Several convenient methods for the synthesis of 2-amido substituted furans

Article abstract of DOI:10.1021/jo026757l

Several new methods for the synthesis of differently substituted 2-amidofurans are described. The thermolysis of furan-2-carbonyl azide results in a Curtius rearrangement and the resulting furanyl isocyanate was trapped with various organometallic reagents. A second method consists of a C-N cross-coupling reaction of a bromo-substituted furan with various amides, carbamates, and lactams. The CuI-catalyzed cross-coupling reaction between furanyl bromides and amides furnished 2- and 3-substituted amidofurans in 45-95% yield. The third protocol used involves the reaction of cyclic carbinol amides with triflic anhydride. The reaction proceeds under very mild conditions to provide α-(trifluoromethyl)sulfonamido-substituted furans in high yield. The resulting iminium ion derived from the reaction of the hydroxy pyrrolidinone with Tf₂O undergoes a facile ring opening as a consequence of the adjacent hydroxyl group to produce an imino triflate intermediate. Subsequent cyclization of this highly electrophilic imine with the oxygen atom of the adjacent carbonyl group leads to an imino dihydrofuran that reacts further with another equivalent of Tf₂O to give the observed product.

Full text of DOI:10.1021/jo026757l

Sever a l Con ven ien t Meth od s for th e Syn th esis of 2-Am id o
Su bstitu ted F u r a n s
Albert Padwa,* Kenneth R. Crawford, Paitoon Rashatasakhon, and Mickea Rose
Department of Chemistry, Emory University, Atlanta, Georgia 30322
chemap@emory.edu
Received November 23, 2002
Several new methods for the synthesis of differently substituted 2-amidofurans are described. The
thermolysis of furan-2-carbonyl azide results in a Curtius rearrangement and the resulting furanyl
isocyanate was trapped with various organometallic reagents. A second method consists of a C-N
cross-coupling reaction of a bromo-substituted furan with various amides, carbamates, and lactams.
The CuI-catalyzed cross-coupling reaction between furanyl bromides and amides furnished 2- and
3-substituted amidofurans in 45-95% yield. The third protocol used involves the reaction of cyclic
carbinol amides with triflic anhydride. The reaction proceeds under very mild conditions to provide
R-(trifluoromethyl)sulfonamido-substituted furans in high yield. The resulting iminium ion derived
from the reaction of the hydroxy pyrrolidinone with Tf2O undergoes a facile ring opening as a
consequence of the adjacent hydroxyl group to produce an imino triflate intermediate. Subsequent
cyclization of this highly electrophilic imine with the oxygen atom of the adjacent carbonyl group
leads to an imino dihydrofuran that reacts further with another equivalent of Tf2O to give the
observed product.
Furans1 and isobenzofurans2 have frequently been
SCHEME 1
employed as dienes in the Diels-Alder reaction to afford
substituted 7-oxabicyclo[2.2.1]heptanes (1) that serve as
key intermediates in the synthesis of a variety of natural
products.3-10 The large number of selective transforma-
tions possible with the oxabicyclic system endow this
nucleus with impressive versatility. A crucial synthetic
transformation employing these intermediates (Scheme
1) involves the cleavage of the oxygen bridge to produce
) Cl or SO2Ph),13 fragmentation,14 hydrolytic ring open-
functionalized cyclohexene derivatives 2. Many groups
ings,15 and alkylative bridge cleavage reactions.16
have developed different approaches including â-elimina-
Several years ago we began a synthetic program to
tion of suitable derivatives,11 treatment with strong
provide general access to a variety of alkaloids by [4+2]-
acids,12 reductive elimination of endo functionalities (R2
cycloaddition chemistry of substituted 2-amidofurans.17
Our synthetic strategy was to take advantage of an
(1) Dean, F. M. Adv. Heterocycl. Chem. 1981, 30, 168. Lipshutz, B.
intramolecular Diels-Alder reaction of an alkenyl-
Chem. Rev. 1986, 86, 795. Murphree, S. S.; Padwa, A. Tetrahedron
substituted furanyl carbamate derivative (IMDAF).18,19
Not only do IMDAF reactions allow for the preparation
1997, 53, 14179.
(2) Friedrichsen, W. Adv. Heterocycl. Chem. 1980, 26, 135. Rickborn,
B. Advances in Theoretically Interesting Molecules; Thummel, R. P.,
Ed.; J AI Press: Greenwich, CT, 1989; Vol. 1. Friedrichsen, W. In
Houben-Weyl, Methoden der Organischen Chemie; Kreher, R., Ed.;
Thieme Verlag: Stuttgart, Germany, 1994; Vol. E6b, pp 163-216.
(3) Vogel, P.; Fattori, D.; Gasparini, F.; Le Drian, C. Synlett 1990,
173. Reymond, J . L.; Pinkerton, A. A.; Vogel, P. J . Org. Chem. 1991,
56, 2128.
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(5) Eggette, T. A.; de Koning, H.; Huisman, H. O. J . Chem. Soc.,
Perkin Trans. 1 1978, 980.
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J ackson, B.; Prout, K.; Witt, F. J . Tetrahedron Lett. 1990, 31, 1885.
Koreeda, M.; J ung, K.-Y.; Hirota, M. J . Am. Chem. Soc. 1990, 112,
7413. Reynard, E.; Reymond, J .-L.; Vogel, P. Synlett 1991, 469. Ogawa,
S.; Yoshikawa, M.; Taki, T. J . Chem. Soc., Chem. Commun. 1992, 406.
Ogawa, S.; Tsunoda, H. Liebigs Ann. Chem. 1992, 637.
(13) J ung, M. E.; Street, L. J . Am. Chem. Soc. 1984, 106, 8327.
Mirsadeghi, S.; Rickborn, B. J . Org. Chem. 1985, 50, 4340.
(14) Grieco, P. A.; Lis, R.; Zelle, R. E.; Finn, J . J . Am. Chem. Soc.
1986, 108, 5908.
(6) Ogawa, S.; Iwasawa, Y.; Nose, T.; Suami, T.; Ohba, S.; Ito, M.;
Saito, Y. J . Chem. Soc., Perkin Trans. 1 1985, 903.
(7) J ust, G.; Kim, S. Tetrahedron Lett. 1976, 17, 1063.
(8) Murai, A.; Takahashi, K.; Taketsuru, H.; Masamune, T. J . Chem.
Soc., Chem. Commun. 1981, 221.
(9) Kotsuki, H.; Nishizawa, H. Heterocycles 1981, 16, 1287.
(10) Cox, P. J .; Simpkins, N. S. Synlett 1991, 321.
(11) Le Drian, C.; Vieira, E.; Vogel, P. Helv. Chim. Acta 1989, 72,
338. Takahashi, T.; Iyobe, A.; Arai, Y.; Koizumi, T. Synthesis 1989,
189. Guilford, A. J .; Turner, R. W. J . Chem. Soc., Chem. Commun.
1983, 466. Yang, W.; Koreeda, M. J . Org. Chem. 1992, 57, 3836.
(15) Takayama, H.; Hayashi, K.; Koizumi, T. Tetrahedron Lett. 1986,
27, 5509. Hanessian, S.; Beaulieu, P.; Dube, D. Tetrahedron Lett. 1986,
27, 5071.
(16) Arjona, O.; Dios, A.; Pradilla, R. F.; Plumet, J .; Viso, A. J . Org.
