A Combination of Tandem Amine-Exchange/Heterocyclization and Biaryl Coupling Reactions for the Straightforward Preparation of Phenanthro[9,10-d]pyrazoles

Article abstract of DOI:10.1021/jo000609i

The tandem amine-exchange/heterocyclization of enaminoketones is successfully applied to the regioselective preparation of a series of new 4,5-diarylpyrazoles by reaction of phenylhydrazine and several 3-N,N-(dimethylamino)-1,2-diarylpropenones. The comparison of a vast array of biaryl coupling procedures provides general, complementary approaches to new phenanthro[9,10-d]-pyrazoles. The most efficient procedures for this final step in the construction of the tetracyclic system are based on a Stille-type tandem stannylation - biaryl coupling of o,o′-dihalogenated diarylpyrazoles and an hypervalent iodine-mediated nonphenolic oxidative coupling of nonhalogenated precursors.

Full text of DOI:10.1021/jo000609i

7010
J . Org. Chem. 2000, 65, 7010-7019
A Com bin a tion of Ta n d em Am in e-Exch a n ge/Heter ocycliza tion a n d
Bia r yl Cou p lin g Rea ction s for th e Str a igh tfor w a r d P r ep a r a tion of
P h en a n th r o[9,10-d ]p yr a zoles
Roberto Olivera, Raul SanMartin, and Esther Dom´ınguez*
Kimika Organikoa Saila, Zientzi Fakultatea, Euskal Herriko Unibertsitatea, P.O. Box 644,
48080 Bilbao, Spain
qopdopee@lg.ehu.es
Received April 20, 2000
The tandem amine-exchange/heterocyclization of enaminoketones is successfully applied to the
regioselective preparation of a series of new 4,5-diarylpyrazoles by reaction of phenylhydrazine
and several 3-N,N-(dimethylamino)-1,2-diarylpropenones. The comparison of a vast array of biaryl
coupling procedures provides general, complementary approaches to new phenanthro[9,10-d]-
pyrazoles. The most efficient procedures for this final step in the construction of the tetracyclic
system are based on a Stille-type tandem stannylation-biaryl coupling of o,o′-dihalogenated
diarylpyrazoles and an hypervalent iodine-mediated nonphenolic oxidative coupling of nonhaloge-
nated precursors.
In tr od u ction
pounds,9 but lower yields and limited substitution pat-
terns have been described in most cases.10
Although scarcely found in nature,1 pyrazoles are
known not only as potent insecticides,2 herbicides,3 and
monomers for the preparation of electroluminiscent and
thermoresistant materials,4 but also as antitumor, anti-
inflamatory, antimicrobial, antipsychotic, or analgesic
agents.5 Thus, due to their wide range of pharmacological
and technological applications, pyrazoles have been the
focus of much synthetic effort in the past decades.6
Among the different methodologies for the synthesis of
the pyrazole framework, only a few examples of the
reaction between hydrazine derivatives and enaminoke-
tones have been reported so far.7 This protocol provides
better regioselectivity compared to (i) the addition of
hydrazines to 1,3-dicarbonyl compounds,8a (ii) the 1,3-
cycloaddition of diazoalkanes to alkynes,8b,c or (iii) the
addition of hydrazines to R,â-unsaturated carbonyl com-
Once we had demonstrated not only the synthetic
potential of the amine-exchange reaction/heterocycliza-
tion to prepare heterocycles such as isoxazoles and
pyrimidines,11 but also the viability of the Stille coupling
reaction of dihaloarylpyrimidines allowing the access to
phenanthro fused pyrimidines,12 we planned to expand
our strategy to the preparation of a new type of pyrazoles,
the phenanthro[9,10-d]pyrazoles 1. Toward this end,
enaminones 3 were selected as the starting material of
* To whom correspondence should be addressed. Tel: 34 94 6012577.
Fax: 34 94 4648500.
(1) Eicher, T.; Hauptmann, S. In The Chemistry of Heterocycles:
Structure, Reactivity, Syntheses and Applications; Thieme-Verlag: New
York, 1995; p 184.
(2) (a) Parlok, J . J . J . Heterocycl. Chem. 1998, 35, 1493-1499. (b)
Okada, J .; Itaru, O.; Shuku, W.; Wada, M.; Fukuchi, T.; Yoshiya, K.;
Takahashi Y. ACS Symp. Ser. 1998, 168-177.
(3) (a) Frinkelstein, B. L.; Strok, C. J . J . Pesticide Sci. 1997, 50,
324-328. (b) Schallner, O.; Heinz, K.-H.; Karl, K.-J . Ger. Offen DE,
1997, 19615259; Chem. Abstr. 1997, 127, 346387.
choice to develop an appealing synthetic approach based
on the biaryl coupling of diarylpyrazole intermediates 2
as the key step. In this context, it is worthy to remark
(8) (a) Coispeau, G.; Elguero, J . Bull. Soc. Chim. Fr. 1970, 7, 2717-
2736. (b) Behr, L. C.; Fusco, R.; J arboe, C. H. In The Chemistry of
Heterocyclic Compounds, Pyrazoles, Pyrazolines, Pyrazolidines, Inda-
zoles and Condensed Rings; Weissberger, A., Ed.; J ohn Wiley & Sons:
New York, 1967. (b) Tkagi, K.; Hubert-Habart, M. J . Heterocycl. Chem.
1996, 33, 1003-1008.
(9) (a) Elnagdi, N. H.; Elgeneie, G. E. H.; Abd-Elaal, F. A. Hetero-
cycles 1985, 23, 3121-3153. (b) Zelenin, K. N. Org. Proc. Int. 1995,
27, 521-540.
(10) (a) Barluenga, J .; Lo´pez-Ortiz, J . F.; Toma´s, M.; Gotor, V. J .
Chem. Soc., Perkin Trans. 1 1981, 1891-1893. (b) Bhardwaj, S.; J olly,
V. S. Orient. J . Chem. 1996, 12, 185-187. (c) Cacchi, S.; Fabrizi, G.;
Caragio, A. Synlett 1997, 959-960. (d) Makino, K.; Kim, H. S.;
Kurasawa, Y. J . Heterocyclic Chem. 1998, 35, 489-497. (e) Kadu, M.
V.; J amode, V. S. Asian J . Chem. 1998, 10, 480-483.
(11) (a) Dom´ınguez, E.; Ibeas, E.; Mart´ınez de Marigorta, E.;
Palacios, J . K.; SanMartin, R. J . Org. Chem. 1996, 61, 5435-5439. (b)
Dom´ınguez, SanMartin, R., Mart´ınez de Marigorta, E.; Olivera, R.
Synlett 1995, 955-956.
(12) Olivera, R.; Pascual, S.; Herrero, M.; SanMartin, R.; Domı´nguez,
E. Tetrahedron Lett. 1998, 39, 7155-7158.
(4) Valberkel, P. M.; Sherrington, D. C. Polymer 1996, 37, 1431-
1435.
(5) (a) Daidone, G.; Maggio, B.; Plescia, S.; Raffa, D.; Musiu, C.;
Milia, C.; Perra, G.; Marongiu, M. E. Eur. J . Med. Chem. 1998, 33,
375-382. (b) Tsuji, K.; Nakamurana, K.; Konishi, N.; Tojo, T.; Ochi,
T.; Scnoh, H.; Masuo, M. Chem. Pharm. Bull. 1997, 45, 987-995. (c)
Nauduri, D.; Reddy, G. Chem. Pharm. Bull. 1998, 46, 1254-1260. (d)
Gajare, A. S.; Bhawsar, S. B.; Shingare, M. S. Ind. J . Chem. 1997, 6,
321-322. (e) Wise, L. D.; Butler, D. E.; Dewald, H. A.; Lustgarten, D.
M.; Pattison, I. C.; Schweiss, D. N.; Coughenour, L. L.; Downs, D. A.;
Heffner, T. G.; Pugsley, T. A. J . Med. Chem. 1987, 30, 1807-1812. (f)
Brune, K. Med. Toxicol. (Suppl. 1) 1986, 1, 1-9.
(6) Elguero, J . In Comprehensive Heterocyclic Chemistry II; Katritz-
ky, A. R., Rees, C. W., Schriven, E. F. V., Eds.; Pergamon Press:
Oxford, 1996; Vol. 3, Chapter 2.1.
(7) Lue, P.; Greenhill, J . V. Adv. Heterocycl. Chem. 1997, 67, 225-
314 and references therein.
10.1021/jo000609i CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/26/2000

Straightforward Preparation of Phenanthro[9,10-d]pyrazoles
J . Org. Chem., Vol. 65, No. 21, 2000 7011
Ta ble 1. Syn th esis of Dia r ylp yr a zoles 2
Sch em e 1
R1
R2
R3
R4
X1
X2
2a (%)
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
OMe
H
H
OMe
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
Br
I
Br
I
Br
I
Br
I
Br
I
Br
I
Br
I
Br
I
2a (90)
2b (71)
2c (90)
2d (82)
2e (89)
2f (91)
2g (88)
2h (94)
2i (79)
2j (81)
2k (91)
2l (99)
2m (97)
2n (95)
2o (99)
OMe
OMe
OMe
OMe
H
H
H
H
H
H
OMe
OMe
OMe
OMe
OCH2Ob
H
OMe
OMe
OMe
Br
I
I
Br
Br
H
H
H
H
Br
H
H
H
H
H
OMe
OMe
OMe
a
b
Yield of pure crystallized compound. R3 + R3) OCH2O.
Sch em e 2
that phenanthro[9,10-d]heterocycles, which constitute
the core of several natural products such as cryptopleu-
rine, thyloforine or anthofine, exhibit very interesting
pharmacological properties related to the planarity of the
system and their DNA-chain intercalating ability.13
drazine can be proposed as the cause of the null regiose-
lectivity observed in this case. This problem was finally
overcome when enaminoketones 1 were reacted with
NH2NHPh, since the corresponding N-phenyl-4,5-diar-
ylpyrazoles 2 were obtained as the only isomers (Table
1).16 A plausible mechanism for the latter transformation,
involving an initial amine-exchange process is indicated
in Scheme 2.
