Selective functionalization of the primary hydroxy group in triols

Article abstract of DOI:10.1134/S1070427215100079

A procedure was suggested for preparing functionally substituted 1,2-diols by O-alkylation of hydroxyalkyl-1,3-dioxacyclanes with alkyl halides, followed by acid hydrolysis. The conditions for selective cleavage of the ethers obtained were found. (2,2-Dimethyl-1,3-dioxolan-4-yl)methyl benzoate under the conditions of acid deacetalization undergoes saponification of the ester group.

Full text of DOI:10.1134/S1070427215100079

ISSN 1070-4272, Russian Journal of Applied Chemistry, 2015, Vol. 88, No. 10, pp. 1599−1604. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © G.Z. Raskil’dina, V.F. Valiev, R.M. Sultanova, S.S. Zlotskii, 2015, published in Zhurnal Prikladnoi Khimii, 2015, Vol. 88, No. 10,
pp. 1414−1419.
VARIOUS PHYSICOCHEMICAL
AND TECHNOLOGICAL PROCESSES
Selective Functionalization of the Primary Hydroxy
Group in Triols
G. Z. Raskil’dina, V. F. Valiev, R. M. Sultanova, and S. S. Zlotskii
Ufa State Petroleum Technical University, ul. Kosmonavtov 1, Ufa, Bashkortostan, 450062 Russia
e-mail: graskildina444@mail.ru
Received April 16, 2015
Abstract—A procedure was suggested for preparing functionally substituted 1,2-diols by O-alkylation of
hydroxyalkyl-1,3-dioxacyclanes with alkyl halides, followed by acid hydrolysis. The conditions for selective
cleavage of the ethers obtained were found. (2,2-Dimethyl-1,3-dioxolan-4-yl)methyl benzoate under the condi-
tions of acid deacetalization undergoes saponification of the ester group.
DOI: 10.1134/S1070427215100079
Cycloacetal protection of the carbonyl group in
polyfunctional aldehydes and ketones is widely used
for preparing reagents, intermediates, and starting
compounds in organic synthesis, including synthesis
of biologically active compounds. The use of the acetal
protection became particularly important in view of the
fact that operation with multifunctional compounds, as
a rule, requires selective introduction of one or another
function into the reaction. Various transformations of
the cycloacetal fragment open new pathways for the
synthesis of important classes of organic compounds
[1–3]. This approach has been applied recently to binding
of vicinal hydroxy groups in triols, followed by selective
functionalization of the free OH group and regeneration
of the desired substituted diols [4, 5].
Previously we studied the transformations of substi-
tuted cyclic acetals into oxygen-, sulfur-, and nitrogen-
containing 1,3-dioxacycloalkane derivatives under the
conditions of phase-transfer catalysis [3].
This study was aimed at developing procedures for
preparing substituted diols, widely used in synthesis of
practically important organic compounds, from available
hydroxyalkyl-1,3-dioxacyclanes.
Proceeding with studies [6] on functionalization
and transformation of triol ketals (hydroxyalkyl-1,3-
Table 1. О-Alkylation of hydroxyalkyl-1,3-dioxacycloalkanes 1–3 with allyl chloride 4а, benzyl chloride 4b, and benzoyl chloridea
4c in the presence of Katamin AB. Reactant molar ratio 1 : 5, solvent system toluene + 50% NaOH solution
Т, °С
Starting reactant
Reaction time, h
Product
Yield, %
1 + 4а
1 + 4b
2 + 4а
3 + 4а
3 + 4b
6
6
6
8
8
30
100
30
5а
5b
6а
7а
7b
95
80
90
90
88
30
100
a
Reactant molar ratio 1 : 1, solvent pyridine, Т = 50°С, 1 h, yield of 5c 80%.
1599

1600
RASKIL’DINA et al.
Scheme 1.
dioxacycloalkanes), we performed O-alkylation of
five- (1, 2) and six-membered (3) heterocyclic alcohols
with allyl (4а), benzyl (4b), and benzoyl (4c) chlorides
(Scheme 1).
which does not allow preparation of the corresponding
monoester.
The diols formed by hydrolysis are convenient
synthons for further transformations, e.g., for the
synthesis of polyketides [8] (Scheme 2).
