationalised using
energies from ab initio calculations and examination of the
HOMOs. Utility of the prepared halopyrazoles was demon-
strated by a series of Pd-catalysed cross-coupling reactions.
Cross-coupling reactions
Experimental
General
The synthetic utility of the prepared halopyrazoles was exam-
ined in halogen–metal exchange and cross-coupling reactions.
Halogen–metal exchange seemed like an attractive route to
substituents at C*.‡‡ However, I–Mg exchange with 7 using
i-PrMgBr at 0 ЊC resulted in migration of the BnO group to
The 1- and 3-(benzyloxy)pyrazoloquinolines/isoquinolines
1a–4a were prepared by the known procedures.1 1-Benzyloxy-
pyrazole was prepared as previously reported.9 Pd(PPh3)4
was prepared as previously described.21 The boronic acids
were purchased from Strem Chemicals, Inc. All other solvents
and reagents were commercially available and used without
further purification, except THF which was distilled from
†† The popular Hartree–Fock theory with a 6-31G(d) basis set is
currently a sensible first choice for this kind of problem, having a
favourable trade-off between accuracy and cost, while semi-empirical
methods are known to be inadequate, DFT methods are less sound for
frontier orbital analysis, and correlated methods significantly more
expensive.13
§§ When less than 1 eq. of i-PrMgBr was used, 7 was isolated together
with the migrated product. A C* non-migrated product could not even
be intercepted by addition of an electrophile (MeOD).
‡‡ This technique has been employed previously to prepare a range of
C-4 substituted 1-benzyloxypyrazoles. See ref. 10.
J. Chem. Soc., Perkin Trans. 1, 2001, 861–866
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Fig. 3 Structures 1c–4c, optimized at HF/6-31G(d),12 with the van der Waals surfaces (isodensity 0.002 electron auϪ3) having the absolute density
coefficient of the HOMOs mapped as spectra from red (0.00) to blue (0.02). Printed in white are the relative gas phase energies (kcal molϪ1, ZPE
uncorrected) pertaining to the adducts formed by the respective bromination of each aromatic methine, i.e. 1cn–4cn, relative to C-3 bromination of 4c.
Bromination
3-Benzyloxy-1-bromo-3H-pyrazolo[3,4-c]quinoline (9). To a
solution of 1a (130 mg, 0.47 mmol) and K2CO3 (240 mg, 1.50
mmol) in CH2Cl2 (20 mL) at rt, was added Br2 (240 mg,
1.50 mmol), with exclusion of light. After 6 h at rt, the reaction
was quenched with 1 M Na2S2O3 (30 mL) and worked up as
described for 5. Flash chromatography (heptane–EtOAc, 4 : 1)
Scheme 1
gave 140 mg (84%) of 9 as white crystals, mp 124–125 ЊC
(EtOAc–heptane). Rf (EtOAc–heptane, 1 : 2) 0.44. δH (CDCl3)
Na–benzophenone under nitrogen and DMF which was
8.82 (dd, J = 7.2, 2.0 Hz, 1H), 8.59 (s, 1H), 8.13 (dd, J = 7.3, 2.0
sequentially dried with and stored over 3 Å molecular sieves.
Hz, 1H), 7.81–7.65 (m, 2H), 7.40–7.22 (m, 5H), 5.49 (s, 2H).
A 1.0 M solution of ZnCl2 was prepared by flame drying
δC (CDCl3) 142.89, 135.41, 133.08, 130.31, 130.30, 130.08,
anhydrous ZnCl2 in vacuo and dissolving it in dry THF. Melting
130.02, 128.98, 128.25, 127.49, 121.50, 120.76, 118.10, 113.27,
points are uncorrected. Elemental analyses were performed
81.64. Found: C, 57.4; H, 3.35; N, 11.65. C17H12BrN3O requires
by Microanalytical Laboratory, Department of Physical
C, 57.65; H, 3.4; N, 11.85%.
Chemistry, University of Vienna, Austria. NMR spectra were
recorded on 300 MHz Bruker and Varian spectrometers with
tetramethylsilane as internal standard.
