Zinc-metal promoted selective α-haloacylation and gem-bisacylation of alkyl aldehydes in the presence of chlorotrimethylsilane

Article abstract of DOI:10.1016/j.tetlet.2004.02.159

Treatment of a mixture of alkyl aldehydes (1) with acid chlorides (2) in the presence of zinc metal powder and a catalytic amount of chlorotrimethylsilane (TMSCl) in dichloromethane brought about highly facile and effective coupling to give selectively th

Full text of DOI:10.1016/j.tetlet.2004.02.159

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3503–3506
Zinc-metal promoted selective a-haloacylation and
gem-bisacylation of alkyl aldehydes in the presence of
chlorotrimethylsilane
Yoshio Ishino,a,* Masatoshi Mihara,a Takeshi Takeuchia and Masanobu Takemotob
aOsaka Municipal Technical Research Institute, 1-6-50, Morinomiya, Joto-ku, Osaka 536-8553, Japan
bYamamoto Chemical Ind. Co. Ltd, 1-4 Funatsu-cho, Wakayama 640-8255, Japan
Received 5 January 2004; revised 23 February 2004; accepted 27 February 2004
Dedicated to Professor N. Sonoda on the occasion of his 70th birthday
Abstract—Treatment of a mixture of alkyl aldehydes (1) with acid chlorides (2) in the presence of zinc metal powder and a catalytic
amount of chlorotrimethylsilane (TMSCl) in dichloromethane brought about highly facile and effective coupling to give selectively
the corresponding a-haloacylation and gem-bisacylation products, a-haloalkyl carboxylates and 1,1-dicarboxylates (acylals), in
good to excellent yields.
Ó 2004 Elsevier Ltd. All rights reserved.
The reaction of organometallics and carbonyl com-
pounds provides a fundamental methodology in syn-
thetic organic chemistry.1 Aldehydes, ketones, esters,
and acid halides are widely used as convenient starting
materials for such transformations. a-Haloacylation and
gem-bisacylation of these are most interesting since these
are useful methods for synthesis of a-haloalkylesters,
acylals, and so on. The reactions of aldehydes with acid
halides, however, are limited, because they are not
simple and straightforward.2 In addition some of these
procedures entail the problems of corrosive and effluent
pollution. Recently, we have reported that metallic zinc
with chlorotrimethylsilane (TMSCl) markedly facilitates
the olefination of aldehydes and ketones by the reaction
with gem-dihalides, gem-bisallyation of acid chlorides,
nucleophilic addition of aldimines, and so on.3
as zeolites, sulfated zirconia, montmorillonite clay,
expansive graphite, and zeolite HSZ-360.6 Many of
these reagents are highly corrosive and difficult to han-
dle while some of them are rather expensive.
On the other hand, a-chloroalkyl acetates are also inter-
esting and important bifunctional derivatives containing
two leaving groups with different reactivity. These are
effectively synthesized by the reaction of carbonyl com-
pounds with acyl halides in the presence of Lewis acid
such as zinc chloride, aluminum chloride, and so on.7
Although a number of catalysts have been reported for
the reactions of aldehydes with acid chlorides, the zinc
metal promoted-reaction and the selective formation of
a-haloalkylesters and acylals have not been reported.
Acylals are synthetically useful protecting groups for
carbonyl compounds due to their stability and also are
important building blocks for the synthesis of dienes in
Diels–Alder reaction.4 Usually the preparation of acyl-
als is carried out using several catalysts such as protic or
Lewis acid, iodine, NBS, and so on.5 Several inorganic
heterogeneous reagents have also been developed such
Herein we wish to disclose a mild, efficient, and conve-
nient zinc metal-promoted cross-coupling of aldehydes
and acid chlorides to provide selectively the corre-
sponding a-chloroalkyl carboxylates and 1,1-dicarb-
oxylates (acylals) in good to excellent yields through
a-haloacylation and gem-bisacylation of aldehydes with
acid chlorides or acid anhydrides using commercial
available zinc powder and a catalytic amount of chlo-
rotrimethylsilane in dichloroethane (Scheme 1).
Keywords: Zinc; TMSCl; Acylals; a-Haloalkyl carboxylates.
* Corresponding author. Tel.: +81-6-6963-8051; fax: +81-6-6963-8040;
e-mail: ishino@omtri.city.osaka.jp
The reactions were usually carried out at rt for 4 h in
anhydrous 1,2-dichloroethane containing powdered
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.159

