Radical one-pot α,β-dual and β-mono-oxymethylation of alkylidenemalonate

Article abstract of DOI:10.1021/jo300944f

Dimethylzinc-mediated radical conjugate addition reaction of dimethyl alkylidenemalonates with iodomethyl pivalate gave a high yield of the α,β-dual oxymethylation product in one pot under air and the β-pivaloyloxymethylation product under argon.

Full text of DOI:10.1021/jo300944f

Article
pubs.acs.org/joc
Radical One-Pot α,β-Dual and β-Mono-Oxymethylation of
Alkylidenemalonate
Ken-ichi Yamada,*,† Takehito Konishi,† Mayu Nakano,† Shintaro Fujii,† Romain Cadou,†
Yasutomo Yamamoto,‡ and Kiyoshi Tomioka*,‡
†Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo, Kyoto 606-8501, Japan
‡Faculty of Pharmaceutical Sciences, Doshisha Women’s College of Liberal Arts, Kodo, Kyotanabe 610-0395, Japan
S
* Supporting Information
ABSTRACT: Dimethylzinc-mediated radical conjugate addi-
tion reaction of dimethyl alkylidenemalonates with iodomethyl
pivalate gave a high yield of the α,β-dual oxymethylation
product in one pot under air and the β-pivaloyloxymethylation
product under argon.
chromatography revealed the expected β-adduct 3a in 29%
yield along with the α,β-bispivaloyloxymethylated adduct 4a in
22% yield (Table 1, entry 1). The addition of boron trifluoride
diethyl etherate5 (3 equiv) as a Lewis acid improved the yield of
3a to 41%, and 4a was also isolated in 8% yield (entry 2). The
formation of 4a is likely due to radical−radical coupling of
pivaloyloxymethyl and the radical intermediate corresponding
to 3a,9,10 implying slow conversion of the initially formed
radical intermediate to a boron enolate with triethylborane.
When dimethylzinc was used as a radical initiator in place of
triethylborane, α-hydroxymethylated β-pivaloyloxymethyl ad-
duct 5a was unexpectedly obtained in 59% yield as a major
product along with 3a and 4a in 21% and 1% yields,
respectively (Table 1, entry 3). The addition of boron
trifluoride diethyl etherate (3 equiv) improved the yield of 5a
to 77%, while 3a and 4a were still obtained in 19% and 3%
yields, respectively (entry 4). Interestingly, migration of the
pivaloyl group to the α-position was not observed in these
reactions, despite the reported migration in the reaction with
fumarate.7 The use of diethylzinc instead of dimethylzinc
resulted in the production of the ethyl conjugate adduct in 78%
yield, without the production of pivaloyloxymethyl adducts 3a−
5a (entry 5).
The reaction of 2a was remarkably accelerated by adding 1.2
equiv of tert-butyl hydroperoxide (TBHP),11 leading to the
complete consumption of 2a within 15 min, and affording both
3a as a major product in 82% yield and 5a in 18% yield (Table
1, entry 7). The amount of TBHP significantly affected the
reaction; the yield of 3a was decreased to 68% with 1.5 equiv of
TBHP (entry 8), whereas the reaction slowed with 1.0 equiv of
TBHP to give 3a and 5a after 0.5 h in 44% and 56% yields,
respectively (entry 6). A prolonged 4 h reaction enabled
complete conversion, giving 5a in 97% yield (entry 9).
The amount of boron trifluoride diethyl etherate also affected
the reaction; with 1.2 equiv of boron trifluoride, the reaction
INTRODUCTION
■
The conjugate addition reaction of nucleophiles to activated
olefins is a versatile tool in synthetic organic chemistry.1,2 We
previously reported the conjugate addition of α-oxy carbon-
centered radicals3 to α,β-unsaturated imines4 and alkylidene-
malonates,5 giving the corresponding adducts in high yield. We
also reported the tin-free generation of acyloxymethyl radicals
from the corresponding iodomethyl esters and their 1,2-
addition reaction to imines.6 During our continued studies to
develop a conjugate addition reaction of an acyloxymethyl
radical with alkylidenemalonates, we unexpectedly observed an
intriguing one-pot α,β-dual functionalization of alkylidenemal-
onates and found that the reaction requires the presence of air.
Although dimethylzinc-mediated conjugate addition of the
acyloxymethyl radical to fumarate and the following intra-
molecular addition of the resulting zinc enolate intermediate to
the acyloxy moiety were reported during this study,7 the
reaction of alkylidenemalonates proceeded more rapidly
without the subsequent intramolecular reaction, providing γ-
pivaloyloxy butanoic acid derivatives with a β-aryl or a β-alkyl
substituent. Herein, we report dimethylzinc-mediated conjugate
addition8 of a pivaloyloxymethyl radical to alkylidenemalonate,
realizing one-pot α,β-dual or β-mono-oxymethylation by
controlling the atmosphere in which the reaction is performed.
