Gram-scale ketone synthesis by direct reductive coupling of alkyl iodides with acid chlorides

Article abstract of DOI:10.1055/s-0033-1339297

Alkyl aryl ketones were prepared on a gram scale by the nickel-catalyzed reductive coupling of alkyl iodides with aroyl chlorides. When scaled up 30-fold, this reaction shows a comparable coupling efficiency to the previously reported reaction performed under small-scale conditions. The mild and convenient reaction conditions show excellent tolerance to a range of functional groups and provide the ketones in good to excellent yields. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1339297

2234▌
PRACTICAL SYNTHETIC PROCEDURES
practical synthetic procedures
Gram-Scale Ketone Synthesis by Direct Reductive Coupling of Alkyl Iodides
with Acid Chlorides
Reductive Preparation of Ketones on a Gram Scale
Wenbin Lu,a,1 Zhuye Liang,b,1 Yuwei Zhang,b,1 Fan Wu,a Qun Qian,*a Hegui Gong*a
a
Department of Chemistry, Shanghai University, 99 Shang-Da Road, Shanghai 200444, P. R. of China
Fax +86(21)66132410; E-mail: hegui_gong@shu.edu.cn
b
College of Chemistry and Molecular Engineering, Zhengzhou University, 100 Science Road,
PSP
Zhengzhou 450001, P. R. of China
Received: 30.04.2013; Accepted after revision: 06.06.2013
No253
Abstract: Alkyl aryl ketones were prepared on a gram scale by the nickel-catalyzed reductive coupling of alkyl iodides with aroyl chlorides.
When scaled up 30-fold, this reaction shows a comparable coupling efficiency to the previously reported reaction performed under small-
scale conditions. The mild and convenient reaction conditions show excellent tolerance to a range of functional groups and provide the ke-
tones in good to excellent yields.
Key words: nickel, catalysis, ketones, halides, reductions
Procedure 1
Ni(acac)2 (10 mol%)
ligand I (15 mol%)
Ph
Ph
Ph
O
TsN
I
+
BzCl
TsN
Zn (300 mol%), MgCl2 (150 mol%)
MeCN (30 mL), 25 °C
N
N
(9 mmol)
1 (4.5 mmol)
2a (85%)
ligand I
Procedure 2
R-X (4.5 mmol, 100 mol%)
O
Ni(acac)2 (10 mol%)
ligand I (15 mol%)
Ph
Ph
O
SOCl2
Ar
OH
Ar
R
Zn (300 mol%), MgCl2 (150 mol%)
MeCN (30 mL), 25 °C
N
(11.3 mmol)
N
ligand I
Scheme 1 Procedures for the nickel-catalyzed reductive coupling of alkyl iodides with aroyl chlorides
The ketone group is a fundamental organic functional 4,7-diphenyl-1,10-phenanthroline, making it a practical
group that is well documented in various textbooks. The method for ketone synthesis. In particular, the reductive
transition-metal-catalyzed coupling of alkyl organometal- coupling protocol is amenable to the preparation of alkyl
lic reagents with acid derivatives represents a major recent ketones bearing active β-leaving groups that would other-
advance in the synthesis of ketones.2 We recently reported wise be difficult to prepare from conventional alkylated
an efficient nickel-catalyzed procedure for the synthesis organometallic nucleophiles, because conversion of those
of alkyl aryl ketones by direct coupling of alkyl halides alkyl halides into the corresponding organometallic re-
with aroyl chlorides or anhydrides that avoids the need for agents would result in severe β-elimination.6 Previously,
prior formation of an alkylated organometallic nucleo- we had only performed the reactions on a small scale
phile.3–5 Our preliminary mechanistic studies indicated (0.15 mmol of alkyl halide as the limiting reactant). For
that the formation of organozinc compounds in situ is not practical applications, larger-scale preparations are im-
necessarily involved in the reaction.3,4 The reaction, portant, so we examined the synthesis of alkyl aryl ke-
which occurs under mild conditions, tolerates a broad tones on a gram scale, representing a 30-fold scale-up of
range of functional groups and generally gives the ketones our original reactions.
