Regioselective ortho lithiation of 3-aryl and 3-styryl furans

Article abstract of DOI:10.1021/ol051205l

(Chemical Equation Presented) An unusual regioselectivity pattern for the ortho lithiation of 3-aryl and 3-styryl furans has been uncovered wherein lithiation occurs preferentially at the sterically encumbered 2-position. The results are attributed, at le

Full text of DOI:10.1021/ol051205l

ORGANIC
LETTERS
2005
Vol. 7, No. 15
3347-3350
Regioselective Ortho Lithiation of 3-Aryl
and 3-Styryl Furans
Maria Tofi, Thomas Georgiou, Tamsyn Montagnon, and
Georgios Vassilikogiannakis*
Department of Chemistry, UniVersity of Crete, 71409 Iraklion, Crete, Greece
Vasil@chemistry.uoc.gr
Received May 23, 2005
ABSTRACT
An unusual regioselectivity pattern for the ortho lithiation of 3-aryl and 3-styryl furans has been uncovered wherein lithiation occurs preferentially
at the sterically encumbered 2-position. The results are attributed, at least in part, to stabilization of the intermediate furyl anion by through-
space donation of
π-electron density from the substituent appended at the 3-position to the lithium cation. This ortho lithiation reaction may
be applied as a useful synthetic tool for accessing 2,3-disubstituted furans.
The large number of natural and designed furans that
constitute synthetic targets indicates that the ability to con-
struct variously substituted furans1 at will is a highly sought
after skill. In this paper, we report the results of a study inves-
tigating the selective ortho lithiation of 3-aryl and 3-styryl
furans at the 2-position, and, thereby, we introduce a method
that could assist those seeking to synthesize 2,3-substituted
furans that are relatively difficult to access by other means.
2-trialkylsilyl-3-(hydroxymethyl) furans and 2-trialkylsilyl-
3-furoic acids, respectively, are also known.8
On the other hand, the ortho lithiation of 3-alkylfurans is
reported to afford a mixture of 2,3- and 2,4-disubstituted
furans with the latter always being the major product,9
presumably for steric reasons. In most cases, the reported
ratio of 2,4- vs 2,3-disubstituted furans varied between from
2:1 to 3:1.
During our studies10 toward the synthesis of a family of
marine secondary metabolites, the prunolides,11 we attempted
to silylate 3-(4-methoxyphenyl)furan (3a) under standard
ortho lithiation conditions (Scheme 1B). Despite our initial
expectations for the predominant silylation occurring at the
less sterically hindered 5-position, this reaction afforded
Heteroatom-directed lithiations at the 2-position of 3-sub-
stituted furans2 (including 3-furoic acids,3 3-arenesulfonyl
furans,4 3-furanmethanols,5 3-furanmethanol derivatives6 and
3-bromofurans7) are known in the literature. The intramo-
lecular [1,4] OfC silyl migrations of 3-(silyloxy)methyl
furans and trialkylsilyl esters of 3-furoic acids to provide
(7) (a) Ly, N. D.; Schlosser, M. HelV. Chim. Acta 1977, 60, 2085. (b)
Weyerstahl, P.; Schenk, A.; Marschall, H. Liebigs Ann. Chem. 1995, 1849.
(8) (a) Bures, E.; Spinazze´, P. G.; Beese, G.; Hunt, I. R.; Rogers, C.;
Keay, B. A. J. Org. Chem. 1997, 62, 8741-8749. (b) Bures, E. J.; Keay,
B. A. Tetrahedron Lett. 1988, 29, 1247-1251. (c) Bures, E. J.; Keay, B.
A. Tetrahedron Lett. 1987, 28, 5965-5968.
(1) For a review in regioselective syntheses of substituted furans, 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.
(2) Gschwend, H. W.; Rodriguez, H. R. Org. React. 1979, 26, 1.
(3) (a) Knight, D. W.; Knott, A. P. J. Chem. Soc., Perkin Trans. 1 1981,
1125. (b) Beese, G.; Keay, B. A. Synlett 1991, 33.
(9) (a) Kernan, M. R.; Faulkner, D. J. J. Org. Chem. 1988, 53, 2773-
2776. (b) Wang, E. S.; Yuen, M. C.; Wong H. N. C. Tetrahedron 1996,
52, 12137-12158.
(4) McCobie, S. W.; Shankar, B. B.; Ganguly, A. K. Tetrahedron Lett.
1987, 28, 4123-4126.
(5) (a) Goldsmith, D.; Liotta, D.; Saindane, M.; Waykole, L.; Bowen,
P. Tetrahedron Lett. 1983, 24, 5835-5838. (b) Tanis, S. P.; Head, D. B.
Tetrahedron Lett. 1984, 25, 4451-4454.
(10) Sofikiti, N.; Tofi, M.; Montagnon, T.; Vassilikogiannakis, G.;
Stratakis, M. Org. Lett. 2005, 7, 2357-2359.
(11) (a) Carroll, A. R.; Healy, P. C.; Quinn, R. J.; Tranter, C. J. J. Org.
Chem. 1999, 64, 2680-2682. (b) Ortega, M. J.; Zub´ıa, E.; Ocan˜a, J. M.;
Naranjo, S.; Salva´, J. Tetrahedron 2000, 56, 3963-3967.
(6) Honda, T.; Kobayashi, Y.; Tsubuki, M. Tetrahedron 1993, 49, 1211-
1222.
10.1021/ol051205l CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/28/2005

