(2E)-4-hydroxyalk-2-enals and 2-substituted furans as products of reactions of (2E)-4,4-dimethoxybut-2-enal with Grignard compounds

Article abstract of DOI:10.1134/S1070428010030188

Methods have been developed for the synthesis of (2E)-1,1-dimethoxyalk-2- en-4-ols and (2E)-4-hydroxyalk-2-enals by reaction of (2E)-4,4-dimethoxybut-2- enals and Grignard compounds. Thermal isomerization of (2E)-4-hydroxyalk-2-enals gave the corresponding 2-alkylfurans.

Full text of DOI:10.1134/S1070428010030188

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 3, pp. 406–409. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © O.A. Garibyan, A.L. Ovanesyan, G.M. Makaryan, A.L. Petrosyan, Zh.A. Chobanyan, 2010, published in Zhurnal Organicheskoi
Khimii, 2010, Vol. 46, No. 3, pp. 412–415.
(2E)-4-Hydroxyalk-2-enals and 2-Substituted Furans
as Products of Reactions of (2E)-4,4-Dimethoxybut-2-enal
with Grignard Compounds
O. A. Garibyan, A. L. Ovanesyan†, G. M. Makaryan, A. L. Petrosyan, and Zh. A. Chobanyan
Institute of Organic Chemistry, National Academy of Sciences of Armenia,
ul. Zakariya Kanakertsi 167a, Erevan, 375091 Armenia
e-mail: hovhghar@freenet.am
Received January 12, 2009
Abstract—Methods have been developed for the synthesis of (2E)-1,1-dimethoxyalk-2-en-4-ols and
(2E)-4-hydroxyalk-2-enals by reaction of (2E)-4,4-dimethoxybut-2-enals and Grignard compounds. Thermal
isomerization of (2E)-4-hydroxyalk-2-enals gave the corresponding 2-alkylfurans.
DOI: 10.1134/S1070428010030188
in 39–50% yield (Scheme 1). (2E)-4-Hydroxynon-2-
enal (IIId) is a lipid metabolite which was isolated
from the red marine alga Liagora farinosa Lamouroux
[6]. Using the reaction with propylmagnesium bromide
(IIb) as model process we examined the effect of
different factors, such as reaction temperature, workup
procedure, and order of mixing of the reactants, on the
reaction course. The reaction occurred at a temperature
below 0°C. Addition of aldehyde I to propylmagne-
sium bromide (IIb) at –55 to 0°C did not change the
reaction pattern to an appreciable extent. The same
products were formed when the reactants were mixed
in the reverse order.
(2E)-4,4-Dimethoxybut-2-enal (I) molecule pos-
sesses a double bond and an aldehyde group, so that
compound I is quite promising as polyfunctional
synthon for the design of various organic compounds.
It is widely used in the synthesis of a number of low-
molecular weight bioregulators such as pheromones
[1], cyclohexane analogs of prostaglandins [2], may-
tansinoids (macrocyclic lactams exhibiting antitumor,
antimyotic, and antifungal activity) [3], cephalosporin
analogs [4], etc.
In continuation of studies in this field, the goal of
the present work was to synthesize from 4,4-dime-
thoxybut-2-enal (I) (2E)-4-hydroxyalk-2-enals which
can be converted into cyclopentenone derivatives (in-
termediate compounds in the synthesis of prostaglan-
dins [5]) via aldol condensation.
Intermediate organomagnesium complex was
decomposed by treatment with a dilute solution of
p-toluenesulfonic or hydrochloric acid or with water.
In the first case, hydroxy aldehyde IIIb was the only
product, regardless of the acid nature. When the mix-
ture was treated with water at room temperature and
then distilled over potassium carbonate, dimethoxy
alcohol IVa may be obtained as the major product.
Further experiments showed that pH value (5–6) is not
a significant factor that could affect the process. The
acetal protection was conserved, and dimethoxy alco-
hol IVb was formed if the reaction mixture was treated
with an acid at –30°C (Scheme 2).
The reaction of aldehyde I with alkylmagnesium
bromides IIa–IId in diethyl ether at 0°C resulted in the
formation of unsaturated hydroxy aldehydes IIIa–IIId
Scheme 1.
