Multicomponent type II anion relay chemistry (ARC): One-pot syntheses of 2,3-disubstituted furans and thiophenes

Article abstract of DOI:10.1021/ol900434k

Effective, one-pot syntheses of 2,3-disubstituted furans and thiophenes, exploiting 2-fert-butyldimethylsilyl-3-formylfuran and -thiophene as the respective Afunctional linchpins, have been developed. The synthetic protocol involves multicomponent type II

Full text of DOI:10.1021/ol900434k

ORGANIC
LETTERS
2009
Vol. 11, No. 8
1861-1864
Multicomponent Type II Anion Relay
Chemistry (ARC): One-Pot Syntheses of
2,3-Disubstituted Furans and
Thiophenes
Nelmi O. Devarie-Baez,† Won-Suk Kim,‡ Amos B. Smith III.,*,‡ and Ming Xian*,†
Department of Chemistry, Washington State UniVersity, Pullman, Washington 99164, and
Department of Chemistry, UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
mxian@wsu.edu; smithab@sas.upenn.edu
Received March 2, 2009
ABSTRACT
Effective, one-pot syntheses of 2,3-disubstituted furans and thiophenes, exploiting 2-tert-butyldimethylsilyl-3-formylfuran and -thiophene as
the respective bifunctional linchpins, have been developed. The synthetic protocol involves multicomponent type II Anion Relay Chemistry
(ARC) mediated by a solvent-controlled C(sp2)fO 1,4-Brook rearrangement. Simple organolithiums and r-disubstituted ester enolates prove
effective as the initiating nucleophiles.
Functionalized furans and thiophenes comprise important
synthetic targets given their application in natural product
total synthesis, drug discovery, and materials science.1,2 Thus,
methods to assemble quickly such diverse substituted
heterocycles are of considerable importance. Although a few
one-step strategies have been recently reported,3 most
methods to access polysubstituted furans and thiophenes rely
upon multiple-step manipulations to install each substituent
sequentially.4 Given the potential utility of multicomponent
Anion Relay Chemistry (ARC),5 we anticipated that this
tactic would constitute an effective protocol to access such
(3) For selected examples, see the following. For furans: (a) Barluenga,
J.; Riesgo, L.; Vicente, R.; Lopez, L. A.; Tomas, M. J. Am. Chem. Soc.
2008, 130, 13528. (b) Babudri, F.; Cicco, S. R.; Farinoia, G. M.; Lopez,
L. C.; Naso, F.; Pinto, V. Chem. Commun. 2007, 3756. (c) Liu, Z.; Yu,
W.; Yang, L.; Liu, Z.-L. Tetrahedron Lett. 2007, 48, 5321. (d) Garcon, S.;
Vassiliou, S.; Cavicchioli, M.; Hartmann, B.; Monteiro, N.; Balme, G. J.
Org. Chem. 2001, 66, 4069. For thiophenes: (e) Mitsudo, K.; Thansandote,
P.; Wilhelm, T.; Mariampillai, B.; Lautens, M. Org. Lett. 2006, 8, 3939.
(f) Ye, X. S.; Li, W. K.; Wong, H. N. C. J. Am. Chem. Soc. 1996, 118,
2511. (g) Fattuoni, C.; Usai, M. G.; Cadoni, E.; De Montis, S.; Cabiddu, S.
Synthesis 2006, 3855. (h) Fattuoni, C.; Usai, M.; Cabiddu, M.; Cadoni, E.;
De Montis, S.; Cabiddu, S. Synthesis 2006, 3855. (i) Wang, Y.; Dong, D.;
Yang, Y.; Huang, J.; Ouyang, Y.; Liu, Q. Tetrahedron 2007, 63, 2724.
(4) For selected reviews, see the following. For furans: (a) Luh, T. Pure
Appl. Chem. 2005, 77, 1213. (b) Keay, B. A. Chem. Soc. ReV. 1999, 28,
209. (c) 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. (d) Wong,
H. N. C. Pure Appl. Chem. 1996, 68, 335. For thiophenes: (e) Ila, H.; Baron,
O.; Wagner, A. J.; Knochel, P. Chem. Commun. 2006, 583. (f) Guernion,
N. J. L.; Hayes, W. Curr. Org. Chem. 2004, 8, 637. (g) Weissberger, A.;
Taylor, E. C. In Thiophenes and Its DeriVatiVes; Gronowitz, S., Ed.; The
Chemistry of Heterocyclic Compounds, Vol. 44; John Wiley: New York,
1985; Part 1, p 1.
† Washington State University.
‡ University of Pennsylvania.
(1) Dunlop, A. P.; Peters, F. N. Reinhold, ‘The Furans’ (A.C.S.
Monograph No. 119). Reinhold: New York, 1953. (b) Hau, X. L.; Yang,
Z.; Wong, H. N. C. In Progress in Heterocyclic Chemistry; Gribble, G. W.,
Gilchrist, T. L., Eds.; Pergamon: Oxford, 2003; Vol. 15, p 167. (c) Keay,
B. A., Dibble, P. W. In ComprehensiVe Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Elsevier: Oxford, 1997; Vol. 2,
p 395. (d) Montagnon, T.; Tofi, M.; Vassilikogiannakis, G. Acc. Chem.
Res. 2008, 41, 1001
.
(2) (a) Bohlmann, F.; Zdero, C. In Thiophenes and Its DeriVatiVes;
Gronowitz, S., Ed.; The Chemistry of Heterocyclic Compounds, Vol. 44;
John Wiley & Sons: New York, 1985; Part 1, p 261. (b) Press, J. B. In
Thiophenes and Its DeriVatiVes; Gronowitz, S., Ed.; The Chemistry of
Heterocyclic Compounds, Vol. 44; John Wiley & Sons: New York, 1991;
Part 4, p 397. (c) Roncali, J. Chem. ReV. 1992, 92, 711. (d) Schopf, G.;
Komehl, G. In AdVances in Polymer Sciences: PolythiophenessElectrically
ConductiVe Polymers; Abel, A., Ed.; Springer-Verlag: Berlin, 1997; Vol.
129, p 1
.
10.1021/ol900434k CCC: $40.75
Published on Web 03/20/2009
2009 American Chemical Society