Performing the reactions under the conditions of
phase-transfer catalysis allowed us to preserve the
cycloacetal fragment and to obtain in quantitative yields
the corresponding ethers 5a, 5b, 6а, 7а, 7b, and ester 5c
(Table 1). The reactions in the presence of Katamin AB
occurred smoothly under mild conditions. These ethers
and ester are used as starting compounds in the synthesis
of heterocyclic nucleosides exhibiting a wide spectrum
of biological activity [7].
It should be noted that both the hydrolysis mechanism
and the acids used have been studied in sufficient detail
previously. For example, under the action of CH3CO2H,
the hydrolysis of cyclic acetals occurs within several
days [9]; therefore, the search for optimum conditions for
performing cleavage of cyclic acetals under the conditions
of acid hydrolysis remains a topical problem.
To determine the stability of oxygen-containing rings
in polyfunctional cyclic ethers under the conditions of
acid hydrolysis in the presence of a 2% Н2SO4 solution
and to evaluate their relative reactivity, we studied by
the method of competing reactions the catalytic cleavage
of 4-[(allyloxy)methyl]-2,2-dimethyl-1,3-dioxolane
(5а) in a mixture with 4-[(benzyloxy)methyl]-2,2-
Treatment of ethers 5a, 5b, 6а, 7а, and 7b with a 2%
aqueous sulfuric acid solution gave the desired vicinal
diols 8a, 8b, 9a, 10a, and 10b in quantitative yield
(Table 2). However, treatment of compound 5c under
these conditions leads to saponification of the ester
group simultaneously with cleavage of the heterocycle,
Table 2. Catalytic cleavage of polyfunctional cyclic ethers 8а, 8b, 9а, 10а, and 10b in the presence of a 2% H2SO4 solution
Starting reactant
Reaction time, h
Т, °С
Product
Yield, %
5а
5b
6а
7а
7b
4
6
4
8
8
60
60
60
60
80
8а
8b
92
90
90
80
60
9а
10а
10b
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 88 No. 10 2015

SELECTIVE FUNCTIONALIZATION OF THE PRIMARY HYDROXY GROUP IN TRIOLS
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Scheme 2.
n
n
8a, 8b, 9a
5a, 5b, 6a
10a, 10b
R = –CH2–CH= CH2 (8a, 9a, 10a); –CH2–C6H5 (8b, 10b); n = 0 (8a, 8b); 1 (9a).
7a, 7b
EXPERIMENTAL
dimethyl-1,3-dioxolane (5b), 4-[(allyloxy)ethyl]-2,2-
dimethyl-1,3-dioxolane (6а), or 5-ethyl-5-[(allyloxy)
methyl]-2,2-dimethyl-1,3-dioxane (7а) in the presence
of a 2% aqueous H2SO4 solution. The relative reactivity
was determined at 60°С by stirring a solution containing
dioxolane 5а and another cyclic ether (5b, 6а, or 7а) in
1 : 1 molar ratio at acetal conversion of ≤30% (Table 3).
Chromatographic analysis of reaction products was
performed with an HRGS 5300 Mega Series Carlo Erba
chromatograph equipped with a flame ionization detector;
carrier gas helium, flow rate 30 mL min–1, 25 m long
column, column temperature 50–280°С (programmed
heating at a rate of 8 deg min–1), detector temperature
250°C, vaporizer temperature 300°С. The chromatograms
in combination with mass spectra were taken with
Fisons (DB 560 capillary quartz column, 50 m) and
Focus devices equipped with a Finingan DSQ II mass
spectrometric detector (ion source temperature 200°C,
direct inlet temperature 50–270°С, sample heating rate
10 deg min–1, Thermo TR-5MS 50 m × 0.25 mm column,
helium flow rate 0.7 mL min–1). The mass spectra were
taken in the electron impact mode. The NMR spectra
were recorded on a BrukerAvance-300 spectrometer (1H,
400.13 MHz) in CDCl3, internal references benzene-d6
and toluene-d8.
According to the results obtained, under the conditions
of acid hydrolysis 4-[(allyloxy)methyl]- (5а) and 4-[(al-
lyloxy)ethyl]-2,2-dimethyl-1,3-dioxolane (6a) undergo
cleavage to virtually equal extent. An increase in the
distance between the allyloxy group and 1,3-dioxacyclane
ring does not influence the cleavage rate, whereas 4-[(ben-
zyloxy)methyl]-2,2-dimethyl-1,3-dioxolane (5b) and
5-ethyl-5-[(allyloxy)methyl]-2,2-dimethyl-1,3-dioxane
(7а) undergo hydrolysis at 3 and 4 times lower rates,
respectively [krel (5b)/(5а) = 0.34, krel (7а)/(5а) = 0.25].
