Novel C-C bond cleavage under mild, neutral conditions: Conversion of electron-deficient aryl alkyl ketones to aryl carboxylic esters

Article abstract of DOI:10.1021/jo016145l

A novel, unique way to cleave the carbon-carbon bond in aryl alkyl ketones under mild, neutral conditions is described. Treatment of aryl alkyl ketones in a refluxing mixture of N,N-dimethylformamide dimethyl acetal and methanol for 16 h provided aryl car

Full text of DOI:10.1021/jo016145l

J . Org. Chem. 2002, 67, 1703-1704
1703
Ta ble 1. Con ver sion of Ar yl Alk yl Keton es 1 to Ar yl
Novel C-C Bon d Clea va ge u n d er Mild ,
Neu tr a l Con d ition s: Con ver sion of
Electr on -Deficien t Ar yl Alk yl Keton es to
Ar yl Ca r boxylic Ester s
Ester s
Nan Zhang* and J oseph Vozzolo1
Chemical Sciences, Wyeth-Ayerst Research,
Pearl River, New York 10965
zhangn@war.wyeth.com
Received September 24, 2001
Abstr a ct: A novel, unique way to cleave the carbon-carbon
bond in aryl alkyl ketones under mild, neutral conditions is
described. Treatment of aryl alkyl ketones in a refluxing
mixture of N,N-dimethylformamide dimethyl acetal and
methanol for 16 h provided aryl carboxylic esters. The scope
and limitations of the reaction are discussed. Useful yields
of the reaction can be obtained with electron-deficient aryl
groups, and the yields are higher when the alkyl group is
larger than a methyl group. Studies toward elucidation of
the reaction mechanism led to a proposed mechanism that
is consistent with all the observations.
a
Isolated yield except entries l and m, where the product was
Carbon-carbon bond cleavage of ketones is widely
utilized to prepare carboxylic acids and derivatives. The
most commonly used method is the Baeyer-Villiger
oxidation,2 which involves treatment of ketones with
peracids, hydrogen peroxides, or other peroxy compounds.
Other methods, such as the haloform reaction3 used
mostly for the cleavage of methyl ketones and the
Haller-Bauer reaction4 for the cleavage of nonenolizable
ketones, are more limited in the scope of substrates. A
general method for the cleavage of aryl methyl or aryl
ethyl ketones to form aromatic carboxylic acids was
recently reported using an excess of KOH in DMF at an
elevated temperature.5 These cleavage methods have a
common feature in that they invariably require a strong
oxidative agent and/or a strong base. Here we report a
novel carbon-carbon bond cleavage reaction of aryl alkyl
ketones to aryl carboxylic esters in a refluxing mixture
of N,N-dimethylformamide dimethyl acetal (DMF‚DMA)
and methanol. Although useful yields of the reaction are
limited to electron-deficient aryl groups, the method
represents a novel, unique way to cleave a carbon-carbon
bond under mild, neutral conditions.
obtained as a nonseparable mixture with the starting material.
Treatment of 3′-nitropropiophenone (1a , Table 1) with
DMF‚DMA under reflux for 16 h yielded methyl 3-nitro-
benzoate (2a ) in 67% yield. Prolonged reaction time (to
40 h) did little to improve the yield. An increase in the
reaction yield (to 87%) was achieved by addition of
methanol as a cosolvent, in agreement with our proposed
reaction mechanism (discussed below). We explored the
scope and limitations of this reaction by treating a variety
of aryl alkyl ketones in a refluxing mixture of DMF‚DMA
and methanol for 16 h. The results are summarized in
Table 1.
The reaction yield is sensitive to the electron density
of the carbonyl group as well as the size of the R group.
As shown in Table 1, with the same alkyl group, the
yields are higher when the carbonyl group is more
electron deficient. Thus, a 4-nitrophenyl gives better
yields than a 3-nitrophenyl (entries c vs a and g vs f),
and a 4-pyridyl gives better yields than a 3-pyridyl
(entries e vs d and i vs h). Useful yields can be obtained
only when the aromatic ring is highly electron-deficient.
In the absence of such electron-deficient aromatic groups,
the reaction yields are very low (entries j-m),6 while the
reaction gives no desired product in the presence of an
electron-donating group (entry n). Another trend of this
reaction is that with the same aromatic ring the yields
are higher when R is bigger than a hydrogen (entries a
and b vs f, c vs g, d vs h, and e vs i).
(1) 2001 Wyeth-Ayerst Chemical Sciences Summer Intern from
Fordham University, Bronx, NY 10458.
(2) For general references, see: March, J . Advanced Organic
Chemistry, 4th ed.; J ohn Wiley & Sons: New York, 1992; pp 1098-
1099 and references therein.
(3) (a) For reviews, see: Chakrabatty, S. K. In Oxidation in Organic
Chemistry, Part C; Trahanovsky, W. S., Ed.; Academic Press: New
York, 1978; pp 348-351. (b) Taschner, M. J .; Shahripour, A. J . Am.
Chem. Soc. 1985, 107, 5570.
To elucidate the mechanism of this novel transforma-
tion, we prepared a possible intermediate, 3-(dimethyl-
amino)-1-(3-nitrophenyl)-2-propen-1-one (3f),7 from 3-nitro-
acetophenone (1f). The resultant 3f was then subjected
(4) (a) Hamlin, K. E.; Weston, A. W. Org. React. 1957, 9, 1. (b)
Kaiser, E. M.; Warner, C. D. Synthesis 1975, 395. (c) Mehta, G.;
Venkateswaran, R. V. Tetrahedron 2000, 56, 1399.
(6) Reaction of 2′-(trifluoromethyl)propiophenone gave an insepa-
rable mixture containing a small quantity of methyl 2-(trifluorometh-
yl)benzoate as evidenced by 1H NMR analysis.
(5) Zˇabjek, A.; Petricˇ, A. Tetrahedron Lett. 1999, 40, 6077.
10.1021/jo016145l CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/05/2002

