Lewis Acid-Promoted Coupling Reactions of Acid Chlorides with Organoaluminum and Organozinc Reagents

Article abstract of DOI:10.1021/jo970244a

An efficient synthesis of α,α-unsaturated ketones by the reaction of acid chlorides with trialkyl-aluminum (1/3 mole equiv) in the presence of AlCl₃ (1 mol equiv) is described. Dialkylzincs were also useful and are easier to prepare than trialkylaluminum. Reaction of RCOCl with R′AlCl₃ or R′₂AlCl gave R′COR, without AlCl₃, in high yield.

Full text of DOI:10.1021/jo970244a

J . Org. Chem. 1997, 62, 4327-4329
4327
Lew is Acid -P r om oted Cou p lin g Rea ction s of Acid Ch lor id es w ith
Or ga n oa lu m in u m a n d Or ga n ozin c Rea gen ts
Mitsuhiro Arisawa, Yasuhiro Torisawa, Michiaki Kawahara, Masamichi Yamanaka,
Atsushi Nishida, and Masako Nakagawa*
Faculty of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263, J apan
Received February 11, 1997X
An efficient synthesis of R,â-unsaturated ketones by the reaction of acid chlorides with trialkyl-
aluminum (1/3 mole equiv) in the presence of AlCl3 (1 mol equiv) is described. Dialkylzincs were
also useful and are easier to prepare than trialkylaluminum. Reaction of RCOCl with R′AlCl2 or
R′2AlCl gave R′COR, without AlCl3, in high yield.
Sch em e 1
The coupling reactions of alkylmetal reagents and acid
halides provide useful method for synthesizing
a
ketones.1-3 During our study of the Diels-Alder reac-
tion,4 we became interested in reacting acid chlorides
with organoaluminum reagents to give ketones in a single
operation. Inspired by some earlier reports,2,3 we devel-
oped a practical method for producing (E)-pent-3-en-2-
one (1) (Scheme 1), a useful precursor for some silyloxy
dienes, by reacting crotonyl chloride and triethylalumi-
num.5 In this report, we describe this reaction in detail
and its extension to an organozinc reagent.
Sch em e 2
When a CH2Cl2 solution of trimethylaluminum (0.4
equiv) was added to a solution of crotonyl chloride and
aluminum chloride (1.0 equiv) in CH2Cl2, alkylation
proceeded to give (E)-pent-3-en-2-one (1) quantitatively
(Table 1). The presence of aluminum chloride was
essential; without aluminum chloride, only 9% of 1 was
obtained. Although aluminum fluoride and gallium
chloride were less effective, methylaluminum chloride
and dimethylaluminum chloride were effective for the
alkylation of crotonyl chloride.
aluminum reagent, such as trioctylaluminum, also worked
without any problems.
The general procedure, which has been reported previ-
ously,5 was generally reproducible for the preparation of
a few grams of 1. However, we encountered a serious
problem when we tried to prepare a large quantity (>10
g) of 1. Specifically, the product was contaminated by a
varying amount of 3-chloropentan-2-one, and it was
difficult to separate these compounds because of their
close boiling points. The amount of contaminating chloro
ketone depended on the workup prodedures (1:chloro
ketone ) 1:1-10:1), such as the washing time using
aqueous base and the time necessary for removal of
CH2Cl2 under atmospheric pressure. Finally, we estab-
lished two procedures for the large-scale preparation of
1. One procedure consists of the elimination of hydrogen
chloride from the chloro ketone to 1, basically as de-
scribed in ref 6. The product obtained using this protocol
sometimes contained a trace amount of â,γ-unsaturated
ketone.
The reaction of phenylpropionyl chloride with tri-
methylaluminum was interesting from a mechanistic
point of view. When a solution of aluminum chloride was
added to a mixture of the acid chloride and trimethyl-
aluminum, the desired propiophenone was obtained in
91% yield (Scheme 2). However, the addition of tri-
methylaluminum to a mixture of aluminum chloride and
the acid chloride under the same conditions gave 1-in-
danone quantitatively. These results suggested that the
reaction did not proceed via the simple acylinium ion
complex (A in Figure 1), but rather proceeded via the acyl
chloride-AlR′3 complex (B) activated by the AlClXY
species (X, Y ) Cl or alkyl) as shown in Figure 1. A bulky
Since the addition of HCl to 1 appeared to occur when
CH2Cl2 was removed by distillation under atmospheric
pressure, the second procedure included the rapid distil-
lation of a mixture of CH2Cl2 and 1 under reduced
pressure at less than 50 °C using a cold trap (-78 °C).
The solvents were then distilled in the presence of
quinoline. Purification of the residue by distillation
under vacuum gave on the order of 30 g of pure 1.
