Synthesis of methyl 3-bromomethylbut-3-enoate and its reactions with aldehydes and tributylchlorostannane in the presence of zinc

Article abstract of DOI:10.1134/S1070428008090029

Methyl 3-bromomethylbut-3-enoate smoothly reacted with prenal, β-ionylideneacetaldehyde, benzyloxyacetaldehyde, and tributylchlorostannane in the presence of zinc and aqueous ammonium chloride in tetrahydrofuran to give the corresponding δ-hydroxy-β-methylidenecarboxylic acid esters. In the absence of ammonium chloride, satisfactory yields of the products were obtained only in the reactions with prenal and benzyloxyacetaldehyde; these reactions involved lactonization of intermediate δ-hydroxy-β- methylidenecarboxylic acid esters, and the double carbon-carbon bond migrated to the conjugated position with the lactone carbonyl group. The condensation of β-ionylideneacetaldehyde with methyl 3-bromomethylbut-3-enoate was successfully used to obtain isotretinoin. Initial methyl 3-bromomethylbut-3- enoate was synthesized in a good yield from readily accessible ethyl 3,3-diethoxypropionate via cyclopropanation with ethylmagnesium bromide in the presence of titanium tetra(isopropoxide), oxidation of the acetal moiety to ester, and cleavage of the cyclopropane ring in intermediate methyl (1-methylsulfonyloxycyclopropyl)acetate.

Full text of DOI:10.1134/S1070428008090029

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 9, pp. 1261–1266. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © I.V. Mineeva, O.G. Kulinkovich, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 9, pp. 1277–1282.
Synthesis of Methyl 3-Bromomethylbut-3-enoate
and Its Reactions with Aldehydes and Tributylchlorostannane
in the Presence of Zinc
I. V. Mineeva and O. G. Kulinkovich
Belarussian State University, pr. Nezavisimosti 4, Minsk, 220030 Belarus
e-mail: kulinkovich@bsu.by
Received December 4, 2007
Abstract—Methyl 3-bromomethylbut-3-enoate smoothly reacted with prenal, β-ionylideneacetaldehyde, ben-
zyloxyacetaldehyde, and tributylchlorostannane in the presence of zinc and aqueous ammonium chloride in
tetrahydrofuran to give the corresponding δ-hydroxy-β-methylidenecarboxylic acid esters. In the absence of
ammonium chloride, satisfactory yields of the products were obtained only in the reactions with prenal and
benzyloxyacetaldehyde; these reactions involved lactonization of intermediate δ-hydroxy-β-methylidenecar-
boxylic acid esters, and the double carbon–carbon bond migrated to the conjugated position with the lactone
carbonyl group. The condensation of β-ionylideneacetaldehyde with methyl 3-bromomethylbut-3-enoate was
successfully used to obtain isotretinoin. Initial methyl 3-bromomethylbut-3-enoate was synthesized in a good
yield from readily accessible ethyl 3,3-diethoxypropionate via cyclopropanation with ethylmagnesium bromide
in the presence of titanium tetra(isopropoxide), oxidation of the acetal moiety to ester, and cleavage of the
cyclopropane ring in intermediate methyl (1-methylsulfonyloxycyclopropyl)acetate.
DOI: 10.1134/S1070428008090029
The use of nucleophilic C5 building blocks with
isopentane carbon skeleton in the synthesis of iso-
prenoids is advantageous due to attributive correspond-
ence of the results of their reactions with carbon elec-
trophiles to those of the transformations of isopentenyl
pyrophosphate in fundamental biosynthesis processes
[1]. Derivatives of 3-methylbut-2-enoic acid belong to
the most frequently used compounds of this type;
carbanionic center therein is generally generated via
deprotonation or replacement of halogen by metal
[2–17]. Derivatives of isomeric 3-methylbut-3-enoic
acid have been studied to a considerably lesser extent;
as far as we know, their use in synthesis has been re-
ported only in recent publications on asymmetric al-
lylation of aldehydes with ethyl 3-(tributylstannyl-
methyl)but-3-enoate [18, 19]. The latter was obtained
by low-temperature stannylation of 3-chloro-2-(chloro-
methyl)prop-1-ene, followed by ethoxycarbonylation
of 3-tributylstannyl-2-(tributylstannylmethyl)prop-1-
ene [20]. It was shown that this transformation ensures
chain extension by five carbon atoms with formation
of δ-hydroxy-β-methylidenealkanoic acids or (after
migration of the double carbon–carbon bond to the
conjugated position) (E)-δ-hydroxy-β-methyl-α,β-un-
saturated acids.