Chem. 1994, 59, 3906. Lautens, M.; Dockendorff, C.; Fagnou, K.;
Malicki, A. Org. Lett. 2002, 4, 1311 and references therein.
(17) Padwa, A.; Brodney, M. A.; Dimitroff, M. J . Org. Chem. 1998,
63, 5304. Padwa, A.; Brodney, M. A.; Satake, K.; Straub, C. S. J . Org.
Chem. 1999, 64, 4617.
10.1021/jo026757l CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/05/2003
J . Org. Chem. 2003, 68, 2609-2617
2609

Padwa et al.
SCHEME 2
SCHEME 3
of complex oxygenated polycyclic compounds, but they
often proceed at lower temperatures than their intermo-
lecular counterparts. Even more significantly, unacti-
vated π-bonds are reactive toward the internal cycload-
dition reaction. Indeed, we discovered that the IMDAF
reaction of a series of furanamide derivatives (i.e., 3)
occurred smoothly to furnish cyclized aromatic carbam-
ates 5 as the only isolable products in high yield when
monosubstituted alkenyl tethers were used (Scheme 2).17
When the alkenyl group possesses a substituent other
than hydrogen at the 2-position of the π-bond, the
thermal reaction furnished a rearranged hexahydroin-
dolinone (i.e., 7). With this system, the initially formed
cycloadduct 4 cannot aromatize. Instead, ring opening
of the oxabicyclic intermediate occurs to generate zwit-
terion 6, which undergoes a subsequent proton elimina-
tion by tautomerization to give the rearranged ketone 7.19
To further probe the cycloaddition method for target-
oriented synthesis, we required a diverse range of stable
secondary and tertiary amidofurans. No broadly ap-
plicable method exists for the synthesis of this class of
compounds. Consequently, we decided to develop several
methods for the preparation of various 2-amido-substi-
tuted furans with the intention of using these substrates
as reactive dienes for alkaloid synthesis. The present
paper documents the results of these studies.
a benzene/toluene mixture at 90 °C so as to generate
isocyanate 10. After being cooled to 0 °C, the solution
was allowed to react with several Grignard reagents.
Thus, treatment of 10 with phenylmagnesium bromide
afforded furan 12 in 63% yield. In a like manner, the
reaction with allylmagnesium bromide gave 13 but only
in 21% yield. The addition of an ortho-substituted
aromatic Grignard to isocyanate 10 was also studied.
2-Vinylphenylmagnesium bromide was prepared by treat-
ing 2-bromostyrene with magnesium turnings in ether
and was allowed to react with isocyanate 10 at 0 °C. The
only product that could be isolated corresponded to the
desired amidofuran 14, but in a modest 32% yield.
So that a cross-section of additional information could
be obtained regarding the trapping of furanyl isocyanate
10 with other organometallic reagents, we investigated
its reaction with a series of alkyl cuprates. Exposure of
a freshly prepared solution of 10 to methyl cuprate in
ether at 0 °C furnished amide 15 in 60% yield. Similarly,
the reaction of 10 with n-butyl, sec-butyl, and tert-butyl
cuprates gave furanyl amides 16, 17, and 18 in 50%, 44%,
and 45% yield, thereby demonstrating that cuprate
reagents can also be used as nucleophiles in these
trapping reactions. Hex-4-enoic acid furan-2-ylamide (19)
was also prepared but in only 32% yield from isocyanate
10 and the cuprate derived from trans-1-iodo-3-pentene.
Finally, treatment of acyl azide 9 with tert-butyl copper
lithium also proceeded very smoothly to give the isomeric
furanyl amide 20 in 58% isolated yield.
(b) Th e Cop p er -Ca ta lyzed Am id a tion Ap p r oa ch .
Since the above method, which makes use of the reaction
of furano isocyanate 10 with various organometallic
reagents, only proceeded in modest yield, we decided to
investigate an alternate approach toward the desired
2-amido-substituted furan. Disconnection of the C-N
bond in 12-19 between the furan carbon and amide
nitrogen represents an alternate and very appealing
approach to this system. C-N cross-coupling of aryl
halides with amines has been the subject of intense
studies in recent years, primarily by the groups of
Buchwald21 and Hartwig.22 Application of this methodol-
ogy to various heteroaromatic compounds is still a
relatively unexplored process.23 There were only limited
reports on the catalyzed amidation of thiophenes24 and,
Resu lts a n d Discu ssion
(a ) Th e Isocya n a te Ap p r oa ch . Previously, we had
used a Curtius reaction to prepare various furano car-
bamate derivatives via a transient isocyanate intermedi-
ate (Scheme 3). This involved the preparation of furan-
2-carbonyl azide (9) using a procedure described by
Edwards and Singleton in 85% yield.20 Thermolysis of 9
in an alcoholic solvent resulted in Curtius rearrangement
to give isocyanate 10, which reacted further with the
alcoholic solvent to furnish the furanyl carbamate 11 in
high yield. We thought that it might also be possible to
use this method to prepare a series of 2-amidofurans
containing tethered π-bonds. Our investigations began
by heating a sample of furanyl acyl azide 9 (R1 ) H) in
(18) Sternbach, D. D.; Rossana, D. M.; Onan, K. D. J . Org. Chem.
1984, 49, 3427. Klein, L. L. J . Org. Chem. 1985, 50, 1770. J ung, M.
E.; Gervay, J . J . Am. Chem. Soc. 1989, 111, 5469.
(19) Padwa, A.; Brodney, M. A.; Lynch, S. M. J . Org. Chem. 2001,
66, 1716. Padwa, A.; Brodney, M. A.; Dimitroff, M.; Liu, B.; Wu, T. J .
Org. Chem. 2001, 66, 3119.
(20) Edwards, W.; Singleton, H. J . Am. Chem. Soc. 1938, 60, 540.
We have had no dificulty with the handling of azide 9. However,
caution should be applied when working with acyl azides in general.
2610 J . Org. Chem., Vol. 68, No. 7, 2003

Synthesis of 2-Amido Substituted Furans
SCHEME 4
SCHEME 5
coupling reaction also occurred in high yield when the
2-iodo-substituted thiophenes 25 and 26 were used
affording 2-thien-2-ylamides 27 (99%) and 28 (90%). A
similar amidation also took place with thiazole 29
furnishing the related pyrrolidinone 30 (58%). In general,
1-10 mol % of CuI in combination with 10 mol % of N,N′-
dimethylethylenediamine or racemic trans-N,N′-dimeth-
ylcyclohexanediamine worked best. As a base, either
K3PO4 or K2CO3 was used with dioxane as solvent at
90-110 °C for 12-24 h.
