Synthesis of 1-hydroxy-substituted pyrazolo[3,4-c]- and pyrazolo[4,3-c]quinolines and -isoquinolines from 4- and 5-aryl-substituted 1-benzyloxypyrazoles

Article abstract of DOI:10.1021/jo000986v

1-Hydroxypyrazolo[3,4-c]quinoline (22), 1-hydroxypyrazolo[4,3-c]quinoline (21), 1-hydroxypyrazolo[3,4-c]isoquinoline (20), and 1-hydroxypyrazolo[4,3-c]isoquinoline (19) were prepared from 1-benzyloxypyrazole (6), establishing the pyridine B-ring in the terminal step. The pyridine ring of pyrazoloquinolines 14 and 18 was formed via cyclization of a formyl group at C-4 or C-5 and an amino group of a 2-aminophenyl substituent at C-5 or C-4 in 1-benzyloxypyrazole. The pyridine ring of pyrazoloisoquinolines 5 and 9 was created via cyclization of a formyl group in a 2-formylphenyl substituent at C-4 or C-5 with an iminophosphorane group installed at C-5 or C-4 of 1-benzyloxypyrazole by lithiation followed by reaction with tosyl azide and then with tributylphoshine utilizing the Staudinger/aza-Wittig protocol. The 2-aminophenyl and the 2-formylphenyl substituent were introduced at C-5 or C-4 by regioselective metalation followed by transmetalation to the pyrazolylzinc halide and subsequent palladium-catalyzed cross-coupling with 2-iodoaniline or 2-bromobenzaldehyde. The order of reactions and use of protecting groups in the individual sequences have been optimized. The 1-benzyloxy-substituted pyrazoloquinolines and isoquinolines thus obtained were debenzylated by strong acid to the corresponding 1-hydroxy-substituted pyrazoloquinolines and isoquinolines 19-22.

Full text of DOI:10.1021/jo000986v

J . Org. Chem. 2000, 65, 9001-9006
9001
Syn th esis of 1-Hyd r oxy-Su bstitu ted P yr a zolo[3,4-c]- a n d
P yr a zolo[4,3-c]qu in olin es a n d -isoqu in olin es fr om 4- a n d
5-Ar yl-Su bstitu ted 1-Ben zyloxyp yr a zoles
J an Pawlas,† Per Vedsø,† Palle J akobsen,‡ Per Olaf Huusfeldt,‡,§ and Mikael Begtrup*,†
Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Universitetsparken 2,
DK-2100 Copenhagen, Denmark, and Novo Nordisk A/S, Medicinal Chemistry Research,
Novo Nordisk Park, DK-2760 Måløv, Denmark
begtrup@dfh.dk
Received J une 29, 2000
1-Hydroxypyrazolo[3,4-c]quinoline (22), 1-hydroxypyrazolo[4,3-c]quinoline (21), 1-hydroxypyrazolo-
[3,4-c]isoquinoline (20), and 1-hydroxypyrazolo[4,3-c]isoquinoline (19) were prepared from 1-ben-
zyloxypyrazole (6), establishing the pyridine B-ring in the terminal step. The pyridine ring of
pyrazoloquinolines 14 and 18 was formed via cyclization of a formyl group at C-4 or C-5 and an
amino group of a 2-aminophenyl substituent at C-5 or C-4 in 1-benzyloxypyrazole. The pyridine
ring of pyrazoloisoquinolines 5 and 9 was created via cyclization of a formyl group in a
2-formylphenyl substituent at C-4 or C-5 with an iminophosphorane group installed at C-5 or C-4
of 1-benzyloxypyrazole by lithiation followed by reaction with tosyl azide and then with tribu-
tylphoshine utilizing the Staudinger/aza-Wittig protocol. The 2-aminophenyl and the 2-formylphenyl
substituent were introduced at C-5 or C-4 by regioselective metalation followed by transmetalation
to the pyrazolylzinc halide and subsequent palladium-catalyzed cross-coupling with 2-iodoaniline
or 2-bromobenzaldehyde. The order of reactions and use of protecting groups in the individual
sequences have been optimized. The 1-benzyloxy-substituted pyrazoloquinolines and isoquinolines
thus obtained were debenzylated by strong acid to the corresponding 1-hydroxy-substituted
pyrazoloquinolines and isoquinolines 19-22.
In tr od u ction
allergic, and antiviral activities,1l,m has also been inves-
tigated. The known synthetic sequences usually involve
formation of the pyrazole ring, typically via a hydrazine
condensation at a late stage of the sequence.1a,h,j,l To our
knowledge, a general, easily extensible technology for the
construction of all four members 19-22 of this structural
family via the pyridine B-ring closure starting from a
substituted pyrazole has not been yet described. No
1-hydroxy-substituted derivatives of ring systems 19-
22 have been reported. The herein presented syntheses
of 19-22 start from 1-benzyloxypyrazole (6), which can
be regioselectively metalated and arylated by cross-
coupling reactions in a highly flexible manner.2,3 Further,
the annelation protocols developed for the construction
of 5, 9, 14, and 18 should provide an easy access to
diverse derivatives of 19-22, e.g., using substituted
2-iodoanilines or 2-bromobenzaldehydes in the cross-
coupling step. Possibly, extending these novel ring closing
tactics will also enable development of versatile routes
to other important classes of condensed N-heteroaromat-
ics. In that respect, the strategy to produce 20 is
particularly relevant, due to the close structural resem-
blance of 1-hydroxypyrazolo[4,3-c]quinoline (20) to the
highly efficient peptide coupling reagent HOAt.4
The parent ring systems of the four isomeric tricyclic
N-hydroxy-substituted pyrazolo[4,3-c]isoquinoline (19),
pyrazolo[3,4-c]isoquinoline (20), pyrazolo[4,3-c]quinoline
(21), and pyrazolo[3,4-c]quinoline (22) are known, usually
as N-1 or N-2 substituted derivatives.1 Structural ana-
logues of 19-22 have been studied for their biological
activity as benzodiazepine antagonists,1a acetylcholinest-
erase inhibitors,1j interleukin 1 antagonists,1h and anti-
inflammatory agents.1e,h,l,m Ability to displace specific
flunitrazepam binding,1g as well as antimalarial, anti-
* To whom correspondence should be addressed. Tel. +45 35 30 60
00. FAX +45 35 30 60 40.
† The Royal Danish School of Pharmacy.