heterocycles. Precedent for this approach derives from our
recent one-pot ARC constructions of both 2,3-disubstituted
thiophenes exploiting 3-bromo-2-silylthiophene (1b)6 and
ortho-disubstituted benzene derivatives employing o-trialkyl-
silylbenzaldehyde (Scheme 1).7
Scheme 2
Scheme 1
2-TBS-3-bromothiophene (1b),6 involving tert-butyllithium
metalation followed by reaction with DMF.
Based on our earlier studies,6,7 we reasoned that the
reaction of 2a or 2b with alkyllithium would form alkoxide
intermediate 6 (Scheme 3), which upon addition of either
Scheme 3
We reasoned that the same 2-trialkylsilyl-3-alkoxy modular
anion derived from 1, generated via lithiation and reaction
with an aldehyde or ketone (Scheme 1, path A), could also
arise upon addition of various nucleophiles to 2-trialkylsilyl-
3-formylfurans (2a) and -thiophenes (2b) (path B). From the
perspective of synthetic planning, it is important to recognize
that these linchpins (1 and 2) are fundamentally different;
linchpin 1 comprises a dianion synthon, while 2 entails a
synthon possessing an electrophilic and nucleophilic site.
Recognition of this difference, also apparent in linchpins 35a
and 4,5d foreshadows significant additional chemical versatil-
ity of the multicomponent type II ARC tactic (Figure 1).
DMPU or HMPA would trigger a C(sp2)fO 1,4-silyl
migration to furnish carbanion 7, which in turn could be
captured by various electrophiles to provide disubstituted
furans and thiophenes (cf., 8). Earlier studies by Keay and
co-workers9 demonstrated the viability of C(sp2)fO 1,4-
silyl migration with a series of silylfuran and -thiophene
substrates when sodium or potassium bases were used.
However, no attempts to extend these reactions to a solvent-
controlled multicomponent union have been reported.
We began with linchpin 2a employing the solvent condi-
tions of DMPU and THF (1:4), which were previously
effective at triggering 1,4-silyl migration when applied to
3-bromo-2-silylthiophene (1b; Scheme 1, path A).6 Surpris-
ingly, silyl migration proved problematic, furnishing only
(5) Anion relay chemistry (ARC) involves the migration of a negative
charge within a molecular system (i.e., through bond or through space, the
latter employing a transfer agent such as a trisubstituted silyl group). Two
types of through-space ARC have been identified. In type I ARC, the anion
after initial migration returns to the site of origin, whereas in type II ARC,
the anion is relayed to a new remote site. For an account on the evolution
of type I and type II anion relay chemistry, see ref 5e. For earlier examples
of anion relay chemistry developed by Smith and co-workers, see refs 5a-d.
(a) Smith, A. B., III.; Duffey, M. O. Synlett 2004, 1363. (b) Smith, A. B.,
III.; Xian, M. J. Am. Chem. Soc. 2006, 128, 66. (c) Smith, A. B., III.; Xian,
M.; Kim, W.-S.; Kim, D.-S. J. Am. Chem. Soc. 2006, 128, 12368. (d) Smith,
A. B., III.; Kim, D.-S.; Xian, M. Org. Lett. 2007, 9, 3307. (e) Smith, A. B.,
III.; Wuest, W. M. Chem. Commun. 2008, 5883.
Figure 1. Linchpin synthon.
With these considerations in mind, we report here the use
of organolithiums and lithium enolates derived from R-di-
substituted esters as nucleophiles to generate, in a single flask,
a series of 2,3-disubstituted furans and thiophenes via the
multicomponent type II ARC tactic.
(6) Devarie-Baez, N. O.; Shuhler, B. J.; Wang, H.; Xian, M. Org. Lett.
2007, 9, 4655.
(7) Smith, A. B., III.; Kim, W.-S.; Wuest, W. M. Angew. Chem., Int.
Ed. 2008, 47, 7082.
The requisite linchpins 2-TBS-3-formylfuran (2a) and
-thiophene (2b) are readily prepared in excellent yield
(Scheme 2): linchpin 2a via PCC oxidation8 of 2-TBS-3-
(hydroxymethyl)furan 59 and linchpin 2b via formylation of
(8) Corey, E. J.; Suggs, W. Tetrahedron Lett. 1975, 16, 2647.
(9) (a) Bures, E.; Spinazze, P. G.; Beese, G.; Hunt, I. R.; Rogers, C.;
Keay, B. A. J. Org. Chem. 1997, 62, 8741. (b) Spinazze, P. G.; Keay, B. A.
Tetrahedron Lett. 1989, 30, 1765.
1862
Org. Lett., Vol. 11, No. 8, 2009