This fact may be due to the stabilizing effect of the phenyl
substituent in the case of ether 5b and to higher stability
of the dioxane ring in 7а compared to the dioxolane ring
in 5a in acid solutions.
Table 3. Relative reactivitya of polyfunctional cyclic ethers 5а, 5b, 6а, and 7а in the formation of 4-alkyloxy-1,2- and -1,3-diols
8а, 8b, 9а, and 10а by catalytic cleavage with a 2% aqueous H2SO4 solution. Reactant molar ratio 1 : 1, Т = 60°С, 1 h
Starting compound
Reaction product
Relative reactivity
5а
5а
5а
5b
7а
6а
8а
8а
8а
8b
10а
9а
5а : 5b = 3 : 1
5а : 7а = 4 : 1
5а : 6а = 1 : 1
a The relative reactivity was calculated by the GLC method using undecane as internal reference.
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RASKIL’DINA et al.
Table 4. Spectral and physicochemical characteristics of the synthesized compounds
Mass spectrum,
Compound
Yield, %
88
NMR (CDCl3, δ, ppm)
m/z (Irel, %)
5-Ethyl-5-[(benzyloxy)methyl]-
2,2-dimethyl-1,3-dioxane (7b),
colorless liquid, Тb 163°С
(5 mmHg)
1H NMR spectrum (C6D6, δ, ppm, J, Hz): 0.65 s M+ = 249 (32), 206 (12),
(3Н, С2″Н3), 1.26 m (2Н, С1″H2), 1.29 s (3Н, 120 (4), 107 (8), 91 (100),
С1′Н3), 1.40 s (3Н, С2′Н3), 3.41 s (2Н, С7Н2), 81 (2), 70 (4), 59 (8), 43 (9)
3.45 d (2Н, С4Н2), 3.68 d (2Н, С6Н2), 4.28 s (2Н,
С8Н2), 7.10 m (5Н, Ph-). 13C NMR spectrum
(C6D6, δ, ppm): 7.29 (С2″), 21.34 (C2′), 24.50
(C1″), 26.71 (C1′), 36.91 (C5), 65.45 (C4 + C6),
70.40 (C7), 73.46 (C8), 98.07 (C2), 127.58,
127.70, 128.00, 128.32, 128.48, 139.24 (Ph)
3-Allyloxypropane-1,2-diol
(8а), colorless liquid,
Тb 108°С (5 mmHg)
92
1H NMR spectrum (CDCl3, δ, ppm, J, Hz): M+ = 132 (none), 101 (6),
3.42–3.53 m (2H, C1Ha, C3Ha), 3.70–3.90 m 84 (8), 71 (19), 61 (35), 43
(3H, C3Hb, C2H, C1Hb), 4.02 d (2H, C4Ha, (48), 41 (100)
C4Hb), 4.35 s (2-OH), 5.13 d.d (1Н, C6Ha, 2J =
1.5, 3J = 10.4), 5.23 d.d (1H, C6Hb, 2J = 1.6, 3J =
17.3), 5.82–5.94 m (1H, C5H)
3-(Benzyloxy)propan-1,2-diol
(8b), colorless liquid,
Тb 192°С (5 mmHg)
88
90
1H NMR spectrum (CDCl3, δ, ppm, J, Hz): M+ = 182 (6), 107 (38), 79
3.27 s (2-ОH), 3.35–3.62 m (3H, C1Ha, C3Ha, (7), 65 (9), 43 (2)
C3Hb), 3.75 m (1H, C1Hb), 4.20 m (C2H), 4.31 m
(2Н, C4Ha, C4Hb), 7.00–7.21 m (5H, Ar)
4-(Allyloxy)butane-1,2-diol
(9а), colorless liquid,
Тb 134°С (5 mmHg)
1H NMR spectrum (CDCl3, δ, ppm, J, Hz): 1.71 M+ = 147 (2), 115 (44), 97
d (2Н, С3Н2), 3.50 m (1Н, С2Н), 3.61 s (2Н, (4), 87 (21), 71 (60), 57
С4H2), 3.75 d (2Н, С1Н2), 3.87 m (2Н, НО–С1– (51), 41 (100)
С2–ОН), 4.02 s (2Н, С6H2), 5.17 d.d (2Н, С8Н2),
5.88 m (1Н, С7Н). 13C NMR spectrum (CDCl3,
δ, ppm): 32.70 (С3), 66.40 (С4), 67.56 (С1),
70.57 (С2), 71.85 (С6), 117.06 (С8), 134.29 (С7)
2-[(Allyloxy)methyl]-2-
ethylpropane-1,3-diol (10а),
colorless liquid, Тb 153°С
(5 mmHg)
80
1H NMR spectrum (C6D6, δ, ppm, J, Hz): 0.78 s M+ = 175 (2), 117 (7), 99
(3Н, С3′Н3), 1.35 d (2Н, С2′Н2), 3.40 d.d (4Н, (12), 86 (36), 71 (43), 54
С1Н2, С3Н2), 3.60 d (2Н, С4′Н2), 3.75 d (2Н, (81), 41 (100)
С5′Н2), 5.05 d (2Н, С7′Н2), 5.72 m (1Н, С6′Н).