‡ Novo Nordisk, Novo Nordisk Park.
§ Present address: Pantheco A/S, Fruebjergvej 3, DK 2100 Copen-
hagen, Denmark.
(1) For illustrative examples of syntheses of these structural classes,
see: (a) Cecchi, L.; Colotta, V.; Melani, F.; Palazzino, G.; Filacchioni,
G.; Martini, C.; Giannaccini, G.; Lucacchini, A. J . Pharm. Sci. 1989,
78, 437 (ring system 19). (b) Nikolyukin, Y. A.; Dulenko, L. V.; Dulenko,
V. I. Khim. Geterotsikl. Soedin. 1990, 26, 1092. (c) Bogza, S. L.;
Nikolyukin, Y. A.; Dulenko, V. I. Khim. Geterotsikl. Soedin. 1994, 30,
1290 (ring system 20). (d) Staskun, B. J . Org. Chem. 1961, 26, 2791.
(e) Katner, S. A. U.S. Patent 3890324, 17 J un 1975; Chem. Abstr. 1975,
83, 1641169b. (f) Ga´l, M.; Fehe´r, O¨ .; Tihanyi, E.; Horva´th, G.;
J erkovich, G. Tetrahedron 1982, 38, 2933. (g) Melani, F.; Cecchi, L.;
Palazzino, G.; Filacchoni, G.; Martini, C.; Pennacchi, E.; Lucacchini,
A. J . Med. Chem. 1986, 29, 291. (h) Skotnicki, J .; Gilman, S. C.;
Steinbaugh, B. A.; Musser, J . H. U.S. Patent 4748246, 31 May 1988;
Chem. Abstr. 1988, 109, 110425u. (i) Daou, B.; Soufiaoui, M. Tetra-
hedron 1989, 45, 3351. (j) Sicker, D. J . Heterocycl. Chem. 1992, 29,
275. (k) Gatta, F.; Del Giudice, M. R.; Pomponi, M.; Marta, M.
Heterocycles 1992, 34, 991. (l) Mekheimer, R. Pharmazie 1994, 49, 486.
(m) Hassan, A. A.; Mekheimer, R.; Mohamed, N. K. Pharmazie 1997,
8, 589 (ring system 21). (n) Nagarajan, K.; Shah, R. K. Indian J . Chem.
1992, 31B, 316 (ring system 22).
Resu lts a n d Discu ssion
Retr osyn th etic An a lysis. The synthetic approach to
the target structures 19-22 is outlined in Scheme 1. The
(2) Kristensen, J .; Begtrup, M.; Vedsø, P. Synthesis 1998, 1604.
(3) Felding, J .; Kristensen, J .; Bjerregaard, T.; Sander, L.; Vedsø,
P.; Begtrup, M. J . Org. Chem. 1999, 64, 4196.
(4) Carpino, L. A. J . Am. Chem. Soc. 1993, 115, 4397.
10.1021/jo000986v CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/05/2000

9002 J . Org. Chem., Vol. 65, No. 26, 2000
Pawlas et al.
Sch em e 1
Sch em e 2
first step of this synthesis involves regioselective C-5 or
C-4 arylation of the pyrazole nucleus using previously
described palladium-catalyzed Negishi type5 cross-cou-
pling methodologies,2,3 followed by protection of the
o-phenyl group introduced in the cross-coupling step. The
salient step involves the introduction of a nitrogen-
containing functionality or a formyl group at the 4- or
5-position of the pyrazole ring (step b). This was envis-
aged via an organometallic intermediate, which could be
quenched with an appropriate electrophile. Subsequent
deprotection followed by an intramolecular cyclization
form the pyridine ring (step a). Finally, the 1-benzyl
group used for protection of the N-OH group in the
synthetic sequences could be removed via hydrogenolysis
or acid-catalyzed debenzylation to give the targets 19 and
22. Analogous approach as for 19 could be used to build
20, and similarly 21 could be made, employing the same
strategy as for the synthesis of 22.
h followed by treatment of the resulting triazene salt with
an aqueous solution of tetrasodium pyrophosphate at
room temperature furnished azide 3.8 4-Azido-1-(benzyl-
oxy)-5-(2-formylphenyl)pyrazole (4) was then obtained by
hydrolysis of ethylene acetal group in 3 by treatment with
2 M HCl at room temperature. Finally, 4 was subjected
to a Staudinger/intramolecular aza-Wittig reaction9 using
tributylphosphine in a 15:1 toluene:THF mixture10 at
room temperature to furnish the cyclized pyrazoloiso-
quinoline 5 in 72% yield (from 2).
P r ep a r a tion of P yr a zoloisoqu in olin es 5 a n d 9.
