Reactivity of dearomatised furans synthesised via the decarboxylative Claisen rearrangement

Article abstract of DOI:10.1016/j.tetlet.2009.03.091

The decarboxylative Claisen rearrangement (dCr) reaction of 1-(furan-2-yl)ethyl 2-tosylacetate afforded 2-ethylidene-3-(tosylmethyl)-2,3-dihydrofuran. Reaction of the dearomatised heterocycle with a variety of electrophiles gave addition products with excellent syn-diastereoselectivity. The furanol adducts were then utilised as functionalised scaffolds for a series of subsequent transformations.

Full text of DOI:10.1016/j.tetlet.2009.03.091

Tetrahedron Letters 50 (2009) 3503–3508
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Reactivity of dearomatised furans synthesised via the decarboxylative
Claisen rearrangement
*
Jason E. Camp, Donald Craig
Department of Chemistry, Imperial College London, South Kensington Campus, London SW7 2AZ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The decarboxylative Claisen rearrangement (dCr) reaction of 1-(furan-2-yl)ethyl 2-tosylacetate afforded
2-ethylidene-3-(tosylmethyl)-2,3-dihydrofuran. Reaction of the dearomatised heterocycle with a variety
of electrophiles gave addition products with excellent syn-diastereoselectivity. The furanol adducts were
then utilised as functionalised scaffolds for a series of subsequent transformations.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 15 January 2009
Revised 19 February 2009
Accepted 5 March 2009
Available online 18 March 2009
Keywords:
Claisen rearrangement
Microwave-assisted synthesis
Heteroaromatic
Polysubstituted furan
Aldol
Polysubstituted furans are an important structural motif found
in many natural products1 and important pharmaceuticals.2 The
synthetic utility of furans stems from their ready conversion into
non-aromatic oxygen heterocycles and the ease with which they
may be elaborated to give other oxygen-containing compounds.3,4
Recently we developed a variant of the Ireland–Claisen rearrange-
ment, the decarboxylative Claisen rearrangement (dCr) reaction,
which provides homoallylic sulfones by exposure of allylic tosy-
lacetates to N,O-bis(trimethylsilyl)acetamide (BSA) and potassium
acetate under relatively mild thermal conditions.5 During the
course of our studies on the heteroaromatic variant of this reac-
tion, it was found that substituted thiophene-, pyrrole- and
indole-containing substrates gave dCr reaction products in good
yields.6 For example, reaction of thiophene-2-methyl ester 1 with
BSA and KOAc under thermal conditions gave thiophene 3, pre-
sumably via non-aromatic intermediate 2 (Scheme 1). In contrast,
subjection of tosyl ester 4, derived from a secondary alcohol, to
the same conditions gave rearranged thiophene 5 without rearo-
matisation. These results can be explained in terms of (i) in-
creased steric buttressing between the furan 2-substituent and
the 3-tosylmethyl group in 5, and (ii) enhanced stabilisation of
the more highly substituted exocyclic olefin in the non-aromatic
rearrangement product 5. The synthesis of other dearomatised
heterocycles has been reported using Claisen rearrangements,7
2,3-Wittig rearrangements,8 intramolecular organometallic-medi-
ated cyclisations,9 annulation,10 Kishner reduction or thermally.11
Many of the methods for the generation of these compounds
rely on forcing conditions, use of toxic metals, or relatively unsta-
ble reagents and intermediates. The most important studies on
the synthesis and reactivity of dearomatised furans were con-
ducted by Miles et al., who developed the synthesis of 2- and
3-methylene-2,3-dihydrofurans and investigated their use as
highly reactive enes in the carbonyl-ene reaction.12 Herein, we
report the use of the dCr reaction for the synthesis of 2-ethyli-
dene-3-(tosylmethyl)-2,3-dihydrofuran, and its use as a potent
nucleophile in diastereoselective addition reactions to give highly
functionalised furans.
To investigate this intriguing dearomatisation process further
we examined the analogous furan system, hoping to take advan-
tage of its lower resonance energy relative to other heteroaromat-
ics.13 Addition of methylmagnesium chloride to furfural (6),
followed by diisopropylcarbodiimide (DIC)-mediated coupling of
the resultant alcohol with commercially available tosyl acetic acid
(7) gave furan ester 8 (Scheme 2). Reaction of 8 with BSA and KOAc
under microwave irradiation,14 using a pulse sequence previously
optimised for dCr reactions of non-aromatic substrates,15 provided
2-ethylidene-3-(tosylmethyl)-2,3-dihydrofuran (9) in good yield as
a 10:1 Z/E mixture of stereoisomers, as determined by NOE analy-
sis.16 Upon standing in untreated commercial CDCl3 overnight, 9
aromatised to give exclusively 2-ethyl-3-(tosylmethyl)furan (10).
In contrast, 9 was found to be stable for over two weeks in CD2Cl2,
and it was thought that the acid impurities present in untreated
CDCl3 were the cause of the rearomatisation. Complete rearrange-
ment from 9 to 10 was achieved in a 10% TFA solution in CD2Cl2 in
less than 7 min as determined by 1H NMR.
* Corresponding author.
E-mail address: d.craig@imperial.ac.uk (D. Craig).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.091