Although from a regiochemical point of view the
preparation of 4,5-diarylpyrazoles 2 had been successful,
the introduction of a bulky group such as phenyl at the
N-1 position provided an additional challenge to our
approach: the need to use a conformationally highly
constrained substrate for the programmed coupling reac-
tion.17
Resu lts a n d Discu ssion
1. Syn th esis of 4,5-Dia r ylp yr a zoles. Regarding the
construction of diarylpyrazoles 2, our initial assays on
enaminoketones 1a -d 11 using NH2NH2‚2HCl as the
reagent for the amine-exchange/heterocyclization af-
forded a mixture of pyrazole tautomers 4a -d (Scheme
1).14 Apart from the observed lack of selectivity of the
heterocyclization, we realized that the so-obtained pyra-
zoles 4 were not compatible with the organometallic
species involved in the scheduled cross-coupling reactions
due to the acidic H-1 hydrogen.15 Consequently, we
explored the preparation of N-methyl pyrazoles such as
5 by reaction of substrate 1c with NH2NHMe, but only a
mixture of regioisomers 5 and 6 (55:45) was obtained. A
similar nucleophilicity of both nitrogens in methyl hy-
2. In itia l Bia r yl Cou p lin g Attem p ts. The coupling
of halogenated pyrazoles 2b and 2c was initially at-
tempted by formation of the corresponding alkylstan-
nanes and boronic acids, usual intermediates of Stille and
(13) (a) Chen, K.-X.; Gresh, N.; Pullmann, B. Nucleic Acid Res. 1986,
14, 9103-9115. (b) Martin, M. A.; del Castillo, B.; Lerner, D. A. Anal.
Chim. Acta 1988, 205, 105-115. (c) Chen, R. X.-F.; Chaudhuri, N. C.;
Paris, P. L.; Rumney IV, S.; Kool, E. T. J . Am. Chem. Soc. 1996, 118,
7671-7678. (d) Kumar, S. J . Org. Chem. 1997, 62, 8535-8539.
(14) Such 3, 4- or 4,5-disubstituted pyrazoles are always found as a
mixture of tautomers. See: Anjaneyulu, A. S. R.; Rani, G. S.; Malla-
vadhani, U. V.; Murthy, Y. L. N. Ind. J . Chem. 1995, 4, 277-280 and
references therein. In fact, 1H NMR spectra of pyrazoles 4 showed an
average signal for H-3(5) at 7.54-7.76 ppm.
(16) NOE Experiments were employed to confirm this regiochem-
istry. In fact, NOE effect was observed between H-3 and H-2′(6′) (the
ortho hydrogen(s) of the aryl group at C-4) and no NOE could be seen
between H-3 and the N-Ph hydrogens. In addition, NOE effect was
observed between H-3 and H-2′′(6′′) (the ortho hydrogen(s) of the aryl
group at C-5). These experiments were first performed for tetra-
methoxylated pyrazoles 2c and 2d and later extended to the whole
series of 2.
(15) The most common organometallic compounds employed in
biaryl coupling reactions, are usually synthesized by reaction of an
organolithium precursor and a suitable electrophile reagent. The
deprotonation of H-1 in pyrazoles by organolithium reagents can
promote several side reactions. See: Elguero, J . In Comprehensive
Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon
Press: Oxford, 1984; Vol. 5, pp 273-290.
(17) According to the X-ray diffractometry data of a 4,5-diarylisox-
azole, both 4- and 5-aryl groups are significantly twisted with respect
to the heterocyclic ring (puckering angles are 25° and 59° respectively).
See: SanMartin, R.; Olivera, R.; Dom´ınguez, E.; Solans, X.; Urtiaga,
M. K.; Font-Bard´ıa, M. Cryst. Res. Technol. 1997, 32, 1015-1020. In
N-phenyl-4,5-diarylisoxazoles 2, the phenyl group should clearly force
the other aryl groups to an even more twisted conformation.

7012 J . Org. Chem., Vol. 65, No. 21, 2000
Olivera et al.
Ta ble 2
activated copper in different solvents (entries 7-12, 15,
16, and 18-21)21a-f afforded moderate yields of the target
phenanthropyrazoles 3a ,b, but much harsher reaction
conditions were required. In comparison with the previ-
ous cross-coupling procedures assayed, the Ullmann
reaction constituted a useful methodology for the access
to phenanthro[9,10-d]pyrazoles 3, but a need for a more
general, efficient methodology still remained.
4. In tr a m olecu la r Stille-Typ e Cou p lin g. A useful
way to generate arylstannanes involves the palladium-
catalyzed reaction between aryl halides and ditin deriva-
tives such as Me6Sn2 and Bu6Sn2.22 We tried the latter
n
substrate
R1
R2
R3
product (%)
protocol on substrate 2c using Pd(PPh3)4 as catalyst and
several solvents (1,4-dioxane, DMF, NMP, toluene) with
the following results: A mixture of products 7b and 2m
was obtained in all cases, and depending on the condi-
tions applied arylstannane 9 was also isolated in moder-
ate yields. Nevertheless, the most important feature was
the isolation of coupled phenanthropyrazole 3b when
Me6Sn2 was used.23 In fact, this evidence together with
the result obtained from the control test carried out in
the absence of Me6Sn2 as reagent (Table 4, entry 19),
discounts the possibility of a biaryl coupling reaction
mediated by a direct intramolecular palladation.
This result encouraged us to improve the tandem
stannylation/biaryl coupling by means of exploring dif-
ferent palladium catalyst-ligand systems. As shown in
Table 4, both Pd(PPh3)4 and PdCl2(PPh3)2 (entries 3, 4,
and 13) were effective to promote the coupling reaction.
The use of bidentate ligands (entries 5-7) or ligands of
poor electron-donating ability (entries 8-11) did not
improve the yield or the kinetic of the reaction, affording
mainly the dehalogenation products. The employment of
ligands such as benzonitrile or acetonitrile (entries 14
and15) were incompatible with the applied reaction
conditions. In fact, palladium black was deposited during
the first moments after the beginning of the reaction. The
addition of common additives or cocatalysts in the Stille
reaction (entries 2, 9, 11, and 12) did not appreciably
affect the kinetic of the reaction. Finally, the pyrazole
2c did not undergo the coupling reaction to an ap-
preciable extent when palladium “naked” (entries 16 and
17) or nickel catalysts (entries 18) were applied.
2b
2b
2b
2c
2c
H
H
H
OMe
OMe
H
I
H
H
H
I
7a (10-21)
8a (7-30)
2l (9-69)
7b (15-77)
2m (11-88)
H
H
Br
H
Suzuki biaryl coupling procedures, respectively. However,
when derivatives 2b and 2c were reacted with BuLi and
B(OR)3 or alternatively with BuLi and R3SnCl under a
wide array of conditions, only dehalogenation products
7-9 were obtained (Table 2). It can be proposed that an
unusually stable aggregation state of the so-formed
organometallic species could avoid the attack of bulky
electrophiles.18 Similar results were obtained by the use
of the methodologies reported by Ziegler19a and Lipshutz.19b
The desired intramolecular cyclization was achieved
when the procedure developed by Lemaire et al. for the
preparation of symmetrical biaryls20 was applied to
diarylpyrazoles 2b-d , as the conditions used (Pd(OAc)2,
Bu4NBr, K2CO3, DMF) provided low yields (12-22%) of
the target tetracycles 3a ,b, but only from diiodo deriva-
tives 2b and 2d .
3. Ullm a n n Cou p lin g Assa ys. As shown in Table 3,
the Ullmann reaction of diaryl derivatives 2b-d was
attempted under a wide range of experimental condi-
tions.21 It is worth pointing out the good results obtained
by the system (CuOTf)2‚PhH, DMF20f (entries 4-6) under
relatively mild conditions. However, it was only ap-
plicable to substrates bearing o,o-diiodo substituents,
since the bromo analogues provided the already men-
tioned dehalogenation products 7 and 9. The use of
(18) (a) Winkler, H. J . S.; Winkler, H. J . Am. Chem. Soc. 1966, 88,
969-974. (b) Bailey, W. F.; Patricia, J . J . J . Organomet. Chem. 1988,
352, 1-46. Several experiments were carried out in order to effect the
insertion of electrophiles B(OR)3 and R3SnCl, including the addition
of metal-complexing agents such as TMEDA and crown ethers (18-
t
crown-6), the use of BuLi or activated magnesium. Along with the
negative results obtained from the latter assays, it was observed that
even Me3SiCl did not react with the organometallic species involved,
and only small electrophiles such as H+ or D+ could be inserted in the
stable organolithium or organomagnesium species (the addition of H2O
or D2O could be carried out after 10 h without observed any changes
in the yields showed in Table 2). Only when trying Negishi coupling
conditions (1. BuLi, THF, -78 °C.; 2. ZnCl2, -78 °C f rt; 3. Pd(PPh3)4,
rt f reflux) a white suspension was observed after treating with ZnCl2,
thus indicating the formation of the corresponding organozinc inter-
mediate. However, on adding the palladium catalyst the reaction
mixture turned to a coagulated gel which was impossible to be worked
up or analyzed.
(19) (a) Ziegler, F. E.; Chliwner, I.; Fowler, K. W.; Kanfer, S. J .; Kuo,
S. J .; Sinha, N. D. J . Am. Chem. Soc. 1980, 102, 790-798. (b) Lipshutz,
B. H.; Sengupta, S. Org. React. 1992, 41, 138-590. Both methodologies
are based on the generation and coupling of arylorganocuprates. We
tried two different Cu(I) systems, CuI‚PEt3 and CuCN-O2, after
performing the lithium-halogen exchange at -78 °C, and in both cases
only single and double dehalogenation products 7 and 2l-m were
isolated.
Both Pd(PPh3)4 and PdCl2(PPh3)2 proved to be efficient
catalysts for the above-described transformation, al-
(21) (a) Suzuki, H.; Enya, T.; Hisamatsu, Y. Synthesis 1997, 1273-
1276. (b) Meyers, A. I.; Mackennon, M. J . Tetrahedron Lett. 1995, 36,
5864-5872. (c) Copper(I) 2-thipophenecarboxylate has been reported
to promote the biaryl Ullmann reaction in extremely mild conditions.
See: Zhang, S.; Zhang, D.; Liebeskind, L. S. J . Org. Chem. 1997, 62,
2312-2313. (d) Horner, L.; Weber K.-H. Chem. Ber. 1967, 100, 2842-
2853. (e) Newman, M. S.; Cella, J . A. J . Org. Chem. 1974, 39, 2084-
2087. (f) Ziegler, F. E.; Schwartz, J . A. J . Org. Chem. 1978, 43, 985-
991.
(22) (a) Azarian, D.; Dua, S. S.; Eaborn, C.; Walton, D. R. M. J .
Organomet. Chem. 1976, 117, C55-C57. (b) Mitchell, T. N. In Metal-
Catalyzed Cross-Coupling Reactions; Diederich, F.; Stang, P. J ., Eds.;
Wiley-VCH: Weinheim, 1998; pp 189-190 and references therein.
(23) The use of nBu6Sn2 as the stannylating agent led to mixtures
of dehalogenation products. This observation could be aduced to the
lower reactivity or to steric interactions of nBu6Sn2 compared to Me6-
Sn2 during the transmetalation steps. See: Azizian, H.; Eaborn, C.;
Pidcock, A. J . Organomet. Chem. 1981, 215, 49-58.
(20) Hassan, J .; Penalva, V.; Lavenot, L.; Gozzi, C.; Lemaire, M.
Tetrahedron 1998, 54, 13793-13804.