In the present article we report on the synthesis of
methyl 3-bromomethylbut-3-enoate (I) and its conden-
sation with electrophiles in the presence of metallic
zinc, as well as on the use of compound I as isoprenoid
building block in the synthesis of isotretinoin (II) [3, 7,
21–28]. The reaction of readily accessible ethyl 3,3-di-
ethoxypropionate (III) with ethylmagnesium bromide
in the presence of titanium(IV) isopropoxide [29, 30]
gave 1-substituted cyclopropanol IV which was treated
with methanesulfonyl chloride. Oxidation of the acetal
moiety in the resulting methanesulfonate V with a mix-
ture of hydrogen peroxide and concentrated hydro-
chloric acid in methanol [31] led to ester VI, and re-
placement of the methylsulfonyloxy group by bromine
by the action of magnesium bromide via cationic
cyclopropyl–allyl isomerization [32, 33] afforded com-
pound I in an overall yield of 42% (Scheme 1). Like-
wise, the corresponding chlorine-containing compound
VII was obtained by treatment of VI with titanium
tetrachloride in methylene chloride.
Allyl halides I and VII were then used as nucleo-
philic C5 building blocks in reactions with aldehydes
VIIIa–VIIIc and tributylchlorostannane (IX). The lat-
ter were selected as electrophiles, taking into account
1261

MINEEVA, KULINKOVICH
1262
Scheme 1.
EtMgBr, Ti(OPr-i)4
THF
MeSO2Cl, Et3N
Et2O
OEt
O
OEt OH
OEt OSO2Me
90%
95%
EtO
OEt
EtO
EtO
III
IV
V
MgBr2, Et2O, CHCl3
or TiCl4, CH2Cl2
O
OSO2Me
O
CH2
H2O2, HCl, MeOH
70%
X
60–70%
MeO
MeO
VI
I, VII
I, X = Br; VII, X = Cl.
Scheme 2.
Me
O
CH2 OH
Zn, THF
53–60%
Zn, THF, NH4Cl
70–75%
I
+
RCHO
MeO
R
O
O
R
XIa, XIc
VIIIa–VIIIc
Xa–Xc
Me
Me
Me
R = Me2C=CH (a),
(b), PhCH2OCH2 (c).
Me
that the expected condensation products could be
promising as intermediate products in the synthesis of
bioactive compounds [6, 7, 19, 34]. Aldehydes VIIIa–
VIIIc reacted with allyl bromide I taken in a slight
excess and zinc powder in a mixture of tetrahydrofuran
with a saturated aqueous solution of ammonium chlo-
ride [35–39] to produce the corresponding δ-hydroxy-
β-methylidenealkanoic acid esters Xa–Xc in good
yields. When the reaction was carried out in the ab-
sence of ammonium chloride, the allylation of alde-
hydes VIIIa and VIIIc was accompanied by lactoniza-
tion and migration of the double C=C bond to the con-
jugated position, As a result, unsaturated δ-lactones
XIa and XIc were obtained (Scheme 2). Under analo-
gous conditions, β-ionylideneacetaldehyde (VIIIb)
gave rise to a complex mixture of products.
satisfactory results were obtained when the reaction
was performed in the absence of ammonium chloride.
Our attempts to react allyl chloride VII with aldehydes
VIII and tributilchlorostannane (IX) in the presence of
zinc were unsuccessful, regardless of whether NH4Cl
was added to the reaction mixture or not.
The cyclization of δ-hydroxy-β-methylidene deriva-
tive Xb and subsequent double bond migration in the
lactone thus formed were used to obtain isotretinoin
(II). By treatment of compound Xb with sodium car-
bonate in methanol at room temperature we obtained
lactone XIII in a high yield, and intramolecular
1,2-elimination in XIII by the action of potassium tert-
butoxide in tetrahydrofuran [21], followed by acidifi-
cation, afforded isotretinoin II (Scheme 4). The yield
of II calculated on the initial aldehyde VIIIb was 46%.
The allylation of tributylchlorostannane (IX) with
compound I in the presence of zinc and aqueous
ammonium chloride [40, 41] involved no considerable
problems, and functionally substituted allylstannane
XII was isolated in a moderate yield by column chro-
matography (Scheme 3). As with aldehyde VIIIc, no
We can conclude that successful allylation of elec-
trophilic substrates VIII and IX with substituted allyl
bromide I by the action of zinc in aqueous–organic
medium makes compound I promising as nucleophilic
C5 building block.