3504
J. E. Camp, D. Craig / Tetrahedron Letters 50 (2009) 3503–3508
Ts
Ts
KOAc (0.1 equiv)
BSA (1.0 equiv)
Ts
O
O
O
PhMe, 110
18 h, 58%
°C
S
S
S
S
1
4
2
3
Ts
Ts
O
KOAc (0.1 equiv)
BSA (1.0 equiv)
PhMe, 110
18 h, 75%
°C
S
5
Scheme 1.
Ts
Ts
H2
H2
H1
O
Ts
O
1. MeMgCl
THF, 0 °C
BSA (3.0 equiv)
KOAc (0.1 equiv)
CDCl3
O
3 x 1 min
at 150 °C
microwave
68%
12 h
quant.
2. 7, DIC, Et3N
CH2Cl2, rt, 12 h
88% (2 steps)
O
O
O
O
O
6
8
9
10
Ts
7
(10:1 Z:E)
OH
Scheme 2.
Table 1
Reactions of 9 with electrophiles
Entry
Electrophile
Conditions temp, solvent, additive, time
Product
Yield (%) (syn:anti)
Ts
O
HO
O
O
1
rt, CH2Cl2, none, 2 h
91 (10:1)a
O
H
O
O
11
Ts
N
I
2
3
4
rt, CH2Cl2, none, 3 h
0 °C, CH2Cl2, ZnCl2, 1 h
0 °C, CH2Cl2, ZnCl2, 1 h
66
N
O
12
Ts
HO
HO
O
H
Ph
59 (10:1)
Ph
O
13
Ts
O
H
60 (10:1)
O
14

