Nucleophilic addition reaction of aromatic compounds in the presence of Lewis acid

Article abstract of DOI:10.1055/s-2002-31925

The epoxide 1 obtained by the Darzens condensation reaction of aldehydes with methyl dichloroacetate, reacted with aromatic compounds in the presence of aluminium chloride to afford α-aryl-chloro-α-hydroxyalkanoate 3. Scope and limitation of this reaction were studied for various aldehydes and aromatic compounds. The reaction was also studied in the presence of aluminium chloride supported on alumina or silica gel, which is thought to be a mild Lewis acid and harmless for the environment.

Full text of DOI:10.1055/s-2002-31925

LETTER
899
Nucleophilic Addition Reaction of Aromatic Compounds in the Presence of
Lewis Acid
N
ucleophi
i
lic
A
dd
n
ition Reactio
g
n
of
A
romat
r
ic Comp
o
ounds ng Lin,a Shu Kanazaki,a Setsuo Kashino,b Sadao Tsuboi*a
a
Department of Environmental Chemistry and Materials, Faculty of Environmental Science and Technology, Okayama University,
Okayama 700-8530, Japan
b
Department of Chemistry, Faculty of Science, Okayama University, Okayama 700-8530, Japan
Fax +81(86)2518898; E-mail: stsuboi6@cc.okayama-u.ac.jp
Received 27 February 2002
Lewis acid-promoted addition reaction of aromatic com-
pounds to -chloroglycidates 1 to give alcohol 3 has never
been reported. Here, we report the results about this re-
action. In 1974, Coutrot et al. has obtained compound 3
Abstract: The epoxide 1 obtained by the Darzens condensation re-
action of aldehydes with methyl dichloroacetate, reacted with aro-
matic compounds in the presence of aluminium chloride to afford -
aryl- -chloro- -hydroxyalkanoate 3. Scope and limitation of this re-
action were studied for various aldehydes and aromatic compounds. by the addition of organomagnesium compounds to
-
chloro- -ketoesters.3
The reaction was also studied in the presence of aluminium chloride
supported on alumina or silica gel, which is thought to be a mild
Lewis acid and harmless for the environment.
-Chloro-, -epoxyalkanoates 1 were prepared in good
yields by Darzens condensation of aldehydes with methyl
dichloroacetate in the presence of potassium tert-butoxide
at –78 °C. Then, the reaction of -chloro- , -epoxyal-
kanoates 1 with aromatic compounds in the presence of
AlCl3 was carried out. The results are shown in Table 1.
-Aryl- -chloro- -hydroxyalkanoates 3 were obtained in
a yield of 19.1–87.4%. The main product was syn type.
The structure of syn-3 was confirmed by single-crystal X-
ray analysis of syn-3d (R1 = i-Pr, R2 = CH3). ORTEP
drawing in Figure 1 illustrates the geometrical aspect of
the molecule6 and explains the chemical structure reason-
ably. When the substitution group R1 became long, this re-
action was more active, and the product yield became
high. The activity of aromatic compounds became high in
the following order: benzene< toluene< ethylbenzene< n-
butylbenzene. Moreover, we tried other aromatic com-
pounds (Table 2). In the case of naphthalene, the addition
products were obtained in a good yield of 47–84% (entries
1–5). But, in the case of anthracene or N,N-dimethyla-
niline, the addition product was obtained in a low yield of
31–35% (entries 6 and 8). On the other hand, the reaction
Key words: Darzens condensation, Lewis acid, nucleophilic addi-
tion, epoxide, aromatic compound
Friedel–Crafts reaction is one of the most typical organic
reaction.1 Concerning the reaction of epoxides with aro-
matic compounds in the presence of Lewis acid, some re-
actions using only simple epoxides are reported.2 In our
laboratory, we have studied Darzens condensation contin-
uously for more than twenty years. By Darzens condensa-
tion, aldehydes react with methyl dichloroacetate in the
presence of potassium tert-butoxide at –78 °Cto give -
chloro- ,-epoxyalkanoates 1, which can be rearranged to
afford isomerization products 2. Using the product ob-
tained by Darzens condensation, we have carried out var-
ious reactions. As a link of this study, we examined the
reaction of -chloro- , -epoxyalkanoates 1 with aromatic
compounds in the presence of Lewis acid (Scheme). Inter-
estingly, this reaction didn’t give Friedel–Crafts reaction
products, but a nucleophilic addition product of aromatic
compounds to 1, -aryl- -chloro- -hydroxyalkanoate 3.