EXPERIMENTAL
Scheme 3.
O
CH2
The 1H and 13C NMR were recorded from solutions
in chloroform on a Bruker AC 400 spectrometer at 400
and 100 MHz, respectively. The IR spectra were meas-
Zn, THF, NH4Cl
60%
I + Bu3SnCl
SnBu3
MeO
IX
XII
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 9 2008

SYNTHESIS OF METHYL 3-BROMOMETHYLBUT-3-ENOATE
1263
Scheme 4.
O
Me
O
Me
Me
O
(1) t-BuOK
Me
Me
Me
Me
Na2CO3, MeOH
76%
(2) H+
Xb
Me
80%
Me
Me
OH
XIII
II
ured from solutions in carbon tetrachloride on Specord
75 IR and Vertex 70 instruments. The products were
isolated by chromatography on silica gel (70–
230 mesh, Merck). All solvents were purified by stand-
ard procedures prior to use. The elemental composi-
tions were determined by a semimicro method. The
melting points were determined on an Apotec melting
point apparatus.
1H NMR spectrum, δ, ppm: 0.78–0.82 m (2H, CH2),
1.19 t (6H, CH3CH2, J = 7 Hz), 1.21–1.25 m (2H,
CH2), 2.13 d (2H, CHCH2C, J = 5.4 Hz), 3.00 s (3H,
CH3S), 3.49–3.57 m (2H, CH2O), 3.62–3.70 m (2H,
CH2O), 4.78 t (1H, OCHO, J = 5.4 Hz). 13C NMR
spectrum, δC, ppm: 11.55 (CH2, cyclopropane), 15.24
(CH3), 39.83 (CH3), 40.33 (CH2), 62.05 (COS), 63.78
(CH2), 100.89 (CH). Found, %: C 47.74; H 7.93.
C10H20O5S. Calculated, %: C 47.60; H 7.99.
1-(2,2-Diethoxyethyl)cyclopropan-1-ol (IV). A so-
lution of 150 mmol of ethylmagnesium bromide in
100 ml of THF was added over a period of 6 h under
stirring to a solution of 9.5 g (50 mmol) of ethyl
3,3-diethoxypropionate (III) [42] and 2.8 ml (10 mmol,
20 mol %) of titanium(IV) isopropoxide in 50 ml of
THF. The mixture was stirred for 12 h, the solvent was
removed under reduced pressure, and 100 ml of meth-
ylene chloride and 15 ml of a saturated aqueous solu-
tion of ammonium chloride were added to the residue.
The mixture was filtered, the precipitate was washed
with methylene chloride (3×50 ml), and the organic
phase was washed with a saturated aqueous solution of
NaHCO3 (3×50 ml) and a solution of NaCl (50 ml)
and dried over Na2SO4. The solvent was removed
under reduced pressure to isolate 7.83 g (90%) of al-
cohol IV as an oily liquid whose spectral parameters
were in agreement with those given in [43].
Methyl (1-methylsulfonyloxycyclopropyl)acetate
(VI). A solution of 42.25 g (166 mmol) of compound
V in 260 ml of methanol was cooled to 0°C, 21.1 ml of
concentrated hydrochloric acid was added, 28.9 ml of
33% hydrogen peroxide was then added, and the mix-
ture was stirred for 1 h and heated for 5 h at 50–55°C.
The mixture was then cooled to 0°C, 14.2 ml of con-
centrated hydrochloric acid and 19.4 ml of 33% hydro-
gen peroxide were added, and the mixture was heated
again for 5 h at 50–55°C. The most part of methanol
was removed under reduced pressure, the residue was
diluted with ethyl acetate and neutralized with a satu-
rated aqueous solution of NaHCO3, and the organic
layer was separated and dried over Na2SO4. Removal
of the solvent gave 24.18 g (70%) of compound VI as
an oily liquid whose spectral parameters were in agree-
ment with those given in [43].
1-(2,2-Diethoxyethyl)cyclopropyl methanesulfo-
nate (V). A solution of 8.6 ml (62 mmol) of triethyl-
amine and 3.6 ml (37 mmol) of methanesulfonyl
chloride in 20 ml of anhydrous diethyl ether was added
under stirring to a solution of 5.38 g (31 mmol) of
compound IV in 35 ml of anhydrous diethyl ether,
cooled to 0°C. The mixture was stirred for 2 h, treated
with a saturated aqueous solution of NaHCO3 (40 ml),
and stirred for 1 h more. The organic layer was sepa-
rated, the aqueous phase was extracted with diethyl
ether (3×25 ml), and the extracts were combined with
the organic phase, washed with a solution of sodium
chloride (50 ml), and dried over Na2SO4. The drying
agent was filtered off, and the solvent was distilled off
to obtain 7.49 g (95%) of compound V as an oily
liquid. IR spectrum, ν, cm–1: 1331, 1171, 1145 (CO2).
