Pd-catalyzed cross-coupling reactions of pyridine carboxylic acid chlorides with alkylzinc reagents

Article abstract of DOI:10.1055/s-0028-1088113

The efficient cross-coupling reaction to afford ketones from pyridine carboxylic acid chlorides and alkylzinc reagents in the presence of Pd(phen)Cl₂ is reported. In the case of chloronicotinoyl chlorides, none of Negishi cross-coupling product

Full text of DOI:10.1055/s-0028-1088113

LETTER
1091
Pd-Catalyzed Cross-Coupling Reactions of Pyridine Carboxylic Acid
Chlorides with Alkylzinc Reagents
C
ross-Coupling
o
Reactions
o
s
f
Pyridine
hCarboxylic
i
cid
C
y
hlorides
w
ith
u
A
lkylzinc
R
k
eagents i Iwai,* Takeo Nakai, Masatoshi Mihara, Takatoshi Ito, Takumi Mizuno, Toshinobu Ohno*
Osaka Municipal Technical Research Institute, 1-6-50, Morinomiya, Joto-ku, Osaka 536-8553, Japan
Fax +81(6)69638049; E-mail: iwai@omtri.city.osaka.jp; E-mail: ohno@omtri.city.osaka.jp
Received 2 February 2009
and limitation of substitution orientation. So, cross-
coupling reaction of pyridine carboxylic acid chlorides
with organometallic reagents would provide a superior
method for them. Knochel et al. reported only one exam-
Abstract: The efficient cross-coupling reaction to afford ketones
from pyridine carboxylic acid chlorides and alkylzinc reagents in
the presence of Pd(phen)Cl2 is reported. In the case of chloronico-
tinoyl chlorides, none of Negishi cross-coupling products of 2-chlo-
roazine moiety was formed. The catalyst loading could be reduced ple of acylation between 6-chloronicotinoyl chloride and
diarylzinc.14a Wang et al. had demonstrated an addition
up to 0.01 mol%.
reaction of Grignard reagents to 6-chloronicotinoyl chlo-
ride in the presence of bis[2-(N,N-dimethylamino)eth-
yl]ether.14b Those examples are limited to alkyl Grignard
reagents and some functionalized aryl organometallics,
and the scope of this method has not been fully explored.
This situation encouraged us to attempt the cross-coupling
reaction between functionalized alkylzinc reagents and
pyridine carboxylic acid chlorides. Here, we would like to
Key words: cross-coupling, alkylzinc reagents, palladium, pyri-
dine, ketone
The acylation reaction of organometallic reagents affords
one of the most important methods for ketone synthesis
and numerous studies have been reported.1 Friedel–Crafts
acylation with acid chlorides is a complementary method
for the synthesis of aromatic ketones;2 however, undesir-
able orientation and/or the usage of more than a stoichio-
metric amount of Lewis acids sometimes limit its
application. Weinreb amide methodology3 is also a useful
technique, but has a limitation to synthesize pharmaceuti-
cals and target molecules for material science because of
poor functional compatibility of Grignard reagents and
organolithium compounds. Therefore, transition-metal-
catalyzed or -mediated reactions of carboxylic acid deriv-
atives with functionalized organometallic reagents4 pro-
vide most potent procedures.
Table 1 Palladium-Catalyzed Cross-Coupling of 1 with 2
O
O
Pd cat. (3 mol%)
PhCh2CH2ZnI (2)
Cl
Solvent, r.t., 2 h
Cl
X
Cl
X
Ph
3a,b
1a X = N
1b X = CH
Entry
1
Palladium catalyst
Pd(PPh3)4
Solvent
toluene
toluene
toluene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Product Yield (%)a
3a
3b
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
68
94
65
47b
58b
5
The use of organozinc reagents has become a subject of
current interest in organic synthesis because of their great
tolerance for broad functional groups.5 Some reactions us-
ing metallic zinc and organozinc reagents with carbonyl
compounds to provide olefins, alcohols, and amines have
been reported in our laboratory.6 Transition-metal-cata-
lyzed C–C bond formation reactions of organozinc com-
pounds with aromatic halides are well known as Negishi
cross-coupling,5,7 as well as acylation reaction with car-
boxylic acid derivatives.1a,5 Since Negishi et al. reported
the palladium-catalyzed acylation of organozinc re-
agents,8 extensive efforts9–12 have been made including
Fukuyama’s thioester cross-coupling13 for various scopes
and wide applications.