tions, the 2,3- and 2,4-substituted furans 8a,b and 9a,b
(respectively) were obtained in ratios of 8a:9a ) 1:1.3 (for
the reaction of 7a) and 8b:9b ) 1.1:1 (for the reaction of
7b). These ratios, representing nearly equal substitution at
the 2- and 5-positions of the furan substrate, not only differ
significantly from those obtained for the previously tested
conjugated substrates where the 2-position was favored but
also differ slightly from the reported results for 3-alkylfurans9
where the 5-position was favored.
Scheme 1. Regioselective Ortho Lithiation of 3-Arylfurans
The next task we identified for our investigation was an
examination of furan substrates where conjugation was
achieved not by an aromatic substituent at the 3-position but
by an olefin appended at this site instead. To this end, furan
substrates 11 and 13 were synthesized, as shown in Scheme
3, using a combination of Wittig olefinations and a Suzuki
Scheme 3. Ortho Lithiation of 3-Alkenylfurans 11 and 13
mainly the 2-silylated product (4a:5a ) 3:1).12 To investigate
the generality of this surprising and interesting observation
we decided to scrutinize the result further by examining a
range of substrates bearing different substituents at the para
position of the appended phenyl ring (Scheme 1).
Akin to 3a, substrates 3b and 3c were easily synthesized
by employing a Suzuki coupling to unite 3-furanboronic acid
(1) with the appropiate para-substituted bromobenzene (2b,c,
Scheme 1A). Following the ortho lithiation/trimethylsilyl
chloride quench sequence of these new substrates (3b and
3c), it quickly became obvious that the more electron-
withdrawing the substituent on the phenyl ring, the greater
the enhancement was in the observed regioselectivity (in
favor of the 2,3-disubstituted product, Scheme 1).
In an attempt to deconvolute the role played by conjuga-
tion, between the furan and the phenyl moieties, in securing
the unusual regioselectivity that we had been observing,
substrates 7a and 7b were prepared using a Suzuki-coupling
protocol (Scheme 2). When the benzylfurans 7a and 7b were
subjected to the established ortho lithiation/silylation condi-
Scheme 2. Ortho Lithiation of 3-Benzylfurans
coupling. For substrates 11 and 13 the selectivity obtained
in the ortho lithiation reaction was lower (ranging between
1.1 and 2.0:1) than we had previously observed with
3-arylfurans; however, once again, the more sterically
hindered 2-position was favored (Scheme 3). Furthermore,
and, once again, electron-donating groups decreased the
selectivity (see (E)-11 vs (E)-13). (E)-Substrates must be
compared when we are talking about this electronic effect
because, in the case of the (Z)-substrates, other factors come
into play. On going from (E)-11 to (Z)-11, the observed
selectivity for the reaction at the 2-position dropped from
2.0:1 to 1.4:1 for steric reasons; however, on going from
(E)-13 to (Z)-13, the selectivity increased possibly due to
the stabilizing influence of coordination of the methoxy group
to the lithium cation (II, Figure 2).
3348
Org. Lett., Vol. 7, No. 15, 2005