OMe
R
+
RMgBr
MeO
CHO
HO
CHO
I
IIa–IId
IIIa–IIId
R = Et (a), Pr (b), Bu (c), C5H11 (d).
Compounds IIIa–IIId were isolated by distillation
or column chromatography on silica gel (eluent hex-
†
Deceased.
406

(2E)-4-HYDROXYALK-2-ENALS AND 2-SUBSTITUTED FURANS
407
Scheme 2.
EXPERIMENTAL
R
The H and 13C NMR spectra were measured on
a Varian Mercury-300 spectrometer at 300 MHz; the
chemical shifts were determined relative to tetra-
methylsilane. The IR spectra were recorded on
Specord and UR-20 instruments from samples pre-
pared as thin films. GLC analysis was performed on
a Chrom-5 chromatograph equipped with a flame-
ionization detector and an SE-30 glass capillary col-
umn, 25 m×0.2 mm; carrier gas nitrogen, flow rate
30 ml/min. Silica gel L 40/100 was used for column
chromatography, and TLC was performed on Silufol
UV-254 plates; spots were detected by UV irradiation
or by treatment with iodine vapor or a solution of
potassium permanganate.
1
OMe
I
+
IIa, IIb
HO
OMe
IVa, IVb
R = Et (a), Pr (b).
ane–diethyl ether, 19:1 to 2:1). The reaction of alde-
hyde I with hexylmagnesium bromide (IIe) under
analogous conditions (diethyl ether, 0°C) gave either
(2E)-4-hydroxydec-2-enal (IIIe) or a mixture of IIIe
and 2-hexylfuran (Ve), depending on the workup
procedure (Scheme 3).
Scheme 3.
Reaction of (2E)-4,4-dimethoxybut-2-enal (I)
with Grignard compounds IIa–IIe (general proce-
dure). A solution of 6.5 g (0.05 mol) of (2E)-4,4-di-
methoxybut-2-enal (I) in 65 ml of anhydrous diethyl
ether was added dropwise under stirring at 0°C to
Grignard compound IIa–IIe prepared from 1.32 g
(0.055 mol) of magnesium and 0.055 mol of the corre-
sponding alkyl halide in 50 ml of anhydrous diethyl
ether. The mixture was stirred for 30 min at 0°C and
for 1 h at room temperature. The mixture was cooled
again to 0°C, and dilute hydrochloric acid was added
dropwise to pH 5–6. The mixture was neutralized with
sodium carbonate and extracted with diethyl ether, the
extract was dried over Na2SO4, the solvent was re-
moved, and the crude product was purified by column
chromatography or distilled under reduced pressure.
OH
I
+ C6H13MgBr
C6H13
CHO
IIe
IIIe
+
C6H13
O
Ve
Aldehyde IIIe was obtained as the only product
when the mixture was subjected to column chromatog-
raphy on silica gel. Distillation (bp 135°C, 1 mm) gave
a mixture of (2E)-4-hydroxydec-2-enal (IIIe) and
2-hexylfuran (Ve) at a ratio of 1:4. Compounds IIIe
and Ve were isolated as individual substances by re-
peated distillation.
It is known that some 4-hydroxyalk-2-enals under-
go cyclization into 2-substituted furans in the presence
of mineral acids or Lewis acids; the double bond in the
initial compounds should have cis-configuration to
ensure cyclization [7]. Hydroxy aldehydes IIIa–IIIe
were converted into the corresponding 2-alkylfurans
Va–Ve [8] above 130°C, and the yields of Va–Ve were
41–45% (Scheme 4).
(2E)-4-Hydroxyhex-2-enal (IIIa). Yield 49%,
bp 89–90°C (2 mm), Rf 0.24 (hexane–diethyl ether,
3:2). IR spectrum, ν, cm–1: 3400–3500 (OH), 1690
1
(C=O), 1610 (C=C), 960 (trans-C=C). H NMR spec-
trum (CDCl3), δ, ppm: 0.94 t (3H, 6-H, J = 7.2 Hz),
1.25–1.70 m (2H, 5-H), 3.85 br.s (1H, OH), 4.25 q
(1H, 4-H, J4,3 = J4,5 = 7.1 Hz), 6.15 d.d (1H, 3-H, J3,2
17.0, J3,4 = 7.1 Hz), 6.82 d.d (1H, 2-H, J1,2 = 7.5, J2,3
=
=
17.0 Hz), 9.52 d (1H, 1-H, J2,1 = 7.5 Hz). Found, %:
C 63.11; H 8.81. C6H10O2. Calculated, %: C 63.14;
H 8.83.