RESULTS AND DISCUSSION
■
We began our studies with the reaction of pivaloyloxymethyl
iodide 1 with dimethyl benzylidenemalonate 2a under orthodox
radical-generating conditions using triethylborane. A 1.0 M
hexane solution of triethylborane (3 mmol) was added to a
solution of 1 (3 mmol) and 2a (1 mmol) in dichloromethane
(1 mL) at room temperature. The mixture was then stirred at
room temperature under an ordinary atmosphere, and a
solution of triethylborane (1 mmol) was added every 2 h.
After the addition of a total of 6 mmol of triethylborane,
another portion of triethylborane (3 mmol) was added, and the
mixture was allowed to stand under stirring at room
temperature for another 15 h. Workup and silica gel column
Received: May 10, 2012
Published: June 5, 2012
© 2012 American Chemical Society
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Table 1. Radical Conjugate Addition of 1 to 2a
entry
initiator/equiv
BF3·OEt2 (equiv)
TBHP (equiv)
time (h)
3a (% yield)
4a (% yield)
5a (% yield)
1
2
Et3B/9
0
0
24
24
24
24
3
29
41
21
19
22
8
1
3
0
0
0
0
0
0
0
0
0
Et3B/9
3
0
3
Me2Zn/9
Me2Zn/9
Et2Zn/3
Me2Zn/3
Me2Zn/3
Me2Zn/3
Me2Zn/3
Me2Zn/3
Me2Zn/3
0
0
59
77
0
4
3
0
a
5
1
0
0
6
1
1
0.5
0.25
0.25
4
44
82
68
0
56
18
20
97
99
76
7
1
1.2
1.5
1.2
1.2
1.2
8
1
9
1
10
11
1.2
1.5
3
0
3
10
a
Ethyl conjugate adduct was obtained in 78% yield.
completed after 3 h to give 5a quantitatively (Table 1, entry
10), although α-hydroxymethylation proceeded slower with 1.5
equiv of the boron reagent to give 5a in 76% yield and 3a in
10% yield (entry 11).
Scheme 2. Radical Pathway to 3a, 4a, and 5a from 1 and 2a
We excluded the possibility that 4a was selectively hydro-
lyzed to 5a based on the fact that treatment of 4a under the
reaction conditions failed to produce 5a, and 4a was
quantitatively recovered unchanged (Scheme 1, eq 1). TLC
Scheme 1. Reaction of 3a and 4a
function as a better formaldehyde donor than paraformalde-
hyde (eq 2 vs eq 3, Scheme 1).
The above speculation of the formaldehyde formation
suggested that, in the absence of air, that is, under an argon
atmosphere, enolate 8 should survive to be protonated at the
workup, affording 3a. This speculation was confirmed by the
reaction under an argon atmosphere for 15 min, giving 3a in
94% yield and 5a in 5% yield (Table 2, entry 1). Under an
argon atmosphere, the reaction proceeded with almost the
monitoring of the reaction clearly revealed the disappearance of
3a with simultaneous production of 5a (Table 1, entries 6−11).
Indeed, treatment of 3a under the reaction conditions gave 5a
in 98% yield (eq 2). A critical experiment was the reaction of 3a
with paraformaldehyde in the absence of 1 under the reaction
conditions to give 5a in 60% yield (Scheme 1, eq 3).
Table 2. Radical Reaction of 1 and 2a under Argon
The reactions shown in Scheme 1 suggest that 5a results
from the reaction of zinc enolate 8 with a formaldehyde
equivalent (Scheme 2). The methyl radical, generated by the
reaction of dimethylzinc with molecular oxygen and/or TBHP,
abstracts an iodine atom from 1 to form pivaloyloxymethyl
radical 6, which undergoes a conjugate addition reaction with
2a to give 7. The resulting radical 7 is then trapped by
dimethylzinc and converted into zinc enolate 8. Formaldehyde
10 is probably generated by the oxidation of 6 with oxygen and
reacts with 8 to afford 5a. In the reactions in eqs 2 and 3
(Scheme 1), dimethylzinc probably deprotonated 3a to
generate 8. Interestingly, iodomethyl pivalate (1) seemed to
1
(CH2O)n
(equiv)
3a
4a
5a
entry (equiv)
(% yield)
(% yield)
(% yield)
1
3
0
0
0
3
94
94
91
5
0
0
0
5
5
2
2
a
3
4
1.2
3
2
b
0
73
a
b
The reaction for 30 min. Recovery of 2a in 4% yield. Recovery of 2a
in 5% yield.
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same efficiency, even with a reduced amount of 1 (2 equiv), to
afford 3a in 94% yield, probably because the reaction of 6 with
molecular oxygen was avoided (entry 2). Although the reaction
was slightly slower, 3a was obtained in comparable yield (91%)
with 1.2 equiv of 1 (entry 3). Even under an argon atmosphere,
α-hydroxymethylation product 5a was obtained in 73% yield
after 15 min when the reaction was conducted in the presence
of 3 equiv of paraformaldehyde (entry 4). Probably due to the
low nucleophilicity of 8 and/or a favored retro-aldol process,
however, the reaction of 1 and 2a with Me2Zn in the presence
of other aldehydes, such as benzaldehyde and acetaldehyde,
failed to provide products corresponding to 5a.
ethylidenemalonate 2d was very rapid, giving 3d in 84% yield
after 5 min (entry 4).