2
Pd(PPh3)4
3
Pd2(dba)3CHCl3
Pd(PPh3)4
4
5
PdCl2(PPh3)2
–
6
7
Pd2(dba)3CHCl3
PdCl2
60
83
75
86
92
91c
94
8
9
Pd(OAc)2
10
11
12
13
Pd(bpy)Cl2
Pd(phen)Cl2
Pd(phen)Cl2
Pd(phen)Cl2
Interestingly, there have been few reports about formation
of pyridyl ketones via the cross-coupling reactions,14
whereas traditional Friedel–Crafts acylation was unsuit-
able for pyridine rings because of their electron deficiency
a Isolated yield.
b Compounds 4–6 were observed.
SYNLETT 2009, No. 7, pp 1091–1094
Advanced online publication: 26.03.2009
DOI: 10.1055/s-0028-1088113; Art ID: U00909ST
x
x.
x
x.
2
0
0
9
c The amount of 2.5 equiv of alkylzinc reagent 2 was used. None of 2-
alkylated product 4 was detected.
© Georg Thieme Verlag Stuttgart · New York

1092
T. Iwai et al.
LETTER
report an efficient cross-coupling reaction of pyridine car-
boxylic acid chlorides with functionalized alkylzinc re-
agents.
O
O
Pd(phen)Cl2 (0.01 mol%)
PhCH2CH2ZnI (2)
Cl
MeCN, r.t., 5 h
Cl
N
Cl
N
Ph
First, we examined the reaction between 6-chloronico-
tinoyl chloride (1a) and alkylzinc reagent 215 based on
Tamaru’s condition as shown in Table 1.12,16 In the pres-
ence of Pd(PPh3)4, cross-coupling reaction carried out at
ambient temperature, and the corresponding ketone 3a
was obtained in 68% yield (Table 1, entry 1). In the previ-
ous report,6d ethyl acetate and acetonitrile were better sol-
vents compared to toluene for nucleophilic addition of
alkylzinc reagents to aromatic aldimines. So, next we
chose acetonitrile as a solvent, however, only 47% of 3a
was obtained with considerable amount of byproducts 4–
6 (Scheme 1, Table 1, entry 4). 2-Alkylated pyridines 4
and 6 were formed from Negishi cross-coupling reaction
between alkylzinc reagent 2 and 2-chloroazine moiety of
6-chloronicotinoyl chloride (1a).17 On the other hands, al-
dehydes 5 and 6 were obtained through the b-H elimina-
tion of a palladium alkyl intermediate followed by the
reductive elimination of the palladium hydride spe-
cies.11,18 Catalytic activity should be controlled to prevent
Negishi cross-coupling reaction of 2-chloroazine moiety
and b-H elimination of alkylzinc reagents from occurring
and achieve selective formation.
1a
3a 79%
Scheme 2
Table 2 Pd-Catalyzed Cross-Coupling of Nicotinoyl Chlorides with
Alkylzinc Reagents
O
O
Pd(phen)Cl2 (3 mol%)
MeCN, r.t., 2 h
+
Cl
FGRZnI
R
X
X
N
N
Entry ArCOCl
FGRZnI
Product Yield
(%)a
1
2
3a
3c
92
87
Ph
IZn
IZn
IZn
IZn
O
Cl
3
3d
77
COOEt
Cl
N
1a
4
5
6
3e
3f
80
83
81
COOEt
Various catalysts and reaction conditions were examined
as shown in Table 1. When PPh3 was used as a ligand,
yields were moderate and considerable amount of byprod-
ucts 4–6 were observed. The yield was remarkably low in
the absence of Pd catalyst (entry 6). Interestingly, in the
case of ligandless catalysts such as PdCl2 or Pd(OAc)2,
better results were obtained in 83% and 75% yields, re-
spectively (entries 8 and 9). This might show the possibil-
ity that 1a or 3a themselves worked as a ligand, so
palladium catalysts having bidentate nitrogen ligands,
such as 2,2¢-bipyridine (bpy) and 1,10-phenanthroline
(phen), were attempted. Among all of conditions,
Pd(phen)Cl2 proved to be the best catalyst and excellent
yield was achieved (entry 11). Under this optimized reac-
tion conditions [1.5 equiv of alkylzinc reagents and 3
mol% of Pd(phen)Cl2],19 none of the byproducts 4–6 was
observed, even if the excess amount (2.5 equiv) of alkyl-
zinc reagent 2 was used (entry 12).20 Pd(phen)Cl2 catalyst
system was also effective to benzoyl chloride (entry 13).
