Regioselective Preparation of 2,4-, 3,4-, and 2,3,4-Substituted Furan Rings. 2. Regioselective Lithiation of 2-Silylated-3-substituted Furan Rings

Article abstract of DOI:10.1021/jo971098b

A new method for the preparation of 3,4- and 2,5-disubstituted furan rings is described. A variety of 2-silylated-3-(hydroxymethyl)furans and 2-silylated-3-furoic acids lithiate exclusively at C-4 when treated with 2.2 equivs of BuLi. The resulting dianions were quenched with a variety of electrophiles to provide 2-silylated-3-(hydroxymethyl)-4-substituted furans and 2-silylated-4-substituted 3-furoic acids in good to excellent yields. Removal of the silyl group (n-Bu₄NF) provided a variety of 4-substituted-3-(hydroxymethyl)furans and methyl 4-substituted-3-furoates, respectively. The latter esters were prepared due to difficulties encountered in isolating 4-substituted-3-furoic acids. The site of lithiation was altered by protecting the 3-hydroxyl group with a triethylsilane. Lithiation of 2-silylated-3-(((triethylsilyl)oxy)methyl)furan with 1.2 equivs of BuLi followed by the addition of electrophiles provided 2-silylated-3-(((triethylsilyl)oxy)methyl)-5-substituted furan rings. Subsequent removal of both silyl groups provided 2,4-disubstituted furan rings in moderate to good yields. A rationale is provided to explain why protection of the hydroxyl group at C-3 leads to a change in lithiation from the C-4 to the C-5 position of the furan ring. In addition, an explanation for the observed effect of adding HMPA or LiCl to the solution during the lithiation of 2-(tert-butyldimethylsilyl)-3-(hydroxymethyl)furan is provided.

Full text of DOI:10.1021/jo971098b

8750
J . Org. Chem. 1997, 62, 8750-8759
Regioselective P r ep a r a tion of 2,4-, 3,4-, a n d 2,3,4-Su bstitu ted
F u r a n Rin gs. 2.1 Regioselective Lith ia tion of
2-Silyla ted -3-su bstitu ted F u r a n Rin gs
Edward Bures, J ames A. Nieman, Shuyuan Yu, Patrick G. Spinazze´, J ean-Louis J . Bontront,
Ian R. Hunt, Arvi Rauk, and Brian A. Keay*
Department of Chemistry, University of Calgary, Calgary, Alberta, Canada T2N 1N4
Received J une 17, 1997X
A new method for the preparation of 3,4- and 2,5-disubstituted furan rings is described. A variety
of 2-silylated-3-(hydroxymethyl)furans and 2-silylated-3-furoic acids lithiate exclusively at C-4 when
treated with 2.2 equivs of BuLi. The resulting dianions were quenched with a variety of electrophiles
to provide 2-silylated-3-(hydroxymethyl)-4-substituted furans and 2-silylated-4-substituted 3-furoic
acids in good to excellent yields. Removal of the silyl group (n-Bu4NF) provided a variety of
4-substituted-3-(hydroxymethyl)furans and methyl 4-substituted-3-furoates, respectively. The latter
esters were prepared due to difficulties encountered in isolating 4-substituted-3-furoic acids. The
site of lithiation was altered by protecting the 3-hydroxyl group with a triethylsilane. Lithiation
of 2-silylated-3-(((triethylsilyl)oxy)methyl)furan with 1.2 equivs of BuLi followed by the addition of
electrophiles provided 2-silylated-3-(((triethylsilyl)oxy)methyl)-5-substituted furan rings. Subse-
quent removal of both silyl groups provided 2,4-disubstituted furan rings in moderate to good yields.
A rationale is provided to explain why protection of the hydroxyl group at C-3 leads to a change in
lithiation from the C-4 to the C-5 position of the furan ring. In addition, an explanation for the
observed effect of adding HMPA or LiCl to the solution during the lithiation of 2-(tert-
butyldimethylsilyl)-3-(hydroxymethyl)furan is provided.
In the preceding paper,1 the difficulty in preparing 3,4-
lithiation of substituted furan rings. The C-4 lithiation
of a 3-substituted furan, however, has not been successful
and 2,4-disubstituted furan rings due to the preference
for furan rings to lithiate2 and add electrophiles3 in the
C-2 or C-5 positions was discussed. New synthetic routes
toward the preparation of furan rings which contain
groups in the 3 and/or 4 positions are useful, since many
natural products incorporate furan rings with either a
3,4- or 2,4-disubstituted or 2,3,4-trisubstituted pattern.4
This paper describes a full account of our work in this
area.
Some previous reports on the preparation of 3,4-
disubstituted furans have involved using Diels-Alder/
retro-Diels-Alder chemistry,5 chemical modifications of
3,4-furandicarboxylic acid,6 and the synthetic modifica-
tion of acyclic precursors.7 An alternative approach to
the preparation of 3,4-disubstituted furans is the direct
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X Abstract published in Advance ACS Abstracts, November 15, 1997.
(1) For part 1, see: Bures, E.; Spinazze, P. G.; Beese, G.; Hunt, I.
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S0022-3263(97)01098-0 CCC: $14.00 © 1997 American Chemical Society

Regioselective Preparation of Substituted Furans
J . Org. Chem., Vol. 62, No. 25, 1997 8751
Sch em e 1
Sch em e 2
Sch em e 3
to date; only products resulting from a C-2 and/or C-5
lithiation have been isolated.8 Recently, Lee and Garst9
have reported that the in situ lithiation of an R-amino
alkoxide from 3-furaldehyde provided some 3,4-disubsti-
tuted furan (3-13%) in addition to the expected 2,3- (24-
36%) and 3,5- (2-8%) disubstituted products. Until
recently, the lithiation of a 2,3-disubstituted furan had
provided the C-5 lithiated species exclusively.8g,h,k,10
We reported the first successful regiospecific C-4 lithia-
tion of a 2,3-disubstituted furan in 1988.11 Thus 2-(tert-
butyldimethylsilyl)-3-(hydroxymethyl)furan (3) provided
2,3,4-trisubstituted furans 5 when treated with 2.2 equivs
of BuLi in DME at 0 °C for 1 h, and the resulting anion
was quenched with an electrophile (Scheme 1). Furan 3
was prepared by a [1,4] O f C silyl migration of 1.12
Removal of the C-2 silyl group from 5 with n-Bu4NF or
by a [1,4] C f O silyl rearrangement (NaH, DMF)
provided the corresponding 3,4-disubstituted furans (7
or 8), respectively.13 These preliminary studies indicated
that direct, high-yielding synthesis of 3,4-disubstituted
furans via lithiation was possible. We later showed that
2-silylated-3-furoic acids would also undergo a C-4 lithia-
tion, which after the removal of the C-2 silyl group
followed by the addition of diazomethane (for ease of
workup) provided 4-substituted-3-furoic esters in good to
excellent yields (Scheme 1, see 2 f 4 f 6 f 9).14,15
As previously mentioned, 2,4-disubstituted furans are
also difficult to prepare. They have been synthesized by
(a) the formation of the furan ring from acyclic precur-
sors,3 (b) a double electrophilic aromatic substitution of
a 2-substituted furan (to give a 2,3,5-trisubstituted
furan)16 followed by removal of the initial C-2 group;17
or (c) the direct C-5 lithiation of a 2,3-disubstituted furan
followed by the removal of the initial C-2 group.8g,h,9,18
Both a bromine atom16,18 and a phenylthio group8g,h,17
have been successfully removed from the C-2 position of
a 2,3,5-trisubstituted furan (i.e., replaced by a hydrogen
atom) thereby producing a 2,4-disubstituted furan.
More recently, we reported that if the hydroxymethyl
group of furan 3 was protected with a silane (i.e., furan
10, Scheme 2), lithiation occurred exclusively at the C-5
position.19 Trapping the resulting anion with electro-
philes provided furans 11, which upon removal of the silyl
groups, gave 2,4-disubstituted furans 11a .
This paper provides a full account of (a) the regio-
specific C-4 lithiation of 2-silyl-3-(hydroxymethyl)furans,
(b) the regiospecific C-4 lithiation of 2-silyl-3-furoic acids,
and (c) the regiospecific C-5 lithiation of 2-silyl-3-(((tri-
ethylsilyl)oxy)methyl)furans as a means of preparing 3,4-
and 2,4-disubstituted furan rings. In addition, a ratio-
nale for the change in regioselectively of the lithiation
when the hydroxyl group of furan 3 is converted into silyl
ether 10 is provided. The previous paper in this issue1
described in detail the preparation of the precursors for
these lithiation studies by [1,4] O f C silyl migrations
of 3-substituted furans.
(9) Lee, G. C. M.; Holmes, J . M.; Harcourt, D. A.; Garst, M. E. J .
Org. Chem. 1992, 57, 3126.
C-4 Lith ia tion of 2-(ter t-Bu tyld im eth ylsilyl)-
3-(h yd r oxym eth yl)fu r a n (3)
(10) Davies, G. M.; Davies, P. S. Tetrahedron Lett. 1972, 13, 3507.
(11) (a) Bures, E. J .; Keay, B. A. Tetrahedron Lett. 1988, 29, 1247.
