Regioselective reactions of organozinc reagents with 2,4- dichloroquinoline and 5,7-dichloropyrazolo[1,5-α]pyrimidine

Article abstract of DOI:10.1021/jo981423a

Strategies for controlling the regioselective reactions between 2,4- dichloroquinoline and organozinc reagents are described. 2,4- Dichloroquinoline has been found to react with benzylic zinc and phenylzinc reagents in the presence of catalytic amounts of palladium complexes to exclusively give α-substituted products. Several metal salts were examined as an additive for γ-selective coupling reactions. The most effective additive for selective coupling reaction at the γ-position has been found to be LiCl. These conditions for α- or γ-selective coupling reactions were applied to the reaction between 5,7-dichloropyrazolo[1,5-α]pyrimidine and a biphenylmethylzinc reagent in the synthesis of the angiotensin II receptor antagonists. This regioselectivity should be generally applicable to other α,γ-dichloroazine systems.

Full text of DOI:10.1021/jo981423a

J . Org. Chem. 1999, 64, 453-457
453
Regioselective Rea ction s of Or ga n ozin c Rea gen ts w ith
2,4-Dich lor oqu in olin e a n d 5,7-Dich lor op yr a zolo[1,5-a ]p yr im id in e
Takeshi Shiota* and Teruo Yamamori
Shionogi Research Laboratories, Shionogi & Co. Ltd., Fukushima-ku, Osaka 553-0002, J apan
Received J uly 21, 1998
Strategies for controlling the regioselective reactions between 2,4-dichloroquinoline and organozinc
reagents are described. 2,4-Dichloroquinoline has been found to react with benzylic zinc and
phenylzinc reagents in the presence of catalytic amounts of palladium complexes to exclusively
give R-substituted products. Several metal salts were examined as an additive for γ-selective
coupling reactions. The most effective additive for selective coupling reaction at the γ-position has
been found to be LiCl. These conditions for R- or γ-selective coupling reactions were applied to the
reaction between 5,7-dichloropyrazolo[1,5-a]pyrimidine and a biphenylmethylzinc reagent in the
synthesis of the angiotensin II receptor antagonists. This regioselectivity should be generally
applicable to other R,γ-dichloroazine systems.
In tr od u ction
the regioselectivity of coupling reaction of R,γ-dichloro-
azines, we investigated the reaction of 2,4-dichloroquino-
line 5 with a benzylic zinc reagent 6 under various
conditions and then successfully established the condi-
tions under which each regioisomeric coupling product
would be selectively produced. Here we report the results
of regioselective reactions of 5 with 6, and application of
the condition to synthesis of the pyrazolo[1,5-a]pyrim-
idines 1 and 2.
Palladium-catalyzed cross-coupling reactions are ver-
satile methods for C-C bond formation between formal
electrophiles C-X (X ) Cl, Br, I, OTf) and organometal-
lics C-M (M ) Li, Mg, Zn, Sn, B, Si, etc.).1 Like
organostannanes and organoboranes, organozinc re-
agents tolerate the presence of various organic functional
groups in the reaction system. Recently, several new
methods for preparing polyfunctional organozinc reagents
have been developed,1f,2 which allow organozinc reagents
to be used more conveniently. Thus, the combination of
reagents and palladium catalyst is a useful C-C bond
formation method for preparing molecules containing
several functional groups,2,3 and these reactions are
becoming more important not only in the area of natural
product synthesis but also in medicinal chemistry.4
In the course of our investigation of nonpeptide angio-
tensin II receptor antagonists, we designed a series of
pyrazolo[1,5-a]pyrimidines in which both 5- and 7-posi-
tions were substituted with biphenylmethyl and phenyl
groups (1 and 2).5 In the preliminary synthetic study of
these compounds, we conducted the reaction of 5,7-
dichloroderivative 3 with biphenylmethylzinc bromide 4
in the presence of a catalytic amount of Pd(Ph3P)4 in
THF. This reaction gave a regioisomeric mixture of 5-
and 7-substituted products. Generally, when two or more
reaction centers are present in the cross-coupling reac-
tion, it is difficult to produce each regioisomer selectively.
To our knowledge, there have been few examples of such
a regioselective cross-coupling reaction in the literature.6
To develop a generally applicable method for controlling
Resu lts a n d Discu ssion
The results of the reactions of 2,4-dichloroquinoline 5
with the benzylic zinc bromide 6 in the presence of
various additives are summarized in Table 1. This
coupling reaction does not proceed without any additive.