The catalyst loading could be reduced up to 0.01 mol%
with prolonged reaction time (Scheme 2).
COOEt
CN
IZn
IZn
3g
O
Cl
7
8
9
88
92
Ph
Ph
IZn
IZn
N
Cl
7
O
F
Cl
10
Cl
N
Cl
8
a Isolated yield.
ined, and the results were summarized in Table 2. Alkyl-
zinc reagents bearing ester and cyano groups could be
smoothly converted into corresponding ketones in high
yields (entries 3–6). Chloronicotinoyl chlorides 7 and 8
also reacted successfully to afford the corresponding
products 9 and 10 without any aldehydes and 2-alkylated
To study the scope and limitations of this transformation,
various acid chlorides and alkylzinc reagents were exam-
O
O
Ph
Ph
O
Cl
Cl
N
N
Ph
N
N
Ph
3a 47%
4 3%
ZnI
Pd(PPh3)4 (3 mol%)
MeCN, r.t., 2 h
Cl
+
Ph
2 (1.5 equiv)
CHO
CHO
Cl
N
1a
5 8%
6 12%
Scheme 1
Synlett 2009, No. 7, 1091–1094 © Thieme Stuttgart · New York

LETTER
Cross-Coupling Reactions of Pyridine Carboxylic Acid Chlorides with Alkylzinc Reagents
1093
Negishi cross-coupling products, respectively. Thus, the tinoyl chlorides with alkylzinc reagents in the presence of
present Pd(phen)Cl2 catalyst system achieved chemo- Pd(phen)Cl2 to afford pyridyl ketones with no formation
selective ketone formation between chloronicotinoyl of Negishi coupling product of 2-chloroazine moiety. This
chlorides and alkylzinc reagents.
catalyst system can be adapted to cross-coupling of vari-
ous pyridine carboxylic acid chlorides with alkylzinc re-
agents. Further explorations for applications of this
system are now in progress.
Furthermore, unsubstituted pyridine carboxylic acid chlo-
rides were also examined (Scheme 3). These acid chlo-
rides were commercially available as hydrochloric acid
salts 11a–c, so one equivalent excess of alkylzinc reagents
were needed in these cases. The reaction between nico-
tinoyl chloride hydrochloride (11a) and alkylzinc reagent
2 gave corresponding ketone 12a in high yield, however,
picolinoyl chloride hydrochloride (11b) and isonicotinoyl
chloride hydrochloride (11c) afforded moderate yields.
References and Notes
(1) (a) Dieter, R. K. Tetrahedron 1999, 55, 4177.
(b) Lawrence, N. J. J. Chem. Soc., Perkin Trans. 1 1988,
1739.
(2) Heaney, H. In Comprehensive Organic Synthesis, Vol. 2;
Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford,
1991, 733.
(3) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1982, 22,
3815. (b) Balasubramaniam, S.; Aiden, I. S. Synthesis 2008,
3703.
O
O
Pd(phen)Cl2 (3 mol%)
PhCH2CH2ZnI (2)
Cl
Ph
MeCN, r.t., 2 h
HCl
N
N
(4) Handbook of Functionalized Organometallics; Knochel, P.,
Ed.; Wiley-VCH: New York, 2005.
11a 3-COCl
11b 2-COCl
11c 4-COCl
12a 75%
12b 44%
12c 42%
(5) (a) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117.
(b) Erdik, E. Organozinc Reagents in Organic Synthesis;
CRC Press: Boca Raton FL, 1996. (c) Organozinc
Reagents: A Practical Approach; Knochel, P.; Jones, P.,
Eds.; Oxford University Press: New York, 1999.
(d) Knochel, P.; Millot, N.; Rodriguez, A.; Tucker, C. E.