J. E. Camp, D. Craig / Tetrahedron Letters 50 (2009) 3503–3508
3505
Table 1(continued)
Entry
Electrophile
Conditions temp, solvent, additive, time
Product
Yield (%) (syn:anti)
Ts
HO
HO
O
H
5
0 °C, CH2Cl2, ZnCl2, 1 h
62 (10:1)
O
15
Ts
O
6
0 °C, CH2Cl2, ZnCl2, 1 h
75 (10:1)
Ph
Br
H
H
Ph
O
16
Ts
O
O
Br
HO
HO
7
0 °C, CH2Cl2, ZnCl2, 1 h
82 (5:3)
O
17
Ts
8
0 °C, CH2Cl2, ZnCl2, 1 h
58 (5:1)
H
O
18
O
Ts
O
OMe
O
OMe
OMe
9
150 °C m-xylene, KOAc, 16 h
73 (5:3)
O
OMe
O
19
a
Lower syn-selectivity was observed at increased temperatures.
Next, reaction of the 10:1 Z/E mixture of 9 with various electro-
philes was investigated. Combination of 9 with the electron-defi-
cient substrates ethyl glyoxalate (entry 1) and Eschenmoser’s salt
(entry 2) in the absence of Lewis acid gave addition products 11
and 12, respectively, in good yields (Table 1). Aliphatic aldehydes
(entries 3–5) reacted with enol ether 9 at 0 °C in the presence of
zinc(II) chloride to give the corresponding furan-containing ad-
ducts. The use of other Lewis acids (TiCl4, BF3ꢀOEt and BBr3) at
0 °C or at rt resulted in either decomposition or rearomatisation
of 9 to give 10. Benzaldehyde (entry 6) and 2-bromobenzaldehyde
(entry 7) also reacted with enol ether 9 under the zinc(II) chloride
conditions to give the secondary alcohol products in good yields. In
contrast, 2-cyanobenzaldehyde was a poor substrate for this reac-
tion, giving only trace amounts of the addition product. Reaction of
enol ether 9 with crotonaldehyde in the presence of ZnCl2 gave
exclusively the 1,2-addition product 18 as a 5:1 diastereoisomeric
mixture. The syn-configuration of the products was anticipated on
the basis of the analogous Z-enol ether additions to aldehydes,17
and was confirmed by X-ray crystallographic analysis of the dini-
trobenzoate ester 14A of alcohol 14 (Fig. 1).18 A decrease in dr
was observed with increasing steric hindrance of the aldehyde,
as observed when 2-bromobenzaldehyde was used as the electro-
Figure 1. The molecular structure of 14A,18 majority of hydrogens omitted for
clarity.

3506
J. E. Camp, D. Craig / Tetrahedron Letters 50 (2009) 3503–3508
phile (entry 7). Additionally, the ene-reaction of dimethyl maleate
with 9 in the presence of KOAc (entry 9) gave addition product 19
in good yield, but as a 5:3 mixture of diastereomers.
We have explored a number of transformations in order to dem-
onstrate the utility of the furan addition products. For example,
treatment of maleate derivative 19 or furanol 21 with ruthenium tri-
chloride-sodium periodate19 gave acids 20 and 22, respectively
(Scheme 3).20 Tosyl furan 14 could be alkylated,21 hydroxy-alkyl-
ated22 and sulfenylated23 to give the desired substitution products
as mixtures of diastereomers at the benzylic position. The tosyl moi-
ety was removed from furan 23 by treatment with either magne-
sium24 or sodium25 to give butenyl-substituted furan 24 in good
yields. Treatment of tosyl furan 23 with t-BuOK resulted in elimina-
tion of the tosyl moiety to yield diene 25.26 Additionally, reaction of
furanol 27 with sodium amalgam resulted in a Julia–Lythgoe27 olef-
ination to afford substituted styrene derivative 28.
Scheme 3.

