5,5-dimethyl-1,3-dioxan-4-ol as orthogonally protected equivalent of 2,2-dimethyl-3-hydroxypropanal

Article abstract of DOI:10.1134/S1070428012060127

Condensation of isobutyraldehyde with aqueous formaldehyde in the presence of Ba(OH)₂ gave a new gem-dimethyl-substituted building block.

Full text of DOI:10.1134/S1070428012060127

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 6, pp. 820–822. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © N.Z. Yagafarov, R.F. Valeev, R.F. Bikzhanov, E.I. Iginasheva, M.S. Miftakhov, 2012, published in Zhurnal Organicheskoi Khimii,
2012, Vol. 48, No. 6, pp. 823–825.
5,5-Dimethyl-1,3-dioxan-4-ol as Orthogonally Protected
Equivalent of 2,2-Dimethyl-3-hydroxypropanal
N. Z. Yagafarov, R. F. Valeev, R. F. Bikzhanov, E. I. Iginasheva, and M. S. Miftakhov
Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
e-mail: bioreg@anrb.ru
Received December 30, 2011
Abstract—Condensation of isobutyraldehyde with aqueous formaldehyde in the presence of Ba(OH)2 gave a
new gem-dimethyl-substituted building block.
DOI: 10.1134/S1070428012060127
α,ω-Functionalized acyclic building blocks having
a geminal dimethyl fragment can be used in the syn-
thesis of natural compounds of the polyketide series
(epothilones, acutiphycin, etc.) [1–6]. The present
communication describes the synthesis of a new gem-
dimethyl-substituted building block, 5,5-dimethyl-1,3-
dioxan-4-ol (I), designed for subsequent selective
transformations. Compound I was prepared from read-
ily accessible starting materials according to a scheme
based on aldol condensation [7]. Isobutyraldehyde
reacted with formaldehyde under mild conditions in
aqueous medium in the presence of barium hydroxide
(Scheme 1).
bromide gave 2,2-dimethylpentane-1,3-diol (V) as the
major product together with diol III as by-product.
The hydroxy groups in diol V can be differentiated via
transformation into benzaldehyde acetal VI; the sub-
sequent oxidative ring opening by the action of RuCl3–
NaIO4 gave 3-benzoyloxy-2,2-dimethylpentanoic acid
(VII) where the secondary hydroxy group remained
protected (Scheme 3). Methyl (2E)-5-hydroxy-4,4-di-
methylpent-2-enoate (VIII) was synthesized in good
yield by reaction of I with methyl (triphenyl-λ5-
phosphanylidene)acetate.
Scheme 2.
S
CHCl3, 6 N HCl
5 to 20°C
Scheme 1.
OH
SH
+
I
S
HS
Me
O
Me
75%
Me
Me
II
OH
Me
BaO, H2O, Δ
+
CH2O
O
Me
CHO
NaBH4, MeOH, 20°C
85%
HO
OH
I
I
Me
Me
III
After chromatographic purification on silica gel, the
yield of I was 65%; the reaction was also accompanied
by formation of polar (TLC) condensation products
whose structure was not determined. Cyclic hemiacetal
I may be regarded as protected unstable 2,2-dimethyl-
3-hydroxypropanal; broad synthetic potential of the
latter is illustrated by Schemes 2 and 3.
Ac2O, pyridine, 20°C
80%
AcO
OAc
Me
Me
IV
EXPERIMENTAL
The IR spectra were recorded from thin films on
1
13
By reaction of I with ethane-1,2-ditiol we obtained
dithio acetal II. Compound I was smoothly reduced
with sodium tetrahydridoborate to afford symmetric
diol III which was converted into diacetate IV
(Scheme 2). The reaction of I with ethylmagnesium
a UR-20 spectrometer. The H and C NMR spectra
were measured on a Bruker AM-300 spectrometer at
300 and 75.47 MHz, respectively, from solutions in
CDCl3. Analysis by thin-layer chromatography was
performed using Sorbfil plates (Russia); spots were
820