Pyrazole 2 was prepared in overall 77% yield by regiose-
lective C-4 iodination of 13, using 3 equiv of iodine
monochloride, followed by acetalization of the formyl
group. No competitive iodination in the C-5 phenyl ring
was observed, most likely due to its deactivation by the
electron-withdrawing formyl group. The presence of
bulky substituents in 2 (iodine and 1,3-dioxolane) caused
restricted rotation around the pyrazole-phenyl C-C
The pyrazoloisoquinoline 9 was synthesized using a
similar approach as for the synthesis of 5. Employing our
recently reported3 methodology for regiospecific arylation
in the 4-position of 1-(benzyloxy)pyrazole via iodine
magnesium exchange of 1-(benzyloxy)-4-iodopyrazole (7)
followed by transmetalation with ZnCl2 and then by Pd-
catalyzed Negishi cross-coupling using 2-bromobenzal-
dehyde furnished 1-(benzyloxy)-4-(2-formylphenyl)pyra-
zole. Immediate protection of the formyl group via
acetalization produced the ethylene acetal 8 in 73% yield
(two steps). Pyrazole 8 was selectively lithiated at C-5
when treated with 1.2 equiv of n-BuLi in THF at -78 °C
for 5 min (Scheme 2). Quenching the pyrazol-5-yllithium
intermediate with 4-toluenesulfonyl azide and subse-
quent workup with tetrasodium pyrophosphate as de-
scribed above produced the C-5 azido intermediate along
with unchanged starting material 8 in a 55:45 ratio as
determined from relative intensities of ethylene acetal
1
bond, giving rise to atropoisomerism, as observed in H
NMR of 2, where the CH2 protons of the benzyloxy group
resonate as a characteristic AB system (J gem ) 10.4 Hz)
at 5.21 and 5.07 ppm. Iodine-lithium exchange with 2
proved to be a suitable method to introduce a nitrogen-
containing electrophile at the C-4 position. In a test
experiment, 2 was treated with n-BuLi at -78 °C for 5
min. Subsequent reaction with MeOD resulted in com-
plete conversion and nearly quantitative (98%) deuterium
incorporation at C-4 (collapse of the benzylic AB system
to a singlet in 1H NMR). Introduction of the azido
functionality was achieved by employing the procedure
described for preparation of azidothiophenes.6,7 Intercep-
tion of the putative pyrazol-4-yllithium intermediate with
4-toluenesulfonyl azide in THF solution at -70 °C for 5
1
CH signals at 5.65 and 5.50 ppm, respectively, in the H
NMR spectrum of the crude product. This ratio appeared
quite constant, even when we attempted to increase the
(8) Almost no (less than 5%) competitive C-4 protonation was seen
in the 1H NMR spectrum of crude 3.
(9) For recent reviews related to the application of the Staudinger/
aza-Wittig protocol in heterocyclic synthesis, see: (a) Gusar, N. I. Russ.
Chem. Rev. 1991, 60, 146. (b) Eguchi, S.; Matsushita, Y.; Yamashita,
K. Org. Prep. Proced. Int. 1992, 24, 209.
(10) As 4 was not well soluble in toluene, used as a common solvent
for this reaction, THF was added to allow a homogeneous mixture.
(5) Negishi, E. I.; King, A. O.; Okukado, N. J . Org. Chem. 1977, 42,
1821.
(6) Spagnolo, P.; Zanirato, P. J . Org. Chem. 1978, 43, 3539.
(7) Spagnolo, P.; Zanirato, P.; Gronowitz, S. J . Org. Chem. 1982,
47, 3177.

Pyrazolo[3,4-c]- and Pyrazolo[4,3-c]quinolines
J . Org. Chem., Vol. 65, No. 26, 2000 9003
Sch em e 3
Sch em e 4
failed.14 Instead, we decided to investigate compounds
containing a properly protected amino group. However,
attempted C-4 iodination of 10a or 10b using ICl (Scheme
3) caused cleavage of the Boc-group in 10b and nonselec-
tive iodination in the phenyl ring, giving rise to a mixture
of three products identified as tri-, di-, and monoiodinated
aniline derivatives according to LC/MS. Moreover, iodine
in the monoiodinated compound was situated in the
phenyl ring, reflecting its activation by the amino group.
Although pyrazole 11a could be made from 7 by LDA-
promoted C-5 lithiation followed by ZnCl2 transmetala-
tion and Negishi type5 cross-coupling with 2-iodoaniline
under Pd(0) catalysis (Scheme 3), the yield of this
reaction was only 43%.15 Moreover, Boc protection of 11a
appeared cumbersome since starting material was re-
covered even after 24 h of reflux with 4 equiv of Boc2O.
We then examined iodination of the more stable pivaloyl-
protected derivative 10c, obtained in 100% yield from
10a . Pyrazole 10c was quantitatively converted into
11b,16 using ICl. To investigate the iodine-metal ex-
change, 11b was reacted with different bases followed
by quenching with MeOD. i-PrMgBr gave ca. 45% (50
min at 0 °C), ca. 50% (30 min at room temperature), and
100% (90 min at room temperature) iodine-magnesium
exchange, n-BuLi afforded ca. 50% iodine-lithium ex-
change (5 min at -78 °C), and MeLi furnished 100%
iodine-lithium exchange (5 min at -78 °C) as deter-
mined from relative intensities of the benzylic CH2 group
signals of 10c and 11b at 5.17 and 5.12 ppm, respectively.
Despite the MeOD quenching after the base treatments,
quantitative competitive protonation took place at C-4
in all the cases. This proton might be transferred from
the secondary amide, indicating that iodine-metal ex-
change is faster than amide deprotonation. This transfer
happened even when we attempted to remove the amide
proton (e.g., with NaH or LDA) prior to treatment with
i-PrMgBr, n-BuLi, or MeLi.
conversion by extending the reaction time (30 h at -78
°C) or raising the reaction temperature (up to 0 °C for 1
h). The noticeably lower (ca 55%) incorporation of the
azido group into 8 than in the case of 2 (>95%) may be
explained by a less-favored conversion of 8 to its triazene
salt due to steric hindrance at the pyrazole C-5 position
caused by the presence of two bulky neighboring groups
(benzyloxy and 2-[1,3]dioxolan-2-yl-phenyl).11 In contrast,
the conversion of 2 to its triazene analogue is only
hampered by the presence of one bulky neighboring group
(2-[1,3]dioxolan-2-yl-phenyl) allowing 4-toluenesulfonyl
azide better access to the reaction center and subse-
quently affording a sterically less-hindered triazene salt.
Subsequent hydrolysis of 8 by 2 M HCl followed by the
Staudinger/intramolecular aza-Wittig reaction afforded
the cyclized pyrazoloisoquinoline 9. The two final steps
were effected in almost quantitative yield, leaving the
triazene salt formation as the only yield limiting reaction
of the 8 to 9 sequence, thereby producing 9 in 52% yield
(from 8). The major side product 1-(benzyloxy)-4-(2-
formyl-phenyl)pyrazole (ca 35%) was easily separated by
chromatography after the final workup and could be
recycled.
