Magnesium mediated carbometallation of propargyl alcohols: Direct routes to furans and furanones

Article abstract of DOI:10.1016/S0040-4039(99)01995-4

The addition of vinyl and aryl Grignard reagents to propargyl alcohols for the direct synthesis of furans and butenolides from a one pot reaction is described. These products arise from a putative magnesium chelate intermediate 2 upon reaction with various electrophiles. This chelate was also generated in situ from alkynyl lithium addition to aldehydes followed by magnesium exchange and Grignard addition. Thus, the complete substitution pattern for the furan ring may be controlled, as desired, through the judicious choice of substrates and reagents.

Full text of DOI:10.1016/S0040-4039(99)01995-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 17–20
Magnesium mediated carbometallation of propargyl alcohols:
direct routes to furans and furanones
Pat Forgione, Peter D. Wilson † and Alex G. Fallis ∗
Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Ontario K1N 6N5, Canada
Received 23 August 1999; accepted 18 October 1999
Abstract
The addition of vinyl and aryl Grignard reagents to propargyl alcohols for the direct synthesis of furans
and butenolides from a one pot reaction is described. These products arise from a putative magnesium chelate
intermediate 2 upon reaction with various electrophiles. This chelate was also generated in situ from alkynyl lithium
addition to aldehydes followed by magnesium exchange and Grignard addition. Thus, the complete substitution
pattern for the furan ring may be controlled, as desired, through the judicious choice of substrates and reagents.
© 1999 Elsevier Science Ltd. All rights reserved.
Keywords: furan; furanone; butenolide; magnesium; propargyl.
In the preceeding Communication we have described the direct addition of vinyl and related Grignard
reagents to propargyl alcohols 1 to generate the intermediate magnesium chelate 2 (or a closely related
species) followed by reaction with aldehydes for the direct synthesis of diene–diols and enediynes.1
We have extended these investigations and wish to report the versatile combinations which permit the
direct synthesis of substituted furans (3) by a novel method as well as 2(5H)-furanones (butenolides) (4)
depending upon the electrophiles selected (Scheme 1).
Scheme 1. Magnesium mediated carbometallation of propargyl alcohols
Furans comprise an important class of oxygen heterocycles. They have been isolated from a broad
cross section of natural sources and have been employed both as key synthetic intermediates and as
∗
†
Corresponding author. Tel: (613) 562-5732; fax: (613) 562-5170; e-mail: afallis@science.uottawa.ca
Present address: Department of Chemistry, Simon Fraser University, Burnaby, BC., V5A 1S6, Canada.
0040-4039/00/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)01995-4

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synthetic targets in their own right.2 Consequently, new preparative routes continue to be developed.3
However, few of these methods allow the synthesis of tetrasubstituted furans.4 Following the Grignard
based carbometallation protocol developed previously, substituted furans 7 may be synthesized directly
upon reaction of 2, derived from 5, by reaction with dimethylformamide (DMF) followed by acidification
without isolation of the intermediate hemiacetal 6 (Scheme 2).
Scheme 2. Route to trisubstituted furans. (a) 3.2 equiv. R2MgCl, C6H12, 80°C, 19 h; (b) DMF or R3CN, 0°C, 0.5 h, 22°C; (c)
p-TsOH, C6H6, 21°C, 30–60 min
Alternatively, condensation with aryl nitriles in place of DMF allowed the direct synthesis of more
highly substituted furans in which the substitution pattern at the 2-, 3-, and 4-positions may be controlled
systematically. Table 1 illustrates various combinations with either DMF or benzonitrile. Unfortunately,
the acidic conditions required for the elimination of water also induced decomposition and reduced yields
for the more labile compounds 11, 13 and 14. These vinyl furan systems contain useful functionality for
the construction of more complex skeletons via a double Diels–Alder strategy and may also be used as
monomers.
Table 1
Synthesis of substituted furans
The versatility and scope of this furan synthesis was extended by the in situ generation of the
intermediate chelate 2 via lithium–magnesium transmetallation. Thus, modification of the standard

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protocol permitted the introduction of substituents at the eventual C-5 position of the furan, to allow
independent control of the substituent at the remaining position. Addition of the alkynyl lithium salt
derived from 15 to an aldehyde afforded the lithium alkoxide 16 as illustrated in Scheme 3. This was
followed by transmetallation with vinyl magnesium chloride and Grignard addition to form the chelate 2
which could then be reacted with either DMF or a nitrile derivative. This protocol generated a family of
furans 17 in which the substitution pattern at all four positions could be predetermined.
Scheme 3. Alkynyllithium route to furans. (a) n-BuLi; (b) R1CHO; (c) 3.2 equiv. R2MgCl, C6H12, 80°C, 19 h; (d) DMF or
R3CN; (e) p-TsOH, C6H6, 21°C, 30–60 min
Table 2 lists various examples generated in this fashion including the 2,20-bis-furan system 19. Current
routes to related bis-furan systems are usually accompanied by a few percent of the parent furan.5 Thus,
depending upon the substrate–reagent–reactant combination selected above, a large number of substituted
furan systems may be prepared.
Table 2
Synthesis of tetrasubstituted furans
Early examples of dialkyl butenolides derived from the condensation of species related to 2 with
carbon dioxide have been reported,6 and other methods are available.7 However, in view of the challenge
and medicinal interest8 in preparing 3,4-diaryl-2(5H)-furanones such as 3,4-diphenylbutenolide (23),
this aspect has also been examined. The lactone 23 was synthesized by the magnesium mediated
carbometallation of phenylpropargyl alcohol (22) with phenylmagnesium chloride to form the chelate
2 followed by exposure to carbon dioxide (52% yield). Modification of this protocol in which 22 was
reacted directly with 4-thiomethylphenylmagnesium chloride and the reaction quenched with carbon
dioxide afforded 24. Oxidation of 24 with m-chloroperoxybenzoic acid generated the sulphone 25 in
quantitative yield. As illustrated in Scheme 4, this butenolide, the new Merck anti-inflammatory drug
Vioxx®, may be synthesized in a facile manner using this method.
In summary, the magnesium mediated carbometallation protocols described above provides direct ac-
cess to various oxygen heterocycles that may be employed for a variety of synthetic objectives.9 Although
in some cases the yields are modest, this short route to multisubstituted furans and 3,4-disubstituted

