Pd-nanoparticle (PdNP)-catalyzed Negishi coupling of acid chlorides using zinc reagents

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Organic Preparations and Procedures
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Pd-Nanoparticle (PdNP)-catalyzed
Negishi Coupling of Acid Chlorides using
Zinc Reagents
Lei Yu a b , Lingfeng Ren a , Tian Chen a , Rong Yi a , Yulan Wu a &
Rong Guo a
a School of Chemistry and Chemical Engineering, Yangzhou
University, Yangzhou, 225002, P. R. China
b Faculty of Chemistry & Material Engineering, Wenzhou University,
Wenzhou, 325027, P. R. China
Published online: 30 Mar 2012.
To cite this article: Lei Yu , Lingfeng Ren , Tian Chen , Rong Yi , Yulan Wu & Rong Guo (2012) Pd-
Nanoparticle (PdNP)-catalyzed Negishi Coupling of Acid Chlorides using Zinc Reagents, Organic
Preparations and Procedures International: The New Journal for Organic Synthesis, 44:2, 169-174,
DOI: 10.1080/00304948.2012.657565
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Organic Preparations and Procedures International, 44:169–174, 2012
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2012.657565
Pd-Nanoparticle (PdNP)-catalyzed Negishi
Coupling of Acid Chlorides using Zinc Reagents
Lei Yu,1,2 Lingfeng Ren,1 Tian Chen,1 Rong Yi,1 Yulan Wu,1
and Rong Guo1
1School of Chemistry and Chemical Engineering, Yangzhou University,
Yangzhou 225002, P. R. China
2Faculty of Chemistry & Material Engineering, Wenzhou University,
Wenzhou, 325027, P. R. China
Ketones are important building blocks and useful intermediates in organic synthesis. In our
investigations on the novel reactions of methylenecyclopropanes (MCPs) and methylenecy-
clobutanes (MCBs),1,2 we needed a series of different substituted ketones to prepare the
substrates.3 One of the usual methods for the preparation of ketones is the reaction of Grig-
nard reagent with aldehydes followed by the Jones oxidation.4 The use of toxic chromium
reagent makes this method harmful to environment and restricts its application in large-scale
preparation.
Transition metal-catalyzed cross-coupling reactions are potent tools in organic synthe-
sis. Over the past 30 years, chemists have paid much attentions in this area and a series of
novel reactions have been discovered, including Kumada,5–9 Negishi,10–13 Suzuki14,15 and
Stille cross-coupling.16,17 Hence, the synthesis of ketones through the cross-coupling of
metal reagents with acid chlorides is attractive.18–23
Recently, the catalytic ability of metal nanoparticles has attracted chemists’ atten-
tion and examples of nanocatalysts have been reported, including CuO nanoparticle,24
In2O3 nanoparticle,25 Co/Rh heterobimetallic nanoparticle26–28 as well as Au nanoparticles
(AuNP).29 In situ reduction of Pd(OAc)2 to Pd (0) in the presence of tetrabutylamonium
salts (TBAX) could generate Pd nanoparticles (PdNP), which recently have been used to
catalyze the cross-coupling reactions of allyl acetates.30–32 In 2008, the first example of
PdNP-catalyzed Negishi cross-coupling reaction of aryl iodides was reported, providing
a convenient access to biphenyls.33 Nano catalysts could catalyze the reactions efficiently
with low loadings. Avoidance of phosphorus ligands made these reactions more environ-
mentally friendly. Thus, stimulated by the report in the literature, we became interested
in the transition metal nanoparticle-catalyzed reactions and developed PdNP-catalyzed
Submitted November 5, 2011.
Address correspondence to Lei Yu, School of Chemistry and Chemical Engineering, Yangzhou
University, Yangzhou 225002, P. R. China. Fax: (+86)-514-8797-5244. E-mail: yulei@yzu.edu.cn
169

