A one-pot synthesis of 3-arylglutaric anhydrides by reaction of ketene with aromatic aldehydes and ketones

Article abstract of DOI:10.1016/j.tetlet.2009.02.193

Aromatic aldehydes and ketones react with ketene under Lewis acid catalysis to produce β-lactones, which in situ react with another molecule of ketene to produce 3-arylglutaric anhydrides. The mechanism, scope, and limitation of this one-pot synthesis of 3-substituted glutaric anhydrides are discussed.

Full text of DOI:10.1016/j.tetlet.2009.02.193

Tetrahedron Letters 50 (2009) 2334–2336
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Tetrahedron Letters
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A one-pot synthesis of 3-arylglutaric anhydrides by reaction of ketene
with aromatic aldehydes and ketones
*
Hirokazu Matsunaga, Kiyoshi Ikeda, Ken-ichi Iwamoto, Yumiko Suzuki, Masayuki Sato
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Aromatic aldehydes and ketones react with ketene under Lewis acid catalysis to produce b-lactones,
which in situ react with another molecule of ketene to produce 3-arylglutaric anhydrides. The mecha-
nism, scope, and limitation of this one-pot synthesis of 3-substituted glutaric anhydrides are discussed.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 29 January 2009
Revised 24 February 2009
Accepted 26 February 2009
Available online 3 March 2009
Desymmetrization of meso- and prochiral compounds is a pow-
erful approach in asymmetric synthesis.1 3-Aryglutaric anhydrides
are particularly useful starting compounds in this approach.2–5 For
example, asymmetric alcoholysis of 3-(p-chlorophenyl)glutaric
anhydride by Novozyme 435 affords the glutaric half ester enanti-
oselectively which serves as chiral building block for (R)-Baclofen,
a selective GABAB receptor agonist.2 Asymmetric methanolysis of
3-aryglutaric anhydrides using cinchona-based catalysts also af-
fords the glutaric half ester enantioselectively which is the key
O
O
(6 equiv.)
O
O
BF3-OEt2 (10 mol%)
H
O
CH2Cl2
-40 °C, 2 h then rt, 2 h
2a
1a
31%
Scheme 1.
intermediate for
avb3 receptor antagonist for the treatment of
osteoporosis.3
3-Aryglutaric acids have been generally synthesized by conden-
sation of arylaldehydes with two molecules of ethyl acetoacetate
followed by deacetylation and hydrolysis of ester groups by strong
base.6 Recently, a one-pot synthesis of 3-aryglutaric acids has been
reported.7 In this method, bis-isoxazole derivatives formed from
3,5-dimethyl-4-nitroisoxazole and arylaldehydes are oxidized
in situ to the dicarboxylic acids by KMnO4. Glutaric anhydrides
are obtained by treatment of glutaric acids with acetic anhydride.
Here, we report the first one-pot synthesis of 3-aryl- or 3-alkyl-
3-arylglutaric anhydrides by reaction of ketene with benzalde-
hydes or acetophenones under a Lewis acid catalysis.
Table 1
Reaction of ketene with benzaldehydes
O
O
O
O
O
BF3-OEt2 (10 mol%)
O
H
or
CH2Cl2, -40 °C, 2 h
then rt, 2 h
O
R
R
1a~k
2
R
3
Entry
R
Product
No
Yield (%)
No.
Yield (%)
It has been well known that ketene reacts with carbonyl com-
pounds to produce b-lactones.8–10 When 6 mol equiv of ketene
generated from acetone by ketene lamp11 was introduced over
1
2
3
4
5
6
7
8
9
H
2a
31
50
39
61
—
—
—
23
—
—
—
—
—
—
3e
3f
3g
—
3i
3j
3k
—
—
—
—
86
82
88
—
62
81
49
p-OMe
p-Cl
2b
2c
2d
—
—
—
2h
—
—
2 h into
a solution of benzaldehyde 1a and BF3 etherate
p-Br
(10 mol %) in dichloromethane at À40 °C and the whole was stirred
at room temperature for 2 h, 3-phenylglutaric anhydride 2a was
obtained in 31% yield (Scheme 1).12,13
We have studied the generality of this new reaction of ketene
with benzaldehydes. The results for reaction of p- and o-substi-
tuted benzaldehydes with ketene under the above-mentioned con-
p-CF3
p-CN
p-NO2
o-OMe
o-NO2
o-Br
10
11
o-Cl
—
—
dition are summarized in Table 1. p-Methoxy-, p-chloro-, and
p-bromo-benzaldehydes 1b–d afforded the corresponding
3-arylglutaric anhydrides 2b–d in 39–61% yields, while
* Corresponding author. Tel./fax: +81 54 264 5754.
E-mail address: msato@u-shizuoka-ken.ac.jp (M. Sato).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.193

