A metathesis-based approach to the synthesis of furans

Article abstract of DOI:10.1021/ol062933r

(Chemical Equation Presented) The enol ether-olefin ring-closing metathesis reaction has been employed to generate 2,3-dihydrofurans that are equipped with a leaving group. These substrates are at the correct oxidation state to undergo an acid-catalyzed a

Full text of DOI:10.1021/ol062933r

ORGANIC
LETTERS
2007
Vol. 9, No. 6
953-956
A Metathesis-Based Approach to the
Synthesis of Furans
Timothy J. Donohoe,*,† Lisa P. Fishlock,† Adam R. Lacy,† and
Panayiotis A. Procopiou‡
Department of Chemistry, UniVersity of Oxford, Chemistry Research Laboratory,
Mansfield Road, Oxford OX1 3TA, U.K., and GlaxoSmithKline Research &
DeVelopment Limited, Medicines Research Centre, Gunnels Wood Road,
SteVenage, Hertfordshire SG1 2NY, U.K.
timothy.donohoe@chem.ox.ac.uk
Received December 4, 2006
ABSTRACT
The enol ether-olefin ring-closing metathesis reaction has been employed to generate 2,3-dihydrofurans that are equipped with a leaving
group. These substrates are at the correct oxidation state to undergo an acid-catalyzed aromatization, and this strategy has been utilized to
provide a mild and rapid route (four steps) to a range of novel 2,5-disubstituted furans.
Ruthenium-catalyzed ring-closing metathesis (RCM) has
recently emerged as a powerful tool for the synthetic organic
chemist.1 This can largely be attributed to the design of well-
defined catalysts that show both increased activity and
functional group tolerance.2 Despite its widespread applica-
tion in organic synthesis, the use of metathesis to produce
aromatic compounds has only recently been highlighted in
the literature.3 One of the most popular approaches has
involved the construction of benzo-fused systems, where the
existing unsaturated framework results in the formation of a
new aromatic ring upon RCM; this protocol has been used
to produce benzofurans,4 indoles,5 and phenanthrenes.6
We have recently reported that the RCM reaction can be
employed to form a 2,5-dihydrofuran unit that is equipped
with a leaving group at the C-2 position.7 This intermediate
is at the correct oxidation state for aromatization, which
proceeds upon treatment with catalytic acid to furnish the
corresponding furan. The efficient synthesis of substituted
furans continues to be of interest in organic synthesis8
because of the presence of the furan nucleus in many
commercially important pharmaceuticals9 and flavors and in
a variety of naturally occurring biologically active com-
pounds.10
We envisaged that the furan core could also be accessed
via the synthesis of a 2,3-dihydrofuran unit containing the
required leaving group at C-3 (Scheme 1). This alternative
† University of Oxford.
‡ GlaxoSmithKline.
(1) (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int.
Ed. 2005, 44, 4490. Fu¨rstner, A. Angew. Chem.. Int. Ed. 2000, 39, 3012.
(b) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371.
(2) (a) Bieniek, M.; Bujok, R.; Cabaj, M.; Lugan, N.; Lavigne, G.; Arlt,
D.; Grela, K. J. Am. Chem. Soc. 2006, 128, 13652. (b) Love, J. A.; Morgan,
J. P.; Trnka, T. M.; Grubbs, R. H. Angew. Chem., Int. Ed. 2002, 41, 4035.
(c) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc. 2001,
123, 6543. (d) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda,
A. H. J. Am. Chem. Soc. 1999, 121, 791. (e) Ulman, M.; Grubbs, R. H. J.
Org. Chem. 1999, 64, 7202.
(5) (a) Bennasar, M. L.; Roca, T.; Monerris, M.; Garc´ıa-D´ıaz, D. J. Org.
Chem. 2006, 71, 7028. (b) Arisawa, M.; Terada, Y.; Nakagawa, M.; Nishida,
A. Angew. Chem., Int. Ed. 2002, 41, 4732.
(6) Iuliano, A.; Piccioli, P.; Fabbri, D. Org. Lett. 2004, 6, 3711.
(7) Donohoe, T. J.; Orr, A. J.; Gosby, K.; Bingham, M. Eur. J. Org.
Chem. 2005, 1969.
(8) For reviews see: (a) Kirsch, S. F. Org. Biomol. Chem. 2006, 2076.
(b) Brown, R. C. D. Angew. Chem., Int. Ed. 2005, 44, 850.
(9) Hou, X. L.; Cheng, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong,
S. Y.; Wong, H. N. C. Tetrahedron 1998, 54, 1955.
(10) (a) Donnelly, D. M. X.; Meegan, M. J. Comp. Heterocycl. Chem.
1984, 4, 657. (b) Dean, F. M. AdV. Heterocycl. Chem. 1982, 30, 167. (c)
Bosshard, P.; Eugster, C. H. AdV. Heterocycl. Chem. 1966, 7, 378.
(3) Donohoe, T. J.; Orr, A. J.; Bingham, M. Angew. Chem. Int. Ed. 2006,
45, 2664.
(4) Fujimura, O.; Fu, G. C.; Grubbs, R. H. J. Org. Chem. 1994, 59, 4029.
10.1021/ol062933r CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/23/2007