Having established an effective catalytic system for the
amidation of 2- and 3-amido-substituted thiophenes, we
next focused on whether the related halogenated furans
would undergo the C-N cross-coupling reaction. The
reactions were conducted under conditions similar to
those used for the thiophene couplings. When 3-bromo-
furan was used as the starting substrate, the cross-
coupling reaction proceeded in high yield (80-98%) with
benzamide, o-toluamide, or 2-pyrrolidinone as the nitro-
gen source, giving 3-furanyl amides 31-33 as the only
isolable products (Scheme 5). Likewise, the coupling of
3-bromofuran and 4-pentenamide furnished the expected
amide 34 in 82% yield. Most importantly, the C-N cross-
coupling reaction with the 2-bromofuran isomer also
provided the desired amides. Thus, the reaction of
2-bromofurans 35-37 with both benzamide and 2-pyr-
rolidinone gave the furanyl-substituted amides 38-41 in
67-99% yield, thereby demonstrating that oxygenated
substituents on the heteroaromatic ring can be readily
tolerated. 4-Pentenamide also underwent the cross-
coupling reaction with 2-bromofuran to give the second-
ary amide 42 in 43% yield. Heating a sample of 42 at
110 °C in toluene for 3 h afforded the known 2-quino-
lone 44 via the initially formed [4+2]-cycloadduct 43
(Scheme 6).
to the best of our knowledge, no examples with furans.25
The first reported case of a Pd-catalyzed amination of a
bromothiophene involved coupling with diarylamines,
using a Pd(OAc)2/P(t-Bu)3 catalyst system.26 These reac-
tions required a strong base (NaOt-Bu) at 120 °C, making
it incompatible with the broader range of functionality
required. More recently, the Buchwald group demon-
strated that the CuI-catalyzed amidation of aryl and
heteroaryl halides provides an excellent complement to
the Pd-catalyzed methodology.21,27 Since the scope of this
method toward heteroaromatics was quite limited, we
became interested in determining whether the amidation
reaction could be used to prepare various 2-amidofurans.
Encouraged by the facility with which thienyl halides
undergo the C-N cross-coupling with various nitrogen
sources, we set out to determine the optimal catalytic
system using several classes of heteroaromatic com-
pounds. After a thorough screening of various catalytic
systems (including several Pd(0) catalysts and bis-phos-
phine ligand combinations), we found that Buchwald’s
CuI catalytic system gave the most consistent and
promising results.27 Thus, heating a mixture of 3-bro-
mothiophenes 21 and 22 and 2-oxazolidone together with
1 mol % of air-stable CuI, 1-mol % of N,N′-dimethyleth-
ylenediamine, and a weak base in dioxane at 110 °C
afforded the expected coupling products 23 and 24 in 99%
and 85% yield, respectively (Scheme 4). The C-N cross-
(21) Wolfe, J . P.; Buchwald, S. L. J . Org. Chem. 2000, 65, 1144.
Wolfe, J . P.; Tomori, H.; Sadighi, J . P.; Yin, J .; Buchwald, S. L. J . Org.
Chem. 2000, 65, 1158. Harris, M. C.; Buchwald, S. L. J . Org. Chem.
2000, 65, 5327. Old, D. W.; Harris, M. C.; Buchwald, S. L. Org. Lett.
2000, 2, 1403. Antilla, J . C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077.
(22) Hartwig, J . F. Angew. Chem., Int. Ed. 1998, 37, 2047. Hamann,
B. C.; Hartwig, J . F. J . Am. Chem. Soc. 1998, 120, 7369. Mann, G.;
Hartwig, J . F.; Driver, M. S.; Fernandez-Rivas, C. J . Am. Chem. Soc.
1998, 120, 827. Hartwig, J . F.; Kawatsura, M.; Hauck, S. I.; Shaugh-
nessy, K. H.; Alcazar-Roman, L. M. J . Org. Chem. 1999, 64, 5575.
Alcazar-Roman, L. M.; Hartwig, J . F.; Rheingold, A. L.; Liable-Sands,
L. M.; Guzei, I. A. J . Am. Chem. Soc. 2000, 122, 4618. Lee, S.;
J orgensen, M.; Hartwig, J . F. Org. Lett. 2001, 3, 2729.
(23) Yu, S.; Saenz, J .; Srirangam, J . K. J . Org. Chem. 2002, 67, 1699.
Rivas, F. M.; Giessert, A. J .; Diver, S. T. J . Org. Chem. 2002, 67, 1708.
(24) Klapars, A.; Antilla, J . C.; Huang, X.; Buchwald, S. L. J . Am.
Chem. Soc. 2001, 123, 7727. Luker, T. J .; Beaton, H. G.; Whiting, M.;
Mete, A.; Cheshire, D. R. Tetrahedron Lett. 2000, 41, 7731. Kang, S.
K.; Kim, D. H.; Park, J . H. Synlett 2002, 427.
The above results clearly demonstrate that 2- and
3-amido-substituted thiophenes and furans can be pre-
pared from the C-N cross-coupling reaction of various
bromo heteroaromatics with amides and lactams. The
route is flexible and allows for the preparation of highly
substituted amido heteroaromatic substrates.
(c) Th e Cyclic Ca r bin ol Am id e-Tr iflic An h yd r id e
Ap p r oa ch . For the past decade our research group has
had a continuing interest in the cyclization chemistry of
N-acyliminium ions derived from R-alkoxy amides.28 The
R-amidoalkylation/cyclization sequence of N-acyliminium
ions represents a powerful method for the synthesis of
nitrogenated heterocyclic compounds.29,30 During the
course of our studies in this general area, we had been
investigating the acid-induced cyclization chemistry of
5-hydroxy-5-methyl pyrrolidinones such as 46. This
(25) For a preliminary report, see: Crawford, K. R.; Padwa, A.
Tetrahedron Lett. 2002, 43, 7365.
(26) Watanabe, M.; Yamamoto, T.; Nishiyama, M. J . Chem. Soc.,
Chem. Commun. 2000, 133.
(27) Klapars, A.; Huang, X.; Buchwald, S. L. J . Am. Chem. Soc. 2002,
124, 7421.
(28) Padwa, A.; Bur, S. K.; Danca, D. M.; Ginn, J . D.; Lynch, S. M.
Synlett 2002, 851.
J . Org. Chem, Vol. 68, No. 7, 2003 2611

Padwa et al.
SCHEME 6
SCHEME 8
SCHEME 7
10% HCl in THF, isoquinolinone 48 was formed as the
major product in 70% yield. Using these conditions, the
initially formed N-acyliminium ion derived from 46
undergoes a well-established electrophilic aromatic sub-
stitution reaction with the tethered benzenoid ring. Since
it is known that the judicious choice of a Lewis acid can
often influence the outcome of the cyclization reaction,32
we opted to study the conversion of 46 to 48 in greater
detail using a variety of Lewis acids. Most interestingly,
when a sample of 46 (or 47) was allowed to stir with 2
equiv of triflic anhydride and pyridine in CH2Cl2, R-tri-
fluoromethylsulfonamido furan 49 was formed in 90%
yield. A related product was obtained with the corre-
sponding N-benzyl hydroxy lactam 50, which afforded
sulfonamido furan 51 in 60% yield. We also investigated
the cyclization of 50 using p-tosyl anhydride as the
electrophile (Scheme 8). In this case, the related p-
toluenesulfonamido furan 51 was formed but only in 23%
isolated yield. Another product that was also obtained
(9%) corresponded to enamide 52, which is the simple
dehydration product of 50. No other characterizable
products could be obtained from the crude reaction
mixture.