in high yields. Furthermore, it uses relatively cheap
bis(acetylacetonato)nickel(II) and commercially available
First, we examined the reaction of 4.5 mmol of 4-iodo-1-
tosylpiperidine (1; 4.5 mmol) with 9 mmol of benzoyl
chloride in the presence of 10 mol% of bis(acetylacetona-
to)nickel(II), 15 mol% of 4,7-diphenyl-1,10-phenanthro-
line (ligand I), 1.5 equivalents of magnesium(II) chloride,
SYNTHESIS 2013, 45, 2234–2240
Advanced online publication: 11.07.2013
DOI: 10.1055/s-0033-1339297; Art ID: SS-2013-Z0322-PSP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

PRACTICAL SYNTHETIC PROCEDURES
Reductive Preparation of Ketones on a Gram Scale
2235
and three equivalents of zinc powder. The desired ketone groups proved to be compatible with the coupling proce-
2a was obtained in 85% yield (Scheme 1, Procedure 1; dure, giving ketones 5a and 6 in 69% and 90% yield, re-
Table 1, entry 1). This yield is slightly lower than that of spectively (entries 8 and 9). We also obtained good yields
the corresponding small-scale reaction using 0.15 mmol from our gram-scale procedure with cyclohexyl iodide
of 1, which gave a 90% yield of the ketone. Reducing the and exo-2-iodobicyclo[2.2.1]heptane (entries 10 and 11),
loading of the nickel precatalyst and ligand to half the pre- suggesting that alkyl iodides without polar substituents
vious values resulted in a significant decrease in the yield are also effective coupling partners. Open-chain second-
to 66%; however, the use of 12 mol% of the ligand instead ary alkyl iodides gave the corresponding ketones 9–12 in
of 15 mol% gave the ketone in 89% yield, which may be high yields (entries 12–15). However, a lower yield (35%)
important in practical terms.
was obtained when 2-furoyl chloride was employed as the
coupling partner (entry 16). Primary alkyl iodides dis-
played moderate to good reactivities to give ketones 13–
19 (entries 17–23). Whereas 1-iodobutane (entry 17) and
3-iodopropyl 4-methoxybenzoate (entry 18) gave compa-
rable yields to those obtained from the corresponding
small-scale reactions, 2-iodo-1,1-dimethoxyethane and 3-
iodo-1-phenylpropan-1-one gave moderate yields that
were much lower than those obtained from small-scale re-
actions (entries 19 and 20). The low yield of ketone 18 ob-
tained from 1-iodo-2,2-dimethylpropane (entry 21) might
be the result of the presence of the sterically demanding
tert-butyl group. Benzyl bromide was also less effective
as a coupling partner in large-scale reactions; coupling re-
actions with benzoyl chloride or 2-phenylacetyl chloride
gave the corresponding ketones 19a and 19b in 40% and
76% yield, respectively (entries 22 and 23).
Next we examined the coupling efficiency of other aroyl
chlorides with a variety of alkyl iodides. The results are
summarized in Table 1. In general, the efficiencies of the
coupling reactions of secondary alkyl iodides remained
high when performed on a gram scale. Coupling of iodide
1 with 4-tert-butylbenzoyl chloride (entry 2), 4-fluoro-
benzoyl chloride (entry 3), or 3-methoxybenzoyl chloride
(entry 4) gave the corresponding ketones 2b–d in excel-
lent yields. Pivaloyl chloride was also compatible with the
reaction conditions (entry 5), giving ketone 2e in 60%
yield, which was 10% more than the corresponding reac-
tion performed on a small scale.