Methyl 3-bromomethylbut-3-enoate (I). A solu-
tion of 23.28 g (112 mmol) of methanesulfonate VI in
150 ml of chloroform was added dropwise under
stirring to a solution of MgBr2 prepared from 8.06 g
(336 mmol) of magnesium turnings and 29.7 ml of
1,2-dibromoethane in 200 ml of anhydrous diethyl
ether. The mixture was heated for 8 h under reflux with
stirring and treated with 100 ml of water. The organic
layer was separated, and the aqueous phase was ex-
tracted with chloroform (3×100 ml). The extracts were
combined with the organic phase, washed in succes-
sion with a saturated aqueous solution of NaHCO3
(3×75 ml) and a solution of NaCl (150 ml) and dried
over MgSO4. The solvent was distilled off under
reduced pressure, and the residue was subjected to
chromatography using petroleum ether–ethyl acetate
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 9 2008

MINEEVA, KULINKOVICH
1264
(40:1) as eluent to isolate 15.26 g (70%) of compound
OH), 2.24–2.32 m (2H, CH2CHOH), 3.07 d (1H,
CH2CO, J = 15.3 Hz), 3.14 d (1H, CH2CO, J =
15.3 Hz), 3.68 s (3H, CH3O), 4.46 d.t (1H, CHOH,
J1 = 9, J2 = 5.6 Hz), 5.02 br.s (1H, CH2=), 5.05 br.s
(1H, CH2=), 5.16 d (1H, CH=, J = 9 Hz). 13C NMR
spectrum, δC, ppm: 18.13 (CH3), 25.65 (CH3), 41.64
(CH2), 44.36 (CH2), 51.90 (CH3O), 66.40 (CH), 117.34
(CH2=), 127.17 (CH), 135.17 (C), 138.92 (C), 172.07
(CO). Found, %: C 66.77; H 9.10. C12H18O3. Calculat-
ed, %: C 66.64; H 9.15.
I as a yellowish oily liquid. IR spectrum: ν 1743 cm–1
1
(C=O). H NMR spectrum, δ, ppm: 3.24 s (2H,
CH2CO), 3.70 s (3H, CH3O), 4.18 s (2H, CH2Br),
13
5.13 br.s (1H, CH2=), 5.31 br.s (1H, CH2=). C NMR
spectrum, δC, ppm: 38.23 (CH2Br), 47.64 (CH2), 51.98
(CH3O), 118.94 (CH2), 138.24 (C), 171.13 (C=O).
Found, %: C 37.45; H 4.65. C6H9BrO2. Calculated, %:
C 37.33; H 4.70.
Methyl 3-chloromethylbut-3-enoate (VII). A so-
lution of 4.3 ml (39 mmol) of titanium tetrachloride in
60 ml of anhydrous methylene chloride was cooled to
0°C, a solution of 4.00 g (19 mmol) of methanesul-
fonate VI in 10 ml of methylene chloride was added,
and the mixture was stirred for 6 h and treated with
a saturated aqueous solution of NaHCO3 (20 ml). The
organic phase was separated, the aqueous phase was
extracted with methylene chloride (3×15 ml), and the
extracts were combined with the organic phase,
washed with a saturated aqueous solution of NaCl
(40 ml), and dried MgSO4. The solvent was distilled
off under reduced pressure, and the residue was sub-
jected to column chromatography using petroleum
ether–ethyl acetate (40:1) as eluent to isolate 1.71 g
(60%) of allyl chloride VII as an oily liquid. IR spec-
Methyl (6E,8E)-5-hydroxy-7-methyl-3-methyli-
dene-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-6,8-
dienoate (Xb). Yield 1.04 g (75%). IR spectrum, ν,
1
cm–1: 3615 (OH), 1741 (C=O). H NMR spectrum,
δ, ppm: 0.99 s (6H, CH3), 1.41–1.46 m [2H,
CH2C(CH3)2], 1.54–1.62 m (2H, CH2CH2CH2), 1.67 s
(3H, CH3C=C), 1.85 s (3H, CH3C=CH), 1.97–2.00 m
(2H, CH2CCH3), 2.32–2.35 m (2H, CH2CHOH),
3.11 d (1H, CH2CO, J = 15.3 Hz), 3.17 d (1H, CH2CO,
J = 15.3 Hz), 3.70 s (3H, CH3O), 4.65 d.t (1H, CHOH,
J1 = 8.2, J2 = 6.4 Hz), 5.07 br.s (1H, CH2=), 5.09 br.s
(1H, CH2=), 5.40 d (1H, CHCHOH, J = 8 Hz), 5.99 d
(1H, CCHCH, J = 16.1 Hz), 6.10 d (1H, CCHCH,
J = 16.1 Hz). 13C NMR spectrum, δC, ppm: 12.75
(9-CH3),19.19 (C3), 21.56 (5-CH3), 28.82 (CH3), 32.82
(C4), 34.12 (C1), 39.43 (C2), 41.65 (C14), 44.35 (C12),
51.95 (CH3O), 66.42 (C11), 117.68 (CH2=), 126.94
(C7), 128.92 (C5), 131.78 (C10), 135.95 (C9), 136.96
(C8), 137.46 (C13), 138.72 (C6), 172.08 (C15). Found,
%: C 76.98; H 9.63. C21H32O3. Calculated, %: C 75.86;
H 9.70.