Straightforward Preparation of Phenanthro[9,10-d]pyrazoles
J . Org. Chem., Vol. 65, No. 21, 2000 7013
Ta ble 3. Su m m a r y of th e Ullm a n n Rea ction Assa ys P er for m ed on P yr a zoles 2b-d
dehalog.
entry
2
reaction conditions
Ta (°C)
t (h)
3a (%)
productsa (%)
convb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
2b
2c
2d
2b
2c
2d
2b
2b
2c
2d
2b
2c
2b
2c
2b
2c
2b
Cu, Pd(PPh3)4 (5 mol %), DMSO
100
77
77
77
34
89
38
31
39
72
33
89
72
56
72
22
72
10
7a -2l (62)
7b-2m (69)
7c-2m (76)
7a -2l (14)
7b-2m (46)
7c-2m (19)
7a -2l (12)
7a -2l (16)
7b-2m (41)
7c-2m (22)
7a -2l (14)
66
79
95
100
52
90
85
92
52
56
15
(CuOTf)2‚PhH, DMF
100
100
130
220
190
220
220
170
3a (86) 77
3b 6
3b (68) 56
3a (73) 68
3a 76
Cuc, DMFd
Cuc, DMFd
CuTCe, NMP
Cu2O, DMF
Cu , Py
3b 32
190
190
260
7a -2l (17)
7a -2l (21)
7a -2l (55)
29
100
100
3a 64
18
19
20
21
22
2b
2d
2b
2d
2b
Cu, NMP
195
175
48
77
41
49
7
3a (79)
3d (51)
3a (81)
3d (72)
7a -2l (15)
7c-2m (29)
7a -2l (19)
7c-2m (26)
7a -2l (85)
94
100
100
100
100
d
Cu, PhNO2
-78 f rt f 100
23
2d
7
7c-2m (78)
88
a
b
GCMS yields. Isolated yields are indicated in italics. Conversion. c Activated copper, which was prepared by treatment of copper
bronze with EDTA‚Na2 and dried over P2O5 at 0.1 mmHg. In the other cases, commercially available copper bronze was used.
d
Complementary assays were carried out sonicating the reaction mixture at 4-65 °C, affording in all cases only unreacted starting
material. e CuTC: Copper(I) 2-thiophenecarboxylate.
though the latter system provided an easier purification
due to the absence of byproducts. The procedure included
the use of a heavy-wall pressure tube as the reaction
flask, since very poor yields of phenanthro derivative 3b
were obtained by simple refluxing. As shown in Table 5,
the application of the so-optimized conditions to o,o-
dihalogenated pyrazoles 2a -k provided tetracycles 3a -e
in good yields. From an examination of these results it
may be proposed that the extended degree of conjugation
of the final tetracyclic product probably compensates the
steric constraint at the transmetalation step of such a
Stille-type process.24 A proposal for the mechanism based
on previous reports regarding Stille coupling reactions
is displayed in Scheme 3.
using methoxylated substrates, even though they are
generally reported to undergo a slower transmetalation
step, due to the electron-donating nature of the OMe
group.25
5. Bia r yl Cou p lin g Med ia ted by P in a col Bor a n e
a n d Bis(p in a cola te)d ibor on Rea gen ts. In a fashion
similar to the intermolecular Stille-Kelly reaction,
Miyaura et al. have reported a sequential generation of
arylboronates/biaryl coupling by reaction of aryl halides
and bis(pinacolate)diboron.26 To improve previous results,
diarylpyrazoles 2b-d were reacted with the latter dibo-
ron reagent using different conditions. A mixture of the
aryl boronates 10 and 11 was detected from diiodo
derivatives 2b and 2d , when the reaction was performed
in a sealed tube using PdCl2(PPh3)2 and NaOAc as the
catalyst-base system (method A), whereas dibromopy-
razole 2c provided complex mixtures under the same
conditions. The coupling of boronates 10 and 11 was
It should be pointed out that the target coupling
products 3a -e were obtained with similar yields from
diiodo, dibromo, or even mixed iodobromo precursors 2a -
k , and that no significant change was observed when
(24) Very few examples of such an intramolecular coupling via
tandem or domino processes have been reported to date. See: (a) Kelly,
T. R.; Li, Q.; Bushan, V. Tetrahedron Lett. 1990, 31, 161-164. (b) Grigg,
R.; Teasdale, A.; Sridharan, V. Tetrahedron Lett. 1991, 32, 3859-3862.
(c) Kelly, T. R.; Xu, W.; Ma, Z.; Li, Q.; Bushan, V. J . Am. Chem. Soc.
1993, 115, 5843-5844. (d) Beddoes, R. L.; Cheeseright, T.; Wang, J .;
Quayle, P. Tetrahedron Lett. 1995, 36, 283-286. (e) This Stille-type
reaction has been recently called “Stille-Kelly reaction”. See: Fuku-
yama, Y.; Yaso, K.; Nakamura, K.; Kodama, M. Tetrahedron Lett. 1999,
40, 105-108.
(25) (a) Saa´, J . M.; Martorell, G.; Garc´ıa-Raso, A. J . Org. Chem.
1992, 57, 678-685. (b) Gonza´lez, J . J .; Garc´ıa, N.; Go´mez-Lor, B.;
Echavarren, A. M. J . Org. Chem. 1997, 62, 1286-1291.
(26) (a) Ishiyama, T.; Murata, M.; Miyaura, N. J . Org. Chem. 1995,
60, 7508-7510. Several variants of this procedure using the Miyaura’s
reagent can be found in: (b) Giroux, A.; Han, Y.; Prasit, P. Tetrahedron
Lett., 1997, 38, 3841-3844. (c) Zembower, D. E.; Zhang, H. J . Org.
Chem. 1998, 63, 9300-9305. (d) Firooznia, F.; Gude, C.; Chan, K.;
Marcopulos, N.; Satoh, Y. Tetrahedron Lett. 1999, 40, 213-216.

7014 J . Org. Chem., Vol. 65, No. 21, 2000
Ta ble 4. Resu lts fr om th e Sta n n yla tion /Bia r yl Cou p lin gAssa ys P er for m ed on P yr a zole 2b
Olivera et al.
yieldd (%)
entry
catalyst systema-c
Pd(PPh3)4
Pd(PPh3)4 [4,5 mol %] (1:4)
Pd(PPh3)4 [6 mol %]
Pd2dba3/PPh3 (1:4)
Pd2dba3/dppf (1:4)
Pd2dba3/(R)-(+)-BINAP (1:4)
PdCl2 (dppe)
Pd2dba3/AsPh3 (1:4)
Pd2dba3/AsPh3 (1:4:4)
Pd2dba3/TPF (1:4)
Pd2dba3/TPF(1:4:4)
Pd(PPh3)4 (1:4) [7 mol %]
PdCl2(PPh3)2 [4 mol %]
PdCl2(CH3CN)2
additive
LiCl
T (°C)
t (h)
2m
7b
9
3b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
105
140
140
140
140
39
74
76
60
96
96
84
96
92
78
75
66
71
72
72
88
72
72
72
13
14
12
18
19
8
39
19
12
27
21
16
5
14
18
5
7
25
6
9
4
8
7
61
0
5
0
0
0
0
0
0
0
0
0
0
11
70
78
71
9 (61)e
140
140
0 (15)e
5 (55)e
100 f 140
100 f 140
100 f 140
100 f 140
140
0 (24)e
CuI
0 (21)e
0 (39)e
CuI
CuI
9
8
0
0 (31)e
71
75
f
f
f
f
140
140
140
140
PdCl2(PhCN)2
Pd2dba3 [1:4]
Pd-C
NiCl2(PPh3)2, Zn, PPh3
LiCl
140
80 f 120
140
16
10
0
0 (42)e
f
a
b
Reactions were generally carried out using a 5 mol % amount of the catalyst; otherwise, the proportion is indicated in brackets. The
Pd:Ligand:Additive ratio is indicated in parentheses. c BINAP: 2,2′-bis(diphenylphosphino)-1.1′-binaphthyl. dppf: 1,1′-Bis(diphenylphos-
d
phino)ferrocene. dppe: 1,2-Bis(diphenylphosphino)ethane. TFP: tri-2-furylphosphine. Isolated yield. GCMS yields are indicated in italics.
e The conversion was complete except for the cases indicated in parentheses. f Unreacted starting material was recovered.
Ta ble 5. P h en a n th r op yr a zoles 3 P r ep a r ed
only inseparable mixtures of pinacolboronates 10-12
were observed.29 It was necessary again the use of a
stronger base (K3PO4) to attain the coupling of interme-
diates 10 and 11, but the yields were moderate (33-45%)
due to the presence of the o,o-diboronate 12 in the
reaction mixture (Scheme 4).
Although valuable and environmentally safer meth-
odologies for the coupling of dihaloarylpyrazoles, the
above-described boron-based procedures showed some
disadvantages compared to the previously developed
Stille-type reaction, since the yields were considerably
lower and significant differences in the reactivity of
dibromo and diiodo precursors were observed.
substrate
R1
R2
X1
X2
producta (%)
6. Non p h en olic Oxid a tive Cou p lin g Med ia ted by
P IF A. Finally, once the biaryl coupling of dihalogenated
derivatives 2a -k was achieved, an alternative approach
to the phenanthro[9,10-d]pyrazole system based on the
oxidative coupling of nonhalogenated pyrazoles 2l-o was
carried out. Such oxidative coupling reactions, formerly
developed for phenols30 and later extended to phenol
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
H
H
H
Br
I
Br
I
Br
I
Br
I
Br
I
Br
I
Br
I
Br
I
3a (88)
3a (80)
3b (78)
3b (40)
3c (80)
3c (74)
3d (81)
3d (77)
3d (59)
3d (40)
3e (79)
OMe
OMe
OMe
OMe
H
H
H
H
H
OMe
OMe
H
H
OMe
OMe
OMe
OMe
OCH2Ob
ethers and other oxygenated, electron-rich arenes,31 are
32
Br
I
Br
I
Br
Br
effected by anodic oxidation
or by using several
2j
2k
oxidants, mostly heavy metal reagents.33 In comparison
with photochemical approaches, oxidative coupling is
reported to show no serious limitations concerning sub-
stitution patterns,34 and as no halogenated precursors are
a
b
Yield of pure crystallized compound. R2 + R2) OCH2O.
effected in situ by addition of potassium phosphate,
affording tetracycles 3a ,b in 41-60% yield.27
As an alternative to generate aryl boronates 10 and
11, pyrazoles 2b-d were reacted with pinacolborane28
and Et3N in the presence of PdCl2(PPh3)2 (method B), and
(29) The analysis of the 1H NMR and 13C NMR spectra of different
chromatograpic fractions indicated the existence of pinacol derivatives,
as concluded by observation of singlet signals in the range of 1.19-
1.27 and 23.2-25.1 ppm, respectively. Likewise, peaks corresponding
to the molecular ions of boronates 10-12 were registered (m/z: 548
for 10a -11a , 668 for 10b-11b, 620 and 622 for 10c-11c, 548 for 12a
and 668 for 12b). In the case of the pinacolboronates 10 and 11, the
peaks corresponding to the fragmentation by dehalogenation were also
detected and of remarkable intensity (44-76%).
