Reactive diene for synthesis of substituted catechols

Article abstract of DOI:10.1016/j.tetlet.2007.11.085

(2R,3R)-2,3-Dimethoxy-2,3-dimethyl-5,6-dimethylene-1,4-dioxane has been synthesized and is a highly efficient diene in Diels-Alder reactions. Reaction with acetylenic dienophiles provides a simple route to substituted catechols. Reactions with some ethyle

Full text of DOI:10.1016/j.tetlet.2007.11.085

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 219–221
Reactive diene for synthesis of substituted catechols
a
a
b
a,
*
Benjamin J. Compton , David S. Larsen , Lesley Larsen , Rex T. Weavers
a
Department of Chemistry, University of Otago, Box 56, Dunedin 9054, New Zealand
Plant Extracts Research Unit, New Zealand Institute for Crop and Food Research Limited, Department of Chemistry,
University of Otago, Box 56, Dunedin 9054, New Zealand
b
Received 12 October 2007; revised 7 November 2007; accepted 14 November 2007
Available online 21 November 2007
Abstract
(2R,3R)-2,3-Dimethoxy-2,3-dimethyl-5,6-dimethylene-1,4-dioxane has been synthesized and is a highly efficient diene in Diels–Alder
reactions. Reaction with acetylenic dienophiles provides a simple route to substituted catechols. Reactions with some ethylenic dieno-
philes are also reported.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Cisoid diene; Diels–Alder; Protected catechol
As part of a study into the metabolism of a natural anti-
oxidant, we required a synthesis of a substituted catechol
labelled with 13C in the benzene ring. We envisaged achiev-
ing this through Diels–Alder chemistry, requiring reaction
of an acetylenic dienophile with an appropriately oxygen-
ated diene. Although this strategy has been achieved previ-
ously by reacting 2,3-bis-(trimethylsilyloxy)-1,3-butadiene
with various dienophiles,1,2 we required an approach that
yielded substituted catechols bearing a more robust protec-
tion than that proffered by the trimethylsilyl groupings.
Furthermore, the reported Diels–Alder reactions required
quite forcing reaction conditions.
2,2-Dimethyl-4,5-dimethylene-1,3-dioxolane has been
reported as a very unreactive diene, despite its cisoid
arrangement.3,4 This lack of reactivity has been ascribed
to a scissoring of the double bonds.4 We reasoned that
enlarging the ring should overcome this problem, and
chose as our platform the 2,3-dimethoxy-2,3-dimethyl-
1,4-dioxane system, previously developed for protection
of vicinal diols.5 Mesylate 5, derived readily from dimethyl
or diethyl tartrate,6 was treated with potassium tert-butox-
ide in DMF at À12 °C to yield the new diene 6 in 40%
yield (Scheme 2). A similar elimination yielding the
The feasibility of our approach was demonstrated by
reaction of 2,3-(dibenzyloxy)butadiene (1) with p-nitro-
phenyl propiolate (2) to yield predominantly diene 3, which
could be aromatised with dichlorodicyanoquinone (DDQ)
to yield the new catechol derivative 4 in 67% overall yield
(Scheme 1). However, reaction of compound 1 with more
electron rich dienophiles proved unproductive and a more
reactive 4p component was sought. It was envisaged that
this could be achieved by using a cyclic acetal that locked
the diene in a cisoid geometry.
OBn
105 oC
OBn
OBn
O
O
O
+
OBn
ArO
OAr
OAr
3
2
1
DDQ/RT
OBn
OBn
4
*
Corresponding author. Tel.: +64 3 4797925; fax: +64 3 4797906.
Scheme 1. Catechol derivative from 2,3-di(benzylyoxy)butadiene.
E-mail address: rweavers@chemistry.otago.ac.nz (R.T. Weavers).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.085