Org. React. 2001, 58, 417. (e) Knochel, P.; Calaza, M. I.;
Hupe, E. In Metal-Catalyzed Cross-Coupling Reactions,
2nd ed.; de Meijere, A.; Diederich, F., Eds.; Wiley-VCH:
New York, 2004.
(6) (a) Ishino, Y.; Mihara, M.; Kageyama, M.; Nishiguchi, I.
Bull Chem. Soc. Jpn. 1998, 71, 2669. (b) Ishino, Y.;
Mihara, M.; Kageyama, M. Tetrahedron Lett. 2002, 43,
6601. (c) Ito, T.; Ishino, Y.; Mizuno, T.; Ishikawa, A.;
Kobayashi, J. Synlett 2002, 2116. (d) Iwai, T.; Ito, T.;
Mizuno, T.; Ishino, Y. Tetrahedron Lett. 2004, 45, 1083.
(7) (a) Negishi, E.; King, A. O.; Okukado, N. J. Org. Chem.
1977, 42, 1821. (b) King, A. O.; Okukado, N.; Negishi, E.
J. Chem. Soc., Chem. Commun. 1977, 683. (c) Negishi, E.
Acc. Chem. Res. 1982, 15, 340.
Scheme 3
In the case of dicarboxylic acid dichlorides 13 and 15, cor-
responding ketones 14a and 16a were obtained in good
yields with small amount of isomerized products 14b and
16b, respectively (Scheme 4, Scheme 5). These isomer-
ized ketones 14b and 16b were presumably formed
through b-H elimination of alkylzinc reagent 2 followed
by alkene reinsertion preceding reductive elimination.21
Ph
Ph
N
Pd(phen)Cl2 (3 mol%)
Ph2CH2CH2ZnI (2)
O
O
Cl
Cl
14a 58%
N
MeCN, r.t., 2 h
O
O
Ph
13
Ph
(8) Negishi, E.; Bagheri, V.; Chatterjee, S.; Luo, F.-T.; Miller,
J. A.; Stoll, A. T. Tetrahedron Lett. 1983, 24, 5181.
(9) (a) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org.
Chem. 1988, 53, 2392. (b) Reddy, C. K.; Knochel, P.
Angew. Chem., Int. Ed. Engl. 1996, 35, 1700.
(10) (a) Sato, T.; Naruse, K.; Enokiya, M.; Fujisawa, T. Chem.
Lett. 1981, 1135. (b) Sato, T.; Itoh, T.; Fujisawa, T. Chem.
Lett. 1982, 1559.
(11) Grey, R. A. J. Org. Chem. 1984, 49, 2288.
(12) (a) Tamaru, Y.; Ochiai, H.; Sanda, F.; Yoshida, Z.
Tetrahedron Lett. 1985, 45, 5529. (b) Tamaru, Y.; Ochiai,
H.; Nakamura, T.; Tsubaki, K.; Yoshida, Z. Tetrahedron
Lett. 1985, 45, 5559.
(13) (a) Tokuyama, H.; Yokoshima, S.; Yamashita, T.;
Fukuyama, T. Tetrahedron Lett. 1998, 39, 3189. (b) Mori,
Y.; Seki, M. Tetrahedron Lett. 2004, 45, 7343.
(14) (a) Kneisel, F. F.; Dochnahl, M.; Knochel, P. Angew. Chem.
Int. Ed. 2004, 43, 1017. (b) Wang, X.-J.; Zhang, L.; Sun, X.;
Xu, Y.; Krishnamurthy, D.; Senanayake, C. H. Org. Lett.
2005, 7, 5593.
N
O
O
O
14b 6%
Scheme 4
Ph
O
O
Pd(phen)Cl2 (3 mol%)
Ph
O
N
Cl
Ph2CH2CH2ZnI (2)
Cl
16a 68%
MeCN, r.t., 2 h
N
O
15
Ph
Ph
N
O
16b 8%
Scheme 5
(15) Typical Procedure for Preparation of Alkylzinc
Reagents
In conclusion, we have developed an efficient and
chemoselective cross-coupling reaction of chloronico-
Under argon atmosphere, to a mixture of Zn metal (196 mg,
3.0 mmol) and DMI (0.43 mL, 4.0 mmol) in MeCN (3.0 mL)
Synlett 2009, No. 7, 1091–1094 © Thieme Stuttgart · New York

1094
T. Iwai et al.
LETTER
was added one drop of TMSCl at 60 °C and stirred for 5 min,
followed by addition of 2-phenylethyl iodide (0.43 mL, 3.0
mmol), stirring at the same temperature for 2 h, and cooling
to r.t.
