Intermolecular reactions of chlorohydrine anions: Acetalization of carbonyl compounds under basic conditions

Article abstract of DOI:10.1021/ol0613113

Nonenolizable aldehydes and ketones react with 2-chloroethanol and 3-chloropropanol under basic conditions (t-BuOK, DMF/THF) with formation of 2-substituted 1,3-dioxolanes and 1,3-dioxanes, respectively. Conversion of the two-step addition-alkylation process depends on the electrophilicity of the carbonyl group that governs the equilibrium of addition of chloroalkoxides. This method of protection of carbonyl groups in the form of cyclic acetals under kinetically controlled conditions is complementary to the acid-catalyzed reaction with diols.

Full text of DOI:10.1021/ol0613113

ORGANIC
LETTERS
2006
Vol. 8, No. 17
3745-3748
Intermolecular Reactions of
Chlorohydrine Anions: Acetalization of
Carbonyl Compounds under Basic
Conditions
Michał Barbasiewicz and Mieczysław Ma¸kosza*
Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52,
01-224 Warsaw, Poland
icho-s@icho.edu.pl
Received May 30, 2006
ABSTRACT
Nonenolizable aldehydes and ketones react with 2-chloroethanol and 3-chloropropanol under basic conditions (t-BuOK, DMF/THF) with formation
of 2-substituted 1,3-dioxolanes and 1,3-dioxanes, respectively. Conversion of the two-step addition alkylation process depends on the
−
electrophilicity of the carbonyl group that governs the equilibrium of addition of chloroalkoxides. This method of protection of carbonyl
groups in the form of cyclic acetals under kinetically controlled conditions is complementary to the acid-catalyzed reaction with diols.
γ-Halocarbanions undergo fast intramolecular substitution
to give cyclopropanes; nevertheless, they can be efficiently
trapped by appropriate electrophilic reagents such as alde-
hydes,1,2 imines,3 and Michael acceptors.4 The resulting
anionic adducts that possess electrophilic and nucleophilic
centers in a 1,5-relation cyclize to five-membered rings of
tetrahydrofurans, pyrrolidines, and cyclopentanes, respec-
tively.
shall enter intramolecular substitution giving 1,3-dioxolaness
cyclic acetals of carbonyl compounds (Scheme 1).5
Scheme 1. Competition of Intramolecular and Intermolecular
Processes: Cyclization to Oxirane and Formation of
1,3-Dioxolane
Ethylene chlorohydrine when treated with base forms the
respective alkoxide anion that enters rapid 1,3-intramolecular
substitution to ethylene oxide. This anion can be considered
as an O-analogue of γ-halocarbanions, thus it may be
expected that it can be trapped by sufficiently active
electrophilic partners, e.g., aldehydes. The produced adducts
Protection of carbonyl groups is widely used in the
synthesis of multifunctional molecules, and its many efficient
methods were described.6 Among them, acetalization is a
primary solution and was applied from early times.7,8 The
general methodology for the acetal formation consists of acid-
catalyzed reaction of carbonyl compounds with diols, where
the equilibrium of the reaction is shifted by azeotropic water
removal or dissicators or by reaction with oxiranes catalyzed
(1) (a) Ma¸kosza, M.; Judka, M. Chem.-Eur. J. 2002, 8, 4234-4240.
(b) Ma¸kosza, M.; Przyborowski, J.; Klain, R.; Kwast, A. Synlett 2000,
1773-1774. (c) Barbasiewicz, M.; Judka, M.; Ma¸kosza, M. Russ. Chem.
Bull., Int. Ed. 2004, 53, 1846-1858 (review).
(2) Fleming, F. F.; Gudipati, V.; Steward, O. W. J. Org. Chem. 2003,
68, 3943-3946.
(3) Ma¸kosza, M.; Judka, M. HelV. Chim. Acta 2005, 88, 1676-1681.
(4) Ma¸kosza, M.; Judka, M. Synlett 2004, 717-719.