Scheme 4.
OH
Δ
R
O
R
CHO
(2E)-4-Hydroxyhept-2-enal (IIIb). Yield 48%,
bp 98–99°C (2 mm), Rf 0.44 (hexane–diethyl ether,
2:1). IR spectrum, ν, cm–1: 3400–3500 (OH), 1690
IIIa–IIIe
Va–Ve
1
Presumably, the observed intramolecular cycliza-
tion requires high temperature. No furans V were
formed when compounds IIIa–IIId were isolated by
distillation.
(C=O), 1610 (C=C), 960 (trans-C=C). H NMR spec-
trum (DMSO-d6), δ, ppm: 0.94 t (3H, 7-H, J = 7.2 Hz),
1.36–1.53 m (4H, 5-H, 6-H), 4.25 q (1H, 4-H, J4,3
=
J4,5 = 7.1 Hz), 4.85 br.s (1H, OH), 6.18 d.d (1H, 3-H,
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GARIBYAN et al.
408
J3,2 = 17.0, J3,4 = 7.1 Hz), 6.82 d.d (1H, 2-H, J1,2 = 7.5,
night. The mixture was then treated (dropwise) with
50 ml of ice water saturated with sodium chloride and
extracted with diethyl ether, the extract was dried over
potassium carbonate, the solvent was removed, and
the residue was distilled under reduced pressure over
anhydrous potassium carbonate. Yield 1.95 g (45%),
bp 85–87°C (2 mm). IR spectrum, ν, cm–1: 3450 (OH),
1120 (C-–O–C), 970 (trans-C=C). H NMR spectrum
(CDCl3), δ, ppm: 0.94 t (3H, 6-H, J6,5 = 7.1 Hz), 1.23–
1.68 m (2H, 5-H), 2.90 br.s (1H, OH), 3.25 s (6H,
J2,3 = 17.0 Hz), 9.52 d (1H, 1-H, J2,1 = 7.5 Hz). Found,
%: C 65.52; H 9.41. C7H12O2. Calculated, %: C 65.60;
H 9.44.
(2E)-4-Hydroxyoct-2-enal (IIIc). Yield 45%,
bp 110–112°C (2 mm), Rf 0.41 (hexane–diethyl ether,
2:1). IR spectrum, ν, cm–1: 3400–3500 (OH), 1690
1
1
(C=O), 1610 (C=C), 960 (trans-C=C). H NMR spec-
trum (DMSO-d6), δ, ppm: 0.94 t (3H, 8-H, J = 7.2 Hz),
1.36–1.53 m (6H, 5-H, 6-H, 7-H), 4.25 q (1H, 4-H,
J4,3 = J4,5 = 7.1 Hz), 4.82 br.s (1H, OH), 6.18 d.d (1H,
3-H, J3, 2 = 17.0, J3, 4 = 7.1 Hz), 6.82 d.d (1H, 2-H,
OCH3), 3.80–4.20 m (1H, 4-H), 4.75 d (1H, 1-H, J1,2
=
7.5 Hz), 5.40 d.d (1H, 2-H, J2,1 = 7.5, J2,3 = 17.0 Hz),
5.70 d.d (1H, 3-H, J3,2 = 17.0, J3,4 = 7.5 Hz). Found,
%: C 59.94; H 10.04. C8H16O3. Calculated, %:
C 59.97; H 10.07.
J1, 2 = 7.5, J2, 3 = 17.0 Hz), 9.52 d (1H, 1-H, J2, 1
=
7.5 Hz). Found, %: C 67.61; H 9.89. C8H14O2. Calcu-
lated, %: C 67.57; H 9.92.