3-Benzyloxy-1-bromo-3H-pyrazolo[3,4-c]isoquinoline (11).
Using the same procedure, 3a after 1 h reaction time and flash
chromatography (heptane–EtOAc, 4 : 1) gave 96% of 11 as
yellow crystals, mp 123–124 ЊC (EtOAc–heptane). Rf (EtOAc–
heptane, 1 : 2) 0.46. δH (CDCl3) 9.00 (s, 1H), 8.81 (d, J = 8.0 Hz,
1H), 8.07 (d, J = 7.7 Hz, 1H), 7.88 (dt, J = 7.1, 1.3 Hz, 1H), 7.63
(dt, J = 7.6, 1.1 Hz, 1H), 7.55–7.30 (m, 5H), 5.50 (s, 2H).
δC (CDCl3) 160.80, 155.31, 142.25, 133.43, 132.37, 129.93,
129.51, 129.35, 128.61, 126.13, 125.60, 121.24, 112.15, 106.55,
81.43. Found: C, 57.45; H, 3.4; N, 11.7. C17H12BrN3O requires
C, 57.65; H, 3.4; N, 11.85%.
Iodination
3-Benzyloxy-1-iodo-3H-pyrazolo[3,4-c]quinoline (5). Com-
pound 1a (20 mg, 0.07 mmol), ICl (34 mg, 0.21 mmol) and
K2CO3 (50 mg, 0.35 mmol) in CHCl3 (10 mL) were refluxed
with exclusion of light. After 93 h, the reaction was cooled to rt,
quenched with 1 M Na2S2O3 (30 mL), extracted with CH2Cl2
(3 × 25 mL), dried over MgSO4 and evaporated to dryness.
Flash chromatography (heptane–EtOAc, 6 : 1) gave 21 mg
(72%) of 5 as yellow crystals, mp 156–158 ЊC (EtOAc–heptane).
Rf (EtOAc–heptane, 1 : 2) 0.34. δH (CDCl3) 9.05 (dd, J = 8.1, 1.6
Hz, 1H), 8.61 (s, 1H), 8.15 (dd, J = 8.1, 1.4 Hz, 1H), 7.80–7.60
(m, 2H), 7.40–7.25 (m, 5H), 5.49 (s, 2H). δC (CDCl3) 160.11,
133.12, 130.36, 130.13, 130.05, 129.80, 129.65, 129.02, 127.91,
127.57, 122.37, 121.06, 120.00, 81.75, 80.11. Found: C, 49.8;
H, 3.15; N, 9.85. C17H12IN3Oؒ0.5 H2O requires C, 49.8; H, 3.2;
N, 10.25%.
1-Benzyloxy-3-bromo-1H-pyrazolo[4,3-c]isoquinoline (12).
Similarly, 4a gave 85% of 12 as pale yellow crystals, mp
166–168 ЊC (EtOAc–heptane). Rf (EtOAc–heptane, 1 : 2) 0.36.
δH (CDCl3) 9.01 (s, 1H), 8.42 (dd, J = 8.0, 0.8 Hz, 1H), 8.10 (dd,
J = 8.0, 1.4 Hz, 1H), 7.85–7.70 (m, 2H), 7.51–7.30 (m, 5H), 5.53
(s, 2H). δC (CDCl3) 150.84, 132.81, 131.30, 131.17, 130.04,
129.64, 128.96, 128.81, 128.32, 127.72, 124.83, 121.98, 121.93,
81.17, one carbon signal consists of overlapping peaks. Found:
C, 57.45; H, 3.25; N, 11.65. C17H12BrN3O requires C, 57.65;
H, 3.4; N, 11.85%.