13C NMR spectrum (C6D6, δ, ppm): 7.78 (С3′),
22.96 (C2′), 43.37 (C2), 65.37 (C1 + C3), 72.48
(C4′+C5′), 116.49 (C7′)
2-[(Benzyloxy)methyl]-2-
ethylpropane-1,3-diol (10b),
colorless liquid, Тb 213°С
(5 mmHg)
60
1H NMR spectrum (C6D6, δ, ppm, J, Hz): 0.82 s M+ = 107 (31), 91 (100), 72
(3Н, С2″Н3), 1.39 m (2Н, С1″Н2), 3.35 s (2Н, (16), 57 (12), 41 (9)
С1′Н2), 3.68 d.d (4Н, С1Н2, С3Н2), 4.30 s (2Н,
С2′Н2), 7.10 m (5Н, Ph). 13С NMR spectrum
(C6D6, δ, ppm): 7.49 (C2″), 22.67 (C1″), 43.15
(C2), 65.13 (C1 + C3), 72,12 (C1′), 73,35 (C2′),
126.44, 127.43, 127.49, 127.74, 128.07, 138.60
(Ph)
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 88 No. 10 2015

SELECTIVE FUNCTIONALIZATION OF THE PRIMARY HYDROXY GROUP IN TRIOLS
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The initial hydroxyalkyl-1,3-dioxacyclanes 1–3
were prepared by condensation of the corresponding
triols with acetone, following the known procedure
[10]. The physicochemical constants of the compounds
obtained (5а–5c, 6а, 7а) coincided with the published
data [8, 11–14].
(7а), or 0.028 mol (7.39 g) of 5-ethyl-5-[(benzyloxy)-
methyl]-2,2-dimethyl-1,3-dioxane (7b) was heated with
25 mL of 2% sulfuric acid with vigorous stirring for
4–8 h at 60°С {or at 80°С for 5-ethyl-5-[(benxyloxy)-
methyl]-2,2-dimethyl-1,3-dioxane (7b)}. After cooling,
the mixture was diluted with 50 mLof water and extracted
with diethyl ether (2 × 30 mL). The ether layers were
combined, washed with a 5% NaHCO3 solution until
the wash waters became weakly alkaline, dried over
freshly calcined MgSO4, and concentrated; the residue
was vacuum-distilled.
General procedure of О-alkylation of hydroxyalkyl-
1,3-dioxacycloalkanes 1–3 with allyl chloride (4а) and
benzyl chloride (4b). To a solution of 0.06 mol (7.92 g)
of 4-hydroxymethyl-2,2-dimethyl-1,3-dioxolane (1),
0.06 mol (8.76 g) of 4-hydroxyethyl-2,2-dimethyl-
1,3-dioxolane (2), or 0.06 mol (10.44 g) of 5-ethyl-5-
hydroxymethyl-2,2-dimethyl-1,3-dioxane (3), 60 mL of
toluene and 0.0006 mol (0.22 g) of Katamin AB catalyst
were added with vigorous stirring at 30°С (or at 100°С
for benzyl chloride), after which 100 g of a 50% NaOH
solution was added. Then, after the lapse of 2 h, 0.30 mol
(23.2 g) of allyl chloride (4а) or 0.30 mol (34.1 g) of
benzyl chloride (4b) was added, and the mixture was
stirred for 6 h. After the reaction completion, the mixture
was washed with water, the aqueous phase was extracted
with diethyl ether (3 × 30 mL), and the combined organic
phases were dried over freshly calcined magnesium
sulfate. After the solvent evaporation, the residue was
vacuum-distilled.