O
O
t - BuOK
H
Cl
R1
R1CHO
Cl2CHCO2Me
CO2Me
+
R1
CO2Me
THF, -78 °C
Cl
1
2
OH
CO2Me
OH
H
H
R1
R1
AlCl3
O
H
Cl
CO2Me
+
+
Cl
R1
CO2Me
Cl
R2
1
R2
R2
syn-3
anti-3
Scheme
Synlett 2002, No. 6, 04 06 2002. Article Identifier:
1437-2096,E;2002,0,06,0899,0902,ftx,en;Y02502ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

900
J. Lin et al.
LETTER
Table 1 The Reactions of 2-Chloro-2,3-epoxyalkanoates with Aromatic Compounds in the Presence of Lewis Acid.
OH
CO2Me
OH
CO2Me
H
H
R1
R1
O
+
H
Cl
+
Cl
Lewis acid
R1
CO2Me
Cl
R2
1
R2
R2
anti-3
syn-3
Entry
1
R1
R2
Lewis acid
Conditions
Yield
syn/anti
(CH3)2CH-
H
AlCl3 (3 equiv)
AlCl3 (3 equiv)
AlCl3 (3 equiv)
AlCl3 (3 equiv)
AlCl3 (5 equiv)
AlCl3 (10 equiv)
AlCl3 (3 equiv)
AlCl3 (3 equiv)
AlCl3 (3 equiv)
TiCl4 (3 equiv)
TiCl4 (3 equiv)
FeCl3 (3 equiv)
FeCl3 (3 equiv)
r.t., 1 h; 50 °C, 1 h 3a, 19.1%
79:21
74:26
79:21
79:21
79:21
78:22
79:21
81:19
77:23
79:21
80:20
79:21
79:21
2
CH3(CH2)2-
CH3(CH2)6-
(CH3)2CH-
(CH3)2CH-
(CH3)2CH-
CH3(CH2)2-
CH3(CH2)4-
CH3(CH2)8-
(CH3)2CH
H
r.t., 1 h
3b, 53.3%
3
H
r.t., 1 h
3c, 68.7%
4
CH3-
CH3-
CH3-
CH3-
r.t., 50 min
r.t., 50 min
r.t., 40 min
r.t., 50 min
r.t., 50 min
r.t., 50 min
50 °C, 2 h
50 °C, 2 h
r.t., 2 h
3d, 55.9%
5
3d, 50.5%
6
3d, 42.1%
7
3e, 57.9%
8
CH3CH2-
3f, 63.6%
9
CH3(CH2)3-
3g, 87. %
10
11
12
13
H
3a, 8.8%; 2a, 47.2%
3e,13.0%; 2e, 51.1%
3b, 9.0%; 2b, 53.4%
3d,14.4%; 2d, 52.3%
CH3(CH2)2-
CH3(CH2)2-
(CH3)2CH-
CH3-
H
CH3-
r.t., 2 h
of aniline or phenol gave the addition product only in a In order to look for better Lewis acid, we examined the re-
poor yield of 15–18% (entries 7 and 9). In the case of bro- action in the presence of TiCl4 or FeCl3 instead of AlCl3.