3-Benzyloxy-1-iodo-3H-pyrazolo[3,4-c]isoquinoline (7). Simi-
larly, 3a after 24 h reaction time and flash chromatography
using heptane–EtOAc (4 : 1) gave 91% of 7 as yellow crystals,
mp 109–111 ЊC (EtOAc–heptane). Rf (EtOAc–heptane, 1 : 2)
0.42. δH (CDCl3) 9.02 (d, J = 8.3 Hz, 1H), 9.00 (s, 1H), 8.05 (d,
J = 8.3 Hz, 1H), 7.90 (dt, J = 7.7, 1.2 Hz, 1H), 7.61 (dt, J = 7.6,
1.0 Hz, 1H), 7.55–7.30 (m, 5H), 5.53 (s, 2H). δC (CDCl3) 154.83,
141.61, 133.40, 131.89, 129.99, 129.86, 129.49, 129.25, 128.53,
126.02, 125.88, 125.51, 119.56, 109.79, 81.55. Found: C, 49.95;
H, 3.05; N, 10.0. C17H12IN3Oؒ0.5 H2O requires C, 49.8; H, 3.2;
N, 10.25%.
General procedure for Suzuki couplings
A solution of halopyrazole 9, 11, 12, (0.1 mmol), boronic acid
(0.1 mmol) and K2CO3 (2.0 M, 0.2 mL) in toluene (2 mL) and
EtOH (0.2 mL) was degassed by bubbling N2 through the solu-
tion for 30 min, before adding Pd(PPh3)4 (4 mol%). After three
cycles of evacuation and re-filling with N2, the mixture was
heated to 80 ЊC, until full conversion was observed by TLC.
The reaction mixture was quenched with sat. aq. NH4Cl and
extracted with CH2Cl2 (3 × 10 mL). Drying (MgSO4) and evap-
oration in vacuo gave the crude product, which was purified by
preparative TLC (silica gel) or flash chromatography.
1-Benzyloxy-3-iodo-1H-pyrazolo[4,3-c]isoquinoline (8). Simi-
larly, 4a gave 78% of 8 as off-white crystals, mp 182–183 ЊC
(EtOAc–heptane). Rf (EtOAc–heptane, 1 : 2) 0.32. δH (CDCl3)
8.82 (dd, J = 7.2, 2.0 Hz, 1H), 8.59 (s, 1H), 8.13 (dd, J = 7.3, 2.0
Hz, 1H), 7.85–7.68 (m, 2H), 7.50–7.30 (m, 5H), 5.53 (s, 2H).
Found: C, 50.8; H, 3.0; N, 10.25. C17H12IN3O requires C, 50.9;
H, 3.0; N, 10.45%.
3-Benzyloxy-1-(4-methylphenyl)-3H-pyrazolo[3,4-c]quinoline
(13). Following the general procedure using 9, p-tolylboronic
acid and a reaction time of 6 h and preparative TLC (heptane–
EtOAc 1 : 1) gave 85% of 13 as off-white crystals, mp 109–
864
J. Chem. Soc., Perkin Trans. 1, 2001, 861–866

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Table 3 Pd-catalysed cross-coupling reactions of halopyrazoles 8, 9, 11 and 12
Reaction
Yieldb
(%)
Entry
Substrate
Product
conditionsa
1
A
A
A
A
85
87
63
86
2
3
4
5
6
A
A
77
94
7
8
B
C
63
77
a Reaction types: (A) Suzuki–Miyaura; (B) Negishi; (C) Sonogashira. Details in Experimental section. b Isolated yields of chromatographically pure
products.
111 ЊC (heptane–EtOAc), Rf (heptane–EtOAc, 2 : 1) 0.30.
δH(CDCl3) 8.71 (s, 1H), 8.22 (dd, J = 8.1, 1.1 Hz, 1H), 8.12 (dd,
J = 7.6, 0.8 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.58 (dt, J = 7.0,
1.4 Hz, 1H), 7.47 (dt, J = 7.5, 1.2 Hz, 1H), 7.42–7.25 (m, 5H),
5.53 (s, 2H), 2.50 (s, 3H). δC (CDCl3) 143.08, 140.70, 138.83,
135.99, 133.55, 130.38, 130.05, 129.83, 129.80, 129.48, 129.44,
128.89, 127.61, 127.14, 126.80, 122.71, 122.04, 116.70, 81.18,
21.46. Found: C, 78.45; H, 5.6; N, 11.0. C24H19N3O requires C,
78.9; H, 5.25; N, 11.5%.
time of 6 h and flash chromatography (heptane–EtOAc
6 : 1 → 3 : 1) gave 87% of 14 as yellow crystals, mp 135–136 ЊC
(heptane–EtOAc), Rf (heptane–EtOAc, 2 : 1) 0.34. δH (CDCl3)
8.83 (s, 1H), 8.13–7.15 (m, 16H), 5.59 (s, 2H), 2.50 (s, 3H).