Utimoto titanium-based olefination protocol was then em-
ployed to convert these precursors into the corresponding
enol ethers 4a-h in good yields. Finally, the cyclization was
executed using 10 mol % of catalyst 1 to furnish the 2,5-
disubstituted furan following acid-catalyzed aromatization.16-18
It was found that the dihydrofuran substrate (see 3) partially
aromatized under the conditions of the RCM reaction, and
therefore the aromatization was carried out in situ. The
specific examples studied are given in Table 1. The studies
Scheme 1. General Strategy for Formation of Furans
Table 1. Yields from the Sequence Depicted in Scheme 2
yield (%)
entry
R1
R4
Ph
Ph
i-Pr
Me
i-Pr
CF3
t-Bu
i-Pr
(i)
(ii)
(iii)
(iv)
disconnection would involve the formation of the cyclic enol
ether 3 via RCM of the acyclic substrate 4. While the enol
ether-olefin RCM reaction using Schrock’s molybdenum
catalyst has been well documented, this transformation has
proven unreliable using Grubbs’ first generation ruthenium
catalyst.11 Recently, a number of research groups have
reported that the more robust second generation catalyst 1
can successfully generate the corresponding cyclic enol
ether.12 The requisite acylic enol ether precursors could be
prepared by olefination of the ester 5;13 thus, access to Vic-
diol mono ethers 6 should allow the rapid synthesis of a range
of functionalized furans.
Our initial synthetic studies focused on the formation of
2,5-disubstitued furans using the approach as outlined in
Scheme 1. It has previously been shown that allyloxy
carbanions generally react with carbonyl compounds at the
R-position14 and that complete regiocontrol can be realized
by the use of γ-alkoxy allylindium reagents.15 This procedure
was exploited to generate a range of Vic-diol mono ethers
6a-h in high yields starting from commercially available
allyl ethyl ether (Scheme 2). These alcohols were then easily
1 (a)
2 (b)
3 (c)
4 (d)
5 (e)
6 (f)
7 (g)
8 (h)
4-Br-C6H4
70
75
91
90
90
90
90
83
93
82
99
95
86
77
70
80
72
71
79
82
79
62
0
58
50a
54
51
52
0
2-furyl
cyclopropyl
Ph
Ph
Ph
Ph
pentafluorophenyl
63
64b
a Reference 19. b Reference 20.
shown have revealed that the R1 substituent can be aromatic,
aliphatic (Table 1, entry 3), heteroaromatic (Table 1, entry
2), cyclic (Table 1, entry 3), or fluorinated (Table 1, entry
8).
The identity of the R4 substituent originating from the ester
proved to be less versatile. Primary and secondary aliphatic