7.42 (1 H, d, J = 8.3 Hz), 7.32–7.18 (5 H, m), 3.31–3.26 (2
H, m), 3.10–3.05 (2 H, m). 13C NMR (75.5 MHz, CDCl3):
d = 196.63, 155.44, 149.67, 140.43, 137.87, 130.84, 128.51,
128.27, 126.25, 124.41, 40.57, 29.60. IR (KBr): 3055, 3025,
1685, 1575, 1466, 1375, 1103, 700 cm–1. MS (EI): m/z
(relative intensity) = 245 (100) [M+], 140 (95). HRMS (EI):
m/z calcd for C14H12ClNO [M+]: 245.0607; found: 245.0617.
Compound 3f: white solid, mp 52.8 °C. 1H NMR (300 MHz,
CDCl3): d = 8.97 (1 H, d, J = 2.3 Hz), 8.21 (1 H, dd, J = 8.3,
2.4 Hz), 7.45 (1 H, d, J = 8.4 Hz), 4.16 (2 H, q, J = 7.1 Hz),
3.28 (2 H, t, J = 6.5 Hz), 2.79 (2 H, t, J = 6.4 Hz), 1.27 (3 H,
t, J = 7.1 Hz). 13C NMR (75.5 MHz, CDCl3): d = 195.84,
172.36, 155.68, 149.73, 137.93, 130.7, 124.49, 60.76, 33.58,
27.87, 14.10. IR (KBr): 3037, 2995, 1730, 1688, 1579, 1373,
1221 cm–1. MS (EI): m/z (relative intensity) = 241 (31) [M+],
196 (65), 140 (100). HRMS (EI): m/z calcd for C11H12ClNO3
[M+]: 241.0506; found: 241.0504.
(16) Toluene–DMI was utilized instead of benzene–DMA.
(17) (a) Hasníl, Z.; Śilhár, P.; Hocek, M. Synlett 2008, 543.
(b) Chekmarev, D. S.; Stepanov, A. E.; Kasatkin, A. N.
Tetrahedron Lett. 2005, 46, 1303.
(18) Stylene was detected by GC-MS.
(19) Typical Procedure for the Pd-Catalyzed Cross-Coupling
Reaction
Under argon atmosphere, to a suspension of 6-chloro-
nicotinoyl chloride (1a, 352 mg, 2.0 mmol) and Pd(phen)Cl2
(21 mg, 0.06 mmol) in MeCN (3.0 mL) was added alkylzinc
reagent 2 and stirring at same temperature. After stirring for
2 h, sat. NH4Cl was added to the reaction mixture and
extracted with EtOAc (2 × 20 mL). The combined EtOAc
extract was washed with sat. NH4Cl, sat. NaHCO3 and brine,
and dried over MgSO4, filtered, and concentrated in vacuo.
The residue was purified by chromatography on SiO2
(hexane–EtOAc, 6:1) to give the product 3a (453 mg, 92%)
as white solid.
(20) When excess amount of 2 (2.5 equiv) was used with
Pd(Ph3P)4 catalyst, 4 and 6 were obtained in 45% and 38%,
respectively.
(21) (a) Luo, X.; Zhang, H.; Duan, H.; Liu, Q.; Zhu, L.; Zhang,
T.; Lei, A. Org. Lett. 2007, 9, 4571. (b) Liu, J.; Deng, Y.;
Wang, H.; Zhang, H.; Yu, G.; Wu, B.; Zhang, H.; Li, Q.;
Marder, T. B.; Yang, Z.; Lei, A. Org. Lett. 2008, 10, 2661.
Selected Spectra Data
Compound 3a: mp 82.9 °C. 1H NMR (300 MHz, CDCl3):
d = 8.91 (1 H, d, J = 2.4 Hz), 8.16 (1 H, dd, J = 8.4, 2.4 Hz),
Synlett 2009, No. 7, 1091–1094 © Thieme Stuttgart · New York

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