δC (CDCl3) 143.04, 138.49, 135.97, 133.79, 133.47, 132.28,
130.53, 130.13, 129.88, 129.66, 129.46, 128.90, 128.81, 128.52,
127.72, 126.86, 126.77, 126.29, 125.91, 125.63, 125.48, 123.00,
121.65, 118.47, 81.12. Found: C, 80.2; H, 4.95; N, 10.1.
C27H19N3Oؒ0.2 H2O requires C, 80.05; H, 4.85; N, 10.35%.
3-Benzyloxy-1-naphthalen-1Ј-yl-3H-pyrazolo[3,4-c]quinoline
(14). Similarly 9 and α-naphthylboronic acid using a reaction
3-Benzyloxy-1-(3-nitrophenyl)-3H-pyrazolo[3,4-c]quinoline
(15). Following the general procedure using 9, 3-nitrophenyl-
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boronic acid, 3 h reaction time and preparative TLC (heptane–
EtOAc 1 : 1), 63% of 15 was obtained as yellow crystals,
mp 153–154 ЊC (heptane–EtOAc), Rf (heptane–EtOAc, 2 : 1)
0.64. δH (CDCl3) 8.73 (s, 1H), 8.71 (t, J = 1.8 Hz, 1H), 8.40 (ddd,
J = 8.3, 2.3, 1.1 Hz, 1H), 8.20–8.16 (m, 2H), 8.09–8.05 (m, 1H),
7.77 (t, J = 8.2 Hz, 1H), 7.63 (dt, J = 8.3, 1.5 Hz, 1H), 7.52 (dt,
J = 8.3, 1.4 Hz, 1H), 7.42–7.30 (m, 5H), 5.55 (s, 2H). δC (CDCl3)
148.60, 143.29, 137.93, 136.04, 135.48, 135.28, 133.25, 130.81,
130.13, 130.08, 130.00, 129.89, 129.05, 128.15, 127.45, 124.55,
123.70, 122.14, 121.35, 116.78, 81.50.¶¶
126.97, 121.96, 121.85, 105.68, 80.86, 80.69, four carbon signals
consisted of overlapping peaks.¶¶
1-Benzyloxy-3-(2-trimethylsilylethynyl)-1H-pyrazolo[4,3-c]-
isoquinoline (20). Compound 8 (10.0 mg, 0.025 mmol) and
ethynyl(trimethyl)silane (3.5 mg, 0.035 mmol) were dissolved in
3 mL of dry Et3N under N2. After three cycles of evacuation
and re-filling with N2, copper iodide (0.4 mg, 0.002 mmol) and
Pd(PPh3)2Cl2 (0.7 mg, 0.001 mmol) were added. The reaction
was stirred at 55 ЊC for 3 h, before cooling to rt and aqueous
work up as described for the Suzuki couplings followed by
preparative TLC (heptane–EtOAc 1 : 1) gave 7.2 mg (77%) of
20 as yellow crystals, mp 134–137 ЊC (heptane–EtOAc). Rf
(heptane–EtOAc, 2 : 1) 0.44. δH (CDCl3) 9.05 (s, 1H), 8.43 (d,
J = 8.1 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.85–7.27 (m, 7H),
5.55 (s, 2H), 0.39 (s, 9H).¶¶
3-Benzyloxy-1-(4-methylphenyl)-3H-pyrazolo[3,4-c]isoquinol-
ine (16). Similarly, 11 and p-tolylboronic acid after 6 h reaction
time and preparative TLC (heptane–EtOAc 1 : 1) afforded 86%
of 16 as yellow crystals, mp 147–148 ЊC (heptane–EtOAc),
Rf (heptane–EtOAc, 2 : 1) 0.33. δH (CDCl3) 9.04 (s, 1H), 8.24
(d, J = 8.1 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.73–7.30 (m,
11H), 5.58 (s, 2H), 2.48 (s, 3H). δC (CDCl3) 154.37, 142.20,
139.21, 138.60, 133.94, 131.71, 131.20, 130.96, 129.92, 129.62,
129.47, 129.34, 129.14, 128.53, 125.68, 125.40, 122.43, 104.88,
80.96, 21.31.¶¶
Acknowledgements
This work was supported by Corporate Research Affairs at
Novo Nordisk A/S, The Graduate School of Drug Research
at The Royal Danish School of Pharmacy (J. P.) and the
Lundbeck Foundation Copenhagen (J. R. G.).