This unanticipated furan cyclization led us to study
the reaction in more detail since we were very interested
in using this method for the synthesis of various N-
alkenyl-substituted 2-amido furans. With this in mind,
we next subjected the related cyclic ketoamide 53 to the
triflic anhydride/pyridine conditions and were pleased to
note that R-trifluoromethylsulfonamido furan 54 was
isolated in 93% yield. Interestingly, cyclization to the
furanyl amide system also occurred when trifluoro-acetic
anhydride was used as the acylating agent. In this case,
the trifluoroacetyl-substituted amidofuran 55 was ob-
tained in 77% yield. As was anticipated from our earlier
studies,33 sulfonamido furan 54 was found to undergo a
compound was readily prepared from the reaction of
R-angelica lactone (45) with 3,4-dimethoxyphenethyl-
amine under aqueous conditions (Scheme 7).31 We noted
that when the reaction was carried out under anhydrous
conditions (i.e., THF as solvent), the isomeric γ-keto
amide 47 was obtained as the exclusive product in 75%
yield. Subjecting a sample of 47 to the aqueous acidic
conditions resulted in the formation of the same cyclic
carbinol amide (i.e., 46) as that obtained from R-angelica
lactone. On the other hand, when 47 was treated with
(29) For reviews see: Speckamp, W. N. Recl. Trav. Chim. Pays-Bas
1981, 100, 345. Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41,
4367. Hiemstra, H.; Speckamp, W. N. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
UK, 1991; Vol. 2, pp 1047-1082.
(30) Hart, D. J . In Alkaloids: Chemical and Biological Perspectives;
Pelletier, S. W., Ed.; Wiley: New York, 1988; Vol. 6, p 227.
(31) For some related work, see: Rashatasakhon, P.; Padwa, A. Org.
Lett. 2003, 5, 189.
(32) Aoyagi, Y.; Williams, R. M. Tetrahedron 1998, 54, 10419. Keum,
G.; Kim, G. Bull. Kor. Chem. Soc. 1994, 15, 278. Martin, S. F.; Bur, S.
K. Tetrahedron Lett. 1997, 38, 7641.
2612 J . Org. Chem., Vol. 68, No. 7, 2003

Synthesis of 2-Amido Substituted Furans
SCHEME 9
Buchwald gave the most consistent and promising re-
sults. Finally, the third protocol examined consists of
treating cyclic carbinol amides with triflic anhydride. The
reaction proceeds under very mild conditions to provide
R-trifluoromethylsulfonamido-substituted furans in high
yield. In one case, the resulting sulfonamidofuran un-
derwent a bimolecular Diels-Alder cycloaddition with
maleic anhydride to furnish an aromatic sulfonamide
derivative. We are further evaluating the [4+2]-cycload-
dition of these novel furans for alkaloid synthesis and
additional results in this area will be reported in due
course.
Exp er im en ta l Section
Melting points are uncorrected. Mass spectra were deter-
mined at an ionizing voltage of 70 eV. Unless otherwise noted,
all reactions were performed in flame-dried glassware under
an atmosphere of dry argon. Solutions were evaporated under
reduced pressure with a rotary evaporator and the residue was
chromatographed on a silica gel column with an ethyl acetate/
hexane mixture as the eluent unless specified otherwise. All
solids were recrystallized from ethyl acetate/hexane for ana-
lytical data.
smooth intermolecular Diels-Alder reaction when heated
with maleic anhydride at 120 °C to give the substituted
dihydronaphthylamine 56 as the major product. The
initial [4+2]-cycloadduct was not isolated, as it rapidly
underwent ready ring opening of the oxabicyclic ring
followed by dehydration and then partial oxidation under
the themal conditions employed.
F u r a n -2-ca r bon yl Azid e (9). To a solution containing 67.8
g (0.6 mol) of 2-furoic acid in 500 mL of benzene was added 66
mL (0.9 mol) of thionyl chloride. The mixture was heated at
reflux for 18 h. After concentration under reduced pressure,
the residue was distilled under water aspirator to give 67.5 g
(86%) of furan-2-carbonyl chloride [bp 79-80 °C (35 mm)]37
as a colorless liquid: 1H NMR (CDCl3, 400 MHz) δ 6.65 (dd,
1H, J ) 3.8 and 1.6 Hz), 7.50 (dd, 1H, J ) 3.8 and 0.8 Hz),
and 7.76 (dd, 1H, J ) 1.6 and 0.8 Hz). To a solution of 66.6 g
(0.5 mol) of the above acid chloride in 200 mL of ether at 0 °C
was added dropwise a solution containing 33 g (0.5 mol) of
sodium azide in 150 mL of water. The mixture was stirred at
0 °C for 15 min, then warmed to room temperature and stirred
for another 2 h. After removal of the ether under reduced
pressure, the resulting suspension was filtered and washed
with cold water. The resulting white solid that formed was
dried under vacuum to give 68.3 g (98%) of furan-2-carbonyl
azide (9):20 IR (neat) 3134, 2145, 1690, and 1292 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 6.56 (dd, 1H, J ) 3.6 and 2.4 Hz), 7.27 (d,
1H, J ) 2.4 Hz), and 7.66 (d, 1H, J ) 3.6 Hz); 13C NMR (CDCl3,
75 MHz) δ 112.6, 120.1, 145.6, 148.2, and 162.5. Anal. Calcd
for C5H3N3O2: C, 43.80; H, 2.21; N, 30.65. Found: C, 43.62;
H, 2.18; N, 30.76.
N-F u r a n -2-ylben za m id e (12). A solution of 0.35 g (2.6
mmol) of azide 9 in 30 mL of a 2:1 benzene-toluene mixture
was heated at reflux for 2 h. The solution was cooled to 0 °C
and 0.9 mL (2.6 mmol) of a 3.0 M phenylmagnesium bromide
solution was added dropwise. After the addition was complete,
the mixture was stirred at room temperature for 1 h, quenched
with a saturated NH4Cl solution, extracted with ether, and
dried over Na2SO4. Removal of the solvent under reduced
pressure followed by flash silica gel chromatography gave 0.3
g (63%) of N-furan-2-ylbenzamide (12) as a pale yellow solid:
37 mp 121-122 °C; 1H NMR (CDCl3, 400 MHz) δ 6.35 (m, 1H),
6.42 (d, 1H, J ) 2.8 Hz), 7.02 (m, 1H), 7.37 (t, 2H, J ) 6.8
Hz), 7.45 (m, 1H), 7.82 (m, 1H), and 8.90 (br s, 1H); 13C NMR
(CDCl3, 100 MHz) δ 95.7, 111.4, 127.2, 128.5, 132.0, 133.1,
135.5, 145.4, and 164.0. Anal. Calcd for C11H9NO2: C, 70.58;
H, 4.85; N, 7.48. Found: C, 70.56; H, 4.91; N, 7.51.
Recently, Charette and co-workers have demonstrated
that secondary and tertiary amides can be activated with
triflic anhydride to generate the corresponding iminium
salts which can react further with various nucleophiles.34
Iminium triflates were originally used by Ghosez as
precursors of ketiminium ions which can function as
electrophilic substrates in [2+2]-cycloadditions.35 It would
seem that when a hydroxy pyrrolidinone such as 46 is
used as the tertiary amide, the resulting iminium ion (i.e.,
57) derived from the reaction of 46 with triflic anhydride
undergoes a facile ring opening as a consequence of the
adjacent hydroxyl group to produce imino triflate 58
(Scheme 9). Subsequent cyclization of this highly elec-
trophilic imine36 with the oxygen atom of the adjacent
carbonyl group results in the formation of imino dihy-
drofuran 59. This transient species reacts further with
another equivalent of triflic anhydride to give the ob-
served furan 49.
In conclusion, three different procedures have been
developed for the synthesis of various 2-amido-substi-
tuted furans. One method involves the thermolysis of
furan-2-carbonyl azide, which results in a Curtius rear-
rangement to produce a furanyl isocyanate intermediate.