trace amounts of the desired product. However, when the
electrophile was added in a mixture of HMPA and Et2O
(1:2) to the alkoxy anion initially derived at -78 °C, the
desired 1,4-Brook process ensued to furnish 2,3-disubstituted
furans in moderate to good yield. A series organolithium
reagents (i.e., n-BuLi, PhLi, and 3-thienyllithium) served to
initiate the multicomponent ARC reaction (Table 1). Alde-
Scheme 4
Table 1. One-Pot Synthesis of 2,3-Disubstituted Furans from
2-TBS-3-formylfuran 2a*
result of irreversible O-methylation 13 is faster than Brook
rearrangement in this system. On the other hand, when either
an aldehyde or ketone was used, 14 was obtained. In essence,
12 serves as a reservoir of the carbonyl electrophile.
Encouraged by the viability of the type II ARC process
employing 2-TBS-3-formylfuran 2a, we turned to the use
of 2-TBS-3-formylthiophene 2b as the bifunctional linchpin
(Table 2). In this case, when DMPU and THF (1:4)6 were
Table 2. One-Pot Synthesis of 2,3-Disubstituted Thiophenes
from 2-TBS-3-formylthiophene 2b*
* Conditions: (step 1) 2a (1.0 equiv), nucleophile (1.1 eq.uiv), Et2O,
-78 °C, 30 min; (step 2) HMPA/Et2O ) (1/1), electrophile (1.5 equiv),
-78 °C to rt, 3 h. a TBS group was removed by TBAF in THF for 30 min
to facilitate purification.
hydes and ketones proved effective electrophiles for the type
II ARC process, providing the 2,3-disubstituted furans
(9a-g) in yields ranging from 62 to 83%. When isobutyral-
dehyde was employed as the electrophile, the Brook rear-
rangement took place to afford 9h without capture of the
aldehyde (entry 8). Presumably, the basicity of the C(2) furan
anion in the presence of HMPA, the latter known to increase
the basicity of organolithium agents,10 leads to aldehyde
deprotonation faster than reaction with the carbonyl group.
Also of interest, use of reactive alkyl halides such as methyl
iodide furnished only oxygen alkylation 9i (entry 9).
* Conditions: (step 1) 2b (1.0 equiv), nucleophile (1.1 equiv), THF,
-78 °C, 30 min; (step 2) DMPU/THF ) (1/1), electrophile (1.5 equiv),
-78 °C to rt, 3 h. a We also obtained O-methylation product (15 i) in 41%.
Brook and retro-Brook rearrangements are known to be
reversible processes proceeding via a pentacoordinate silicon
intermediate (Scheme 4).11 Given that such an equilibrium
exists between alkoxide 10 and the Brook-rearranged org-
anolithium 11, product formation would be based on the
relative rate of the 1,4-Brook/retro-Brook rearrangement in
conjunction with the stability of two anions (oxy anion vs
carbanion). When MeI was employed as an electrophile, the
employed as the solvent system, 2b provided the 2,3-
disubstituted thiophenes in moderate to good yield. Alde-
hydes, nonenolizable ketones, and in this case methyl iodide
proved competent as electrophiles for the 1,4-Brook rear-
ranged anion, with isolated yields of 15a-h ranging from
45 to 87%. Unlike the reaction with 2a, enolizable aldehydes
(cf. isobutyraldehyde) furnished 15a and 15g in moderate
yield (entries 1 and 7), presumably due to the decreased
(10) Clayden, J.; Yasin, S. A. New J. Chem. 2002, 26, 191.
Org. Lett., Vol. 11, No. 8, 2009
1863

