A practical preparation of 2-hydroxymethyl-2-cyclopenten-1-one by Morita-Baylis-Hillman reaction

Article abstract of DOI:10.1055/s-2005-916030

Tributylphosphine or dimethylphenylphosphine (1-5 mol%) catalyzed the Morita-Baylis-Hillman reaction of 2-cyclo-penten-1-one (1) with 1.2 equivalents of formalin proceeded nicely to give 2-hydroxymethyl-2-cyclopenten-1-one (2) within a short period and in

Full text of DOI:10.1055/s-2005-916030

PAPER
3035
A Practical Preparation of 2-Hydroxymethyl-2-cyclopenten-1-one by
Morita–Baylis–Hillman Reaction
M
orita–Baylis–Hil
i
lma
n
R
s
eaction anaka Ito,* Yosuke Takenaka, Shouhei Fukunishi, Kazuo Iguchi*
School of Life Science, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Fax +81(426)767282; E-mail: itohisa@ls.toyaku.ac.jp; E-mail: onocerin@ls.toyaku.ac.jp
Received 9 May 2005; revised 15 June 2005
action; however a hindered tertiary amine like 1,4-diaza-
bicyclo[2.2.2]octane (DABCO) has been most commonly
used. Among them, tributylphosphine has been focused
on as the catalyst because of its high reactivity and neutral
Abstract: Tributylphosphine or dimethylphenylphosphine (1–5
mol%) catalyzed the Morita–Baylis–Hillman reaction of 2-cyclo-
penten-1-one (1) with 1.2 equivalents of formalin proceeded nicely
to give 2-hydroxymethyl-2-cyclopenten-1-one (2) within a short pe-
riod and in an excellent yield. The efficiency of the reaction (yield property.5
and time) was strongly dependent on the solvent and the best result
The direct approach for the synthesis of compound 2
was obtained in the case of an aqueous MeOH–CHCl3 solvent sys-
tem.
through Morita–Baylis–Hillman reaction has been exam-
ined by several groups.6 Although compound 2 was ob-
tained in satisfactory yield, these reaction conditions
require a long reaction time, excess of formalin, and/or
exact stoichiometric amount of catalyst. In the case of im-
idazole-catalyzed reaction, 17 days were required to ob-
tain compound 2 in 86% yield.6b Very recently, the
N,N,N¢,N¢-tetramethyl-1,3-propanediamine-catalyzed
preparative method of compound 2 was reported, but 50
mol% of catalyst, 5 equivalents of formalin and long reac-
tion time (72 h) were required to obtain the satisfactory
yield (56%).6c Uskokovic et al. reported the tributylphos-
phine-catalyzed Morita–Baylis–Hillman reaction of 2-cy-
clopenten-1-one (1) with formalin for the synthesis of
vitamin D3 metabolites in 1996, but the reaction condi-
tions and yield of compound 2 were not mentioned.1d Now
we report herein a practical preparative method for com-
pound 2 by phosphine-catalyzed Morita–Baylis–Hillman
reaction.
Key words: addition reactions, carbocycles, catalysis, enones,
phosphorus
2-Hydroxymethyl-2-cyclopenten-1-one (2) is a useful
building block for the synthesis of naturally occurring and
biologically active compounds which contain a polyfunc-
tionalized cyclopentane ring in the structure.1 One of the
most common synthetic methods for compound 2 was re-
ported by Smith et al.2 This procedure requires 4 steps for
the synthesis of compound 2 from commercially available
2-cyclopenten-1-one (1). As a part of our program fo-
cused on the synthesis of marine prostanoids containing a
cyclopentane ring3 the development of a practical and ef-
ficient preparative method for 2-hydroxymethyl-2-cyclo-
penten-1-one (2) was required (Scheme 1).