mobenzene or nitrobenzene, the reaction gave no product. But we got unsatisfactory results, and the addition product
Besides these, we investigated how the stoichiometry of was obtained only in 9–14% yield. The isomerization pre-
AlCl3 influences the reaction. Using 3 equiv, 5 equiv or 10 vailed in such case to give -chloro- -oxoalkanoates 2 in
equiv of AlCl3 we carried this reaction and found that in- a good yield of 70–76% (Table 1, entries 10–13). Further-
creasing the relative amounts of AlCl3 afforded the prod- more, we also investigated this reaction in the presence of
uct in a lower yield, and had no influence on the aluminium chloride supported on alumina or silica gel,
stereoselectivity (Table 1, entries 4–6). So, using 3 equiv which is thought to be a mild Lewis acid and harmless for
of AlCl3 was best.
the environment (Table 3). In the case of reactions in the
presence of AlCl3 supported on Al2O3, although the yield
of addition products 3 became higher than that of only in
the presence of AlCl3, the stereoselectivities changed well
somewhat (entries 4–6). And in the case of reactions in the
presence of AlCl3 supported on SiO2, the yield of addition
products 35 depends on the nature of substrate. For exam-
ple, when R1 = iPr or nPr, the yield became higher (entries
10 and 11), but with increasing the number of the carbon
in R1, the yield became lower than that of only in the pres-
ence of AlCl3 (entry 12). All the stereoselectivities were
not changed so much. And then, we examined effects of
the ratio of AlCl3 and Al2O3 or SiO2. Using AlCl3 support-
ed on Al2O3 or SiO2 with the ratio of 1:2, 1:5 or 1:10, we
carried this reaction and found that using AlCl3 supported
on Al2O3 or SiO2 with the ratio of 1:2 afforded the product
in a highest yield, and no influence on the stereoselectivity
was observed (entries 1 and 7).
Figure 1 ORTEP drawing of syn-3d6
Synlett 2002, No. 6, 899–902 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Nucleophilic Addition Reaction of Aromatic Compounds
901
Table 2 The Reactions of 2-Chloro-2,3-epoxyalkanoates with Naphtalene, Anthracene and Aniline Conductor in the Presence of AlCl3
OH
Ar
OH
CO2Me
H
H
O
Aromatic compound
AlCl3 , CH2Cl2
H
Cl
R1
R1
CO2Me
+
R1
CO2Me
Ar
Cl
Cl
1
anti-3
syn-3
Entry
R1
Aromatic compounds
naphtalene
Conditions
r.t., 1 h
Yield
syn/anti
89:11
90:10
75:25
75:25
78:22
71:29
80:20
77:23
70:30
1
2
3
4
5
6
7
8
9
(CH3)2CH-
CH3(CH2)2-
CH3(CH2)4-
CH3(CH2)6-
CH3(CH2)8-
CH3(CH2)4-
CH3(CH2)4-
CH3(CH2)8-
CH3(CH2)8-
3h, 46.8%
3i, 52.2%
3j, 56.4%
3k, 73.2%
3l, 83.6%
3m, 31.2%
3n, 18.5%
3o, 35.4%
3p, 15.3 %
naphtalene
r.t., 50 min
r.t., 40 min
r.t., 30 min
r.t., 15 min
r.t., 40 min
r.t., 1 h
naphtalene