1
trum: ν 1744 cm–1 (C=O). H NMR spectrum, δ, ppm:
3.23 s (2H, CH2CO), 3.69 s (3H, CH3O), 4.17 s (2H,
CH2Cl), 5.11 br.s (1H, CH2=), 5.29 br.s (1H, CH2=).
13C NMR spectrum, δC, ppm: 38.17 (CH2), 47.61
(CH2Cl), 51.93 (CH3O), 118.90 (CH2), 138.21 (C),
171.10 (CO). Found, %: C 48.64; H 6.07. C6H9ClO2.
Calculated, %: C 48.50; H 6.11.
Methyl 3-[3-(benzyloxy)-2-hydroxypropyl]but-3-
Methyl δ-hydroxy-β-methylidene carboxylates
Xa–Xc (general procedure). A saturated solution of
ammonium chloride, 25 ml, was added to a solution of
4 mmol of aldehyde VIIIa, VIIIb [44], or VIIIc in
2.5 ml of THF, 0.32 g (5 mmol) of zinc powder was
added under vigorous stirring, and a solution of 1.00 g
(5 mmol) of allyl bromide I in 2.5 ml of tetrahydro-
furan was added over a period of 20 min. The mixture
was vigorously stirred for 1 h and extracted with di-
ethyl ether (3×15 ml), and the extracts were combined,
washed with a saturated solution of NaHCO3 (20 ml),
and dried over MgSO4. The solvent was distilled off
under reduced pressure, and the product was isolated
by column chromatography using petroleum ether–
ethyl acetate (25:1) as eluent.
enoate (Xc). Yield 0.80 g (73%). IR spectrum, ν, cm–1:
1
3589 (OH), 1742 (C=O). H NMR spectrum, δ, ppm:
2.25 d.d (1H, CH2CHOH, J1 = 14.3, J2 = 8.7 Hz),
2.32 d.d (1H, CH2CHOH, J1 = 14.3, J2 = 4 Hz),
2.73 br.s (1H, OH), 3.07–3.16 m (2H, CH2CO),
3.39 d.d (1H, CH2OBzl, J1 = 9.5, J2 = 7.2 Hz), 3.49 d.d
(1H, CH2OBzl, J1 = 9.5, J2 = 3.8 Hz), 3.67 s (3H,
CH3O), 3.93–3.99 m (1H, CHOH), 4.55 s (2H,
CH2Ph), 5.01 br.s (1H, CH2=), 5.05 br.s (1H, CH2=),
7.27–7.36 m (5H, Ph). 13C NMR spectrum, δC, ppm:
40.09 (CH2), 41.46 (CH2), 51.80 (CH3O), 68.41
(CHOH), 73.29 (CH2Ph), 73.97 (CH2OBzl), 117.06
(CH2=), 127.64 (Co, Cp), 128.33 (Cm), 137.86 (Ci),
138.70 (C), 171.99 (CO). Found, %: C 68.36; H 7.54.
C15H20O4. Calculated, %: C 68.16; H 7.63.