H. Matsunaga et al. / Tetrahedron Letters 50 (2009) 2334–2336
2335
p-trifluoromethyl-, p-cyano-, and p-nitro-benzaldehydes 1e–g pro-
duced the corresponding b-lactones 3e–g in 82–86% yields.
o-Methoxybenzaldehyde 1h also afforded the glutaric anhy-
dride 2h in 23% yield, while o-nitro, o-bromo-, and o-chloro-benz-
aldehydes afforded the corresponding b-lactones 3i, 3j, and 3k in
62%, 81%, and 49% yields, respectively.
This indicates that benzaldehydes without electron-withdraw-
ing substituent generally produce the corresponding glutaric anhy-
drides, while those with strong electron-withdrawing substituent
produce only b-lactones.
anhydride 5a in 40% yield. p-Substituted acetophenones 4b–e also
afforded the corresponding 3,3-disubstituted glutaric anhydrides
5b–e in 25–55% yields, while p-nitroacetophenone 4f gave b-lac-
tone 6f in 71% yield.
We have studied the mechanism of this new reaction of ketene
with carbonyl compounds. It is reasonable to assume that ketene
reacts with carbonyl compounds to form b-lactones as initial prod-
ucts, to which another molecule of ketene adds by BF3 catalyst.
Reaction of p-chlorobenzaldehyde 1c with 1.2 equiv of ketene in
the presence of BF3 etherate (10 mol %) gave b-lactone 3c in ca. 90%
yield as revealed by 1H NMR analysis of the reaction mixture. This
lactone was isolated by silica gel column chromatography and was
treated with 3 mol equiv of ketene under BF3 etherate catalyst
(10 mol %) to produce the glutaric anhydride 2c in 46% yield,
clearly showing the intermediary of b-lactones for 3-substituted
glutaric anhydrides (Scheme 2).
The reactions of ketene with acetophenone and the p-substi-
tuted derivatives 4a–f were also examined. The results are summa-
rized in Table 2. Acetophenone 4a gave 3-methyl-3-phenylglutaric
Table 2
Reaction of ketene with acetophenones
A possible mechanism for the formation of 3-substituted glu-
taric anhydrides is illustrated in Scheme 3. b-Lactones 3 and 6
are formed from the carbonyl compounds. b-Lactones with strong
electron-withdrawing substituents such as trifluoromethyl, cyano,
and nitro groups on the aromatic ring are stable enough under the
reaction condition and they are obtained in good yields. b-Lactones
without electron-withdrawing group on the aromatic ring are ring-
opened by the Lewis acid catalyst to form dipolar intermediates 7,
which are intercepted by another molecule of ketene to form glu-
taric anhydrides 2 and 5. Halogens on aromatic ring have an elec-
tron-withdrawing inductive effect and an electron-donating
resonance effect. The formation of glutaric anhydrides 2c,d from
the corresponding p-halophenyl lactones is rationalized by the res-
onance effect. In the o-halophenyl lactones 3j,k, the inductive ef-
fect of nearby halogen operates strongly to disturb the formation
of benzylic cation 7.
O
O
O
(6 equiv.)
BF3-OEt2 (10 mol%)
O
O
O
Me
Me
6f
or
O
Me
5a~e
R
CH2Cl2
-40 °C, 2 h then rt, 2 h
R
R
4a~f
Entry
R
Product
No.
Yield (%)
No.
Yield (%)
1
2
3
4
5
6
H
5a
40
42
55
32
25
—
—
—
—
—
—
6f
—
—
—
—
—
71
OMe
Me
Br
Cl
NO2
5b
5c
5d
5e
—
O
O
O
O
O
(1.2 equiv.)
(3 equiv.)
O
O
BF3-OEt2 (10 mol%)
BF3-OEt2 (10 mol%)
H
O
CH2Cl2
Cl
CH2Cl2
-50 °C
12 h
Cl
-50 °C
0.5 h
Cl
3c
2c
1c
(90% by 1H-NMR analysis)
46%
Scheme 2.
O
O
BF3
O
O
BF3
O
O
O
O
O
O
BF3-OEt2
R2
R2
O
R2
R2
R1
2, 5
R1
1, 4
R1
R1
3, 6
7
R1 = H, EDG, p-Cl, p-Br
R2 = H, Me
O
O
Cl
- CO2
MeO
O
Δ
Cl
O
Cl
Cl
Cl
Cl
MeO
MeO
10
8
9
Scheme 3.