The reactions in the presence of Pd(Ph3P)4 catalyst in
THF or DMF proceeded at room temperature to exclu-
sively give R-substituted product 8 (entries 1 and 2). A
higher reaction temperature accelerated the reaction rate
and improved the chemical yield (entry 3). This excellent
R-selectivity was notable because it had been known that
the reaction of the dichloro derivative 5 with various
nucleophiles gave a regioisomeric mixture.7 But recently,
some examples of regioselective reaction of a similar R,γ-
dichloroazine system were also reported. The Suzuki
coupling reaction of 2,4-dichloropyridine in THF took
place at only the R-position,8 and Stille cross-coupling
reaction of 2,4,6-tribromophosphinines with organotin
(1) (a) Stille, J . K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b)
Kalinin, V. N. Synthesis 1992, 413. (c) Mitchell, T. N. Synthesis 1992,
803. (d) Hatanaka, Y.; Hiyama T. Synlett 1991, 845. (e) Miyama, N.;
Suzuki, A. Chem. Rev. 1995, 95, 2457. (f) Knochel, P.; Singer, R. D.
Chem. Rev. 1993, 93, 2117. (g) Ritter, K. Synthesis 1993, 735.
(2) (a) Knochel, P. Act. Met. 1996, 191. (b) Erdik, E. Tetrahedron
1987, 43, 2203. (c) Zhu, L.; Wehmeyer, R. M.; Rieke, R. D. J . Org.
Chem. 1991, 56, 1445. Rieke, R. D. Science 1989, 246, 1260.
(3) Negishi, E. Acc. Chem. Res. 1982, 15, 340.
(4) For some applications of Pd-catalyzed coupling reactions to
combinatorial chemistry, see: Thompson, L. A.; Ellman, J . A. Chem.
Rev. 1996, 96, 555.
(5) Biological results of these compounds will be published else-
where.
(6) (a) Kamikawa, T.; Hayashi, T. Tetrahedron Lett. 1997, 38, 7087.
(b) Sekiya, K.; Nakamura, E. Tetrahedron Lett. 1988, 29, 5155.
(7) (a) Samalley, R. K. The Chemistry of Heterocyclic Compounds;
Gurnos, J ., Ed.; J . Wiley & Sons, Inc.: New York, 1977; Vol 32,
Quinolines, Chapt. 3. (b) Illuminati, G.; Marino, G. Atti Accad. Naz.
Lincei, Cl. Sci. Fis. Mat. Nat., Rend. 1965, 38, 525.
10.1021/jo981423a CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/08/1999

454 J . Org. Chem., Vol. 64, No. 2, 1999
Shiota and Yamamori
Ta ble 1. Regioselective Rea ction s of 2,4-Dich lor oqu in olin e a n d Ben zyl Zin c Rea gen t 6 in th e P r esen ce of Va r iou s
Ad d itives
yield(%)b
entry
additive (equiv)a
solvent
THF
DMF
THF
THF
THF
temp (°C)
time (h)
7
8
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Pd(Ph3P)4 (0.05)
Pd(Ph3P)4 (0.05)
Pd(Ph3P)4 (0.05)
bipyridine (1.0)
tBuOK (1.0)
CuBrMe2S (1.0)
MgBr2 (1.0)
LiCl (1.5)
LiCl (4.0)
LiCl (1.0)
LiCl (0.5)
LiCl (2.0)
LiCl (4.0)
LiBr (2.0)
LiI (2.0)
LiClO4 (2.0)
LiCl (2.0)
NaCl (2.0)
KCl (2.0)
MgBr2 (2.0)
rt
rt
18
18
2
-
-
-
-
-
-
59
60
80
-
60
60
60
-70-0
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
18
18
18
18
24
24
24
24
24
6
24
24
16
16
16
16
16
-
c
THF
-
THF+DMPUd
THF
9.6
-
18
39
65
34
77
83
77
54
-
71
56
45
34
-
THF
4.2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
-
-
<2.0
<2.0
4.0
5.0
-
<2.0
3.0
4.0
9
rt
a
b
d
Based on 5. Yields based on isolated products. c A homodimer of 6 was obtained. N,N′-Dimethylpropyleneurea.
reagents occurred selectively at the R-position to the
phosphorus.9 In the latter example, coordination of the
phosphorus to the palladium was hypothesized to control
the regioselectivity. Similar coordination-controlled re-
gioselectivity was proposed in the reaction of 2,4-dichlo-
roquinoline with sodium alkoxide in toluene, which
exclusively gave the 2-alkoxy-4-halogenoquinolines.10
Taking these observations into account, in this case also,
R-selective coupling reaction should be controlled by
coordination of the quinoline nitrogen to the palladium.