(b) Keay, B. A.; Bontront, J .-L. J . Can. J . Chem. 1991, 69, 1326. (c)
Cristofoli, W. A.; Keay, B. A. Tetrahedron Lett. 1991, 32, 5877. (d)
Cristofoli, W. A.; Keay, B. A. Synlett 1994, 625. (e) Maddaford, S. P.;
Keay, B. A. J . Org. Chem. 1994, 59, 6501. (f) We have recently used
this chemistry for the synthesis of the furan portion of (+)-xesto-
quinone, see: Maddaford, S. P.; Andersen, N. G.; Cristofoli, W. A.;
Keay, B. A. J . Am. Chem. Soc. 1996, 118, 10766. (g) Scott has used
our methodology for the preparation of 2,3,4-trisubstituted furans,
see: Danso-Danquah, R. E.; Scott, A. I. Tetrahedron 1993, 49, 8195.
(12) Bures, E. J .; Keay, B. A. Tetrahedron Lett. 1987, 28, 5965.
(13) Spinazze, P. G.; Keay, B. A. Tetrahedron Lett. 1989, 30, 1765.
(14) Beese, G.; Keay, B. A. Synlett 1991, 13.
Treatment of furan 3 with 2.2 equivs of BuLi in DME
at -78 °C, warming the mixture to 0 °C, and stirring for
15 min, followed by the addition of MeOD, provided
4-deuterio-3-hydroxymethyl-2-(tert-butyldimethylsilyl)-
furan (12) in 95% yield (Scheme 3). The 1H NMR
spectrum of furan 12 showed the presence of the R-furan
signal at δ 7.6, the hydroxymethyl hydrogens at δ 4.6,
and the groups attached to the silane at δ 0.9 (tert-butyl)
(15) Yu, S.; Keay, B. A. J . Chem. Soc., Perkin Trans. 1 1991, 2600.
(16) Chiarello, J .; J oullie, M. M. Tetrahedron 1988, 44, 41.
(17) Nolan, S. M.; Cohen, T. J . Org. Chem. 1981, 46, 2473.
(18) Bock, I.; Bornowski, H.; Ranft, A.; Theis, H. Tetrahedron 1990,
46, 1199.
(19) Nieman, J . A.; Keay, B. A. Tetrahedron Lett. 1994, 35, 5335.

8752 J . Org. Chem., Vol. 62, No. 25, 1997
Ta ble 1. Resu lts fr om th e C-4 Lith ia tion of F u r a n 3
Bures et al.
entry
electrophile
product (% yield)a
product (% yield)a
1
2
3
4
5
6
7
8
9
MeOD
I2
MeI
Me3SiCl
Cl(CH2)3I
ClCO2Me
ClCONEt2
Bu3SnCl
Me3SnCl
DMF
12, E ) D; R ) H (95)
26 (92)
27 (91)
28 (90)
17, E ) I; R ) H (92)
15, E ) Me; R ) H (82)
18, E ) SiMe3; R ) H (78)
19, E ) (CH2)3Cl; R ) H (66)
20, E ) R ) CO2Me (57)
21, E ) R ) CONEt2 (75)
22, E ) SnBu3; R ) H (89)
23, E ) SnMe3; R ) H (88)
24, E ) CHO; R ) H (91)
25, E ) CH2CH ) CH2; R ) H (83)
29 (94)
30b (91)
31 (90)
32 (92)
10
11
allyl bromide
a
b
Isolated yields. Desilylation was performed on methyl 2-(tert-butyldimethylsilyl)-3-(hydroxymethyl)-4-furoate which was formed by
hydrolysis of the carbonate group (K2CO3/MeOH) in 20.
and 0.01 (2 × CH3). The absence of a signal at δ 6.5
(present in furan 3) indicated that the deuterium was at
the C-4 position of furan ring in compound 12.20 Further
confirmation was obtained from the broad band 13C NMR
spectrum. The 13C NMR spectrum of compound 12 was
similar to that of furan 3 except for a set of three lines
in a 1:1:1 ratio centered at δ 110.5 (very weak in
intensity). This was indicative of a carbon atom directly
attached to one deuterium atom. The signal at δ 110.5
in the 13C NMR spectrum of furan 3 had been previously
assigned to the C-4 carbon atom,21 since the C-5 carbon
atom appeared downfield as a singlet at δ 146.7. Lithia-
tion had occurred therefore at C-4 of furan 3 and not at
C-5.
of 15 with n-Bu4NF followed by Swern oxidation22
provided 4-methyl-3-furfural (16). The spectral data of
synthetic 16 were identical to those reported for the same
compound prepared by Reich7c from an acyclic acetylenic
precursor.
The C-4 lithiation of furan 3 was optimized by treating
3 with 2.2 equivs of BuLi in DME at 0 °C for 15 min.
The resultant dianion was quenched with a variety of
electrophiles (Table 1), in the presence of 15 equivs of
LiCl and stirred at 0 °C overnight to provide 2,3,4-
trisubstituted furans in moderate to good yields. Only
methyl chloroformate and N,N-diethylcarbamyl chloride
reacted with both the C-Li and O-Li anions (entries 6
and 7, Table 1).
To further confirm that lithiation had occurred at the
C-4 position, two synthetic sequences were performed.
First, treatment of 10 with 1.3 equivs of BuLi in THF
(-40 °C, 2 h), followed by a quench with MeOD, provided
furan 13 (Scheme 3). Compound 13 was immediately
treated with a 8:8:1 mixture of AcOH:THF:H2O for 1 h
to provide 5-deuteriofuran 14 in 77% yield. The furan
region of the 1H NMR spectrum of compound 14 only
showed the absence of a peak at δ 7.6 and a signal at δ
6.5, while the broad band 13C NMR spectrum showed a
very weak three-line signal (line ratio 1:1:1) at δ 146.7
and a strong signal at δ 110.5. These data indicate that
lithiation of 10 had occurred at the C-5 position. The
preparation of the two possible deuterium isomers (com-
pounds 12 and 14) of 3-(hydroxymethyl)furan clearly
showed that the lithiation of furans 3 and 10 provided
the C-4 and C-5 carbanions, respectively.
One important point regarding this reaction is note-
worthy. If 15 equivs of LiCl was not added to the dianion
prior to the electrophile, the yields of compounds 15 and
17-25 ranged from approximately 30 to 55% depending
on the electrophile. The addition of TMEDA23 or
HMPA23c,24 did not increase the yield of the products. This
was surprising, since it has been reported2,23,24 that
additives such as TMEDA or HMPA usually increase the
yield of products due to their ability to dissociate hex-
amers and tetramers of lithium-containing compounds,
thereby making the anionic species more reactive to
electrophiles. Only the addition of LiCl increased the
yields of the products.
One explanation for the decreased reactivity of the
dilithiated intermediate is the formation of a stabilized
bridged dilithio species (33) (Scheme 4). It is well
documented that some dilithiated compounds preferen-
tially form bridged dilithio species rather than existing
as two distinct lithium atoms. Supporting evidence for
the formation of bridged dilithio species in other systems
have been obtained by X-ray crystallography25 and
through semiempirical and ab initio level calculations.26
With our system, ab initio calculations at the MP2/6-
31+G*//6-21G* level on 33-35 indicated that 33 was
The second piece of evidence to support a C-4 lithiation
of furan 3 was the preparation of 4-methyl-3-furfural (16)
(Scheme 3). The dianion of furan 3 was treated with 1
equiv of iodomethane to provide furan 15. Desilylation
(20) We have often found the integration of the proton spectrum of
substituted furan rings provides values which do not correspond to
the structure if a normal pulse delay of zero seconds is used. T1
measurements of the hydrogen atoms on substituted furan rings
indicated that they fall in the range of 10-15 s. To obtain accurate
integrals in the 1H NMR spectra, we normally use a pulse delay of 60
s.
(21) It is well documented that the R-hydrogen and R-carbon atoms
on a furan ring appear downfield relative to the â-hydrogen and
â-carbon atoms in the 1H and 13C NMR spectra, respectively. See: (a)
Silverstein, R. M.; Bassler, G. C.; Morrill, T. C. Spectrometric Identi-
fication of Organic Compounds, 5th ed.; J ohn Wiley & Sons, Inc., 1991.
(b) Biemann, K. (Translator from German). Tables of Spectral Data
for Structure Determination of Organic Compounds; Boschke, F. L.,
Fresenius, W., Huber, J . F. K., Pungor, E., Rechnitz, G. A., Simon W.,
West, Th. S., Eds.; Springer-Verlag: Berlin, 1983.
(22) Swern, D.; Huang, C. C.; Mancuso, D. T. J . Org. Chem. 1978,
43, 2480.
(23) (a) Collum, D. B. Acc. Chem. Res 1992, 25, 448. (b) Snieckus,
V. Chem. Rev. 1990, 90, 979. (c) Seebach, D. Angew. Chem., Int. Ed.
Engl. 1988, 27, 1624. (d) Beak, P. Chem. Rev. 1984, 84, 471. (e) Beak,
P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356. (f) Beak, P.; Snieckus,
V. Acc. Chem. Res. 1982, 15, 306.
(24) Romesberg, F. E.; Gilchrist, J . H.; Harrison, A. T.; Fuller, D.
