A novel multicomponent reaction of dimethoxycarbene and DMAD with aldehydes and quinones: Facile synthesis of dihydrofuran derivatives

Article abstract of DOI:10.1016/S0040-4039(01)00070-3

The zwitterionic species generated by the addition of dimethoxy carbene to dimethyl acetylenedicarboxylate (DMAD) is trapped by aldehydes and quinones to yield dihydrofuran derivatives in good yields.

Full text of DOI:10.1016/S0040-4039(01)00070-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2043–2044
A novel multicomponent reaction of dimethoxycarbene and
DMAD with aldehydes and quinones: facile synthesis of
dihydrofuran derivatives†
Vijay Nair,* S. Bindu and Lakshmi Balagopal
Organic Chemistry Division, Regional Research Laboratory (CSIR), Trivandrum 695019, India
Received 4 December 2000; revised 3 January 2001; accepted 10 January 2001
Abstract—The zwitterionic species generated by the addition of dimethoxy carbene to dimethyl acetylenedicarboxylate (DMAD)
is trapped by aldehydes and quinones to yield dihydrofuran derivatives in good yields. © 2001 Elsevier Science Ltd. All rights
reserved.
The chemistry of nucleophilic carbenes, such as
dimethoxy carbene, has been the subject of intense
investigations by Hoffmann,1 and more recently by
Warkentin,2 who has devised a very convenient method
for generating the carbene. A reaction of dimethoxy
carbene that has received much attention is its addition
to activated triple bonds, e.g. DMAD leading to a
zwitterionic species. Although the latter has been shown
to undergo further reaction with excess DMAD,1 no
attempt has been made to trap it with other elec-
trophiles. In the context of our recent observation that
a facile multicomponent reaction (MCR) occurs with
isocyanides, DMAD and aldehydes,3 we surmised that
a similar reaction would readily occur between the
zwitterionic species derived from dimethoxy carbene,
DMAD and aldehydes leading to dihydrofuran deriva-
tives. The preliminary results of our investigations vali-
dating this assumption are presented here.
The reaction appears to be general as illustrated by its
application to a number of aldehydes; moderate to
excellent yields‡ of the furan derivatives were obtained.
It is interesting to note that 4 on standing at rt for
several hours lost methanol slowly to afford the furan
derivative 5. Subsequently it was found that microwave
irradiation of 4 accelerated its aromatisation dramati-
cally (Scheme 2).
Scheme 1. Reagents and conditions: (i) toluene, reflux, 15 h,
argon; 4a: R1, R2=H, R3=CH3, 85%; 4b: R1, R3=H, R2=
NO2, 77%; 4c: R1, R2=H, R3=Cl, 66%; 4d: R1, R3=H,
R2=Cl, 75%; 4e: R1, R2=H, R3=OMe, 43%; 4f: R1, R2,
R3=H, 45%; 4g: R1, R2=H, R3=OCH2Ph, 69%; 4h: R1,
R2=benzo, R3=H, 90%.
In our initial experiment, we exposed p-tolualdehyde to
the zwitterionic species, resulting from DMAD and
dimethoxycarbene, the latter being generated in situ by
the thermolysis of 2 in refluxing toluene following the
Warkentin protocol.2 A facile reaction leading to the
dihydrofuran derivative 4a4 in 85% yield occurred
(Scheme 1). The product was characterised by spectro-
scopic analysis.
Scheme 2. Reagents and conditions: (ii) microwave (800 W),
silica gel, 5 min, 90%; R1, R2=H, R3=CH3.
Keywords: dimethoxycarbene; acetylenedicarboxylate; aldehydes;
quinones; dihydrofuran.
* Corresponding
author.
Fax:
+91-471-491712;
e-mail:
gvn@csrrltrd.ren.nic.in
This paper is dedicated with best wishes to Professor Alfred Hass-
ner, on the occasion of his retirement.
†
‡ All yields are for isolated compounds. Yield given in parenthesis is
based on the recovered p-benzoquinone.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00070-3