(27) The use of a weak base such as NaOAc proved to be essential
for the synthesis of pinacolboronates 11 and 12 as reported by Miyaura
et al. (See ref 25a). In one attempt of carrying out the reaction in a
tandem process, the addition of K3PO4 instead NaOAc did not succeed,
affording an intractable mixture of products.
(28) Murata, M.; Watanabe, S.; Masuda, Y. J . Org. Chem. 1997,
6451-6459. Tucker, C. H.; Davidson, J .; Knochel, P. Pinacolborane
was prepared according to the procedure reported in J . Org. Chem.
1992, 57, 3482-3485.
(30) Taylor, W. I.; Battersby, A. B. In Oxidative coupling of phenols;
Arnold: London, 1967.
(31) Whiting, A. D. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Exeter, 1991; vol. 3, pp 659-703.
(32) Chapuzet, J .-M.; Simonet, J . Tetrahedron 1991, 47, 791-798.
(33) Kumar, S.; Manickam, M. Chem. Commun. 1997, 1615-1616.
(34) Mallory, F. B.; Mallory, C. W. Org. React. 1984, 30, 1-456.

Straightforward Preparation of Phenanthro[9,10-d]pyrazoles
Sch em e 3
J . Org. Chem., Vol. 65, No. 21, 2000 7015
Ta ble 6
Sch em e 4
substrate
R1
R2
R3
R4
producta (%)
2l
H
H
H
OMe
OMe
H
H
H
H
OMe
3a (16)
3b (86)
3f (55)
2m
2n
2o
OMe
OMe
OMe
OMe
OMe
OMe
a
Yield of pure crystallized compound.
oselectively the corresponding tetracycles 3a , 3b, and 3f
with the results summarized in Table 6. In addition,
phenanthro[9,10-d]pyrazole 3a was unexpectedly ob-
tained in a low but significant yield from the non-
methoxylated substrate 2l. It can be proposed that the
pyrazole ring could promote a slight stabilization of the
aromatic radical cation intermediate, otherwise very
unstable due to the lack of electron-donating groups.
Under the same conditions the polymethoxylated pyra-
zole 2o provided a complex mixture, a result that could
be rationalized if steric factors are considered.
To sum up, an expeditious approach to the phenanthro-
[9,10-d]pyrazole system is presented, featuring as the key
steps the tandem amine-exchange/heterocyclization of
diaryl enaminoketones with phenylhydrazine, and the
biaryl coupling of the so-obtained 4,5-diarylpyrazoles. A
complete comparative study of the applicability of the
main cross-coupling methodologies to the o,o-dihaloge-
nated pyrazoles was carried out, resulting that the Stille-
Kelly reaction based on a tandem stannylation/biaryl
coupling, derivatives constitutes a general, convenient
procedure for the target transformation. In addition, the
tetracycles 3 can be also synthesized by oxidative non-
phenolic coupling of nonhalogenated diarylpyrazoles
mediated by phenyliodine bis(trifluroacetate) (PIFA).
required, it may constitute a valid alternative to Ull-
mann, Suzuki, or Stille cross-coupling methodologies. A
recent communication on the oxidative coupling of isox-
azoles and pyrimidines has presented the system PhI-
(OCOCF3)-BF3‚OEt2 as an efficient and nontoxic oxidant
which avoids the formation of electrophilic metalation
byproducts.35 Thus, nonhalogenated diarylpyrazoles 2l-o
were submitted to the latter conditions, providing regi-
(35) Olivera, R.; SanMartin, R.; Pascual, S.; Herrero, M.; Domı´nguez,
E. Tetrahedron Lett. 1999, 40, 3479-3480.

7016 J . Org. Chem., Vol. 65, No. 21, 2000
Olivera et al.
114.1, 114.4, 115.4, 115.5, 120.2, 125.9, 126.8, 130.6, 148.1,
148.2, 149.4; FTIR (neat film, cm-1): 1605; EIMS (m/z) 514
(M + 2, 8), 512 (M+, 15), 510 (M - 2, 7), 352 (M - 2Br, 100).
Anal. Calcd for C20H20Br2N2O4: C, 46.90; H, 3.94; N, 5.47.
Found: C, 46.95; H, 3.86; N, 5.41.
Exp er im en ta l Section
Gen er a l Meth od s. For general experimental details, see
ref 11a.
Syn t h esis of Dia r ylp yr a zoles. 3(5),4-Bis(2-b r om o-
p h en yl)p yr a zole (4a ). Typ ica l P r oced u r e. Hydrazine di-
hydrochloride (98%, 0.146 g, 1.368 mmol) was added to a
solution of enaminoketone 1a (0.509 g, 1.244 mmol) and
ground Na2CO3 (99%, 88.6 mg, 0.83 mmol) in MeOH (13 mL)
and H2O (26 mL) under stirring at room temperature. The
resulting mixture was acidified with glacial acetic acid (0.49
mL) to pH∼4 and refluxed for 6 h. After cooling, the mixture
was parcially (1/2) evaporated in vacuo, and H2O (50 mL) was
added. This aqueous solution was extracted with CH2Cl2 (5 ×
25 mL) and the combined organic layers were washed with
brine (1 × 10 mL) and H2O (1 × 10 mL). The organic layers
were dried over anhydrous sodium sulfate, evaporated under
reduced pressure and the resulting yellow residue was purified
by chromatography using 5% EtOAc/CH2Cl2 as eluent. Pyra-
zole 4a (0.393 g, 76%) was obtained as a yellow oil: Rf 0.25
Syn th esis of 4,5-Dia r yl-1-p h en ylp yr a zoles 2. 4,5-Bis-
(2-br om op h en yl)-1-p h en ylp yr a zole (2a ). Typ ica l P r oce-
d u r e. Phenylhydrazine hydrochloride (99%, 1,566 g, 10.7
mmol) was added to a solution of enaminoketone 1a (3,654 g,
8.9 mmol) and ground Na2CO3 (99%, 0,538 g, 5,02 mmol) in
MeOH (89 mL) and H2O (178 mL) under stirring at room
temperature. The resulting mixture was acidified with glacial
acetic acid (3.51 mL) to pH ∼4 and heated at 135 °C overnight.
After cooling, the suspension was filtered, and the filtrate was
partially (1/3) evaporated in vacuo. This aqueous solution was
extracted with CH2Cl2 (5 × 25 mL), and the organic layer was
washed with brine (1 × 10 mL) and H2O (1 × 10 mL), dried
over anhydrous sodium sulfate, and evaporated under reduced
pressure. The residue was mixed with the filtrand previously
obtained and triturated with a mixture of 75% MeOH/H2O to
afford pyrazole 2a (4.12 g, 90%) as a white powder: 124-125
°C (MeOH/H2O); Rf 0.40 (30% hexane/EtOAc); 1H NMR (CDCl3)
δ 7.30-7.01 (11H, m), 7.48 (1H, dd, J ) 7.9, 1.7 Hz), 7.60 (1H,
dd, J ) 7.8, 1.2 Hz), 7.96 (1H, s); 13C NMR (CDCl3) δ 122.7,
124.0, 124.3, 124.9, 126.9, 127.3, 128.6, 128.7, 130.4, 131.9,
132.8, 133.0, 133.3, 139.1, 139.9, 140.7; FTIR (neat film, cm-1):
1596; EIMS (m/z) 456 (M + 2, 46), 454 (M+, 92), 452 (M + 2,
46), 375 (M - 79Br, 61), 373 (M - 81Br, 59), 293 (100). Anal.
Calcd for C21H14Br2N2: C, 55.54; H, 3.11; N, 6.17. Found: C,
55.39; H, 3.06; N, 6.29.
1
(40% hexane/EtOAc); H NMR (CDCl3) δ 7.02-7.28 (6H, m),
7.54-7.66 (2H, m), 7.73 (1H, s); 13C NMR (CDCl3) δ 119.9,
123.5, 123.9, 127.0, 127.2, 128.4, 129.9, 131.9, 132.2, 132.8,
133.0, 133.1, 133.8, 149.4; FTIR (neat film, cm-1): 3413, 1584;
EIMS (m/z) 380 (M + 2, 9), 378 (M+, 18), 376 (M - 2, 9), 218
(M - 2Br, 100). Anal. Calcd for C15H10Br2N2: C, 47.65; H, 2.67;
N, 7.41. Found: C, 47.49; H, 2.77; N, 7.58.
By use of the same procedure the following compounds were
prepared:
3(5),4-Bis(2-iod op h en yl)p yr a zole (4b): 81%; yellow oil;
Rf 0.27 (40% hexane/EtOAc); 1H NMR (CDCl3) δ 6.73-7.32
(6H, m), 7.54 (1H, s) 7.76-7.88 (2H, m); 13C NMR (CDCl3) δ
99.1, 100.8, 122.5, 127.8, 128.5, 129.9, 131.3, 131.8, 133.7,
136.5, 136.7, 139.3, 147.4; FTIR (neat film, cm-1):3413, 1584;
EIMS (m/z) 472 (M+, 42), 218 (M - 2I, 100). Anal. Calcd for
By use of the same procedure the following compounds were
prepared:
4,5-Bis(2-iod op h en yl)-1-p h en ylp yr a zole (2b) was puri-
fied by flash column chromatography using 30% EtOAc/hexane
as eluent and obtained as an amber oil: 71%; Rf 0.50 (10%
hexane/CH2Cl2); 1H NMR (CDCl3) δ 6.90 (1H, ddd, J ) 7.7,
7.4, 1.7 Hz), 6.91 (1H, ddd, J ) 7.8, 7.7, 1.5 Hz), 7.00-7.01
(2H, m), 7.05 (1H, dd, J ) 7.7, 1.8 Hz), 7.13 (1H, dd, J ) 7.3,
1.2 Hz), 7.33-7.22 (5H, m), 7.74 (1H, d, J ) 7.9, 1.4 Hz), 7.89
(1H, dd, J ) 7.9, 1.2 Hz), 7.95 (1H, s); 13C NMR (CDCl3) δ 100.7,
100.8, 124.2, 125.5, 127.1, 127.7, 128.6, 128.7, 130.3, 131.3,
132.5, 135.4, 137.2, 139.4, 139.9, 140.7, 141.6; FTIR (neat film,
cm-1) 1596; EIMS (m/z) 548 (M+, 62), 421 (M - I, 42), 294 (M
- 2I, 71), 293 (100). Anal. Calcd for C21H14I2N2: C, 46.01; H,
2.57; N, 5.11. Found: C, 46.19; H, 2.66; N, 5.01.