J .; Collum, D. B. J . Am. Chem. Soc. 1991, 113, 5751 and references
therein.
(25) Schubert, U.; Neugebauer, W.; Schleyer, P.v. R. J . Chem. Soc.,
Chem. Commun. 1982, 1184.

Regioselective Preparation of Substituted Furans
J . Org. Chem., Vol. 62, No. 25, 1997 8753
Sch em e 4
Ta ble 2. Effect of C-2 Su bstitu en ts on th e C-4:C-5
An ion Ra tiosa
more stable than 34 and 35 by 119.4 and 109.2 kJ /mol,
respectively (Scheme 4). Thus the increased stability of
33 relative to that of 34 may be responsible for the
decreased reactivity of the dilithiated species toward
nucleophiles (at least in the gas phase). An increase in
the rate of reaction with electrophiles, upon the addition
of excess LiCl, may be explained by a deaggregation of
the bridged dilithio compound 33 by an exchange of Li
cations.27,28
The effect of substituents at the C-2 position of the
furan ring on the regioselectivity of the lithiation was
studied (Table 2). All of the substituted silanes prepared
resulted in lithiation at the C-4 position of the furan ring
(entries 1-5). Only the smaller methyl group resulted
in a mixture of C-4 and C-5 (2:1) monolithiated species.
These results would indicate that perhaps the size of the
C-2 substituent could be in part responsible for the C-4
lithiation. The larger groups at C-2 could be hindering
coordination of the BuLi to the furan oxygen atom,
thereby allowing the hydroxymethyl group to direct the
lithiation. Two pieces of data do not support this notion.
First, when the alcohol of the hydroxymethyl group is
entry
compd (R ))
C-4:C-5 anion ratiob,c
1
2
3
4
5
6
SiMe3
100:1
100:1
100:1
100:1
100:1
64:36
Si(i-Pr)Me2
Si(t-Bu)Me2
Si(t-Bu)Ph2
Si(i-Pr)3
CH3
a
All reactions performed by treating the compound with 2.2
equivs of BuLi in DME at either -20 or 0 °C for 1 h, followed by
b
a MeOD quench. Ratio determined by integration of the 1H NMR
spectrum using a pulse delay of 60 s.20 c Ratio was adjusted for
the %H content of the MeOD as determined by mass spectrometry.
protected with a silane, lithiation occurs exclusively at
the C-5 position (Scheme 3, eq 2). Thus, the C-2
substituent cannot be completely blocking coordination
of the BuLi with the furan oxygen atom. Second, we have
shown by competitive NMR binding studies29 and by ab
initio calculations30 that dialkyl ethers are much more
Lewis basic than furan oxygen atoms. By analogy, the
BuLi would be expected to coordinate preferentially with
the hydroxymethyl (or LiOCH2R) group than with the
furan oxygen atom. Thus, the bulkiness of the C-2
substituent in blocking the coordination of the BuLi with
the furan oxygen should play a minor role in effecting
the regioselectivity of the lithiation. The presence of a
smaller methyl group at C-2, however, results in a 2:1
ratio of C-4:C-5 lithiated furans.31 An alternative expla-
(26) (a) Saa´, J . M.; Morey, J .; Frontera, A.; Deya´, P. M. J . Am. Chem.
Soc. 1995, 117, 1105 and references therein. (b) Bauer, W.; Schleyer,
P. v. R. J . Am. Chem. Soc. 1989, 111, 7191. (c) Schleyer, P. v. R. Pure
Appl. Chem. 1984, 56, 151. (d) Schleyer, P. v. R. Pure Appl. Chem.
1983, 55, 355.
(27) For papers related to the effect of adding lithium salts to
asymmetric alkylations and aldol reactions, see: (a) Seebach, D.; Beck,
A. K.; Studer, A. Mod. Synth. Methods 1995, 7, 1 and references
therein. (b) J uaristi, E.; Beck, A. K.; Hansen, J .; Matt, T.; Mukho-
padhyay, T.; Simson, M.; Seebach, D. Synthesis 1993, 1271. (c)
Hasegawa, Y.; Kawasaki, H.; Koga, K. Tetrahedron Lett. 1993, 34,
1963. (d) Loupy, A.; Tchoubar, B.; Astruc, D. Chem. Rev. 1992, 92, 1141.
(e) Hall, P. L.; Gilchrist, J . H.; Collum, D. B. J . Am. Chem. Soc. 1991,
113, 9571. (f) Thaler, A.; Seebach, D.; Cardinaux, F. Helv. Chim. Acta
1991, 74, 617. (g) Seebach, D.; Thaler, A.; Beck, A. K. Helv. Chim. Acta
1989, 72, 857.
(29) (a) Hunt, I. R.; Rogers, C.; Woo, S.; Rauk, A.; Keay, B. A. J .
Am. Chem. Soc. 1995, 117, 1049. (b) Hunt, I. R; Rauk, A.; Keay, B. A.
J . Org. Chem. 1996, 61, 751.
(28) Henderson, K. W.; Dorigo, A. E.; Liu, Q.-Y.; Williard, P. G.;
Schleyer, P. v. R.; Bernstein, P. R. J . Am. Chem. Soc. 1996, 118, 1339.
(30) Rauk, A.; Hunt, I. R.; Keay, B. A. J . Org. Chem. 1994, 59, 6808.

8754 J . Org. Chem., Vol. 62, No. 25, 1997
Bures et al.
Ta ble 3. Solven t Effects on th e C-4:C-5 An ion Ra tios
of F u r a n 3a
nation is that the size of the C-2 substituent results in
an unfavorable steric interaction with the C-3 hydroxy-
methyl group. This interaction causes the hydroxy-
methyl or carboxylate group to rotate into a conformation
whereby the hydroxyl is in close proximity to the C-4
hydrogen atom.32,33 Lithiation occurs at C-4 due to
preferential coordination of the BuLi with the hydroxy-
methyl group rather than with the furan oxygen atom.
Thus the presence of bulky groups at C-2 enhances the
ortho-directing effect of the hydroxymethyl group. The
smaller methyl group invokes less steric interaction with
the adjacent hydroxymethyl group, thereby leading to a
diminished directing effect by this group and both C-4
and C-5 lithiation compete.
The observed exclusive C-5 lithiation with silyl-
protected hydroxymethyl groups at C-4 (vide infra) can
be explained simply by (1) a reduced basicity of the
oxygen atom due to the attached silicon atom,34 and (2)
by an increased steric bulk around the same oxygen atom
due to the attached silyl group. Both factors reduce the
tendency for BuLi to coordinate to the ether oxygen atom
and thus C-5 lithiation occurs.
The effect of various solvents and the addition of
HMPA on the regioselectivity of metalation of furan 3
was determined (Table 3). Lithiation of 3 in hexane (with
or without HMPA), ether, and THF (with and without
TMEDA) provided C-4:C-5 ratios ranging from 65:35 to
75:25 (entries 1-3, 5, and 6). The addition of HMPA to
ether and THF prior to the addition of BuLi resulted in
the regiospecific lithiation of 3 at C-4 (entries 4 and 7).
Interestingly, DME provided only C-4 lithiation in the
presence and absence of HMPA (entries 8 and 9).35
Stirring the anions prepared in hexane, ether, or THF
for 6 h at 0 °C did not result in an “equilibration-
disproportionation”36 of the C-5 anion to the C-4 anion.
That equilibration did not take place was initially
surprising since the C-5 dianion 35 is less stable than
entry
solvent
additive
C-4:C-5 ratiob,c
1
2
3
4
5
6
7
8
9
hexane
hexane
ether
ether
THF
THF
THF
DME
DME
70:30
66:34
68:32
100:0
75:25
65:35
100:0
100:0
100:0
HMPA
HMPA
TMEDA
HMPA
HMPA
a
All reactions performed by treating adding 2.2 equivs of BuLi
to a mixture of compound 3, the appropriate solvent, and HMPA
or TMEDA (if required) at 0 °C for 1 h, followed by a MeOD
b
quench. Ratio determined by integration of the 1H NMR spec-
trum using a pulse delay of 60 s.20 c Ratio was adjusted for the
%H content of the MeOD as determined by mass spectrometry.
the bridged dilthio species 33 by 109.2 kJ /mol (at least
in the gas phase) (Scheme 4). If the lithiation reaction
is under thermodynamic control, then the C-5 anion
should have equilibrated to the C-4 anion. To test if the
addition of HMPA would cause the equilibration, it was
added to a mixture of the C-4 and C-5 anions generated
in ether. The C-5 anion did not equilibrate to the C-4
position. These results indicated that the presence of
HMPA in ether or THF or DME alone enhanced the
ortho-directing effect of the hydroxymethyl group.