Bearing all the results obtained thus far in mind, we
decided next to examine the effect of extended conjugation
at the 3-position of the furan ring. For this purpose, we
targeted the 3-styrylfurans 17a-c (both the (E)- and (Z)-
isomers). These new substrates were easily prepared using
standard Wittig protocols (Scheme 4). Crucially, careful
Figure 1. Sterically governed ortho lithiation of 3-prenyl and 3-(2-
phenyl)ethyl furans.
Scheme 4. Regioselective Ortho Lithiation of 3-â-Styrylfurans
was easily prepared by hydrogenation (H2, Pd/C) of 17b (a
mixture containing both geometrical isomers was used). In
both cases, the standard ortho lithiation reaction (n-BuLi,
TMSCl, -25 f 25 °C) resulted in formation of the less
sterically hindered 2,4-disubstituted furan in stark contrast
to the results for the previously examined conjugated
substrates. It had, therefore, become obvious that simple
hydrogenation of the double bond of 17b to furnish 21
produced a change in the regioselectivity in the subsequent
ortho lithiation reaction by a factor of approximately 11 and
led to the preferential formation of the opposite regioisomer.
At this point we should note that TMSCl was used as the
quenching electrophile in all the ortho lithiation reactions
for the purpose of directly comparing the results obtained.
However, numerous other electrophiles may be employed
to give access to a broad range of synthetically useful 2,3-
disubstituted furans (starting from 3-aryl and 3-styryl furans).
Further elaboration in the case of 2-substituted 3-styrylfurans
might readily be achieved by functionalization (i.e., oxidative
cleavage) of the double bond.
chromatographic separation of the mixture of geometrical
isomers obtained from the Wittig reactions allowed us access
to pure samples of each isomer. Separate ortho lithiation, under
our established conditions, of each of the (E)- or (Z)-con-
figured isomers of 17a-c afforded a set of interesting new
results in which the selectivity in favor of the 2,3-disubsti-
tuted product was universally higher than had been recorded
for any of our previously tested substrates (Scheme 4).
Within this latest set of results, a similar increase in the
observed regioselectivity was recorded in the cases of the
unsubstituted and p-CF3-substituted substrate when compared
to the p-OMe-substituted substrate ((E)-17a vs (E)-17b vs
(E)-17c). The most impressive feature for this batch of
results, however, was the high selectivity (for the 2,3-
disubstituted product) obtained for the (Z)-substrates ((Z)-
17a-c) in which the 2-position was severely sterically
encumbered by the proximal phenyl ring (Scheme 4).
To investigate the postulate that conjugation of the 3-sub-
stituent (aryl, alkenyl, or styryl) with the furan is pivotal to
the unexpected regioselectivity (of the ortho lithiation reaction
of these substrates), two more unconjugated substrates were
prepared (20 and 21, Figure 1). In 3-prenylfuran (20), the
olefin was included as a potential through-space π-donor for
the lithium cation in order to test whether an alternative inter-
action of this sort was important in producing the observed
regioselectivity. Likewise, in 3-(2-phenyl)ethyl furan (21), the
aryl group was included to act similar to a potential π-donor.
3-Prenylfuran (20; Figure 1) was synthesized by lithium
halogen exchange (between 3-bromofuran and n-BuLi)
followed by alkylation of the resulting furyl anion with
prenyl-Br. 3-(2-Phenyl)ethyl furan (21), on the other hand,
In an effort to further explain our ortho lithiation results,
1
the J(13C-H) coupling constants for both ortho positions
of some representative substrates were measured. It is well-
known that this coupling constant can be associated with
the kinetic acidity of the corresponding hydrogens.13 It is
important to note here that the full assignment of the relevant
13C NMR peaks was accomplished using HMQC experi-
ments. The results obtained from this NMR study are
summarized in Table 1.
Table 1. 1J(13C-H) for C-2 and C-5 of Selected Substrates
substrate
1J(13C2-H)
1J(13C5-H)
3a
3b
7a
(E)-17b
(Z)-17b
200.1
201.0
199.5
201.2
201.2
202.1
203.4
201.3
202.2
202.2
1
The J(13C-H) coupling constants measured reveal that
for substrates 3a, 3b, and 7a, the 5-position hydrogen would
1
(12) All product ratios reported in Schemes 1-4 were measured by H
NMR of the crude reaction mixtures, while yields refer to isolated yields
after chromatographic purification.
(13) Pedersen, E. B. J. Chem. Soc., Perkin Trans. 2 1977, 473
Org. Lett., Vol. 7, No. 15, 2005
3349

