A novel, air-stable phosphine ligand for the palladium-catalyzed suzuki-miyaura cross-coupling reaction of chloro arenes

Article abstract of DOI:10.1021/jo100643j

(Figure presented) A novel, air-stable phosphine ligand, prepared from readily available 2-bromonitrobenzene and vinylmagnesium bromide, combines with Pd(CH₃CN)₂Cl₂ to afford an effective catalyst for Suzuki-Miyaura cross-coupling of aryl, heteroaryl, and allyl chlorides with phenylboronic acid.

Full text of DOI:10.1021/jo100643j

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SCHEME 1. Synthesis of Ligand
A Novel, Air-Stable Phosphine Ligand for
the Palladium-Catalyzed Suzuki-Miyaura
Cross-Coupling Reaction of Chloro Arenes
Raju Ghosh, N. N. Adarsh,† and Amitabha Sarkar*
Department of Organic Chemistry, Indian Association for the
Cultivation of Science, Jadavpur, Kolkata 700032, India.
X-ray structure determination.
†
ocas@iacs.res.in
Received April 5, 2010
Recently significant progress has been made toward acti-
vation of aryl chlorides in the Suzuki coupling reaction
t
through the use of alkylphosphine ligands, e.g., Bu3P by
Fu,6 biphenyl based aryldialkylphosphines by Buchwald,7
heteroaromatic phosphines by Beller,8 and ferrocene-based
dialkylphosphine by Hartwig.9 Trialkyl- or dialkylarylpho-
sphines make the metal center electron rich, which facilitates
oxidative addition by less active C-Cl bonds. It is known
that various palladium-10 and nickel-based11 catalysts and nano-
sized palladium12 are also very effective with aryl chlorides.
Phosphine ligands containing amino phosphine donor have
been successfully used in cross-coupling reactions.13 It was
explained that an alkyl amino group provides an electron-
rich σ-donor character to the phosphorus atom14a whereas a
pyrrolyl nitrogen attached to phosphorus makes it a poorer
σ-donor but better π-acceptor.14b In this report, we describe
the synthesis and molecular structure of a novel bidentate
A novel, air-stable phosphine ligand, prepared from
readily available 2-bromonitrobenzene and vinylmagne-
sium bromide, combines with Pd(CH3CN)2Cl2 to afford
an effective catalyst for Suzuki-Miyaura cross-coupling
of aryl, heteroaryl, and allyl chlorides with phenylboro-
nic acid.
(6) (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 37, 3387.
(b) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020. (c)
Kudo, N.; Perseghini, M.; Fu, G. C. Angew. Chem., Int. Ed. 2006, 45, 1282.
(7) (a) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
120, 9722. (b) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am.
Chem. Soc. 1999, 121, 9550. (c) Wolfe, J. P.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 1999, 38, 2413. (d) Walker, S. D.; Barder, T. E.; Martinelli, J. R.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2004, 43, 1871. (e) Anderson, K. W.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2005, 44, 6173. (f) Barder, T. E.;
Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127,
4685. (g) Billingsley, K. L.; Anderson, K. W.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2006, 45, 3484. (h) Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc.
2007, 129, 3358.
(8) (a) Andreu, M. G.; Zapf, A.; Beller, M. Chem. Commun. 2000, 2475.
(b) Harkal, S.; Rataboul, F.; Zapf, A.; Fuhrmann, C.; Riermeier, T.;
Monsees, A.; Beller, M. Adv. Synth. Catal. 2004, 346, 1742. (c) Zapf, A.;
Jackstell, R.; Rataboul, F.; Riermeier, T.; Monsees, A.; Fuhrmann, C.;
Shaikh, N.; Dingerdissen, U.; Beller, M. Chem. Commun. 2004, 38.
(9) Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem.
2002, 67, 5553.