20
Scheme 4. A direct route to furanones including Vioxx® (25). (a) 3.2 equiv. PhMgCl or 4-MeSC6H4MgCl, C6H12, 80°C, 19 h;
(b) CO2; (c) m-CPBA, 0–21°C, 99%
butenolides in a controlled fashion is very useful. Thus, depending upon the substrate–reagent–reactant
combination selected, a large number of compounds may be synthesized. In addition, the ease with which
these compounds are prepared in one synthetic step renders this sequence attractive for the use of these
building blocks for more complex targets. These investigations will be reported in due course.
Acknowledgements
We are grateful to the Natural Sciences and Engineering Research Council of Canada, the Canadian
Breast Cancer Research Initiative (NCI, Canada) and the Saunders–Matthey Foundation for Breast
Cancer Research for financial support of this research. P. Forgione thanks Torcan Chemical Ltd and
the Government of Ontario for an OGSST Fellowship.
References
1. Forgione, P.; Fallis, A. G. Tetrahedron Lett. 1999, 41, 11.
2. For leading references, see: (a) Gilchrist, T. L. Contemp. Org. Syn. 1994, 1, 205. (b) Gilchrist, T. L. J. Chem. Soc., Perkin
Trans. 1 1998, 615.
3. (a) Araadi, A.; Cacci, S.; Larock, R. C.; Marinelli, F. Tetrahedron Lett. 1993, 34, 2816. (b) Da Silva, G. V.; Pelisson, J. M.
M.; Constantino, M. G. Tetrahedron Lett. 1994, 35, 7327. (c) Bures, E.; Spinazze, P. G.; Beese, G.; Hunt, I. R.; Rogers,
C.; Keay, B. A. J. Org. Chem. 1997, 62, 8741. (d) Wipf, P.; Rahman, L. T.; Rector, S. R. J. Org. Chem. 1998, 63, 7132.
4. (a) Kajikawa, S.; Noiri, Y.; Shudo, H.; Nishimo, H.; Kurosawa, K. Synthesis 1998, 1457. (b) Antonioletti, R.; Cecchini,
C.; Ciani, B.; Magnanti, S. Tetrahedron Lett. 1995, 40, 4841.
5. Jeevanandam, A.; Narkunan, K.; Cartwright, C.; Ling, Y.-C. Tetrahedron Lett. 1999, 34, 2816.
6. (a) Jousseaume, B.; Duboudin, J.-G. J. Organomet. Chem. 1971, 91, C1. (b) Mornet, R.; Gouin, L. Bull. Soc. Chim. Fr.
1977, 737. (c) Duboudin, J.-G.; Jousseaume, B. J. Organomet. Chem. 1979, 168, 233.
7. For butenolides, see: (a) Ma, S.; Shi, Z. J. Org. Chem. 1998, 63, 6387. (b) Ma, S.; Shi, Z. Tetrahedron Lett. 1999, 40, 2393.
8. Talley, J. J. Exp. Opin. Ther. Patents 1997, 7, 55.
9. General procedure for the magnesium mediated carbometallation of propargyl alcohols to furans: Phenylmagnesium
chloride (3.7 mL, 1.87 M in THF, 6.7 mmol) was added to a solution of 3-phenyl-2-propyn-1-ol (0.28 g, 2.1 mmol)
in cyclohexane (4.1 mL) at 22°C. The solution was refluxed for 19 h. The solution was cooled to 0°C and N,N-
dimethylformamide (0.53 mL, 6.7 mmol) was added. The mixture was stirred for 5 min at 0°C and refluxed for 3 h.
Standard workup yielded the crude lactol which was immediately dissolved in benzene and treated with a catalytic
amount of p-toluenesulfonic acid and stirred at 22°C for 2 h. The reaction was neutralized with saturated aqueous
sodium bicarbonate, extracted with ether (3×10 mL), dried, concentrated, and chromatographed (20:1 to 12:1 petroleum
1
ether:ether) to afford 3,4-diphenylfuran (10) as a white solid (0.42 g, 91%); mp 108–110°C; H NMR δ 7.00–7.06 (m,
6H), 7.17–7.20 (m, 4H), 7.26 (s, 2H); 13C NMR δ 126.4, 127.2, 128.7, 128.9, 132.6, 141.1; IR (NaCl) 1135, 803, 757,
696; MS (M+) calcd 220.0889; obsd 220.0894. Anal. calcd for C16H12O: C, 87.25; H, 5.49. Found: C, 87.24; H, 5.37.