(2E)-1,1-Dimethoxyhept-2-en-4-ol (IVb). A solu-
tion of 1.58 g (0.012 mol) of compound I in 25 ml of
anhydrous diethyl ether was added dropwise under
stirring at –55 to –50°C to Grignard compound IIb
prepared from 0.429 g (0.018 mol) of magnesium and
2.27 g (0.018 mol) of propyl bromide in 28 ml of an-
hydrous diethyl ether. The mixture was stirred for 3 h,
allowed to warm up to room temperature, and left
overnight. The mixture was then treated dropwise with
a solution of 4 ml of water in 20 ml of diethyl ether on
cooling to –30 to –20°C. The organic phase was sepa-
rated, washed with several portions of water, and 9 mg
of p-toluenesulfonic acid in 0.25 ml of water was
added under stirring at –30°C. After 0.5 h, 5 mg of
anhydrous sodium carbonate was added, the mixture
was extracted with diethyl ether, the extract was dried
over Na2SO4, the solvent was removed, and the residue
was distilled under reduced pressure. Yield 1.1 g
(53%), bp 98–100°C (12 mm). IR spectrum, ν, cm–1:
3450 (OH), 1110 (C–O–C), 970 (trans-C=C). 1H NMR
(2E)-Hydroxynon-2-enal (IIId). Yield 44%,
bp 125–127°C (2 mm), Rf 0.37 (hexane–diethyl ether,
2:1). IR spectrum, ν, cm–1: 3400–3500 (OH), 1690
1
(C=O), 1610 (C=C), 960 (trans-C=C). H NMR spec-
trum (CDCl3), δ, ppm: 0.94 t (3H, 9-H, J = 7.2 Hz),
1.28–1.60 m (8H, 5-H, 6-H, 7-H, 8-H), 3.90 br.s (1H,
OH), 4.35 q (1H, 4-H, J4,3 = J4,5 = 7.1 Hz), 6.25 d.d
(1H, 3-H, J3,2 = 17.0, J3,4 = 7.1 Hz), 6.82 d.d (1H, 2-H,
J1, 2 = 7.5, J2, 3 = 17.0 Hz), 9.52 d (1H, 1-H, J2, 1
=
7.5 Hz). Found, %: C 69.11; H 10.30. C9H16O2. Calcu-
lated, %: C 69.19; H 10.32.
(2E)-4-Hydroxydec-2-enal (IIIe). Yield 50%,
bp 133–135°C (2 mm), Rf 0.33 (hexane–diethyl ether,
2:1). IR spectrum, ν, cm–1: 3400–3500 (OH), 1690
1
(C=O), 1610 (C=C), 960 (trans-C=C). H NMR spec-
trum (CDCl3), δ, ppm: 0.94 t (3H, 10-H, J = 7.2 Hz),
1.28–1.55 m (10H, 5-H, 6-H, 7-H, 8-H, 9-H), 3.52 br.s
(1H, OH), 4.30 q (1H, 4-H, J4, 3 = J4, 5 = 7.1 Hz),
6.22 d.d (1H, 3-H, J3,2 = 17.0, J3,4 = 7.1 Hz), 6.82 d.d
(1H, 2-H, J1,2 = 7.5, J2,3 = 17.0 Hz), 9.54 d (1H, 1-H,
J2,1 = 7.5 Hz). Found, %: C 70.49; H 10.68. C10H18O2.
Calculated, %: C 70.55; H 10.66.
spectrum (CCl4), δ, ppm: 0.94 t (3H, 7-H, J7, 6
=
7.1 Hz), 1.36–1.53 m (4H, 5-H, 6-H), 2.90 br.s (1H,
OH), 3.24 s (6H, OCH3), 4.20–4.29 m (1H, 4-H),
In the reaction of aldehyde I with hexylmagnesium
bromide, 2-hexylfuran (Ve) was also isolated in addi-
tion to compound IIIe. Its yield and physical and spec-
tral parameters are given below.
4.76 d (1H, 1-H, J = 7.5 Hz ), 5.44 d.d (1H, 2-H, J2,1
=
7.5, J2, 3 = 17.0 Hz), 5.80 d.d (1H, 3-H, J3, 2 = 17.0,
J3,4 = 7.5 Hz). Found, %: C 62.01; H 10.39. C9H18O3.
Calculated, %: C 62.04; H 10.41.