10.1021/ol0613113 CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/21/2006

by Lewis acids9 and tetraalkylammonium halides.10 The last
of these reactions proceeds via nucleophilic opening of the
oxirane ring with formation of 2-haloethoxide, which sub-
sequently adds to the carbonyl group with the formation of
an O-anion of the hemiacetal. All these steps are reversible
except the last one, cyclization of an anion with the formation
of 2-substituted 1,3-dioxolanes, that drives the reaction to
completion.11 The main drawback of this protocol is the
necessity of operation with highly toxic gaseous ethylene
oxide, thus limiting its routine use. Application of 2-chloro-
and 2-bromoethanol as sources of 2-haloalkoxide anions was
reported12 but was limited to highly electrophilic carbonyl
groups, such as, e.g., 4-nitrobenzaldehyde,13 1,2-dicarbonyl
compounds,14 and highly chlorinated15 or fluorinated ke-
tones.16 For the less-electrophilic carbonyl compounds, such
as benzaldehyde, irreversible intramolecular substitution to
ethylene oxide dominates, making formation of 1,3-diox-
olanes unsuccessful.17
benzaldehyde was chosen as a model carbonyl compound
possessing intermediate electrophilicity. On the basis of our
early studies of reactions of γ-halocarbanions and optimiza-
tion of the reaction conditions, we have found that t-BuOK
in a DMF/THF mixture at low temperature ensures good
results of the desired process. A series of reactions with
aldehydes were carried out on the preparative 50 mmol scale,
and the products were isolated by distillation (Table 1).19,20
In most cases, aldehydes were cleanly converted into
dioxolanes, without competing side processes, thus conver-
sions and purities of products were determined by 1H NMR
(integration of formyl and benzylidene protons). We observed
that the total conversion of an aldehyde is strongly dependent
on temperature. At -60 °C, it reaches the optimum. At higher
temperatures, conversions are lower, and at lower temper-
atures, problems with efficient stirring occurred as a con-
sequence of the viscosity of the mixture.21 An interesting
influence of substituents on conversion was noticed. In this
system, two competing processes operate (Scheme 1)sintra-
and intermolecularsand only the latter depends on the
electrophilicity of the aldehyde carbonyl group. Thus, the
results obtained correlate with the “effective electrophilicity”
of the carbonyl group as a superposition of electronic and
steric effects of the substituents. A methoxy group located
at the para position (entry 1) retards the reaction strongly,
whereas at the ortho position (entry 3), this mesomeric
influence is diminished. Finally, the m-MeO substituent
(entry 2) exhibits the weakest deactivating effect as can be
expected from simple resonance considerations. It should be
emphasized that even a weak donor-like methyl group
(entries 4 and 5) induced a measurable effect on the
conversion. Most other aldehydes reacted quantitatively, and
in some cases, isolated yields were affected by the isolation
procedure.22 Nonenolizable aliphatic aldehyde (entry 19)
reacted quantitatively, whereas enolizable 2-methylbutanal
underwent self-condensation as determined by GC/MS
analysis of the reaction mixture.23
In this communication, we present a practical protocol for
the protection of nonenolizable aldehydes and ketones under
basic, kinetically controlled conditions.18
For our initial attempts of synthesis of 1,3-dioxolanes,
(5) For carbanions, cyclization to a three-membered ring is faster than
that to a five-membered ring, whereas for O-anions, the opposite is true:
Gronert, S.; Azizian, K.; Friedman, M. A. J. Am. Chem. Soc. 1998, 120,
3220-3226.
(6) For a review of protecting group chemistry, see, for example: (a)
Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic Synthesis,
3rd ed.; John Wiley & Sons, Inc.: New York, 1999. (b) Kocien˜ski, P. J.
Protecting Groups 3rd ed.; Thieme Verlag: New York, 1994.
(7) (a) Showler, A. J.; Darley, P. A. Chem. ReV. 1967, 67, 427-440. (b)
Klausener, A.; Fraunrath, H.; Mikhail, G. K.; Lange, W.; Schneider, S.;
Schro¨der, D. In Houben-Weyl Methoden der organischen Chemie; Hage-
mann, H., Klamann, D., Eds.; Georg Thieme Verlag Stuttgart: 1991; Vol.
E14a, Part 1, pp 232-234. (c) MacPherson, D. T.; Rawi, H. K. In Function
Bearing Two Oxygens R1 C(OR2)2 in ComprehensiVe Organic Functional
2
Group Transformations; Katritzky, A. R., Meth-Cohn, O., Rees, Ch. W.,
Eds.; Pergamon Elsevier Science: Oxford, 1995; Vol. 4, pp 159-214. (d)