The radical conjugate addition reaction was applicable for the
synthesis of hinokinin (11), a representative lignin13 with
antiviral, antifungal, and pesticidal activities.14 The reaction of
arylethylidenemalonate 1215 with 1 under an argon atmosphere
gave conjugate pivaloyloxymethylation adduct 13 in 71% yield
(Scheme 3).16 Treatment of 13 with sodium methoxide in
Scheme 3. Short-Step Total Synthesis of Hinokinin 11 via
Conjugate Pivaloyloxymethylation of 12
The established conditions (Table 1, entry 10) were
successfully applied to one-pot α,β-dual oxymethylation of
other alkylidenemalonates 2 (Table 3). 4-Chlorobenzylidene-
Table 3. One-Pot Dual Oxymethylation of 2 with 1 Giving
a
5
entry
2
R
time (h)
5
% yield
1
2
3
4
2a
2b
2c
2d
Ph
3
4
4
3
5a
5b
5c
5d
99
99
99
83
4-ClC6H4
4-MeOC6H4
Me
a
With 2 (1 mmol) in CH2Cl2 (1 mL) under an ordinary atmosphere.
methanol afforded lactone 14, which was then subjected to
alkylation with 15,17 followed by decarboxylation18 to give 11
in 93% yield as an 85:15 mixture with isohinokinin. Spectral
malonate 2b gave 5b in quantitative yield (entry 2). 4-
Methoxybenzylidenemalonate 2c also gave 5c in quantitative
yield (entry 3). Ethylidenemalonate 2d was also a good radical
acceptor to give 5d in 83% yield (entry 4). Notably, this radical
polar crossover reaction with alkylidenemalonate occurred
intermolecularly, which is unprecedented.12
The conditions for the conjugate β-pivaloyloxymethylation
(Table 2, entry 2) were applied to the reactions of other
alkylidenemalonates 2 (Table 4). Although the reaction was
somewhat slower with 2b and 2c, bearing an electron-
withdrawing 4-chloro and an electron-donating 4-methoxy
substituent on the phenyl group, conjugate adducts 3b and 3c
were obtained in reasonably high yield, 95% and 92%, after 1
and 1.5 h, respectively (entries 2 and 3). The reaction with
1
data, including H and 13C NMR and IR, were consistent with
those reported in the literature.19
CONCLUSION
■
We successfully developed a dimethylzinc-mediated radical
one-pot dual oxymethylation and β-pivaloyloxymethylation of
alkylidenemalonate with pivaloyloxymethyl iodide by control-
ling the atmosphere in which the reaction is performed. The
synthetic utility of the reaction was clearly demonstrated by the
synthesis of bioactive hinokinin.
EXPERIMENTAL SECTION
■
General Methods. Alkylidenemalonates 2a−2c20 and bromide
1517 were prepared according to the literature. Iodomethyl pivalate
(1) was prepared by the reported procedure21 and decolorized by
being passed through Al2O3 prior to use. Anhydrous solvents, CH2Cl2,
DMF, and THF, and hexane solutions of Me2Zn and Et3B were
purchased and used as received. BF3·OEt2 was distilled prior to use.
MeOH was distilled from sodium prior to use. Reactions were
performed using dried glassware in dry solvent, unless otherwise
mentioned. Column chromatography was performed using silica gel.
Table 4. Conjugate Pivaloyloxymethylation of 2 with 1
Giving 3
1
All melting points are uncorrected. H and 13C NMR spectra were
a
recorded in CDCl3 at 500 and 125 MHz, respectively. Chemical shifts
and coupling constants are presented in parts per million (ppm δ)
relative to Me4Si and hertz (Hz), respectively. Data are reported as
follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet,
br = broad, and m = multiplet), coupling constants, integration. 13C
peak multiplicity assignments were made on the basis of DEPT
spectra. IR spectroscopy of oil and solid samples were measured as
neat liquid films and KBr pellets, respectively. The wave numbers of
entry
2
R
time (min)
3
% yield
1
2
3
4
2a
2b
2c
2d
Ph
15
60
90
5
3a
3b
3c
3d
94
95
92
84
4-ClC6H4
4-MeOC6H4
Me
a
With 2 (1 mmol) in CH2Cl2 (2 mL). A 3−5% yield of 5 was
produced.
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maximum absorption peaks of IR spectroscopy are presented in cm−1.
A double-focusing magnetic sector mass spectrometer was used for
both low- and high-resolution FABMS, while low-resolution EIMS was
measured with a quadrupole mass spectrometer.
