Preparation of aryl ketones via Ni-catalyzed Negishi-coupling reactions with acid chlorides

Article abstract of DOI:10.1016/j.tetlet.2011.01.135

A Ni-catalyst-catalyzed cross-coupling reaction of organozinc reagents with acid chlorides has been successfully developed. Mild reaction conditions were required to complete the coupling reactions affording the corresponding aryl ketones in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2011.01.135

Tetrahedron Letters 52 (2011) 1523–1526
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Preparation of aryl ketones via Ni-catalyzed Negishi-coupling reactions
with acid chlorides
Seung-Hoi Kim a, , Reuben D. Rieke b
⇑
a Department of Chemistry, Dankook University, 29 Anseo, Cheonan 330-714, Republic of Korea
b Rieke Metals, Inc., 1001 Kingbird Rd. Lincoln, NE 68521, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A Ni-catalyst-catalyzed cross-coupling reaction of organozinc reagents with acid chlorides has been suc-
cessfully developed. Mild reaction conditions were required to complete the coupling reactions affording
the corresponding aryl ketones in good to excellent yields.
Received 16 December 2010
Revised 22 January 2011
Accepted 27 January 2011
Available online 1 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
The transition metal-catalyzed cross-coupling reactions of orga-
nometallics with acid chlorides have been the most widely used
approach for the preparation of ketones.1 To this end, numerous
efficient synthetic methodologies using mainly organomagne-
sium,2 -copper,3 -manganese,4 -lithium,5 -boron,6 -stannane,7 and
-zinc8 have been developed. Among those, the most considerable
effort has been devoted to utilizing organozinc reagents simply
due to the highly efficient functional group tolerance. Conse-
quently, transition metal-catalyzed coupling reactions of organo-
zinc with acid chlorides have been considered as one of the most
effective routes for the ketone synthesis. In most cases of coupling
reactions, copper and palladium were the most frequently used
catalysts. Unfortunately, this route contains some limitations such
as inconvenience of using copper-catalyst and high price of palla-
dium catalyst. Therefore, there is still a need to develop an eco-
nomically and environmentally more efficient method for the
synthesis of ketones albeit Cu- or Pd-catalyzed coupling reactions
of organozincs are useful tools.
To date, relatively few outstanding studies on the coupling reac-
tion of organozinc with acid halides have been reported to avoid
these restrictions. For examples, Gosmini and co-workers9 re-
ported a method for the preparation of aromatic ketones using
the cobalt-catalyzed coupling reaction of organozinc prepared
in situ with acid chlorides or carboxylic anhydrides. More recently,
preparation of ketones using the coupling reaction of mixed
organozincs with acid chlorides in the presence of tri-n-butylphos-
phine has been revealed.10,11 It was performed by the palladium-
phosphinous acid-catalyzed cross-coupling reaction of organozinc
with acid halides. Compared to other organometallics, however,
there has been considerably less progress in developing effective
catalytic system for producing ketone compounds using organo-
zinc reagents. One of the more interesting routes in Negishi cou-
pling with acid halides has been accomplished by Rovis.12 This
approach employed organozinc reagent along with Ni pre-catalyst
in the presence of an appropriate ligand. In spite of good to excel-
lent isolated yields, a limited number of organozinc reagents were
used in this study.
We have developed several efficient routes for the synthesis of
organozinc reagents and their subsequent coupling reactions.13
However, a significant improvement in this methodology would
be the development of a nickel-catalyst for constructing carbonyl
compounds. Thus, we herein would like to report a versatile appli-
cation of readily available organozinc reagents for ketone synthesis
in the presence of a nickel-catalyst.
As mentioned before, most of the coupling reactions of organo-
zincs for the preparation of ketones were performed with copper or
palladium catalyst. In search of a more efficient catalyst in terms of
easy availability, we first attempted the coupling reaction of 2-
(ethoxycarbonyl)phenylzinc bromide (A) prepared by the direct
insertion of active zinc13 with benzoyl chloride.
To investigate the proper conditions, several nickel-catalysts
were employed and the results were summarized in Table 1. Even
though each catalyst required a little different reaction time
(20 min to 24 h) at room temperature, the coupling product (1a)
was obtained in good to excellent isolated yields in the presence
of a nickel-catalyst. It was of interest that the coupling reaction
was completed in the absence of any extra ligand under the given
conditions with 2 mol % of a nickel-catalyst.14 As described in Table
1, among the nickel-catalysts used in this study, Ni(acac)2 is shown
to be a very efficient catalyst for the preparation of ketones. Gen-
erally, the coupling reaction was conducted at room temperature
in THF. The subsequent cross-coupling reaction using 2 mol % of
Ni(acac)2 as a catalyst was completed in 20 min at room tempera-
ture and resulted in the formation of the product (1a) in 89% iso-
lated yield (Table 1, entry 1). All the rest of the coupling
reactions in this study were carried out with Ni(acac)2-catalyst at
room temperature.