We next attempted the γ-selective coupling reaction
by direct nucleophilic substitution.11 Several additives
which have been reported to allow increase in the
nucleophilicities of organozinc reagents6b,12 resulted in no
reaction or homodimer formation (entries 4-6). But when
reaction was considered as an aromatic nucleophilic
substitution reaction. The polar solvent DMF would be
suitable for this reaction, because DMF assists in stabi-
lizing partially ionized transition states and intermediate
more effectively than THF. Various molar ratios of LiCl
were examined in DMF solvent (entries 11-13). Although
4 equiv of LiCl provided the best result, 2 equiv of LiCl
gave a comparable result with longer reaction times
(entry 12).
Various counteranions for lithium cation were exam-
ined in DMF solvent (entries 14-16). Whereas the
reactions in the presence of Cl-, Br-, I-, which are known
to coordinate with zinc ion,14 gave 7 in good yields (entries
13-15), ClO4-, which has little coordination ability, gave
no coupling product (entry 16). These results suggest that
the halogen ligands increase the zinc-carbon bond
polarity through coordination to the zinc and then
enhance the reactivity of 6 toward electrophilic species.
The lithium cation was more effective than sodium,
potassium, or magnesium salts (entries 17 vs 18, 19 and
20) for increasing the reactivity of 6.
13
MgBr2 was added to the reaction mixture, the γ-sub-
stituted product was obtained in low yield (entry 7). In
the presence of 1.5 equiv of LiCl, the yield of the
γ-substituted product was slightly improved (entry 8).
Although an increased amount of LiCl gave a higher yield
of 7 (entry 9), the choice of the solvent proved more
critical in this reaction. When it was DMF, the yield and
selectivity were dramatically improved (entry 10). This
The structures of the regioisomers 7 and 8 were
confirmed by NOE studies. The product from the pal-
ladium-catalyzed reaction was assigned as the 2-substi-
tuted 8 from the NOE observed between the benzylic
methylene protons and the proton at the 3-position of
quinoline. On the other hand, the NOE study of 7 showed
(8) Cruskie, M. P., J r.; Zoltewicz, J . A. Abboud, K. A. J . Org. Chem.
1995, 60, 7491.
(9) (a) Floch, P. L.; Carmichael, D.; Ricard, L.; Mathey, F. J . Am.
Chem. Soc. 1993, 115, 10665. (b) Trauner, H.; Floch, P. L.; Lefour,
J .-M.; Ricard, L.; Mathey, F. Synthesis 1995, 717.
(10) Osborne, A. G.; Miller, L. A. D. J . Chem. Soc., Perkin Trans. 1
1993, 181.
(11) A referee pointed out a literature reference which reported the
4-selective reaction of 2,3,4,5,6-pentachloropyridine with benzylmag-
nesium chloride. Dua, S. S.; Gilman H. J . Organomet. Chem. 1968,
12, 299.
(13) (a) Marx, B.; Basch, E, H.; Freon, P. C. R. Acad. Sci., Ser. C
1967, 264, 527. (b) Marx, B.; Basch, E, H.; Freon, P. C. R. Acad. Sci.,
Ser. C 1968, 266, 1646.
(14) Kimura, E.; Shiota, T.; Koike, T.; Shiro, M.; Kodama, M. J . Am.
Chem. Soc. 1990, 112, 5805.
(12) Rathke, M. W.; Yu, H. J . Org. Chem. 1972, 37, 1732.

Cross-Coupling of Organozincs with R,γ-Dichloroazines
J . Org. Chem., Vol. 64, No. 2, 1999 455
Ta ble 2. Regioselective Cou p lin g Rea ction s of
2,4-Dich lor oqu in olin e a n d Va r iou s P h en yl Meta l
Rea gen ts
product 7, whose structure was previously determined
by NOE study, reacted with phenylboronic acid in the
presence of palladium catalyst to give 10. The cross-
coupling product from the reaction of 9 with the benzyl-
zinc bromide 6 showed the same analytical and spectral
properties as those of the product obtained from 7.