The transition metal-catalyzed cross-coupling reaction of
aryl and vinyl halides/sulfonates is one of the most efficient
methods for carbon-carbon bond formation.1 In this class,
the Suzuki-Miyaura coupling reaction stands out as a power-
ful, convenient, and versatile method for cross-coupling of aryl
bromides, iodides, or triflates with arylboronic acids.2 It has
several practical advantages: excellent functional group toler-
ance, wide substrate scope, and ready separation of nontoxic
boron-containing byproduct.3 A benchmark for catalytic ac-
tivity in such a reaction is the ability of the catalyst to activate
inexpensive aryl or vinyl chlorides, rather than expensive
bromides or iodides.4 The challenge essentially lies in the fact
that the aryl chlorides are less reactive due to their relatively
high C-Cl bond strength and their reluctance to undergo
oxidative addition.5
(10) (a) Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org. Chem.
ꢀ
1999, 64, 3804. (b) Botella, L.; Najera, C. Angew. Chem., Int. Ed. 2002, 41,
179. (c) Botella, L.; Najera, C. J. Organomet. Chem. 2002, 663, 46. (d) Alonso,
ꢀ
ꢀ
ꢀ
D. A.; Najera, C.; Pacheco, M. C. J. Org. Chem. 2002, 67, 5588. (e) Najera,
€
ꢀ
(1) For reviews see: Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E.-i., Ed.; Wiley-Interscience: New York, 2002.
(2) (a) Miyaura, N. In Metal-Catalyzed Cross-Coupling Reaction; Diederich,
F., de Meijere, A., Eds.; Wiley-VCH: New York, 2004; Chapter 2. (b) Miyaura, N.;
Suzuki, A. Chem. Rev. 1995, 95, 2457.
C.; Gil-Molto, J.; Karlstrom, S.; Falvello, L. R. Org. Lett. 2003, 5, 1451.
(f) Bedford, R. B.; Blake, M. E.; Butts, C. P.; Holder, D. Chem. Commun.
ꢀ
2003, 466. (g) Najera, C.; Gil-Molto, J.; Karlstrom, S. Adv. Synth. Catal.
2004, 346, 1798. (h) Gil-Molto, J.; Karlstrom, S.; Najera, C. Tetrahedron
2005, 61, 12168. (i) Ohta, H.; Tokunaga, M.; Obora, Y.; Iwai, T.; Iwasawa,
ꢀ
€
ꢀ
€
ꢀ
ꢀ
T.; Fujihara, T.; Tsuji, Y. Org. Lett. 2007, 9, 89. (j) Alacid, E.; Najera, C.
J. Organomet. Chem. 2009, 694, 1658. (k) Alonso, D. A.; Cıvicos, J. F.;
(3) Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
(4) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
(5) (a) Grushin, V. V.; Alper, H. In Activation of Unreactive Bonds and
Organic Synthesis; Murai, S., Ed.; Springer- Verlag: Berlin, Germany, 1999;
p 193. (b) Grushin, V. V.; Alper, H. Chem. Rev. 1994, 94, 1047.
´
ꢀ
Najera, C. Synlett 2009, 3011. (l) Doherty, S.; Knight, J. G.; McGrady, J. P.;
Ferguson, A. M.; Ward, N. A. B.; Harrington, R. W.; Clegga, W. Adv. Synth.
Catal. 2010, 352, 201.
5320 J. Org. Chem. 2010, 75, 5320–5322
Published on Web 06/30/2010
DOI: 10.1021/jo100643j
r
2010 American Chemical Society

Ghosh et al.
