Stereoselective preparation of 3-alkanoylprop-2-en-1-ol derivatives

Article abstract of DOI:10.1055/s-0028-1087930

3-Alkanoylprop-2-en-1-ol derivatives were prepared stereoselectively by ring-opening reaction of β,γ-epoxyketone with amines. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087930

724
LETTER
Stereoselective Preparation of 3-Alkanoylprop-2-en-1-ol Derivatives
S
ynthesis of 3-Alkanoy
u
lprop-2-en-1
t
-
ol De
s
rivatives umi Sada, Shizue Ueno, Keisuke Asano, Kenichi Nomura, Seijiro Matsubara*
Department of Material Chemistry, Kyoto University, Kyoutodaigaku-katsura, Nishikyo, Kyoto 615-8510, Japan
Fax +81(75)3832459; E-mail: matsubar@orgrxn.mbox.media.kyoto-u.ac.jp
Received 10 November 2008
O
HO
Br
Abstract:: 3-Alkanoylprop-2-en-1-ol derivatives were prepared
stereoselectively by ring-opening reaction of b,g-epoxyketone with
amines.
, Zn
PCC
H
R
R
O
O
O
MCPBA
Key words: epoxide, amine, enone, rearrangement, alcohol
R
R
2
Scheme 2 Preparation of 2-(oxiran-2-yl)-1-alkylethanone 2
The high reactivity of 3-alkanoylprop-2-en-1-ol deriva-
tives 1 as a Michael acceptor was explained by an assis-
tance of oxygen atom at g-position.1 Various
transformations starting from 1 such as furan1a or b,g-di-
hydroxy ketone formation1b have been already reported. A
preparation of the substrate had been performed by Wittig
reaction between benzoylmethylenetriphenyphosphorane
and glycoaldehyde dimer (Scheme 1).2 Although the reac-
tion was proceeded efficiently in the reported literature,
the availability of Wittig reagent, however, will cause a
limitation for this method, so we had tried to develop the
sively. Treatment of 2a with pyridine, imidazole, or
Hünig’s base (i-Pr2NEt) was suffered from low conver-
sion. A use of catalytic amount of DMAP with a stoichio-
metric amount of pyridine or K2CO3 did not give a
satisfactory result (entries 6 and 7). Other epoxides, 2b
and 2c, were also converted into the corresponding E-
enones 1b,c efficiently (entries 9–12) with triethylamine
or DMAP.
more general scheme for the preparation of 3-alkanoyl- Table 1 Reaction of b,g-Epoxy Ketone with Various Basesa
prop-2-en-1-ol.3
CH2Cl2
25 °C, 0.5 h
R
R
+
base
OH
O
THF
80 °C
O
O
O
O
O
1
PPh3
2
+
HO
OH
OH
R
R
O
Entry
R
Base
Recovered Yield
E/Zb
1
2 (%)
of 1 (%)
Scheme 1 Preparation of 3-alkanoylprop-2-en-1-ol (1) by Wittig
reaction
1
2
3
4
5
6
Ph
Ph
Ph
Ph
Ph
Ph
Et3N (1.0)
2a 0
1a 93
1a 0
95:5
–
pyridine (1.0) 2a 90
i-Pr2NEt (1.0) 2a 55
imidazole (1.0) 2a 53
DMAP (1.0) 2a 0
We planned to prepare the series of 3-alkanoylprop-2-en-
1-ol 1 stereoselectively by a ring opening of b,g-epoxy ke-
tone with base. As shown in Scheme 2, a homoallylic al-
cohol, which was prepared by a reaction of aldehyde, allyl
bromide, and zinc,4 was converted into b,g-unsaturated
ketone by PCC. Treatment of the unsaturated ketone with
MCPBA gave the corresponding b,g-epoxy ketone 2. All
steps proceeded in good yields. For example, starting
from benzaldehyde (R = Ph), the corresponding epoxide
2a was obtained in 53% overall yield. Starting from 2, a
ring opening of b,g-epoxy ketone with a base was exam-
ined.5
1a 42
1a 14
1a 82
1a 36
97:3
95:5
98:2
98:2
DMAP (0.2), 2a 43
pyridine (1.0)
7
8
Ph
Ph
DMAP (0.2), 2a 37
K2CO3 (1.0)
1a 37
1a 94
98:2
96:4
Et3N (0.2),
pyridine (1.0)
2a 3
2b 0
As shown in Table 1, 2-(oxiran-2-yl)-1-phenylethanone
(2a, R = Ph) was treated with various amines (entries 1–
5). Among them, triethylamine and N,N-dimethylpyridin-
4-amine (DMAP) gave the satisfactory results. In both
cases, the corresponding E-isomer was obtained exclu-
9
10
11
12
4-F3CC6H4 Et3N (1.0)
1b 82
1b 82
1c 98
1c 51
93:7
4-F3CC6H4 DMAP (1.0) 2b 0
PhCH2CH2 Et3N (1.0) 2c 0
PhCH2CH2 DMAP (1.0) 2c 0
98:2
E only6
94:6
a Compound 2 (0.5 mmol) was treated with base in CH2Cl2 (1.0 mL)
for 0.5 h at 25 °C.