177.4 (C), 178.1 (C). IR: 2970, 1736, 1481, 1396, 1281, 1227, 1150,
1034, 995, 918, 733. FABMS m/z: 451 (M + H), 349 (M − t-BuCO2),
335 (M − t-BuCO2CH2). HRMS−FAB (m/z): [M + H]+ calcd for
C24H35O8, 451.2326; found, 451.2332.
Typical Procedure for Table 4. Dimethyl 2-(1-Phenyl-2-
pivaloyloxyethyl)malonate (3a) (Entry 1). A magnetic stir bar and
2a (220 mg, 1.0 mmol) were placed in a dried 20 mL round-bottom
flask that was capped with an argon balloon. To the flask were added
CH2Cl2 (2.0 mL), 1 (0.5 mL, 3.0 mmol), and a 5.3 M decane solution
of TBHP (0.23 mL, 1.2 mmol) at rt. The solution was degassed by
freeze−pump−thaw three times and then cooled in an ice−water bath.
To the solution were added BF3·OEt2 (0.15 mL, 1.2 mmol) and a 1.0
M hexane solution of Me2Zn (3.0 mL, 3.0 mmol). The cooling bath
was removed, and the mixture was stirred at rt under an argon
atmosphere for 15 min. The reaction was quenched by the addition of
sat. NH4Cl, and the mixture was extracted three times with EtOAc.
The combined organic layers were washed with 10% Na2S2O3 and
brine, dried over Na2SO4, and then concentrated. The purification of
the resulting residue by column chromatography (hexane/EtOAc 9/1
Typical Procedure for Table 3. Dimethyl 2-Hydroxymethyl-
2-(1-phenyl-2-pivaloyloxyethyl)malonate (5a) (Entry 1). A
magnetic stir bar and 2a (220 mg, 1.0 mmol) were placed in a dried
20 mL round-bottom flask that was capped with an argon balloon. To
the flask were added CH2Cl2 (1.0 mL), 1 (0.33 mL, 2.0 mmol), and a
5.3 M decane solution of TBHP (0.23 mL, 1.2 mmol) at rt. To the
stirred solution cooled in an ice−water bath were added BF3·OEt2
(0.15 mL, 1.2 mmol) and a 1.0 M hexane solution of Me2Zn (3.0 mL,
3.0 mmol). The cooling bath was removed, and the mixture was stirred
at rt under an ordinary atmosphere for 3 h. The reaction was quenched
by the addition of sat. NH4Cl, and the mixture was extracted three
times with EtOAc. The combined organic layers were washed with
10% Na2S2O3 and brine, dried over Na2SO4, and then concentrated.
Purification of the resulting residue by column chromatography
(hexane/EtOAc 9/1 to 4/1) gave the title compound (361 mg, 99%)
1
1
to 4/1) gave the title compound (316 mg, 94%) as a colorless oil: H
as colorless prisms of mp 70−71 °C (Et2O−hexane): H NMR: 0.96
NMR: 1.09 (s, 9H), 3.48 (s, 3H), 3.78 (s, 3H), 3.79 (ddd, J = 4.5, 6.5,
10.5, 1H), 3.90 (d, J = 10.5, 1H), 4.20 (dd, J = 4.5, 11.5, 1H), 4.41 (dd,
J = 6.5, 11.5, 1H), 7.22−7.31 (m, 5H). 13C NMR: 27.0 (CH3), 38.7
(C), 44.4 (CH), 52.4 (CH3), 52.8 (CH3), 54.4 (CH), 65.6 (CH2),
127.5 (CH), 128.3 (CH), 128.5 (CH), 138.4 (C), 167.8 (C), 168.3
(C), 178.1 (C). IR: 2963, 1736, 1458, 1435, 1281, 1157, 1026, 764,
702. FABMS m/z: 337 (M + H), 235 (M − t-BuCO2), 221 (M − t-
BuCO2CH2). HRMS−FAB (m/z): [M + H]+ calcd for C18H25O6,
337.1646; found, 337.1649.
(s, 9H), 2.51 (dd, J = 5.0, 9.0, 1H), 3.73−3.78 (m, 2H), 3.79 (s, 3H),
3.84 (m, 1H), 3.84 (s, 3H), 4.40 (dd, J = 4.5, 11.0, 1H), 4.78 (dd, J =
11.0, 11.0, 1H), 7.17 (d, J = 6.5, 2H), 7.23−7.30 (m, 3H). 13C NMR:
26.8 (CH3), 38.5 (C), 47.7 (CH), 52.7 (CH3), 52.9 (CH3), 62.3 (C),
65.0 (CH2), 65.7 (CH2), 127.8 (CH), 128.6 (CH), 129.0 (CH), 136.6
(C), 170.3 (C), 170.5 (C), 178.1 (C). IR: 3518, 2963, 1728, 1458,
1281, 1218, 1165, 1042, 910, 733, 702. EIMS m/z: 335 (M −
HOCH2), 251 (M − t-BuCO2CH2). FABMS m/z: 367 (M + H), 265
(M − t-BuCO2), 251 (M − t-BuCO2CH2). HRMS−FAB (m/z): [M +
H]+ calcd for C19H27O7, 367.1757; found, 367.1766. Anal. Calcd for
C19H26O7: C, 62.28; H, 7.15. Found: C, 62.20; H, 7.04.