170
Yu et al.
Table 1
PdNP-catalyzed Reactions of Zinc Reagents with Acid Chloridesa
O
O
Pd(OAc)2 (0.5 mol%)
R1ZnCl
+
R2
Cl
R1
R2
Bu4NBr, THF, rt
Yield of 3
mp.
(◦C)
lit. mp.
(◦C)
Entry
R1
R2
(%)b
1
2
3
4
5
6
7
8
Ph
Ph
82 (3a)
84 (3b)
79 (3c)
73 (3d)
80 (3e)
81 (3c)
75 (3e)
70 (3f)
78 (3g)
74 (3h)
67 (3i)
72 (3j)
48–49
—
56–57
—
61–62
56–57
61–62
73–75
140–141
—
49–5134
—
1-Naph
p-MeC6H4
o-MeC6H4
p-MeOC6H4
Ph
Ph
Ph
Ph
Ph
57–5835
—
62–6436
57–5835
62–6436
73–7437
140–14238
—
p-MeC6H4
Ph
Ph
p-MeOC6H4
p-ClC6H4
p-MeOC6H4
CH3
CH3
CH3
9
p-MeOC6H4
α-Naph
Ph
10
11
12
—
—
—
—
p-MeC6H4
a) Five mmol of zinc reagent, 2.5 mmol of acid chloride, 2.5 mmol of TBAB, 10 ml of THF and
0.0125 mmol of Pd (OAc)2 were employed. b) Yields based on acid chloride.
Negishi-coupling of acid chlorides with zinc reagents to aromatic ketones. Herein, we
report our results.
On the basis of results of Liu et al.33 we chose tetrabutylammonium bromide (TBAB)
as the stabilizer and Pd(OAc)2 as the Pd precursor. Under the protection of a nitrogen
atmosphere, TBAB and Pd(OAc)2 were added to phenylzinc (in THF) successively. Then,
benzoyl chloride was injected via a syringe, and the mixture was stirred at room temperature.
TLC analysis indicated that the reaction proceeded rapidly and was complete within 1 hour.
Further purifications by preparative TLC gave the desired product benzophenone (3a) in
82% yield. The scope of this reaction was then examined by employing a series of different
arylzinc reagents and acid chlorides. The corresponding ketones were obtained smoothly
with both aroyl chlorides (Table 1, Entries 1–9) as well as aliphatic acid chlorides (Table 1,
Entries 10–12). The zinc reagents were prepared by the metal exchange of Grignard
reagents with anhydrous ZnCl2. Since both the Grignard and the zinc reagents aresensitive
to moisture and might partially decompose during the operations, we employed an excess
of the zinc reagents (two equivalents); the yields are calculated on the acid chlorides.
With these results in hand, we then synthesized aryl ketones on a larger scale for
practical application; for example, ketone 3c was prepared from 40 mmol of the zinc
reagent and 20 mmol of the acid chloride in 83% yield.
The reaction of alkyl zinc reagents with acid chlorides was also examined. However,
the results were not satisfactory. Reaction of benzylzinc with benzoyl chloride led to the

Negishi Coupling of Acid Chlorides using Zinc Reagents
171
desired ketone 3k in only 36% yield; an unexpected by-product benzyl benzoate (4a)
was also obtained in 45% yield (Scheme 1). When cyclohexylzinc was employed, only
cyclohexyl benzoate (4b) was obtained (Scheme 1).
O
O
O
PdNP
THF, rt
BnZnCl
+
+
Ph
Cl
Bn
Ph
Bn
Ph
O
3k (36%)
4a (45%)
O
O
ZnCl
PdNP
THF, rt
+
Ph
O
Ph
Cl
4b (52%)
Scheme 1
In conclusion, we have developed a direct synthesis of ketones from aryl zinc reagent
and acid chlorides. To the best of our knowledge, this is the first example for the synthesis
of ketones through Negishi cross-coupling catalyzed by a nano catalyst. Although the scope
of this reaction is limited to only aryl ketones, it still has some obvious advantages. The
reaction occurred rapidly at room temperature. The dosage of catalyst was very low (0.5%)
and no phosphorus ligand was required. Considering these advantages, we believe that this
reaction is environmentally friendly and may have more application value in large-scale
preparation.
Experimental Section
1H NMR and 13C NMR were recorded for a solution in CDCl3 with TMS as the internal
standard. J-values are in Hz. Melting points are uncorrected. Organic solvents were dried by
standard methods. All reactions were performed under a nitrogen atmosphere and monitored
by TLC with silica gel coated plates. Zinc reagents were prepared by the reaction of Grignard
reagents with anhydrous ZnCl2 in THF. Aryl Grignard reagents were prepared in ether and
the ether was evaporated and replaced by THF; alkyl Grignard reagents were generated in
THF directly.
General Procedure
To a solution of arylzinc (5 mmol) in THF (10 mL) under a nitrogen atmosphere was
added TBAB (2.5 mmol) and Pd(OAc)2 (0.0125 mmol) successively. The mixture was
then stirred at rt for 5 min. Then, the acid chloride (2.5 mmol) was injected using a
syringe; the reaction was monitored by TLC (eluent:petroleum ether). When the reaction
was complete, water (20 mL) was added. The mixture was extracted with ether (20 mL ×
3). The combined organic layers were dried (anhydrous MgSO4). And evaporated under