220
B. J. Compton et al. / Tetrahedron Letters 49 (2008) 219–221
trifluoroacetic acid. Deprotection of the carbomethoxy
OMe
H
ref 6
MeOOC OH
MsO
MsO
O
derivative 9c gave the commercially available methyl prot-
ocatechuate (10c) in 85% yield, while compounds 9a and 9b
yielded new catechol derivatives 10a and 10b in yields of
82% and 80%, respectively (Table 2).
O
MeOOC OH
H
OMe
5
-12 oC
t-BuOK/DMF
Diene 6 also reacted with a range of ethylenic dieno-
philes (Table 3). Some measure of the reactivity of the
diene can be gauged by its reaction with unsaturated
nitriles. Tetracyanoethylene (11c) reacted rapidly at room
temperature, heating to 60 °C was required for fumaronit-
rile (11b) to react at a reasonable rate, and acrylonitrile
(11a) showed no appreciable conversion at 60 °C. Maleic
anhydride reacted with 6 at room temperature in 30 min,
in contrast to the reported reaction of this dienophile with
2,3-bis-(trimethylsilyloxy)-1,3-butadiene, which was con-
ducted in boiling toluene over 24 h.1 Adduct 12e, the prod-
uct of reaction of 6 with 1,4-naphthoquinone (11e), readily
underwent aerial oxidation, and it was fully characterised
as quinone 14. Diene 6 was also reacted with diethyl azodi-
carboxylate at room temperature to yield the heterocyclic
compound 13 in 93% yield. The NMR spectra of this dia-
zine were complicated by the presence of atropisomers as a
result of the two amide linkages and broadened spectra
were obtained over a wide range of temperatures. Com-
pounds 12b–12e, 13 and 14 are new dioxane derivatives.
OMe
OMe
O
O
6
Scheme 2. Synthesis of diene 6.
corresponding monomethylene-1,4-dioxane has been
reported previously.7
Uncatalysed Diels–Alder reactions with a range of
acetylenic dienophiles 7 were conducted in KimaxÒ tubes
flushed with argon (Table 1).
Reaction with diethyl acetylenedicarboxylate proceeded
at room temperature; mild heating (40–60 °C) was used in
the other cases to achieve a satisfactory reaction rate. This
contrasts very favourably with the literature reports of the
reactions of 2,3-bis-(trimethylsilyloxy)-1,3-butadiene with
diethyl acetylenedicarboxylate and methyl propiolate,
which required reaction temperatures of 90–110 °C1,2 and
150 °C1 and reaction times of 10 and 24 h, respectively.
In the case of the phenylethylketone 7b the intermediate
dienes were isolated and the major component identified
as 8b, but in other cases the reaction mixture was treated
with DDQ at room temperature to give the corresponding
catechol derivative in a one-pot procedure. When the
Diels–Alder reactions of 6 were conducted at temperatures
of 60 °C and above, product mixtures became more com-
plex and yields diminished. Nonetheless, the relatively
unreactive dehydrochalcone 7e did give a low yield of the
corresponding aromatised adduct 9e. Compounds 9a–9e
have not been reported previously.
Table 2
Deprotection to form substituted catechols
OMe
X
Y
O
O
X
Y
OH
OH
TFA
reflux
OMe
9
10
X, Y
Reaction time (h)
Isolated yield (%)
9a
9b
9c
COOEt, COOEt
Ph(CH2)2CO, H
COOMe, H
4
2.3
6
10a (82)
10b (80)
10c (85)
Although similar dimethoxydioxanes have been depro-
tected by treatment with aqueous trifluoroacetic acid at
room temperature,8 generation of free catechols from the
compounds prepared in this study required heating in
Table 3
Reaction of diene 6 with ethylene dienophiles
OMe
OMe
A
B
C
O
A
C
B
D
+ 6
conditions
Table 1
O
Reaction of diene 6 with acetylenic dienophiles and subsequent aromat-
isation
D
11
12
A, C
B, D
Conditions Isolated yield (%)
OMe
OMe
OMe
OMe
Y
X
Y
O
O
X
Y
O
O
DDQ
RT
60 °C, 18 h — (0)a
+ 6
11a CN, H
11b CN, H
11c CN, CN
11d –CO–O–CO–
11e –CO–O–C6H4–CO– H, H
H, H
H, CN
CN, CN rt, 1 h
H, H
conditions
60 °C, 4 h
12b (79)
12c (90)
12d (91)
12e (75 )
X
7
9
8
rt, 0.5 h
30 °C, 6 h
X, Y
Conditions
Isolated yield (%)a
a
Only starting materials present by 1H NMR analysis.
7a
7b
7c
7d
7e
a
COOEt, COOEt
Ph(CH2)2CO, H
COOMe, H
MeN(OMe)CO, H
PhCO, Ph
rt, 3.3 h
9a (90)
9b (75)
9c (67)
9d (69)
9e (15)
50 °C, 1 h
50 °C, 5 h
40 °C, 48 h
60 °C, 16 h
O
OMe
OMe
EtOOC
EtOOC
O
O
O
O
N
N
OMe
OMe
O
13
14
Isolated yield from a one-pot process.

B. J. Compton et al. / Tetrahedron Letters 49 (2008) 219–221
221
Compound 6 is an effective diene for use in Diels–Alder
Supplementary data
chemistry. It reacts readily with a range of dienophiles.
Reaction temperatures are considerably lower and reaction
times appreciably shorter than those reported for the bistri-
methylsilyl protected analogue.1,2 The 2,3-oxygenation pat-
tern provides ready access to compounds containing vicinal
dihydroxylation in a six-membered ring and the acetal
function provides durable protection for subsequent chem-
istry. The one-pot reaction of diene 6 with an acetylenic
dienophile coupled with subsequent oxidation by DDQ,
followed by treatment with TFA provides a very conve-
nient and short synthesis of substituted catechols.
Full experimental details and copies of 1H and 13C spec-
tra data for all new compounds. Supplementary data asso-
ciated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2007.11.085.
References and notes
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3. Miller, J. B. J. Org. Chem. 1960, 25, 1279–1285.
4. Scharf, H.; Plum, H.; Fleischhauer, J.; Schleker, W. Chem. Ber. 1979,
112, 862–882.
5. Berens, U.; Leckel, D.; Oepen, S. C. J. Org. Chem. 1995, 60,
8204–8208.
6. Li, W.; Waldkirch, J. P.; Zhang, X. J. Org. Chem. 2002, 67, 7618–7623.
Acknowledgements
´
7. Dıez, E.; Dixon, D. J.; Ley, S. V. Angew. Chem., Int. Ed. 2001, 40,
Funding from the Chemistry Department and Division
of Sciences of the University of Otago and from Crop
and Food Research Limited is acknowledged.
2906–2909.
8. Dixon, D. J.; Ley, S. V.; Reynolds, D. J. Chem. Eur. J. 2002, 8,
1621–1636.