Dimethyl 2-(1-(4-Chlorophenyl)-2-pivaloyloxyethyl)-2-hydroxy-
methylmalonate (5b): Purified by column chromatography (hex-
ane/EtOAc 4/1 to 2/1). Colorless oil (399 mg, 99%): 1H NMR: 0.97
(s, 9H), 2.58 (brs, 1H), 3.76−3.79 (m, 2H), 3.78 (s, 3H), 3.81 (s, 3H),
3.85 (d, J = 11.5, 1H), 4.40 (dd, J = 4.5, 11.0, 1H), 4.75 (dd, J = 11.0,
11.0, 1H), 7.16 (d, J = 8.5, 2H), 7.27 (d, J = 8.5, 2H). 13C NMR: 26.8
(CH3), 38.5 (C), 46.8 (CH), 52.7 (CH3), 53.0 (CH3), 62.2 (C), 64.6
(CH2), 65.1 (CH2), 128.7 (CH), 130.5 (CH), 133.7 (C), 135.3 (C),
170.0 (C), 170.1 (C), 178.1 (C). IR: 3510, 2963, 1728, 1489, 1435,
1281, 1220, 1165, 1096, 1042, 972, 756. FABMS m/z: 403 (M + 2 +
H), 401 (M + H), 385 (M + 2 − OH), 383 (M − OH), 301 (M + 2 −
t-BuCO2), 299 (M − t-BuCO2). HRMS−FAB (m/z): [M + H]+ calcd
for C19H26O7Cl, 401.1367; found, 401.1369.
Dimethyl 2-(1-(4-Chlorophenyl)-2-pivaloyloxyethyl)malonate
(3b): Purified by column chromatography (hexane/EtOAc 9/1).
1
Colorless oil (352 mg, 95%): H NMR: 1.10 (s, 9H), 3.51 (s, 3H),
3.75−3.81 (m, 4H), 3.86 (d, 1H, J = 11.0), 4.17 (dd, 1H, J = 11.5, 4.5),
4.38 (dd, 1H, J = 11.5, 7.0), 7.20 (dt, 2H, J = 8.5, 2.0), 7.25−7.30 (m,
2H). 13C NMR: 27.0 (CH3), 38.7 (C), 43.7 (CH), 52.6 (CH3), 52.9
(CH3), 54.1 (CH), 65.3 (CH2), 128.6 (CH), 129.7 (CH), 133.3 (C),
137.0 (C), 167.5 (C), 167.9 (C), 177.8 (C). IR: 2963, 1736, 1489,
1281, 1150. FABMS m/z: 373 (M + 2 + H), 371 (M + H), 271 (M +
2 + H − t-BuCO2), 269 (M + H − t-BuCO2). HRMS−FAB (m/z):
[M + H]+ calcd for C18H24ClO6, 371.1261; found, 371.1264.
Dimethyl 2-(1-(4-Methoxyphenyl)-2-pivaloyloxyethyl)malonate
(3c): Purified by column chromatography (hexane/EtOAc 9/1).
1
Colorless oil (338 mg, 92%): H NMR: 1.11 (s, 9H), 3.50 (s, 3H),
3.74 (ddd, 1H, J = 11.0, 6.5, 4.5), 3.77 (s, 3H), 3.78 (s, 3H), 3.85 (d,
1H, J = 11.0), 4.16 (dd, 1H, J = 11.5, 4.5), 4.37 (dd, 1H, J = 11.0, 6.5),
6.82 (dt, 2H, J = 8.5, 3.0), 7.17 (dt, 2H, J = 8.5, 3.0). 13C NMR: 27.0
(CH3), 38.7 (C), 43.6 (CH), 52.5 (CH3), 52.8 (CH3), 54.5 (CH),
55.2 (CH3), 65.8 (CH2), 113.8 (CH), 129.4 (CH), 130.3 (C), 158.8
(C), 167.8 (C), 168.2 (C), 178.0 (C). IR: 2963, 1736, 1512, 1250,
1150. FABMS m/z: 367 (M + H), 265 (M − t-BuCO2). HRMS−FAB
(m/z): [M + H]+ calcd for C19H27O7, 367.1757; found, 367.1757.
Dimethyl 2-(1-Methyl-2-pivaloyloxyethyl)malonate (3d): Purified
by column chromatography (hexane/EtOAc 9/1). Colorless oil (231
mg, 84%): 1H NMR: 1.07 (d, 3H, J = 7.0), 1.21 (s, 9H), 2.63 (m, 1H),
3.45 (d, 1H, J = 8.0), 3.74 (s, 3H), 3.75 (s, 3H), 4.02 (dd, 1H, J = 11.0,
5.5), 4.05 (dd, 1H, J = 11.0, 5.5). 13C NMR: 14.6 (CH3), 27.0 (CH3),
32.9 (CH), 38.7 (C), 52.2 (CH3), 52.3 (CH3), 53.7 (CH), 66.1
(CH2), 168.4 (C), 168.5 (C), 177.9 (C). IR: 2970, 1736, 1435, 1281,
1157. FABMS m/z: 275 (M + H), 173 (M − t-BuCO2), 57 (t-Bu).
HRMS−FAB (m/z): [M + H]+ calcd for C13H23O6, 275.1489; found,
275.1496.