172
Yu et al.
vacuum to afford the crude product, which was purified by column chromatography (silica
gel, eluent:petroleum/EtOAc 10:1).
Spectral Data
Compound 3b, oil, IR (film): 3059, 1660, 1594 cm−1; 1H NMR (600 MHz, CDCl3, TMS):
δ 7.43–7.58 (m, 7H), 7.86–8.10 (m, 5H); 13C NMR (150 MHz, CDCl3): δ 124.4, 125.7,
126.5, 127.3, 127.8, 128.4, 128.5, 130.4, 131.0, 131.3, 133.3, 133.8, 136.4, 138.3, 198.0;
MS (EI, 70 eV): m/z (%) 233 (20) [M+ + 1], 232 (100) [M+].
Anal. Calcd for C17H12O: C, 87.90; H, 5.21. Found: C, 87.63; H, 5.47
1
Compound 3d, oil, IR (fim) 3063, 1667, 1599 cm−1. H NMR (600 MHz, CDCl3,
TMS): δ 2.33 (s, 3H), 7.24–7.80 (m, 9H); 13C NMR (150 MHz, CDCl3): δ 20.0, 125.2,
128.5(d), 130.2, 130.3, 131.0, 133.2, 136.8, 137.8, 138.7, 198.7.
Anal. Calcd for C14H12O: C, 85.68; H, 6.16. Found: C, 85.72; H, 6.34.39
Compound 3h, oil, IR (film): 3054, 1678, 1596 cm−1; 1H NMR (600 MHz, CDCl3,
TMS): δ 2.68 (s, 3H), 7.41–8.76 (m, 7H); 13C NMR (150 MHz, CDCl3): δ 30.0, 124.4,
126.1, 126.5, 128.1, 128.5, 128.8, 130.2, 133.1, 134.0, 135.4, 201.9;
Anal. Calcd for C12H10O: C, 84.68; H, 5.92. Found: C, 84.56; H, 6.00.40
1
Compound 3i, oil, IR (film): 2960, 1691, 1600 cm−1; H NMR (600 MHz, CDCl3,
TMS): δ 2.57 (s, 3H), 7.30–7.89 (m, 5H).
Anal. Calcd for C8H8O: C, 79.97; H, 6.71. Found: C, 80.12; H, 6.73.41
Compound 3j, oil, IR (film): 1679, 1600 cm−1; 1H NMR (600 MHz, CDCl3, TMS):
δ 2.36 (s, 3H), 2.51 (s, 3H), 7.18–7.76 (m, 4H).
Anal. Calcd for C9H10O: C, 80.56; H, 7.51. Found: C, 80.42; H, 7.79.42
1
Compound 3k, oil, IR (film): 3087, 3060, 3029, 1686 cm−1; H NMR (600 MHz,
CDCl3, TMS): δ 4.28 (s, 2H), 7.25–8.02 (m, 10H); 13C NMR (150 MHz, CDCl3): δ 45.5,
126.9, 128.6, 128.7(d), 129.5, 133.2, 134.6, 136.6, 197.7.
Anal. Calcd for C14H12O: C, 85.68; H, 6.16. Found: C, 85.53; H, 6.08.43
Compound 4a, oil, IR (film): 3034, 1720 cm−1; 1H NMR (600 MHz, CDCl3, TMS):
δ 5.36 (s, 2H), 7.33–8.08 (m, 10H); 13C NMR (150 MHz, CDCl3): δ66.7, 128.2, 128.3,
128.4, 128.6, 129.8, 130.2, 133.1, 136.1, 166.5.
Anal. Calcd for C14H12O2: C, 79.22; H, 5.70. Found: C, 79.48; H, 5.88.44
Compound 4b, oil, IR (film): 2937, 1716 cm−1; 1H NMR (600 MHz, CDCl3, TMS):
δ 1.34–1.37 (m, 1H), 1.42–1.47 (m, 2H), 1.56–1.62 (m, 3H), 1.78–1.79 (m, 2H), 1.91–1.93
(m, 2H), 5.03 (t, J = 3.6 Hz, 1H), 7.41–8.06 (m, 5H); 13C NMR (150 MHz, CDCl3): δ
23.7, 25.5, 31.7, 73.0, 128.3, 129.5, 131.0, 132.7, 166.0.
Anal. Calcd for C13H16O2: C, 76.44; H, 7.90. Found: C, 76.23; H, 8.04.45
Acknowledgment
This work was supported by the Priority Academic Program of Jiangsu Higher Education
Institutions, Natural Scientific Foundation of Jiangsu Province (NO. BK2010321), Univer-
sity Natural Scientific Foundation of Jiangsu Province (NO. 09KJB150014), the Opening
Laboratory Foundation of Jiangsu Province (K100027); the Opening Laboratory Founda-
tion of Zhejiang Province (100061200138) and the National Natural Scientific Foundation
of China (20773106).

Negishi Coupling of Acid Chlorides using Zinc Reagents
173
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