Other cyclic secondary iodides were also effective reac-
tants, giving products in 3–8 in good to excellent yields
(entries 6–11, respectively). The alkyl substrates contain-
ing active β-H atoms or β-tert-butyl(dimethyl)siloxy
Table 1 Scope and Limitations of Ketone Preparation by Procedure 1
Entrya
Product
Small-scale yieldb (%)
Large-scale yieldc (%)
O
O
O
O
O
1
90
85
N
Ts
2a
2
3
4
5
90
77
89
50
90
N
Ts
t-Bu
2b
90
N
Ts
F
2c
90
N
Ts
F
2d
t-Bu
60
N
Ts
2e
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2234–2240

2236
W. Lu et al.
PRACTICAL SYNTHETIC PROCEDURES
Table 1 Scope and Limitations of Ketone Preparation by Procedure 1 (continued)
Entrya
Product
Small-scale yieldb (%)
Large-scale yieldc (%)
O
6
72
75
N
Boc
t-Bu
3
O
7
8
75
72
70
69
O
4
O
OMe
OMe
5a
O
TBSO
9
10
11
12
76d
83d
65
90d
72d
80
6
7
8
O
OMe
O
t-Bu
O
Ph
O
84
85
O
MeO
9
t-Bu
O
O
13
82
90
O
NC
10
O
14
15
70
76
90
80
t-Bu
11
O
t-Bu
12
Synthesis 2013, 45, 2234–2240
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Reductive Preparation of Ketones on a Gram Scale
2237
Table 1 Scope and Limitations of Ketone Preparation by Procedure 1 (continued)
Entrya
16
Product
Small-scale yieldb (%)
Large-scale yieldc (%)
O
O
O
45
35
70
O
MeO
13
O
17
70
75
t-Bu
14
O
Ph
O
18
19
70
53
O
MeO
15
O
t-Bu
MeO
79
70
MeO
16
O
Ph
O
Ph
20
21
60
30
17
t-Bu
e
–
O
18
O
Ph
22f
23f
Ph
76
90
40
76
19a
O
Ph
Ph
19b
a Unless otherwise noted, alkyl iodides were used as the halide coupling partners.
b Isolated yield from 0.15 mmol of alkyl halide.
c Isolated yield from 4.5 mmol of alkyl halide.
d dr >20:1.
e Not available.
f Standard conditions except that BnBr was used with bis(cyclooctadienyl)nickel(II) and 4,4′-di-tert-butyl-2,2′-bipyridine.
To evaluate the compatibility of the reaction with various do not generally show a loss of coupling efficiency com-
substituents on the aroyl chloride, we converted a series of pared with the previously reported small-scale reactions
arylcarboxylic acids (2.5 equivalents) into the corre- (entries 1–10 and 14). Aroyl chlorides bearing ortho sub-
sponding acyl chlorides. After completely removing ex- stituents or electron-withdrawing substituents generally
cess thionyl chloride, we subjected the resulting acid gave moderate yields (entries 2, 5, and 6). Alkyl iodides
chloride to reductive coupling reactions in situ (Scheme 1, containing phthalimidyl moieties separated from the io-
Procedure 2; Table 2). Modified Procedure 2 gave compa- dide group by three carbon atoms were also moderately
rable results to those obtained from Procedure 1 with effective reactants under the coupling conditions (entries
commercially available acyl chlorides (Table 2, entries 1, 12 and 14).
7, 11, and 13). Note that the present gram-scale reactions
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2234–2240

2238
W. Lu et al.
PRACTICAL SYNTHETIC PROCEDURES
We also studied a ring closure–reductive ketone forma- formation method might be suitable for large-scale appli-
tion reaction using iodo derivative 23 as the reactant cation.
(Scheme 2), and we obtained ketone 24 in 90% yield,
which is 20% more than that previously obtained from the
O
same reaction performed on a small scale.