esters were successfully transformed into the desired furans
in good yields (Table 1, entries 3-5 and 8), whereas the
olefination failed with the tertiary substrate, presumably due
to the steric bulk (Table 1, entry 7). The RCM of the
trifluoromethyl-enol ether proceeded well to give the cyclic
product in 70% yield (Table 1, entry 6); unfortunately, this
did not aromatize under the previously developed conditions,
and decomposition was eventually observed without forma-
tion of the corresponding furan. This failure was attributed
to the electron-withdrawing nature of the trifluoromethyl
group, which would destabilize the cation formed upon loss
of ethanol in an E1 process.
Scheme 2. Protocol for Synthesis of 2,5-Disubstituted Furans
(13) Hartley, R. C.; McKlernan, G. J. J. Chem. Soc., Perkin Trans. 1
2002, 2763.
(14) Yamamoto, Y.; Yatagai, H.; Saito, Y.; Maruyama, K. J. Org. Chem.
1984, 49, 1096 and references therein.
(15) Hirashita, T.; Kamei, T.; Horie, T.; Yamamura, H.; Kawai, M.;
Araki, S. J. Org. Chem. 1999, 64, 172.
(16) (a) Takai, K.; Kataoka, Y.; Kahiuchi, T.; Utimoto, K. J. Org. Chem.
1994, 59, 2668. (b) Takai, K.; Okazoe, T.; Oshima, K.; Utimoto, K. J. Org.
Chem. 1987, 52, 4410.
(17) Rainier has reported that the cyclic product of metathesis can be
generated directly upon treatment with the Takai-Utimoto reagent: (a)
Allwein, S. P.; Cox, J. M.; Howard, B. E.; Johnson, H. W. B.; Rainier, J.
D. Tetrahedron 2002, 58, 1997. (b) Majunder, U.; Rainier, J. D. Tetrahedron
Lett. 2005, 46, 7209. However, this cyclization was not observed in our
system, despite the use of modified conditions that used lead(II) chloride
and high dilution in dichloromethane.
(18) (a) Nicolaou, K. C.; Postema, M. H. D.; Claiborne, C. F. J. Am.
Chem. Soc. 1996, 118, 1565. (b) Nicolaou, K. C.; Postema, M. H. D.; Yue,
E. W.; Nadin, A. J. Am. Chem. Soc. 1996, 118, 10335.
transformed into a number of ester derivatives 5a-h using
the appropriate acid chloride or anhydride. The Takai-
(11) (a) Hekking, K. F. W.; van Delft, F. L.; Rutjes, P. J. T. Tetrahedron
2003, 59, 6751. (b) Clark, J. S.; Kettle, J. G. Tetrahedron Lett. 1997, 38,
123.
(12) (a) Aggarwal, V. K.; Daly, A. M. Chem. Commun. 2002, 2490. (b)
Rainier, J. D.; Cox, J. M.; Allwein, S. P. Tetrahedron Lett. 2001, 42, 179.
(c) Okada, A.; Ohshima, T.; Shibasaki, M. Tetrahedron Lett. 2001, 42, 8023.
954
Org. Lett., Vol. 9, No. 6, 2007