3504
Y. Ishino et al. / Tetrahedron Letters 45 (2004) 3503–3506
A combination of zinc metal and a catalytic amount of
Zn, cat. TMSCl
DCE, rt
R1-CHO
R2-COX
TMSCl has been found to promote selectively the
transformation of various acyl chlorides with aldehydes
to the corresponding cross-coupling acylation products,
such as a-haloalkyl carboxylation and gem-biscarboxyl-
ation products under mild reaction conditions.
+
1
2
R1= Alkyl. R2, R3 = Alkyl, Aryl
X = Cl, Br, OCOR3, CN
OCOR2
OCOR2
OCOR2
R1CH
R1CH
+
X
To demonstrate the efficiency and scope of the present
method, we applied this combination system to a variety
of acid chlorides. The results are summarized in Table 2.
3B
3A
Y = 52 - 100%
Scheme 1.
The a-chloroalkyl carboxylates were selectively
obtained. Under the optimized conditions, 1a was
treated with benzoyl chloride (2a) and acetyl chloride
(2b) to give 3A and 3B in 95% yield (3A/3B ratios were 4/
1 and 2/1, respectively). Aromatic and aliphatic acid
chlorides were smoothly reacted with aldehydes to give
the corresponding cross-coupling products in high
yields. For a vast number of alkyl aldehydes, for
example, primary, secondary, and tertiary aldehydes,
the reaction with benzoyl chloride (2a) had no signifi-
cant effect on the product yields. Aliphatic and aromatic
ketones did not give any of these products.
metallic zinc (60 mmol), a catalytic amount of TMSCl
(3 mmol), acid chlorides (10 mmol), and aldehydes
(30 mmol).8 Commercially available zinc dust (purity;
95%) was used without any pre-treatment. Detailed
studies on the reaction of benzoyl chloride (2a) with
butyraldehyde (1a) showed that this catalytic cross-
coupling is considerably influenced by the molar ratio of
2/1, Zn/1, and the solvents used, as shown in Table 1.
1-Chlorobutyl benzoate (3Aa) was obtained selectively
by the treatment of a mixture of butyraldehyde (1a) and
benzoyl chloride (2a) in the presence of zinc powder and
a catalytic amount of TMSCl in dichloromethane in
good yields (entry 3). Though 3Aa was obtained in the
absence of TMSCl (entry 4), the reaction proceeded
more smoothly and more efficiently with the addition of
TMSCl. When the reaction carried out at reflux tem-
perature, butyl 1,1-dibenzoate (3Ba) was selectively and
quantitatively obtained (entry 7). DCE as solvent and
Zn metal as the metal were found to be much better for
this reaction than other aprotic solvents and metals such
as DMF, THF, acetonitrile, and Mn, Ca, and Mg.
Excess of Zn was needed. As shown in Table 1, the best
result for formation of products was obtained when the
relative proportion of 1a:2a:Zn:TMSCl was 1:3:6:0.3.
Further applications of the reaction were studied using
acid bromides (2c), acid cyanide (2d), and acid anhy-
drides (2e, 2f) instead of acid chlorides (Table 3). The
reaction of 1a with benzoyl bromide (2c) gave
a-bromoesters (3Ac) as a minor product in only 8%
yield. Benzoyl cyanide (2d) gave selectively 1-cyano-
butyl benzoate (3Ad) in 56% yield as a mixture with 3Bd,
while the reaction of acid anhydrides (2e, 2f) with 1a
yielded selectively and quantitatively bis-acylation
product, acylal (3B) as the sole product. These results
well demonstrated that the zinc reagent from the reac-
tion of zinc with acyl chloride in the presence of a cat-
alytic amount of TMSCl has enough and wide reactivity
for some of the aliphatic aldehydes.
Table 1. Zinc-promoted reaction of benzoyl chloride with butyraldehyde in the presence of TMSCla
Zn/TMSCl, DCE
OCOPh
n-PrCHO
n-PrCH
n-PrCH(OCOPh)2
+
Cl
3Aa
(2a)
PhCOCl
1a
3Ba
Entry
2a/1a
TMSCl/1a
Metal/1a (mol equiv)
Solvents
Yield of 3Aa and 3Ba (%)b
1
1
2
3
3
3
3
3
3
3
3
3
3
3
0.3
0.3
0.3
0
Zn (6)
Zn (6)
Zn (6)
Zn (6)
Zn (0)
Zn (2)
Zn (6)
Zn (6)
Zn (6)
Zn (6)
Mn (6)
Ca (6)
Mg (6)
CH2ClCH2Cl
CH2ClCH2Cl
CH2ClCH2Cl
CH2ClCH2Cl
CH2ClCH2Cl
CH2ClCH2Cl
CH2ClCH2Cl
THF0
1
71
75
61
0
35
8
2
3
20
20
0
4
5
0
6
7c
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
54
0
12
100
8
0
9
DMF0
CH3CN
0
10
11
12
13
1
0
0
0
2
0
0
0
CH2ClCH2Cl
CH2ClCH2Cl
CH2ClCH2Cl
a General reaction conditions: benzoyl chloride 30 mmol, aldehydes 10 mmol, Zn 60 mmol, and TMSCl 3 mmol in DCE 40 mL at rt for 4 h.
b Isolated yield by SiO2 column chromatography.
c At reflux temperature.

