A direct synthesis of α-(hydroxymethyl) and α-alkyl-vinyl alkyl ketones

Article abstract of DOI:10.1016/j.tetlet.2006.07.093

Reaction of 2,4-diketoesters 3a-c with aqueous formaldehyde using potassium carbonate solution as base affords the corresponding α-methylene-β-hydroxyalkanones 4a-c which provide a route to α,β-unsaturated alkyl ketones 6a-e via coupling of α-acetoxymethy

Full text of DOI:10.1016/j.tetlet.2006.07.093

Tetrahedron Letters 47 (2006) 7077–7079
A direct synthesis of a-(hydroxymethyl) and a-alkyl-vinyl
alkyl ketones
a
b
a,
*
`
Jihene Ben Kra¨ıem, Ta¨ıcir Ben Ayed and Hassen Amri
aLaboratoire de Chimie Organique & Organome´tallique, Faculte´ des Sciences, Campus Universitaire, 2092-Tunis, Tunisia
bInstitut National des Sciences Applique´es et de Technologie, Centre Urbain Nord B.P. 676, 1080 Tunis-cedex, Tunisia
Received 9 March 2006; revised 7 July 2006; accepted 20 July 2006
Available online 14 August 2006
Abstract—Reaction of 2,4-diketoesters 3a–c with aqueous formaldehyde using potassium carbonate solution as base affords the
corresponding a-methylene-b-hydroxyalkanones 4a–c which provide a route to a,b-unsaturated alkyl ketones 6a–e via coupling
of a-acetoxymethyl alkyl vinyl ketone 5a with Grignard reagents in the presence of a catalytic amount of LiCuBr2 at low
temperature.
ꢀ 2006 Elsevier Ltd. All rights reserved.
During the past decade, the preparation of a-hydroxy-
alkyl carbonyl compounds 11–10 has attracted signi-
ficant attention because of their ability to act as
Michael acceptors11,12 (Scheme 1). Furthermore, these
compounds show a range of applications as starting
materials for the preparation of a-methylene-
c-lactones,13 a-methylene-c-lactams14 and cyclo-
pentenones.15
CO,20–22 DBU23 or 3-hydroxyquinuclidine24 as cata-
lysts. However, most of these methods suffer from low
yields or the use of expensive chemicals and there is
no general method which covers the different types of
a-methylene-b-hydroxyalkanones 2. To the best of our
knowledge, a-hydroxyalkyl acrylic ketones 2, where
R = Ph, p-CH3–C6H4, Et, R0 = H have not been
reported in the literature with practical yields.25
Although studies have been reported,16,17 there are only
a few examples of the preparation of a-methylene-
b-hydroxyalkanones 2. According to the literature, the
synthetic methods mainly consist of the alkoxyalkyla-
tion at the a-position of methyl vinyl ketones,18 aldol
condensation,19 Wittig–Horner reaction of phospho-
nates and aqueous formaldehyde under heterogeneous
conditions3 and Baylis–Hilman reactions of aldehydes
with a,b-unsaturated ketones in the presence of DAB-
In connection with our previous studies2 on the develop-
ment of new routes to 2, we report herein a simple and
convenient synthesis of b-hydroxy ketones 4 starting
from 2,4-diketoesters 3 prepared according to the
literature by condensation of ketones with diethyl oxa-
late in the presence of sodium ethoxide in ethanol.26
As shown in Scheme 2, the condensation of aqueous
formaldehyde with the 2,4-diketoesters 3, at room tem-
perature in the absence of any organic solvent gave the
R'
R'
OH
OH
EWG
R
R': H, alkyl, aryl
R': H, alkyl, aryl
R : Me, Et, nPr
O
2
1
EWG : CO2R, CO2NH2, P(O)(OEt)2
Scheme 1.
Keywords: Baylis–Hillman; a-Hydroxmethyl alkyl vinyl ketones; a,b-Unsaturated alkyl ketones.
*
Corresponding author. Tel.: +216 71 872 600; fax: +216 71 885 008; e-mail: hassen.amri@fst.rnu.tn
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.093

7078
J. Ben Kraı¨em et al. / Tetrahedron Letters 47 (2006) 7077–7079
K
O
O
O
O
OH
K2CO3 (6-10M)
HCHO aq.(30%)
r.t.
EtO2C
R
EtO2C
R
O
R
CH2OH
O
3
4 (52-82%)
Scheme 2.
Table 2. a-Alkylated a,b-unsaturated ketones 6a–e
Yield (%)a
Table 1. a-Methylene-b-hydroxyalkanones 4a–c
Product
RMgX (equiv)
Product
R
Yield (%)a
6a
6b
6c
6d
6e
MeMgI (2.5)
EtMgBr (2.2)
n-PrMgCl (2.0)
i-BuMgBr (2.3)
PhCH2MgBr (2.0)
54
68
87
63
80
4a
4b
4c
Ph
52
56
82
p-CH3–C6H5
Et
a Yields refer to the pure isolated products characterized by IR, 1H, 13
NMR and mass spectrometry.
C
a Yields refer to the pure isolated products characterized by IR, 1H, 13
NMR and mass spectrometry.
C
R1
novel a-methylene-b-hydroxyalkanones 4 via the well-
established tandem hydroxymethylation–cyclisation–
elimination mechanism, in acceptable to good yields.
Spectroscopic data27 were in accord with structures 4.
The results are summarized in Table 1.
OAc
R
R
5
O
O
Scheme 4.
When other bases, for example, potassium or sodium
hydroxide were used, the reaction was not reproducible
and only low yields of ketones 4 were obtained. In order
to investigate the potential synthetic utility of a-methyl-
ene-b-hydroxyalkanone 4a, we studied the electrophilic
reactivity of the allylic acetate derivative 5a using
organometallics as nucleophilic reagents. Indeed, the
conjugate addition of dialkyl organocuprates, generated
in situ at low temperature from Grignard reagents in
the presence of a catalytic amount of LiCuBr2, to the
acetate 5a led to the corresponding a,b-unsaturated
alkyl ketones 627 in good yields through tandem reac-
tion28 involving nucleophilic SN20 addition–elimination
(Scheme 3). The results are summarized in Table 2.
References and notes
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In conclusion, a simple and expedient method for the di-
rect synthesis of a-methylene-b-hydroxyalkanones 4a–c
is described which completes the existing routes18–24
for preparation of a-functional alkyl-vinyl ones 2. We
have also demonstrated that allylic acetate 5a can be
easily displaced by organometallic species, at low tem-
perature, to provide the corresponding a,b-unsaturated
phenyl ketones 6a–e. Moreover, the allylic acetate 5
could be used as an electrophilic synthon in the total
synthesis of various natural products such as methyleno-
mycin B29,30 and various analogues31 (Scheme 4). This
work will be the subject of a future report.
OH
R
OAc
Ph
Ac2O, H+
RMgX, LiCuBr2 (cat.)
Et2O, 0 ºC
THF, -78 ºC
Ph
Ph
O
4a
O
O
5a (73%)
6 (54-87%)
Scheme 3.

