A carbonyl ylide approach to substituted furans

Article abstract of DOI:10.1055/s-2001-13355

The diazosulphone 1 undergoes intermolecular reaction with aldehydes to form carbonyl ylides 2. This reactive intermediate can then be trapped, in an inter- or intramolecular reaction, by alkynes or alkenes to yield substituted furans or tetrahydrofurans

Full text of DOI:10.1055/s-2001-13355

646
LETTER
A Carbonyl Ylide Approach to Substituted Furans
Tim Johnson,a* David R. Cheshire,a Michael J. Stocks,a Vicky T. Thurstonb
aDepartment of Medicinal Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, LE11 5RH, UK
bDepartment of Chemistry, The University of Leicester, University Road, Leicester, LE1 7RH, UK
Fax +44 1509 645571; E-mail: tim.johnson1@astrazeneca.com
Received 21 January 2001
dichloroethane gave the dihydrofuran 5a as an inseperable
mixture of isomers in 27% isolated yield. Heating 5a with
3 equiv. of triethylamine effected the elimination of phe-
nylsulphinic acid to give the furan 6a in a low yield
(Scheme 2). Subsequently, it was found that 5a could be
formed at room temperature from equimolar amounts of
1, 4a, and DMAD in the presence of rhodium octanoate
dimer. Conversion to 6a was then carried out in situ. This
procedure was then applied to other aldehyde components
(Table 1).4 The reaction was restricted to non-enolisable
aldehydes, possibly due to the intervention of intramolec-
ular -proton abstraction from the carbonyl ylide.5 Al-
though a number of alkyne components were tried in the
reaction, it was found that only DMAD gave any furan
product. The yields obtained could not be improved even
by using DMAD in excess. It was also observed that,
when propionitrile replaced the aldehyde component, the
intermediate nitrile ylide could not be trapped with
DMAD but was trapped intramolecularly by the ester
functionality to form the oxazole 7 (52%) (Scheme 3),
consistent with the findings of Moody et al.3
Abstract: The diazosulphone 1 undergoes intermolecular reaction
with aldehydes to form carbonyl ylides 2. This reactive intermediate
can then be trapped, in an inter- or intramolecular reaction, by
alkynes or alkenes to yield substituted furans or tetrahydrofurans re-
spectively.
Key words: diazo compounds, carbonyl ylide, ring closure, furans
The formation of carbonyl ylides from the reaction of
metallocarbenoids with carbonyl compounds continues to
be an important tool in the synthesis of oxygen containing
heterocyclic systems.1 Carbonyl ylides are usually gener-
ated by an intramolecular reaction; however, the intermo-
lecular generation of carbonyl ylides has also been
employed in heterocycle synthesis.2 An example of inter-
molecular generation of nitrile ylides from nitriles and the
ethyl ester of the diazosulphone 1 has been demonstrated
by Moody et al.3 We envisaged that 1 would react with al-
dehydes, under rhodium(II) catalysis, in an analogous
manner to yield carbonyl ylides 2. These could then un-
dergo inter- or intramolecular trapping with dipolaro-
philes such as alkynes or alkenes. If 2 were trapped
intermolecularly by an alkyne we expected the intermedi-
ate dihydrofuran 3 to readily aromatise by elimination of
phenylsulphinic acid to yield substituted furans. Similar
chemistry would be anticipated to occur for aldehydes
bearing a tethered alkyne, giving rise to annulated furans
(Scheme 1).
Table 1 Synthesis of Furans 5
Initially we decided to explore the intermolecular trapping
of 2. We found that heating 1 with 3 equiv. of crotonalde-
hyde 4a, 3 equiv. of dimethylacetylenedicarboxylate
(DMAD) and 5 mol% rhodium octanoate dimer in 1,2-
aIsolated.
Scheme 1
Synlett 2001, No. 5, 646–648 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Carbonyl Ylide Approach to Substituted Furans
647
Scheme 4
Scheme 2
Table 2 Synthesis of Annulated Furans 9a-f
aSee Refs. 6 to 11 respectively. bIsolated. cRef. 15.
available carboxylic acid by standard methods.12 The lac-
tone product was obtained as a single diastereomer of un-
known relative stereochemistry. In this case in situ
elimination of phenylsulphinic acid did not occur.
Scheme 3
Changing the dipolarophile from DMAD to N-phenylma-
leimide increased the efficiency of trapping to furnish the
tetrahydrofuran derivative 8 in good yield (77%), albeit as
an inseperable mixture of isomers (Scheme 3).
Clearly the intermolecular trapping of 2 by alkynes was
inefficient and limited in scope.
We next turned our attention to the intramolecular trap-
ping of 2. The required aldehydes 9a-f, bearing a tethered
alkyne, were readily prepared by known methods (Table
2). Heating equimolar amounts of 1 and the aldehyde 9a-
f in the presence of 5 mol% rhodium octanoate dimer gen-
Scheme 5
erated the annulated furans 10a-f (Scheme 4, Table 2).12 By the same procedure we found that we could react 1
No separate step for the elimination of phenylsulphinic with aldehydes 12a and 12b bearing a tethered alkene
acid was required as elimination was found to occur under thereby generating the tetrahydrofurans 13a and 13b
the reaction conditions. Interestingly, in a competition re- (Scheme 6, Table 3).13 In these cases elimination of phe-
nylsulphinic acid did not occur under the reaction condi-
tions. As with the tethered alkynes, a substituent on the
alkene was tolerated, 13b.
action between the acetylenic aldehydes 9d and 9e only
9d was found to react with 1 to give exclusively 10d as de-
termined by GC/MS analysis of the crude reaction mix-
ture. This tends to suggest that the cyclisation event and
not the formation of the presumed carbonyl ylide interme-
diate is rate limiting. Also gratifying was the tolerance of
alkyne substituents giving rise to potentially useful func-
tionality at the 3-position in furans 10a-c.
Although attempted formation of the furan annulated
cycloheptane 10f failed, the formation of an annulated
seven-membered ring was achieved by reaction of 1 with
the ester 11 (Scheme 5), which was prepared from the
Scheme 6
Synlett 2001, No. 5, 646–648 ISSN 0936-5214 © Thieme Stuttgart · New York