The fact that lithiation of 3, under a variety of
conditions, occurs primarily at C-4 can possibly be
explained by invoking a complex induced proximity effect
(CIPE).23e This CIPE process has been postulated to
explain the regiospecific lithiation of other systems
containing hydroxymethyl groups,37 alcohols (some gen-
erated in situ),38,39 phenols,40 aryl anions,41 and allylic
anions.42 The initially formed lithium species directs the
subsequent lithiation to an adjacent site. Closer exami-
nation of examples given in the account written by Beak
and Meyers23e indicate that the addition of HMPA to
systems exhibiting a CIPE process usually results in an
interference with the CIPE process which results in a
decreased directing effect.43 In our case, however, the
addition of HMPA appears to increase the CIPE effect
since only C-4 lithiation is observed with HMPA in ether
or THF. In the examples cited, in which the addition of
HMPA results in a diminished CIPE effect, coordination
of BuLi was to a carbonyl oxygen atom43a or a thioether;43b
there were no reports of this effect for systems in which
a lithium alkoxide was initially formed. Therefore, the
(31) An alternative explanation is that the acidity of the C-4
hydrogen atom has increased relative to that of the C-5 hydrogen atom
due to electronic factors resulting from the presence of a silicon atom
at C-2 of the furan ring. Semiempirical calculations (PM3) on 2-(tri-
methylsilyl)-3-(hydroxymethyl)furan indicated that the electronic den-
sity at the furan carbon atoms and the C-4 and C-5 hydrogen atoms
were not significantly changed relative to the electronic densities
calculated for similar atoms in 3-(hydroxymethyl)furan; therefore we
believe stereoelectronic factors are not the driving force for the observed
C-4 lithiation.
(32) This explanation is akin to a “gearing” or “cogwheeling”
phenomenon, which leads to a “conformational lock”. For a discussion
on “gearing”, etc., see: Eliel, E.; Wilen, S. H.; Mander, L. N. Stereo-
chemistry of Organic Compounds; J ohn Wiley and Sons: New York,
1994; p 1160 and references therein.
(33) Semiempirical PM3 geometry optimization calculations on
compound 3 indicated that any initial geometry that had the hydroxyl
group orientated toward the C-2 silyl group (including structures which
had the hydroxyl group initially bisecting two of the silyl substituents)
resulted in minimum energy structures in which the hydroxyl group
was rotated away from the silyl group toward the C-4 hydrogen atom.
The local minima structures (nine in total) had the C1-C2-C3-O4
dihedral angle ranging from +36° to +85°.
(36) (a) Ziegler, F. E.; Fowler, K. W. J . Org. Chem. 1976, 41, 1564.
(b) Leonard, N. J .; Bryant, J . D. J . Org. Chem. 1979, 44, 4612. (c)
Ronald, R. C.; Winkle, M. W. Tetrahedron 1983, 39, 2031. (d) Marsais,
F.; Quegwiner, G. Tetrahedron 1983, 39, 2009.
(37) MacDonald, T. L.; Narayanan, B. A. J . Org. Chem. 1983, 48,
1131.
(38) Taylor, S. L.; Lee, D. Y.; Martin, J . C. J . Org. Chem. 1983, 48,
4156.
(39) Commins, D. L.; Brown, J . D.; Mantlo, N. B. Tetrahedron Lett.
1982, 23, 3979.
(40) Posner, G. H.; Canella, K. A. J . Am. Chem. Soc. 1985, 107, 2571.
(41) Boche, G.; Decker, G.; Etzrodt. H.; Mahdi, W.; Kos, A. J .;
Schleyer, P. v. R. J . Chem. Soc., Chem. Commun. 1984, 1483.
(42) Bates, R. B.; Gordan, B., III; Highsmith, J . H.; White, J . J . J .
Org. Chem. 1984, 49, 298.
(43) (a) Harris, F. L.; Weiler, L. J . Chem. Soc., Chem. Commun.
1985, 1124. (b) Ekogha, C. B. B.; Ruel, O.; J ulia, S. A. Tetrahedron
Lett. 1983, 24, 4825 and 4829.
(34) (a) Shambayati, S.; Blake, J . F.; Wierschke, S. G.; J orgensen,
W. L.; Schreiber, S. L. J . Am. Chem. Soc. 1990, 112, 697. (b) Beak, P.;
Kerrick, S. T.; Gallagher, D. J . J . Am. Chem. Soc. 1993, 115, 10628.
(c) Shepherd, B. D. J . Am. Chem. Soc. 1991, 113, 5581.
(35) We do not understand why compound 3 lithiates exclusively
at C-4 in DME in the absence of an additive. The bidendate nature of
this solvent may not be the reason since the lithiation of 3 in a THF-
TMEDA mixture resulted in a C-4:C-5 mixture.

Regioselective Preparation of Substituted Furans
J . Org. Chem., Vol. 62, No. 25, 1997 8755
Sch em e 5
HMPA must be having an alternative effect on the
system in 3 when treated with BuLi.
J ackman and Chen have recently reported44 that the
addition of HMPA to a variety of lithium phenolates can
result in an increase or decrease of aggregation as well
as the formation of “triple ion species”.45 The observed
behavior depends on the basicity of the anion, steric
factors, and the polarity of the solvent. Thus, we
postulate that the presence of HMPA during the lithia-
tion of 3 might be enhancing the directing ability of the
lithium alkoxide group by increasing its ability to com-
plex with another molecule of BuLi (i.e., through in-
creased aggregation).
Sch em e 6
Although the addition of HMPA enhances the C-4
lithiation of 3 in THF and ether, other factors must be
playing an important role in the lithiation, since C-4
lithiation occurs exclusively at C-4 in DME without
HMPA. These factors include (1) the presence of a silyl
compound at C-2, (2) the presence of a hydroxymethyl
group at C-3, (3) the solvent employed, and (4) whether
HMPA is added prior to the addition of BuLi. Whatever
the reason, 2-silylated-3-(hydroxymethyl)furan systems
lithiate at C-4 and provide a short simple entry for the
preparation of 2,3,4-trisubstituted furan rings and as the
next section describes, a simple entry into 3,4-disubsti-
tuted furans rings.
be lithiated at the C-4 position (Scheme 1).15 Although
we15 and others47 have reported that the treatment of
benzoic acid (39) with 2 equivs of BuLi leads to the
formation of the butyl ketone 40 (Scheme 6),15 there have
been some reports that carboxylate salts at low temper-
atures are resistant to addition of alkyllithiums (<-78
°C).48 This fact, combined with the reports49 that ortho-
lithiated lithium benzoates can be formed by halogen-
lithium exchange indicated that it may be possible to use
carboxylic acids to direct lithiation. In fact, a search of
the literature revealed that in 1964 Canton and co-
workers50 lithiated 3-methylisothiazole-4-carboxylic acid
in the C-5 position by treating the acid with 2 equivs of
BuLi! Since then, a number of heteroaromatic carboxylic
acids have been ortho-lithiated using either BuLi48d,51 or
LDA.8e,52 More recently Mortier et al. have shown that
various benzoic acids will direct lithiation to the ortho
position when treated with s-BuLi/TMEDA at -90 °C in
THF.53 Their work indicated ortho-lithiation with car-
boxylic acids was a general reaction when the lithiation
was performed at -90 °C. This section describes the C-4
lithiation of 2-(tert-butyldimethylsilyl)-3-furoic acid (4).15
Treatment of acid 4 with 2.2 equivs of LDA at -78 °C
for 1 h in either THF or DME (with or without HMPA)
followed by quenching any dianion with MeOD provided
only unreacted starting material. Repeating the reaction
at -20 °C (1 h) did not result in any C-4 or C-5
deuteration. This failure led us to investigate the use of
BuLi as the base for deprotonation. Treatment of acid 4
with 2.5 equivs of BuLi in THF or 1 h at -20 °C followed
P r ep a r a tion of 3,4-Disu bstitu ted F u r a n s
3,4-Disubstituted furan rings were easily prepared by
the removal of the C-2 silyl group. Treatment of 2-silyl-
ated-3,4-disubstituted furans 12, 17, 15, and 19-22 with
n-Bu4NF in THF (entries 1-3 and 5-8, Table 1) provided
3,4-disubstituted furans 26-32, respectively, in excellent
yield. The carbonate and urethane groups of furans 20
and 21 were removed prior to the desilylation by treating
them with K2CO3/MeOH/1 h/rt and NaOMe/MeOH/12
h/60 °C, respectively. An alternative procedure for the
preparation of 3,4-disubstituted furans was to reuse the
C-2 silyl group as a protecting group for the hydroxy-
methyl group at C-3. A [1,4] C f O silyl migration46 on
compounds 22, 24, and 25 provided furans 36-38,
respectively, in excellent yield (Scheme 5) according to
the procedures reported in the previous paper.1
C-4 Lith ia tion of
2-(ter t-Bu tyld im eth ylsilyl)-3-fu r oic Acid (4) a n d
P r ep a r a tion of 4-Su bstitu ted -3-F u r oic Ester s
(47) See ref 2, p 68.
Due to low yields associated with the oxidation of
3-substituted-2-(tert-butyldimethylsilyl)-3-furaldehydes
to the corresponding 3-furoic acids, we investigated
whether 2-(tert-butyldimethylsilyl)-3-furoic acid (4) could
(48) (a) Harper, R. J ., J r.; Solosky, E. J .; Tamborski, C. J . Org. Chem.
