A novel synthesis of 4-methyl-1,3-dioxolane-4-carbaldehydes by epoxidation of 5-methyl-4H-1,3-dioxins and acid-catalyzed rearrangement

Article abstract of DOI:10.1055/s-1999-2601

A straightforward procedure for the synthesis of 4-methyl-1,3-dioxolane- 4-carbaldehydes 2 is reported. The new procedure involves m-CPBA oxidation of 5-methyl-4H-1,3-dioxins 5 in dichloromethane to give 4-(m-chlorobenzoyloxy)- 5-hydroxy-5-methyl-1,3-dioxanes 6 and acid-catalyzed rearrangement of 6 to carbaldehydes 2. By using commercially available m-CPBA the oxidation and rearrangement can be carried out as a one-pot reaction. The procedure is also applicable to 4H-1,3-dioxins. Oxidation of 5 in methanol led to 4-methoxy-5- hydroxy-1,3-dioxanes 7, which did not undergo acid-catalyzed rearrangement.

Full text of DOI:10.1055/s-1999-2601

LETTER
303
A Novel Synthesis of 4-Methyl-1,3-Dioxolane-4-Carbaldehydes by
Epoxidation of 5-Methyl-4H-1,3-Dioxins and Acid-Catalyzed Rearrangement
Carsten Wattenbach, Martin Maurer, Herbert Frauenrath*
Universität Gh Kassel, Fachbereich 19 - Biologie/Chemie, Heinrich-Plett-Straße 40, D-34109 Kassel, Germany
Fax: + 49 (561) 8044649; E-mail: frauenra@hrz.uni-kassel.de
Received 1 December 1998
dation of cyclic vinyl acetals has not yet been
Abstract: A straightforward procedure for the synthesis of 4-meth-
investigated, but we concluded from the well-known m-
yl-1,3-dioxolane-4-carbaldehydes 2 is reported. The new procedure
CPBA oxidation of cyclic vinyl ethers12 that reaction of 5
with m-CPBA should lead to acylals 6 rather than to ep-
involves m-CPBA oxidation of 5-methyl-4H-1,3-dioxins 5 in
dichloromethane to give 4-(m-chlorobenzoyloxy)-5-hydroxy-5-
methyl-1,3-dioxanes 6 and acid-catalyzed rearrangement of 6 to oxides, which should be hydrolyzed to give 1.
carbaldehydes 2. By using commercially available m-CPBA the ox-
idation and rearrangement can be carried out as a one-pot reaction.
The procedure is also applicable to 4H-1,3-dioxins. Oxidation of 5
in methanol led to 4-methoxy-5-hydroxy-1,3-dioxanes 7, which did
not undergo acid-catalyzed rearrangement.
Key words: 1,3-dioxolane-4-carbaldehydes, vinyl acetals, 4H-1,3-
dioxins, m-CPBA oxidation, rearrangement
Derivatives of 2-C-methylglyceraldehyde 1 such as
4-methyl-1,3-dioxolane-4-carbaldehydes 2 and related
4-hydroxymethyl-4-methyl-1,3-dioxolanes 3 (Figure 1)
have found many applications in natural product synthe-
ses, e.g., the synthesis of brevetoxin B,1 bicyclomycin,2 to-
copherol,3 and pheromones.4 Several methods have been
developed for the preparation of 2 and 3. Enantiomerical-
ly pure carbaldehydes 2 and corresponding open-chain
derivatives have been obtained from D-mannitol,1,5 D-glu-
cose,6 penam derivatives,7 or by resolution of racemic 38
in multi-step reaction sequences. Other syntheses involve
enzymatic methods to give hydroxymethyl derivatives 3,
which have been oxidized to carbaldehydes 2.9 Sharpless