General procedure of competing acid cleavage
of cyclic acetals 5а, 5b, 6а, and 7а. To a mixture
of 1.21 g (0.007 mol) of 4-[(allyloxy)methyl]-2,2-
dimethyl-1,3-dioxolane (5а) with 1.56 g (0.007 mol)
of 4-[(benzyloxy)methyl]-2,2-dimethyl-1,3-dioxolane
(5b), of 1.21 g (0.007 mol) of 4-[(allyloxy)methyl]-2,2-
dimethyl-1,3-dioxolane (5а) with 1.30 g (0.007 mol) of
4-[(allyloxy)-ethyl]-2,2-dimethyl-1,3-dioxolane (6а),
or of 1.21 g (0.007 mol) of 4-[(allyloxy)methyl]-2,2-
dimethyl-1,3-dioxolane (5а) with 1.50 g (0.007 mol) of
5-ethyl-5-[(allyloxy)methyl]-2,2-dimethyl-1,3-dioxane
(7а), 12.5 mL of 2% sulfuric acid was added, and the
mixture was heated with vigorous stirring for 1 h at
60°С. The sample was diluted with a twofold amount of
water and extracted with diethyl ether (2 × 5 mL). The
ether layers were combined, washed with a 5% NaHCO3
solution until the wash waters became weakly alkaline,
and dried over freshly calcined MgSO4. The reaction
progress was monitored by GLC. The calculations were
performed after 1-h reaction at the reactant conversion
no higher than 25–35%.
The structural characteristics of the synthesized
compounds are given in Table 4.
(2,2-Dimethyl-1,3-dioxolan-4-yl)methyl benzoate
(5c) [14]. To a solution of 4 g (0.03 mol) of 4-hydroxy-
methyl-2,2-dimethyl-1,3-dioxolane (1) in 2.4 g (0.03 mol)
of pyridine, 4.8 g (0.034 mol) of benzoyl chloride (4c)
was added with stirring. The mixture was gently heated
with continuous stirring for 1 h. The resulting oily mass
crystallized on cooling within 1 day. Then, the reaction
mixture was poured into a mixture of 30 g of ice and
60 mL of 1 M HCl and was stirred until a finely crystal-
line suspension formed. The crude product was filtered
off on a Büchner funnel, washed with ice-cold water, and
recrystallized from 52.5 mL of 80% МеОН.
CONCLUSIONS
(1) О-Alkylation of hydroxyalkyl-1,3-dioxacycloal-
kanes with allyl chloride and benzyl chloride under the
conditions of phase-transfer catalysis gives the corre-
sponding ethers in almost quantitative yields without
cleavage of the heterocyclic moiety. Cleavage of alkyl-
ated hydroxyalkyl-1,3-dioxacycloalkanes with a dilute
aqueous H2SO4 solution gives the corresponding vicinal
diols in 60–80% yield.
General procedure of catalytic cleavage of poly-
functional cyclic ethers 5а, 5b, 6а, 7а, and 7b. A solu-
tion of 0.028 mol (4.82 g) of 4-[(allyloxy)methyl]-2,2-
dimethyl-1,3-dioxolane (5а), 0.028 mol (6.22 g) of
4-[(benzyloxy)methyl]-2,2-dimethyl-1,3-dioxolane
(5b), 0.028 mol (5.21 g) of 4-[(allyloxy)ethyl]-2,2-
dimethyl-1,3-dioxolane (6а), 0.028 mol (5.99 g ) of
5-ethyl-5-[(allyloxy)methyl]-2,2-dimethyl-1,3-dioxane
(2) The developed procedure allows preparation of
triol ethers with high selectivity. These ethers are key
compounds in the production of compounds exhibiting
high biological activity: di- and and polyesters, monoes-
ters of hydroxy and amino acids, and heterocycles.
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RASKIL’DINA et al.
Chem., 2009, vol. 52, pp. 1126–1143.
ACKNOWLEDGMENTS
6. Valiev, V.F., Raskil’dina, G.Z., Mudrik, T.P., et al., Bashk.
Khim. Zh., 2014, vol. 21, no. 3, pp. 25–27.
The studies were supported by the Russian Federation
President (Russian Federation President’s scholarship
for young scientists and postgraduate students no. SP-
1960.2015.4 for the period 2015–2017, order no. 184 of
March 10, 2015).
7. Merino, P., Franco, S., Mates, J.A., et al., ARKIVOC, 2004,
vol. 4, pp. 48–58.
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