naphtalene
naphtalene
anthracene
anliline
N,N-dimethylaniline
phenol
r.t., 20 min
r.t., 2 h
Table 3 The Reactions of 2-Chloro-2,3-epoxyalkanoates with Aromatic Compounds in the Presence of AlCl3 Supported on Al2O3 or SiO2
OH
CO2Me
OH
CO2Me
H
H
R1
AlCl3
R1
O
+
H
Cl
+
Al2O3
Cl
R1
CO2Me
Cl
R2
or SiO2
1
R2
R2
syn-3
anti-3
Entry
1
R1
R2
Conditions
Yield
syn/anti
82:18
73:27
80:20
84:16
78:22
80:20
83:17
77:23
81:19
79:21
81:19
81:19
CH3(CH2)2-
CH3(CH2)2-
CH3(CH2)2-
(CH3)2CH-
CH3(CH2)2-
CH3(CH2)6-
CH3(CH2)2-
CH3(CH2)2-
CH3(CH2)2-
(CH3)2CH-
CH3(CH2)2-
CH3(CH2)6-
CH3-
CH3-
CH3-
H
AlCl3–Al2O3 =1:2 ; r.t., 50 min
AlCl3–Al2O3 =1:5 ; r.t., 50 min
AlCl3–Al2O3 =1:10 ; r.t., 50 min
AlCl3–Al2O3 =1:2 ; r.t., 1 h
AlCl3–Al2O3 =1:2 ; r.t., 1 h
AlCl3–Al2O3 =1:2 ; r.t., 1 h
AlCl3–SiO2 =1:2 ; r.t., 2 h
AlCl3–SiO2 =1:5 ; r.t., 2 h
AlCl3–SiO2 =1:10 ; r.t., 1 h
AlCl3–SiO2 =1:2 ; r.t., 1 h
AlCl3–SiO2 =1:2 ; r.t., 1 h
AlCl3–SiO2 =1:2 ; r.t., 1 h
3e, 70.1%
3e, 51.7%
3e, 45.8%
3a, 37.2%
3b, 59.6%
3c, 76.7%
3e, 63.2%
3e, 57.2%
3e, 54.0%
3a, 33.9%
3b, 62.0%
3c, 55.3%
2
3
4
5
H
6
H
7
CH3-
CH3-
CH3-
H
8
9
10
11
12
H
H
In summary, we found that the reaction of -chloro- , - the major products are syn products. Utilization of this re-
epoxyalkanoates with aromatic compounds in the pres- action for total synthesis of
a natural product,
ence of Lewis acid doesn’t give Friedel–Crafts reaction donaxaridine4 is currently under investigation.
products, but -aryl- -chloro- -hydroxyalkanoates, and
Synlett 2002, No. 6, 899–902 ISSN 0936-5214 © Thieme Stuttgart · New York

902
J. Lin et al.
LETTER
(S,S)-( )-3f: yellow liquid, Rf = 0.30 (hexane–ether = 2:1);
1H NMR (200 MHz, CDCl3) 0.83 (t, J = 6.4 Hz, 3 H), 1.24
(t, J = 7.6 Hz, 3 H), 1.18–1.76 (m, 8 H), 2.66 (q, J = 7.6 Hz,
2 H), 3.82 (s, 3 H), 3.91 (s, 1 H), 4.68 (dd, J = 1.8 Hz and
10.8 Hz, 1 H), 7.21 (d, J = 8.4 Hz, 2 H), 7.57 (d, J = 8.4 Hz,
2 H); 13C NMR (200 MHz, CDCl3) 13.89, 15.28, 22.38,
26.58, 28.37, 30.51, 30.87, 53.53, 68.30, 81.23, 125.85,
127.98, 134.97, 144.34, 173.58; IR(neat): 3514, 2958, 2932,
2864, 1742, 1512, 1437, 1257, 1147, 756 cm–1; Anal. Calcd
for C17H25ClO3: C, 65.27; H, 8.05; Found: C, 65.51; H, 8.22.
(S,R)-( )-3f: yellow liquid, Rf = 0.23 (hexane–ether = 2.1);
1H NMR(200 MHz, CDCl3) 0.90 (t, J = 6.4 Hz, 3 H), 1.24
(t, J = 7.6 Hz, 3 H), 1.20–2.10 (m, 8 H), 2.66 (q, J = 7.6 Hz,
2 H), 3.73 (s, 1 H), 3.81 (s, 3 H), 4.61 (dd, J = 1.6 Hz and
10.8 Hz, 1 H), 7.21 (d, J = 8.4 Hz, 2 H), 7.53 (d, J = 8.4 Hz,
2 H); 13C NMR (200 MHz, CDCl3) 13.97, 15.22, 22.42,
26.57, 28.37, 31.05, 33.11, 53.58, 67.65, 81.25, 125.70,
127.83, 136.63, 144.32, 173.10; IR(neat): 3512, 2962, 2934,
2864, 1734, 1514, 1458, 1253, 1143, 835, 665 cm–1; Anal.