SYNLETT 2009, No. 5, pp 0724–0726
Advanced online publication: 24.02.2009
DOI: 10.1055/s-0028-1087930; Art ID: U11908ST
x
x.
x
x.
2
0
0
9
b The ratio of diastereomers were determined with 1H NMR analysis.
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 3-Alkanoylprop-2-en-1-ol Derivatives
725
MgBr
The ring-opening reaction of 2-(oxiran-2-yl)-1-phenyl-
propan-1-one (3) was also examined as shown in Table 2.
The substrate will give trisubstituted alkene. In this case,
treatment with triethylamine or DMAP at 25 °C did not af-
ford the ring-opening product. Under increased reaction
temperature, the product was obtained in only 5% yield.
The configuration of the product was determined to be Z.7
A use of DBU as a base at 25 °C gave the corresponding
product in 97% yield with the perfect Z-diastereoselectiv-
ity.
O
OH
OH
CeCl3
+
H
Ph
Ph
Ph
5a (50%)
5b (5%)
1) PCC
2) MCPBA
O
OH
O
Ph
Ph
5a
6 (81%)
Ph
base
CH2Cl2
O
OH
Table 2 Reaction of 2-(Oxiran-2-yl)-1-phenylpropan-1-one (3) with
7
Aminesa
base: Et3N
>99%
DMAP
42% (56% recovery)
Me
Me
CH2Cl2
Ph
Ph
Scheme 3 Preparation of 2-(3-methyloxiran-2-yl)-1-phenylethan-
one (6) and its transformation into (E)-4-hydroxy-1-phenylpent-2-en-
1-one (7)
+
base
O
O
O
OH
4
3
Entry Temp Time Base
Yield of 4 E/Zb
(%)
ZnBr
(°C)
(h)
0.5
3
O
O
1) PCC (75%)
–15 °C
THF
2) MCPBA (86%)
1
2
3
4
5
6
25
Et3N (1.0)
0
–
50
Et3N (1.0)
5
Z only
–
CHO
9 (78%)
8
OH
25
0.5
3
DMAP (1.0)
DMAP (1.0)
DBU (1.0)
DBU (1.0)
0
Et3N
O
O
50
5
Z only
Z only
Z only
CH2Cl2, 25 °C
25
0.5
0.5
97
94
OH
11 (96%)
50
O
10
O
O
a Compound 3 (0.5 mmol) was treated with base in CH2Cl2 (1.0 mL)
for 0.5 h at 25 or 50 °C.
Scheme 4 Preparation of (E)-4-hydroxy-1-(4-propionylphenyl)but-
2-en-1-one (11)
b The ratio of diastereomers was determined with 1H NMR analysis.
Preparation of 3-hydroxy-a,b-unsaturated ester was also
studied (Scheme 5). Benzyl 2-(oxiran-2-yl)acetate, which
was prepared from benzyl 3-betenoate and MCPBA, was
treated with amines. While treatment with triethylamine
and DMAP in dichloromethane resulted in a complete re-
covery of starting material, 12 was obtained in the pres-
ence of DBU in 91% yield.
Derivatives of 2-(3-methyloxiran-2-yl)-1-alkylethanone 6
can be prepared starting from aldehyde and crotylmagne-
sium bromide as shown in Scheme 3. In this transforma-
tion, a-selective nucleophilic addition of crotyl-
magnesium was necessary. We chose cerium(III) chloride
mediated reaction developed by Imamoto.8 The exclu-
sively formed a-adduct 5a was converted into b,g-epoxy
ketone 6 in good yield. Treatment of 6 with triethylamine
gave (E)-4-hydroxy-1-phenylpent-2-en-1-one (7) quanti-
tatively (Scheme 3).