I
Ni(acac)2 (10 mol%)
ligand I (15 mol%)
Ph
Finally, we examined the coupling reaction of four grams
+
BzCl
O
Zn (300 mol%)
MgCl2 (150 mol%)
MeCN (30 mL), 25 °C
of 2-iodopropane with 4-tert-butylbenzoyl chloride by
following Procedure 2 (Scheme 3). Ketone 12 was ob-
tained in 75% yield, showing that our reductive ketone-
O
O
O
23 (4.5 mmol)
(9 mmol)
24 (90%)
Scheme 2 Reductive ring closure/ketone formation
Table 2 A Modified Procedure Using Crude Acid Chlorides
Entrya
Product
Small-scale yieldb (%)
Large-scale yieldc (%)
O
O
O
O
O
1
90
90
N
Ts
t-Bu
2b
2
3
4
66
82
81
60
90
74
N
Ts
2f
N
Ts
2g
N
Ts
Cl
2h
5b
5c
OMe
5
6
7
54
42
52
45
O
O
CO2Me
72
70
OMe
5a
7
O
OMe
8
83d
79d
Synthesis 2013, 45, 2234–2240
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Reductive Preparation of Ketones on a Gram Scale
2239
Table 2 A Modified Procedure Using Crude Acid Chlorides (continued)
Entrya
Product
Small-scale yieldb (%)
Large-scale yieldc (%)
O
TBSO
OMe
9
76d
70d
6
O
10
11
65
80
80
t-Bu
20
O
Ph
O
e
–
O
MeO
9
O
N
e
12
–
40
t-Bu
O
O
21
O
e
13
14
–
70
40
t-Bu
14
22
O
N
t-Bu
40
O
O
a Alkyl iodides were used unless otherwise mentioned.
b Isolated yield from 0.15 mmol of alkyl halide.
c Isolated yield from 4.5 mmol of alkyl halide.
d dr >20:1.
e Not available.
O
showed comparable coupling effectiveness to the same re-
actions performed on a small scale. The excellent func-
tional group compatibility with a broad substrate scope,
together with the convenient procedures and the good to
excellent coupling efficiencies suggest that the method
might have practical applications in the preparation of al-
kyl aryl ketones.
O
I
Cl
procedure 2
+
t-Bu
t-Bu
12, 75%
(3.6 g, 17.6 mmol)
(4 g, 23.5 mmol) (crude, ~ 94.1 mmol)
Scheme 3 Coupling of 2-iodopropane with 4-tert-butylbenzoyl
chloride using Procedure 2 on a multigram scale
All reagents were of reagent grade quality and used as received, un-
less otherwise indicated. All reactions were carried out under N2 un-
less otherwise indicated. Ni(acac)2 (J&K, China), Ni(COD)2
(Aldrich), zinc powder (Aldrich), anhyd MgCl2 (Alfa Aesar) were
purchased and used as received. MeCN (ACS, ≥99.5%) was pur-
chased from Aladdin Co. (China). Ligand I was synthesized accord-
ing to the literature procedure.7 2-Iodopropane (Aldrich), 1-
In conclusion, we examined the nickel-catalyzed reduc-
tive coupling of alkyl iodides with aroyl chlorides to give
alkyl aryl ketones under mild reaction conditions on a
gram scale. The reactions under the scaled-up conditions
© Georg Thieme Verlag Stuttgart · New York
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2240
W. Lu et al.
PRACTICAL SYNTHETIC PROCEDURES
3,3-Dimethyl-1-(4-tolyl)butan-1-one (18)
This was prepared from t-BuCH2I (0.596 mL, 4.50 mmol, 100
mol%) and 4-MeC6H4COCl (9.0 mmol, 1.19 mL, 200 mol%) ac-
cording to Procedure 2, and purified by column chromatography
(silica gel, 3% EtOAc–hexanes) to give a colorless oil; yield: 0.257
g (1.35 mmol, 30%).
iodobutane (Aladdin), iodocyclohexane (Alfa Aesar), iodocyclo-
pentane (Alfa Aesar), and 1-iodo-2,2-dimethylpropane (Acros)
were used as received. Column chromatography was performed on
silica gel (300–400 mesh; Qingdao-Haiyang Co. China). All NMR
spectra were recorded on Bruker Avance 500-MHz spectrometer at
STP unless otherwise indicated. IR spectra were recorded by using
a Thermo Nicolet Avatar 370 FTIR spectrometer (Thermo Nicolet).