JOCNote
SCHEME 2. Synthesis of Palladium Complex
TABLE 3. Cross-Coupling of Aryl, Heteroaryl, and Allyl Chlorides
with Phenylboronic Acida
TABLE 1. Optimization of Cross-Coupling Reaction of Aryl Chloride
with Boronic Acida
entry
Pd (mol %)
L (mol %)
base
yield (%)b
1
2
3
4
5
6
7
8
9
Pd(CH3CN)2Cl2 (2)
Pd(CH3CN)2Cl2 (3)
Pd(CH3CN)2Cl2 (4)
Pd(CH3CN)2Cl2 (4)
Pd(OAc)2 (4)
2
3
4
4
4
4
4
4
4
4
4
8
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
Cs2CO3
K2CO3
K3PO4
CsF
80
89
98
75c
80
55
85
30
42
80
81
0
Pd2(dba)3 (4)
Pd(CH3CN)2Cl2 (4)
Pd(CH3CN)2Cl2 (4)
Pd(CH3CN)2Cl2 (4)
Pd(CH3CN)2Cl2 (4)
Pd(CH3CN)2Cl2 (4)
Pd(CH3CN)2Cl2 (4)
10
11
12
KOH
NaOH
aReaction condition: 4-chloroacetophenone (1 mmol), phenylboro-
nic acid (1.5 mmol), base (2 mmol), DMF (2.5 mL); argon atmosphere.
bIsolated yield. cAt 100 °C.
TABLE 2. Screening of Solvents
entry
solvent
T (°C)
time (h)
yield (%)b
1
2
3
4
5
6
DMF
THF
DCM
toluene
DMSO
DMAc
125
65
40
110
125
125
8
10
10
10
10
8
98
2
0
25
30
95
aReaction condition: 4-chloroacetophenene (1 mmol), phenylboronic
acid (1.5 mmol), Pd(CH3CN)2Cl2 (4 mol %), L (4 mol %), NaOH
(2 mmol), solvent (2.5 mL); argon atmosphere bIsolated yield of the
product.
phosphine ligand (1d), its coordination with Pd metal, and its
utility in activating aryl, heteroaryl, and allyl chloride for ex-
cellent yield in the Suzuki-Miyaura cross-coupling reaction.
aReaction condition: Chloro arene (1 mmol), phenylboronic acid
(1.5 mmol), Pd(CH3CN)2Cl2 (4 mol %), L (4 mol %), NaOH
(2 mmol), DMF (2.5 mL); argon atmosphere. In the case of allyl and
benzyl chloro arenes Cs2CO3 was used as a base. bIsolated yield of the
product. c1-Naphthaleneboronic acid was used. dDMAc as a solvent.
ep-Tolylboronic acid was used.
(11) (a) Saito, S.; Oh-tani, S.; Miyaura, N. J. Org. Chem. 1997, 62, 8024.
(b) Lu, Y.; Plocher, E.; Hu, Q.-S. Adv. Synth. Catal. 2006, 348, 841.
ꢀ
(c) Gonzalez-Bobes, F.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 5360.
(d) Tang, Z.-Y.; Spinella, S.; Hu, Q.-S. Tetrahedron Lett. 2006, 47, 2427.
(e) Lee, C.-C.; Ke, W.-C.; Chan, K.-T.; Lai, C.-L.; Hu, C.-H.; Lee, H. M.
Chem.;Eur. J. 2007, 13, 582. (f) Chen, C.; Yang, L.-M. Tetrahedron Lett.
2007, 48, 2427. (g) Xi, Z.; Zhang, X.; Chen, W.; Fu, S.; Wang, D. Organo-
metallics 2007, 26, 6636. (h) Lipshutz, B. H.; Butler, T.; Swift, E. Org. Lett.
2008, 10, 697.
7-Bromoindole (1c) was readily synthesized following a litera-
ture procedure.15a Condensation of 2-bromonitrobenzene (1b)
J. Org. Chem. Vol. 75, No. 15, 2010 5321

Ghosh et al.
JOCNote
and vinylmagnesium bromide solution (1a) in THF at -45 °C
afforded 1c in 60% yield (Scheme 1). Treatment of 1c with
2.2 equiv of nBuLi at -78 °C followed by trapping the
dilithiated intermediate by PPh2Cl afforded the correspond-
ing bidentate phosphine ligand (1d) in 25% yield. The product
was purified by flash column chromatography followed by
crystallization from petroleum ether. This ligand (1d) is stable
in air and can be stored in a bottle without any special care for
more than a week.15b
This novel bidentate phosphine ligand (1d) was treated
with Pd(CH3CN)2Cl2 in dichloromethane to afford16 a yellow-
orange complex (1e) (Scheme 2). The molecular structure of
the ligand (1d) and the palladium complex (1e) were deter-
mined by single-crystal X-ray analysis. This palladium com-
plex (1e) has a distorted square planar geometry around the
palladium center with a ligand bite angle of 96.60°.