Hoffman, W. Ch. Ethylene Glycol. In Handbook of Reagents for Organic
Synthesis. ActiVating Agents and Protecting Groups; Pearson, A. J., Roush,
W. J., Eds.; Wiley: Chichester, 1999.
(8) For recent examples, see: (a) Yu, M.; Pagenkopf, B. L. Tetrahedron
2003, 59, 2765-2771. (b) Chen, Ch.-T.; Weng, S.-S.; Kao, J.-Q.; Lin, Ch.-
Ch.; Jan, M.-D. Org. Lett. 2005, 7, 3343-3346. (c) Fuchs, B.; Nelson, A.;
Star, A.; Stoddart, J. F.; Vidal, S. Angew. Chem., Int. Ed. 2003, 42, 4220-
4224. (d) Kim, Y. J.; Varma, R. S. Tetrahedron Lett. 2005, 46, 7447-
7449. (e) Kumar, R.; Chakraborti, A. K. Tetrahedron Lett. 2005, 46, 8319-
8323.
(18) Some specific methods of formation of acetals under basic conditions
were described. (a) Base-promoted acetal formation with phenyl salicy-
lates: Perlmutter, P.; Puniani, E. Tetrahedron Lett. 1996, 37, 3755-3756.
(b) Acetalization of aldehydes catalyzed by TiCl4 in a basic medium: Clerici,
A.; Pastori, N.; Porta, O. Tetrahedron 1998, 54, 15679-15690. (c) Synthesis
of acetals from phenols and 1,1-dihaloalkanes: Dehmlow, E. V.; Schmidt,
J. Tetrahedron Lett. 1976, 95-96.
(19) Typical procedure: To a vigorously stirred solution of benzalde-
hyde (5.30 g; 50 mmol) and 2-chloroethanol (6.04 g; 75 mmol) in DMF
(20 mL) and THF (10 mL) at -60 °C under argon was added dropwise a
solution of t-BuOK (8.40 g; 75 mmol) in DMF (15 mL) for 30 min. Then,
the mixture was stirred for 90 min and aqueous NH4Cl, brine, and water
were added. The mixture was extracted with ethyl acetate (5 × 70 mL),
and combined organic phases were washed with brine (3 × 100 mL) and
dried with MgSO4. The solvent was removed in vacuo, and the residue
was distilled under reduced pressure (see Supporting Information for details).
(20) p-NO2- and p-NMe2-substituted benzaldehydes and terephthalalde-
hyde were unsoluble under the reaction conditions. Cinnamaldehyde
substantially polymerized during the reaction; however, small amounts of
the acetal were obtained.
(9) Torok, D. S.; Figueroa, J. J.; Scott, W. J. J. Org. Chem. 1993, 58,
7274-7276 and references therein.
(10) Nerdel, F.; Buddrus, J.; Scherowsky, G.; Klamann, D.; Fligge, M.
Liebigs Ann. Chem. 1967, 710, 85-89.
(11) Font, J.; Gala´n, M. A.; Virgili, A. J. Chem. Soc., Perkin Trans. 2
1986, 75-78 and references therein.
(12) (a) Newkome, G. R.; Sauer, J. D.; McClure, G. L. Tetrahedron Lett.
1973, 1599-1602. (b) Newkome, G. R.; Sauer, J. D.; Staires, S. K. J. Org.
Chem. 1977, 42, 3524-3527.
(13) Schmitz, E. Ber. 1958, 91, 410-414.
(14) (a) Kuhn, R.; Trischmann, H. Ber. 1961, 94, 2258-2263. (b) Abe,
M.; Adam, W.; Borden, W. T.; Hattori, M.; Hrovat, D. A.; Nojima, M.;
Nozaki, K.; Wirz, J. J. Am. Chem. Soc. 2004, 126, 574-582. (c) Magnus,
Ph.; Giles, M.; Bonnert, R.; Kim, Ch. S.; McQuire, L.; Merritt, A.; Vicker,
N. J. Am. Chem. Soc. 1992, 114, 4403-4405. (d) Magnus, Ph.; Giles, M.;
Bonnert, R.; Johnson, G.; McQuire, L.; Deluca, M.; Merritt, A.; Kim, Ch.
S.; Vicker, N. J. Am. Chem. Soc. 1993, 115, 8116-8129.
(15) Stedman, R. J.; Davis, L. D. Tetrahedron Lett. 1967, 4915-4916.
(16) (a) Simmons, H. E.; Wiley, D. W. J. Am. Chem. Soc. 1960, 82,
2288-2296. (b) He, Y.; Junk, Ch. P.; Cawley, J. J.; Lemal, D. M. J. Am.
Chem. Soc. 2003, 125, 5590-5591. (c) Ref 7b and references therein.