The above procedure was applied to the synthesis of
regioisomeric pyrazolo[1,5-a]pyrimidines 12 and 14 as
shown in Scheme 2. Dichloro derivative 3 was treated
with the organozinc reagent 4 in the presence of 2 equiv
of LiCl to exclusively give 11 in 52% yield. Coupling
reaction of 3 with 4 in the presence of a catalytic amount
of Pd(Ph3P)4 in DMF solvent gave 52% of 13 and 7% of
11. The same reaction which was performed in THF
showed no regioselectivity (vide supra). DMF was the
preferred solvent for giving the R-selective cross-coupling
product in the palladium-catalyzed reaction. Although
the reason for the lower R-regioselectivity of 5,7-dichlo-
ropyrazolo[1,5-a]pyrimidine than 2,4-dichloroquinoline
was unclear, we speculate that the lower basicity of 5,7-
dichloropyrazolo[1,5-a]pyrimidine may diminish the co-
ordination-controlled reaction pathway. The products 11
and 13 were independently coupled with phenylboronic
acid in the presence of palladium catalyst affording 5,7-
disubstituted products 12 and 14 in 90 and 77%, respec-
tively.
entry
phenyl reagent
additive
9, yielda
1
2
3
4
PhZnCl
Pd(Ph3P)4 (0.05)
Pd(Ph3P)4 (0.05)
Pd(Ph3P)4 (0.05)
94
79
74
-
PhSn(Me)3
PhB(OH)2
PhZnCl
LiCl
(2.0)
a
Yields are based on isolated products.
Sch em e 1
Structure determination of these regioisomeric prod-
ucts was carried out by regiospecific synthesis of 5-phenyl
derivative 12 as shown in Scheme 3. According to the
literature, â-keto ester 15 and 3-aminopyrazole were
condensed to give 5-phenylpyrazolo[1, 5-a]pyrimidin-7-
(4H)-one 17,15 which was then converted to 7-chloro
derivative 18 by treatment with phosphorus oxychloride.
Coupling reaction of 18 with 4 gave the product whose
analytical and spectral properties were identical to those
of 12.
NOE’s between the benzylic methylene protons and the
protons at both 3- and 5-positions of quinoline.
Thus, regioselectivity in the cross-coupling reaction
between 5 and 6 could be controlled or switched by using
two different additives, Pd(PPh3)4 for the R-coupling
product and LiCl for the γ-coupling product.
The general applicability of the palladium-catalyzed
R-selective coupling reaction of 2,4-dichloroquinoline with
various organometallics was investigated using the
phenylorganometallics (Table 2). As was expected, pal-
ladium-catalyzed reactions (entries 1-3) exclusively gave
R-coupling product 9, suggesting that the regioselectivity
is not affected by the kind of organometal. On the other
hand, no coupling product was obtained in the reaction
using LiCl. This is in marked contrast to the reactivity
and regioselectivity observed for the benzylic zinc reagent
6. This difference would be due to the lower reactivity of
phenylzinc than benzylzinc reagent 6.
Con clu sion s
The reaction conditions for controlling the regioselec-
tivities of the reactions of 2,4-dchloroquinoline and 5,7-
dichloropyrazolo[1,5-a]pyrimidine with organozinc re-
agents were developed: Pd(Ph3P)4 for R-position to the
aromatic nitrogen, and LiCl for γ-position. While regio-
selectivities have been demonstrated only in two systems,
2,4-dichloroquinoline and 5,7-dichloropyrazolo[1,5-a]py-
The structure of 9 was confirmed by two independent
preparations of compound 10 (Scheme 1). The γ-coupling
Sch em e 2

456 J . Org. Chem., Vol. 64, No. 2, 1999
Shiota and Yamamori
was worked up and purified by a similar procedure to that
Sch em e 3
described in the preparation of 7 to give 249 mg (80%) of 8 as
1
white crystals: mp 100-101 °C; H NMR (CDCl3) δ 3.90 (s,
3H), 4.36 (s, 2H), 7.29 (s, 1H), 7.34 (d, J ) 7.8 Hz, 2H), 7.61
(ddd, J ) 1.0, 7.05, 8.4 Hz, 1H), 7.77 (ddd, J ) 1.5, 7.05, 8.55
Hz, 1H), 8.00 (m, 2H), 8.09 (dd, J ) 1.0, 8.4 Hz, 1H), 8.18 (dd,
J ) 1.5, 8.3 Hz, 1H); IR (Nujol): 3438, 1730, 1273 cm-1. Anal.