Regarding the preparation of organometallic reagents,
dialkylzinc reagents are much easier to prepare and
sometimes more stable than trialkylaluminums.1,7 Thus,
we next focused our attention on the use of dimethylzinc
X Abstract published in Advance ACS Abstracts, J une 1, 1997.
* To whom correspondence should be addressed. Tel.: 81-43-290-
2908. Fax: 81-43-255-1574. E-mail: nakagawa@p.chiba-u.ac.jp.
(1) See as general references: (a) Tamao, K. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press:
New York, 1991; Vol. 3, pp 463-464. (b) Larock, R. C. Comprehensive
Organic Transformations; VCH Publishers: New York, 1989; pp 686-
691. (c) Posner, G. A. Org. React. 1975, 22, 253-400. (d) Shirley, D. A.
Org. React. 1954, 8, 28-58.
(2) Tolstikov, G. A.; Valitov, F. K.; Kuchin, A. V. J . Gen. Chem.
(USSR) 1982, 51, 1359-1361.
(3) (a) Wakamatsu, K.; Okuda, Y.; Oshima, K.; Nozaki, H. Bull.
Chem. Soc. J pn. 1985, 58, 2425-2426. (b) Takai, K.; Oshima, K.;
Nozaki, H. Ibid. 1987, 54, 1281-1282.
(4) Nagata, T.; Koide, Y.; Nara, K.; Itoh, E.; Arisawa, M.; Naruto,
S.; Torisawa, Y.; Hino T.; Nakagawa, M. Chem. Pharm. Bull. 1996,
44, 451-453.
(5) Arisawa, M.; Torisawa, Y.; Nakagawa, M. Synthesis 1995, 1371-
1372.
(6) Odom, H. C.; Pinder, A. R. Organic Syntheses; Wiley: New York,
1988; Collect. Vol. VI, pp 883-886.
S0022-3263(97)00244-2 CCC: $14.00 © 1997 American Chemical Society

4328 J . Org. Chem., Vol. 62, No. 13, 1997
Ta ble 1. Rea ction of Acid Ch lor id es w ith Tr ia lk yla lu m in u m
Arisawa et al.
entry
RCOCl
R′3Al
Lewis acid
AlCl3
product
yield (%)
1
2
3
4
5
6
7
8
CH3CHdCHCOCl
CH3CHdCHCOCl
CH3CHdCHCOCl
CH3CHdCHCOCl
CH3CHdCHCOCl
CH3CHdCHCOCl
CH3CHdCHCOCl
C8H17COCl
Me3Al
Me3Al
Me3Al
Me3Al
MeAlCl2
Me2AlCl
Oct3Al
Oct3Al
CH3CHdCHCOCH3 (1)
CH3CHdCHCOCH3 (1)
CH3CHdCHCOCH3 (1)
CH3CHdCHCOCH3 (1)
CH3CHdCHCOCH3 (1)
CH3CHdCHCOCH3 (1)
CH3CHdCHCOC8H17 (2)
C8H17COC8H17 (3)9
100
9
25
48
100
77
AlF3
GaCl3
AlCl3
AlCl3
88
100
Ta ble 2. Rea ction of Acid Ch lor id es w ith Dia lk ylzin cs
entry
RCOCl
R′2Zn
product
yield (%)
1
2
3
4
5
6
CH3CHdCHCOCl
PhCHdCHCOCl
C7H15COCl
CH3CHdCHCOCl
PhCOCl
Me2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
CH3CHdCHCOCH3 (1)5
PhCHdCHCOC2H5 (4)10
C7H15COC2H5 (5)11
100
71
94
77
86
99
CH3CHdCHCOC2H5 (6)5
PhCOC2H5 (7)12
PhCH2COCl
PhCH2COC2H5 (8)13
ease of preparation and the stability of dialkylzincs
compared to trialkylaluminum make these reactions
useful for ketone synthesis.14
Exp er im en ta l Section
Acid chlorides, trialkylaluminum, and dialkylzinc were used
as obtained from commercial sources. Dichloromethane and
THF were freshly distilled over CaH2 and sodium/benzophe-
none, respectively. All of the reactions were usually carried
out under an argon atmosphere in well-dried glassware, unless
noted otherwise. Column chromatography was performed
using Merck silica gel 60.
Typ ica l P r oced u r e for th e Rea ction of Acid Ch lor id e
w ith Tr ia lk yla lu m in u m . To a cooled (-50 °C) suspension
of AlCl3 (31.3 mmol) in CH2Cl2 (25 mL) was added a solution
of the acid chloride (31.3 mmol) in CH2Cl2 (10 mL) over 15
min under an argon atmosphere. The mixture was stirred for
about 1 h and cooled to -30 °C. A solution of trialkylalumi-
num (12.6 mmol) in CH2Cl2 (13 mL) was added over 30-60
min. The mixture was then kept at rt for 2 h, recooled to 0
°C, and quenched by the addition of water. The organic layer
was separated, and the aqueous layer was washed with Et2O.