4,5-Bis(2-br om o-4,5-d im eth oxyp h en yl)-1-p h en ylp yr a -
zole (2c): 90%; white powder; mp 165-166 °C (MeOH/H2O);
Rf 0.49 (40% hexane/EtOAc); 1H NMR (CDCl3) δ 3.59 (3H, s),
3.65 (3H, s), 3.82 (3H, s), 3.84 (3H, s), 6.58 (1H, s), 6.69 (1H,
s), 6.93 (1H, s), 7.04 (1H, s), 7.23-7.35 (5H, m), 7.91 (1H, s);
13C NMR (CDCl3) δ 55.6, 56.0, 114.0, 114.4, 114.7, 115.2, 115.2,
115.4, 122.7, 123.3, 123.7, 125.4, 127.0, 128.6, 139.1, 139.9,
140.4, 147.7, 148.2, 148.4, 149.9; FTIR (neat film, cm-1):. 1599;
EIMS (m/z) 495 (M + 2, 6), 493 (M+, 6), 414 (M - 79Br, 100).
Anal. Calcd for C25H22Br2N2O4: C, 52.29; H, 3.86; N,. 4.88.
Found: C, 52.38; H, 3.88; N, 4.81.
4,5-Bis(4,5-d im e t h oxy-2-iod op h e n yl)-1-p h e n ylp yr a -
zole (2d ): 82%; white powder; mp 149-150 °C (MeOH/H2O);
Rf 0.41 (40% hexane/EtOAc); 1H NMR (CDCl3) δ 3.63 (3H, s),
3.72 (3H, s), 3.83 (3H, s), 3.85 (3H, s), 6.56 (1H, s), 6.80 (1H,
s), 7.12 (1H, s), 7.24-7.35 (7H, m), 7.88 (1H, s); 13C NMR
(CDCl3) δ 55.7, 56.0, 88.6, 89.3, 114.2, 114.7, 121.1, 123.8,
125.7, 126.9, 127.8, 128.7, 130.0, 140.0, 140.4, 141.7, 148.6,
149.1, 149.8; FTIR (neat film, cm-1) 1596; EIMS (m/z) 541 (5),
414 (M - I, 100). Anal. Calcd for C25H22I2N2O4: C, 44.93; H,
3.32; N, 4.19. Found: C, 45.11; H, 3.21; N, 4.30.
C
15H10I2N2: C, 38.16; H, 2.14; N, 5.93. Found: C, 38.01; H,
2.06; N, 5.83.
3(5),4-Bis(2-br om o-4,5-d im eth oxyp h en yl)p yr a zole (4c):
75%; white powder; mp 159-160 °C (Et2O); Rf 0.28 (30%
1
hexane/EtOAc); H NMR (CDCl3) δ 3.57 (3H, s), 3.67 (3H, s),
3.84 (3H, s), 3.85 (3H, s), 6.56 (1H, s), 6.75 (1H, s), 6.95 (1H,
s), 7.02 (1H, s), 7.76 (1H, s); 13C NMR (CDCl3) δ 55.7, 55.9,
56.0, 113.8, 113.9, 114.2, 114.3, 115.3, 115.4, 119.8, 124.5,
125.8, 134.2, 144.8, 147.8, 147.9, 148.3, 149.4; FTIR (neat film,
cm-1) 3335, 1604; EIMS (m/z) 500 (M + 2, 5), 498 (M+, 19),
496 (M - 2, 3). Anal. Calcd for C19H18Br2N2O4: C, 45.81; H,
3.64; N, 5.62. Found: C, 45.88; H, 3.77; N, 5.56.
3(5),4-Bis(4,5-d im eth oxy-2-iod op h en yl)p yr a zole (4d ):
85%; yellow powder; mp 197-198 °C (hexane); Rf 0.24 (30%
1
hexane/EtOAc); H NMR (CDCl3) δ 3.62 (3H, s), 3.69 (3H, s),
3.84 (3H, s), 3.86 (3H, s), 6.63 (1H, s), 6.76 (1H, s), 7.19 (1H,
s), 7.24 (1H, s), 7.75 (1H, s); 13C NMR (CDCl3) δ 55.7, 55.9,
56.0, 87.5, 88.8, 114.2, 114.3, 121.3, 121.4, 124.3, 128.9, 130.2,
134.1, 147.1, 148.2, 148.4, 148.7, 149.4; FTIR (neat film, cm-1):
3335, 1598; EIMS (m/z) 465 (M - I, 5), 338 (M - 2I, 100). Anal.
Calcd for C19H18I2N2O4: C, 38.54; H, 3.06; N, 4.73. Found: C,
38.39; H, 3.17; N, 4.89.
The same procedure on enaminoketone 1c, substituting the
reagent NH2NH2‚2HCl for MeNHNH2 provided the following
products:
4,5-Bis(2-br om o-4,5-d im eth oxyp h en yl)-1-m eth ylp yr a -
zole (5): 49%; colorless oil, Rf 0.48 (60% hexane/EtOAc); H
NMR (CDCl3) δ 3.62 (3H, s), 3.74 (6H, s), 3.84 (3H, s), 3.89
(3H, s), 6.60 (1H, s), 6.69 (1H, s), 7.01 (1H, s), 7.08 (1H, s),
7.73 (1H, s); 13C NMR (CDCl3) δ 37.1, 55.7, 56.0, 56.1, 56.2,
113.9, 114.3, 114.5, 115.2, 115.3, 120.9, 123.1, 125.9, 138.7,
140.0, 147.7, 148.3, 150.2; FTIR (neat film, cm-1): 1600; EIMS
(m/z) 514 (M + 2, 16), 512 (M+, 33), 510 (M - 2, 16), 352 (M
- 2Br, 100). Anal. Calcd for C20H20Br2N2O4: C, 46.90; H, 3.94;
N, 5.47. Found: C, 46.78; H, 3.89; N, 5.55.
1
5-(2-Br om o-4,5-d im eth oxyp h en yl)-4-(2-br om op h en yl)-
1-p h en ylp yr a zole (2e): 89%; white powder; mp 140-142 °C
1
(MeOH/H2O); Rf 0.43 (40% hexane/EtOAc); H NMR (CDCl3)
δ 3.64 (3H, s), 3.83 (3H, s), 6.67 (1H, s), 6.92 (1H, s), 7.04-
7.18 (4H, m), 7.27-7.34 (5H, m), 7.60 (1H, dd, J ) 7.1, 1.2
Hz), 7.92 (1H, s); 13C NMR (CDCl3) δ 55.8, 114.5, 115.2, 122.7,
122.8, 123.8, 124.2, 126.9, 127.0, 128.7, 131.9, 132.7, 133.4,
139.0, 139.9, 140.5, 147.9, 149.7; FTIR (neat film, cm-1) 1597;
EIMS (m/z) 516 (M + 2, 22), 514 (M+, 42), 512 (M - 2, 22),
3,4-Bis(2-br om o-4,5-d im eth oxyp h en yl)-1-m eth ylp yr a -
zole (6): 40%; colorless oil; Rf 0.53 (60% hexane/EtOAc); H
NMR (CDCl3) δ 3.51 (3H, s), 3.78 (3H, s), 3.84 (6H, s), 4.01
(3H, s), 6.52 (1H, s), 6.89 (1H, s), 6.98 (1H, s), 7.02 (1H. s),
7.67 (1H, s); 13C NMR (CDCl3) δ 39.2, 55.6, 56.0, 56.16, 113.4,
1

Straightforward Preparation of Phenanthro[9,10-d]pyrazoles
435 (M - 79Br, 100), 433 (M - 81Br, 100). Anal. Calcd for
J . Org. Chem., Vol. 65, No. 21, 2000 7017
6.56-7.32 (15H, m), 7.93 (1H, s); 13C NMR (CDCl3) δ 122,4,
125.2, 126.4, 127.2, 128.0, 128.4, 128.6, 128.7, 130.2, 130.4,
132.8, 139.2, 139.7, 139.9; FTIR (neat film, cm-1) 1590; EIMS
(m/z) 296 (M+, 100). Anal. Calcd for C21H16N2: C, 85.11; H,
5.44; N, 9.45. Found: C, 84.97; H, 5.32; N, 9.71.
C
23H18Br2N2O2: C, 53.72; H, 3.53; N, 5.45. Found: C, 53.70;
H, 3.51; N, 5.61.
5-(4,5-Dim e t h oxy-2-iod op h e n yl)-4-(2-iod op h e n yl)1-
p h en ylp yr a zole (2f) (91%) was purified by flash column
chromatography using 30% EtOAc/hexane as eluent and
4,5-Bis(3,4-d im eth oxyp h en yl)-1-p h en ylp yr a zole (2m ):
97%; white powder; mp 146-147 °C (MeOH); Rf 0.24 (4%
1
obtained as an colorless oil: Rf 0.34 (60% hexane/EtOAc); H
1
NMR (CDCl3) δ 3.69 (3H, s), 3.82 (3H, s), 6.78 (1H, s), 6.92
(1H, ddd, J ) 7.5, 7.1, 1.8 Hz), 7.09 (1H, dd, J ) 7.5, 1.6 Hz),
7.11 (1H, s), 7.21 (1H, ddd, J ) 7.9, 7.1, 1.2 Hz), 7.25-7.37
(5H, m), 7.84 (1H, s), 7.90 (1H, dd, J ) 7.9, 1.2 Hz); 13C NMR
(CDCl3) δ 55.8, 56.1, 89.0, 101.0, 114.6, 121.2, 123.8, 125.5,
126.9, 127.2, 127.8, 128.6, 128.8, 131.4, 137.4, 139.1, 139.8,
140.3, 141.3, 148.7, 149.4; FTIR (neat film, cm-1): 1598; EIMS
(m/z) 608 (M+, 27), 481 (M - I, 100), 354 (M - 2I, 60). Anal.
Calcd for C23H18I2N2O2: C, 45.42; H, 2.98; N, 4.60. Found: C,
45.41; H, 2.88; N, 4.37.
EtOAc/CH2Cl2); H NMR (CDCl3) δ 3.56 (3H, s), 3.66 (3H, s),
3.86 (6H, s), 6.60 (1H, d, J ) 1.5 Hz), 6.73-6.80 (4H, m), 7.22-
7.33 (6H, m), 7.86 (1H, s); 13C NMR (CDCl3) δ 55.6, 55.7, 111.0,
111.1, 111.2, 113.2, 120.2, 121.8, 122.5, 123.2, 125.1, 125.6,
127.2, 128.7, 138.6, 139.4, 140.0, 147.6, 148.6, 148.7, 148.9;
FTIR (neat film, cm-1) 1597; EIMS (m/z) 416 (M+, 100). Anal.
Calcd for C25H24N2O4: C, 72.10; H, 5.81; N, 6.73. Found: C,
71.89; H, 5.89; N, 6.80.