Trapping of this transient species with several different
organometallic reagents delivers the desired 2-amidofu-
ran in good to moderate yield. A second method consists
of a C-N cross-coupling reaction of a bromosubstituted
furan with various amides, carbamates, and lactams.
After a thorough screening of various catalytic systems,
we found that the CuI conditions recently described by
(33) Padwa, A.; Dimitroff, M.; Waterson, A. G.; Wu, T. J . Org. Chem.
1997, 62, 4088.
(34) Charette, A. B.; Chua, P. Tetrahedron Lett. 1997, 38, 1997.
Charette, A. B.; Chua, P. Tetrahedron Lett. 1997, 38, 8499. Charette,
A. B.; Chua, P. Tetrahedron Lett. 1998, 39, 245. Charette, A. B.; Chua,
P. J . Org. Chem. 1998, 63, 908. Charette, A. B.; Chua, P. Synlett 1998,
163. Charette, A. B.; Grenon, M. Tetrahedron Lett. 2000, 41, 1677.
(35) Falmagne, J . B.; Escudero, J .; Taleb-Saharaoui, S.; Ghosez, L.
Angew. Chem., Int. Ed. Engl. 1981, 20, 879. Barbaro, G.; Battaglia,
A.; Bruno, C.; Giorgianni, P.; Guerrini, A. J . Org. Chem. 1996, 61, 8480.
(36) Sisti, N. J .; Fowler, F. W.; Grierson, D. S. Synlett 1991, 816.
Sisti, N. J .; Zeller, E.; Grierson, D. S.; Fowler, F. W. J . Org. Chem.
1997, 62, 2093. Thomas, E. W. Synthesis 1993, 767.
Bu t-3-en oic Acid F u r a n -2-yla m id e (13). A solution of 1.0
g (7.6 mmol) of azide 9 in 60 mL of a 2:1 benzene-toluene
mixture was heated at reflux for 2 h. After the mixture was
cooled to 0 °C, 7 mL (7.6 mmol) of a 1.1 M allylmagnesium
bromide solution was added dropwise. After the addition was
(37) Devitt, P.; Timothy, A.; Vickars, M. J . Org. Chem. 1961, 26,
4941.
J . Org. Chem, Vol. 68, No. 7, 2003 2613

Padwa et al.
complete, the mixture was stirred at room temperature for 1
h, quenched with a saturated NH4Cl solution, extracted with
ether, and dried over Na2SO4. Removal of the solvent under
reduced pressure followed by flash silica gel chromatography
gave 0.24 g (21%) of but-3-enoic acid furan-2-yl amide (13) as
a pale yellow solid: mp 67-70 °C; IR (KBr) 3196, 3040, 1658,
and 1582 cm-1; 1H NMR (CDCl3, 400 MHz) δ 3.18 (d, 2H, J )
7.2 Hz), 5.32-5.37 (m, 2H), 5.97-6.04 (m, 1H), 6.32 (d, 1H, J
) 3.2 Hz), 6.37 (dd, 1H, J ) 3.2 and 2.0 Hz), 7.05 (dd, 1H, J
) 2.0 and 1.0 Hz), and 7.60 (br s, 1H); 13C NMR (CDCl3, 100
MHz) δ 41.5, 95.5, 111.4, 120.7, 130.4, 135.4, 145.0, and 167.2.
Anal. Calcd for C8H9NO2: C, 63.57; H, 6.00; N, 9.27. Found:
C, 63.47; H, 6.05; N, 9.21.
N-F u r a n -2-yl-2-vin ylben za m id e (14). To a suspension of
0.15 g (6.2 mmol) of magnesium turnings in 10 mL of ether at
room temperature were added dropwise 0.5 mL (4.0 mmol) of
2-bromostyrene and one drop of 1,2-diiodoethane. The mixture
was heated at reflux for 30 min and then stirred at room
temperature for 18 h. The suspension was filtered through a
pad of glass wool and the resulting 2-vinylphenylmagnesium
bromide was used directly in the next step. A solution of 0.5 g
(4.0 mmol) of azide 9 in 40 mL of a 2:1 benzene-toluene
mixture was heated at reflux for 2 h. The resulting dark
solution was cooled to 0 °C and cannulated into the above
Grignard reagent solution at 0 °C. The mixture was warmed
to room temperature, stirred for 1 h, diluted with ether,
quenched with an aqueous NH4Cl solution, extracted with
ether, and dried over Na2SO4. Removal of the solvent under
reduced pressure followed by flash silica gel chromatography
gave 0.27 g (32%) of N-furan-2-yl-2-vinylbenzamide (14) as a
pale yellow solid: mp 92-93 °C; IR (KBr) 3241, 1656, and 1551
cm-1; 1H NMR (CDCl3, 400 MHz) δ 5.40 (d, 1H, J ) 11.2 Hz),
5.73 (dd, 1H, J ) 9.4 and 1.0 Hz), 6.41 (t, 1H, J ) 2.4 Hz),
6.46 (d, 1H, J ) 3.2 Hz), 7.05-7.12 (m, 2H), 7.30 (t, 1H, J )
7.6 Hz), 7.43 (t, 1H, J ) 7.4 Hz), 7.52-7.58 (m, 2H), and 8.16
(br s, 1H); 13C NMR (CDCl3, 100 MHz) δ 95.3, 111.5, 117.6,
126.7, 127.6, 127.8, 130.9, 133.5, 134.3, 135.4, 136.4, 145.2,
and 164.9. Anal. Calcd for C13H11NO2: C, 73.22; H, 5.20; N,
6.57. Found: C, 73.48; H, 5.25; N, 6.52.
organic layer was dried over Na2SO4 and the solvent was
evaporated under reduced pressure. The residue was subjected
to flash silica gel chromatography to give 0.2 g (50%) of
pentanoic acid furan-2-ylamide (16) as a pale yellow solid: mp
87-89 °C; IR (KBr) 3253, 1666, and 1554 cm-1 1H NMR
;
(CDCl3, 400 MHz) δ 0.92 (t, 3H, J ) 7.4 Hz), 1.38 (m, 2H),
1.69 (m, 2H), 2.37 (t, 2H, J ) 7.6 Hz), 6.29 (d, 1H, J ) 3.2
Hz), 6.35 (m, 1H), 7.02 (s, 1H), and 8.34 (br s, 1H); 13C NMR
(CDCl3, 100 MHz) δ 13.7, 22.3, 27.5, 36.3, 95.2, 111.3, 135.1,
145.3, and 170.1; HRMS calcd for C9H13NO2 167.0946, found
167.0943.
N-F u r a n -2-yl-2-m eth ylbu tyr a m id e (17). To a suspension
of 0.25 g (2.8 mmol) of CuCN in 7 mL of THF at -78 °C was
added dropwise 4.3 mL (5.6 mmol) of a 1.3 M sec-BuLi solution
and the mixture was stirred at -78 °C for 1 h. A solution of
0.4 g (2.8 mmol) of azide 9 in a mixture of 20 mL of benzene
and 10 mL of toluene was heated at reflux for 2 h. The
resulting dark solution was cooled to -5 °C and cannulated
into the above cuprate solution. The mixture was warmed to
room temperature, stirred for 1 h, diluted with ether, quenched
with an aqueous NH4Cl solution, and extracted with ether.