Y. Ishino et al. / Tetrahedron Letters 45 (2004) 3503–3506
Table 2. Reaction of aldehydes and benzoyl chloridea
3505
OCOR2
X
OCOR2
R1CH
3A
R1CH
Zn/TMSCl
DCE, rt
R2-COX
R1-CHO +
+
OCOR2
3B
2
1
Entry
RCHO (1)
R0COX (2)
Yield of 3 (%)
Ratio of 3A/3B (%)b
1
2
n-PrCHO (1a)
1a
1a
PhCOCl (2a)
2a
MeCOCl (2b)
95
100
95
4/1
0/1c
2/1
2/1
2/1
0/1c
1/2
2/1
1/1
0/1c
3
4
n-HexCHO (1b)
iso-PrCHO (1c)
1c
2a
2a
2a
2a
2a
2a
2a
98
85
5
6
47
52
7
sec-BuCHO (1d)
8
PhCH2CH2CHO (1e)
t-BuCHO (1f)
1f
71
9
10
100
62
a General reaction conditions: benzoyl chloride 30 mmol, aldehydes 10 mmol, Zn 60 mmol, and TMSCl 3 mmol in DCE 40 mL at rt for 4 h.
b Isolated yield by SiO2 column chromatography.
c At reflux temperature.
Table 3. Reaction of aldehydes and acylating agenta
acyl chlorides in the presence of TMSCl could be effec-
tively reacted with aldehydes to give selectively the
corresponding a-haloacylation and gem-bisacylation
products, a-haloalkylesters (3A), and 1,1-dicarboxylates
(acylals) (3B), in good to excellent yields. The present
method complements the existing synthetic methodol-
ogy due to some advantageous properties of zinc
reagents such as availability and selectivity, operational
simplicity, and low toxicity.
Entry RCHO (1)
R0COX (2)
Yield of 3 Ratio of
3A/3B (%)b
(%)
1
2
3
4
5
6
1a
1a
1a
1a
1c
1e
PhCOBr (2c)
PhCOCN (2d)
(PhCO)2O (2e)
(MeCO)2O (2f)
2f
59
56
1/7
13/1
0/1
100
100
78
0/1
0/1
2f
52
0/1
a General reaction conditions: 2 30 mmol, 1 10 mmol, Zn 60 mmol, and
TMSCl 3 mmol in DCE 40 mL at rt for 4 h.
b Isolated yield by SiO2 column chromatography.
References and notes
Although the details concerning the mechanism still
remain ambiguous, the reaction may proceed through
in situ generated organozinc compounds (I) as reaction
intermediates. In the reaction zinc metal may act as
Lewis acid, and then the complex (II) generated by the
reaction with aldehydes gave the products 3 by intra-
molecular transformation of chloro or carboxyl groups.9
The elucidation of the detailed reaction mechanism must
await further study (Scheme 2).
1. For example, (a) Knochel, P.; Singer, R. D. Chem. Rev.
1993, 93, 2117; (b) Erdik, E. Organozinc Reagents in
Organic Synthesis; CRC: Boca Raton, FL, 1996; (c)
Organozinc Reagents: A Practical Approach; Knochel, P.,
Jones, P., Eds.; Oxford University Press: New York, 1999;
(d) Knochel, P.; Millot, N.; Rodrigguez, A. L.; Tucker,
C. E. Org. React. 2001, 58, 417.
2. (a) Cardillo, G.; Simone, A. D.; Mingardi, A.; Tomasini, C.
Synlett 1995, 1131; (b) Yadav, J. S.; Srinivaa, D.; Reddy, G.
S.; Bindu, K. H. Tetrahedron Lett. 1997, 38, 8745; (c) Inoue,
K.; Shimizu, Y.; Shibata, I.; Baba, A. Synlett 2001, 1659;
(d) Haslam, E. Shikimic Acid Metabolism and Metabolites;
John Wiley and Sons: New York, 1993.
In conclusion, we have demonstrated that in situ gen-
erated zinc reagents from the reaction of zinc metal and
3. (a) Ishino, Y.; Mihara, M.; Nishihama, S.; Nishiguchi, I.
Bull. Chem. Soc. Jpn. 1998, 71, 2669; (b) Ishino, Y.;
Mihara, M.; Kageyama, M. Tetrahedron Lett. 2002, 43,
6601; (c) Ito, T.; Ishino, Y.; Mizuno, T.; Ishikawa, A.;
Kobayashi, J. Synlett 2002, 2116; (d) Iwai, T.; Ito, T.;
Mizuno, T.; Ishino, Y. Tetrahedron Lett., 2004, 45, 1083.
4. Greene, T. W. M.; Wuts, P. M. G. Protective Groups in
Organic Synthesis; 3rd ed.; John Wiley and Sons: New
York, 1999.
5. (a) Michie, J. K.; Miller, J. A. Synthesis 1981, 824; (b)
Thomas, J. M. Angew. Chem., Int. Ed. Engl. 1988, 27, 1673;
(c) Karimi, B.; Seradj, H.; Ebrahimian, R. G. Synlett 2000,
623; (d) Carrigan, M. D.; Eash, K. J.; Oswald, M. C.;
Mohan, R. S. Tetrahedron Lett. 2001, 42, 8133; (e)
Norihiko, S.; Kuniaki, N.; Tsuneo, S. Synlett 2001, 1921;
(f) Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O.;
Nocchetti, M. Tetrahedron Lett. 2002, 43, 2709.
O
Zn
RCHO
+
Zn
PhCOX
X
Ph
I
Zn
H
O
O
O
R
O
R
Ph
Ph
X
X
H
II
X = Cl
3A
X = OCOR' 3B
Scheme 2. Possible reaction pathway.