J. Ben Kraı¨em et al. / Tetrahedron Letters 47 (2006) 7077–7079
7079
1
14. Belaud, C.; Roussakis, C.; Letourneux, Y.; El Alami, N.;
afford ketone 4a. IR mmax neat/cmꢀ1 3300, 1650, 1445: H
NMR (300 MHz, CDCl3): 7.74 (2H, d, J = 7.5 Hz), 7.54
(1H, t, J = 7.35 Hz), 7.45 (2H, t, J = 7.5 Hz), 6.15 (1H, s),
5.81 (1H, s), 4.50 (2H, s), 2.77 (1H, m,); 13C NMR
(75 MHz, CDCl3): 197.9 (C@O), 146.23 (CH2@),
137.2 (@C), 132.4 (CHaromatic), 129.3 (CHaromatic), 128.2
(CHaromatic), 127.3 (Caromatic), 63.0 (CH2); Mass (EI,
70 eV) m/z (%): 51 (35), 77 (89), 105 (100), 116 (13), 144
(9), 161 (96).
´
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Organocuprate addition to allylic acetate 5a: Typical
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procedure: A solution of propylmagnesium chloride
nPrMgCl (2 equiv) was added dropwise over a period of
15 min to a mixture of a-acetoxymethyl phenyl vinyl
ketone 5a (2 mmol) and a 1 M solution of LiCuBr2
(0.15 mL) diluted in dry THF (10 mL) at ꢀ78 ꢁC under
nitrogen. After a few minutes (TLC), the reaction mixture
was quenched with saturated NH4Cl solution (10 mL) then
extracted with ether (3 · 15 mL). The combined organic
layers were dried over MgSO4, filtered and evaporated
under reduced pressure. The crude product was purified by
column chromatography on silica gel (EtOAc/hexane, 2:8)
to afford 2-methylene-1-phenylhexan-1-one 6c. IR mmax
23. Hwu, J. R.; Hakimelahi, G. H.; Chou, C. T. Tetrahedron
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4438–4444.
26. Cox, A. In Comprehensive Organic Chemistry; Barton, D.,
Ollis, W. D., Sutherland, I. O., Eds.; Pergamon Press: New
York, 1969; Vol. 2, p 702.
27. Synthesis of a-methylene-b-hydroxypropanone 4a: To a
magnetically stirred mixture of 2,4-diketoester 3a
(16 mmol) and 30% aqueous formaldehyde (3.5 mL) was
added at room temperature a gelatinous solution of
potassium carbonate (6–10 M, 33 mmol). The heteroge-
neous reaction mixture was stirred for 3 h then treated
with water. The solution was extracted with ether
(3 · 25 mL). The combined organic layers were dried over
anhydrous MgSO4, filtered and evaporated under reduced
pressure. The crude product was purified by column
chromatography on silica gel (EtOAc/hexane, 3:7) to
1
neat/cmꢀ1 1630, 1670, H NMR (300 MHz, CDCl3): 7.78
(2H, d, J = 7.50 Hz), 7.59 (1H, t, J = 7.35 Hz), 7.45 (2H, t,
J = 7.50 Hz), 5.81 (1H, s), 5.56 (1H, s), 2.47 (2H, t,
J = 6.9 Hz), 1.42 (4H, m), 0.92 (3H, t, J = 7.35 Hz);
13C NMR (75 MHz, CDCl3): 198.5 (C@O), 148.5
(CH2@), 137.9 (@C), 132.1 (CHaromatic), 129.5 (CHaromatic),
128.1 (CHaromatic), 125.0 (Caromatic), 32.0 (CH2), 30.3
(CH2), 22.4 (CH2), 13.9 (CH3). Mass (EI, 70 eV) m/z (%):
51 (19), 77(67), 105 (100), 145 (24), 159 (22), 188 (14).
28. Chamakh, A.; M’hirisi, M.; Amri, H. Synth. Commun.
1997, 27, 1157–1163.
29. Mikolajczyk, M.; Grzejszczac, S.; Midura, W.; Zatorski,
A. Phosphorus Sulfur 1983, 18, 175–178.
´
30. Chamakh, A.; M’hirsi, M.; Villieras, J.; Lebreton, J.;
Amri, H. Synthesis 2000, 2, 295–299.
31. Mikolajczyk, M.; Grzejszczac, S.; Lyzwa, P. Tetrahedron
Lett. 1982, 23, 2237–2240.