The organic layer was dried over Na2SO4 and the solvent was
evaporated under reduced pressure. The residue was subjected
to flash silica gel chromatography to give 0.2 g (44%) of
N-furan-2-yl-2-methylbutyramide (17) as a white solid: mp
85-86 °C; IR (KBr) 3260, 1671, 1651, and 1555 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 0.96 (t, 3H, J ) 7.4 Hz), 1.23 (d, 3H, J )
7.2 Hz), 1.47-1.58 (m, 1H), 1.72-1.82 (m, 1H), 2.23-2.32 (m,
1H), 6.33-6.34 (m, 1H), 6.38 (t, 1H, J ) 2.6 Hz), 7.04 (t, 1H,
J ) 1.0 Hz), and 7.49 (br s, 1H); 13C NMR (CDCl3, 100 MHz)
δ 11.8, 17.3, 27.3, 43.2, 95.0, 111.5, 135.1, 145.2, and 172.8;
HRMS calcd for C9H13NO2 167.0946, found 167.0943.
N-F u r a n -2-yl-2,2-d im eth ylp r op ion a m id e (18). To a sus-
pension of 0.25 g (2.8 mmol) of CuCN in 7 mL of THF at -78
°C was added dropwise 3.7 mL (5.6 mmol) of a 1.5 M t-BuLi
solution and the mixture was stirred at -78 °C for 1 h. A
solution of 0.4 g (2.8 mmol) of azide 9 in a mixture of 20 mL
of benzene and 10 mL of toluene was heated at reflux for 2 h.
The resulting dark solution was cooled to -5 °C and cannu-
lated into the above cuprate solution. The mixture was warmed
to room temperature, stirred for 1 h, diluted with ether,
quenched with an aqueous NH4Cl solution, and extracted with
ether. The organic layer was dried over Na2SO4 and the solvent
was removed under reduced pressure. The residue was sub-
jected to flash silica gel chromatography to give 0.21 g (45%)
of N-furan-2-yl-2,2-dimethylpropionamide (18) as a white
N-F u r a n -2-yla ceta m id e (15). To a suspension of 0.25 g
(2.8 mmol) of CuCN in 10 mL of THF at -78 °C was added
dropwise 4.0 mL (5.5 mmol) of a 1.4 M methyllithium solution
and the mixture was stirred at -78 °C for 40 min. A solution
of 0.4 g (2.8 mmol) of azide 9 in a mixture of 20 mL of benzene
and 10 mL of toluene was heated at reflux for 2 h. The
resulting dark solution was cooled to 0 °C and cannulated into
the above cuprate solution. The mixture was warmed to room
temperature, stirred for 1 h, diluted with ether, quenched with
an aqueous NH4Cl solution, and extracted with ether. The
organic layer was dried over Na2SO4 and the solvent was
evaporated under reduced pressure. The residue was subjected
to flash silica gel chromatography to give 0.2 g (60%) of
N-furan-2-ylacetamide (15) as a white solid:38 mp 92-94 °C;
solid: mp 101-102 °C; IR (KBr) 3274, 1663, and 1529 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 1.30 (s, 9H), 6.32-6.34 (m, 1H),
6.37-6.38 (m, 1H), 7.04-7.05 (m, 1H), and 7.70 (br s, 1H);
13C NMR (CDCl3, 100 MHz) δ 27.5, 39.2, 94.7, 111.6, 135.0,
145.5, and 174.5. Anal. Calcd for C9H13NO2: C, 64.65; H, 7.84;
N, 8.38. Found: C, 64.47; H, 7.78; N, 8.27.
Hex-4-en oic Acid F u r a n -2-yla m id e (19). To a solution
containing 1.2 g (6.1 mmol) of trans-1-iodo-3-pentene in 10 mL
of ether at -78 °C was added dropwise 8.1 mL (12 mmol) of a
1.5 M t-BuLi solution. The mixture was stirred at -78 °C for
30 min, warmed to room temperature, and cannulated through
a pad of glass wool into a suspension containing 0.25 g (2.8
mmol) of CuCN in 6 mL of THF at -78 °C. The mixture was
stirred at -78 °C for 1 h. A solution of 0.4 g (2.8 mmol) of
azide 9 in a mixture of 20 mL of benzene and 10 mL of toluene
was heated at reflux for 2 h. The resulting dark solution was
cooled to 0 °C and cannulated into the above cuprate solution.
After being stirred at room temperature for 1 h, the mixture
was diluted with ether, quenched with an aqueous NH4Cl
solution, and extracted with ether. The organic layer was dried
over Na2SO4 and the solvent was evaporated under reduced
pressure. The residue was subjected to flash silica gel chro-
matography to give 0.17 g (32%) of hex-4-enoic acid furan-2-
ylamide (19) as a white solid: mp 65-66 °C; IR (KBr) 3203,
3063, 1667, and 1560 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.66
(d, 3H, J ) 6.0 Hz), 2.41 (br s, 4H), 5.44-5.55 (m, 2H), 6.31
IR (KBr) 3196, 3033, and 1660 cm-1 1H NMR (CDCl3, 400
;
MHz) δ 2.17 (s, 3H), 6.29-6.36 (m, 2H), 7.05 (t, 1H, J )
2.0 Hz), and 7.90 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ
23.3, 103.6, 111.4, 135.4, 145.2, and 167.0. Anal. Calcd for
C6H7NO2: C, 57.59; H, 5.64; N, 11.19. Found: C, 57.60; H,
5.61; N, 11.29.
P en ta n oic Acid F u r a n -2-yla m id e (16). To a suspension
of 0.25 g (2.8 mmol) of CuCN in 6 mL of THF at -78 °C was
added dropwise 2.2 mL (5.5 mmol) of a 2.5 M n-BuLi solution
and the mixture was stirred at -78 °C for 1 h. A solution of
0.4 g (2.8 mmol) of azide 9 in a mixture of 16 mL of benzene
and 8 mL of toluene was heated at reflux for 2 h. The resulting
dark solution was cooled to -5 °C and cannulated into the
above cuprate solution. The mixture was warmed to room
temperature, stirred for 1 h, diluted with ether, quenched with
an aqueous NH4Cl solution, and extracted with ether. The
(38) Ramsden, C. A.; Rose, H. L. J . Chem. Soc., Perkin Trans. 1 1997,
16, 2319.
2614 J . Org. Chem., Vol. 68, No. 7, 2003

Synthesis of 2-Amido Substituted Furans
(d, 1H, J ) 3.2 Hz), 6.34 (m, 1H), 7.04 (d, 1H, J ) 0.8 Hz),
and 7.61 (br s, 1H); 13C NMR (CDCl3, 100 MHz) δ 17.9, 28.2,
36.5, 95.2, 111.5, 127.0, 129.0, 135.2, 145.0, and 168.8. Anal.
Calcd for C10H13NO2: C, 67.02; H, 7.31; N, 7.82. Found: C,
67.30; H, 7.32; N, 7.68.
1409, 1301, and 1235 cm-1; 1H NMR (CDCl3, 400 MHz) δ 2.08-
2.24 (m, 2H), 2.38 (s, 3H), 2.49-2.60 (m, 2H), 3.71-3.84 (m,
2H), 6.20-6.30 (m, 1H), and 6.42-6.52 (m, 1H); 13C NMR
(CDCl3, 100 MHz) δ 14.7, 17.5, 31.0, 48.3, 110.1, 121.2, 131.6,
137.8, and 171.5. Anal. Calcd for C9H11NOS: C, 59.64; H, 6.12;
N, 7.73. Found: C, 59.60; H, 6.13; N, 7.72.