Dimethyl 2-Hydroxymethyl-2-(1-(4-methoxyphenyl)-2-
pivaloyloxyethyl)malonate (5c): Purified by column chromatography
1
(hexane/EtOAc 4/1 to 2/1). Colorless oil (396 mg, 99%): H NMR:
0.98 (s, 9H), 2.55 (dd, J = 4.5, 9.0, 1H), 3.70 (dd, J = 4.5, 10.5, 1H),
3.75−3.85 (m, 2H), 3.78 (s, 3H), 3.79 (s, 3H), 3.82 (s, 3H), 4.37 (dd,
J = 4.5, 11.0, 1H), 4.74 (dd, J = 10.5, 11.0, 1H), 6.81 (d, J = 8.5, 2H),
7.09 (d, J = 8.5, 2H). 13C NMR: 26.8 (CH3), 38.5 (C), 46.8 (CH),
52.6 (CH3), 52.9 (CH3), 55.1 (CH3), 62.5 (C), 65.0 (CH2), 65.6
(CH2), 113.9 (CH), 128.5 (C), 130.0 (CH), 159.1 (C), 170.3 (C),
170.5 (C), 178.2 (C). IR: 3510, 2962, 1728, 1612, 1512, 1458, 1288,
1250, 1180, 1034, 841, 756. FABMS m/z: 397 (M + H), 295 (M − t-
BuCO2). HRMS−FAB (m/z): [M + H]+ calcd for C20H29O8,
397.1862; found, 397.1871.
Dimethyl 2-Hydroxymethyl-2-(1-methyl-2-pivaloyloxyethyl)-
malonate (5d): Purified by column chromatography (hexane/EtOAc
1
4/1 to 2/1). Colorless oil (253 mg, 83%): H NMR: 1.07 (d, J = 7.0,
3H), 1.20 (s, 9H), 2.55 (m, 1H), 2.81 (dd, J = 6.5, 7.5, 1H), 3.79 (s,
3H), 3.80 (s, 3H), 4.01 (dd, J = 7.5, 11.5, 1H), 4.05 (dd, J = 8.0, 11.5,
1H), 4.07 (dd, J = 6.5, 11.5, 1H), 4.19 (dd, J = 4.5, 11.5, 1H). 13C
NMR: 13.8 (CH3), 27.1 (CH3), 35.9 (CH), 38.7 (C), 52.60 (CH3),
52.62 (CH3), 62.4 (C), 64.8 (CH2), 66.3 (CH2), 170.7 (C), 178.4
(C). IR: 3518, 2970, 1728, 1458, 1404, 1288, 1234, 1165, 1057, 980,
771. FABMS m/z: 305 (M + H), 203 (M − t-BuCO2). HRMS−FAB
(m/z): [M + H]+ calcd for C14H25O7, 305.1600; found, 305.1599.
Dimethyl 2-(2-(3,4-Methylenedioxyphenyl)ethylidene)-
malonate (12). Although the title compound could be prepared
Dimethyl 2-(1-Phenyl-2-pivaloyloxyethyl)-2-(pivaloyloxymethyl)-
malonate (4a): Purified by column chromatography (hexane/EtOAc
9/1 to 3/1). Colorless oil (98 mg, 22%): 1H NMR: 0.92 (s, 9H), 1.21
(s, 9H), 3.68 (s, 3H), 3.79 (s, 3H), 3.93 (dd, J = 4.0, 11.0, 1H), 4.14
(d, J = 11.5, 1H), 4.49 (d, J = 11.5, 1H), 4.52 (dd, J = 4.0, 11.0, 1H),
4.74 (dd, J = 11.0, 11.0, 1H), 7.12 (d, J = 7.0, 2H), 7.23−7.29 (m, 3H).
13C NMR: 26.7 (CH3), 27.0 (CH3), 38.5 (C), 38.7 (C), 47.0 (CH),
52.6 (CH3), 52.8 (CH3), 59.9 (C), 63.9 (CH2), 64.4 (CH2), 127.9
(CH), 128.5 (CH), 129.0 (CH), 136.4 (C), 168.5 (C), 168.7 (C),
5778
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Article
according to the reported modified conditions for Knoevenagel
condensation,15 the following procedure was utilized, for we were
unable to reproduce the results reported with phenylacetaldehyde: A
mixture of 5-(1-iodoethyl)-3,4-methylenedioxybenzene22 (1.9 g, 6.9
mmol), K2CO3 (4.8 g, 35 mmol), and dimethyl malonate (0.8 mL, 6.9
mmol) in acetone (140 mL) was heated under reflux for 21 h. After
the mixture was cooled to rt, water was added, and the whole was
extracted three times with EtOAc. The combined organic layers were
washed with brine, dried over Na2SO4, and then concentrated.