It has also been shown that the use of excess Takai-
Utimoto reagent can result in the cyclopropanation of
aromatic esters.21 While this unwanted product was observed
in some cases, it could be minimized by careful optimization
of the conditions, which allowed access to triaryl aromatic
compounds in good overall yields (Table 1, entries 1 and
2).
of the increased steric bulk around it, which has exceeded
the limit tolerated by the catalyst.
Finally, the scope of the R2 substituent was investigated.
The metalation of the γ-alkoxy allylindium reagent 12,
followed by reaction with benzaldehyde, proceeded in good
yield to give the alcohol 13 (Scheme 4).22 This was converted
In some cases, it was found that the phosphine ligands
from the catalyst coeluted with the furan product during
column chromatography. Recently, a number of phosphine-
free catalysts have been developed,2 although these have
rarely been utilized in the RCM of enol ethers.22 We found
that this transformation was possible with the Hoveyda-
Grubbs second generation ruthenium catalyst 7; pleasingly,
this also resulted in shorter reaction times and increased yield
for the metathesis of aliphatic enol ethers (Table 2).
Scheme 4. Elaboration of R2
Table 2. Yields of Metathesis/Aromatization (iv) Using
Second Generation Hoveyda-Grubbs Catalyst
entry
R1
R4
yield (%)
into enol ether 15, and the RCM was carried out with catalyst
1 to give the desired trisubstituted furan 2i in 38% yield.
Alcohol 13, formed by hydrolysis of unreacted enol ether,
was also recovered in 56% yield; thus, the yield of furan 2i
is 86% based on recovered starting material. This conversion
could not be improved by increasing catalyst loadings or by
extending the reaction time. The RCM was also successful
with catalyst 7, but this did not lead to an enhancement in
the yield. We believe that by creating a more sterically
hindered alkene initation of the RCM process is retarded,
resulting in competing initiation on the enol ether.12a,25 This
process may lead to the formation of a Fischer carbene that
is not reactive toward metathesis and effectively sequesters
the catalyst.
1 (c)
2 (d)
3 (e)
4 (h)
cyclopropyl
Ph
Ph
pentafluoro-
phenyl
i-Pr
Me
i-Pr
i-Pr
60
56
72
75a
a Reference 20.
Unfortunately, this improvement in the process was not
observed with the corresponding aromatic enol ethers.
Our attention then turned to the elaboration of substituents
R2 and R3 (Scheme 1). The R3 group was altered first, and
a R3 ) Me series was synthesized using lithiation of 1-(2-
methylallyloxy)butane 8 (Scheme 3).24 The corresponding
Despite limitations regarding the nature of the R2/3 groups,
it is noteworthy that by using this new method to prepare
furans, the R1 substituent is derived from an aldehyde, and
R4 is derived from a carboxylic acid equivalent (Scheme 5).
Scheme 3. Elaboration of R3
Scheme 5. Origin of the Furan Core
Thus, these substituents can be easily introduced from readily
available precursors, providing great flexibility.
To conclude, we have developed a novel and mild
synthetic approach to the furan core via an olefination/RCM
enol ether 11 was then generated using the previously
developed protocol. Unfortunately, the RCM of this substrate
was unsuccessful under a variety of conditions and returned
only starting material. We believe that the catalyst is unable
to initiate on the 1,1-disubstituted alkene within 11 as a result
(19) 2-(Furan-2-yl)-5-phenylfuran was unstable, and decomposition was
observed within hours after purification by column chromatography.
(20) The dihydrofuran product decomposed upon treatment with TFA;
therefore, the aromatization was carried out by heating the metathesis
reaction mixture at 60 °C with 1 equiv of PPTS until TLC analysis showed
complete consumption of starting material.
Org. Lett., Vol. 9, No. 6, 2007
955

protocol. This four-step method has been applied to generate
an extensive range of 2,5-disubstituted furans where the
substituents are readily derived from easily accessible
carbonyl compounds.
of this sequence should provide excellent scope for future
studies.
Acknowledgment. We would like to thank GlaxoSmith-
Kline for funding this project. AstraZeneca, Merck, Novartis,
Pfizer, and the ESPRC are also thanked for support.
Not only are we able to prepare differently substituted
furans, but we are also able to introduce substituents that
are not always easy to install by other methods (e.g., i-Pr,
cyclopropyl). The flexibility and functional group tolerance
Supporting Information Available: Copies of 1H NMR
spectra and detailed spectroscopic data for all new com-
pounds and representative experimental procedures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(21) Fallahpour, R. A.; Hansen, H. J. HelV. Chim. Acta 1994, 77, 2297.
(22) Lee, A.-L.; Malcolmson, S. J.; Puglisi, A.; Schrock, R. R.; Hoveyda,
A. H. J. Am. Chem. Soc. 2006, 128, 5153.
(23) Formed in one step from 2-methyl-2-propen-1-ol.
(24) Formed in one step from 3-buten-2-ol.
(25) Louie, J.; Grubbs, R. H. Organometallics 2002, 21, 2153.
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