epoxidation of 2-methyl-2-propen-1-ol and monopro-
tected 2-methylene-1,3-propanediol, respectively, or
Sharpless dihydroxylation of O-protected 2-methyl-2-
propen-1-ol derivatives gave precursors for the synthesis
of 2 with 47-95% ee.8,10
Scheme 1
However, first experiments on the m-CPBA oxidation of
5d in dichloromethane surprisingly afforded 4-methyl-
1,3-dioxolane-4-carbaldehyde 2d in a single step upon
distillative workup of the crude reaction mixture (Scheme
1).11 Since 2d still carries the tert-butyl substituent in the
2-position of the dioxolane ring, we argued that the prim-
arily formed oxidation product immediately undergoes ei-
ther a thermal or an acid-catalyzed rearrangement. In or-
der to get further information about the mechanism of this
unexpected type of rearrangement, we studied the m-
CPBA oxidation of 5-methyl-4H-1,3-dioxins 5a-e in var-
ious solvents (Tables 1, 2). Treatment of 5-methyl-4H-
1,3-dioxins 5a-e with commercially available m-CPBA13
in methanol readily afforded a diastereomeric mixture of
4-methoxy-5-hydroxy-1,3-dioxanes 7a-e (Scheme 2, Ta-
ble 1). Acetals 7 proved to be thermally very stable.
Figure 1
Recently we reported a novel nickel-catalyzed asym-
metric double-bond isomerization of 5-methylene-1,3-di-
oxanes 4, which afforded optically active 5-methyl-4H-
1,3-dioxins 5 with high ee (5d 92% ee).11 We envisaged,
that dioxins 5 might be suitable building blocks for the
synthesis of 1 by m-CPBA oxidation and subsequent hy-
drolysis (Scheme 1). To our knowledge the m-CPBA oxi-
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304
C. Wattenbach et al.
LETTER
ing to give a carboxonium ion 8, which then rearranges to
2. The appearance of an intermediate carboxonium ion in
the rearrangement step emerges from the low yields ob-
tained for the reaction of 5a, which can be rationalized by
the formation of a less favoured primary carboxonium ion
8a.
Scheme 2
Table 1 m-CPBA oxidation of 5-methyl-4H-1,3-dioxins 5 in MeOH
a) Reaction with 1.1 equivalents of technical m-CPBA13 at room tem-
perature for 4 h, then workup. b) Isolated yields. Values in brackets
refer to yields of the crude products (GC). c) Determined by NMR
spectroscopy; cf. Figure 2. d) The second diastereomer has not been
determined.
Scheme 3
Table 2 m-CPBA oxidation of 5-methyl-4H-1,3-dioxins 5 in CH2Cl2
Figure 2
a) Reaction with 1.05 equivalents of dry acid-free m-CPBA14 in di-
chloromethane at room temperature for 4 h, then workup. b) Melting
of crude 6 in the presence of 2 mol-% m-chlorobenzoic acid. Distilla-
tive removal of 2 at 120 °C reaction temperature and reduced pressure
(2b: bp 64 °C/31 Torr; 2c: bp 53 °C/1 Torr; 2d: bp 56 °C/11 Torr; 2e:
52 °C/11 Torr). c) Reaction with 1.2 equivalents technical m-CPBA13
in dichloromethane at room temperature for 4 h, then heating to
120°C and distillative removal of 2 under reduced pressure.15 d) De-
termined by NMR spectroscopy;16 cf. Figure 2.