Calcd for C17H25ClO3: C, 65.27; H, 8.05; Found: C, 65.51;
H, 8.22.
Acknowledgement
We are grateful to SC-NMR laboratory of Okayama University for
the measurement of NMR spectra.
References
(1) Friedel–Crafts and Related Reaction; Olah, G. A., Ed.;
Interscience: New York, 1964.
(2) (a) Hata, S.; Matsuda, H.; Mastuda, S. Kogyo Kagaku Zasshi
1967, 70(12), 2291. (b) Nakamoto, Y.; Nakajima, T.; Suga,
S. Kogyo Kagaku Zasshi 1969, 72(12), 2594. (c) Nakajima,
T.; Nakamoto, Y.; Suga, S. Bull. Chem. Soc. Jpn. 1975,
48(3), 960. (d) Inoue, M.; Chano, K.; Itoh, O.; Sugita, T.;
Ichikawa, K. Bull. Chem. Soc. Jpn. 1980, 53, 458.
(3) Juy, M.; Combert, J. C.; Coutrot, P. C. R. Hebd. Seances
Acad. Sci., Ser. C 1974, 279, 469.
(4) (a) Ubaidullaev, K. A.; Shakairov, R.; Yunosov, S. Y. Khim.
Prir. Soedin. 1976, 12, 553. (b) Hasse, B. R.; John, K. M. J.
Nat. Prod. 1997, 60, 1152.
(5) Typical procedure for ( )-2-hydroxy-2-(p-ethylphenyl)-3-
chlorooctanoate(3f): To a stirred solution of aluminium
chloride (430 mg, 3 mmol) in CH2Cl2 (4 mL) was added the
solution of methyl 2-chloro-2,3-epoxyoctanoate (206 mg, 1
mmol) and ethylbenzene (319 mg, 3 mmol) in CH2Cl2 (2
mL) at room temperature. The mixture was stirred for 50
minutes, then reaction was stopped by pouring the ice (10
mL), and the aqueous layer was extracted with EtOAc. The
combined extract was washed with saturated NaHCO3
solution and brine, then dried over MgSO4. Removal of the
solvent gave 232 mg of a clean oil, which was purified by
column chromatography (hexane–ether = 160:1) to give 161
mg (51.5%) of (S,S)-( )-3f and 38 mg (12.1%) of (S,R)-( )-
3f.
(6) X-ray crystallographic data of syn-3d: data collection,
solution, and refinement.
Chemical formula: C14H19O3Cl; F. W. = 270.76; crystal size:
0.50 0.25 0.43 mm3; crystal system: triclinic; lattice
parameters: a = 10.495(3), b = 11.755(3), c = 6.608(2) Å,
= 100.36(2), = 107.25(3), = 69.213(18)º, V = 725.4(4)
Å3; space group: P (#2); Z = 2; Dcalc = 1.240 g/cm3; F(000)
= 288; (Mo K ) = 0.26 mm–1; diffractometer: Rigku
AFC5R; T: 25 ºC; no. of reflections measured: total 3880,
unique 3334; structure solution: direct methods (SIR92);
refinement: full-matrix least-squares on F2; function mini-
mized: w (Fo2 – Fc2)2; least squares weights: 1/ 2(Fo) =
4Fo2/ 2 (Fo2); no. obsd [I > 0.5 (I)]: 2886; no. variables:
240; residuals R1, wR2: 0.063, 0.099; goodness of fit
indicator: 1.94; max
/
min: 0.23 / – 0.28 e / Å3.
Synlett 2002, No. 6, 899–902 ISSN 0936-5214 © Thieme Stuttgart · New York