basicity of the thiophene anion. Interestingly, use of HMPA
was not an effective agent to trigger the 1,4-Brook process
with 2b.6
We next turned to the possibility of using ester enolates
as the initiating nucleophile in the ARC process (Scheme
5). We reasoned that intramolecular capture after silyl
Table 3. Synthesis of 3- and 2,3-Disubstituted Furans and
Thiophenes from 2a and 2b Employing Ester Enolates
Scheme 5
a Conditions A: (step 1) 2b (1.0 equiv), ester enolate (1.1 equiv), THF,
-78 °C, 25 min; (step 2) DMPU, -78 °C to rt, 19 h. b Conditions B:
(step 1) 2a (1.0 equiv), ester enolate (1.2 equiv), Et2O, -78 °C, 30 min;
(step 2) HMPA, -78 °C to rt, 19 h. c Conditions C: same as conditions A
except for the amount of DMPU. d Conditions D: (step 1) silyl enol ether
(1.36 equiv), MeLi (1.28 equiv), Et2O, rt, 1 h; (step 2) 2a (1.0 equiv), Et2O,
-78 °C, 30 min; (step 3) HMPA, -78 °C to rt, 19 h.
migration might occur to form 5-membered cyclic products
(cf., 18).
As illustrated in Table 3, enolates derived from a series
of methyl esters, generated upon treatment with LDA, were
reacted with linchpins 2a and 2b. After initial generation of
the intermediate 16, addition of either HMPA or DMPU
triggered the C(sp2)fO 1,4-Brook rearrangement. In the case
of the thiophene linchpin (2b), cyclization occurred. Good
to excellent yields of 18a-c (entries 1-3) were obtained
when esters possessing R-disubstitution were used. However,
only trace amounts of cyclized products were observed when
enolates derived from R-unsubstituted esters were employed
as the initiating nucleophiles (entry 4). Again, acidic protons
present on the initially derived adducts are presumably
sufficiently acidic to be protonated by the intermediate
carbanion. In the case of the enolate derived from isopropyl
acetate, ꢀ-elimination product 18d was isolated in moderate
yield. Also of interest, when 2-TBS-3-formylfuran 2a was
used as the linchpin, 1,4-Brook-rearranged products (19a-c)
not having undergone intramolecular cyclization were ob-
tained as the major product (entries 1-3). The latter results
presumably derived either from the reactivity (i.e., geometry)
and/or basicity differences of the C(2) anion of the furan
and thiophene.12
relay chemistry (ARC) has been developed employing
2-TBS-3-formylfuran and -thiophene as the bifunctional
linchpins. Central to this process is a solvent-mediated
C(sp2)fO 1,4-Brook rearrangement. As such, this study
foreshadows the use of other nucleophiles (cf., organozin-
cates, organocuprates, etc.) as well as the use of cross-
coupling reactions as recently demonstrated with o-TMS
benzaldehyde,7 to access a wide variety of diverse poly-
functionalized heterocycles. Progress toward this end will
be reported in due course.
Acknowledgment. This work has been supported by
Washington State University and at the University of
Pennsylvania through Grant No. CA-19033. We are also
grateful to Cephalon, Inc. for a Dr. Horst Witzel fellowship
awarded to W.-S.K.
Supporting Information Available: Experimental pro-
cedures and characterization data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, a multicomponent one-pot synthesis of 2,3-
disubstituted furans and thiophenes exploiting type II anion
OL900434K
(11) (a) Jiang, X.; Bailey, W. F. Organometallics. 1995, 14, 5704. (b)
Kawashima, T.; Naganuma, K.; Okazaki, R. Organometallics. 1998, 17,
367. (c) Naganuma, K.; Kawashima, T.; Okazaki, R. Chem. Lett. 1999,
1139.
(12) Fraser, R. R.; Mansour, T. S.; Savard, S. Can. J. Chem. 1985, 63,
3505.
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