Purification of the resulting residue by column chromatography
(hexane/EtOAc 9/1) gave a pale yellow oil (1.7 g), which was
dissolved in anhydrous THF (5 mL). To the solution cooled in an
ice−water bath was added a 1.0 M THF solution of LiHMDS (7.0 mL,
7.0 mmol), and the mixture was stirred for 10 min. To the solution
was added PhSeBr (2.8 g, 12 mmol) as a solution in THF (8 mL), and
the cooling bath was removed. After 20 h, the mixture was diluted with
Et2O; washed with 10% HCl twice, water, sat NaHCO3, and brine;
dried over Na2SO4; and then concentrated. Purification of the resulting
residue by column chromatography (hexane/EtOAc 19/1) gave a pale
yellow oil (2.2 g). To a solution of the oil in THF (40 mL) was added
30% H2O2 (21 mL, 200 mmol). The mixture was stirred for 12 h and
diluted with Et2O. The organic layer was separated, washed with water
three times and brine, dried over Na2SO4, and then concentrated.
Purification of the resulting residue by column chromatography
(neutral silica gel, hexane/EtOAc 9/1) gave the title compound as a
column chromatography (hexane/EtOAc 9/1) gave a 92:8 diastereo-
meric mixture of the title compound as a colorless oil (67 mg, 62%).
The diastereomeric ratio was determined by the integration area of 1H
NMR signals at 3.74 and 3.81 ppm. 1H NMR: 2.54 (dd, J = 14.0, 10.0,
0.08H), 2.72 (dd, J = 14.0, 8.0, 0.92H), 2.78 (dd, J = 14.0, 7.0, 0.92H),
2.88 (dd, J = 14.0, 6.0, 0.08H), 3.06 (m, 0.08H), 3.23 (m, 0.92H), 3.32
(d, J = 8.5, 0.92H), 3.59 (d, J = 9.0, 0.08H), 3.74 (s, 2.76H), 3.81 (s,
0.24H), 3.99 (dd, J = 9.0, 8.0, 0.92H), 4.23 (dd, J = 9.0, 9.0, 0.08H),
4.28 (dd, J = 9.0, 7.5, 0.08H), 4.42 (dd, J = 9.0, 7.5, 0.92H), 5.95 (s,
2H), 6.55−6.62 (m, 1H), 6.63−6.68 (m, 1H), 6.70−6.80 (m, 1H). 13C
NMR: 37.5 (CH2), 41.7 (CH), 51.7 (CH), 53.0 (CH3), 71.3 (CH2),
101.1 (CH2), 108.5 (CH), 109.0 (CH), 121.8 (CH), 130.6 (C), 146.6
(C), 148.0 (C), 167.6 (C), 171.6 (C). IR: 2916, 1782, 1736, 1497,
1442, 1250, 1150, 1034. FABMS m/z: 279 (M + H), 278 (M), 277 (M
− H), 247 (M − OMe). HRMS−FAB (m/z): [M + H]+ calcd for
C14H15O6, 279.0863; found, 279.0859.
Hinokinin (11) and Isohinokinin. A solution of 14 (67 mg, 0.24
mmol), K2CO3 (57 mg, 0.41 mmol), and 1517 (58 mg) in anhydrous
DMF (1.3 mL) was stirred for 2 h at rt. To the solution were added
LiCl (52 mg, 1.2 mmol) and water (8.4 μL, 0.47 mmol), and the
resulting solution was heated at 130 °C for 3 h. After cooling the
solution to rt, EtOAc and water were added, and the separated
aqueous phase was extracted three times with EtOAc. The combined
organic layers were washed with 0.1 N HCl and brine, dried over
MgSO4, and concentrated. Purification of the resulting residue by
column chromatography (hexane/EtOAc 19/1) gave an 85:15 mixture
of hinokinin (11) and isohinokinin (79 mg, 93%) as a colorless oil: 1H
NMR: 2.30 (t, J = 13.5, 0.15H), 2.41−2.64 (m, 3.55H), 2.74 (dd, J =
15.0, 11.0, 0.15H), 2.84 (dd, J = 14.0, 7.5, 0.85H), 2.89 (dd, J = 13.0,
3.0, 0.15H), 2.99 (dd, J = 14.0, 5.0, 0.85H), 3.05 (m, 0.15H), 3.23 (dd,
J = 15.0, 5.0, 0.15H), 3.86 (dd, J = 9.5, 7.5, 0.85H), 3.97−4.10 (m,
0.3H), 4.13 (dd, J = 9.5, 7.0, 0.85H), 5.92−5.96 (m, 3.7H), 5.97 (s,
0.3H), 6.44−6.49 (m, 1.7H), 6.49−6.55 (m, 0.3H), 6.58−6.65 (m,
1.7H), 6.69−6.81 (m, 2.3H). The diastereomeric ratio was determined
1
pale yellow oil (1.0 g, 54%). H NMR: 3.53 (d, J = 8.0, 2H), 3.78 (s,
3H), 3.88 (s, 3H), 5.94 (s, 2H), 6.66 (dd, J = 8.0, 1.5, 1H), 6.71 (d, J =
1.5, 1H), 6.75 (d, J = 8.0, 1H), 7.08 (t, J = 8.0, 1H). 13C NMR: 35.6
(CH2), 52.4 (CH3), 101.0 (CH2), 108.5 (CH), 109.2 (CH), 121.7
(CH), 127.8 (C), 130.6 (C), 146.5 (C), 147.9 (C), 164.2 (C), 165.6
(C). IR: 3024, 1724, 1489, 1438, 1219, 1037. FABMS m/z: 279 (M +
H), 246 (M − MeOH). HRMS−FAB (m/z): [M + H]+ calcd for
C14H15O6, 279.0863; found, 279.0859.