Methyl 5-hydroxy-7-methyl-3-methylideneoct-6-
Lactones XIa and XIc (general procedure). Alde-
hyde VIIIa or VIIIc, 5.0 mmol, was dissolved in 3 ml
of anhydrous THF, 1.00 g (5 mmol) of allyl bromide I
and 0.55 g (9 mmol) of zinc powder were added to the
enoate (Xa). Yield 0.57 g (70%). IR spectrum, ν, cm–1:
1
3615 (OH), 1741 (C=O). H NMR spectrum, δ, ppm:
1.67 s (3H, CH3), 1.70 s (3H, CH3), 2.01 br.s (1H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 9 2008

SYNTHESIS OF METHYL 3-BROMOMETHYLBUT-3-ENOATE
1265
solution, and the mixture was heated for 20 min under
reflux with stirring. The solvent was distilled off under
reduced pressure, 25 ml of diethyl ether and 3 ml of
a saturated aqueous solution of NH4Cl were added to
the residue, the mixture was filtered, and the organic
phase was separated, washed with a saturated aqueous
solution of NH4Cl (3×15 ml), and dried over MgSO4.
The solvent was distilled off under reduced pressure,
and the product was isolated by column chromatog-
raphy using petroleum ether–ethyl acetate (20:1) as
eluent.
petroleum ether–ethyl acetate (80:1) as eluent to iso-
late 5.16 g (60%) of compound XII as a colorless oily
1
liquid. IR spectrum: ν 1742 cm–1 (C=O). H NMR
spectrum, δ, ppm: 0.78–0.95 m (15H, CH3), 1.24–
1.33 m (6H, CH2CH2Sn), 1.39–1.53 m (6H, CH3CH2),
1.84 s (2H, CH2Sn), 2.95 s (2H, CH2CO), 3.68 s (3H,
CH3O), 4.59 br.s (1H, CH2=), 4.68 br.s (1H, CH2=).
13C NMR spectrum, δC, ppm: 9.44 (CH2), 13.63 (CH3),
18.85 (CH2), 27.30 (CH2), 29.00 (CH2), 43.78 (CH2),
51.74 (CH3O), 109.13 (CH2=), 142.75 (C), 171.89
(CO). Found, %: C 54.83; H 9.08. C19H38O2Sn. Cal-
culated, %: C 54.70; H 9.18.
4-Methyl-6-(2-methylprop-1-en-1-yl)-5,6-dihy-
dro-2H-pyran-2-one (XIa). Yield 0.49 g (60%). IR
4-Methyl-6-[(1E,3E)-2-methyl-4-(2,6,6-tri-
methylcyclohex-1-en-1-yl)buta-1,3-dien-1-yl]-5,6-
dihydro-2H-pyran-2-one (XIII). Sodium carbonate,
0.8 g, was added to a mixture of 1 g (3 mmol) of
alcohol Xb in 20 ml of methanol, and the mixture was
stirred for 2 h at room temperature, treated with 20 ml
of water, and extracted with diethyl ether (3×20 ml).
The extracts were combined and dried over MgSO4,
the solvent was distilled off under reduced pressure,
and the residue was subjected to column chromatog-
raphy using petroleum ether–ethyl acetate (25:1) as
eluent to isolate 0.7 g (76%) of compound XIII as
a bright yellow oily liquid whose spectral parameters
were consistent with those reported in [17].
1
spectrum: ν 1729 cm–1 (C=O). H NMR spectrum, δ,
ppm: 1.66 s (3H, CH3), 1.71 s (3H, CH3), 1.94 s (3H,
CH3), 2.17 d.d (1H, CH2CHO, J1 = 17.9, J2 = 4.1 Hz),
2.33 d.d (1H, CH2CHO, J1 = 17.9, J2 = 11.1 Hz),
5.04 d.d.d (1H, CH2CHO, J1 = 11.1, J2 = 8.7, J3 =
4.1 Hz), 5.26 d [1H, CH=C(CH3)2, J = 8.7 Hz],
5.75 br.s (1H, CHCO). 13C NMR spectrum, δC, ppm:
18.18 (CH3), 22.82 (CH3), 25.53 (CH3), 34.88 (CH2),
74.05 (CH), 116.35 (CH), 121.95 (CH), 139.11 (C),
157.03 (C), 165.12 (CO). Found, %: C 72.39; H 8.32.
C10H14O2. Calculated, %: C 72.26; H 8.49.