1964, 29, 2385. (b) Tamborski, C.; Soloski, E. J . J . Org. Chem. 1966,
31, 743 and 746. (c) Hauser, F. M.; Rhee, R. J . Am. Chem. Soc. 1977,
99, 4533. (d) Beak, P.; Brown, R. A. J . Org. Chem. 1979, 44, 4463. (e)
Beak, P.; Brown, R. A. J . Org. Chem. 1982, 47, 34. (f) Winkle, M. R.;
Ronald, R. C. J . Org. Chem. 1982, 47, 2101. (g) Palmer, B. D.; Boyd,
M.; Denny, W. A. J . Org. Chem. 1990, 55, 438. (h) Cantegril, R.;
Croisat, D.; Desbordes, P.; Guigues, F.; Mortier, J .; Peignier, R.; Vors,
J .-P. Wo. Pat. 932287, 1993.
(49) (a) Gilman, H.; Melstrom, D. S. J . Am. Chem. Soc. 1948, 70,
4177. (b) Parham, W. E.; Sayed, Y. A.; J . Org. Chem. 1974, 39, 2051
and 2053. (c) Raynolds, P. W.; Manning M. J .; Swenton, J . S.
Tetrahedron Lett. 1977, 2383. (d) Parham, W. E.; Bradsher, C. K.;
Edgar, K. J . J . Org. Chem. 1981, 46, 1057.
(50) Canton, M. P.; J ones, D. H.; Slack, R.; Woolridge, K. R. H. J .
Chem. Soc. 1964, 446.
(51) Carpenter, A. J .; Chadwick, D. J . Tetrahedron Lett. 1985, 26,
1777.
(52) (a) Davies, G. M.; Davies, P. S. Tetrahedron Lett. 1972, 3507.
(b) Knight, D. W.; Nott, A. P. J . Chem. Soc., Perkin Trans. 1 1983,
791. (c) Gammill, R. B.; Hyde, B. R. J . Org. Chem. 1983, 48, 3863. (d)
Buttery, C. D.; J ones, R. G.; Knight, D. W. Synlett 1991, 315.
(53) Mortier, J .; Moyroud, J .; Bennetau, B.; Cain, P. A. J . Org. Chem.
1994, 59, 4042.
(44) J ackman, L. M.; Chen, X. J . Am. Chem. Soc. 1992, 114, 403.
(45) (a) J ackman, L. M.; Scarmoutzos, L. M.; Porter, W. J . Am.
Chem. Soc. 1987, 109, 6524. (b) Romesberg, F. E.; Gilchrist, J . H.;
Harrison, A. T.; Fuller, D. J .; Collum, D. B. J . Am. Chem. Soc. 1991,
113, 5751.
(46) .(a) Woodbury, R. P.; Rathke, M. W. J . Org. Chem. 1978, 43,
1947. (b) Isobe, M.; Kitamura, M.; Goto, T. Tetrahedron Lett. 1979,
20, 3465. (c) Matsuda, I.; Murata, S.; Izumi, Y. Bull. Chem. Soc. J pn.
1979, 52, 2389. (d) Matsuda, I.; Murata, S.; Ishii, Y. J . Chem. Soc.,
Perkin Trans. 1 1979, 26. (e) Isobe, M.; Kitamura, M.; Goto, T.
Tetrahedron Lett. 1980, 21, 4727. (f) Fleming, I.; Floyd, C. D. J . Chem.
Soc., Perkin Trans. 1 1981, 969. (g) Takeda, T.; Naito, S.; Ando, K.;
Fujiwara, T. Bull. Chem. Soc. J pn. 1983, 56, 967. (h) Brook, A. G.;
Chrusciel, J . J . Organometallics 1984, 3, 1317. (i) Isobe, M.; Ichikawa,
Y.; Funabashi, Y.; Mio, S.; Goto, T. Tetrahedron 1986, 42, 2863. (j)
Tietze, L. F.; Feissler, H.; Gewert, J . A.; J akobi, U. Synlett 1994, 2863.
(k) Lautens, M.; Delanghe, P. H. M.; Goh, J . B.; Zhang, C. H. J . Org.
Chem. 1995, 60, 4213.

8756 J . Org. Chem., Vol. 62, No. 25, 1997
Ta ble 4. P r ep a r a tion of 4-Su bstitu ted -3-fu r oic Ester s
Bures et al.
entry
1
E+
solvent
THF
additive
product (%)a
product (%)a
MeOD
41 (90)
49 (86)
E ) D
50 (90)
E ) Me
E ) D; R1 ) H
42 (88)
2
3
4
5
6
7
8
MeI
DME
DME
DME
THF
THF
THF
THF
HMPA
HMPA
HMPA
HMPA
HMPA
MgBr2
MgBr2
E ) Me; R1 ) H
43 (87)
DMF
E ) CHO; R1 ) H
44 (86)
Me3SiCl
Me3SnCl
CO2
E ) SiMe3; R1 ) H
45 (86)
E ) SnMe3
46 (69)b
51 (40)
E ) CO2Me
52 (31)
E ) CH(OH)Et
53 (87)
E ) I
E ) CO2Me; R1 ) Me
47 (52)
propanal
I2
E ) CH(OH)Et; R1 ) H
48 (71)
E ) I; R1 ) H
b
aIsolated yields. The diacid was difficult to isolate so the crude mixture was treated with excess diazomethane to provide diester 46.
Sch em e 7
by the addition of MeOD provided 4-deuterio-2-(tert-
butyldimethylsilyl)-3-furoic acid (41) (Table 4). The H
1
NMR spectrum of 41 indicated that the C-4 proton
resonance which was at δ 6.80 in 4, was absent. The
C-5 hydrogen appeared as a broad singlet at δ 7.63. The
13C NMR spectrum of 4 also confirmed the presence of a
deuterium atom at C-4 by the presence of a very weak
three line signal at δ 111.0 with intensities of 1:1:1.
Further confirmation that a deuterium atom had been
introduced was found in the mass spectrum of 41. A base
peak at m/e 170 (M•+ - t-Bu) confirmed the presence of
a single deuterium atom.
The dianion of 4 could be trapped with a number of
electrophiles (Table 4) to provide 2,3,4-substituted furans
42-48. The yields of compounds 42-46 were higher in
for 1 h followed by the addition of iodomethane, provided
the presence of HMPA, while treatment of the dianion
2-methyl-3-furoic acid (55) in 81% yield (Scheme 7). The
remainder of material in the crude mixture was unre-
of 4 with either propanal or iodine required an exchange
of the lithium counterion to magnesium by the addition
of MgBr2 for reasonable yields to be obtained (entries 7
and 8, Table 4).
acted 3-furoic acid. Butyl ketone 56 was not detected
by 1H NMR or by GC/MS. Subsequent treatment of acid
55 with 2 equivs of BuLi (THF, -20 °C, 1 h) resulted in
Compounds 41, 42, and 46-48 were desilylated by
lithiation at the methyl group. Deuteration with MeOD
treatment with n-Bu4NF in THF. The corresponding
desilylated acids were difficult to purify by either column
chromatography or distillation, so the crude materials
afforded furoic acid 58 (85%) and ketone 57 (8%).56 These
results indicate that BuLi can be used directly on some
furoic acids to direct lithiation; however, the presence of
were immediately treated with diazomethane in ether to
ketone 57 indicates that some side reactions at higher
provide esters 49-53 (Table 4).
temperatures may occur (Scheme 7). Lowering the
We attempted to remove the C-2 silyl group by per-
reaction temperature, however, may reduce the ability
forming a [1,4] C f O silyl migration.1 Treatment of
of BuLi to attack the carboxylate group.53
furan 42 with catalytic amounts of NaH in DMF provided
The regioselectivity of lithiation with acids 54 and 55
only 4-methyl-3-furoic acid (by 1H NMR of the crude
can be explained by the increase in acidity of the C-2
material) after workup. Either the NaH/DMF mixture
furan hydrogen in 5457 and γ hydrogen in 5558 relative
was reductively removing the silyl group from the
to the C-4 hydrogen atom. The regioselective C-4 lithia-
tion of 4 must be due, in part, to the presence of the C-2
expected silyl ester54 or the aqueous workup removed the
silyl group to provide the acid. Silyl esters are known to
be sensitive to hydrolysis by water.55
(55) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; J ohn Wiley & Sons Inc.: New York, 1991.
The use of BuLi to direct ortho-lithiation with furans
was not limited to only furoic acid 4. 3-Furoic acid (54),
when treated with 2 equivs of BuLi in THF at -20 °C
(56) We have shown that the γ anion can be trapped with a variety
of electrophiles in good to excellent yields, see: Yu, S.; Beese, G.; Keay,
B. A. J . Chem. Soc., Perkin Trans. 1 1992, 2729.
(57) (a) Wakefield, B. J . The Chemistry of Organolithium Com-
pounds; Pergamon: New York, 1974; p 26 and 44. (b) Paquette, L. A.
Principles of Modern Heterocyclic Chemistry; W. A. Benjamin Inc.: New
York, 1968; p 102 and references therein.
(54) For an example of a reductive desilylation using NaH/HMPA,
see: Shekani, M. S.; Kahn, K. M.; Mahmood, K. Tetrahedron Lett. 1988,
29, 6161.

