Stereoselective synthesis of β,γ-unsaturated ketones by acid-mediated Julia-type transformation from 2-(1-hydroxyalkyl)-1- alkylcyclopropanols

Article abstract of DOI:10.1055/s-2008-1067077

An efficient transformation of 2-(1-hydroxyalkyl)-1-alkylcyclopropanols, obtained from α,β-unsaturated ketones, to β,γ-unsaturated ketones was achieved by trifluoroacetic acid (TFA)-mediated reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067077

1412
LETTER
Stereoselective Synthesis of b,g-Unsaturated Ketones by Acid-Mediated
Julia-Type Transformation from 2-(1-Hydroxyalkyl)-1-alkylcyclopropanols
Stereoselective
Sy
e
nthesis of
b
n
,
g
-Unsatura
t
i
edKet
cones hi Nomura, Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University Kyoutodaigaku-katsura,
Nishikyo-ku, Kyoto 615-8510, Japan
E-mail: matsubar@orgrxn.mbox.media.kyoto-u.ac.jp
Received 11 March 2008
Table 1 Acid-Mediated Transformation of 1a into 2a
Abstract: An efficient transformation of 2-(1-hydroxyalkyl)-1-
HO
OH
O
alkylcyclopropanols, obtained from a,b-unsaturated ketones, to
b,g-unsaturated ketones was achieved by trifluoroacetic acid
(TFA)-mediated reaction.
acid
CH2Cl2
Ph
Ph
1a
2a
Key words: b,g-unsaturated ketone, methylene insertion, cyclopro-
panol, carbocation, stereoselective
Entry
Acid
Time
(h)
Temp
(°C)
Yield
(%)b
E/Zc
(equiv)a
1
2
3
4
5
6
TFA (0.2)
TsOH (0.2)
TfOH (0.2)
TFA (1.0)
TFA (2.0)
TFA (5.0)
24
6
r.t.
r.t.
r.t.
r.t.
r.t.
0
67
89
76
90
90
90
75:25
68:32
62:38
88:12
92:8
In 1960, Julia reported acid-catalyzed isomerization of
(1-hydroxyalkyl)cyclopropanes to (E)-homoallylic alco-
hols.1 This reaction has been studied intensively and ap-
plied for various natural product synthesis.2,3 When it was
applied to 2-(1-hydroxyalkyl)-1-alkylcyclopropanols as
starting materials, b,g-unsaturated ketones were obtained
via carbocation intermediate (Scheme 1).4,5 This transfor-
mation, however, has not been studied well, because the
starting materials are difficult to obtain. We had reported
stereoselective and stereospecific cyclopropanations of
a,b-epoxyketones with bis(iodozincio)methane to give
2-(1-hydroxyalkyl)-1-alkylcyclopropanols.6 With these
cyclopropane derivatives, we studied the transformation
into b,g-unsaturated ketones.
6
24
24
0.5
95:5
a TFA: trifluoroacetic acid, TsOH: p-toluenesulfonic acid, TfOH tri-
fluoromethanesulfonic acid.
b Yield was determined by 1H NMR using bromoform as internal stan-
dard.
c The E/Z ratio was determined by 1H NMR analysis.
–78 °C, however, improved the yield (entry 2). Trisubsti-
tuted alkene 2d was obtained with high diastereoselectiv-
ity from 1d (entry 4). From bicyclic compound 1f, ring-
expanded (E)-cycloalkene 2f was obtained in excellent
yield (entry 6). In the case of a primary alcohol, such as
HO
R1
OH
O
HO
R1
OH2
R2
+ H+
– H+
R2
R2
R1
Scheme
1
Julia-type transformation of 2-(1-hydroxyalkyl)-1- 1g, this acid-mediated transformation did not proceed ef-
alkylcyclopropanol into (E)-b,g-unsaturated ketone
ficiently because of the lack of stability of the primary cat-
ion intermediate (entry 7). Treatment of 1g with mesyl
chloride and pyridine,8 however, gave the corresponding
b,g-unsaturated ketone 2g in good yield (Scheme 2).
As shown in Table 1, treatment of 2-(1-hydroxyethyl)-1-
phenylcyclopropanol (1a) with a catalytic amount of var-
ious acids resulted in moderate E/Z selectivity (entries 1–
3). Among them, TFA gave the best diastereoselectivity.
Increasing the amount of TFA improved the yield and
diastereoselectivity (entries 4 and 5). We found that treat-
ment with five equivalents of TFA gave the desired b,g-
unsaturated ketone with high diastereoselectivity (entry
6).7
These substrates, 2-(1-hydroxyalkyl)-1-alkylcyclopro-
panols, are available from a,b-epoxyketones with bis(io-
dozincio)methane6 in one step; a,b-epoxyketones can
easily be prepared from a,b-unsaturated ketones with ba-
HO
O
R2
MsCl (1.2 equiv)
R1
OH
R1
pyridine, CH2Cl2
r.t., 3 h
Other examples are shown in Table 2. Although a reaction
of tertiary alcohol 1b at 0 °C gave the desired product 2b
in 70%, it proceeded sluggishly (entry 1). The reaction at
R2
1
2
R1 = Ph,
R2 = H; 2g 86%
R
R
R
R
1 = Ph,
2 = Me; 2h 93%
2 = H; 2i 85%
1 = n-Pent,
SYNLETT 2008, No. 9, pp 1412–1414
Advanced online publication: 07.05.2008
DOI: 10.1055/s-2008-1067077; Art ID: U01808ST
x
x.
x
x.
2
0
0
8
Scheme 2 Formation of b,g-unsaturated ketones via mesylate elimi-
nation
© Georg Thieme Verlag Stuttgart · New York