Calcd for C18H14ClNO2: C, 69.35; H, 4.53; Cl, 11.37; N, 4.49.
Found: C, 69.37; H, 4.54; Cl, 11.33; N, 4.51.
Cou plin g Reaction s of 2,4-Dich lor oqu in olin e an d P h en -
yl Or ga n om eta llics. En tr y 1: To a solution of phenyl
bromide (210 mL, 2.0 mmol) in THF (5 mL) at -78 °C was
added dropwise n-butyllithium (2.1 mmol) in n-hexane. The
resulting mixture was stirred for 0.5 h at -78 °C. Next, 2.1
mL of 1 M ZnCl2 solution in THF was added to this mixture,
and the reaction was stirred at -78 °C for another 1 h. 5 (300
mg, 1.5 mmol) and Pd(Ph3P)4 (87 mg, 0.075 mmol) were added
to the mixture which was then stirred for 16 h at room
temperature. The reaction mixture was worked up and purified
by a similar procedure to that described in the preparation of
7 to give 337 mg (94%) of 9 as white crystals: mp 60-61 °C;
1H NMR (CDCl3) δ 7.47-7.63 (m, 3H), 7.61 (ddd, J ) 1.6, 6.9,
8.4 Hz, 1H), 7.77 (ddd, J ) 1.6, 6.9, 8.4 Hz, 1H), 7.97 (s, 1H),
rimidine, the reaction should have synthetic utility in
other R,γ-dichloroazine systems.
Exp er im en ta l Section
Gen er a l. Unless otherwise stated, all reactions were carried
out under a nitrogen atmosphere. Tetrahydrofuran (THF),
ether, xylene and N,N-dimethylformamide (DMF) were dried
over 4-Å molecular sieves. Flash chromatography was per-
formed on silica gel (Merck Kieselgel: Art9385). 5,7-Dichlo-
ropyrazolo[1,5-a]pyrimidine,16 2,4-dichloroquinoline,17 and 4′-
(bromomethyl)-1,1′-biphenyl-2-carbonitrile18 were prepared by
literature methods. Zinc dust, Pd(Ph3P)4, ZnCl2 in THF solu-
tion, methyl 4-(bromomethyl)benzoate, and n-butyllithium in
n-hexane solution were purchased from Aldrich, Inc.
P r ep a r a tion of Ben zylic Zin c Br om id e Stock Solu tion
(6). A suspension of zinc dust (1.634 g, 25 mmol) and
1,2-dibromoethane (87 µL, 1 mmol) in DMF (5 mL) was stirred
for 10 min at 70 °C. After the mixture was cooled to room
temperature, chlorotrimethylsilane (100 µL, 0.8 mmol) was
added and stirred for 30 min at room temperature. To this
activated zinc dust was added dropwise methyl 4-(bromo-
methyl)benzoate (5.14 g, 22 mmol) in DMF (20 mL) over a
period of 120 min at 0 °C. After 2 h of stirring at 0 °C, the
total volume of this mixture was adjusted to 40 mL, which
gave about 0.5 M stock solution of the zinc reagent. This stock
solution was stable for a few weeks in the refrigerator under
N2 atmosphere. THF stock solution could be obtained by the
similar procedure.
Gen er a l P r oced u r e for Cou p lin g Rea ction s of 2,4-
Dich lor oqu in olin e (5) a n d Ben zylic Zin c Br om id e (6) in
th e P r esen ce of Va r iety of Ad d itives. LiCl as an additive:
To the solution of 5 (199 mg, 1 mmol) and 6 (2.4 mL, 1.2 mmol)
in DMF (5 mL) was added LiCl (85 mg, 2 mmol). After stirring
24 h at room temperature, the mixture was poured into
saturated aqueous ammonium chloride and ice and extracted
with three 30 mL portions of EtOAc. The combined extracts
were washed with water (20 mL) and saturated brine (20 mL)
and then dried (MgSO4). The solvent was evaporated in vacuo,
and the residue was purified by flash chromatography (toluene:
EtOAc ) 20:1 as an eluent) to give 240 mg (77%) of 7 as white
prisms: mp 137-138 °C; 1H NMR (CDCl3) δ 3.91 (s, 3H), 4.46
(s, 2H), 7.12 (s, 1H), 7.27 (d, J ) 8.2 Hz, 2H), 7.54 (ddd, J )
1.4, 7.0, 8.3 Hz, 1H), 7.73 (ddd, J ) 1.4, 7.0, 8.4 Hz, 1H), 7.92-
8.07 (m, 4H); IR (Nujol): 2924, 2854, 1716, 1284 cm-1. Anal.