(17) Attempts to protect benzaldehyde as 1,3-dioxolane with bromo-
ethanol were unsuccessful; see footnote 12 in: Sammakia, T.; Hurley, T.
B. J. Org. Chem. 2000, 65, 974-978.
(21) A substantially decreased temperature (-60 °C) favors addition of
a 2-haloethoxide anion to the carbonyl group; however, for more electro-
philic aldehydes, such as p-bromobenzaldehyde, complete conversion of
the substrate is reached also at higher temperatures, e.g., -30 °C.
(22) E.g., solubility of products in the water phase containing DMF during
workup or small differences of boiling points of ingredients of the reaction
mixture.
(23) In the reaction with pivalaldehyde, we were unable to separate the
acetal from the mixture of solvents in a pure form.
3746
Org. Lett., Vol. 8, No. 17, 2006

ketone, described by Newkome12 to be acetalized with
difficulty under acidic conditions, reacted quantitatively.24
Table 1. Formation of 1,3-Dioxolanes from Aldehydes under
Next, we investigated the behavior of 3-chloropropanol,25
a homologue of 2-chloroethanol, in this reaction, as 1,3-
dioxanes that should be produced are also applied as carbonyl
protecting groups.6 As cyclization to the six-membered ring
proceeds slower than that to the five-membered ring, a much
higher temperature (-5 to 0 °C) was necessary for this
reaction to be completed (Table 3).
Basic Conditions
conversion
(1H NMR)a
isolated yield
(purity)
entry
R
1
2
3
4
5
p-MeO-C6H4
m-MeO-C6H4
o-MeO-C6H4
p-Me-C6H4
o-Me-C6H4
C6H5
32%
85%
78%
67%
83%
95%
>98%
96%
>98%
>98%b
>98%
>98%b
95%
-
68% (98%)
45% (95%)
52% (93%)
64% (95%)
80% (>98%)
89% (98%)
86% (95%)
87% (>98%)
93% (>98%)
92% (>98%)
86% (>98%)c
92% (98%)
63% (>98%)
66% (98%)
75% (>98%)
78% (95%)
70% (98%)d
Table 3. Formation of 1,3-Dioxanes from Aldehydes under
Basic Conditions
6
7
8
9
p-Cl-C6H4
m-Cl-C6H4
o-Cl-C6H4
p-Br-C6H4
o-Br-C6H4
m-NO2-C6H4
o-NO2-C6H4
2-furyl
2-thienyl
2-Py
m-MOM-O-C6H4
p-H2CdCH-C6H4
10
11
12
13
14
15
16
17
18
conversion
(1H NMR)a
isolated yield
(purity)b
entry
R1
R2
1
2
3
4
C6H5
p-MeO-C6H4
2-Py
H
H
H
H
>98%
85%
>98%
>98%
90% (95%)
72% (93%)
52% (85%)c
79% (>98%)
>98%
90%
98%
87%
75%
o-Br-C6H4
a Description “>98%” means that substrate was not detected in the
reaction mixture. b 1,3-Dioxanes were contaminated with traces of unreacted
3-chloropropanol and/or its oligomers. c Partial decomposition of product
under the reaction conditions was observed.
19
>98%
93% (>98%)
a The description “>98%” means that substrate was not detected in the
reaction mixture. b Reaction was performed at -30 °C to ensure solubility
of the aldehyde in the reaction mixture. c Isolated by recrystallization from
ethanol. d Reaction was performed on a 10 mmol scale, and product was
isolated via column chromatography.