648
T. Johnson et al.
LETTER
temperature for 1 hour. Triethylamine (0.5 mmol) and 1,2-
Table 3 Synthesis of Tetrahydrofurans 13a,b
dichloroethane (0.5 mL) were added and the solution was
heated at 65 °C for 2 hours. Column chromatography (silica,
eluent iso-hexane/ether 95:5) was used to obtain pure products
6.
(5) Lottes, A. C.; Landgrebe, J. A.; Larsen, K. Tetrahedron Lett.
1989, 30, 4089.
(6) Lowinger, T. B.; Weiler, L. J. Org. Chem. 1992, 57, 6099.
(7) Cruciani, P.; Stammler, R.; Aubert, C.; Malacria, M. J. Org.
Chem. 1996, 61, 2699.
aRef. 14. bIsolated.
(8) Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119,
9065.
(9) Adams, T. C.; Combs, D. W.; Daves, G. D., Jr.; Hauser, F. M.
J. Org. Chem. 1981, 46, 4582.
The tetrahydrofuran 13a was obtained as a 9:1 mixture of
diastereoisomers. However, NOE studies did not allow us
to determine the relative stereochemistry of the major dia-
stereoisomer. The product 13b arising from cis-6-nonen-
(10) Ma, D.; Lu, X. Tetrahedron 1990, 46, 6319.
1-al, was also obtained as a single diastereoisomer. In this (11) Kalabin, G. A.; Krivdin, L. B.; Proidakov, A. G.; Kushnarev,
D. F. Zh. Org. Khim. 1983, 19, 476.
case NOE studies indicated that 13b was cis-ring fused
and that the cis-stereochemistry in the alkene starting ma-
(12)
terial was retained in the product (Figure 1).
Figure 1
(13) General experimental procedure for the synthesis of
annulated furans 10 and tetrahydrofurans 12.
To a mixture of aldehyde 9 or 11 (0.5 mmol),
Further studies on the reaction of 1 with carbonyl com-
pounds are underway.
methyldiazo(benzenesulphonyl) acetate 1 (0.5 mmol) and 1,2-
dichloroethane (0.1 mL) at 65 °C was added a slurry of
rhodium octanoate dimer (0.025 mmol) in 1,2-dichloroethane
(0.3 mL). The reaction mixture was heated at 65 °C for a
further 0.75 hour. Column chromatography (silica, eluent iso-
hexane/ether 95:5) was used to obtain pure products 10 or 12.
(14) Spino, C.; Barriault, N. J. Org. Chem. 1999, 64, 5292.
(15) All new compounds gave satisfactory NMR and mass spectral
data. For example, 10c: colourless oil; 1H NMR (300 MHz,
CDCl3): 7.56 (d, 2H), 7.40-7.34 (m, 3H), 3.83 (s, 3H), 2.81
(t, 2H), 2.65 (t, 2H), 2.16 (t, 2H); MS m/z (relative intensity
%) 242 (100); Anal. calcd. for C15H14O3: C, 74.36; H, 5.82.
Found: C, 74.16; H, 6.26.
References and Notes
(1) Padwa, A.; Weingarten, D. M. Chem. Rev. 1996, 96, 223.
(2) For some examples of intermolecular carbonyl ylide
generation see: Hamaguchi, M.; Matsubara, H.; Nagai, T.
Tetrahedron Lett. 2000, 41, 1457. Doyle, M. P.; Forbes, D. C.;
Xavier, K. R. Russ. Chem. Bull. 1998, 47, 932. Ibata, T.; Liu,
M. T. H.; Toyoda, J. Tetrahedron Lett. 1986, 27, 4383.
(3) Doyle, K. J.; Moody, C. J. Tetrahedron 1994, 50, 3761.
(4) General experimental procedure for the synthesis of
furans 6.
A mixture of aldehyde 4 (0.5 mmol), dimethylacetylene
dicarboxylate (0.5 mmol), methyldiazo(benzenesulphonyl)
acetate 1 (0.5 mmol), rhodium octanoate dimer (0.025 mmol)
and 1,2-dichloroethane (0.5 mL) was stirred at room
Article Identifier:
1437-2096,E;2001,0,05,0646,0648,ftx,en;D01501ST.pdf
Synlett 2001, No. 5, 646–648 ISSN 0936-5214 © Thieme Stuttgart · New York