1704 J . Org. Chem., Vol. 67, No. 5, 2002
Sch em e 1. P r op osed Rea ction Mech a n ism
Notes
to the standard reaction conditions, refluxing in a mix-
ture of DMF‚DMA and methanol for 16 h. Methyl
3-nitrobenzoate (2f) was obtained in 4% yield, suggesting
that 3f is not an obligatory intermediate, but can be
converted to the intermediate in low yield. Further
evidence of the reaction mechanism is provided by the
reaction of 1-(4-nitrophenyl)-3-phenylpropan-1-one (4),8
which has a large alkyl group that enables us to follow
up on the alkyl portion of the molecule. A mixture of
methyl 4-nitrobenzoate (2c, 93% yield) and 3-phenylpro-
panal (5, 62% yield) was obtained from the reaction.
nyl group in 6 is also more favored (over formation of 3)
when the carbonyl group is more electrophilic. As a
result, higher yields of ester 2 were obtained when the
Ar group was more electron deficient. Formation of 6 is
also facilitated by the electron-deficient Ar groups, since
when the Ar groups are electron-rich, starting materials
were recovered. Larger R groups disfavor elimination of
6 to 3 owing to their unfavorable steric interaction with
the dimethylamino group in the planar enone 3. Ad-
ditionally, larger R groups may also facilitate pathway
b from the intermediate 7 owing to relief of the steric
congestion.
In conclusion, we have demonstrated a novel, unique
way to cleave the carbon-carbon bond in aryl alkyl
ketones to furnish esters under mild, neutral conditions.
Useful yields of the reaction are limited to electron-
deficient aryl groups, and the yields are higher when the
alkyl group (CH2R) is larger than a methyl group. The
reaction is under further investigation with more elabo-
rate alkyl groups.
Exp er im en ta l Section
All reactions were conducted under nitrogen atmosphere with
magnetic stirring. All reagents and solvents were commercial
grade. Column chromatography was performed on Baker silica
gel (40 µm). Starting materials (Table 1, entries a, b, and e-l)
were purchased from Aldrich and Lancaster and used without
purification. The starting materials of Table 1, entries c (com-
pound 1c)9 and d (compound 1d )10 were prepared according to
the literature procedure.
Gen er a l P r oced u r e of th e Rea ction . A mixture of the aryl
alkyl ketone 1 (5 mmol) in a mixture of N,N-dimethylformamide
dimethyl acetal (DMF‚DMA) (10 mL) and anhydrous methanol
(2 mL) was refluxed under nitrogen for 16 h. The reaction time
was not optimized. The solvents were removed, and the product
was then purified using flash column chromatography over silica
gel eluting typically with hexanes-ethyl acetate, providing the
ester 2. Yields are given in Table 1. Structural confirmation of
the esters 2 was accomplished by comparison to the authentic
commercially available material.
Based on these results, we propose the reaction mech-
anism shown in Scheme 1. Reaction of the aryl alkyl
ketone 1 (via its enol) with DMF‚DMA generates the first
intermediate 6, which can either eliminate 1 equiv of
methanol to form the dimethylaminoenone 3 or undergo
an addition reaction with methanol to another intermedi-
ate 7. Intermediate 7, which can adopt the cyclic confor-
mation as shown in Scheme 1, can either eliminate
methanol (pathway a) to regenerate 6 or eliminate
enamine 8 (pathway b) to generate ester 2. This mech-
anism is consistent with our observed results. We found
that the yields of the ester 2 were higher when methanol
was used as a cosolvent. This is because excess methanol
helps formation of 7 (vs formation of 3) from 6 in the two
competing pathways. Addition of methanol to the carbo-
Ack n ow led gm en t. We thank Dr. Semiramis Ayral-
Kaloustian for the support of the Summer Intern
Program and helpful discussions on this work. We are
very grateful to Professor Michael J ung (UCLA) for
helpful discussions and suggestions.
J O016145L
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