Synthesis of acetals under nonequilibrating basic condi-
tions elaborated in this paper is particularly useful when acid-
catalyzed processes give mixtures of products.26 For instance,
acid-catalyzed reaction of benzaldehyde with glycerol gives
all possible diastereoisomers of 1,3-dioxolanes and 1,3-
dioxanes.27 We expected that in the model reaction of
benzaldehyde with 3-chloro-1,2-propanediol only 1,3-diox-
olanes would be produced. Equilibration of the isomeric
alkoxide anions and the reversibility of the addition of these
anions to the carbonyl group, which connected with much
faster 1,5-substitution leading to 1,3-dioxolanes than 1,6-
substitution leading to 1,3-dioxanes, should drive the system
to produce the former. Indeed, treatment of a mixture of
benzaldehyde and 3-chloro-1,2-propanediol in DMF with
t-BuOK at -5 to 0 °C gave the expected 1,3-dioxolane in
good yield as a 1:1 mixture of diastereoisomers. Finally, we
applied in this reaction enantiomerically enriched (R)-
The influence of substituents on conversion was also
observed for a series of ketones (Table 2). Less-electrophilic
Table 2. Formation of 1,3-Dioxolanes from Ketones under
Basic Conditions
conversion
(GC)a
isolated yield
(purity)
entry
R1
C6H5
p-Cl-C6H4 C6H5
2-Py
CO2Me
CF3
R2
1
2
3
4
5
C6H5
12%b
60%b
>98%b
97%
-
-
(24) The mechanism of the reaction of 2,2′-bipyridyl ketone with
2-bromoethanol with Li2CO3 at reflux temperature postulated by Newkome
(ref 12a) included the assistance (initiated by quaternization) of one ring
nitrogen atom in the acetalization process. This idea was further presented
elsewhere (ref 17). However, these conditions differ substantially from ours;
we assume that the main effect of nitrogen atoms in pyridine rings is
inductive in nature.
(25) Reaction of 3-bromopropanol with benzaldehyde at -60 °C gave
uncomplete conversion.
(26) Strong substituent effects and nonequilibrating conditions may be
applied, e.g., for protection of one of the two distinct carbonyl groups (see
Supporting Information for details).
2-Py
C6H5
C6H5
62% (>98%)c
67% (mixture of esters)d
75% (>98%)
>98%
a The description “>98%” means that substrate was not detected in the
reaction mixture. b Reaction was performed on a 10 mmol scale. c Isolated
by recrystallization from hexanes/ethyl acetate 5:1 d Mixture of methyl
and tert-butyl esters from transesterification with base (86:14, according to
GC).
(27) Compare, for example: (a) Piantadosi, C.; Anderson, C. E.; Brecht,
E. A.; Yarbro, C. L. J. Am. Chem. Soc. 1958, 80, 6613-6617. (b) Carlsen,
P. H. J.; Sørbye, K.; Ulven, T.; Aasbø, K. Acta Chim. Scand. 1996, 50,
185-187.
benzophenone gave only 12% of the respective acetal,
whereas the p-chloro analogue gave 60%. 2,2′-Bipyridyl
Org. Lett., Vol. 8, No. 17, 2006
3747

3-chloro-1,2-propanediol28,29 obtained from reaction of ep-
ichlorohydrine with water under kinetic resolution conditions
with the Jacobsen cobalt-salen complex.30 The resulting
product possessed the same optical purity as the substrate
(Scheme 2), whereas its preparation31 under acidic conditions
In conclusion, we presented a practical protocol for the
synthesis of 1,3-dioxolanes and 1,3-dioxanes from noneno-
lizable carbonyl compounds under basic conditions. This
approach, extended to a wide range of substrates, opens up
new possibilities based on different reaction mechanisms,
irreversibility of process, and functional group tolerance.
Scheme 2. Reaction of Benzaldehyde with
3-Chloro-1,2-propanediol Giving Substituted 1,3-Dioxolane
Acknowledgment. This work was supported by the State
Commitee for Scientific Research (KBN), Grant 4T09A 05
625. The authors thank Mr. Sławomir Mie¸sowicz and Mr.
Wojciech Chaładaj (IOC PAS, Warsaw) for chiral GC
analyses.
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds with
reprints of 1H and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
is obviously impossible as a consequence of equilibration
and the achiral character of the glycerol.32
(28) For reactions of a nonracemic γ,δ-epoxycarbanion precursor with
aldehydes, see: Ma¸kosza, M.; Barbasiewicz, M.; Krajewski, D. Org. Lett.
2005, 7, 2945-2948.
OL0613113
(29) Both enantiomers of this compound are commercially available.
(30) (a) Furrow, M. E.; Schaus, S. E.; Jacobsen, E. N. J. Org. Chem.
1998, 63, 6776-6777. (b) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.;
Tokunaga, M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E.
N. J. Am. Chem. Soc. 2002, 124, 1307-1315.
(32) This product can be easily transformed via DIBAL reduction into
sn-1-O-benzylglycerol, an interesting intermediate in biological research:
Marguet, F.; Cavalier, J.-F.; Verger, R.; Buono, G. Eur. J. Org. Chem. 1999,
1671-1678 and references therein.
(31) Compare: Carman, R. M.; Kibby, J. J. Aust. J. Chem. 1976, 29,
1761-1767.
3748
Org. Lett., Vol. 8, No. 17, 2006