3506
Y. Ishino et al. / Tetrahedron Letters 45 (2004) 3503–3506
6. (a) Kumar, P.; Hedge, V. R.; Kumar, T. P. Tetrahedron
Lett. 1995, 601; (b) Pereira, C.; Gigante, B.; Marcelo-Curto,
M. J.; Carreyra, H.; Perot, G.; Guisnat, M. Synthesis 1995,
1077; (c) Ballini, R.; Bordoni, M.; Bosica, G.; Maggi, R.;
Sartori, G. Tetrahedron Lett. 1998, 39, 7587.
7. (a) Neuenschwnder, M.; Bigler, P.; Christen, K.; Iseli, R.;
Kyburz, R. Helv. Chim. Acta 1978, 61, 2047; (b) Bigler, P.;
Schonholzer, S.; Neuenschwnder, M. Helv. Chim. Acta
1978, 61, 2059; (c) Bigler, P.; Muhle, H.; Neuenschwnder,
M. Synthesis 1978, 593; (d) Chou, T.-S.; Knochel, P. J. Org.
Chem. 1990, 55, 4791.
8. General procedure: A suspension of Zn metal (60 mmol,
3.94 g) and TMSCl (3 mmol, 0.33 g) in dichloroethane
(10 mL) was stirred under nitrogen atmosphere for about
15 min at 50 °C. A mixture of benzoyl chloride (30 mmol)
and aldehydes (10 mmol) in 10 mL of dichloroethane was
slowly added to the suspended solution at room tempera-
ture, and the reaction mixture was then stirred for about 4 h
at the same temperature. The reaction mixture was then
poured into 200 mL of saturated aqueous ammonium
chloride solution and the crude reaction products were
extracted using three 100 mL portions of ether. The
combined ethereal solution was washed with a 100 mL
portion of water, and then dried over anhydrous magne-
sium sulfate. After removing the drying agent by filtration,
the solvent was evaporated by distillation. Then, the
products were isolated by silica-gel column chromatogra-
phy of the resulting residue. All new compounds, 3A and
3B prepared in this study, were identified by 1H and 13C
NMR, IR and mass spectroscopies. Typical spectral data is
as follows: 1-chloro butylbenzoate (3Aa) 1H NMR
(300 MHz, CDCl3) d 7.70 (m, 5H), 7.00 (t, J ¼ 11:93 Hz,
1H), 1.58 (m, 2H), 1.01 (t, J ¼ 14:87 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 164.33, 133.75, 129.99, 128.97, 128.53,
84.49, 40.24, 18.26, 13.38; IR (film) 2963, 1736, 1449, 1264,
1085, 709 cmÀ1; HRMS (EI) calcd for C11H13ClO2 Mþ
1
212.0604, found 212.0601. 1,1-Dibenzoxy butane (3Ba) H
NMR (300 MHz, CDCl3)
d 7.68 (m, 5H), 7.33 (t,
J ¼ 11:01 Hz, 1H), 1.60 (m, 2H), 1.04 (t, J ¼ 4:68 Hz,
3H); 13C NMR (75 MHz, CDCl3) d 164.63 133.38, 129.92,
129.38, 128.40, 91.37, 35.51, 16.96, 13.80; IR (film) 1739,
1452, 1249, 1061, 946, 709 cmÀ1; HRMS (EI) calcd for
C18H18O4 Mþ 298.1205, found 298.1208.
9. Lewis acid catalyzed allylation by indium metal was
reported: Lim, H. J.; Keum, G.; Kang, S. B.; Kim, Y.;
Chung, B. Y. Tetrahedron Lett. 1999, 40, 1547.