2336
H. Matsunaga et al. / Tetrahedron Letters 50 (2009) 2334–2336
3. Keen, S. P.; Cowden, C. J. Org. Chem. 2005, 70, 1771–1779.
It should be noted that previous attempts to intercept a dipolar
4. Shintani, R.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 1057–1059.
5. Chen, Y.; Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2000, 122, 9542–9543.
6. Smith, W. T., Jr.; Shelton, R. W. J. Am. Chem. Soc. 1954, 76, 2731–2732; Smith, W.
T.; Kort, P. G. J. Am. Chem. Soc. 1950, 72, 1877–1878.
7. Adamo, M. F. A.; Konda, V. R.; Donati, D.; Sarti-Fantoni, P.; Torroba, T.
Tetrahedron 2007, 63, 9741–9745.
intermediate 9 derived from 4-aryl-3,3-dichlorooxetan-2-one 8
with vinyl ether or methyl acrylate under heating were unsuccess-
ful; the reactions exclusively afforded styrene derivative 10.14
In conclusion, we have found that ketene reacts with aromatic
aldehydes and ketones under BF3 catalyst to give b-lactones, which
further react with another molecule of ketene to produce 3-aryl-
and 3-alkyl-3-arylglutaric anhydrides. This reaction is very attrac-
tive for the synthesis of 3-substituted glutaric anhydrides that are
starting materials for the preparation of useful compounds. The
reaction uses one-pot procedure and has a high degree of atom
economy. Since ketene is economically produced on an industrial
scale, this method would be applicable to a large-scale production.
8. Ketenes; Tidwell, T. T., Ed.; John Wiley
& Sons: New York, 1995; pp
564–619.
9. Org. React.; Hyatt, J. A., Raynolds, P. W., Eds.; John Wiley & Sons: New York,
1994; Vol. 45, pp 159–646.
10. Pommier, A.; Pons, J.-M. Synthesis 1993, 442–459.
11. Clark, R. D.; Fuerholzer, J. J.; Baumgarten, H. E.. In Organic Synthesis;
Baumgarten, H., Ed.; John Wiley & Sons: New York, 1973; Coll. Vol. 5, pp
679–684.
12. General procedure for reaction of ketene with benzaldehydes and
acetophenones: To a solution of benzaldehyde (531 mg, 5 mmol) and BF3–
OEt2 (32 lL, 0.25 mmol) in dichloromethane (40 mL), ketene (30 mmol) was
introduced over 45 min at À40 °C and the mixture was stirred at À40 °C
for 2 h and at room temperature for 2 h. Water (40 mL) was added to the
reaction mixture and the whole was extracted with dichloromethane. The
organic layer was dried over anhydrous magnesium sulfate and condensed
under reduced pressure to give oily residue. Purification by silica gel
column chromatography (hexane–AcOEt, 5:1) gave 2a (228 mg, 31%) as
colorless needles of mp 105 °C (recrystallized from hexane–AcOEt). 1H NMR
(CDCl3) d: 7.40 (2H, t, J = 7.4 Hz), 7.34 (1H, t, J = 7.4 Hz), 7.20 (2H, d,
J = 7.4 Hz), 3.40–3.46 (1H, m), 3.12 (2H, dd, J = 17.0, 4.0 Hz), 2.87 (2H, dd,
J = 17.0, 12.0 Hz).
Acknowledgment
We gratefully acknowledge financial support from Chisso
Corporation.
References and notes
1. (a) Willis, M. C. J. Chem. Soc., Perkin Trans. 1 1999, 1765–1784; (b) García-
Urdiales, E.; Alfonso, I.; Gotor, V. Chem. Rev. 2005, 105, 313–354.
2. Fryszkowska, A.; Komar, M.; Koszelewski, D.; Ostaszewski, R. Tetrahedron:
Asymmetry 2006, 17, 961–966.
13. The reaction of aromatic carbonyl compounds with ketene afforded b-lactones
or glutaric anhydrides as the only isolable product.
14. Krabbenhoft, H. O. J. Org. Chem. 1978, 43, 1305–1311.