The combined organic layer was washed with 5% aqueous
NaHCO3 and then with water and finally dried over Na2SO4.
After removal of the solvent, the residue was purified by
column chromatography on silica gel to give the corresponding
ketone. Each product was characterized by IR, NMR, and
mass spectroscopy.
F igu r e 1.
instead of trimethylaluminum in this transformation. As
expected, the ketone (1) was obtained quantitatively
under comparable reaction conditions. Without alumi-
num chloride, 1 was not obtained at all. Various cata-
lysts have been reported to be effective in the reaction of
acid chlorides with organoaluminum reagents,3 while
only a palladium catalyst has been effective in the
reaction of acid chlorides with organozinc reagents.7,8 The
results of the current study are summarized in Table 2
and clearly demonstrate its general synthetic utility.
In summary, we have developed a novel synthetic
method for ketones: i.e., the Lewis acid-promoted reac-
tion of acid chlorides with dialkylzincs, as well as a
comparable reaction with alkylaluminum chlorides. The
Typ ica l P r oced u r e for th e Rea ction of Acid Ch lor id e
w ith Meth yla lu m in u m Dich lor id e or Dim eth yla lu m i-
n u m Ch lor id e. To a cooled (-30 °C) solution of crotonyl
chloride (31.3 mmol) in CH2Cl2 (35 mL) was added a solution
of methylaluminum dichloride (37.5 mmol) or dimethylalumi-
num chloride (18.8 mmol) in CH2Cl2 (13 mL) over 30 min. The
mixture was then kept at rt for 2 h, recooled to 0 °C, and
quenched by the addition of water. The workup as above gave
a residue that was subjected to distillation under reduced
pressure to afford (E)-pent-3-en-2-one (1) (31.4 mmol and 24.1
mmol, 100% and 77%, respectively; bp 40 °C/30 mmHg) as a
colorless oil: IR (neat) cm-1 3040, 2980, 2330, 1720, 1700,
1680, 1640, 1450, 1380, 1360, 1320, 1290, 1280, 1260, 1190,
(7) See, for example: (a) Knochel, P. In Comprehensive Organic
Synthesis; Trost, B. M, Fleming, I., Eds.; Pergamon Press: New York,
1991; Vol. 1, pp 211-223. (b) Knochel, P.; Singer, R. D. Chem. Rev.
1993, 93, 2117-2188.
(8) (a) Negishi, E.; Bagheri, V.; Chatterjee, S.; Luo, F.; Miller, J . A.;
Stoll, T. Tetrahedron Lett. 1983, 24, 5181-5184. (b) Tamaru, Y.; Ochiai,
H.; Sanda, F.; Yoshida, Z. Tetrahedron Lett. 1985, 26, 5529-5532. (c)
Gray, R. A. J . Org. Chem. 1984, 49, 2288-2289. (d) Sato, T.; Naruse,
K.; Enokiya, M.; Fujisawa, T. Chem. Lett. 1981, 1135-1138.
(9) Stiles, M.; Wolf, D.; Hudson, G. V. J . Am. Chem. Soc. 1959, 81,
628-631.
(10) Rathmann, G. B.; Curtis, A. J .; McGeer, P. L.; Smith, C. P. J .
Chem. Phys. 1956, 25, 413-416.
(11) Rabjohn, N.; Phillips, L. V.; DeFeo, R. J . J . Org. Chem. 1959,
24, 1964-1967.
(12) The Aldrich Library of 13C and 1H FT NMR Spectra; Pouchert,
C. P., Behnke, J ., Ed.; Aldrich Chemical Company, Inc.: Milwaukee,
1993; Vol. 2, 802B.
(14) (a) See, for recent examples: Malanga, C.; Aronica, L. A.;
Lardicci, L. Tetrahedron Lett. 1995, 36, 9185-9188. Evans, P. A.;
Nelson, J . D.; Stanley, A. L. J . Org. Chem. 1995, 60, 2298-2301. Harn,
N. K.; Gramer, C. J .; Anderson, B. A. Tetrahedron Lett. 1995, 36, 9453-
9456.
(13) The Aldrich Library of 13C and 1H FT NMR Spectra; Pouchert,
C. P., Behnke, J ., Ed.; Aldrich Chemical Company, Inc.: Milwaukee,
1993; Vol. 2, 789B.