CH2Cl2
25 °C
BnO
BnO
+ base
(1.0)
OH
12
O
O
O
As mentioned above, the b,g-epoxy ketone was prepared
from aldehyde via three steps. Because the first step, allyl-
ation of aldehyde, is able to be performed in the presence
of ketone, the transformations to the g-hydroxyenones
were applied to the ketoaldehyde such as ethyl 4-
formylphenyl ketone (8) (Scheme 4). Reaction of the ke-
toaldehyde 8 with allylzinc bromide at –15 °C gave ho-
moallylic alcohol 9 in 78% yield. Treatment of 9 with
PCC and MCPBA sequentially afforded the epoxy dike-
tone 10 in 86% yield. The compound 10 was converted
into g-hydroxyenones containing keto group 11 in 96%
yield.
base: Et3N
<1% (99% recovery)
<1% (99% recovery)
DMAP
Scheme 5 Preparation of (E)-benzyl 4-hydroxybut-2-enoate
The stereoselective formation of 3-alkanoylprop-2-en-1-
ol via ring-opening of the b,g-epoxy carbonyl compounds
can be achieved efficiently by the amine having the appro-
priate basicity. As the substrates 2, 3, and 6 are easily ob-
tained via a three-step transformation from the aldehyde
as shown in Scheme 2, we can solve the problem concern-
ing the availability of the title compound.
Synlett 2009, No. 5, 724–726 © Thieme Stuttgart · New York

726
M. Sada et al.
LETTER
2-(Oxiran-2-yl)-1-phenylethanone (2a)
(E)-4-Hydroxy-1-(4-propionylphenyl)but-2-en-1-one (11)
To a dispersion of zinc dust (70 mmol) in THF (20 mL), allyl bro-
mide (5.0 mmol) was added at 25 °C. After exothermic reaction
started, a mixture of allyl bromide (55 mmol) and benzaldehyde (50
mmol) in THF (50 mL) was added dropwise. The whole was stirred
vigorously for 10 h at 25 °C. After addition of 1 M HCl, the mixture
was extracted with EtOAc–hexane (1:1). The combined organic
phases were dried over Na2SO4 and concentrated in vacuo. The ob-
tained residue was dissolved into CH2Cl2 (70 mL). Then, PCC (65
mmol) was added to the solution in several portions at 0 °C. After
an addition of PCC, the mixture was stirred vigorously at 25 °C for
6 h. The mixture was diluted with CH2Cl2 (100 mL) and passed
through a short silica gel column. The residue was washed with
EtOAc (50 mL). The EtOAc solution was also passed through the
silica gel column. The combined organic solution was dried over
Na2SO4, and concentrated in vacuo. The residue was dissolved into
CH2Cl2 (50 mL). Then, MCPBA (55 mmol) was added to the solu-
tion in several portions at 0 °C. After addition of MCPBA, the
whole was stirred for 10 h at 25 °C. Saturated aq solution of
Na2S2O3 (50 mL) was added to the mixture. The whole was stirred
for 0.5 h, and extracted with EtOAc several times. The combined or-
ganic phases were washed with sat. aq solution of NaHCO3 (3×),
dried over Na2SO4, and concentrated in vacuo. Purification by a
short silica gel column chromatography (hexane–EtOAc, 3:1) gave
epoxy ketone 2a in 53% overall yield.
1H NMR (500 MHz, CDCl3): d = 8.00 (s, 4 H), 7.22 (ddt, J = 20.0,
3.5, 1.2 Hz, 1 H), 7.14 (ddt, J = 20.0, 3.0, 1.2 Hz, 1 H), 4.52–4.45
(m, 2 H), 3,03 (q, J = 6.3 Hz, 2 H), 2.60–2.30 (m, 1 H), 1.2 (t,
J = 6.3, Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): d = 200.4,
189.9, 148.5, 141.0, 140.0, 128.9, 128.3, 123.7, 62.6, 32.6, 8.5 ppm.