5,5-DIMETHYL-1,3-DIOXAN-4-OL AS ORTHOGONALLY PROTECTED EQUIVALENT
821
Scheme 3.
Me
Et
Et
O
EtMgBr, THF
5 to 20°C
PhCH(OMe)2
PhH, 20°C
RuCl3–NaIO4
MeCN–CCl4–H2O, 20°C
O
Me
Et
I
HO
OH
BzO
OH
64%
70%
88%
Me
Me
Me
Me
Ph
O
V
VI
VII
O
Ph3P=CHCOOMe, PhH, Δ
I
HO
OMe
80%
Me
Me
VIII
detected by treatment with an acidified solution of
4-methoxybenzaldehyde. The purity of the isolated
compounds was checked by GLC on a Chrom 5
chromatograph. The mass spectra were obtained on
Shimadzu LCMS-2010 (atmospheric pressure chemi-
cal ionization, 20 eV; positive and negative ion detec-
tion) and Thermo Finnigan MAT 95XP instruments
(electron impact, 70 eV; ion source temperature 200°C).
raphy on silica gel using petroleum ether–ethyl acetate
(10:1) as eluent. Yield 0.12 g (75%), oily liquid. IR
1
spectrum, ν, cm–1: 3408, 2924, 1045. H NMR spec-
trum, δ, ppm: 1.06 s (6H, CH3), 3.19–3.21 m (4H, 4-H,
5-H), 3.54 s (2H, CH2OH), 4.71 s (1H, 2-H). 13C NMR
spectrum, δC, ppm: 22.52 (CH3), 39.01 (C4, C5), 40.70
(CMe2), 62.35 (C2), 70.90 (CH2OH). Mass spectrum,
m/z (Irel, %): 217 (100) [M + H]+, 195 (55), 479 (48),
403 (44).
5,5-Dimethyl-1,3-dioxan-4-ol (I). A mixture of
2.1 g (70 mmol) of paraformaldehyde, 4.2 ml of water,
and 0.1 ml of concentrated sulfuric acid was heated
under reflux until it became homogeneous. The mix-
ture was cooled to room temperature, 0.72 g
(4.7 mmol) of barium(II) oxide and 1 g (14 mmol) of
isobutyraldehyde were added, and the mixture was
heated for ~12 h under reflux with stirring, cooled, and
extracted with methylene chloride (3×30 ml). The ex-
tracts were combined, dried over Na2SO4, filtered, and
evaporated, and the residue was subjected to column
chromatography on silica gel using petroleum ether–
ethyl acetate (2:1, 1:1) as eluent. Yield 0.65 g (65%),
oily liquid. IR spectrum, ν, cm–1: 3419, 2958, 1726,
2,2-Dimethylpropane-1,3-diol (III). Compound I,
0.3 g (2.2 mmol), was dissolved in 7 ml of anhydrous
methanol, 0.08 g (2.2 mmol) of NaBH4 was added, and
the mixture was stirred for 2 h at room temperature.
The mixture was treated with 10 ml of water, stirred
for 15 min, saturated with NaCl, and extracted with
ethyl acetate (3×30 ml), the combined extracts were
dried over Na2SO4 and evaporated, and the residue was
subjected to column chromatography on silica gel
using petroleum ether–ethyl acetate (4:1) as eluent.
Yield 0.26 g (85%), mp 58°C. IR spectrum, ν, cm–1:
1
3284, 1454, 1032, 721, 379. H NMR spectrum, δ,
ppm: 0.92 s (6H, CH3), 2.10 br.s (2H, OH), 3.52 s
13
1
(4H, CH2). C NMR spectrum, δ, ppm: 21.80 (CH3),
1024. H NMR spectrum, δ, ppm: 0.96 s and 0.97 s
32.51 (C2), 70.28 (C1, C3).
(3H each, CH3), 3.60–3.69 m (2H, 6-H), 4.63–4.70 m
(2H, 2-H), 5.10 d (1H, 4-H, J = 6.0 Hz). 13C NMR
spectrum, δC, ppm: 15.52 and 22.41 (CH3), 36.70 (C5),
76.14 (C6), 90.88 (C2), 100.85 (C4). Mass spectrum,
m/z (Irel, %): 87 (100) [M + H]+, 102 (90), 130 (75),
133 (25).
2,2-Dimethylpropane-1,3-diyl diacetate (IV).
A solution of 0.1 g (0.76 mmol) of diol III in 3 ml of
pyridine and 1 ml of acetic anhydride was stirred for
8 h at room temperature. The solution was evaporated,
and the residue was subjected to column chromatog-
raphy on silica gel using petroleum ether–ethyl acetate
(3:1). Yield 0.08 g (80%), oily liquid. IR spectrum, ν,
2-(1,3-Dithiolan-2-yl)-2-methylpropan-1-ol (II).
A solution of 0.16 g (1.2 mmol) of compound I in
chloroform was cooled to 5°C, 0.63 ml of 6 N aqueous
HCl and 0.22 ml (2.7 mmol) of ethane-1,2-dithiol were
added in succession, and the mixture was allowed to
warm up to room temperature and stirred for 30 min.
The mixture was treated with a saturated aqueous
solution of NaHCO3 and extracted with chloroform
(3×20 ml), the combined extracts were evaporated,
and the residue was subjected to column chromatog-
1
cm–1: 2968, 1739, 1043. H NMR spectrum, δ, ppm:
0.88 s (6H, CH3), 1.98 s (6H, CH3), 3.80 s (4H, CH2).
13C NMR spectrum, δC, ppm: 20.85 (CH3), 21.69
(CH3), 34.47 (C2), 69.15 (C1, C3), 171.09 (C=O). Mass
spectrum, m/z (Irel, %): 211 (100) [M + H]+, 311 (31),
297 (15), 206 (8).
2,2-Dimethylpentane-1,3-diol (V). A solution of
0.3 g (2 mmol) of compound I in 5 ml of THF was
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 6 2012