To examine the usefulness of this new ligand (1d), we
selected 4-chloroacetophenone (2a) and phenylboronic acid
(3a) as model substrates. Molar ratio of ligand, effect of
different base and solvents, and comparison of different Pd-
precursors were studied (Table 1). It was found that Pd-
(CH3CN)2Cl2 (entry 3) worked best as the catalyst precursor
rather than Pd(OAc)2 and Pd2(dba)3 (entries 5 and 6). The
use of a phosphane:Pd ratio of 1:1 was found to be optimal
for this catalytic system. Use of excess ligand was found to be
detrimental to catalytic efficiency (entry 12).
We screened several bases, e.g., NaOH, K2CO3, CsF,
Cs2CO3, KOH, and K3PO4. Among them, NaOH was found
to be the most suitable base (Table 1, entry 3). We found that
a polar and coordinating solvent like DMF or DMAC was
ideal for this reaction (Table 2, entries 1 and 6).
equally well with cinnamyl chloride and its analogues
(entries 12-15), sometimes with double-bond isomerization
but without any rearrangement. Benzyl chlorides (entry
16-18) on the other hand provided around 65% yield of
the product.
In summary, we have developed a novel bidentate phos-
phine ligand containing an indole scaffold and a N-P bond
in the Suzuki-Miyaura coupling cross-coupling reaction
of aryl, heteroaryl, and allyl chlorides that provides an excellent
yield of desired products. The thermal stability of this novel
phosphine ligand in solid as well as in solution phase makes
for easer handling. Use of this ligand in related coupling
reactions is currently being investigated in our laboratory.
Experimental Section
Preparation of Ligand (1d) from 7-Bromoindole (1c). To a
stirred solution of 7-bromoindole (1c) (1.57 g, 8 mmol) in THF
(30 mL), under argon atmosphere, was added BuLi (11 mL,
n
17.6 mmol, 1.60 M in hexane) dropwise at -78 °C. The mixture
was then slowly warmed to rt and then stirred for a further 2 h at rt.
After the mixture cooled to -78 °C, chlorodiphenylphosph-
ine (3.25 mL, 17.6 mmol) in THF (10 mL) was added dropwise.
The mixture was then warmed to rt and stirred for a further 2 h.
It was then quenched with saturated NH4Cl solution at 0 °C and
extracted with diethyl ether (2 Â 100 mL). The combined org-
anic layer was washed subsequently with water and brine and
dried over anhydrous Na2SO4. Evaporation of solvent under
reduced pressure gave the crude product. Purification by flash
column chromatography (silica gel, 2.2% ethyl acetate/petro-
leum ether) afforded ligand (1d) as white solid (970 mg, 25%).
1H NMR (CDCl3, 300 MHz, ppm) δ 7.63 (d, J = 7.73 Hz, 1H),
7.38-7.27 (m, 16H), 7.10-7.04 (m, 5H), 6.90 (d, J = 2.7 Hz,
1H), 6.72 (t, J = 6.21 Hz, 1H), 6.65 (d, J = 2.9 Hz, 1H); 13C
NMR (CDCl3, 75 MHz, ppm) δ 138.13, 138.00, 137.83, 137.74,
137.58, 137.51, 134.68, 134.66, 134.41, 132.30, 132.03, 131.39,
131.30, 129.61, 129.38, 128.57, 128.49, 121.96, 121.13, 107.23;
31P NMR (CDCl3, 202.44 MHz, ppm) δ 36.70 (d, J = 160 Hz),
-16.18 (d, J = 160 Hz). Anal. Calcd for C32H25NP2: C, 79.17;
H, 5.19; N, 2.89. Found: C, 79.15; H, 5.20; N, 2.87.