Regioselective Preparation of Substituted Furans
J . Org. Chem., Vol. 62, No. 25, 1997 8757
Ta ble 5. Resu lts fr om th e Lith ia tion of F u r a n 10 a n d Su bsequ en t Desilyla tion s
entry
electrophile
lithiation product (% yield)a
desilylation conditions
desilylation product (% yield)a
1
2
3
4
MeOD
MeI
ICH2CHdCH2
DMF
13, R ) Db
AcOH:THF:H2O (8:8:1)
AcOH:THF:H2O (8:8:1)
AcOH:THF:H2O (8:8:1)
(a) AcOH:THF:H2 (8:8:1)
(b) Bu4N+F-/THF
65, R ) D; R1 ) Si(t-Bu)Me2 (77)
66, R ) Me; R1 ) Si(t-Bu)Me2 (70)
67, R ) CH2CHdCHdCH2; R1 ) Si(t-Bu)Me2 (54)
68, R ) CHO; R1 ) Si(t-Bu)Me2 (72)
69, R ) CHO; R1 ) H (83)
59, R ) Me (66)
b
60, R ) CH2CHdCH2
61, R ) CHO (61)
5
6
7
ClCONEt2
ClSnBu3
ClCO2Me
62, R ) CONEt2 (92)
63, R ) SnBu3 (40)
64, R ) CO2Me (34)d
Bu4N+F-/THF
70, R ) CONEt2; R1 ) H (68)
decomposedc
AcOH:THF:H2O (8:8:1)
K2CO3/MeOHc
complex mixture
a
b
c
Isolated yields. The crude reaction mixture was treated directly with a mixture of AcOH:THF:H2O. 2-Stannylfurans were very
unstable to various types of acids and Bu4N+F-/THF. The yield is low due to the concomitant formation of methyl 3-(((methoxycarbon-
d
yl)oxy)methyl)-2-(tert-butyldimethylsilyl)-5-furanoate (35%) and is estimated by integration of the 1H NMR spectrum of the mixture.
e The above mixture (d) was treated with K2CO3/MeOH.
Sch em e 8
silyl group (vide supra). Similar complex induced prox-
imity effects that occur with the hydroxymethyl group
in furan 3 may be happening with the carboxylate group
in furan 4. In addition, the adjacent silyl group may be
sterically hindering attack of the BuLi at the carbon atom
of the carboxylate group. A rigid rotor search at the
semiempirical level (PM3)59 on the lithium salt of furan
4 indicated that structures which constituted >92% of
the Boltzman distribution had the carboxylate in the
plane of the furan ring. In these conformations, the
carbon atom of the carboxylate is sterically blocked to
attack by BuLi by the adjacent silyl group. This hin-
drance must allow the second equivalent of BuLi to
coordinate to the carboxylate group, which results in
lithiation at C-4, rather than the BuLi adding to the
carboxylate group. In addition to this steric argument,
the conjugate base of the furoic acid is deactivated by
the strong donor/acceptor interaction between the electron-
rich furan ring and the electron-deficient carboxylate,
thereby slowing nucleophilic attack on the carboxylate.
The above results indicate that 2-silylated-3-furoic
acids can be regiospecifically lithiated at the C-4 position
and the resulting dianion quenched with electrophiles.
Subsequent treatment with diazomethane followed by
desilylation provided a simple entry into the preparation
of 4-substituted-3-furoic esters.
A variety of 2,4-disubstituted furans were prepared by
trapping the C-5 anion with electrophiles followed by
removal of the silyl group(s) (Table 5). The reaction was
limited to reactive electrophiles since the addition of
1-chloro-3-iodopropane to the anion only provided only a
30% yield of the expected product. Products were gener-
ally isolated in moderate to good yields, but furan 60 and
stannane 63 were sensitive to the workup procedure. The
addition of methyl chloroformate resulted in a low yield
of furan 64 and the formation of a product which was
the result of a desilylation of the triethylsilyl group in
product 64 and subsequent reaction of the resulting
alcohol reacting with methyl chloroformate (35%). Work-
up involved stirring the mixtures with a solution of
saturated ammonium chloride; however, stirring longer
than 15 min resulted in partial removal of the triethyl-
silyl group. Although the reaction mixtures could be
worked up and the products isolated, we found it conve-
nient to treat some of the crude mixtures directly with a
mixture of AcOH:THF:H2O (8:8:1). This resulted in
complete removal of the triethylsilyl group. Thus, alco-
hols 59 and 61 were isolated and then treated with the
acetic acid mixture or the crude mixture containing 13
and 60 was directly treated with the acetic acid mixture
to provide furans 65-68, respectively, in moderate to
good yields. Both silyl groups could be removed by
treatment with n-Bu4NF; compounds 61 and 62 provided
furans 69 and 70, respectively (entries 4b and 5, Table
5). The stannane 63 was found to be very sensitive to
acids and bases, and decomposition occurred while
removing the silyl groups. Various attempts to remove
the silyl groups from ester 64 also failed, resulting in
complex mixtures.
P r ep a r a tion of 2,4-Disu bstitu ted F u r a n Rin gs
Protection of the hydroxymethyl group in furan 3 with
a triethylsilyl group results in a change in the regio-
selectivity of lithiation (Scheme 2). Lithiation of 10 with
1.3 equivs of BuLi results in lithiation at C-5 exclusively.
This was proven by trapping the anion with MeOD. The
1
absence of a signal at δ 7.6 in the H NMR spectrum of
furan 13 (Scheme 3, eq 2, and Table 5, entry 1) indicated
that lithiation had occurred at C-5.
(58) (a) Kraus, G. A. J . Org. Chem. 1981, 46, 201. (b) Vaulz, R. L.;
Puterbaugh, W. H.; Hauser, C. R. J . Org. Chem. 1964, 29, 3514. (c)
Braun, M.; Ringer, E. Tetrahedron Lett. 1983, 24, 1233.
The hydroxymethyl group could be protected as a tert-
butyldimethylsilyl ether by migrating the silyl group at
C-2 to the oxygen atom using a [1,4] C f O silyl
migration.1 Thus, treatment of furan 66 with a catalytic
amount of NaH in DMF afforded 71 in 96% yield (Scheme
8). This reaction illustrates that the somewhat expensive
tert-butyldimethylsilyl group can be used as both a
blocking group at C-2 in 10, so lithiation occurs at C-5
(59) Semiempirical PM3 level calculations were performed on the
carboxylate anion of furan 4 using SPARTAN version 4.0 (Wavefunc-
tion, Inc., 18401 Von Karman Ave., #370, Irvine, CA, 92715). A rigid
rotor search was performed in which the Si-C2 and C-C3 bonds were
rotated independently by increments of 36° and a geometry optimiza-
tion performed on the resulting intermediate structure. A total of 23
structures were obtained, and the Boltzman distribution was calculated
at 298 K.

8758 J . Org. Chem., Vol. 62, No. 25, 1997
Bures et al.
7.40 (s, 1H); 13C NMR δ 56.4, 109.8 (three lines equal
intensity), 125.1, 139.8, 143.3; mass spectrum m/e 99 (M+).
4-Meth yl-3-fu r a ld eh yd e (16). To a solution of oxalyl
chloride (0.16 mL, 1.1 equivs) in dry CH2Cl2 (5 mL) at -50 °C
was added dimethyl sulfoxide (0.25 mL, 2.2 equivs). After 2
min furan 15 (0.18 g) in CH2Cl2 (2 mL) was added. After 15
min, Et3N (1.13 mL, 5.0 equivs) was added and the mixture
warmed slowly to rt. Water (10 mL) was added, and the CH2-
Cl2 extracts were washed with saturated NaCl (10 mL), 1%
HCl (10 mL), water (10 mL), 5% Na2CO3 (10 mL), and water
(10 mL). The CH2Cl2 was dried (Na2SO4) and removed in
vacuo to provide an oil which was purified by distillation to
yield 16 (89%): bp 67-72 °C/20 Torr; IR (neat) 1690 cm-1; 1H
NMR δ 2.06 (s, 3H), 7.07 (s, 1H), 7.80 (s, 1H), 9.81 (s, 1H);
(or C-4 vide supra), and then reused as a protecting group
for the hydroxymethyl moiety at C-3 in 66.
Con clu sion s
2-Silylated-3-(hydroxymethyl)furan and 2-silylated-3-
furoic acids lithiate exclusively at C-4 upon treatment
with 2.2 equivs of BuLi. 3,4-Disubstituted furan rings
were prepared in good to excellent yields by the addition
of various electrophiles followed by subsequent removal
of the silyl group. The regioselectivity of lithiation could
be changed to the C-5 position by protection of the
hydroxymethyl group with a silyl ether. Trapping the
C-5 anion with electrophiles followed by the removal of
both silyl-protecting groups afforded 2,5-disubstituted
furans in moderate to good yields. Work is continuing
to apply these methods to the synthesis of natural
products.11f
mass spectrum m/e 110 (M+) [lit.7c IR (neat) 1685 cm-1 1H
;
NMR δ 2.08 (s, 3H), 7.08 (s, 1H), 7.82 (s, 1H), 9.82 (s, 1H)].
1-Phenyl-1-pentanone (40). Benzoic acid (0.14 g, 1.15 mmol)
in dry THF (5 mL) at -20 °C under argon was treated with
BuLi (2.2 equivs). The mixture was stirred at -20 °C for 1 h.