4-(3,4-Dim e t h oxyp h e n yl)-1-p h e n yl-5-(2,3,4-t r im e t h -
oxyp h en yl)p yr a zole (2n ): 95%; white powder; mp 132-133
1
4-(2-Br om o-4,5-d im eth oxyp h en yl)-5-(2-br om op h en yl)-
1-p h en ylp yr a zole (2g: 88%; white powder; mp 130-131 °C
°C (MeOH); Rf 0.66 (EtOAc); H NMR (CDCl3) δ 3.37 (3H, s),
3.64 (3H, s), 3.72 (3H, s), 3.86 (6H, s), 6.63 (1H, d, J ) 8.7
Hz), 6.69 (1H, d, J ) 1.5 Hz), 6.78 (1H, d, J ) 8.3 Hz), 6.86
(1H, d, J ) 8.3 Hz), 7.21-7.33 (6H, m), 7.93 (1H, s); 13C NMR
(CDCl3) δ 55.3, 55.7, 55.9, 60.1, 60.7, 107.0. 110,4, 111.0, 116.9,
119.4, 122.5, 123.9, 125.7, 126.6, 128.5, 135.4, 138.8, 140.3,
142.1, 147.3, 148.4, 152.0, 154.6; FTIR (neat film, cm-1) 1600;
EIMS (m/z) 446 (M+, 100). Anal. Calcd for C26H26N2O5: C,
69.94; H, 5.87; N, 6.27. Found: C, 70.06; H, 5.82; N, 6.34.
1-P h en yl-5-(2,3,4-tr im eth oxyp h en yl)-4-(3,4,5-tr im eth -
oxyp h en yl)p yr a zole (2o): 99%; white powder; mp 157-158
1
(MeOH/H2O); Rf 0.48 (50% hexane/EtOAc); H NMR (CDCl3)
δ 3.50 (3H, s), 3.85 (3H, s), 6.50 (1H, s), 7.05 (1H, s), 7.19-
7.33 (8H, m), 7.52 (1H, dd, J ) 7.5, 1.2 Hz), 7.99 (1H, s); 13C
NMR (CDCl3) δ 55.2, 55.6, 113.5, 114.0, 115.2, 122.3, 123.6,
124.7, 126.8, 127.1, 128.3, 130.2, 131.4, 132.6, 138.7, 139.5,
140.4, 147.3, 148.0; FTIR (neat film, cm-1) 1597; EIMS (m/z)
516 (M + 2, 23), 514 (M+, 56), 512 (M - 2, 26), 354 (M - 2Br,
100). Anal. Calcd for C23H18Br2N2O2: C, 53.72; H, 3.53; N, 5.45.
Found: C, 53.80; H, 3.56; N, 5.39.
1
4-(4,5-Dim et h oxy-2-iod op h en yl)-5-(2-iod op h en yl)-1-
p h en ylp yr a zole (2h : 94%; white powder; mp 185-186 °C
°C (MeOH); Rf 0.60 (EtOAc); H NMR (CDCl3) δ 3.38 (3H, s),
3.67 (6H, s), 3.72 (3H, s), 3.82 (3H, s), 3.87 (3H, s), 6.45 (2H,
s), 6.65 (1H, d, J ) 8.3 Hz), 6.88 (1H, d, J ) 8.3 Hz), 7.22-
7.34 (5H, m), 7.95 (1H, s); 13C NMR (CDCl3) δ 55.2, 55.4, 59.7,
60.2, 60.4, 103.6, 106.6, 116.5,122.1, 123.6, 126.1, 128.0, 135.1,
135.8, 138.8, 139.8, 141.7, 151.6, 152.5, 154.2; FTIR (neat film,
cm-1) 1598; EIMS (m/z) 476 (M+, 100). Anal. Calcd for
1
(MeOH/H2O); Rf 0.44 (50% hexane/EtOAc); H NMR (CDCl3)
δ 3.52 (3H, s), 3.84 (3H, s), 6.53 (1H, s), 6.98-7.04 (1H, m),
7.28-7.33 (8H, m), 7.78 (1H, dd, J ) 7.5, 1.6 Hz), 7.98 (1H, s);
13C NMR (CDCl3) δ 55.8, 55.9, 88.1, 100.9, 113.9, 121.3, 124.0,
125.2, 127.0, 128.1, 128.6, 129.4, 130.3, 132.4, 137.2, 139.8,
140.7, 141.7, 148.2, 148.4; FTIR (neat film, cm-1): 1597; EIMS
(m/z) 608 (M+, 58), 354 (M - 2I, 11). Anal. Calcd for
C
27H28N2O6: C, 68.05; H, 5.92; N, 5,88. Found: C, 68.21; H.
5.84; N, 5.80.
C
23H18I2N2O2: C, 45.44; H, 2.98; N, 4.60. Found: C, 45.39; H,
Attem p ts a t Syn th esis of Ar ylbor on ic Acid s or Ar yl-
t r im et h ylst a n n a n es b y t h e Cor r esp on d in g Or ga n o-
lith iu m Der iva tives. Typ ica l P r oced u r e. A solution of
pyrazole 2c (0.6 g, 1.044 mmol) in dry THF (105 mL) at -78
°C was treated with n-BuLi (1.32 mL, 1.30 M solution in
hexane, 1.72 mmol) under Ar. This mixture was stirred at the
same temperature for 35 min. A solution of B(OMe)3 (tridis-
tilled from Na) (0.54 mL, 4.70 mmol) in dry THF (1 mL) was
added slowly, during which time the solution changed color
from pale yellow to dark orange. The resulting mixture was
stirred for 2 h at -78 °C, allowed to reach room temperature,
and poured onto a HCl 5% solution (80 mL) and stirred for 15
min. Brine (5 mL) was added, and the aqueous layer was
separated and extracted with Et2O (5 × 25 mL). The combined
organic layers were washed with H2O (1 × 50 mL) and brine
(1 × 50 mL) and dried over anhydrous sodium sulfate, and
the solvent was evaporated under reduced pressure. The
residue was purified by flash column chromatography using
6% EtOAc/CH2Cl2 as eluent affording the following products:
4-(2-Br om o-4,5-d im et h oxyp h en yl)-5-(3,4-d im et h oxy-
p h en yl)-1-p h en ylp yr a zole (7b): 0.398 g, 77%; white powder;
mp 154-156 °C (MeOH); Rf 0.45 (6% EtOAc/CH2Cl2); 1H NMR
(CDCl3) δ 3.49 (3H, s), 3.60 (3H, s), 3.82 (3H, s), 3.87 (3H, s),
6.50 (1H, d, J ) 1.8 Hz), 6.59 (1H, dd, J ) 8.2, 1.9 Hz), 6.60
(1H, s), 6.69 (1H, d, J ) 8.3 Hz), 7.07 (1H, s), 7.29-7.33 (5H,
m), 7.84 (1H, s); 13C NMR (CDCl3) δ 55.6, 55.7, 55.8, 56.1,
110.8, 113.0, 114.6, 114.9, 115.4, 121.3, 122.0, 122.7, 123.8,
125.1, 126.0, 127.2, 128.7, 140.0, 140.8, 147.9, 148.4, 148.6,
148.8; FTIR (neat film, cm-1) 1598; EIMS (m/z) 496 (M + 1,
3.06; N, 4.56.
5-(2-Br om op h en yl)-4-(4,5-d im eth oxy-2-iod op h en yl)-1-
p h en ylp yr a zole (2i): 79%; white powder; mp 155-157 °C
(MeOH/H2O); Rf 0.32 (20% hexane/CH2Cl2); 1H NMR (CDCl3)
δ 3.54 (3H, s), 3.83 (3H, s), 6.55 (1H, s), 7.16-7.33 (9H, m),
7.50 (1H, dd, J ) 7.2, 1.4 Hz), 7.95 (1H, s); 13C NMR (CDCl3)
δ 55.4, 55.8, 88.0, 113.8, 121.2, 123.7, 125.6, 126.9, 127.2, 128.5,
129.5, 130.4, 131.6, 138.9, 139.7, 140.5, 148.2, 148.4; FTIR
(neat film, cm-1) 1597; EIMS (m/z) 562 (M + 1, 16), 561 (M+,
63), 560 (M - 1, 63), 436 (15), 434 (M - I, 14), 355 (33), 354
(M - I - Br, 100). Anal. Calcd for C23H18BrIN2O2: C, 49.22;
H, 3.23; N, 4.99. Found: C, 49.29; H, 3.21; N, 5.01.
4-(2-Br om o-4,5-d im eth oxyp h en yl)-5-(2-iod op h en yl)-1-
p h en ylp yr a zole (2j): 81%; white powder; mp 138-140 °C
(MeOH/H2O); Rf 0.42 (20% hexane/CH2Cl2); 1H NMR (CDCl3)
δ 3.50 (3H, s), 3.85 (3H, s), 6.47 (1H, s), 7.01 (1H, ddd, J )
8.0, 8.0, 2.1 Hz), 7.04 (1H, s), 7.23-7.33 (8H, m), 7.79 (1H, dd,
J ) 7.9, 1.3 Hz), 8.01 (1H, s); 13C NMR (CDCl3) δ 55.5, 55.9,
100.9, 113.8, 114.2, 115.4, 122.1, 124.1, 124.9, 127.0, 128.6,
130.3, 132.4, 135.8, 139.3. 139.7, 140.7, 141.7, 147.5, 148.2;
FTIR (neat film, cm-1): 1596; EIMS (m/z) 562 (M + 1, 59), 560
(M - 1, 59), 436 (22), 355 (27), 354 (M - I - Br, 100). Anal.
Calcd for C23H18BrIN2O2: C, 49.22; H, 3.23; N, 4.99. Found:
C, 49.37; H, 3.19; N, 5.18.
4-(5-Br om o-1,3-ben zod ioxol-6-yl)-5-(2-br om op h en yl)-1-
p h en ylp yr a zole (2k ): 91%; white powder; mp 143-144 °C
(MeOH/H2O); Rf 0.42 (50% hexane/EtOAc); H NMR (CDCl3)
1
δ 5.92 (2H, s), 6.54 (1H, s), 7.04 (1H, s), 7.29-7.50 (8H, m),
7.52, (1H, dd, J ) 7.5, 1.9 Hz), 7.87 (1H, s); 13C NMR (CDCl3)
δ 101.6, 111.3, 112.7, 115.0, 122.7, 124.0, 124.8, 126.3, 127.1,
127.3, 128.7, 130.5, 131.4, 132.7, 133.0, 139.0, 139.9, 140.8,
146.8, 147.5; FTIR (neat film, cm-1): 1586; EIMS (m/z) 500
(M + 2, 18), 498 (M+, 34), 496 (M - 1, 18), 338 (M - 2Br,
100). Anal. Calcd for C22H14Br2N2O2: C, 53.04; H, 2.83; N, 5.62.
Found: C, 53.19; H, 2.80; N, 5.51.