P r ep a r a tion of P yr a zoloqu in olin es 14 a n d 18. As
suggested in the retrosynthetic analysis (Scheme 1),
construction of 14 was intended starting from 10a -d
(Scheme 3).2 Halogenation followed by halogen-metal
exchange would give a C-4 metalated pyrazole. Reacting
such species with a suitable electrophile (e.g., DMF)
followed by acidic workup would then produce a C-4
formylated intermediate and lead to a facile cyclization
to 14 (Scheme 4). In search for useful precursors for a
convenient C-4 metalated pyrazole, we initially synthe-
sized 11c, in a quantitative yield via regioselective C-4
iodination of 10d ,2 using ICl. Introduction of formyl group
via iodine-metal exchange would allow examination of
a ring-closing methodology involving nitro and formyl
groups used successfully for synthesis of furo[2,3-c]-
quinolines12 and phenanthridines.13 However, all our
attempts to introduce even a fast electrophile such as
deuterium (MeOD) into 11c via iodine-magnesium
exchange using i-PrMgBr (used smoothly for functional-
ization of 73) or iodine-lithium exchange using t-BuLi
Hence we decided to di-protect the amino group in 10a
as a benzophenoneimine. Using the method described by
Love and Ren17 for preparation of sterically hindered
(14) There are successful examples of iodine-lithium exchange of
nitro-functionalized aryl and alkenyl iodides, typically performed at
-80 to -100 °C: (a) Tucker, C. E.; Majid, T. N.; Knochel, P. J . Am.
Chem. Soc. 1989, 114, 3983 and the references therein. (b) Klement,
I.; Rottla¨nder, M.; Tucker, C. E.; Majid, T. N.; Knochel, P. Tetrahedron
1996, 52, 7201.
(15) Quenching of the putative 5-lithio-4-iodo-1-benzyloxypyrazole
gave 83% deuteration and 17% of starting material, according to 1H
NMR.
(11) A control experiment consisting of reacting the pyrazol-5-
yllithium intermediate with the fast, less bulky electrophile methyl
iodide resulted in quantitative conversion to the corresponding 5-me-
thylated compound, clearly demonstrating complete formation of the
anion within 5 min at -78 °C.
(16) Alternatively 11b was made by pivaloylation of 11a in 92%
yield, but this route is clearly disfavored by the low yield (43%) in the
cross-coupling step from 7 to 11a .
(12) Yang, Y. Synth. Commun. 1989, 19, 1001.
(13) Li, D.; Zhao, B.; LaVoie, E. J . J . Org. Chem. 2000, 65, 2802.

9004 J . Org. Chem., Vol. 65, No. 26, 2000
Pawlas et al.
Sch em e 5
Sch em e 6
imines, 12 was prepared in 68% yield by heating a
mixture of amine 10a , benzophenone, tetraethyl ortho-
silicate, and catalytic amounts of concentrated sulfuric
acid with continuous removal of ethanol using a Dean-
Stark trap. Subsequent iodination produced 13 in 87%
yield. Careful reaction time control (2 h at room temper-
ature) was required to obtain good results, as prolonged
reaction time caused substantial cleavage of the imine
followed by iodination in the aminophenyl ring. To
optimize formation of 14 via a C-4 formylated intermedi-
ate, iodine-magnesium and iodine-lithium exchange in
13 was investigated. Treatment of 13 with i-PrMgBr at
0 °C for 1 h followed by a MeOD quench gave almost
complete cleavage of the imino group, resulting in forma-
tion of benzophenone and 11a . Almost no iodine-
magnesium exchange was observed. MeLi exhibited only
partial (ca 25%) iodine-lithium exchange at -78 °C,
whereas reaction of 13 with n-BuLi under similar condi-
tions gave almost complete I-Li exchange and no sig-
nificant addition to the imine.18 However, approximately
30% competitive protonation at C-4 took place. This
reaction was suppressed by adding 13 to a solution of
n-BuLi (2.2 equiv) in THF at -78 °C, and after 15 min
the putative 4-lithio intermediate was reacted with DMF
for 1 h at room temperature. Quench with 4 M HCl
provided the C-4 formylated intermediate, and simulta-
neous hydrolysis of the imine followed by spontaneous
cyclization afforded the desired tricyclic pyrazoloquino-
line 14 in 70% yield (Scheme 4).
been described for the synthesis of a series of function-
alized phenantridines,20 though in this case the formyl
group was preinstalled in the cross-coupling step.
Deben zyla tion . Debenzylation of 5, 9, 14, and 18 to
give corresponding N-hydroxypyrazoloquinolines/isoquin-
olines 19-22 was examined by two different strategies.
First we investigated palladium-catalyzed hydrogenoly-
sis, as related structures previously were deprotected this
way.21 However, it appeared that this methodology is of
limited applicability to our case, since attempted deben-
zylation of 5 using 10% Pd/C in MeOH at 1 atm H2
resulted in unchanged starting material even at elevated
temperature (68 °C) for prolonged time (36 h). When 18
was subjected to the same treatment with H2 at 2 atm,
a mixture of 22 and its dehydroxylated analogue was
formed in approximately 1:1 ratio according to 1H NMR.
On the basis of the preliminary studies, it seems difficult
to achieve a Pd-catalyzed hydrogenolysis debenzylation
protocol for 5, 9, 14, and 18 to give 19-22 with acceptable
chemoselectivity, and we turned to investigate acid-
induced debenzylation. In fact, selective debenzylation
of 5, 9, 14, and 18 to give 19-22 could be effected using
concentrated H2SO4 at 70 C° for 30 min to afford 19-22
in 91-94% yields (Scheme 6). Alternatively, the deben-
zylation could be achieved with 47% HBr at 70 C° for 1
h, as shown by deprotecting 18 to 22.
In conclusion, we furnished 19-22 starting from C-4
and C-5 substituted benzyloxypyrazoles 1, 7, 10a , and
15 in short, relatively high yielding de novo sequences.
Benzyloxypyrazoles 5, 9, 14, and 18 were produced in a
few steps, with focus on organometallics containing
suitably protected electron-donating and electron-with-
drawing groups, generated using metalation and halogen-
metal exchange tactics. These key intermediates were
then used as sources for ring closure precursors in a new,
uncommon way. Quantitative and easily extensible meth-
odology for deprotection of 5, 9, 14, and 18 to 19-22 was
developed. In that manner, a family of four classes of
unique, novel tricyclic fused N-hydroxyheteroaromatics
was accessed.