Table 2 shows the general applications of this strategy for the
preparation of highly functionalized benzophenones. As aforemen-
⇑
Corresponding author.
E-mail address: kimsemail@dankook.ac.kr (S.-H. Kim).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.135

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S.-H. Kim, R. D. Rieke / Tetrahedron Letters 52 (2011) 1523–1526
Table 1
Table 2
Catalyst screening
Coupling reactions with benzoyl chlorides
CO2Et
ZnBr
O
CO2Et
O
CO2Et
CO2Et
COCl
COCl
FG
ZnBr
THF
rt
2 % Ni(acac)2
THF/rt/1.0 h
+
+
FG
1a
A
1.2 eq
2a - 2h
1.2 eq
A
1.0 eq
1.0 eq
Catalysta
Ni(acac)2
Ni(dppe)Cl2
Ni(PMe3)2Cl2
Ni(PPh3)2Cl2
Co(acac)2
Entry
Timeb
Resultc (%)
Entry
FG
Product
Yield (%)a
1
2
3
4
5
20 min
24 h
1 h
30 min
1 h
89
80
82
85
1
2
3
4
5
6
7
8
2-Br
3-Br
4-Br
2-l
3-l
4-l
2a
2b
2c
2d
2e
2f
75
82
83
70
75
79
60
65
(20)d
a
2 mol % used.
No acid chloride observed.
Isolated yield (based on benzoyl chloride).
Determined (conversion) by GC.
b
2-NO2
4-NO2
2g
2h
c
d
a
Isolated yield (based on benzoyl chloride).
tioned, a catalytic amount of Ni(acac)2 was employed and the reac-
tion was carried out at room temperature in THF. To compare the
results depending upon the benzoyl chlorides, the same reaction
conditions were maintained during the coupling reaction in pro-
gress (1 h instead of 20 min). A bromine atom on the benzoyl chlo-
Table 3
Coupling reactions with acid chlorides
CO2Et
ZnBr
2 % Ni(acac)2
Products
+
R(Ar)-COCl
conditions
3a - 3h
THF
1.0 eq
1.2 eq
Entry
1
Acid chloride
Conditions
Product
Yield (%)a
79
O
3a
CH3(CH2)3COCl
rt/20 min
CO2Et
O
Cl
3b
2
3
4
ClCH2(CH2)3COCl
rt/20 min
rt/60 min
rt/10 min
81
89
75
CO2Et
COCl
O
CO2Et
3c
O
O
Cl
O
CO2Et
CO2Et
CO2Et
3d
O
COCl
O
5
6
7
8
rt/30 min
rt/30 min
reflux/24 h
rt/30 min
86
79
68
66
3e
3f
S
S
O
CO2Et
COCl
O
O
COCl
O
CO2Et
3g
Cl
Cl
N
Cl
N
COCl
O
CO2Et
3h
Cl
a
Isolated yield (based on acid chloride).

S.-H. Kim, R. D. Rieke / Tetrahedron Letters 52 (2011) 1523–1526
1525
ride tolerated the reaction conditions (Table 2, entries 1–3) and the
corresponding coupling products (2a–2c) were achieved in good
yields. Interestingly, the presence of iodine on the benzoyl chloride
was also not affected resulting in the formation of iodine-substi-
tuted benzophenones (2d–2f, Table 2) in excellent yields. 2-Nitro-
and 4-nitrobenzoyl chlorides also effectively reacted with organo-
zinc A to give rise to the ketones (2g and 2h, Table 2) in 60% and
65% isolated yield, respectively, under the same conditions.
In order to examine the generality of this catalytic system, we
expanded our study to include a wide variety of acid chlorides to
be completed with A.15 The results are summarized in Table 3.