6-(Benzyloxymethyl)-4-methyl-5,6-dihydro-2H-
pyran-2-one (XIc). Yield 0.61 g (53%). IR spectrum:
ν 1731 cm–1 (C=O). 1H NMR spectrum, δ, ppm: 1.98 s
(3H, CH3), 2.26 d.d (1H, CH2CHO, J1 = 17.9, J2 =
4 Hz), 2.55 d.d (1H, CH2CHO, J1 = 17.9, J2 =
11.7 Hz), 3.63–3.71 m (2H, CH2OBzl), 4.53–4.57 m
(1H, CH2CHO), 4.59 br.s (2H, CH2Ph), 5.80 br.s (1H,
CHCO), 7.28–7.40 m (5H, Ph). 13C NMR spectrum,
δC, ppm: 22.95 (CH3), 31.33 (CH2), 70.74 (CH2OBzl),
73.59 (CH2Ph), 75.86 (CH), 116.20 (CH), 127.96 (Co),
128.31 (Cm), 128.41 (Cp), 131.61 (Ci), 157.07 (C),
164.51 (CO). Found, %: C 72.47; H 6.86. C14H16O3.
Calculated, %: C 72.39; H 6.94.
(2Z,4E,6E,8E)-3,7-Dimethyl-9-(2,6,6-trimethyl-
cyclohex-1-en-1-yl)nona-2,4,6,8-tetraenoic acid (II,
isotretinoin). A solution of 0.4 g (1 mmol) of com-
pound XIII in 2 ml of tetrahydrofuran was cooled to
0°C, 0.13 g (1 mmol) of potassium tert-butoxide was
added under argon, and the mixture was stirred for 1 h.
The mixture was then treated with 10 ml of diethyl
ether and 2 ml of 1 N hydrochloric acid, the organic
phase was separated, the aqueous phase was extracted
with diethyl ether (3×10 ml), and the extracts were
combined with the organic phase and dried over
MgSO4. The solvent was removed, and the residue was
recrystallized twice from methanol to obtain 0.32 g
(80%) of isotretinoin (II) as yellow–orange crystals
with mp 171–173°C; published data [21]: mp 171–
172°C (from MeOH). The spectral parameters of the
product coincided with those reported in [23].
Methyl 3-(tributylstannylmethyl)but-3-enoate
(XII). Tributylchlorostannane, 7 g (22 mmol), was
dissolved in 10 ml of THF, 130 ml of a saturated
aqueous solution of NH4Cl and 1.68 g (26 mmol) of
zinc powder were added under vigorous stirring, and
a solution of 5 g (26 mmol) of allyl bromide I in 26 ml
of THF was added over a period of 20 min. An ad-
ditional portion of zinc, 1.68 g (26 mmol), was then
added, and the mixture was stirred for 1 h and ex-
tracted with diethyl ether (3×75 ml). The extracts were
combined, washed with a saturated aqueous solution of
NaHCO3 (40 ml), and dried over MgSO4. The solvent
was distilled off under reduced pressure, and the resi-
due was subjected to column chromatography using
REFERENCES
1. Hanson, J.R., Comprehensive Organic Chemistry, Bar-
ton, D. and Ollis, W.D., Eds., Oxford: Pergamon, 1979,
vol. 6. Translated under the title Obshchaya organiche-
skaya khimiya, Moscow: Khimiya, 1986, vol. 11, p. 482.
2. Huisman, H.O., Pure Appl. Chem., 1977, vol. 49, p. 1307.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 9 2008

MINEEVA, KULINKOVICH
1266
3. Cainelli, G. and Cardillo, G., Acc. Chem. Res., 1981,
24. Valla, A., Andriamialisoa, Z., Prat, V., Laurent, A.,
Giraud, M., Labia, R., and Potier, P., Tetrahedron, 2000,
vol. 56, p. 7211.
vol. 14, p. 89.
4. Constantino, M.G. and Losco, P., J. Org. Chem., 1989,
25. Solladie, G. and Girardin, A., J. Org. Chem., 1989,
vol. 54, p. 681.
vol. 54, p. 2620.
5. Gedye, R.N., Arora, P., and Khalil, A.H., Can. J. Chem.,
1975, vol. 53, p. 1943.
26. Paust, J., Pure Appl. Chem., 1991, vol. 63, p. 45.
6. Cardillo, G., Orena, M., and Sandri, S., Tetrahedron,
1976, vol. 32, p. 107.
7. Salman, M., Babu, S.J., Kaul, V.K., Ray, P.R., and
27. Pattenden, G., Weedon, C.L., Garbers, C.F., Schnei-
der, D.F., and van der Merve, J.P., Chem. Commun.,
1965, p. 347.
28. Korver, P.K., Kruk, C., van der Haak, P.J., Baas, J.L.,
Kumar, N., Org. Proc. Res. Dev., 2005, vol. 9, p. 302.
and Huisman, H.O., Tetrahedron, 1966, vol. 22, p. 277.