24), 494 (M - 1, 25), 415 (M - Br, 100). Anal. Calcd for C25H23
-
BrN2O4: C, 60.62; H, 4.68; N, 5.65. Found: C, 60.81; H, 4.69;
N, 5.34.
4,5-Bis(3,4-d im eth oxyp h en yl)-1-p h en ylp yr a zole (2m )
(11%) was also obtained as a green oil.
The same procedure on pyrazole 2b provided the 1,4,5-
triphenylpyrazole 2l (9%) as an amber oil and the correspond-
ing monodehalogenated products 4-(2-iod op h en yl)-1,5-d i-
p h en ylp yr a zole (7a ) and 5-(2-iod op h en yl)-1,4-d ip h en -
1,4,5-Tr ip h en ylp yr a zole (2l): 99%; white powder; mp
197-198 °C (MeOH); Rf 0.28 (CH2Cl2); 1H NMR (CDCl3) δ

7018 J . Org. Chem., Vol. 65, No. 21, 2000
Olivera et al.
2
ylp yr a zole (8a ), which were purified by column chromatog-
raphy on alumina using 5% EtOAc/hexane as eluent. The exact
assignation of the structures is not possible on the basis of
spectrometric data. The major product (30%) was obtained as
1H NMR (CDCl3) δ 0.11 (satel. Sn, J (119Sn-1H) 29 Hz), 0.22
(9H, s), 0.33 (satel. 2J (117Sn-1H) 27 Hz), 3.60 (3H, s), 3.62 (3H,
s), 3.84 (3H, s), 3.89 (3H, s), 6.56 (1H, s), 6.65 (1H, s), 6.96
(1H, s), 6.97 (1H, s), 7.27-7.34 (5H, m), 7.74 (1H, s); 13C NMR
(CDCl3) δ -7.42, 55.4, 55.8, 56.0, 56.1, 113.4, 114.7, 115.9,
118.3, 123.6, 123.9, 126.6, 127.2, 128.8, 132.9, 133.4, 138.8,
139.9, 140.1, 147.4, 148.2, 148.7, 150.0; FTIR (neat film, cm-1):
1596; EIMS (m/z) 645 (26), 643 (14), 641 (15), 640 (14), 419
(10), 415 (37), 414 (87), 399 (48), 383 (11), 371 (25), 356 (21),
355 (24), 341 (14), 339 (10), 327 (12), 320 (100), 318 (95). Anal.
Calcd for C28H31BrN2O4Sn: C, 51.10; H, 4.75; N, 4.26. Found:
C, 51.29; H, 4.86; N, 4.34.
1
an amber oil: Rf 0.26 (CH2Cl2); H NMR (CDCl3) δ 6.92 (1H,
d, J ) 7.7, 1.5 Hz), 6.99 (1H, d, J ) 6.6, 1.7 Hz), 7.09 (1H, d,
J ) 7.6, 1.5 Hz), 7.13-7.27 (10H, m), 7.82 (1H, s), 7.88 (1H, d,
J ) 7.9 Hz); 13C NMR (CDCl3) δ 101.3, 125.1, 125.3, 127.0,
127.2, 127.9, 128.2, 128.3, 128.4, 128.8, 129.7, 130.0, 131.7,
138.1, 139.2, 140.0, 140.8; FTIR (neat film, cm-1): 1595; EIMS
(m/z) 422 (M+, 96), 295 (M - I, 100). Anal. Calcd for C21H15
-
IN2: C, 59.73; H, 3.58; N, 6.63. Found: C, 59.94; H, 3.69; N,
6.59. The minor product (21%) was isolated as a yellow oil: Rf
0.26 (CH2Cl2); 1H NMR (CDCl3) δ 7.00 (1H, ddd, J ) 7.9, 7.9,
1.7 Hz), 7.09-7.28 (12H, m), 7.77 (1H, d, J ) 7.8 Hz), 7.92
(1H, s); 13C NMR (CDCl3) δ 98.6. 125.5, 126.6. 127.4, 127.9,
128.6, 131.1. 131.9, 138.8. 139.2, 139.6, 140.6; FTIR (neat film,
cm-1) 1595 (CdN); EIMS (m/z) 422 (M+, 100), 295 (M - I, 85).
Anal. Calcd for C21H15IN2: C, 59.73; H, 3.58; N, 6.63. Found:
C, 60.14; H, 3.22; N, 6.79.
Syn th esis of P h en a n th r o[9,10-d ]p yr a zoles via Sta n -
n yla tion /Bia r yl Cou p lin g. 1-P h en ylp h en a n th r o[9,10-d ]-
p yr a zole (3a ). Typ ica l P r oced u r e. A heavy wall-pressure
tube was charged with diarylpyrazole 2a (207 mg, 0.456
mmol), PdCl2(PPh3)2 (16.0 mg, 22.8 µmol), and degassed 1,4-
dioxane (1.8 mL) under Ar. A solution of Me6Sn2 (225 mg, 0.684
mmol) in degassed 1,4-dioxane (0.8 mL) was added to resulting
suspension, and after flushing with Ar at room temperature
for 15 min and closing the tube, the mixture was heated at
140 °C in an autoclave for 40 h. After cooling, the resulting
black suspension was centrifuged, and the deposited black
palladium was abundantly washed with CH2Cl2. The combined
organic solvents were washed with saturated KF solution. The
organic layer was dried over anhydrous sodium sulfate and
the solvent was evaporated in vacuo. The resulting residue
was purified by crystallization from hexane/EtOAc 50% to
afford phenanthropyrazole (3a ) (119 mg, 88%) as a white
powder: mp 181-182 °C (EtOAc); Rf 0.47 (40% hexane/EtOAc);
1H NMR (CDCl3) δ 7.34 (1H, ddd, J ) 7.9, 7.9, 1.5 Hz), 7.56-
7.90 (9H, m), 8.28 (1H, dd, J ) 7.9, 1.5 Hz), 8.58 (1H, s), 8.64
(1H, dd, J ) 7.9, 1.5 Hz), 8.70 (1H, dd, J ) 8.0, 1.2 Hz); 13C
NMR (CDCl3) δ 119.1, 121.6, 122.8, 123.4, 124.0, 125.3, 126.3,
127.1, 127.6, 127.8, 127.9, 129.1, 129.5, 134.1, 135.1, 141.8;
FTIR (neat film, cm-1) 1596; EIMS (m/z) 294 (M+, 100). Anal.
Calcd for C21H14N2: C, 85.69; H, 4.79; N, 9.52. Found: C, 85.46;
H, 4.69; N, 9.85.
The same procedure on pyrazole 2c provided 1-p h en yl-
5,6,9,10-t et r a m et h oxyp h en a n t h r o[9,10-d ]p yr a zole (3b )
(78%) as a yellow powder: mp 181-182 °C (EtOAc); Rf 0.47
(40% hexane/EtOAc); 1H NMR (CDCl3) δ 3.48 (3H, s), 4.09 (3H,
s), 4.12 (6H, s), 6.97 (1H, s), 7.58-7.67 (6H, m), 7.81 (1H, s),
7.83 (1H, s), 8.49 (1H, s); 13C NMR (CDCl3) δ 55.0, 55.9, 56.0,
56.2, 104.1, 104.7, 114.8, 118.1, 120.6, 121.2, 125.1, 127.8,
129.1, 129.4, 133.4, 134.6, 141.7, 147.7, 147.9, 148.7, 149.4;
FTIR (neat film, cm-1) 1596; EIMS (m/z) 414 (M+, 100). Anal.
Calcd for C25H22N2O4: C, 72.45; H, 5.35; N, 6.76. Found: C,
72.39; H, 5.41; N, 6.81.
The variation of the reaction conditions (temperature (-100
°C f -40 °C), stoichiometry of the organolithium reagent
(1.1-2.3 equiv), nature of the organolithium (nBuLi, tBuLi) and
of the electrophile reagents ((B(OMe)3, B(OiPr)3, TMSCl, Me3-
SnCl)) led to the obtention of the former products in different
yields ranged in Table 2.
Syn th esis of P h en a n th r o[9,10-d ]p yr a zoles via Ull-
m a n n Bia r yl Cou p lin g Rea ction . A selection of the most
advantageous Ullmann biaryl coupling procedures assayed
(Table 3) are described below.
P r oced u r e 1. A suspension of diarylpyrazole 2b (0.06 g,
0.11 mmol) and (CuOTf)2‚PhH (90%, 0.218 g, 0.39 mmol) in
degassed DMF (5 mL) was stirred at 100 °C under Ar for 39
h. The mixture was allowed to reach room temperature, poured
into H2O (50 mL) and extracted with EtOAc (3 × 10 mL). The
organic layers were dried over anhydrous sodium sulfate and
evaporated in vacuo. The residue was purified by flash column
chromatography using 20% EtOAc/hexane as eluent, providing
1-phenylphenanthro[9,10-d]pyrazole (3a ) (0.035 g, 77%) as a
colorless oil.
The same procedure on diarylpyrazole 2d provided 1-phenyl-
5,6,9,10-tetramethoxyphenanthro[9,10-d]pyrazole (3b) (56%)
as a yellow oil.
P r oced u r e 2. A suspension of diarylpyrazole 2b (0.09 g,
0.157 mmol) and copper bronze (99%, 0.039 g, 0.63 mmol) in
dry nitrobenzene (9 mL) was heated in a heavy-wall pressure
tube at 175 °C under Ar for 41 h. The mixture was allowed to
reach room temperature and filtered. It was diluted with
CHCl2 (30 mL) and washed with NH4OH (3 × 3 mL). The
organic extract was dried over anhydrous sodium sulfate and
filtered off, and the solvent was evaporated under pressure (1
mmHg. 90 °C). The residue was analyzed by GC/MS showing
the presence of 1-phenylphenanthro[9,10-d]pyrazole 3a in a
81% yield.
The same procedure on pyrazole 2e provided 9,10-dim eth oxy-
1-p h en ylp h en a n th r o[9,10-d ]p yr a zole (3c) (80%) as a white
powder, mp 155-157 °C (80% hexane/EtOAc); Rf 0.28 (60%
1
hexane/EtOAc); H NMR (CDCl3) δ 3.48 (3H, s), 4.03 (3H, s),
6.96 (1H, s), 7.55-7.67 (7H, m), 8.03 (1H, s), 8.28 (1H, dd, J )
8.3, 2.0 Hz), 8.49 (1H, dd, J ) 8.0, 1.2 Hz), 8.56 (1H, s); 13C
NMR (CDCl3) δ 55.0, 55.9, 104.1, 105.0, 115.8, 118.2, 122.9,
123.5, 125.1, 126.0, 126.7, 127.4, 127.8, 129.2, 129.4, 134.1,
135.1, 141.7, 148.2, 148.4; FTIR (neat film, cm-1): 1596; EIMS
(m/z, %) 355 (M+, 28), 354 (100). Anal. Calcd for C23H18N2O2:
C, 77.95; H, 5.12; N, 7.90. Found: C, 77.84; H, 5.29; N, 8.19.
