Direct conversion of carboxylic esters into ketones using organoaluminum complexes

Full text of DOI:10.1021/jo981643o

7590
J . Org. Chem. 1998, 63, 7590-7591
Ta ble 1. Con ver sion of Meth yl Ben zoa te to
Acetop h en on e Usin g Me3Al-Dia m in e Com p lexes
Dir ect Con ver sion of Ca r boxylic Ester s in to
Keton es Usin g Or ga n oa lu m in u m Com p lexes
Eun-Ae Chung, Chang-Woo Cho, and Kyo Han Ahn*
Department of Chemistry and Center for Biofunctional
Molecules, POSTECH, San 31 Hyoja-dong,
Pohang 790-784, Republic of Korea
molar equiv
entry diamine Me3Al rxn time temp (°C) % conversiona
Received August 17, 1998
1
2
3
4
5
6
1.1
2.2
1.1
1.1
1.1
0
1.2
2.2
2.2
3.0
3.0
1.2
2 h
2 h
13 h
1 h
2 d
18 h
reflux
reflux
reflux
reflux
rt
43
77
83
98
0
The conversion of carboxylic esters into the corresponding
ketones is a fundamental organic reaction. Direct conver-
sion of esters to ketones using nucleophiles, however, is
difficult to achieve because ketones are more reactive toward
nucleophiles than the starting esters, and in most cases over-
reacted products such as tertiary alcohols and/or reduced
products are obtained.1 An organoaluminum reducing
agent, DIBALH, is widely used for the direct conversion of
esters into the corresponding aldehydes.2 In this case, a
tetrahedral alkoxyaluminum intermediate is stable under
the reaction conditions and provides the mono-addition
product upon hydrolyzing the reaction mixture. However,
a similar process with carbon nucleophiles has been rarely
reported. Therefore, indirect approaches are usually em-
ployed for the transformation. For example, the Weinreb’s
amide is the preferred intermediate for the delivery of
nucleophiles to give ketones selectively.3 In this case, the
addition product is stabilized by a five-membered metal
chelate during the reaction. We wish to report our findings
that the direct conversion of esters into ketones, without the
formation of the over-addition products, can be realized by
organoaluminum complexes generated from a trialkylalu-
minum and a diamine. The system is unique in that
aldehydes and ketones survive under the reaction conditions.
We have found that the reaction of methyl benzoate with
an equimolar mixture of trimethylaluminum and N,N′-
dimethylethylenediamine (DMEDA) in refluxing toluene
followed by an aqueous workup produces only acetophenone.
The conversion requires both DMEDA and Me3Al. Variation
of molar equivalents of DMEDA and Me3Al indicates that
the reaction is stoichiometric with regard to DMEDA.
Although reasonable conversion (83%) was observed with
two equiv of Me3Al, near-quantitative conversion was guar-
anteed when three equiv was used. The results are sum-
marized in Table 1. Other organoaluminum reagents
such as Et3Al can be equally used to give the corresponding
ethyl ketones. The reaction requires the refluxing temper-
ature of toluene and does not proceed at all at room
temperature. Also, the reaction does not proceed in solvents
such as THF or CHCl3. Under the established conditions,
various substrates have been tested and some of the results
are summarized in Table 2.4 Particularly notable is that
reflux
0
a
Determined by GC analyses.
acetophenone and even benzaldehyde survived under the
reaction conditions and recovered after aqueous workup. We
have carried out several experiments depicted in eqs 1-4
to get a reasonable mechanistic picture for the transforma-
tion.5 We observed that the conversion proceeded through
transamidation and the reaction intermediate can be iso-
lated. This is not an unexpected result since similar
transamidation using 1,2-diaminoethane- or 1,2-amino
alcohol-trialkylaluminum complexes has been utilized in
the literature.6 When the intermediate amide, N-methyl-
2-(N-methylamino)ethylbenzamide,7 was treated with 1.1
(1) Kikkawa, I.; Yorifuji, T. Synthesis 1980, 877-880.
(2) (a) Zakharkin, L. I.; Khorlina, I. M. Tetrahedron Lett. 1962, 619-
620. (b) Winterfeldt, E. Synthesis, 1975, 617-630. (c) Chandrasekhar, S.;
Kumar, M. S.; Muralidhar, B. Tetrahedron Lett. 1998, 39, 909-910.
(3) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-3818.
(b) For other examples, see: Larock, R. C. Comprehensive Organic Trans-
formations; VCH: New York, 1989; pp 695-697.
(5) We have carried out 27Al NMR study on the aluminum complexes.
The NMR spectra of 1:1 complex of Me3Al and DMEDA in toluene exhibited
a singlet downfield (177.1 ppm) compared to that of Me3Al (154.0 ppm)
(relative to Al(OH)3 in D2O). We suspect that it may exist as dimeric or
oligomeric complexes, as usually observed with many organoaluminum
complexes, see: (a) Eisch, J . J . Comprehensive Organometallic Chemistry
I; Willinson, G., Ed.; Pergamon: Oxford, 1995; Vol. 1, pp 555-682. (b)
Robinson, G. H. Coordination Chemistry of Aluminum; VCH: New York,
1993. (c) Smith, J . D. Organometallic Compounds of Aluminum, Gallium,
Indium and Thallium; McKillop, A., Smith, J . D., Worrall, I. J ., Eds.;
Chapman and Hall: New York, 1985.
(6) (a) Neef, G.; Eder, U.; Sauer, G. J . Org. Chem. 1981, 46, 2824-2826.
(b) Ahn, K. H.; Cho, C.-W.; Baek, H.-H.; Park, J .; Lee, S. J . Org. Chem.
1996, 61, 4937-4943.
(7) Prepared from DMEDA by the following sequence: i) 1.0 equiv of
TsCl, Py, 0 °C, CH2Cl2, 53%; (ii) PhCOCl, Et3N, 0 °C, CH2Cl2, 96%; (iii) Na,
naphthalene, 25 °C, DME, 20%.
(4) A representative procedure: To a toluene (6.0 mL) solution of N,N ′-
dimethylethylenediamine (0.14 mL. 1.32 mmol) at 0 °C under an argon
atmosphere was added dropwise trimethylaluminum (1.86 mL, 2.0 M in
toluene). The reaction mixture was stirred at room temperature for 1 h
before adding methyl 3-phenylpropionate (0.20 mL, 1.2 mmol). The resulting
mixture was heated to reflux until the reaction was complete judged from
TLC analysis (1 h). The reaction mixture was cooled to room temperature
and quenched with 1 N aqueous HCl solution (or 20% aqueous solution of
Rochelle salt). Extractive workup with ethyl acetate and chromatography
through
a short-pad of SiO2 (eluent: 10% ether in hexanes) afforded
4-phenyl-2-butanone (135 mg, 76% yield).
10.1021/jo981643o CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/01/1998