Finally, 18 was made from 153 in a simple two-step
sequence. First the amino group in 15 was Boc protected
to give 16 in 90% yield. Compound 16 was then treated
with 2.2 equiv of n-BuLi for 5 min at -78 °C to produce
a positionally stable lithiodianion 17.19 This dianion was
then reacted with DMF. Subsequent heating to room
temperature and quenching with 4 M HCl triggered
three, spontaneous processes: (i) Acid-induced Boc-
deprotection; (ii) hydrolysis of the aminal to give a formyl
group; (iii) condensation of the amino and the formyl
groups thus formed to produce 18 in 83% yield (Scheme
5). A similar ring-closing strategy involving interaction
of N-(tert-butoxycarbonyl)amino- and formyl groups based
on directed metalation and cross-coupling tactics has
Exp er im en ta l Section
(17) Love, B. E.; Ren, J . J . Org. Chem. 1993, 58, 5556.
Gen er a l Meth od s. See ref 3. The assignment of 1H and
13C NMR signals of the tricyclic compounds were based on the
two singlets from the R-pyridine and H-3 protons having
distinct shift values at ca. 9.1 ppm and 8.1-8.6 ppm, respec-
(18) Buchwald and co-workers have reported that benzophenone
imine protected 4-bromoaniline undergoes bromine-lithium exchange
without substantial (<5%) addition to the imine when subjected to
n-BuLi in THF at -78 °C: Wolfe, J . P.; A° hman, J .; Sadighi, J . P.;
Singer, R. A.; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6367.
(19) The positions of the charges were confirmed quenching the
dianion 17 with excess of methyl iodide, producing the corresponding
N,C-5 dimethylated derivative in quantitative yield.
(20) Siddiqui, M. A.; Snieckus, V. Tetrahedron Lett. 1988, 29, 5463.
(21) Vedsø, P.; Begtrup, M. J . Org. Chem. 1995, 60, 4995.

Pyrazolo[3,4-c]- and Pyrazolo[4,3-c]quinolines
J . Org. Chem., Vol. 65, No. 26, 2000 9005
tively. The remaining protons could then be assigned from 2D
H-H correlated (COSY and/or NOESY) spectra. The C-H
carbon signals were then assigned from correlations in the
HSQC spectra, and finally the quaternary carbon signals were
determined from correlations in the HMBC spectra. Aromatic
1H NMR and 13C NMR signals from the benzyloxy group are
referred to as arom H and arom C; quaternary carbon signals
from the same group are referred to as Ci.
i-PrMgBr in THF (4.5 mL, 3.9 mmol) over 2 min. Stirring was
continued for 1 h at 0 °C, before 1 M ZnCl2 in Et2O (4.5 mL,
4.5 mmol) was added. After stirring for 1 h at room temper-
ature, 2-bromobenzaldehyde (830 mg, 4.5 mmol) and Pd(PPh3)4
(0.06 mmol) in DMF (7.5 mL) was added. After heating to 80
°C for 1 h, saturated aqueous NH4Cl (20 mL) and water (20
mL) were added. Extraction with dichloromethane (3 × 20
mL), drying of the combined organic phases (MgSO4), filtration,
and removal of the dichloromethane gave crude 1-(benzyloxy)-
4-(2-formylphenyl)pyrazole. FC (heptane/EtOAc 3:1) and ac-
etalization as described for 2 gave 0.70 g (73%) of 8 as yellow
brownish crystals, mp 112-113 °C (EtOAc-heptane). Rf
(EtOAc-heptane, 1:2) 0.30. δH (CDCl3): δ 7.70-7.66 (m, 1H),
7.49 (d, J ) 1.0 Hz, 1H), 7.39-7.25 (m, 9H), 5.50 (s, 1H), 5.33
(s, 2H), 4.21-3.90 (m, 4H). δC (CDCl3): δ 134.00, 133.86,
133.05, 131.84, 129.88, 129.35, 129.30, 129.19, 128.68, 127.14,
126.02, 122.90, 117.40, 101.06, 80.47, 65.32. Anal. Calcd for
1-Ben zyloxy-5-(2-[1,3]d ioxola n -2-yl-p h en yl)-4-iod op y-
r a zole (2). 12 (1.7 g, 6.1 mmol) was dissolved in CH2Cl2 (10
mL), K2CO3 (2.63 g, 18.3 mmol) was added, and the reaction
mixture was treated with ICl (2.98 g, 18.3 mmol) dissolved in
CH2Cl2 (10 mL). After stirring for 16 h at room temperature,
the reaction was quenched with Na2SO3 (1 M, 20 mL) and
extracted with CH2Cl2 (3 × 10 mL). The organic phase was
dried over MgSO4 and evaporated to dryness. A mixture of
the crude product (2.45 g, 6.1 mmol), dry ethylene glycol (0.75
g, 12 mmol), benzenesulfonic acid (0.10 g), and toluene (100
mL) was refluxed for 2 h, removing the water formed in a
Dean-Stark trap. Most of the solvent was removed under
reduced pressure, and extraction with ether (3 × 10 mL),
washing with 5% aqueous sodium hydrogen carbonate and
water, drying over MgSO4, and removal of the ether gave the
crude product, which was subjected to flash chromatography
(FC) (EtOAc-heptane, 1:2), to give 2.1 g (77%) of 1-benzyloxy-
5-(2-[1,3]dioxolan-2-yl-phenyl)-4-iodopyrazole 2 as colorless
crystals, mp 101-102 °C (EtOAc-heptane). Rf (EtOAc-
heptane, 1:2) 0.37. δH (CDCl3) 7.72 (dd, J ) 7.9, 0.9 Hz, 1H),
7.50 (dt, J ) 7.6, 1.1 Hz, 1H), 7.44 (s, 1H), 7.35-7.18 (m, 4H),
7.00-6.97 (m, 2H), 6.78 (dd, J ) 7.6, 1.0 Hz, 1H), 5.71 (s, 1H),
5.21 (d, J ) 10.4 Hz, 1H), 5.07 (d, J ) 10.4 Hz, 1H), 4.05-
3.88 (m, 4H). δC (CDCl3): 137.75, 137.70, 136.47, 133.20,
131.27, 129.92, 129.81, 129.10, 128.97, 128.48, 126.75, 126.58,
C
20H22N2O3: C, 70.79; H, 5.63; N, 8.69. Found: C, 70.91; H,
5.73; N, 8.65.