Calcd for C18H14ClNO2: C, 69.35; H, 4.53; Cl, 11.37; N, 4.49.
Found: C, 69.39; H, 4.66; Cl, 11.09; N, 4.52.
8.11-8.25 (m, 4H); IR (Nujol): 2923, 1578, 1545, 1488 cm-1
.
Anal. Calcd for C15H10ClN: C, 75.16; H, 4.20; Cl, 14.79; N, 5.84.
Found: C, 75.11; H, 4.32; Cl, 14.66; N, 5.87. En tr y 2: A
solution of 5 (397 mg, 2 mmol), phenyltrimethyltin (390 mL,
2.1 mmol), and Pd(Ph3P)4 (120 mg, 0.01 mmol) in toluene (10
mL) was refluxed for 16 h. The reaction mixture was worked
up and purified by a similar procedure to that described in
the preparation of 7 to give 9 (378 mg, 79%). En tr y 3: A
solution of 5 (300 mg, 1.5 mmol), phenylboronic acid (220 mg,
1.8 mmol), Na2CO3 (335 mg, 3.16 mmol), and Pd(Ph3P)4 (120
mg, 0.01 mmol) in 7 mL of toluene and 2 mL of H2O was
refluxed for 16 h. The reaction mixture was worked up and
purified by a similar procedure to that described in the
preparation of 7 to give 9 (265 mg, 74%).
Meth yl 4-(2-p h en ylqu in olin -4yl)m eth ylben zoa te (10).
This compound was prepared from 7 according to the proce-
dure described for the coupling reactions of 2,4-dichloroquino-
line and phenylboronic acid. Colorless needles. Yield 95%.
1
mp111-112 °C; H NMR (CDCl3) δ 3.89 (s, 3H), 4.53 (s, 2H),
7.30 (d, J ) 8.4 Hz, 2H), 7.42-7.54 (m, 4H), 7.63 (s, 1H), 7.68-
7.73 (m, 1H), 7.93-8.00 (m, 3H), 8.08-8.12 (m, 2H), 8.20 (d,
J ) 8.1 Hz, 1H); IR (Nujol): 2951, 2923, 2854, 1714, 1594,
1282 cm-1. Anal. Calcd for C24H19NO2: C, 81.56; H, 5.42; N,
3.96. Found: C, 81.36; H, 5.55; N, 3.93.
5-Ch lor o-7-[[2′-cya n ob ip h en yl-4-yl]m et h yl]p yr a zolo-
[1,5-a ]p yr im id in e (11). To a suspension of zinc dust (acti-
vated with 1, 2-dibromoethane and chlorotrimethylsilane as
same manner described in the preparation of 6; 330 mg, 5
mmol) in DMF (1.0 mL) at 0 °C was added dropwise 4′-
(bromomethyl)-1,1′-biphenyl-2-carbonitrile (1.02 g, 3.75 mmol)
in DMF (5 mL) over a period of 30 min. The resulting mixture
was stirred for 1 h at 0 °C and then left standing for 1 h at 0
°C. The supernatant was transferred to a solution of 3 (376
mg, 2.0 mmol) and LiCl (206 mg, 4.9 mmol) in DMF (2 mL)
and stirred for 1 h at room temperature. The reaction mixture
was worked up and purified by a similar procedure to that
described in the preparation of 7 to give 360 mg (52%) of 11
as colorless prisms: mp 154-155 °C; 1H NMR (CDCl3) δ 4.56
(s, 2H), 6.49 (s, 1H), 6.68 (d, J ) 2.4 Hz, 1H), 7.42-7.82 (m,
8H), 8.18 (d, J ) 2.4 Hz, 1H); IR (Nujol): 2924, 2855, 2226,
1606, 1540 cm-1. Anal. Calcd for C20H13ClN4: C, 69.67; H, 3.80;
Cl, 10.28; N, 16.25. Found: C, 69.68; H, 3.94; Cl, 10.14; N,
16.31.