Coupling Reactions of Acid Chlorides
J . Org. Chem., Vol. 62, No. 13, 1997 4329
1040, 1020 cm-1; 1H-NMR (400 MHz, CDCl3) δ (ppm) 1.92 (3H,
dd, J ) 6.9, 1.7 Hz), 2.24 (3H, s), 6.10 (1H, dd, J ) 15.9, 9.1
Hz), 6.83 (1H, dq, J ) 13.8, 6.7 Hz).
(31.3 mmol) in CH2Cl2 (25 mL) was added a solution of the
acid chloride (31.3 mmol) in CH2Cl2 (10 mL) over 15 min under
an argon atmosphere. The mixture was stirred for ∼1 h and
cooled to -30 °C. A solution of dialkylzinc (18.8 mmol) in
CH2Cl2 (19 mL) was added over 30-60 min. The mixture was
then kept at rt for 2 h, recooled to 0 °C, and quenched by the
addition of water. Usual workup afforded a residue that was
subjected to distillation under reduced pressure or purified by
column chromatography on silica gel to give the corresponding
ketone. Each product was characterized by IR, NMR and mass
spectroscopy.
(E)-2-Dod ecen -4-on e (2): Rf ) 0.66 (n-hexane:AcOEt ) 10:
1); IR (KBr) cm-1 2940, 2855, 1695, 1685, 1460, 1440, 1380,
1280, 1200; 1H-NMR (400 MHz, CDCl3) δ (ppm) 0.87 (3H, m),
1.28 (12H, m), 1.90 (3H, dd, J )6.8, 1.7 Hz), 2.51 (2H, d, J )
7.6 Hz), 6.12 (1H, dd, J ) 15.7, 1.7 Hz), 6.84 (1H, dd, J ) 15.7,
6.7 Hz); 13C-NMR (100 MHz, CDCl3) δ (ppm) 14.05, 18.16,
22.61, 24.29, 29.11, 29.30, 29.36, 31.79, 40.04, 131.95, 142.21,
200.74; LRMS (FAB) m/z 183 (20), 141 (100%); HRMS (EI)
calcd for C12H22O (M+) 182.1761, found 182.1761.
4-P h en ylbu ta n -2-on e. A solution of trimethylaluminum
(1.05 M, n-hexane solution, 7.99 mL, 8.35 mmol) and CH2Cl2
(12 mL) at -50 °C over 30 min was added to a solution of
3-phenylpropionyl chloride (3.52 g, 20.87 mmol) in CH2Cl2 (50
mL). After the mixture was stirred for 1 h at under the
previously described reaction conditions, aluminum chloride
(2.78 g, 20.87 mmol) was added. The mixture was stirred for
1.5 h at room temperature and poured over ice. Usual workup
gave a residue that was purified with silica gel column
chromatography (AcOEt:n-hexane, 1:10) to afford 4-phenylbu-
tan-2-one15 (2.82 g, 91%).
P r ep a r a tion of ∼30 g of (E)-P en t-3-en -2-on e. A solution
of 1.0 M MeAlCl2 in hexane (574 mL) was added dropwise to
a solution of crotonyl chloride (478.3 mmol) in CH2Cl2 (400
mL) at -30 °C. After being stirred for an additional 1 h, the
reaction mixture was stirred for 2 h at room temperature. The
reaction mixture was poured over ice (500 g), and the sepa-
rated organic layer was washed with saturated K2CO3 (aq)
(300 mL) and brine (200 mL × 3). The organic layer was dried
over anhydrous MgSO4 and filtered. The filtrate was distilled
under reduced pressure (room temperature/120 mmHg to 50
°C/20 mmHg). After quinoline (10 mL) was added to the
distillate, the remaining CH2Cl2 was removed by distillation
under atmospheric pressure. Distillation of the residue under
reduced pressure gave (E)-pent-3-en-2-one (44-47 °C/40 mmHg,
30.72 g, 76.3%).
Ack n ow led gm en t. Financial support from the Min-
istry of Education, Science and Culture in the form of a
Grant-in Aid for Scientific Research and from the
Fujisawa Foundation is gratefully acknowledged. We
also thank Ms R. Hara at the Chemical Analysis Center
of Chiba University for measuring mass spectral data.
Su p p or t in g In for m a t ion Ava ila b le: NMR spectra of 1
and 2 (4 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
Typ ica l P r oced u r e for th e Rea ction of Acid Ch lor id e
w ith Dia lk ylzin c. To a cooled (-50 °C) suspension of AlCl3
(15) The Aldrich Library of 13C and 1H FT NMR Spectra; Pouchert,
C. P., Behnke, J ., Ed.; Aldrich Chemical Company, Inc.: Milwaukee,
1993; Vol. 2, 789A.
J O970244A