(2E)-1,1-Dimethoxyhex-2-en-4-ol (IVa). A solu-
tion of 3.5 g (0.027 mol) of aldehyde I in 25 ml of
anhydrous diethyl ether was added dropwise at –20°C
to Grignard compound IIa prepared from 0.97 g
(0.027 mol) of magnesium and 2.9 g (0.027 mol) of
ethyl bromide in 15 ml of anhydrous diethyl ether. The
mixture was stirred for 2 h at –20°C, allowed to warm
up to room temperature, stirred for 4 h, and left over-
Thermal cyclization of hydroxy aldehydes IIIa–
IIIe (general procedure). A Claisen flask was charged
with 0.004 mol of compound IIIa–IIIe, and the flask
was placed in a metal bath and slowly heated to 100–
150°C at a residual pressure of 200–300 mm. The dis-
tillate was extracted with diethyl ether, the extract was
dried over Na2SO4, the solvent was removed, and the
residue was distilled under reduced pressure.
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(2E)-4-HYDROXYALK-2-ENALS AND 2-SUBSTITUTED FURANS
409
22.84 (C9), 28.29 (C6), 29.15 (C7), 31.85 (C5, C8),
104.79 (C4), 110.23 (C2), 140.79 (C1), 156.68 (C3).
Found, %: C 78.84; H 10.61. C10H16O. Calculated, %:
C 78.90; H 10.59.
2-Ethylfuran (Va). Yield 42%, bp 56–58°C
(200 mm). IR spectrum: ν 600 cm–1 (furan ring).
1H NMR spectrum (CDCl3), δ, ppm: 0.96 t (3H, CH3,
J = 7.0 Hz), 2.57 t (2H, CH2CH3, J = 7.5 Hz), 5.93 s
(1H, 3-H), 6.21 s (1H, 4-H), 7.26 s (1H, 5-H). Found,
%: C 74.97; H 8.39. C6H8O. Calculated, %: C 74.94;
H 8.36.
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2-Propylfuran (Vb). Yield 41%, bp 56–58°C
(80 mm). IR spectrum: ν 600 cm–1 (furan ring).
1H NMR spectrum (DMSO-d6), δ, ppm: 0.96 t (3H,
CH3, J = 7.0 Hz), 1.60–1.69 m (2H, CH2CH3), 2.57 t
(2H, 2-CH2, J = 7.5 Hz), 5.93 s (1H, 3-H), 6.21 s (1H,
4-H), 7.26 s (1H, 5-H). Found, %: C 76.26; H 9.12.
C7H10O. Calculated, %: C 76.33; H 9.15.
2-Butylfuran (Vc). Yield 43%, bp 60–62°C
(40 mm). IR spectrum: ν 600 cm–1 (furan ring).
1H NMR spectrum (DMSO-d6), δ, ppm: 0.95 t (3H,
CH3, J = 7.0 Hz), 1.60–1.70 m (4H, CH2CH2CH3),
2.58 t (2H, 2-CH2, J = 7.5 Hz), 5.93 s (1H, 3-H), 6.21 s
(1H, 4-H), 7.26 s (1H, 5-H). Found, %: C 77.34;
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2-Pentylfuran (Vd). Yield 43%, bp 64–66°C
(18 mm). IR spectrum: ν 600 cm–1 (furan ring).
1H NMR spectrum (DMSO-d6), δ, ppm: 0.92 t (3H,
CH3, J = 7.0 Hz), 1.57–1.70 m [6H, (CH2)3CH3], 2.60 t
(2H, 2-CH2, J = 7.5 Hz), 5.94 s (1H, 3-H), 6.20 s (1H,
4-H), 7.27 s (1H, 5-H). Found, %: C 78.15; H 10.23.
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2-Hexylfuran (Ve). Yield 45%, bp 70–72°C
(10 mm). IR spectrum: ν 600 cm–1 (furan ring).
1H NMR spectrum (DMSO-d6), δ, ppm: 0.91 t (3H,
CH3, J = 7.0 Hz), 1.33–1.41 m [6H, (CH2)3CH3], 1.60–
1.70 m (2H, 2-CH2CH2), 2.62 t (2H, 2-CH2), 5.95 s
(1H, 3-H), 6.20 s (1H, 4-H), 7.27 s (1H, 5-H).
13C NMR spectrum (CDCl3), δC, ppm: 14.33 (C10),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 3 2010