Communications
J . Org. Chem., Vol. 63, No. 22, 1998 7591
Ta ble 2. Con ver sion of Va r iou s Ester s to Keton es Usin g
Sch em e 1
Me3Al-Dia m in e Com p lexes
lecular transfer of the Me-nucleophile from the corresponding
alkoxyaluminum group must be less favorable compared to
the case of aluminum amide group. This result indicates
that the intramolecular transfer of the nucleophile is the
rate-determining step. The intramolecular transfer of the
Me-nucleophile to the carbonyl group activated by Lewis-
acidic Me3Al and stabilization of the subsequent addition
intermediate as the chelated aluminum species would
explain the occurrence of the rather difficult transformation
of the intermediate amide to the corresponding ketone. The
addition intermediate, a seven-membered aminal compound,
may have additional coordination of Me3Al and thus overall
3 equiv of trialkylaluminum are necessary for the fast
reaction. On the basis of this mechanism, we could explain
the complete chemoselectivity observed toward aldehyde and
ketone. In both cases, the addition of DMEDA to the
carbonyl group would provide an aluminum-chelated tetra-
hedral intermediate that is inert toward the subsequent
nucleophilic attack. Upon hydrolysis, the starting material
is readily regenerated. Carboxylic esters of secondary and
tertiary alcohols are readily converted to the ketones. The
conversion was near-quantitative for the substrates that do
not have multiple Lewis-basic atoms.10 For those substrates
that contain Lewis-basic atoms such as THP-ether, the
transamidation intermediates remained as the major com-
ponent, resulting in the lower conversion to the correspond-
ing ketones.
equiv of Me3Al, a mixture of acetophenone and the starting
material was obtained. When 2.1 equiv of Me3Al was used,
a complete conversion was observed. Thus, activation of the
carbonyl oxygen by Lewis-acidic aluminum species seems
to be required for the nucleophilic attack. No change was
observed when a simple amide, N,N-diethylbenzamide, was
treated with a 3:1 complex of Me3Al and DMEDA. These
results indicate that the amino group of the intermediate
plays an important role for the subsequent nucleophilic
attack. Based on these experiments, we could draw a
possible reaction pathway as shown in Scheme 1.8 Between
the two pathways, intermolecular attack of “Me”-nucleophile
vs intramolecular attack, the latter is believed to be the
preferred route because N-methoxy-N-methylbenzamide,
which would proceed through the intermolecular version if
it were the case, gave less than 10% of acetophenone even
after refluxing for 5 h (eq 4). When 2-(N-methylamino)-
ethanol was used instead of DMEDA, the same transforma-
tion occurred but with a much slower rate.9 The intramo-
In summary, a direct and selective conversion of esters
into ketones that is a fundamental reaction but difficult to
achieve is now possible through organoaluminum-diamine
complexes. Aldehydes and ketones survive under the reac-
tion conditions. A mechanistic study established that the
conversion proceeds through transamidation and subsequent
intramolecular nucleophilic attack mediated by organoalu-
minum complexes.
Ack n ow led gm en t . This work was supported by the
CBM center and Basic Science Research Institute Program
(BSRI-98-3437), Ministry of Education, Korea.
(8) The depicted structures of organoaluminum intermediates are merely
based on the stoichiometry.
(9) The transamidation product, N-(hydroxyethyl)-N-methylbenzamide,
was slowly, but not completely, converted to the acetophenone (40%
conversion after 5 h).
J O981643O
(10) The moderate to good yields shown in the table is due to the loss
occurred during the isolation of volatile products.