(E)-Benzyl 4-Hydroxybut-2-enoate (12)
1H NMR (500 MHz, CDCl3): d = 7.38–7.31 (m, 5 H), 7.09 (dt,
J = 16.0, 4.0 Hz, 1 H), 6.16 (dt, J = 16.0, 2.0 Hz, 1 H), 5.20 (s, 2 H),
4.37–4.34 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl3): d = 166.1,
147.4, 135.9, 128.5, 128.2, 128.1, 119.8, 66.2, 61.9 ppm.
Acknowledgment
This work was supported financially by the Japanese Ministry of
Education, Culture, Sports, Science and Technology.
References and Notes
(1) (a) Greatrex, B. W.; Kimber, M. C.; Taylor, D. K.; Tiekink,
E. R. T. J. Org. Chem. 2003, 68, 4239. (b) Li, D. R.;
Murugan, A.; Falck, J. R. J. Am. Chem. Soc. 2008, 130, 46.
(c) Kato, H. JP 2008214276, 2008.
(2) (a) Avery, T. D.; Taylor, D. K.; Tiekink, E. R. T. J. Org.
Chem. 2000, 65, 5531. (b) Palmer, F. N.; Taylor, D. K.
J. Chem. Soc., Perkin Trans. 1 2000, 1323.
(3) The following patent shows the same type of reaction in
Table 1 without showing diastereoselectivity of the reaction.
See: (a) Kato, H. JP 2008143880, 2008. (b) Kato, H. JP
2008143881, 2008.
(4) (a) Erdik, E. Tetrahedron 1992, 48, 9577. (b) Knochel, P.;
Millot, N.; Rodriguez, A. L.; Tucker, C. E. Org. React. 2001,
58, 417.
(E)-4-Hydroxy-1-phenylbut-2-en-1-one (1a)
To a solution of epoxide 2a (10 mmol) in CH2Cl2 (15 mL), Et3N (11
mmol) was added dropwise at 25 °C. The mixture was stirred for 30
min, and diluted with EtOAc (30 mL) and poured into 1 M HCl aq
(30 mL). The aqueous phase was extracted with EtOAc. The com-
bined organic phases was dried over Na2SO4, and concentrated in
vacuo. Purification by a short silica gel column chromatography
(hexane–EtOAc, 3:1) gave 1a.
1H NMR (400 MHz, CDCl3): d = 8.00–7.90 (m, 2 H), 7.57–7.42 (m,
3 H), 7.23 (dt, J = 15.2, 1.6 Hz, 1 H), 7.13 (dt, J = 15.2, 3.6 Hz, 1
H), 4.48 (br s, 2 H), 2.05 (br s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): d = 190.5, 147.2, 137.8, 133.1, 128.8, 128.7, 123.9, 62.7
ppm.
(5) Smith, J. G. Synthesis 1984, 629.
(6) The reaction was monitored by 1H NMR for 2 h using
CD2Cl2 as solvent. Through the whole reaction, Z-form was
not detected in the product.
(7) From a 1H NMR analysis, 4 was considered to have Z-
configuration. Alkenoic proton was detected at d = 6.34
ppm. See experimental procedure.
(Z)-4-Hydroxy-2-methyl-1-phenylbut-2-en-1-one (4)
1H NMR (500 MHz, CDCl3): d = 8.00–7.90 (m, 2 H), 7.57–7.42 (m,
1 H), 7.42–7.25 (m, 2 H), 6.34 (qt, J = 6.2, 1.2 Hz, 1 H), 4.42 (dq,
J = 6.2, 0.8 Hz. 2 H), 2.35 (br s, 1 H), 1.92 (dt, J = 1.2, 0.8 Hz, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): d = 198.3, 143.7, 137.6, 136.1,
131.6, 129.1, 128.0, 59.9, 12.9 ppm.
(8) (a) Matsukawa, S.; Funabashi, Y.; Imamoto, T. Tetrahedron
Lett. 2003, 44, 1007. (b) Tan, K.-T.; Chng, S.-S.; Cheng,
H.-S.; Loh, T.-P. J. Am. Chem. Soc. 2003, 125, 2958.
(c) Yanagisawa, A.; Habaue, S.; Yasue, K.; Yamamoto, H.
J. Am. Chem. Soc. 1994, 116, 6130.
Synlett 2009, No. 5, 724–726 © Thieme Stuttgart · New York

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