Typical Procedure for the Cross-Coupling Reaction. A solu-
tion of ligand (19.4 mg, 0.04 mmol), Pd(CH3CN)2Cl2 (10.3 mg,
0.04mmol), chloroarene(1.0mmol), arylboronicacid(1.5mmol),
and NaOH (80 mg, 2.0 mmol) in DMF (2.5 mL) was stirred
under argon atmosphere at 125 °C for 3.5-10 h (depending on
substrate). The reaction mixture was then cooled to rt and
diluted with diethyl ether (20 mL). The organic layer was suc-
cessively washed with cold water (3 Â 10 mL) and brine and
dried over anhydrous Na2SO4. The solvent was removed under
reduced pressure and the residue was purified by flash chroma-
tography on silica gel (230-400 mesh) with 2-8% acetone in
petroleum ether or petroleum ether alone as a eluent.
Under the optimized condition with Pd(CH3CN)2Cl2
(4 mol %), ligand (4 mol %), and NaOH (2 equiv) in DMF,
we examined the cross-coupling reaction of a wide range of
electronically and structurally diverse aryl chlorides with
phenylboronic acid (Table 3). In all cases, the desired pro-
ducts were isolated in good to excellent yield, irrespective of
activating and deactivating groups being present on the aryl
chlorides. Ortho-substituted chlorides also afforded a high
yield of expected products (entry 8 and 11).
Heteroaryl chlorides (entries 9, 10, and 11) afforded al-
most quantitative yield of products. The reaction proceeded
(12) (a) Han, W.; Liu, C.; Jin, Z.-L. Org. Lett. 2007, 9, 4005. (b) Gallon,
B. J.; Kojima, R. W.; Kaner, R. B.; Diaconescu, P. L. Angew. Chem., Int. Ed.
2007, 46, 7251. (c) Han, W.; Liu, C.; Jin, Z. Adv. Synth. Catal. 2008, 350, 501.
(13) (a) Clarke, M. L.; Cole-Hamilton, D. J.; Woollins, J. D. J. Chem.
Soc., Dalton Trans. 2001, 2721. (b) Urgaonkar, S.; Nagarajan, M.; Verkade,
J. G. Tetrahedron Lett. 2002, 43, 8921. (c) Schareina, T.; Kempe, R. Angew.
Chem., Int. Ed. 2002, 41, 1521. (d) Cheng, J.; Wang, F.; Xu, J.-H.; Pan, Y.;
Zhang, Z. Tetrahedron Lett. 2003, 44, 7095. (e) So, C. M.; Lau, C. P.; Kwong,
F. Y. Org. Lett. 2007, 9, 2795. (f) Kingston, J. V.; Verkade, J. G. J. Org.
Chem. 2007, 72, 2816.
(14) (a) Clarke, M. L.; Cole-Hamilton, D. J.; Slawin, A. M. Z.; Woollins,
J. D. Chem. Commun. 2000, 2065. (b) Moloy, K. G.; Petersen, J. L. J. Am.
Chem. Soc. 1995, 117, 7696. We thank a reviewer for bringing this paper to our
attention.
Acknowledgment. We thank the CSIR and the Depart-
ment of Science and Technology, India, for financial sup-
port. R.G. is thankful to CSIR and N.N.A. is thankful to
DST, India, for their fellowships.
(15) (a) Dobbs, A. J. Org. Chem. 2001, 66, 638. (b) If a sample of the ligand
is left exposed to air, it takes more than a week to show the presence of phosphine
oxide. The ligand can be stored in a stoppered bottle closed under argon in a
refrigerator for several months without oxidation.
(16) The procedure was adopted from: Grossman, O.; Azerraf, C.;
Gelman, D. Organometallics 2006, 25, 375.
Supporting Information Available: Detailed experimental
procedures and characterization data for all compounds and
CIF file of 1d and 1e. This material is available free of charge via
the Internet at http://pubs.acs.org.
5322 J. Org. Chem. Vol. 75, No. 15, 2010