1-Ben zyloxyp yr a zolo[3,4-c]isoqu in olin e (9). 8 (320 mg,
1 mmol) was subjected to the same procedure as described for
2. FC (heptane/EtOAc 3:1) gave 140 mg (52%) of 9 as yellow
crystals, mp 91-92 °C (EtOAc-heptane). Rf (EtOAc-heptane,
1:2) 0.35. δH (CDCl3): 9.01 (s, 1H, H-8), 8.17 (d, J ) 8.2 Hz,
1H, H-4), 8.12 (s, 1H, H-3), 8.07 (d, J ) 8.1 Hz, 1H, H-7), 7.83
(dt, J ) 7.1, 1.2 Hz, 1H, H-5), 7.59 (dt, J ) 7.0, 1.0 Hz, 1H,
H-6), 7.55-7.32 (m, 5H, H arom), 5.52 (s, 2H, OCH2Ph). δC
(CDCl3): 153.83 (C-8), 141.12 (C-9a), 133.82 (Ci), 132.00 (C-
5), 130.23 (C-7a), 129.81 (arom C), 129.37 (arom C), 129.13
(arom C), 128.50 (arom C), 125.55 (C-6), 125.36 (C-3b), 124.72
(C-3), 122.24 (C-4), 107.75 (C-3a), 81.02 (CH2 Bn). Anal. Calcd
for C17H13N3O: C, 74.17; H, 4.76; N 15.26. Found: C, 74.16;
H, 4.83; N, 15.13.
N-2-(1-Ben zyloxyp yr a zol-5-yl)p h en ylb en zop h en on e-
im in e (12). A mixture of benzophenone (4.15 mmol), 10a 2 (3.77
mmol), Si(OEt)4 (4.6 mmol), and one drop of concd H2SO4 was
placed in a flask equipped with a still head. The solution was
heated at 160 °C under nitrogen overnight. The distillate
(EtOH) was discarded, the residue was dissolved in Et2O (20
mL), washed with saturated NaHCO3 solution and H2O (10
mL each), and dried (MgSO4), and the solvents were removed.
FC (heptane/EtOAc 5:1) gave 1.1 g (68%) of 12 as bright yellow
crystals, mp 128-130 °C (EtOAc-heptane). Rf (EtOAc-
heptane, 1:2) 0.46. δH (CDCl3) 7.75-6.75 (m, 20H), 6.24 (d, J
) 2.3 Hz, 1H), 4.62 (s, 2H). δC (CDCl3): 167.85, 149.41, 139.09,
135.99, 133.44, 132.90, 132.35, 130.86, 129.93, 129.63, 129.43,
129.04, 128.91, 128.83, 128.69, 128.41, 128.25, 127.86, 123.04,
121.52, 117.96, 105.21, 80.21. Anal. Calcd for C29H23N3O: C,
81.09; H, 5.40; N, 9.78. Found: C, 81.18; H, 5.11; N, 9.60.
N-2-(1-Ben zyloxy-4-iod op yr a zol-5-yl)p h en ylben zop h e-
n on eim in e (13). 12 (0.40 g, 0.92 mmol) was iodinated the
same way as 1, quenching the reaction after 2 h. FC (heptane/
EtOAc 5:1) gave 0.45 g (87%) of 13 as yellow brownish crystals,
mp 144-146 °C (EtOAc-heptane). Rf (EtOAc-heptane, 1:2)
0.56. δH (CDCl3) 7.66-6.70 (m, 19H), 7.31 (s, 1H), 5.22 (d, J )
10 Hz, 1H), 5.19 (d, J ) 10 Hz, 1H). δC (CDCl3): 168.13, 149.94,
139.45, 138.03, 136.11, 135.85, 133.51, 131.37, 130.63, 129.62,
129.55, 129.45, 128.94, 128.85, 128.42, 128.02, 127.94, 125.90,
101.49, 80.49, 65.35, 65.24, 58.36. Anal. Calcd for C19H17
IN2O3: C, 50.91; H, 3.82; N, 6.25. Found: C, 51.02; H, 3.81;
N, 6.22.
-
1-Ben zyloxyp yr a zolo[4,3-c]isoqu in olin e (5). To a solu-
tion of 2 (200 mg, 0.45 mmol) in THF (2 mL) was added
dropwise n-BuLi (0.23 mL, 0.49 mmol, 2.12 M in hexanes) with
stirring at -78 °C. After 5 min, tosyl azide22 (110 mg, 0.54
mmol) in THF (1 mL) was added dropwise. When the addition
was complete, the resulting mixture was stirred for 5 h at -78
°C, and the solution was allowed to warm to room temperature.
Tetrasodium pyrophosphate decahydrate (240 mg, 0.54 mmol)
in water (10 mL) was added, and after stirring overnight at
room temperature, the organic layer was separated and the
aqueous solution was extracted twice with ether (2 × 10 mL).