LETTER
Stereoselective Synthesis of b,g-Unsaturated Ketones
1413
General Procedure for the Transformation into b,g-Unsaturat-
ed Ketone
Table 2 Examples of the Transformation of 2-(1-Hydroxyalkyl)-1-
alkylcyclopropanols into (E)-b,g-Unsaturated Ketones
To a solution of 2-(1-hydroxyalkyl)-1-alkylcyclopropanol (0.5
mmol) in CH2Cl2 (2 mL), TFA (2.5 mmol) was added at 0 °C. The
mixture was stirred at 0 °C for 30 min, then the solvent was removed
under reduced pressure. The residue was purified by SiO2 column
chromatography (eluting with hexane–EtOAc) to give the corre-
sponding b,g-unsaturated ketone.
HO
OH
O
R2
TFA (5.0 equiv)
R3
R1
R3
R1
CH2Cl2
R2
0 °C, 30 min
Entry Substrate
Product
Yield (%) E/Za
cis-2-(1-Hydroxyethyl)-2-methyl-1-phenylcyclopropanol (1d)
1H NMR (500 MHz, C6D6): d = 7.29–7.26 (m, 2 H), 7.18–7.14 (m,
2 H), 7.10–7.07 (m, 1 H), 4.03 (q, J = 7.0 Hz, 1 H), 2.73 (br s, 1 H),
2.62 (br s, 1 H), 1.29 (d, J = 7.0 Hz, 3 H), 0.83 (d, J = 5.5 Hz, 1 H),
0.80 (d, J = 5.5 Hz, 1 H), 0.70 (s, 3 H). 13C NMR (125 MHz, C6D6):
d = 141.2, 128.7, 128.3, 127.4, 70.6, 65.6, 32.0, 22.3, 19.6, 14.9.
HRMS: m/z calcd for C12H16O2: 192.1150; found: 192.1146.
O
HO
OH
1
70
Ph
Ph
1b
2b
2b
>99
HO
OH
O
3
4
96
95
E only
E only
(E)-3-Methyl-1-phenyl-3-penten-1-one (2d)
Ph
Ph
1H NMR (500 MHz, CDCl3): d = 7.99–7.97 (m, 2 H), 7.57–7.53 (m,
1 H), 7.47–7.43 (m, 2 H), 5.39 (qqt, J = 7.0, 1.5, 1.5 Hz, 1 H), 3.47
(t, J = 1.0 Hz, 2 H), 1.69 (dt, J = 1.0, 1.0 Hz, 3 H), 1.64 (dtq, J = 7.0,
1.5, 1.5 Hz, 3 H). 13C NMR (125 MHz, CDCl3): d = 198.8, 136.9,
132.9, 130.0, 128.5, 128.3, 123.6, 49.2, 16.2, 13.6. HRMS: m/z
calcd for C12H14O: 174.1045; found: 174.1042.
2c
1c
HO
OH
O
Ph
Ph
2d
1d
(E)-3-Cyclohexadecen-1-one (2f)
1H NMR (500 MHz, CDCl3): d = 5.58–5.47 (m, 2 H), 3.03 (d,
J = 6.5 Hz, 2 H), 2.49 (t, J = 7.0 Hz, 2 H), 2.09 (dt, J = 6.5, 6.0 Hz,
2 H), 1.59 (tt, J = 7.0, 7.0 Hz, 2 H), 1.42–1.21 (m, 18 H). 13C NMR
(125 MHz, CDCl3): d = 210.4, 135.6, 123.2, 47.7, 40.9, 32.1, 28.2,
27.4, 27.2, 27.1, 26.9, 26.5, 26.2, 26.1, 25.6, 22.3. HRMS: m/z calcd
for C16H28O: 236.2140; found: 236.2136.
OH
OH
5
86
O
2e
1e
OH
O
HO
6
>99
35d
E only
1-Phenyl-3-buten-1-one (2g)
16
15
To a solution of 2-hydroxymethyl-1-phenylcyclopropanol (1g, 0.5
mmol) in CH2Cl2 (2 mL), pyridine (2 mmol), and MsCl (0.6 mmol)
was added at r.t. The mixture was stirred at r.t. for 3 h, then sat. aq
solution of NaHCO3 was added. The organic layer was extracted
with EtOAc, and the combined organic layers were dried over
Na2SO4. The solvent was removed under reduced pressure, and the