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V. Nair et al. / Tetrahedron Letters 42 (2001) 2043–2044
References
1. (a) Hoffmann, R. W.; Lilienblum, W.; Dittrich, B. Chem.
Ber. 1974, 107, 3395–3407; (b) Hoffmann, R. W.; Stein-
bach, K.; Lilienblum, W. Chem. Ber. 1976, 109, 1759–
1768; (c) Hoffmann, R. W.; Reiffen, M. Chem. Ber. 1976,
109, 2565–2571; (d) Hoffmann, R. W.; Steinbach, K.;
Dittrich, B. Chem. Ber. 1973, 106, 2174–2184.
2. (a) Warkentin, J. J. Chem. Soc., Perkin Trans. 1 2000,
2161–2169 and references cited therein; (b) Pezacki, J. P.;
Loncke, P. G.; Ross, J. P.; Warkentin, J.; Gadosy, T. A.
Org. Lett. 2000, 2, 2733; (c) Lu, X.; Warkentin, J. Org.
Lett. 2000, 2, 3501–3503.
Scheme 3. Reagents and conditions: (iii) toluene, sealed tube,
15 h, argon; 7a: R1, R2=H, 75%; 7b: R1, R2=CH3, 65%; 7c:
R1=H, R2=Ph, 59%§ (82).
3. Nair, V.; Vinod, A. U. J. Chem. Soc., Chem. Commun.
2000, 1019–1020.
4. All new compounds were fully characterised.
Typical experimental procedure and selected data for com-
pound 4a:
Scheme 4.
A mixture of p-tolualdehyde 1 (0.100 g, 0.83 mmol),
DMAD 3 (0.177 g, 1.25 mmol) and 2,2 dimethoxy D3-
1,3,4-oxadiazoline 2 were refluxed in dry toluene under an
argon atmosphere for 15 h. The solvent was then removed
under vacuum and the residue on chromatographic separa-
tion on silica gel using hexane–ethyl acetate (90:10) gave
the dihydrofuran 4a as a colourless viscous liquid (0.24 g,
85%).
In view of the encouraging results obtained with alde-
hydes and in the context of our interest in the addition
of zwitterionic species to quinones,5 it was obligatory to
extend the present reaction to quinones also. An illus-
trative example involving p-benzoquinone leading to a
spiro dihydrofuran derivative is presented in Scheme 3.
The reaction appears to be general and applicable to
other p-benzoquinones.‡
Compound 4a: Colourless viscous liquid. IR (neat) wmax
:
3012, 2949, 2843, 1738, 1725, 1676, 1607, 1513, 1445, 1333,
1
1251, 1102, 983 cm−1. H NMR (300 MHz, CDCl3–CCl4,
v/v, 3:1): 2.34 (s, 3H, CH3), 3.40 (s, 3H, OCH3), 3.46 (s,
3H, OCH3), 3.65 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 5.84
(s, 1H, CH), 7.26–7.13 (m, 4H, ArH). 13C NMR (75 MHz,
CDCl3–CCl4, v/v, 3:1): 20.03, 21.18, 50.99, 51.01, 51.42,
52.27, 52.41, 52.61, 58.38, 83.97, 123.97, 125.43, 125.57,
129.28, 127.5, 129.2, 133.81, 135.21, 138.65, 141.07, 161.61,
162.38.
Similar reactions were observed with anthraquinone
and 1,4-naphthoquinone and the spirodihydrofurans
were obtained in 31 and 52% yields, respectively.
Mechanistically, the reaction may be considered to
involve the cycloaddition of a zwitterion to the car-
bonyl group (Scheme 4).
Compound 5: Colourless solid, recrystallised from
dichloromethane–hexane mixture, mp 112–113°C. IR
(KBr) wmax: 3012, 2956, 1732, 1723, 1601, 1457, 1264, 1095,
952 cm−1 1H NMR (300 MHz, CDCl3–CCl4, v/v, 3:1):
.
In conclusion, we have devised a facile method for the
synthesis of substituted dihydrofuran derivatives by the
one pot reaction of dimethoxycarbene, generated in situ
from 2,2-dimethoxy D3-1,3,4-oxadiazoline, and DMAD
with aldehydes and quinones. Further investigations in
this area are in progress.
2.36 (s, 3H, CH3), 3.81 (s, 3H, OCH3), 3.88 (s, 3H, OCH3),
4.19 (s, 3H, OCH3), 7.47–7.16, (m, 4H, ArH). 13C NMR
(75 MHz, CDCl3–CCl4, v/v, 3:1): 21.38, 51.56, 52.55,
58.44, 125.51, 125.86, 128.89, 129.39, 138.60, 142.51,
162.22, 164.93. Elemental analysis calcd: C, 63.15, H, 5.30.
Found: C, 63.09, H, 5.29.
Compound 7a: Yellow amorphous solid. IR (KBr) wmax
3055, 3005, 2949, 2837, 1743, 1727, 1673, 1632, 1444, 1394,
1332, 1276, 1119, 976, 914 cm−1 1H NMR (300 MHz,
:
Acknowledgements
.
CDCl3–CCl4, v/v, 3:1): 3.48 (s, 6H, OCH3), 3.71 (s, 3H,
OCH3), 3.88 (s, 3H, OCH3), 6.32 (d, 2H, J=9.9 Hz), 6.69
(d, 2H, J=9.9 Hz). 13C NMR (75 MHz, CDCl3–CCl4, v/v,
3:1): 51.44, 52.70, 52.97, 80.01, 116.03, 123.81, 130.52,
138.47, 139.44, 143.72, 160.38, 161.60, 184.13.
S.B. and L.B. thank CSIR, New Delhi for research
fellowships. Thanks are also due to Mr. A. U. Vinod
for useful discussion, Ms. Soumini Mathew for record-
ing high resolution NMR spectra and Mrs. S. Viji for
elemental analysis.
5. Nair, V.; Vinod, A. U.; Nair, J. S.; Sreekanth, A. R.;
Rath, N. P. Tetrahedron Lett. 2000, 41, 6675–6679.
§ The product in the case of 7c was a mixture of regioisomers in a 2:1
ratio.
.