3-Benzyloxy-1-(3-thienyl)-3H-pyrazolo[3,4-c]isoquinoline
(17). In the same way, 11 and 3-thienylboronic acid after 2 h
reaction time and preparative TLC (heptane–EtOAc 6 : 1) gave
77% of 17 as off-white crystals, mp 117–119 ЊC (heptane–
EtOAc), Rf (heptane–EtOAc, 2 : 1) 0.28. δH (CDCl3) 9.05
(s, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.07 (d, J = 8.3 Hz, 1H), 7.73–
7.30 (m, 10H), 5.58 (s, 2H). δC (CDCl3) 154.48, 142.06, 134.60,
134.46, 133.86, 131.91, 130.85, 129.91, 129.67, 129.18, 128.60,
128.55, 126.25, 125.72, 125.50, 125.00, 122.39, 105.27, 81.05.¶¶
References
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mp 211–212 ЊC (heptane–EtOAc), Rf (heptane–EtOAc, 2 : 1)
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1-Benzyloxy-3-(1-benzyloxypyrazol-5-yl)-1H-pyrazolo[4,3-c]-
isoquinoline (19). To a solution of 1-benzyloxypyrazole (25 mg,
0.14 mmol) in THF (2 mL) at –78 ЊC under N2, was added a
solution of n-BuLi in hexanes (0.085 mL, 2.0 M), and after
5 min at –78 ЊC a solution of ZnCl2 in THF (0.22 mL, 1.0 M)
was added. The solution was allowed to warm to rt, stirred at
rt for an additional 30 min, before 8 (88 mg, 0.22 mmol) and
Pd(PPh3)4 (3 mg, 0.0029 mmol) in DMF (4 mL) was added, the
reaction was heated to 80 ЊC for 1 h, cooled to rt and quenched
with sat. aq. NH4Cl (10 mL). Addition of H2O (10 mL), extrac-
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vacuo, and preparative TLC (eluent ethyl acetate–heptane, 2 : 1)
afforded 42 mg (63%) of 19 as yellow crystals, mp 174–175 ЊC
(heptane–EtOAc). Rf (heptane–EtOAc, 2 : 1) 0.34. δH (CDCl3)
9.04 (s, 1H), 8.51 (d, J = 8.2 Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H),
7.82 (dt, J = 7.5, 1.1 Hz, 1H), 7.72 (dt, J = 7.5, 1.1 Hz, 1H),
7.61–7.55 (m, 2H), 7.46 (d, J = 2.3 Hz, 1H), 7.50–7.40 (m, 2H),
7.36–7.20 (m, 8H), 7.18 (d, J = 2.3 Hz, 1H), 5.55 (s, 2H), 5.54
(s, 2H). δC (CDCl3) 150.49, 134.13, 133.36, 133.09, 131.14,
129.91, 129.81, 129.55, 128.85, 128.81, 128.34, 127.91, 127.32,
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¶¶ The compound was unstable and a correct microanalysis could
not be obtained. When dissolved in CDCl3 NMR signals from benz-
aldehyde emerged upon standing. A clean 1H-NMR spectrum of the
freshly prepared compounds is included in the supplementary material.
21 D. R. Coulson, Inorg. Synth., 1972, 13, 121.
866
J. Chem. Soc., Perkin Trans. 1, 2001, 861–866