residue was purified by SiO2 column chromatography eluting with
hexane and EtOAc to give 1-phenyl-3-buten-1-one (2g, 86%, 0.43
mmol).
2f
1f
O
HO
7c
Ph
OH
Ph
2g
1g
a Stereochemistry was determined by NOE analysis.
b Reaction carries out at –78 °C.
c Reaction carried out at r.t. for 24 h.
d Corresponding a,b-unsaturated ketone was also obtained in 25%.
References and Notes
(1) (a) Julia, M.; Julia, S.; Guegan, R. Bull. Soc. Chim. Fr. 1960,
1072. (b) Julia, M.; Julia, S.; Tchen, S.-Y. Bull. Soc. Chim.
Fr. 1961, 1849.
(2) For examples, see: (a) Sakaguchi, K.; Fujita, M.; Ohfune, Y.
Tetrahedron Lett. 1998, 39, 4313. (b) Sakaguchi, K.;
Higashino, M.; Ohfune, Y. Tetrahedron 2003, 59, 6647.
(c) Honda, M.; Yamamoto, Y.; Tsuchida, H.; Segi, M.;
Nakajima, T. Tetrahedron Lett. 2005, 46, 6465. (d) Honda,
M.; Mita, T.; Nishizawa, T.; Sano, T.; Segi, M.; Nakajima,
T. Tetrahedron Lett. 2006, 47, 5751.
(3) (a) Wilson, S. R.; Davey, A. E.; Guazzaroni, M. E. J. Org.
Chem. 1992, 57, 2007. (b) Singh, C.; Pandey, S.; Saxena,
G.; Srivastava, N.; Sharma, M. J. Org. Chem. 2006, 71,
9057.
(4) (a) Sato, T.; Kikuchi, T.; Sootome, N.; Murayama, E.
Tetrahedron Lett. 1985, 26, 2205. (b) Sato, T.; Kikuchi, T.;
Tsujita, H.; Kaetsu, A.; Sootome, N.; Nishida, K.;
Tachibana, K.; Murayama, E. Tetrahedron 1991, 47, 3281.
(5) Toratsu, C.; Fujii, T.; Suzuki, T.; Takai, K. Angew. Chem.
Int. Ed. 2000, 39, 2725.
sic hydroperoxide. So the net transformation can be re-
garded as methylene insertion between a carbonyl group
and an alkenyl group of a,b-unsaturated ketone
(Scheme 3).
In conclusion, we showed the stepwise transformation of
a,b-unsaturated ketones to (E)-b,g-unsaturated ketones
via cyclopropanation. Further applications for organic
synthesis, especially natural product synthesis, are being
studied in our laboratory.
1) H2O2
NaOH
O
HO
OH
O
TFA
CH2
R2
R1
R2
R1
R2
2) CH2(ZnI)2
R1
methylene insertion
Scheme 3 The entire transformation
Synlett 2008, No. 9, 1412–1414 © Thieme Stuttgart · New York

1414
K. Nomura, S. Matsubara
LETTER
(6) Nomura, K.; Oshima, K.; Matsubara, S. Angew. Chem. Int.
Ed. 2005, 44, 5860.
(7) Treatment of diastereomixture of 2a with 5 equiv of TFA at
r.t. for 6 h did not change the E/Z ratio. An addition of 1
equiv of H2O to this system did not also change the ratio.
These experiments mean that the diastereoselectivity does
not come from isomerization of the initial product.
(8) Grob, C. A.; Baumann, W. Helv. Chim. Acta 1955, 38, 594.
Synlett 2008, No. 9, 1412–1414 © Thieme Stuttgart · New York

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