Saturated ammonium chloride was added, followed by an
extraction with ethyl acetate (2 × 5 mL). The solvent was
dried (Na2SO4) and removed in vacuo to leave an oil which
was purified to provide ketone 40 (85%): bp 128-132 °C/20
Exp er im en ta l Section
Torr [lit.61 bp 105-107 °C/5 Torr]; IR (neat) 1685 cm-1 1H
;
1H NMR spectra were run at 200 or 300 MHz and 13C NMR
spectra were run at 50 or 75 MHz in CDCl3 as a solvent unless
noted otherwise. Elemental analyses were performed by either
Guelph Chemical Laboratories, Guelph, Ontario, Canada, or
by Ms. Dorothy Fox at the University of Calgary. tert-
Butyldimethylsilyl chloride was supplied from the Lithium
Corporation of America (now FMC), Gastonia, NC. All
solvents were dried and distilled prior to use. The oil from
the NaH was removed by three successive washes with
anhydrous ether. The remaining ether was removed under a
high vacuum (4 h, rt). Flash column chromatography was
performed using E. Merck silica gel (230-400 mesh A.S.T.M.)
by the method developed by Still et al.60 Compounds 1-4, 37,
381 and 22, 23, 32, 3611b were prepared as previously described.
Gen er a l P r oced u r e 1: Lith ia tion of F u r a n 3. To a
solution of furan 3 (0.25 g, 1.2 mmol) in dry DME (5 mL) at
-78 °C under argon was added BuLi (1.04 mL of 2.5 M in
hexane, 2.6 mmol). The mixture was stirred at 0 °C for 15
min and treated with 15 equivs of anhydrous LiCl (dried under
a high vacuum by heating the a flask containing the LiCl with
a Bunsen burner). After 15 min of stirring, an electrophile
was added and the solution stirred at rt overnight. Saturated
ammonium chloride (5 mL) was added and the mixture
extracted with ethyl acetate (2 × 5 mL). The solvent was dried
(Na2SO4) and removed in vacuo to leave an oil. If the oil was
NMR δ 0.96 (t, 3H), 1.40 (sextet, J ) 7.3 Hz, 2H), 1.72 (quintet,
J ) 7.3 Hz, 2H), 2.95 (t, J ) 7.3 Hz, 2H), 7.4-7.5 (m, 2H),
7.5-7.6 (m, 1H), 7.92-7.96 (m, 2H); 13C NMR δ 13.9, 22.9,
26.7, 38.0, 128.1, 128.6, 132.9, 137.3, 200.3; mass spectrum
m/e 162 (M+).
Gen er a l P r oced u r e 3: Lith ia tion of F u r oic Acid 4. To
a solution of furan 4 (1.0 mmol) in dry THF (5 mL) at -78 °C
under argon was added BuLi (2.2 equivs). The mixture was
stirred at -20 °C for 1 h and treated with HMPA (2.5 mmol)
(or MgBr2, 5 mmol). After 1 h an electrophile was added and
the mixture stirred at 0 °C for 6 h. The mixture was poured
into a separatory funnel, and ethyl acetate (10 mL) was added
followed by the addition of water (10 mL). The mixture was
acidified by the addition of 10% HCl (10 mL) and shaken
vigorously, and the ethyl acetate was immediately separated
from the acid layer (this minimizes decomposition of the furan
ring by the HCl). The ethyl acetate extract was dried (Na2-
SO4) and removed in vacuo. The crude material was purified
by column chromatography using silica gel.
2-(ter t-Bu tyldim eth ylsilyl)-4-deu ter io-3-fu r oic Acid (41).
Using general procedure 3, compound 41 was prepared in 90%
yield by adding MeOD (1.1 equivs) to the dianion. 41: column
chromatography, petroleum ether:EtOAc (20:1); mp 83-88 °C;
1
IR (KBr) 3500-2500 (b), 1685 cm-1; H NMR δ 0.01 (s, 6H),
0.96 (s, 9H), 7.93 (s, 1H), 9.5 (bs, 1H, exchanges with D2O);
13C NMR δ -5.7, 16.0, 26.7, 110.5 (three lines equal intensity),
126.0, 146.4, 166.0, 170.1; mass spectrum m/e 170 (M+ - t-Bu);
HRMS calcd for C7H8DO3Si 170.0384, found 170.0382.
Gen er a l P r oced u r e 4: Desilyla tion a n d Ester ifica tion
of F u r oic Acid s 41, 42, a n d 46-48. To a solution of a furoic
acid (1.3 mmol) in dry THF (5 mL) at 0 °C under argon was
added n-Bu4NF (1.5 equivs). The mixture was stirred at 0 °C
for 1 h, and the mixture extracted with ethyl acetate (2 × 10
mL). The ethyl acetate was dried (Na2SO4) and removed in
vacuo. The crude material was immediately dissolved in dry
ether (20 mL) and cooled to 0 °C. Excess diazomethane was
added slowly, and the mixture was warmed to rt. Argon was
bubbled through the solution for 1 h, and the ether was
removed in vacuo to leave an oil.
a
mixture, column chromatography using silica gel was
performed to separate the mixture. All compounds were
purified by distillation.
2-(t er t -Bu t yld im e t h ylsilyl)-4-d e u t e r io-3-(h yd r oxy-
m eth yl)fu r a n (12). Using general procedure 1, compound
12 was prepared in 95% yield by adding MeOD (1.1 equivs) to
the dianion: bp 76-78 °C/0.02 Torr; IR (KBr) 3319, 1070 cm-1
;
1H NMR δ 0.01 (s, 6H), 0.89 (s, 9H), 1.5 (bs, 1H, exchanges
with D2O), 4.57 (s, 2H), 7.57 (s, 1H); 13C NMR δ -5.7, 18.1,
25.7, 57.1, 110.5 (three lines equal intensity), 135.9, 146.7,
155.0; mass spectrum m/e 213 (M+).
Gen er a l P r oced u r e 2: Desilyla tion To P r ep a r e F u r a n s
26-32. Furan 12 (1 equiv) was stirred with n-Bu4NF (2
equivs) in dry THF (1 mL per mmol of 12) under argon until
TLC indicated the reaction was complete. Saturated am-
monium chloride (1 mL per mmol of 12) was added and the
mixture extracted with ethyl acetate (2 × 3 mL). The solvent
was dried (Na2SO4) and removed in vacuo to leave an oil. If
the oil was a mixture column chromatography using silica gel
was performed to separate the mixture. All compounds were
purified by distillation.
4-Deu ter io-3-(h yd r oxym eth yl)fu r a n (26). Using general
procedure 2, compound 26 was prepared in 92% from furan
12: bp 87-90 °C/0.02 Torr; IR (KBr) 3350, 1050 cm-1; 1H NMR
δ 3.2 (bs, 1H, exchanges with D2O), 4.55 (s, 2H), 7.39 (s, 1H),
Meth yl 4-Deu ter io-3-fu r oa te (49). Using general proce-
dure 4, compound 49 was prepared in 86% yield from furoic
1
acid 41: IR (KBr) 1734 cm-1; H NMR δ 3.85 (s, 3H), 7.43 (s,
1H), 8.02 (s, 1H); mass spectrum m/e 127 (M+), 96 (M+ - OMe);
HRMS calcd for C6H5DO3 127.0378, found 127.0388.
2-Meth yl-3-fu r oic Acid (55). To a solution of furan 54
(0.10 g, 0.89 mmol) in dry THF (7.0 mL) at -78 °C under N2
was added BuLi (2.0 equivs of 2.5 M in hexanes). The mixture
was stirred at -20 °C for 1 h and treated with freshly distilled
iodomethane (excess, passed through basic alumina prior to
(60) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
(61) Dictionary of Organic Compounds, 5th ed.; Vol. 5, p 4653.

Regioselective Preparation of Substituted Furans
J . Org. Chem., Vol. 62, No. 25, 1997 8759
distillation). The mixture was stirred at rt overnight. The
THF was removed in vacuo, and ether (5 mL) and saturated
ammonium chloride (5 mL) were added. HCl (5 mL of 10%)
was added, and the ether was separated within 5 min, dried
(Na2SO4), and removed in vacuo to leave an oil which was
purified by distillation to provide acid 55 (81%) as a solid: mp
102-105 °C [lit.8f mp 101-102 °C]; 1H NMR δ 2.55 (s, 3H),
6.43 (d, 1H, J ) 1.6 Hz), 7.0 (d, 1H, J ) 1.6 Hz); mass spectrum
m/e 126 (M+).
2-(Deu ter iom eth yl)-3-fu r oic Acid (58). To a solution of
furan 55 (0.12 g, 0.95 mmol) in dry THF (7.0 mL) at -78 °C
under N2 was added BuLi (2.0 equivs of 2.5 M in hexanes).
The mixture was stirred at -20 °C for 1 h and treated with
MeOD. The mixture was stirred at rt for 1 h and the THF
removed in vacuo. Diethyl ether (5 mL) and saturated
ammonium chloride (5 mL) were added. HCl (5 mL of 10%)
was added, and the ether was separated within 5 min, dried
(Na2SO4), and removed in vacuo to leave a mixture of acid 58
(85%) and ketone 57 (identified by GC/MS and not purified,
8% by 1H NMR); column chromatography, petroleum ether:
EtOAc (1:1) provided acid 58: 1H NMR δ 2.55 (broadened s,
2H), 6.43 (d, 1H, J ) 1.6 Hz), 7.0 (d, 1H, J ) 1.6 Hz); mass
spectrum m/e 127 (M+).