F u r a n -2-ca r boxylic Acid ter t-Bu tyla m id e (20). To a
suspension of 0.25 g (2.8 mmol) of CuCN in 7 mL of THF at
-78 °C was added dropwise 3.7 mL (5.6 mmol) of a 1.5 M
t-BuLi solution and the mixture was stirred at -78 °C for 1 h.
To the above solution was added dropwise a solution contain-
ing 0.38 g (2.8 mmol) of azide 9 in 15 mL of THF. The mixture
was warmed to room temperature, diluted with ether, quenched
with aqueous NH4Cl solution, and extracted with ether. The
organic layer was dried over Na2SO4 and the solvent was
evaporated under reduced pressure. The residue was subjected
to flash silica gel chromatography to give 0.26 g (58%) of furan-
2-carboxylic acid tert-butylamide (20) as a white solid:39 mp
N-Th ia zol-2-ylp yr r olid in on e (30). Using the general
procedure for Cu(I)-catalyzed C-N cross-couplings described
above, 2-bromothiazole (29) and 2-pyrrolidinone afforded 0.1
g (58%) of 30 as beige crystals: mp 83-84 °C; IR (film) 3129,
3078, 1696, 1506, 1460, 1383, and 1173 cm-1; 1H NMR (CDCl3,
400 MHz) δ 2.10-2.30 (m, 2H), 2.65 (t, 2H, J ) 8.0 Hz), 4.12
(t, 2H, J ) 7.2 Hz), 6.97 (d, 1H, J ) 3.8 Hz), and 7.43 (d, 1H,
J ) 3.8 Hz); 13C NMR (CDCl3, 100 MHz) δ 18.0, 31.6, 47.8,
113.4, 137.4, 157.7, and 173.3. Anal. Calcd for C7H8N2OS: C,
49.98; H, 4.79; N, 16.65. Found: C, 50.08; H, 4.97; N, 16.66.
N-F u r a n -3-ylben za m id e (31). Using the general proce-
dure for Cu(I)-catalyzed C-N cross-couplings described above,
3-bromofuran and benzamide afforded 0.17 g of 31 (98%): mp
147-148 °C (lit.41 mp 141-142 °C); IR (film) 3278, 3109, 1650,
1568, and 1158 cm-1; 1H NMR (CDCl3, 400 MHz) δ 6.42-6.48
(m, 1H), 7.30-7.35 (m, 1H), 7.37-7.45 (m, 2H), 7.46-7.54
(m, 1H), 7.79-7.86 (m, 2H), 8.14-8.20 (m, 1H), and 8.23
(br s, 1H); 13C NMR (CDCl3, 100 MHz) δ 104.8, 124.3, 127.0,
128.7, 131.8, 132.8, 133.7, 141.5, and 165.1. Anal. Calcd for
C11H9NO2: C, 70.58; H, 4.85; N, 7.48. Found: C, 70.38; H, 4.84;
N, 7.44.
N-F u r a n -3-yl-o-tolyla m id e (32). Using the general pro-
cedure for Cu(I)-catalyzed C-N cross-couplings described
above, 3-bromofuran and o-tolylamide gave 0.17 g (86%) of 32:
mp 139-140 °C; IR (film) 1644, 1562, and 1163 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 2.41 (s, 3H), 6.34 (d, 1H, J ) 1.2 Hz),
7.10-7.25 (m, 3H), 7.26-7.40 (m, 2H), 7.88 (br s, 1H), and
8.08 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 19.7, 104.6, 124.2,
125.7, 126.7, 130.2, 131.1, 132.6, 135.3, 136.5, 141.4, and 167.4.
Anal. Calcd for C12H11NO2: C, 71.63; H, 5.51; N, 6.96. Found:
C, 71.62; H, 5.54; N, 6.94.
97-98 °C; IR (KBr) 3317, 1644, and 1537 cm-1 1H NMR
;
(CDCl3, 400 MHz) δ 1.46 (s, 9H), 6.20 (br s, 1H), 6.47 (dd, 1H,
J ) 3.4 and 1.8 Hz), 7.05 (dd, 1H, J ) 3.4 and 1.0 Hz), and
7.39 (dd, 1H, J ) 1.8 and 1.0 Hz); 13C NMR (CDCl3, 100 MHz)
δ 28.9, 51.4, 112.0, 113.4, 143.2, 148.7, and 157.7. Anal. Calcd
for C9H13NO2: C, 64.65; H, 7.84; N, 8.38. Found: C, 64.56; H,
7.90; N, 8.38.
Gen er a l P r oced u r e for Cu (I)-Ca t a lyzed C-N Cr oss-
Cou p lin gs. To a sample of CuI (0.1 mmol, 10 mol %) and
K2CO3 (4.3 mmol) or K3PO4 (2.1 mmol) under argon was added
1,4-dioxane (3 mL) followed by N,N′-dimethylethylenediamine
or (()-trans-N,N′-dimethylcyclohexanediamine40 (0.1 mmol, 10
mol %), the heteroaromatic halide (1.0 mmol), and the ap-
propriate amide (1.2 mmol). The reaction mixture was heated
at 110 °C for 24 h, cooled to 25 °C, diluted with CH2Cl2 (5 mL),
filtered through a short plug of silica gel, and concentrated
under reduced pressure. The crude residue was purified by
flash chromatography to give the desired product.
N-Th ien -3-yloxa zolid on e (23). Using the general proce-
dure for Cu(I)-catalyzed C-N cross-couplings described above,
3-bromothiophene (21) and 2-oxazolidone gave 0.17 g (99%)
of N-thien-3-yloxazolidone (23): mp 91-92 °C; IR (film) 1731,
1115, and 1041 cm-1; 1H NMR (CDCl3, 400 MHz) δ 3.98-4.05
(m, 2H), 4.42-4.51 (m, 2H), 6.98 (dd, 1H, J ) 3.2 and 1.6 Hz),
7.30 (dd, 1H, J ) 5.3 and 3.2 Hz), and 7.41 (dd, 1H, J ) 5.3
and 1.6 Hz); 13C NMR (CDCl3, 100 MHz) δ 45.5, 61.6, 107.2,
119.6, 125.5, 136.7, and 154.9. Anal. Calcd for C7H7NO2S: C,
49.69; H, 4.17; N, 8.28. Found: C, 49.48; H, 4.16; N, 8.23.
N-5-F or m ylth ien -3-yloxa zolid on e (24). Using the gen-
eral procedure for Cu(I)-catalyzed C-N cross-couplings de-
scribed above, 4-bromothiophene-2-carboxaldehyde (22) and
2-oxazolidone afforded 0.17 g (85%) of 24 as a white solid: mp
171-172 °C; IR (film) 1734, 1661, 1552, 1455, 1401, 1262, and
N-F u r a n -3-ylp yr r olid in on e (33). Using the general pro-
cedure for Cu(I)-catalyzed C-N cross-couplings described
above, 3-bromofuran and 2-pyrrolidinone gave 0.12 g (80%) of
33: mp 74-75 °C; IR (film) 1681, 1593, 1425, 1316, and
1
1173 cm-1; H NMR (CDCl3, 300 MHz) δ 2.08-2.24 (m, 2H),
2.44-2.56 (m, 2H), 3.61-3.73 (m, 2H), 6.63-6.70 (m, 1H),
7.28-7.35 (m, 1H), and 7.77-7.85 (m, 1H); 13C NMR (CDCl3,
75 MHz) δ 18.2, 31.3, 47.7, 103.9, 126.5, 130.9, 141.8, and
173.0. Anal. Calcd for C8H9NO2: C, 63.56; H, 6.00; N, 9.27.
Found: C, 63.65; H, 6.05; N, 9.30.