O
O
37% HCHO in H2O
phosphine catalyst
The results are shown in Table 1. At first, tributylphos-
phine was used as a catalyst. The reaction proceeded in
THF or dioxane at room temperature in the presence of 10
mol% of catalyst to give compound 2 in 60% and 58%
yields, respectively (entries 1 and 2). In both cases, the re-
action did not complete within 55 hours and a significant
amount of dimer of 1 was also obtained. The reaction was
dramatically accelerated by the use of MeOH as solvent
and was completed within 30 minutes along with a small
amount of by-products (entry 3). In the case of CHCl3–
water biphasic system, the reaction was shown to be faster
than that in THF and dioxane and compound 2 was ob-
tained in 81% yield (entry 4). Therefore, a MeOH–CHCl3
solvent system was examined. In the presence of 10 mol%
of tributylphosphine, the adduct 2 was obtained in 97%
yield (entry 5). The reaction was complete within 30 min-
utes and almost no by-product was observed. A decreased
amount of catalyst could be used in this solvent system
and use of 5 mol% of catalyst was enough for the reaction
and compound 2 was obtained within 2.5 hours in 96%
yield (entry 7). Other phosphine catalysts were also exam-
ined. Dimethylphenylphosphine also worked nicely and
OH
solvent
1
2
Scheme 1
The Morita–Baylis–Hillman reaction is one of the most
useful reactions for the construction of a-methylene-b-hy-
droxycarbonyl compounds through the addition of an un-
saturated carbonyl group to aldehyde in the presence of a
catalytic amount of tertiary amine or trialkylphosphine.4
Although this reaction has been applied to the construc-
tion of many building blocks with the aim of synthesizing
natural and/or biologically active compounds, there are
some problems (yield and/or reaction time). Recently, a
number of modified reaction conditions have been report-
ed to improve the yield and long reaction time. Many
bases have been employed for the acceleration of the re-
SYNTHESIS 2005, No. 18, pp 3035–3038
x
x.
x
x
.
2
0
0
5
Advanced online publication: 06.10.2005
DOI: 10.1055/s-2005-916030; Art ID: F08005SS
© Georg Thieme Verlag Stuttgart · New York

3036
H. Ito et al.
PAPER
O
O
O
O
O
O
the product 2 was obtained in 97% yield within one hour
(entry 12). This case also showed the best result by the use
of the MeOH–CHCl3 solvent system. The amount of cat-
alyst could be decreased to 1 mol% (entry 13). Although
the reaction proceeded to give compound 2, the reaction
rate was significantly slower in the case of methyldiphe-
nylphosphine as a catalyst (entries 14 and 15). In all cases,
the use of 1.2 equivalents of formalin was enough to give
compound 2 in a satisfactory yield.
37% HCHO in H2O
5 mol% phosphine catalyst
OH
OH
OH
MeOH–CHCl3, r.t., 2 h
Bu3P: 82%
Me2PhP: 80%
3
5
7
4
6
8
37% HCHO in H2O
5 mol% Me2PhP
MeOH–CHCl3, r.t., 6 h
72%
Table 1 Preparation of 2 by Phosphine-Catalyzed Morita–Baylis–
Hillman Reaction
37% HCHO in H2O
5 mol% Me2PhP
MeOH–CHCl3, r.t., 4 h
75%
Entry Catalysta
Solventb
Temp Time Yield
(°C)
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
(h)
55
55
(%)c
O
O
1
2
Bu3P (10)
Bu3P (10)
Bu3P (10)
Bu3P (10)
Bu3P (10)
Bu3P (5)
THF
60
37% HCHO in H2O
5 mol% Me2PhP
OH
dioxane
58
MeOH–CHCl3, r.t., 24 h
71%
3
MeOH
0.5 74
9
10
4
CHCl3
2
81
Scheme 2
5
MeOH–CHCl3
MeOH–CHCl3
MeOH–CHCl3
MeOH–CHCl3
MeOH
0.5 97
0.5 88
2.5 96
2.5 89
0.5 84
Table 2 Morita–Baylis–Hillman Reaction of 2-Cyclopenten-1-one
(2) with Various Aldehydes
6
7
Bu3P (5)
O
O
OH
RCHO (11a–d)
5 mol% Me2PhP
8
Bu3P (5)
R
MeOH–CHCl3, r.t.
9
Me2PhP (5)
Me2PhP (5)
Me2PhP (5)
Me2PhP (5)
Me2PhP (1)
MePh2P (10)
MePh2P (5)
r.t.
r.t.
0
1
12a (R = phenyl)
12b (R = 2-phenylethyl)
12c (R = cyclohexyl)
12d (R = 2-furanyl)
10
11
12
13
14
15
CHCl3
24
20
97
97
80
90
67
MeOH–CHCl3
MeOH–CHCl3
MeOH–CHCl3
MeOH–CHCl3
MeOH–CHCl3
3
1
Entry Aldehyde
Time (h) Yield (%)
r.t.
r.t.
0
1
2
3
4
benzaldehyde (11a)
24
23
22
21
76
98
70
76
24
24
21
3-phenylpropionaldehyde (11b)
cyclohexanecarboxaldehyde (11c)
furfural (11d)
r.t.
a Numbers in parentheses are the mol% of the catalyst.
b All solvent systems contained water derived from 37% formalin.
c Isolated yield.