On the other hand, reaction of 5 with commercially avail-
able m-CPBA in dichloromethane followed by distillative
workup of the crude products led to aldehydes 2a-e. How-
ever, inspection of the NMR spectra indicated, that the
crude products mainly comprised m-chlorobenzoic esters
6 and less amounts of aldehydes 2. Since commercially
available m-CPBA contains a large amount of m-chlo-
robenzoic acid and water (about 30%),13 we therefore in-
vestigated the oxidation of 5 with dry m-chlorobenzoic
acid-free m-CPBA.14 In this case, the m-chlorobenzoic es-
ters 6 could be obtained in 90-98% yield (Scheme 3). At-
tempted distillation of recrystallized esters 6 only led to
decomposition, but distillation of crude 6 in the presence
of small amounts of m-chlorobenzoic acid again gave al-
dehydes 2 in high yields (Table 2). The rearrangement of
6d and 6e results in a 75:25 diastereomeric mixture of
S*,S*-2d,e and S*,R*-2d,e. From these results it can be
concluded, that attack of an acid on 6 induces ring-open-
To evaluate the applicability of this new process we also
examined the m-CPBA oxidation of 4H-1,3-dioxins
(Scheme 4). In a typical example the reaction of 4H-1,3-
dioxin 11 readily prepared from 1,3-dioxane-5-one 9 with
m-CPBA in dichloromethane again produced m-chloro-
benzoic ester 12, which rearranged upon distillation in the
presence of acid to give 1,3-dioxolane-4-carbaldehyde
13.17
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A Novel Synthesis of 4-Methyl-1,3-Dioxolane-4-Carbaldehydes
305
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Scheme 4
(13) Purchased from Acros Organics, Fisher Scientific GmbH,
Germany.
(14) For the purification of commercially available m-CPBA, see:
a) Schwartz, N. N.; Blumbergs, J. H. J. Org. Chem. 1964, 29,
1976. b) Fieser, L. F.; Fieser, M. Reagents for Organic Syn-
thesis; Wiley: New York, 1967; Vol. 1, p 135.
In summary, m-CPBA oxidation of 5-methyl-4H-1,3-di-
oxins 5 in dichloromethane and acid-induced ring-con-
traction of the primarily formed acylals 6 provide a
practical method for the synthesis of 4-methyl-1,3-diox-
olane-4-carbaldehydes 2. The procedure is generally ap-
plicable to 4H-1,3-dioxins. Work on the synthesis of
enantiomerically pure carbaldehydes 2 by starting with
enantiomerically pure 5-methyl-4H-1,3-dioxins 5 is cur-
rently in progress.
(15) All new compounds gave satisfactory spectroscopic and
microanalytical data. Selected data of 2d (diastereomeric ratio
A/B = 75:25). - 1H-NMR of diastereomer A (500 MHz,
CDCl3): δ = 0.96 (9H, s, tert-Bu), 1.34 (3H, s, Me), 3.59 (1H,
d, 2J = 9.0, CHHO), 4.30 (1H, d, 2J = 9.0, CHHO), 4.74 (1H,
s, O-CHR-O), 9.62 (1H, s, CHO). - 13C-NMR (125 MHz,
CDCl3): δ = 18.4 (1C, Me), 24.3 (3C, tert-Bu), 34.0 (1C, tert-
Bu), 72.8 (1C, OCH2), 83.4 (1C, C-CHO), 111.0 (1C, O-CHR-
O), 201.8 (1C, CHO). - MS(PCI, m/z (%)): 173 (68), 157 (8),
143 (11), 87 (100). - 1H-NMR of diastereomer B (500 MHz,
CDCl3): δ = 0.95 (9H, s, tert-Bu), 1.37 (3H, s, Me), 3.65 (1H,
d, 2J = 8.4, CHHO), 4.05 (1H, d, 2J = 8.4, CHHO), 4.69 (1H,
s, O-CHR-O), 9.70 (1H, s, CHO). - 13C-NMR (125 MHz,
CDCl3): δ = 19.1 (1C, Me), 24.2 (3C, tert-Bu), 34.4 (1C, tert-
Bu), 70.7 (1C, OCH2), 84.1 (1C, C-CHO), 111.1 (1C, O-CHR-
O), 202.0 (1C, CHO). - MS(PCI, m/z (%)): 173 (67), 157 (10),
143 (12), 87 (100).