8. Eiter, K., Truscheit, E., and Oediger, H., Angew. Chem.,
29. Kulinkovich, O.G., Sviridov, S.V., Vasilevskii, D.A., and
1960, vol. 72, p. 948.
Pritytskaya, T.S., Zh. Org. Khim., 1989, vol. 25, p. 2244.
9. Julia, M. and Arnold, D., Bull. Soc. Chim. Fr., 1973,
30. Kulinkovich, O.G., Sviridov, S.V., and Vasilevskii, D.A.,
p. 746.
Synthesis, 1991, p. 234.
31. Takeda, T., Watanabe, H., and Kitahara, T., Synlett,
10. Wang, Y., Woo, W.S., Hoef, I., and Lugtenburg, J., Eur.
J. Org. Chem., 2004, p. 2166.
1997, p. 1149.
11. Wang, Y. and Lugtenburg, J., Eur. J. Org. Chem., 2004,
32. Kozyrkov, Yu.Yu. and Kulinkovich, O.G., Synlett, 2002,
p. 3497.
p. 443.
12. Wang, Y. and Lugtenburg, J., Eur. J. Org. Chem., 2004,
33. Kulinkovich, O.G., Kozyrkov, Yu.Yu., Bekish, A.V.,
Matiushenkov, E.A., and Lysenko, I.L., Synthesis, 2005,
p. 1713.
p. 5100.
13. Jeon, H.-S., Yeo, J.E., and Jeong, Y.C., Synthesis, 2004,
p. 2813.
34. Keck, G.E., Covel, J.A., Schiff, T., and Yu, T., Org.
Lett., 2002, vol. 4, p. 1189.
35. Mattes, H. and Benezra, C., Tetrahedron Lett., 1985,
vol. 26, p. 5697.
14. Boehm, M.F., McClurg, M.R., Pathirana, C., Mangels-
dorf, D., White, S.K., Hebert, J., Goldman, M.E., and
Heyman, R.A., J. Med. Chem., 1994, vol. 37, p. 408.
15. Bennani, Y.L. and Boehm, M.F., J. Org. Chem., 1995,
36. Einhorn, C. and Luche, J.L., J. Organomet. Chem.,
1987, vol. 322, p. 177.
37. Petrier, C., Einhorn, J., and Luche, J.L., Tetrahedron
Lett., 1985, vol. 26, p. 1449.
vol. 60, p. 1195.
16. Valla, A., Prat, V., Lauren, A., Andriamialisoa, Z.,
Cartier, D., Giraud, M., Labia, R., and Potier, P., Helv.
Chim. Acta, 2001, vol. 84, p. 3423.
38. Wilson, S.R. and Guazzaroni, M.E., J. Org. Chem.,
1989, vol. 54, p. 3087.
17. Dugger, R.W. and Heathcock, C.H., J. Org. Chem.,
1980, vol. 45, p. 1181.
39. Petrier, C. and Luche, J.L., J. Org. Chem., 1985, vol. 50,
p. 912.
40. Von Gyldenfeldt, F., Marton, D., and Tagliavini, G.,
18. Keck, G.E. and Yu, T., Org. Lett., 1999, vol. 1, p. 289.
19. Sanchez, C.C. and Keck, G.E., Org. Lett., 2005, vol. 7,
p. 3053.
Organometallics, 1994, vol. 13, p. 906.
41. Carofiglio, T., Marton, D., and Tagliavini, G.,
20. Keck, G.E. and Palani, A., Tetrahedron Lett., 1993,
vol. 34, p. 3223.
Organometallics, 1992, vol. 11, p. 2961.
42. Holy, A., Collect. Czech. Chem. Commun., 1974,
21. Cainelli, G., Cardillo, G., Contento, M., Grasselli, P., and
Ronchi, A.U., Gazz. Chim. Ital., 1973, vol. 103, p. 117.
vol. 39, p. 3177.
43. Limbach, M., Dalai, S., and de Meijere, A., Adv. Synth.
Catal., 2004, vol. 346, p. 760.
22. Valla, A., Andriamialisoa, Z., Giraud, M., Prat, M.,
Laurent, A., and Potier, P., Tetrahedron Lett., 1999,
vol. 40, p. 9235.
23. Cahard, D., Mammeri, M., Poirier, J.-M., and Duha-
44. Andrewes, A.G. and Liaaen-Jensen, S., Acta Chem.
Scand., 1973, vol. 27, p. 1401.
mel, L., Tetrahedron Lett., 2000, vol. 41, p. 3619.
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