Melting points were measured on a Yazawa YB-1 apparatus. 1H
and 13C NMR spectra were measured on a Bruker AV-300 (1H; 300
MHz, 13C; 75 MHz) and the chemical shifts are given in ppm using
CHCl3 (7.26 ppm) in CDCl3 for 1H NMR and CDCl3 (77.0 ppm) for
13C NMR as an internal standard, respectively. IR spectra were tak-
en with a Perkin-Elmer PARAGON 1000 FT-IR and only notewor-
thy absorptions are listed. Mass spectra were measured on a
Micromass LCT. Materials and solvents were obtained from com-
mercial suppliers and were used without further purification. Meth-
yl substituted 2-cyclohexen-1-one derivatives were prepared
according to the literature procedure.8 The reactions were carried
out under an Ar atmosphere. Column chromatography was per-
formed on silica gel 60 (70–230 mesh).
2-Hydroxymethyl-2-cyclohexen-1-one (4) is also a useful
building block for the synthesis of biologically active
compounds. The approaches for the synthesis of com-
pound 4 by Morita–Baylis–Hillman reaction have been
reported.7 Morita–Baylis–Hillman reactions of 2-cyclo-
hexen-1-one (3) and related compounds (5, 7, and 9) with
formalin were also examined by employing our developed
conditions and hydroxymethylated compounds were ob-
tained in good yields (Scheme 2).
We also examined the Morita–Baylis–Hillman reaction of
2-cyclopenten-1-one with various aldehydes under the
above-mentioned conditions, which were optimized for
the preparation of 2. The results are shown in Table 2.
2-Hydroxymethyl-2-cyclopenten-1-one (2); Typical Procedure
To a solution of 2-cyclopenten-1-one (1; 100 mg, 1.22 mmol) in
CHCl3 (1.5 mL) and MeOH (1 mL) was added 37% formaldehyde
in water (0.12 mL, 1.46 mmol) at ambient temperature. A solution
Synthesis 2005, No. 18, 3035–3038 © Thieme Stuttgart · New York

PAPER
Morita–Baylis–Hillman Reaction
3037
of dimethylphenylphosphine (8.4 mg, 0.06 mmol) in CHCl3 (1 mL)
was added to the reaction mixture and the mixture was stirred at am-
bient temperature for 1 h. The resulting mixture was purified direct-
ly by silica gel column chromatography (hexane–EtOAc, 1:2–1:4)
and compound 2 was obtained in 97% yield (132.1 mg, 1.18 mmol)
as white crystals; mp 71–73 °C.
IR (KBr): 3368, 1679, 1633 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.40–2.48 (m, 2 H), 2.59–2.66 (m,
2 H), 2.69 (t, J = 5.9 Hz, 1 H), 4.32–4.37 (m, 2 H), 7.50–7.57 (m, 1
1H NMR (300 MHz, CDCl3): d = 2.43–2.50 (m, 2 H), 2.56–2.66 (m,
2 H), 3.46 (d, J = 4.0 Hz, 1 H), 5.57 (br s, 1 H), 7.24–7.43 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 26.5, 35.1, 69.4, 126.2, 127.6,
128.3, 141.4, 147.7, 159.3, 209.3.
HR–ESI–MS: m/z [M + H]+ calcd for C12H13O2: 189.0916; found:
189.0926.
Anal. Calcd for C12H12O2: C, 76.57; H, 6.43. Found: C, 76.74; H,
6.55.
H).
2-(1-Hydroxy-3-phenylpropyl)-2-cyclopenten-1-one (12b)
Colorless oil.
IR (neat): 3418, 1694, 1496 cm–1.
13C NMR (75 MHz, CDCl3): d = 26.8, 35.0, 57.5, 144.9, 159.0,
209.9.
Anal. Calcd for C6H8O2: C, 64.27; H, 7.19. Found: C, 63.94; H,
7.21.
1H NMR (300 MHz, CDCl3): d = 1.96–2.07 (m, 2 H), 2.40–2.46 (m,
2 H), 2.56–2.63 (m, 2 H), 2.65–2.99 (m, 2 H), 3.03 (br s, 1 H), 4.48
(br s, 1 H), 7.14–7.34 (m, 5 H), 7.44 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 26.6, 31.6, 35.2, 37.1, 67.1, 125.8,
128.4, 128.5, 141.6, 147.5, 158.0, 210.0.