(16) Selected data of 6d (diastereomeric ratio A/B/C/D =
36:48:9:7). - 1H-NMR of diastereomer A (500 MHz, CDCl3):
δ = 0.92 (9H, s, tert-Bu), 1.12 (3H, s, Me), 2.56 (1H, s, OH),
3.80 (1H, dd, 2J = 11.6, 4J = 1.9, OCHH (eq)), 4.04 (1H, d,
2J = 11.6, OCHH (ax)), 4.58 (1H, s, OCHRO), 6.06 (1H, d,
4J = 1.9, O-CH-O(C=O)), 7.45 (1H, dd, 3J = 7.8, 3J = 8.0,
ArH), 7.60 (1H, ddd, 3J = 8.0, 4J = 2.1, 4J = 1.1, ArH), 7.96
(1H, ddd, 3J = 7.8, 4J = 1.6, 4J = 1.1, ArH), 8.01 (1H, dd,
4J = 1.6, 4J = 2.1, ArH). - 1H-NMR of diastereomer B (500
MHz, CDCl3): δ = 0.90 (9H, s, tert-Bu), 1.53 (3H, d, 4J = 0.8,
Me), 2.56 (1H, s, OH), 3.73 (1H, dd, 2J = 10.8, 4J = 1.6, OCHH
(eq)), 3.95 (dq, 1H, 2J = 10.8, 4J = 0.8, OCHH (ax)), 4.59 (1H,
s, OCHRO), 6.13 (1H, d, 4J = 1.6, O-CH-O(C=O)), 7.39 (1H,
dd, 3J = 7.7, 3J = 8.0, ArH), 7.55 (1H, ddd, 3J = 8.0, 4J = 1.1,
4J = 2.2, ArH), 7.94 (1H, ddd, 3J = 7.7, 4J = 1.1, 4J = 1.7, ArH),
7.99 (1H, dd, 4J = 1.7, 4J = 2.2, ArH). - 1H-NMR of diastereo-
mer C (500 MHz, CDCl3): δ = 0.95 (9H, s, tert-Bu), 1.12 (3H,
s, Me), 2.56 (1H, s, OH), 3.65 (1H, d, 2J = 11.8, OCHH (eq)),
3.86 (1H, d, 2J = 11.8, OCHH (ax)), 4.40 (1H, s, OCHRO),
5.86 (1H, s, O-CH-O(C=O)), 7.40 (1H, dd, 3J = 8.0, 3J = 8.0,
ArH), 7.58 (1H, ddd, 3J = 8.0, 4J = 2.2, 4J = 1.1, ArH), 7.94
(1H, ddd, 3J = 8.0, 4J = 1.1, 4J = 1.7, ArH), 8.11 (dd, 1H, 4J =
2.2, 4J = 1.7, ArH). - 1H-NMR of diastereomer D (500 MHz,
CDCl3): δ = 0.97 (s, 9H, tert-Bu), 2.09 (s, 3H, Me), 2.56 (1H,
Acknowledgement
This work was supported by the Fonds der Chemischen Industrie.
References and Notes
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s, OH), 3.69 (d, 1H, 2J = 11.6, OCHH (eq)), 3.88 (d, 1H, 2J =
11.6, OCHH (ax)), 4.77 (s, 1H, OCHRO), 5.80 (d, 1H, 4J =
1.0, O-CH-O(C=O)), 7.37 (dd, 1H, 3J = 8.0, 3J = 8.0, ArH),
7.52 (ddd, 1H, 3J = 8.0, 4J = 2.1, 4J = 1.1, ArH), 7.86 (ddd, 1H,
3J = 8.0, 4J = 1.1, 4J = 1.7, ArH), 8.03 (dd, 1H, 4J = 1.7, 4J =
2.1, ArH).
(17) Taken in part from the diploma work of M. Prall, Universität
Gh Kassel 1998.
Synlett 1999, No. 3, 303–306 ISSN 0936-5214 © Thieme Stuttgart · New York