Mass spectra were obtained by using a Shimadzu GCMS-QP2010
SE instrument.
IR (KBr): 3088, 3034, 2955, 2868, 1687, 1671, 1607, 1572, 1465,
1363, 1252, 1234, 1179, 1010, 800, 776, 578 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.86 (d, J = 8.3 Hz, 2 H), 7.26 (d,
J = 8.14 Hz, 2 H), 2.85 (s, 2 H), 2.43 (s, 3 H), 1.07 (s, 9 H).
Reaction of Alkyl Halides with Commercial Aroyl Chlorides;
Procedure 1
13C NMR (125 MHz, CDCl3): δ = 200.2, 143.4, 136.1, 129.1, 128.4,
A flame-dried Schlenk tube was charged with the alkyl iodide (4.50
mmol, 100 mol%), 4,7-diphenyl-1,10-phenanthroline (ligand I;
0.222 g, 0.675 mmol, 15 mol%), MgCl2 (0.642 g, 6.75 mmol, 150
mol%), Ni(acac)2 (0.117 g, 0.45 mmol, 10 mol%), and Zn powder
(0.882 g, 13.5 mmol, 300 mol%). The tube was capped with a rub-
ber septum then evacuated and backfilled three times with N2. The
aroyl chloride (9.0 mmol, 200 mol%) and MeCN (30 mL) were then
added from a syringe, and the mixture was stirred for 12 h under a
N2 at 25 °C. The resulting mixture was filtered through a pad of
Celite that was then washed with CH2Cl2 (3 × 30 mL). The organic
phases were combined and concentrated to give a residue that was
purified by flash column chromatography.
49.9, 31.4, 30.1, 21.6.
MS (EI, 70 eV): m/z (%) = 190 (5) [M+], 175 (7), 134 (55), 119
(100), 91 (25), 89 (2), 65 (10).
Acknowledgment
We thank Dr. Hongmei Deng (Shanghai University) for help regar-
ding the use of the NMR facility. Financial support was provided by
the Chinese NSF (Nos. 2097209 and 21172140), the Program for
Professor of Special Appointment at Shanghai Institutions of High-
er Learning, Shanghai Education Committee, and Shanghai
Leading Academic Discipline Project (No. S30107).
Reaction of Alkyl Halides with Crude Aroyl Chlorides; Proce-
dure 2
A mixture of the arylcarboxylic acid (11.25 mmol, 100 mol%) and
SOCl2 (4.2 mL, 500 mol%) was refluxed for 4 h. Excess SOCl2 was
removed under reduced pressure to give a crude aroyl chloride that
was used for reductive coupling without further purification. The
coupling reaction was conducted by an identical procedure to that
adopted in Procedure 1, except that 11.3 mmol (250 mol%) of the
crude aroyl chloride was used instead of the commercial material.
References
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A flame-dried Schlenk tube was charged with BnBr (4.50 mmol,
100 mol%), 4,4′-di-tert-butyl-2,2′-bipyridine (0.181 g, 0.675 mmol,
15 mol%), MgCl2 (0.642 g, 6.75 mmol, 150 mol%), and Zn powder
(0.882 g, 13.5 mmol, 300 mol%). The tube was placed in a dry glove
box and Ni(COD)2 (0.124 g, 0.45 mmol, 10 mol%) was added. The
tube was then capped with a rubber septum and removed from the
glove box. The aroyl chloride (9.0 mmol, 200 mol%) and MeCN
(30 mL) were added from a syringe and the mixture was stirred for
12 h under N2 at 25 °C. The resulting mixture was filtered through
a pad of Celite that was then washed with CH2Cl2 (3 × 30 mL). The
organic phases were combined and concentrated to give a residue
that was purified by flash column chromatography.
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Synthesis 2013, 45, 2234–2240
© Georg Thieme Verlag Stuttgart · New York