HR–ESI–MS: m/z [M + H]+ calcd for C14H17O2: 217.1229; found:
217.1232.
2-Hydroxymethyl-2-cyclohexen-1-one (4)
Colorless oil.
IR (neat): 3412, 1667 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.96 (quint, J = 6.2 Hz, 2 H), 2.31–
2.43 (m, 4 H), 2.93 (br s, 1 H), 4.19 (s, 2 H), 6.91 (t, J = 4.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 22.6, 25.5, 38.1, 61.5, 138.2, 146.8,
200.5.
2-(1-Hydroxycyclohexylmethyl)-2-cyclopenten-1-one (12c)
Colorless oil.
Anal. Calcd for C7H10O2: C, 66.65; H, 7.99. Found: C, 66.35; H,
7.90.
IR (neat): 3437, 1694 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.90–1.10 (m, 2 H), 1.10–1.32 (m,
3 H), 1.46–1.90 (m, 6 H), 2.41–2.47 (m, 2 H), 2.59–2.65 (m, 2 H),
2.81 (br s, 1 H), 4.18 (d, J = 5.8 Hz, 1 H), 7.41 (dt, J = 0.9, 2.7 Hz,
1 H).
13C NMR (75 MHz, CDCl3): d = 25.8, 26.0, 26.3, 26.6, 27.7, 29.4,
35.2, 42.5, 72.6, 146.4, 159.2, 210.1.
2-Hydroxymethyl-6-methyl-2-cyclohexen-1-one (6)
Colorless oil.
IR (neat): 3436, 1668 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.12 (d, J = 6.8 Hz, 3 H), 1.64–
1.80 (m, 1 H), 1.98–2.08 (m, 1 H), 2.33–2.48 (m, 3 H), 2.70 (br s, 1
H), 4.21 (s, 2 H), 6.86 (t, J = 4.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.8, 25.0, 30.7, 41.6, 62.1, 137.6,
146.0, 203.1.
HR–ESI–MS: m/z [M + H]+ calcd for C12H19O2: 195.1385; found:
195.1381.
2-(1-Hydroxyfurylmethyl)-2-cyclopenten-1-one (12d)
Pale yellow oil.
IR (neat): 3396, 1694, 1253, 1070 cm–1.
Anal. Calcd for C8H12O2: C, 68.54; H, 8.63. Found: 68.20; H, 8.69.
2-Hydroxymethyl-5-methyl-2-cyclohexen-1-one (8)
Colorless oil.
IR (neat): 3417, 1668 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.04 (d, J = 6.2 Hz, 3 H), 1.98–
2.29 (m, 3 H), 2.38–2.54 (m, 2 H), 2.69 (br s, 1 H), 4.22 (s, 2 H),
6.85–6.92 (m, 1 H).
1H NMR (300 MHz, CDCl3): d = 2.45–2.51 (m, 2 H), 2.62–2.69 (m,
2 H), 3.48 (br s, 1 H), 5.58 (s, 1 H), 6.28 (d, J = 3.2 Hz, 1 H), 6.34
(dd, J = 1.9, 3.2 Hz, 1 H), 7.38 (br s, 1 H), 7.53 (dt, J = 1.1, 2.6 Hz,
1 H).
13C NMR (75 MHz, CDCl3): d = 26.8, 35.1, 63.9, 107.3, 110.4,
142.5, 144.7, 153.7, 160.1, 209.2.
13C NMR (75 MHz, CDCl3): d = 21.0, 30.3, 33.9, 46.3, 61.7, 137.9,
146.0, 200.7.
Anal. Calcd for C10H10O3: C, 67.41; H, 5.66. Found: C, 67.25; H,
5.80.
Anal. Calcd for C8H12O2: C, 68.54; H, 8.63. Found: 68.31; H, 8.51.
References
2-Hydroxymethyl-4-methyl-2-cyclohexen-1-one (10)
Colorless oil.
IR (neat): 3414, 1668 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.14 (d, J = 7.2 Hz, 3 H), 1.64
(dddd, J = 4.7, 9.5, 12.4, 13.3 Hz, 1 H), 2.03–2.12 (m, 1 H), 2.34
(ddd, J = 4.9, 12.4, 16.8 Hz, 1 H), 2.49 (td, J = 4.9, 16.8 Hz, 1 H),
2.51–2.63 (m, 1 H), 2.68 (s, 1 H), 4.21 (s, 2 H), 6.72 (br s, 1 H).
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Synthesis 2005, No. 18, 3035–3038 © Thieme Stuttgart · New York