The same procedure on pyrazole 2g provided 5,6-dim eth oxy-
1-p h en ylp h en a n th r o[9,10-d ]p yr a zole (3d ) (81%) as a white
powder: mp 199-201 °C (MeOH); Rf 0.32 (50% hexane/
The same procedure was applied on diarylpyrazole 2d , and
the GC/MS analysis of the residue indicated the formation of
1-phenyl-5,6,9,10-tetramethoxyphenanthro[9,10-d]pyrazole 3b
(56%) in a 77% yield.
Syn th esis of Ar ylsta n n a n e (9). 5-(2-Br om o-4,5-d im eth -
oxyph en yl)-4-(4,5-dim eth oxy-2-tr im eth ylstan n ylph en yl)-1-
p h en ylp yr a zole (9). A heavy wall-pressure tube was charged
with pyrazole 2c (0.151 g, 0.261 mmol), Pd(PPh3)4 (99%, 15,2
mg, 13 µmol) and degassed 1,4-dioxane (1 mL) under Ar. A
solution of Me6Sn2 (0.425 g, 1.30 mmol) in degassed 1,4-dioxane
(1.6 mL) was added to resulting suspension, and after flushing
with Ar at room temperature for 15 min and closing the tube,
the mixture was heated at 105 °C in an autoclave for 4 h. After
cooling, the resulting black suspension was centrifugated and
the deposited black palladium was washed with CH2Cl2. The
combined organic solvents were washed with saturated KF
solution. The organic layer was dried over anhydrous Na2SO4
and filtered off, and the solvent was evaporated in vacuo. The
resulting residue was purified by flash column chromatogra-
phy using 40% EtOAc/hexane as eluent providing stannane 9
(0.104 g, 61%) as a colorless oil: Rf 0.55 (60% hexane/EtOAc);
1
EtOAc); H NMR (CDCl3) δ 4.13 (6H, s), 7.27 (1H, d, J ) 8.0
Hz), 7.55-7.63 (8H, m), 7.99 (1H, s), 8.50 (1H, s), 8.54 (1H, d,
J ) 8.1 Hz); 13C NMR (CDCl3) δ 56.0, 104.0, 104.9, 111.1, 119.0,
120.7, 121.2, 121.6, 122.9, 123.4, 125.3, 126.5, 127.1, 129.0,
129.5, 133.5, 134.6, 141.8, 148.0, 149.9; FTIR (neat film, cm-1):
1597; EIMS (m/z) 354 (M+, 100). Anal. Calcd for C23H18N2O2:
C, 77.95; H, 5.12; N, 7.90. Found: C, 78.02; H, 5.21; N, 7.94.
The same procedure on pyrazole 2g provided 1-p h en yl[1,3]-
d ioxolo[2,3-d ]p h en a n th r o[9,10-d ]p yr a zole (3e) (79%) as
a yellow powder: mp 209-210 °C (MeOH); Rf 0.35 (50%
hexane/EtOAc); 1H NMR (CDCl3) δ 6.13 (2H, s), 7.30 (1H, d, J
) 7.1 Hz), 7.53-7.62 (8H, m), 8.00 (1H, s), 8.46 (1H, s), 8.50

Straightforward Preparation of Phenanthro[9,10-d]pyrazoles
J . Org. Chem., Vol. 65, No. 21, 2000 7019
(1H, d, J ) 7.1 Hz); 13C NMR (CDCl3) δ 101.3, 101.7, 102.3,
119.4, 120.7, 122.6, 122.8, 123.1, 123.6, 125.5, 126.6, 127.1,
129.0, 129.5, 130.8. 133.7. 134.6. 141.8, 147.0, 148.2; FTIR
(neat film, cm-1): 1596; EIMS (m/z) 338 (M+, 100). Anal. Calcd
for C22H14N2O2: C, 78.09; H, 4.17; N, 8.28. Found: C, 78.27;
H, 4.07; N, 8.41.
resulting mixture was heated at 120 °C in an autoclave for 55
h until TLC showed the completion of the reaction. After
cooling, the resulting black suspension was centrifugated and
the deposited black palladium was abundantly washed with
CH2Cl2. The combined organic solvents were washed with
saturated NH4Cl solution (2 × 10 mL), dried over anhydrous
sodium sulfate, and filtered off. The solvent was evaporated
under pressure (1 mmHg, 90 °C) and the resulting residue was
purified by flash column chromatography using 20% EtOAc/
hexane as eluent, providing 1-phenylphenanthro[9,10-d]pyra-
zole 3a (0,037 g, 45%) as a colorless oil.
The same procedure on diarylpyrazole 2c afforded 1-phenyl-
5,6,9,10-tetramethoxyphenanthro[9,10-d]pyrazole 3b (41%) as
a yellow oil.
The same procedure on diarylpyrazole 2d afforded 1-phenyl-
5,6,9,10-tetramethoxyphenanthro[9,10-d]pyrazole 3b (33%) as
a yellow oil.
Assa ys of Bia r yl Cou p lin g Usin g Bis(p in a cola to)-
dibor on . 1-P h en ylph en a n th r o[9,10-d ]p yr a zole (3a ). Typ i-
ca l P r oced u r e. A heavy wall-pressure tube was charged with
diarylpyrazole 2b (0.25 g, 0.46 mmol), PdCl2(PPh3)2 (61.5 mg,
87.6 µmol), bis(pinacolato)diboron (0.128 g, 0.51 mmol), NaOAc
(0.253 g, 1.38 mmol), and degassed DMF (2 mL) and purged
with Ar at room temperature for 15 min. After closing the tube,
the mixture was heated at 120 °C in an autoclave for 17 h
until TLC showed the completion of the reaction. After cooling,
the resulting black suspension was centrifugated and the
deposited black palladium was removed. The reaction mixture
was degassed again, and anhydrous K3PO4 (0.376 g, 2.3 mmol)
and PdCl2(PPh3)2 (16.5 mg, 23.5 µmol) were added. After
closing the tube, the resulting mixture was heated at 120 °C
in an autoclave for 55 h. After cooling, the resulting black
suspension was centrifugated and the deposited black pal-
ladium was abundantly washed with dichlromethane. The
combined organic solvents were washed with saturated NH4-
Cl solution (2 × 10 mL), dried over anhydrous sodium sulfate
and filtered off. The solvent was evaporated under pressure
(1 mmHg, 90 °C). The resulting residue was purified by flash
column chromatography using 20% EtOAc/hexane as eluent
providing 1-phenylphenanthro[9,10-d]pyrazole 3a (0.081 g,
60%) as a white powder.
Syn th esis of P h en a n th r o[9,10-d ]p yr a zoles via Oxid a -
t ive Cou p lin g R ea ct ion . 5,6,9,10,11-P en t a m et h oxy-1-
p h en ylp h en a n th r o[9,10-d ]p yr a zole (3f). Typ ica l P r oce-
d u r e. A solution of PIFA (0.137 g, 0.31 mmol) in dry CH2Cl2
(1 mL) was added to a stirred solution of diarylpyrazole 2n
(0.125 g, 0.28 mmol) in dry CH2Cl2 (7 mL) at -40 °C under
Ar. After the addition of BF3‚OEt2 (35.6 µL, 0.32 mmol), the
resulting brown solution was stirred for 15 min at -40 °C,
allowed to warm at room temperature and absorbed on silica
gel (0.725 g). Purification by flash column chromatography
using 50% hexane/EtOAc as eluent provided phenanthro-
pyrazole 3f as a yellow powder (0.068 g, 55%): mp 188-190
1
°C (MeOH); Rf 0.52 (30% hexane/EtOAc); H NMR (CDCl3) δ
The same procedure on diarylpyrazole 2d afforded 1-phenyl-
5,6,9,10-tetramethoxyphenanthro[9,10-d]pyrazole 3b (41%) as
a yellow oil.
3.29 (3H, s), 3.81 (3H, s), 4.11 (9H, s), 7.30-7.36 (1H, m), 7.40-
7.42 (4H, m), 7.57 (1H, s), 7.66 (1H, s), 7.80 (1H, s), 8.52 (1H,
s); 13C NMR (CDCl3) δ 56.0, 56.1, 56.2, 60.0, 61.2, 100.2, 104.0,
105.0, 111.0, 119.7, 121.3, 123.2, 126.7, 127.9, 128.6, 134.0,
134.4, 141.0, 145.1, 148.1, 148.6, 150.0, 153.0; FTIR (neat film,
cm-1):1597; EIMS (m/z) 444 (M+, 100). Anal. Calcd for
Assa ys of Bia r yl Cou p lin g Usin g P in a colb or a n e. 1-
P h en ylp h en a n th r o[9,10-d ]p yr a zole (3a ). Typ ica l P r oce-
d u r e. A heavy wall-pressure tube was charged with dia-
rylpyrazole 2b (0.156 g, 0.29 mmol), PdCl2(PPh3)2 (24.4 mg,
34.8, µmol), anhydrous Et3N (0.12 mL, 0.87 mmol), and
degassed 1,4-dioxane (5 mL). Pinacolborane (50 µL of a stock
solution prepared as previously reported,27 0.50 mmol) was
added dropwise, and the mixture was purged with Ar at room
temperature for 15 min. After closing the tube, the mixture
was heated at 120 °C in an autoclave for 6 h. After cooling,
the resulting black suspension was centrifugated and the
deposited black palladium was removed. The reaction mixture
was diluted with H2O (40 mL) and extracted with Et2O (5 × 5
mL). The organic layer was dried over anhydrous sodium
sulfate, filtered off and the solvent was evaporated in vacuo.
The residue was dried under pressure (1 mmHg) at room
temperature over P2O5 for 6 h. It was transferred into a heavy-
wall presure tube and disolved in degassed DMF (1.25 mL). A
mixture K3PO4 (0.235 g, 1.43 mmol) and PdCl2(PPh3)2 (10.2
mg, 14.5 µmol) were added, and after closing the tube, the
C
26H24N2O5: C, 70.26; H, 5.44; N, 6.30. Found: C, 70.21; H,
5.42; N, 6.39.
The same procedure on diarylpyrazole 2l afforded 1-phen-
ylphenanthro[9,10-d]pyrazole 3a (16%) as a colorless oil.
The same procedure on diarylpyrazole 2m afforded 1-phen-
yl-5,6,9,10-tetramethoxyphenanthro[9,10-d]pyrazole 3b (86%)-
as a white powder.
Ack n ow led gm en t. This research was supported by
the University of the Basque Country (Project UPV
170.310G37/98), the Ministry of Education and Culture
(PB97-0600) and the Basque Government (GV170.310-
G0053/96). R.O. thanks the Basque Government for a
predoctoral scholarship.
J O000609I