Under the same conditions (2 mol % of Ni(acac)2 in THF) used
before, the coupling reaction with a simple alkyl acid chloride as
well as chlorine-substituted acid chloride were completed in
20 min at room temperature affording the corresponding product
(3a, 3b) in 79% and 81% isolated yields (Table 3, entries 1 and 2),
respectively. A bulky acid chloride was also reacted with A to give
rise to the ketone (3c) in excellent yield (Table 3, entry 3). Signifi-
cantly, ketone (3d) containing two ester functionalities was suc-
cessfully prepared from the coupling reaction with ethyl
2-chloro-2-oxoacetate in good yield (Table 3, entry 4). Not only
alkyl acid chlorides but other heteroaryl acid chlorides were good
coupling partners to prepare heteroaryl ketones. As depicted in
Table 3, thiophene, furan and pyridine carbonyl chlorides were
coupled with A under mild conditions to afford the corresponding
ketones (3e, 3f and 3g, Table 3) in good yields, respectively. Even
though a slightly longer reaction time (24 h at refluxing tempera-
ture) was required in the case of pyridine carbonyl chloride, the
coupling reaction occurred selectively on the acid chloride (Table
3, entry 7). Another significant result was formed in the reaction
with 4-(chloromethyl)benzoyl chloride (Table 3, entry 8). As noted
in Table 3, a chlorine atom in the benzylic position was intact
Table 4
Preparation of functionalized ketones
2 % Ni(acac)2
+
Products
ArZnX
R(Ar)COCl
conditions
THF
1.2 eq
1.0 eq
4a - 4h
Entry
1
Organozinc
Acid chloride
Conditions
Product
Yielda (%)
ZnI
COCl
O
rt/30 min
rt/30 min
84
Br
NC
Br
F
CN
4a
O
ZnI
COCl
2
3
86
89
F
4b
ZnBr
ZnBr
COCl
O
rt/30 min
H3CO
NC
S
H3CO
EtO2C
CN
4c
EtO2C
ZnI
COCl
COCl
S
S
S
4
5
rt/30 min
rt/30 min
81
83
O
4d
O
S
S
S
4e
Br
COCl
O
ZnBr
O
6
7
rt/60 min
rt/30 min
77
78
S
Br
4f
COCl
COCl
O
O
EtO2C
ZnBr
EtO2C
4g
ZnBr
X
8
9
rt/10 min
rt/10 min
87 (4h)
72 (4i)
X
O
X = 3-F, 4-Cl
Isolated yield (based on acid chloride).
X = 3-F (4h), 4-Cl (4i)
a

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S.-H. Kim, R. D. Rieke / Tetrahedron Letters 52 (2011) 1523–1526
during the coupling reaction under the conditions used in this
study and was not attacked in the cross-coupling reaction (3h,
Table 3).
References and notes
1. (a) Dieter, R. K. Tetrahedron 1999, 55, 4177; (b)Comprehensive Organic
Transformations; Larock, R. C., Ed., 2nd ed.; Wiley-VCH: Weinheim, 1999; (c)
Diederich, F.; Stang, P. J. Metal-Catalyzed Cross-Coupling Reactions; Wiley-VCH:
Weinheim, 1998.
2. (a) Maeda, H.; Okamato, J.; Ohmori, H. Tetrahedron Lett. 1996, 37, 5381; (b)
Malanga, C.; Aronica, L. A.; Lardicci, L. Tetrahedron Lett. 1995, 36, 9185.
3. (a)Modern Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim,
2001; (b)Organocopper Reagents. A Practical Approach; Taylor, R. J. K., Ed.;
Oxford University Press, 1994.
4. (a) Rieke, R. D.; Suh, Y. S.; Kim, S. H. Tetrahedron Lett. 2005, 46, 5961; (b) Kim, S.
H.; Rieke, R. D. J. Org. Chem. 2000, 65, 2322; (c) Kim, S. H.; Rieke, R. D.
Tetrahedron Lett. 1999, 40, 4391; (d) Cahiez, G.; Laboue, B. Tetrahedron Lett.
1989, 30, 7369; (e) Cahiez, G.; Laboue, B. Tetrahedron Lett. 1989, 30, 3545.
5. Wakefield, B. J. Organolithium Methods in Organic Synthesis; Academic: London,
1990; (a) Tucker, C. E.; Majid, T. N.; Knochel, P. J. Am. Chem. Soc. 1992, 114, 3893.
6. (a) Haddach, M.; McCarthy, J. R. Tetrahedron Lett. 1999, 40, 3109; (b) Bumagin,
N. A.; Korolev, D. N. Tetrahedron Lett. 1999, 40, 3057; (c) Goosen, L. J.; Ghosh, K.
Angew. Chem., Int. Ed. 2001, 40, 3458.
7. (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508; (b) Lerebours, R.;
Camacho-Soto, A.; Wolf, C. J. Org. Chem. 2005, 70, 8601.
8. (a) Karzmierski, I.; Bastienne, M.; Gosmini, C.; Paris, J. M.; Perichon, J. J. Org.
Chem. 2004, 69, 936. and references cited therein; (b) Knochel, P.; Yeh, M. C. P.;
Berk, S. C.; Talbert, J. J. Org. Chem. 1988, 53, 2390.