J. E. Camp, D. Craig / Tetrahedron Letters 50 (2009) 3503–3508
3507
Scheme 4.
Preliminary investigations into prefunctionalisation at the C20
References and notes
and ester methylene positions to introduce mutually reactive func-
tionality were also undertaken. Ethyl ester 30 was synthesised
from furfural (6) and subjected to the standard heterocyclic dCr
conditions to afford enol ether 31 as a 10:1 mixture of E/Z isomers.
Reaction of enol ether 31 with acetaldehyde gave alcohol 32, indi-
cating that this overall transformation works on homologous sub-
strates. Additionally, allylation of tosyl ester 8 yielded 33 as a 1:1
mixture of diastereomers. Treatment of 33 with BSA and KOAc un-
der microwave irradiation gave enol ether 34, which was com-
bined with acetaldehyde in the presence of ZnCl2 to give alcohol
23. This route provides an alternative synthesis of allyl alcohol
23 to that outlined in Scheme 3, and increases the utility and flex-
ibility of this method. These transformations are depicted in
Scheme 4.
1. Lipshutz, B. H. Chem. Rev. 1986, 86, 795–819.
2. Nakanishi, K. Natural Products Chemistry; Kondansha: Tokyo, 1974.
3. For example, see: (a) Tsubuki, M.; Tarumoto, N.; Honda, T. Heterocycles 2001,
54, 341–350; (b) Sauers, A. L.; Ho, D. M.; Bernhard, S. J. Org. Chem. 2004, 69,
8910–8915; (c) Liu, G.; Sieburth, S. M. Org. Lett. 2005, 7, 665–668.
4. For a review, see: Hou, X. L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.;
Tong, S. Y.; Wong, H. N. C. Tetrahedron 1998, 54, 1955–2020. and references
therein.
5. (a) Bourgeois, D.; Craig, D.; King, N. P.; Mountford, D. M. Angew. Chem., Int. Ed.
2005, 44, 618–621; (b) Craig, D.; Grellepois, F. Org. Lett. 2005, 7, 463–465; (c)
Craig, D.; Grellepois, F.; White, A. J. P. J. Org. Chem. 2005, 70, 6827–6832; (d)
Bourgeois, D.; Craig, D.; Grellepois, F.; Mountford, D. M.; Stewart, A. J. W.
Tetrahedron 2006, 62, 483–495.
6. Craig, D.; King, N. P.; Kley, J. T.; Mountford, D. M. Synthesis 2005, 3279–3282.
7. (a) Thomas, A. F.; Ozainne, M. J. Chem. Soc. C 1970, 220–224; (b) Raucher, S.; Lui,
A. S.-T.; MacDonald, J. E. J. Org. Chem. 1979, 44, 1885–1887.
8. (a) Caruana, P. A.; Frontier, A. J. Tetrahedron 2004, 60, 10921–10926; (b) Usami,
T.; Shirai, N.; Sato, Y. J. Org. Chem. 1992, 57, 5419–5425.
In conclusion, we have utilised a heterocyclic dCr reaction for
the facile synthesis of novel dearomatised furan 9, which was
found to react diastereoselectively with various electrophiles un-
der relatively mild conditions. These addition products are useful
substrates for accessing highly substituted furans. Additionally,
the dCr precursors could be prefunctionalised, increasing the flex-
ibility of this method for synthetic applications. Currently we are
investigating the enantioselective dCr reactions of (S)- and (R)-1-
(furan-2-yl)ethyl 2-tosylacetate, and the addition reactions of the
derived enantiomerically pure dearomatised furans with electro-
philes. We are also evaluating the factors that affect the diastereo-
meric ratio of the heterocyclic dCr reaction. The results of these
studies will be reported in due course.
9. (a) Tidwell, J. H.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 11797–11810; (b)
Elder, A. M.; Rich, D. H. Org. Lett. 1999, 1, 1443–1446; (c) Sakamato, T.; Kondo,
Y.; Uchiyama, H. J. Chem. Soc., Perkin Trans. 1 1993, 1941–1942.
10. Ojida, A.; Abe, A.; Kanematsu, K. Heterocycles 1994, 38, 2585–2588.
11. Padwa, A.; Cohen, L. A. Tetrahedron 1982, 23, 915–918.
12. (a) Miles, W. H.; Dethoff, E. A.; Tuson, H. H.; Ulas, G. J. Org. Chem. 2005, 70,
2862–2865; (b) Miles, W. H.; Connell, K. B. Tetrahedron Lett. 2003, 44, 1161–
1163; (c) Miles, W. H.; Berreth, C. L.; Anderton, C. A. Tetrahedron Lett. 1996, 37,
7893–7896; (d) Miles, W. H.; Berreth, C. L.; Smiley, P. M. Tetrahedron Lett. 1993,
34, 5221–5222.
13. Joule, J. A.; Mills, K.; Smith, G. E. Heterocyclic Chemistry; Chapman & Hall:
London, 1995.
14. Microwave irradiation reactions were performed on
microwave reactor, with the temperature determined by IR.
15. Craig, D.; Paina, F.; Smith, S. C. Chem. Commun. 2008, 3408–3410.
a biotage initiator
16. An NOE was observed between H1 and H2. Additionally,
a characteristic
downfield quartet corresponding to H1 was detected in the proton NMR.
17. For examples of diastereoselective Z-enolate addition, see: Heathcock, C. H.;
Buse, C. T.; Kleschick, W. A.; Pirrung, M. C.; Sohn, J. E.; Lampe, J. J. Org. Chem.
1980, 45, 1066–1081.
Acknowledgements
18. The 3,5-dinitrobenzoate ester of 14 was crystallised as two different
polymorphs, 14A and 14B, the molecular structures of which are very
similar. Polymorph A is reported here, and polymorph B is reported in the
This work was supported by the EPSRC (Postdoctoral fellowship
to J.E.C. through responsive-mode grant EP/F015356). We thank Dr.
Andrew White for determining the X-ray structure and Mr. Pete
Haycock for the NOE structural determination of 9.
ꢀ
Supplementary data. Crystal data for 14A: C23H22N2O9S, M = 502.49, triclinic, P1
(no. 2), a = 9.2313(3), b = 11.4829(2), c = 12.2474(4) Å,
b = 88.253(3),
= 68.460(3)°, V = 1139.98(7) Å3, Z = 2, Dc = 1.464 g cmꢁ3
(Mo-K
) = 0.200 mm–1
Diffraction Xcalibur
a = 71.534(3),
c
,
l
a
,
3
T = 173 K, pale yellow hexagonal blocks, Oxford
diffractometer; 7292 independent measured
Supplementary data
reflections, F2 refinement, R1 = 0.038, wR2 = 0.109, 6062 independent
observed absorption-corrected reflections [|Fo| > 4r(|Fo|), 2hmax = 64°], 317
parameters. CCDC 703903.
19. Miles, W. H.; Fialcowitz, E. J.; Halstead, E. S. Tetrahedron 1993, 57, 9925–9929.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.03.091.