YAGAFAROV et al.
822
added to a solution of ethylmagnesium bromide pre-
pared from 0.19 g of magnesium turnings and 0.5 ml
of ethyl bromide in 50 ml of THF. The mixture was
stirred for 30 min at room temperature 30 min and
treated with a saturated aqueous solution of ammo-
nium chloride, the aqueous phase was separated and
extracted with ethyl acetate (3×40 ml), and the com-
bined extracts were dried over Na2SO4, filtered, and
evaporated. The residue was subjected to column chro-
matography on silica gel using petroleum ether–ethyl
acetate (2:1) as eluent. Yield 0.19 g (64%), oily liquid.
bined extracts were dried over Na2SO4, filtered, and
evaporated. The residue was subjected to column
chromatography on silica gel using petroleum ether–
ethyl acetate (1:1) as eluent. Yield 0.07 g (88%), oily
liquid. IR spectrum, ν, cm–1: 2976, 1718, 1271, 712.
1H NMR spectrum, δ, ppm: 0.95 t (3H, 5-H, J =
7.3 Hz), 1.30 s (6H, CH3), 1.69–1.74 m (2H, CH2),
5.40–5.45 m (1H, 3-H), 7.41–7.60 m and 8.05–8.11 m
(5H, Harom), 11.30 br.s (1H, COOH). 13C NMR spec-
trum, δC, ppm: 10.90 (C5), 20.39 (CH3), 22.34 (CH3),
23.72 (C4), 46.71 (C2), 79.01 (C3); 128.43, 129.56, and
133.03 (Carom); 166.25 (C=O), 181.03 (C1). Mass spec-
trum, m/z (Irel, %): 413 (100) [M + H]+, 361 (98), 301
(77), 237 (51).
1
IR spectrum, ν, cm–1: 3100, 1520, 1070. H NMR
spectrum, δ, ppm: 0.84 s and 0.85 s (3H each, CH3)
0.98 t (3H, CH3, J = 7.2 Hz), 1.30–1.34 m and 1.50–
1.58 m (1H each, 4-H), 3.32–3.39 m (1H, 3-H), 3.41 d
and 3.52 d (1H each, 1-H, J = 10.7 Hz). 13C NMR
spectrum, δC, ppm: 11.14 (C5), 18.68 (CH3), 22.53
(CH3), 24.44 (C4), 38.37 (C2), 72.31 (C1), 81.12 (C3).
Mass spectrum, m/z (Irel, %): 131 (100) [M + H]+, 255
(72), 474 (67), 571 (29).
Methyl (2E)-5-hydroxy-4,4-dimethylpent-2-
enoate (VIII). Methyl (triphenyl-λ5-phosphanylidene)-
acetate, 0.38 g (1.14 mmol), was added to a solution of
0.1 g (0.76 mmol) of compound I in 10 ml of benzene,
the mixture was heated for 2 h under reflux with
stirring and evaporated, and the residue was subjected
to column chromatography on silica gel using petro-
leum ether–ethyl acetate (2:1) as eluent. Yield 0.08 g
(80%), yellow oily liquid. IR spectrum, ν, cm–1: 3463,
4-Ethyl-5,5-dimethyl-2-phenyl-1,3-dioxane (VI).
Compound V, 0.06 g (0.45 mmol), was dissolved in
5 ml of benzene, 0.1 g (0.675 mmol) of dimethoxy-
(phenyl)methane and a catalytic amount of p-toluene-
sulfonic acid were added, and the mixture was stirred
for 30 min at room temperature and evaporated. The
residue was subjected to column chromatography on
silica gel using petroleum ether–ethyl acetate (3:1) as
eluent. Yield 0.07 g (70%), light yellow liquid. IR
1
2958, 1722, 1315. H NMR spectrum, δ, ppm: 1.03 s
(6H, CH3), 2.50 s (1H, OH), 3.38 s (2H, 5-H), 3.68 s
(3H, OCH3), 5.79 d (1H, 3-H, J = 16.3 Hz), 6.92 d
13
(1H, 2-H, J = 16.3 Hz). C NMR spectrum, δC, ppm:
23.11 (CH3), 39.23 (C4), 51.52 (OCH3), 70.84 (C5),
119.27 (C2), 155.57 (C3), 167.40 (C1). Mass spectrum,
m/z (Irel, %): 342 (100) [M + H]+, 145 (80), 105 (65).
1
spectrum, ν, cm–1: 2963, 1703, 1116, 698. H NMR
spectrum, δ, ppm: 0.78 s (3H, CH3), 1.01 t (3H, CH3,
J = 7.3 Hz), 1.52–1.67 m (2H, 1′-H) 1.12 s (3H, CH3),
3.35–3.39 m (2H, 4-H), 3.58 d (1H, 6-H, J = 11.0 Hz),
5.48 s (1H, 2-H), 7.36 d (2H, Harom, J = 7.7 Hz), 7.52 d
(2H, Harom, J = 5.7 Hz), 7.89 d (1H, Harom, J = 6.9 Hz).
13C NMR spectrum, δC, ppm: 11.06 (C2′), 18.72 (C1′),
21.60 and 22.21 (CH3), 32.89 (C5), 78.94 (C6), 87.23
(C4), 101.82 (C2); 126.04, 128.19, 128.60 (Carom). Mass
spectrum, m/z (Irel, %): 371 (100) [M + H]+, 489 (65),
391 (51), 105 (43), 295 (20).
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 6 2012