9. Fillon, H.; Gosmini, C.; Perichon, J. Tetrahedron 2003, 59, 8199.
10. Erdik, E.; Pekel, ö. ö. Tetrahedron Lett. 2009, 50, 1501.
11. Xu, H.; Ekoue-Kovi, K.; Wolf, C. J. Org. Chem. 2008, 73, 7638.
12. (a) Bercot, E. A.; Rovis, T. J. Am. Chem. Soc. 2005, 127, 247; (b) Zhang, Y.; Rovis, T.
J. Am. Chem. Soc. 2004, 126, 15964; (c) Bercot, E. A.; Rovis, T. J. Am. Chem. Soc.
2001, 124, 174.
The utility of this methodology in the preparation of a number
of ketones was extended to the coupling reactions with a variety of
organozinc reagents. Again, all of the organozinc reagents used in
this study were prepared by the direct insertion of active zinc to
the corresponding halides and the results obtained from this study
are described in Table 4. For most of the cases, the coupling reac-
tions were conducted in the presence of 2 mol % Ni(acac)2 at room
temperature in THF and completed within 30 min except in the
case of 3-bromothiophene-2-ylzinc bromide (Table 4, entry 6). Hal-
ogen-substituted phenylzinc iodide underwent the coupling reac-
tion with aryl acid chlorides under mild conditions and
successfully gave the aryl ketones (4a and 4b, Table 4). No signifi-
cant effect on the coupling reaction was observed when an elec-
tron-donating group was present (Table 4, entry 3). Again, the
aforementioned mild conditions worked well for the coupling reac-
tions with heteroarylzinc reagents. 5-(Ethoxycarbonyl)thiophene-
2-ylzinc bromide reacted with 2-thiophenecarbonyl chloride to
give rise to the formation of heteroaryl ketone (4d, Table 4) in
81% yield. The coupling reactions of similar organozincs, 3-thienyl-
zinc iodide and 3-bromothien-2-ylzinc bromide, led to the forma-
tion of ketones 4e and 4f in 83% and 77% yields (Table 4, entries 5
and 6), respectively. It is also significant that 5-(ethoxycar-
bonyl)furan-2-ylzinc bromide was coupled with benzoyl chloride
to yield ethyl 5-benzoylfuran-2-carboxylate (4g) in 78% yield (Ta-
ble 4, entry 7). Additionally, it was found that treatment of benzyl-
zinc reagents under the same conditions generated functionalized
coupling products 4h and 4i in 10 min at room temperature (Table
4, entries 8 and 9).
13. For the general procedure of the preparation of active zinc and organozinc
reagents, see: Rieke, R. D.; Hanson, M. V. Tetrahedron 1997, 53, 1925.
14. A lignad-less Pd system: Iwai, T.; Nakai, T.; Mihara, M.; Ito, T.; Mizuno, T.;
Ohno, T. Synlett 2009, 7, 1091.
15. A representative procedure of coupling reaction; In a 25 mL round-bottomed
flask, Ni(acac)2, (0.06 g, 2 mol%) and 10 mL (5 mmol) of 0.5 M solution of 2-
(ehtoxycarbonyl)phenylzinc bromide in THF was added into the flask at room
temperature. Next, 6-chloronicotinoyl chloride (0.70 g, 4 mmol) dissolved in
5.0 mL of THF was added. The resulting mixture was refluxed overnight, then
cooled down to room temperature. Quenched with saturated NH4Cl solution,
then extracted with ethyl acetate (30 mL Â 3). Combined organics were
washed with saturated Na2S2O3 solution and brine. Dried over anhydrous
MgSO4. A flash column chromatography (50% EtOAc/50% Heptane) gave 0.78 g
of 3g as yellow solid in 68% isolated. Mp = 48–51 °C. 1H NMR (CDCl3, 500 MHz):
d 8.59 (s, 1H), 8.11 (d, 2H, J = 10 Hz), 7.69 (t, 1H, J = 5 Hz), 7.62 (t, 1H, J = 5 Hz),
7.43 (d, 1H, J = 5 Hz), 7.38 (d, 1H, J = 10 Hz), 4.17 (q, 2H, J = 5 10 Hz), 1.19 (t, 3H,
J = 10 Hz); 13C NMR (CDCl3, 125 MHz): d 194.8, 165.6, 155.6, 151.2, 140.6,
138.8, 133.0, 131.9, 130.6, 130.4, 129.2, 127.5, 124.6, 61.9, 14.0.
From these results, it can be concluded that the mild conditions
and nickel catalyst have resulted in a wider tolerance of functional
groups and a greater scope of the reaction. Significantly, this strat-
egy affords a more economically and environmentally useful and
valuable synthetic procedure for the preparation of ketones utiliz-
ing organozinc reagents, which are readily available. Additional
studies using the nickel catalyst are underway.