Dimethyl 2-(2-(3,4-Methylenedioxypheny)-1-pivaloyloxy-
methylethyl)malonate (13). A magnetic stir bar and 12 (139 mg,
0.50 mmol) were placed in a dried 20 mL round-bottom flask that was
capped with an argon balloon. To the flask were added CH2Cl2 (1.0
mL), 1 (0.42 mL, 2.5 mmol), and a 5.3 M decane solution of TBHP
(0.10 mL, 0.53 mmol). To the stirred solution cooled in an ice−water
bath was added a 1.0 M hexane solution of Me2Zn (1.5 mL, 1.5
mmol). The cooling bath was removed, and the mixture was stirred at
rt under an argon atmosphere while additional portions of Me2Zn
(0.50 mL, 0.50 mmol each) and TBHP (0.03 mL, 0.2 mmol each)
were added every 1 h. After total addition of 8 equiv of Me2Zn and 3.2
equiv of TBHP, the mixture was stirred for another 1 h, and the
reaction was quenched by the addition of sat. NH4Cl. The mixture was
extracted three times with EtOAc, and the combined organic layers
were washed with 10% Na2S2O3 and brine, dried over Na2SO4, and
then concentrated. The resulting residue was purified by column
chromatography (hexane/EtOAc 9/1) to give the title compound
1
1
by the integration area of H NMR signals at 2.99 and 3.05 ppm. H
and 13C NMR, IR, and MS of hinokinin (11) and 1H NMR of
isohinokinin were identical to those reported.19b
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR charts of the new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: yamak@pharm.kyoto-u.ac.jp (K.Y.), tomioka@pharm.
kyoto-u.ac.jp (K.T.).
■
Notes
1
The authors declare no competing financial interest.
(140 mg, 71%) as a colorless oil: H NMR: 1.22 (s, 9H), 2.60 (m,
1H), 2.65−2.78 (m, 2H), 3.56 (d, 1H, J = 7.5), 3.75 (s, 3H), 3.76 (s,
3H), 3.96 (dd, 1H, J = 11.5, 5.0), 4.03 (dd, 1H, J = 11.5, 4.5), 5.93 (s,
2H), 6.62 (dd, 1H, J = 7.5, 1.5), 6.68 (d, 1H, J = 1.5), 6.73 (d, 1H, J =
7.5). 13C NMR: 27.1 (CH3), 34.9 (CH2), 38.8 (C), 40.2 (CH), 52.5
(CH), 52.6 (CH3), 62.9 (CH2), 100.8 (CH2), 108.2 (CH), 109.3
(CH), 122.1 (CH), 132.3 (C), 146.2 (C), 147.7 (C), 168.5 (C), 168.7
(C), 178.0 (C). IR: 2963, 1736, 1489, 1443, 1157, 1042. FABMS m/z:
395 (M + H), 394 (M), 393 (M − H), 293 (M − t-BuCO2), 292 (M
− H − t-BuCO2), 262 (M − H − CH(CO2Me)2). HRMS−FAB (m/
z): [M + H]+ calcd for C20H27O8, 395.1700; found, 395.1707.
Methyl 4-(3,4-Methylenedioxyphenylmethyl)-2-oxotetrahy-
drofuran-3-carboxylate (14). To a solution of 13 (152 mg, 0.39
mmol) in MeOH (1.0 mL) was added a 1.0 M methanolic solution of
NaOMe (1.9 mL, 1.9 mmol) at rt. The mixture was stirred for 5 h, and
then another portion of the NaOMe solution (1.9 mL, 1.9 mmol) was
added again. After 2 h, the reaction was quenched by the addition of
sat. NH4Cl, and the mixture was extracted three times with EtOAc.
The combined organic layers were washed with brine, dried over
Na2SO4, and then concentrated. Purification of the resulting residue by
ACKNOWLEDGMENTS
We are grateful to JSPS and JST for financial support.
■
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