Pd(Ph3P)4 as an additive: A mixture of 5 (397 mg, 2 mmol),
6 (4.2 mL, 2.1 mmol), and Pd(Ph3P)4 (120 mg, 0.1 mmol) in
THF (5 mL) was stirred for 2 h at 60 °C. The reaction mixture
5-P h en yl-7-[[2′-cya n ob ip h en yl-4-yl]m et h yl]p yr a zolo-
[1,5-a ]p yr im id in e (12). This compound was prepared from
5 according to the procedure described for the coupling
reactions of 2,4-dichloroquinoline and phenylboronic acid.
Colorless prisms. Yield 90%. mp 152-153 °C; 1H NMR (CDCl3)
δ 4.64 (s, 2H), 6.78 (d, J ) 2.4 Hz, 1H), 6.97 (s, 1H), 7.42-
7.80 (m, 11H), 7.98-8.04 (m, 2H), 8.19 (d, J ) 2.4 Hz, 1H); IR
(15) Senga, K.; Novinson, T.; Wilson, H. R.; Robins, R. K. J . Med.
Chem. 1981, 24, 610.
(16) O’Brien, D. E.; Viejo, M.; Robins, R. K.; Simon, L. N. U.S. Patent
3,907,799, Sept 23, 1975.
(17) Koller, G. Chem. Ber. 1927, 60, 8.
(18) Carini, D. J .; Duncia, J . V.; Aldrich, P. E.; Chiu, A. T.; J ohnson,
A. L.; Pierce, M. E.; Price, W. A.; Santella III, J . B.; Wells, G. J .; Wexler,
R. R.; Wong, P. C.; Yoo, S.-E.; Timmermans, P. B. M. W. M. J . Med.
Chem. 1991, 34, 2525.
(Nujol): 2925, 2229, 1621, 1555 cm-1
. Anal. Calcd for

Cross-Coupling of Organozincs with R,γ-Dichloroazines
J . Org. Chem., Vol. 64, No. 2, 1999 457
C26H18N4: C, 80.81; H, 4.69; N, 14.50. Found: C, 80.77; H,
4.80; N, 14.36.
colorless needles. Yield 77.3%. mp 150-151 °C; 1H NMR
(CDCl3) δ 4.28 (s, 2H), 6.73 (d, J ) 2.4 Hz, 1H), 6.77 (s, 1H),
7.40-7.55 (m, 9H), 7.60-7.66 (m, 1H), 7.74-7.77 (m, 1H),
7.96-7.99 (m, 2H), 8.14 (d, J ) 2.1 Hz, 1H); IR (Nujol): 2924,
2854, 2228, 1617, 1603 cm-1. Anal. Calcd for C26H18N4: C,
80.81; H, 4.69; N, 14.50. Found: C, 80.94; H, 4.97; N, 14.24.
7-Ch lor o-5-[[2′-cya n ob ip h en yl-4-yl]m et h yl]p yr a zolo-
[1,5-a ]p yr im id in e (13). A solution of 4 (3.0 mmol; prepared
by the same method as described for the synthesis of 11), 3
(452 mg, 2.4 mmol), and Pd(Ph3P)4 (110 mg, 0.1 mmol) in DMF
(10 mL) was stirred for 4 h at 60 °C. The reaction mixture
was worked up and purified by a similar procedure to that
described in the preparation of 7 to give 430 mg (52%) of 13
as colorless prisms: mp 145-148 °C; 1H NMR (CDCl3) δ 4.23
(s, 2H), 6.76 (d, J ) 2.2 Hz, 1H), 6.85 (s, 1H), 7.41-7.80 (m,
8H), 8.20 (d, J ) 2.2 Hz, 1H); IR (Nujol): 3434, 2228, 1616
cm-1. Anal. Calcd for C20H13ClN4‚0.1toluene: C, 70.23; H, 3.93;
Cl, 10.01; N, 15.83. Found: C, 70.01; H, 4.14; Cl, 9.72; N, 15.61.
7-P h en yl-5-[[2′-cya n ob ip h en yl-4-yl]m et h yl]p yr a zolo-
[1,5-a ]p yr im id in e (14). This compound was prepared from
13 according to the procedure described for the coupling
reactions of 2,4-dichloroquinoline and phenylboronic acid as
Ack n ow led gm en t. We thank Dr. Mitsuaki Yodo for
useful comments on the manuscript.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 7 and 8, including NOE spectra (5 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
J O981423A