4-(Hyd r oxym eth yl)-2-fu r a ld eh yd e (69). A solution of
furan 61 (0.22 g, 0.62 mmol) in THF (5 mL) at 0 °C was treated
with n-Bu4NF (1.5 equivs, 1 M solution in THF). The mixture
was warmed to rt and stirred overnight. The THF was
removed in vacuo, and ether (5 mL) and saturated ammonium
chloride (5 mL) was added. The ether was separated, dried
(Na2SO4), and removed in vacuo to leave an oil. The compound
was purified by distillation: yield 83%; bp 62-7 °C/0.02 Torr;
IR (neat) 3464, 1679 cm-1; 1H NMR δ 3.10 (bs, 1H, exchanges
with D2O), 4.57 (s, 2H), 7.24 (s, 1H), 7.64 (s, 1H), 9.54 (s, 1H);
13C NMR δ 55.8, 120.8, 128.4, 145.3, 153.1, 176.1; mass
spectrum m/e 126 (M+), 125 (M+ - H); HRMS calcd for C6H6O3
126.0317, found 126.0308.
Gen er a l P r oced u r e 6: C-5 Lith ia tion of F u r a n 10 a n d
Im m ed ia te Rem ova l of th e Tr ieth ylsilyl Gr ou p . To a
solution of furan 10 (0.25 g, 0.76 mmol) in dry THF (9.4 mL)
at -78 °C under N2 was added BuLi (1.3 equivs of 2.5 M in
hexanes). The mixture was stirred at -40 °C for 3 h and
treated with an electrophile. The mixture was stirred at rt
overnight. The THF was removed in vacuo, and ether (5 mL)
and saturated ammonium chloride (5 mL) were added. The
ether was separated within 5 min, dried (Na2SO4), and
removed in vacuo to leave an oil. The oil was immediately
treated with an AcOH:THF:H2O (1:1:1) mixture (10 mL total
volume) and stirred at rt overnight. Saturated Na2CO3 was
added slowly to neutralize the AcOH. The THF was removed
in vacuo and ether (5 mL) was added. The ether was
separated within 5 min, dried (Na2SO4), and removed in vacuo
to leave an oil. The compound was purified by distillation.
2-(t er t -Bu t yld im e t h ylsilyl)-5-d e u t e r io-3-(h yd r oxy-
m eth yl)fu r a n (65). Using general procedure 6, compound
65 was prepared in 77% yield by adding MeOD to the anion:
bp 72-79 °C/0.04 Torr; IR (KBr) 3560, 1253 cm-1; 1H NMR δ
0.30 (s, 6H), 0.92 (s, 9H), 4.59 (s, 2H), 6.48 (s, 1H); 13C NMR
δ -5.7, 17.3, 25.9, 57.1, 110.2, 135.9, 146.8, 155.0 (three lines
equal intensity); mass spectrum m/e 156 (M+ - t-Bu).
2-(ter t-Bu tyld im eth ylsilyl)-3-(((tr ieth ylsilyl)oxy)m eth -
yl)fu r a n (10). To a solution of imidazole (84 mmol) in DMF
(20 mL) at 0 °C was added chlorotriethylsilane (40 mmol).
After 10 min, alcohol 3 (40 mmol) was added and the mixture
stirred 12 h at rt. Saturated sodium chloride (20 mL) and
ether (20 mL) were added, and the ether layer was separated,
dried (Na2SO4), and removed in vacuo to leave an oil. Distil-
lation provided furan 10 in 89% yield: bp 76-84 °C/0.05 Torr;
IR (KBr) 2911, 1100 cm-1 1H NMR δ 0.28 (s, 6H), 0.65 (q,
;
6H), 0.90 (s, 9H), 0.98 (t, 9H), 4.62 (s, 2H), 6.47 (d, 1H, J )
1.4 Hz), 7.58 (d, 1H, J ) 1.4 Hz); 13C NMR δ -5.60, 4.5, 6.7,
17.5, 26.4, 57.2, 110.6, 136.7, 146.2, 153.5; mass spectrum m/e
269 (M+ - t-Bu); HRMS calcd for C13H25O2Si2 269.1383, found
269.1393. Anal. Calcd for C17H34O2Si2: C, 62.51; H, 10.49.
Found: C, 63.08; H, 11.05.
4-(((t er t -Bu t yld im e t h ylsilyl)oxy)m e t h yl)-2-m e t h yl-
fu r a n (71). A solution of freshly distilled 66 (0.74 g, 3.3 mmol)
and HMPA (3.6 mmol, dried over CaH2, distilled and stored
over 4 Å molecular sieves) in dry THF (10 mL) was cooled to
-78 °C under argon and treated with BuLi (1.43 mL of 2.5 M
in hexanes, 3.6 mmol). The solution was allowed to come to
rt over 6 h and stirred at rt overnight. Saturated ammonium
chloride was added and the solution extracted with ether. The
organic layer was washed three times with saturated copper
sulfate and dried (Na2SO4), and the solvent was removed in
vacuo to afford after distillation 71: yield 71%; bp 88-94 °C/
Gen er a l P r oced u r e 5: C-5 Lith ia tion of F u r a n 10. To
a solution of furan 10 (0.25 g, 0.76 mmol) in dry THF (9.4 mL)
at -78 °C under N2 was added BuLi (1.3 equivs of 2.5 M in
hexanes). The mixture was stirred at -40 °C for 3 h and
treated with an electrophile. The mixture was stirred at rt
overnight. The THF was removed in vacuo, and ether (5 mL)
and saturated ammonium chloride (5 mL) were added. The
ether was separated within 5 min, dried (Na2SO4), and
removed in vacuo to leave an oil. The compound was either
purified by distillation.
2-(ter t-Bu t yld im et h ylsilyl)-5-m et h yl-3-(((t r iet h ylsil-
yl)oxy)m eth yl)fu r a n (59). Using general procedure 5, com-
pound 59 was prepared in 66% yield by adding freshly distilled
MeI (2 equivs, passed through basic alumina prior to distil-
lation): bp 88-94 °C/0.04 Torr; IR (neat) 1250 cm-1; 1H NMR
δ 0.25 (s, 6H), 0.66 (q, J ) 6.9 Hz, 6H), 0.91 (s, 9H), 0.95 (t, J
) 6.9 Hz, 9H), 2.28 (s, 3H), 4.54 (s, 2H), 6.05 (s, 1H); 13C NMR
δ -5.9, 4.5, 6.8, 13.7, 17.4, 26.4, 57.3, 117.0, 137.8, 151.6, 158.1;
mass spectrum m/e 283 (M+ - t-Bu). Anal. Calcd for C18H36O2-
Si2: C, 63.47; H, 10.65. Found: C, 63.84; H, 10.93.
2-(ter t-Bu tyld im eth ylsilyl)-3-(h yd r oxym eth yl)-5-m eth -
ylfu r a n (66). Furan 59 (0.1 g, 0.29 mmol) was treated with
an AcOH:THF:H2O (1:1:1) mixture (5 mL total volume) and
stirred at rt overnight. Saturated Na2CO3 was added slowly
to neutralize the AcOH. The THF was removed in vacuo, and
ether (5 mL) was added. The ether was separated within 5
min, dried (Na2SO4), and removed in vacuo to leave an oil.
The compound was purified by distillation: yield 70%; mp 50-
51 °C; IR (neat) 3349, 1253 cm-1; 1H NMR δ 0.28 (s, 6H), 0.91
(s, 9H), 2.30 (s, 3H), 4.52 (s, 2H), 6.07 (s, 1H); 13C NMR δ -5.9,
13.7, 17.1, 26.3, 57.3, 106.7, 137.0, 153.0, 156.6; mass spectrum
m/e 169 (M+ - t-Bu).
1
20 Torr; IR (neat) 1259 cm-1; H NMR δ 0.10 (s, 6H), 0.92 (s,
9H), 2.26 (s, 3H), 4.54 (s, 2H), 5.96 (s, 1H), 7.19 (s, 1H); 13C
NMR δ -5.2, 13.5, 16.4, 25.9, 57.6, 105.7, 126.5, 137.8, 152.7;
mass spectrum m/e 226 (M+), 169 (M+ - t-Bu).
Ack n ow led gm en t. We thank the Natural Sciences
and Engineering Research Council of Canada (NSERC),
the University of Calgary, and the University of Wind-
sor for financial support. We also thank NSERC for
scholarships (to J .-L.J .B. and I.R.H.) and the Royal
Society of London and the Alberta Heritage Foundation
for Medical Research for scholarships (to I.R.H.). We
also thank the referees for helpful suggestions.
Su p p or tin g In for m a tion Ava ila ble: Complete spectral
data for 14, 15, 17-21, 24, 25, 27-29, 30, 32, 42-48, 50-53,
61-64, 67, 68, and 70 (11 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
J O971098B