3508
J. E. Camp, D. Craig / Tetrahedron Letters 50 (2009) 3503–3508
20. Furans have been used extensively as protected ester and 1,4 diketone
equivalents in complex organic syntheses. For examples, see: (a) Raczo,
J. Tetrahedron 2003, 59, 10181–10186; (b) Kusakabe, M.; Kitano, Y.;
Kobayashi, Y.; Sato, F. J. Org. Chem. 1989, 54, 2085–2091; (c)
Pearlman, B. A.; Padilla, A. G.; Hach, J. T.; Havens, J. L.; Pillai, M.
D. Org. Lett. 2006, 8, 2111–2113.
21. Mori, K.; Komatsu, M. Tetrahedron 1987, 43, 3409–3412.
22. Roush, W. R.; Russo-Rodriguez, S. J. Org. Chem. 1985, 50, 5465–5468.
23. Craig, D.; McCague, R.; Potter, G. A.; Williams, M. R. V. Synlett 1998, 55–57.
24. (a) Brown, A. C.; Carpino, L. A. J. Org. Chem. 1985, 50, 1749–1750; (b) Baker, K.
V.; Brown, J. M.; Hughes, N.; Skarnulis, A. J.; Sexton, A. J. Org. Chem. 1991, 56,
698–703.
25. Taber, D. F.; Jiang, Q. J.; Chen, B.; Zhang, W.; Campbell, C. L. J. Org. Chem. 2002,
67, 4821–4827.
26. Du Penhoat, C. H.; Julia, M. Tetrahedron 1986, 42, 4807–4816.
27. Ermolenko, L.; Sasaki, N. A.; Potier, P. J. Chem. Soc., Perkin Trans. 1 2000, 2465–
2473.