appear to be more acidic than the other ortho hydrogen at
the 2-position (the C-5 coupling constant is higher by ∼2
Hz than the corresponding C-2 coupling constant). Despite
this fact, the deprotonation of 3a and 3b occurs predomi-
nantly at the 2-position. In cases where the kinetic acidity of
the two ortho protons is closer (such as substrates (E)-17b
and (Z)-17b with ∼1 Hz difference) the observed regioselec-
tivity in favor of the 2-position hydrogen is even higher. The
kinetic acidity of the ortho hydrogens is not, therefore, by
itself sufficient to explain the observed regioselectivity. How-
ever, an increase in the acidity of the 2-position proton com-
pared to the position-5 proton (on going from conjugated
substrates 3a and 3b to (E)-17b and (Z)-17b) is in accord
with higher regioselectivity in favor of the 2-position. While
the data also make it obvious (Table 1) that having conjuga-
ted substituents at the 3-position increases the kinetic acidity
of the ortho furan protons (see 7a vs 3a, 3b, and 17b), elec-
tron-donating groups appended to the conjugated 3-substitu-
ent decrease the kinetic acidity (3a vs 3b). The latter effect
can easily be rationalized as being the result of destabilization
of the furyl anion by the electron-donating substituent.
A plausible mechanistic explanation for how this compli-
cated situation arises has to do with the presence of a
stabilizing interaction between the π-electronic system of the
conjugated 3-aryl, 3-alkenyl, and 3-styryl substituents (I, III,
and IV, Figure 2) and the lithium cation. These through-
space interactions, known as π-stacking interactions,14 are
not included in the measured kinetic acidity. The stabilization
of a late transition state in the deprotonation step, due to
interactions of this nature, may be of key importance. For
this hypothesis to be correct, we need to assume that the
π-donating group of 21 is positioned at too great a distance
to participate strongly in such a stabilizing coordination.
Likewise, the 3-benzyl furans (7a and 7b) and 3-prenylfuran
(20) readily adopt different conformations (due to their extra
degrees of rotational freedom) many of which do not
facilitate the stabilizing coordination between the π-system
and the lithium cation; thus, overall, the stabilization in these
substrates is of reduced strength.
Figure 2. Through-space stabilizing interactions.
In summary, we have revealed an unusual regioselectivity
pattern in the ortho lithiation of 3-aryl and 3-styryl furans
(lithiation at the sterically encumbered 2-position is favored
over lithiation at the 5-position) that may be attributed to
stabilization of the intermediate furyl anion by through-space
donation of π-electron density from the substituent appended
at the 3-position to the lithium cation. The means by which
to access sterically encumbered 2,3-disubstituted furans in
preference to the alternative 2,4-disubstituted furans that we
have uncovered is a useful synthetic tool.
Acknowledgment. This project was cofunded by the
European Social Fund and National Resources (B EPEAEK,
Pythagoras Program). This research was also supported by
a Marie Curie Intra-European Fellowship (T.M.) within the
6th European Community Framework Program and the
European Science Foundation (Cost D-28 program). We
thank Dr. Iain Simpson for helpful discussions.
Supporting Information Available: Experimental pro-
cedures and 1H, 13C, and GC-MS spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) Ma, J. C.; Dougherty, D. A. Chem. ReV. 1997, 97, 1303-1324.
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