The combined organic extracts were stirred with 2 N HCl (50
mL) at room temperature for 3 h, to give 2-(4-azido-1-
benzyloxy-pyrazol-5-yl)benzaldehyde (4), which was washed
with 5% aqueous sodium hydrogen carbonate and water, dried
over MgSO4, and evaporated to dryness. The residue was
dissolved in toluene (15 mL) with dry THF (1 mL) under
nitrogen, and tributylphosphine (100 mg, 0.49 mmol) was
added. The mixture was stirred for 2 h at room temperature,
washed with saturated aqueous KOH (10 mL), and dried over
MgSO4, before the solvents were evaporated. FC (heptane/
EtOAc, 4:1 f 1:1) gave 86 mg (72%) of 5 as slightly yellowish
crystals, mp 91-92 °C (EtOAc-heptane). Rf (EtOAc-heptane,
1:2) 0.18. δH (CDCl3) 8.98 (s, 1H, H-5), 8.47 (d, J ) 8.2 Hz,
1H, H-9), 8.10 (s, 1H, H-3), 8.08 (d, J ) 7.9 Hz, 1H, H-6), 7.80
(dt, J ) 7.1, 1.2 Hz, 1H, H-8), 7.68 (dt, J ) 7.6, 1.2 Hz, 1H,
H-7), 7.48-7.31 (m, 5H, H arom), 5.50 (s, 2H, OCH2Ph). δC
(CDCl3): 150.18 (C-5), 133.21 (Ci) 132.78 (C-3A), 130.87 (C-8),
129.93 (arom C), 129.45 (C-6), 128.73 (arom C and C-3), 127.58
(C-7), 127.26 (arom C-5A), 122.58 (C-9B), 122.10 (C-9A), 121.81
(C-9), 80.72 (CH2 Bn). Anal. Calcd for C17H13N3O: C, 74.17;
H, 4.76; N 15.26. Found: C, 73.98; H, 4.78; N, 14.96.
122.94, 121.28, 118.89, 80.30, 58.09. Anal. Calcd for C29H22
-
IN3O: C, 62.71; H, 3.99; N, 7.57. Found: C, 62.69; H, 4.07; N,
7.48.
1-Ben zyloxyp yr a zolo[4,3-c]qu in olin e (14). To a solution
of n-BuLi (1.05 mL, 2.20 mmol, 2.12 M in hexanes) in THF (2
mL) was added dropwise 13 (0.55 g, 1 mmol) in THF (2 mL)
with stirring at -78 °C. After 15 min, DMF (1.50 mL, 19.5
mmol) was added. Stirring was continued for 1 h, and the
reaction mixture was allowed to warm to room temperature
over 1 h and stirred for a further 1 h before 5 mL of 4 M HCl
was added. The solution was stirred overnight and extracted
with CH2Cl2 (3 × 10 mL), the organic layer was washed with
saturated NaHCO3 solution and H2O (10 mL each) and dried
(MgSO4), and the solvents were removed. FC (heptane/EtOAc
2:1 f 1:2) gave 190 mg (70%) of 14 as yellow brownish crystals,
mp 112-113 °C (EtOAc-heptane). Rf (EtOAc-heptane, 1:2)
0.23. δH (CDCl3) 9.10 (s, 1H, H-4), 8.50 (dd, J ) 8.3, 1.3 Hz,
1-Ben zyloxy-4-[2-(d ioxola n -2-yl)p h en yl]p yr a zole (8).
To a stirred solution of 1-(benzyloxy)-4-iodopyrazole (7)3 (900
mg, 3 mmol) in THF (3 mL) at 0 °C was added 0.85 M
(22) Regitz, M.; Hocker, J .; Liedhegener, A. Organic Syntheses;
Wiley: New York, 1973; Collect. Vol. V, p 179.

9006 J . Org. Chem., Vol. 65, No. 26, 2000
Pawlas et al.
1H, H-9), 8.18 (dd, J ) 8.0, 0.5 Hz, 1H, H-6), 8.01 (s, 1H, H-3),
7.73 (m, 1H, H-7), 7.64-7.55 (m, 1H, H-8), 7.49-7.31 (m, 5H,
H arom), 5.52 (s, 2H, OCH2Ph). δC (CDCl3): 145.61 (C-4),
145.43 (C-5a), 132.90 (Ci), 132.63 (C-9b), 129.95 (arom C),
129.86 (C-6), 129.59 (arom C), 129.19 (C-7), 128.79 (arom C),
128.67 (C-3), 126.85 (C-8), 122.34 (C-9), 114.89 (C-9a), 114.68
(C-3a), 81.00 (CH2 Bn). Anal. Calcd for C17H13N3O: C, 74.17;
H, 4.76; N 15.26. Found: C, 74.20; H, 4.78; N, 15.08.
1-Ben zyloxyp yr a zolo[3,4-c]qu in olin e (18). A solution of
153 (0.25 g, 0.95 mmol) and di-tert-butyl dicarbonate (0.23 g,
1.04 mmol) in THF (10 mL) was heated at reflux temperature
for 16 h, THF was removed, the residue was dissolved in ethyl
acetate, and this solution was washed successively with 1 M
citric acid solution and brine (15 mL each). FC (heptane/EtOAc
0:1 f 1:4) gave 310 mg (90%) of 16 as a yellow oil. To a solution
of 16 (100 mg, 0.27 mmol) in THF (1 mL) was added dropwise
with stirring at -78 °C n-BuLi (0.31 mL, 0.66 mmol, 2.12 M
in hexanes). After 5 min, DMF (4.0 mmol, 0.31 mL) was added,
and the reaction was worked up the same way as 14. FC
(heptane/EtOAc 3:1) gave 62 mg (83%) of 18 as slightly yellow
crystals, mp 105-106 °C (Et2O-hexane). Rf (EtOAc-heptane,
3:5) 0.33. δH (CDCl3): 8.65 (s, 1H, H-9), 8.19 (s, 1H, H-3), 8.18-
8.08 (m, 2H, H-4, H-7), 7.70-7.58 (m, 2H, H-5, H-6), 7.38-
7.25 (m, 5H, H-arom), 5.48 (s, 2H, OCH2Ph). δC (CDCl3):
142.62 (C-7A), 135.72 (C-9), 133.43 (Ci), 130.18 (C-7), 129.99
(arom C), 129.83 (arom C), 128.86 (arom C), 128.62 (C-9a),
128.01 (C-5 or C-6), 127.00 (C-5 or C-6), 125.90 (C-3), 122.60
(C-4), 121.25 (C-3b), 120.13 (C-3a), 81.23 (CH2 Bn). Anal. Calcd
for C17H13N3O: C, 74.17; H, 4.76; N 15.26. Found: C, 74.44;
H, 4.75; N, 15.00.
OH), 9.17 (s, 1H, H-8), 8.37 (d, J ) 7.9 Hz, 1H, H-4), 8.21 (s,
1H, H-3), 8.25 (d, J ) 8.0 Hz, 1H, H-7), 7.91 (dt, J ) 7.0, 1.2
Hz, 1H, H-5)0.7.63 (dt, J ) 7.1, 1.0 Hz, 1H, H-6). δC (DMSO-
D6): 153.34 (C-8), 140.42 (C-9A), 132.10 (C-5), 129.64 (C-3B),
129.44 (C-7), 125.43 (C-6), 124.72 (C-7A), 123.58 (C-3), 122.32
(C-4), 106.97 (C-3A). HRMS (ESI) calcd for C10H8N3O (M +
H)+ 186.0667, found 186.0669 ( 0.0005. Anal. Calcd for
C
10H7N3O‚10H2O: C, 64.22; H, 3.88; N 22.48. Found: C, 64.43;
H, 3.86; N, 22.12.
1-Hyd r oxyp yr a zolo[4,3-c] qu in olin e (21). Following the
procedure described for preparation of 19 using 14, continuous
extraction with Et2O for 12 h gave 31 mg (91%) of 21 as yellow
crystals, mp 211-212 °C (methanol). Rf (EtOAc-heptane-
methanol, 4:1:1) 0.36. δH (DMSO-D6): 13.50 (br s, OH), 9.16
(s, 1H, H-4), 8.68 (dd, J ) 7.9, 1.1 Hz, 1H, H-6), 8.12 (d, J )
6.3 Hz, 1H, H-9), 8.11 (s, 1H, H-3), 7.82-7.65 (m, 2H, H-7,
H-8). δC (DMSO-d6): δ 146.04 (C-4), 144.62 (C-5A), 130.97 (C-
9B), 129.28 (C-3), 128.81 (C-7), 127.42 (C-6), 126.67 (C-8),
122.32 (C-9), 115.04 (C-9A), 114.38 (C-3A). HRMS (ESI) calcd
for C10H8N3O (M + H)+ 186.0667, found 186.0672 ( 0.0005.
Anal. Calcd for C10H7N3O‚24H2O: C, 63.78; H, 3.91; N 21.60.
Found: C, 63.38; H, 3.98; N, 22.17.
1-Hyd r oxyp yr a zolo[3,4-c]qu in olin e (22). Following the
procedure described for preparation of 19 using 18, extraction
with Et2O (3 × 10 mL) gave 31 mg (91%) of 22 as orange
crystals, mp 191-192 °C (methanol). Rf (EtOAc-heptane-
methanol, 4:1:1) 0.28. δH (CD3OD): 9.18 (s,1H, H-9), 8.37-
8.31 (m, 1H, H-4), 8.27 (s, 1H, H-3), 8.18-8.12 (m, 1H, H-7),
7.77-7.65 (m, 2H, H-5, H-6). δC (CD3OD): 143.18 (C-7a),
137.54 (C-9), 130.07 (C-7), 129.65 (C-5), 129.34 (C-9a), 128.44
(C-6), 125.72 (C-3), 124.30 (C-4), 123.21 (C-3a), 121.90 (C-3b).
HRMS (ESI) calcd for C10H8N3O (M + H)+ 186.0667, found
186.0665 ( 0.0005.
Deben zyla tion of 1-(Ben zyloxy)p yr a zoles 5, 9, 14, a n d
18.
1-Hyd r oxyp yr a zolo[4,3-c]isoqu in olin e (19). A mixture
of 5 (50 mg, 0.18 mmol) and concentrated H2SO4 (10 mL) was
stirred for 1 h at 80 °C. Washing with toluene (1 mL),
adjustment of the pH of the aqueous solution with 4 M NaOH
to pH 10, washing with dichloromethane (3 × 10 mL), addition
of concentrated HCl to pH ca. 5, extraction with Et2O (3 × 10
mL), drying of the combined organic phases, and removal of
the solvent afforded 32 mg (94%) of 19 as slightly yellowish
crystals, mp 202-203 °C (methanol). Rf (EtOAc-heptane-
methanol, 4:1:1) 0.52. δH (CD3OD): 8.98 (s, 1H, H-5), 8.77 (d,
J ) 7.9 Hz, 1H, H-9), 8.25 (d, J ) 8.1 Hz, 1H, H-6), 8.00-7.90
(m, 1H, H-8), 7.93 (s, 1H, H-3), 7.84-7.76 (m, 1H, H-7). δC
(CD3OD): 151.16 (C-5), 133.35 (C-9b), 132.91 (C-8), 130.45 (C-
6), 129.24 (C-7), 128.81 (C-5a), 127.41 (C-3), 124.20 (C-9a),
124.00 (C-3a), 123.24 (C-9). HRMS (ESI) calcd for C10H8N3O
(M + H)+ 186.0667, found 186.0665 ( 0.0005.
1-Hyd r oxyp yr a zolo[3,4-c]qu in olin e (22). A mixture of 18
(50 mg, 0.18 mmol) and 10 mL of aqueous hydrogen bromide
(47%) was stirred for 1 h at 60 °C, before washing with toluene
(1 mL). Evaporation of HBr and FC (EtOAc-heptane-
methanol, 4:1:2) gave 33 mg (97%) of 22, identical with the
material described above.
Ack n ow led gm en t. This work was supported by the
Corporate Research Affairs at Novo Nordisk A/S and
The Graduate School of Drug Research at The Royal
Danish School of Pharmacy by a graduate fellowship
to J .P. We thank Dr. J ørgen Møller from the University
of Southern Denmark for performing HRMS analyses.
Su p p or tin g In for m a tion Ava ila ble: The description of
the synthesis of compounds 11a -c, and 1H and 13C NMR
spectra of compounds 11a , 11c, and 19-22. This material is
available free of charge via the Internet: http://pubs.acs.org.
1-Hyd r oxyp yr a zolo[3,4-c]isoq u in olin e (20). Following
the procedure described for preparation of 19 using 9, extrac-
tion with Et2O (3 × 10 mL) gave 32 mg (94%) of 20 as green
yellowish crystals, mp 182-185 °C (methanol). Rf (EtOAc-
heptane-methanol, 4:1:1) 0.48. δH (DMSO-d6): 13.55 (br s,
J O000986V