P en t-4-en oic Acid F u r a n -3-yla m id e (34). Using the
general procedure for Cu(I)-catalyzed C-N cross-couplings
described above, 3-bromofuran and 4-pentenamide42 afforded
0.14 g (82%) of pent-4-enoic acid furan-3-ylamide (34): mp
1
1111 cm-1; H NMR (CDCl3, 400 MHz) δ 3.98-4.10 (m, 2H),
75-76 °C; IR (film) 1656, 1568, and 1168 cm-1 1H NMR
;
4.42-4.54 (m, 2H), 7.64-7.78 (m, 1H), 8.28 (d, 1H, J ) 2.0
Hz), and 9.92 (d, 1H, J ) 1.2 Hz); 13C NMR (CDCl3, 100 MHz)
δ 45.1, 62.2, 116.9, 128.6, 138.0, 142.2, 154.7, and 184.4. Anal.
Calcd for C8H7NO3S: C, 48.72; H, 3.58; N, 7.10. Found: C,
48.87; H, 3.71; N, 6.88.
(CDCl3, 400 MHz) δ 2.37-2.52 (m, 4H), 4.99-5.15 (m, 2H),
5.79-5.92 (m, 1H), 6.29 (dd, 1H, J ) 1.9 and 0.6 Hz), 7.29 (t,
1H, J ) 1.9 Hz), and 8.00-8.20 (m, 1H); 13C NMR (CDCl3, 75
MHz) δ 29.4, 35.6, 104.6, 115.8, 124.1, 132.5, 136.6, 141.3, and
170.3; Anal. Calcd for C9H11NO2: C, 65.44; H, 6.71; N, 8.48.
Found: C, 65.17; H, 6.70; N, 8.50.
N-Th ien -2-ylp yr r olid in on e (27). Using the general pro-
cedure for Cu(I)-catalyzed C-N cross-couplings described
above, 2-bromothiophene (25) and 2-pyrrolidinone gave 0.17
g (99%) of N-thien-2-ylpyrrolidinone (27) as a white solid: mp
116-117 °C (lit.24 mp 116-117 °C); 1H NMR (CDCl3, 400 MHz)
δ 2.07-2.29 (m, 2H), 2.57 (t, 2H, J ) 8.1 Hz), 3.82 (t, 2H, J )
7.2 Hz), 6.48 (dd, 1H, J ) 3.6 and 1.2 Hz), and 6.75-6.95 (m,
2H).
N-5-Meth ylth ien -2-ylp yr r olid in on e (28). Using the gen-
eral procedure for Cu(I)-catalyzed C-N cross-couplings de-
scribed above, 2-iodo-5-methylthiophene (26) and 2-pyrroli-
dinone gave 0.16 g (90%) of N-5-methylthien-2-ylpyrrolidinone
(28) as a white solid: mp 136-137 °C; IR (film) 1675, 1506,
N-5-F or m ylfu r a n -2-ylben za m id e (38). Using the general
procedure for Cu(I)-catalyzed C-N cross-couplings described
above, 5-bromofuran-2-carboxaldehyde and benzamide af-
forded 0.17 g (98%) of 38: mp 137-138 °C; IR (film) 1701,
1670, 1552, 1265, and 1035 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 6.84 (d, 1H, J ) 3.9 Hz), 7.33 (d, 1H, J ) 3.9 Hz), 7.47-7.56
(m, 2H), 7.61 (ddt, 1H, J ) 7.2 and 1.2 Hz), 7.88-7.95 (m,
2H), 9.12 (br s, 1H), and 9.43 (s, 1H); 13C NMR (CDCl3, 100
(41) Bridson, J . N.; Bennett, S. M.; Butler, G. J . Chem. Soc., Chem.
Commun. 1980, 9, 413.
(42) 4-Pentenamide was prepared according to the method of Favino
and co-workers and was carried forward without purification: Favino,
T. F.; Fronza, G.; Fuganti, C.; Fuganti, D.; Grasselli, P.; Mele, A. J .
Org. Chem. 1996, 61, 8975.
(39) Carpenter, A. J .; Chadwick, D. J . J . Org. Chem. 1985, 50, 4362.
(40) Bennani, Y. L.; Hanessian, S. Tetrahedron 1996, 52, 13837.
J . Org. Chem, Vol. 68, No. 7, 2003 2615

Padwa et al.
MHz) δ 97.6, 127.3, 129.0, 132.2, 133.0 (2), 145.3, 152.2, 163.6,
and 175.6. Anal. Calcd for C12H9NO3: C, 66.97; H, 4.22; N,
6.51. Found: C, 66.47; H, 4.29; N, 6.43.
3H), 3.87 (s, 3H), 5.85 (br s, 1H), and 6.69-6.78 (m, 3H). The
spectral data of this compound are identical with those
reported in the literature.44
N-5-Ca r bom eth oxyfu r a n -2-ylben za m id e (39). Using the
general procedure for Cu(I)-catalyzed C-N cross-couplings
described above, 5-bromo-2-furoic acid methyl ester and ben-
zamide gave 0.17 g (67%) of N-5-carbomethoxyfuran-2-ylben-
zamide (39): mp 130-131 °C (lit.43 mp 128-129 °C); 1H NMR
(CDCl3, 300 MHz) δ 3.81 (s, 3H), 6.66 (d, 1H, J ) 3.6 Hz),
7.19 (d, 1H, J ) 3.6 Hz), 7.40-7.50 (m, 2H), 7.50-7.60 (m,
1H), 7.84-7.94 (m, 2H), and 9.27 (s, 1H).
N-5-Ca r bom eth oxyfu r a n -2-ylp yr r olid in on e (40). Using
the general procedure for Cu(I)-catalyzed C-N cross-couplings
described above, 5-bromo-2-furoic acid methyl ester and 2-pyr-
rolidinone gave 0.16 g (77%) of N-5-carbomethoxyfuran-2-
ylpyrrolidinone (40) as a white solid: mp 137-138 °C; IR (film)
1706, 1539, 1316, and 1227 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 2.16 (p, 2H, J ) 5.7 Hz), 2.52 (t, 2H, J ) 5.7 Hz), 3.79 (s,
3H), 3.98 (t, 2H, J ) 5.7 Hz), 6.54 (t, 1H, J ) 2.8 Hz), and
7.15 (d, 1H, J ) 2.8 Hz); 13C NMR (CDCl3, 100 MHz) δ 18.2,
31.4, 46.3, 51.6, 95.9, 121.2, 136.7, 149.9, 158.9, and 172.6.
Anal. Calcd for C10H11NO4: C, 57.41; H, 5.30; N, 6.70. Found:
C, 57.34; H, 5.24; N, 6.66.
8,9-Dim eth oxy-10b-m eth yl-1,5,6,10b-tetr ah ydr o-2H-pyr -
r olo[2,1-a ]isoqu in olin -3-on e (48). To a solution of the above
amide 47 (1.0 mmol) in 5 mL of THF was added 2 mL of 10%
HCl solution. The mixture was stirred at room temperature
for 16 h, diluted with CHCl3, and washed with water. The
organic layer was separated, dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude mixture was
purified by flash silica gel chromatography, using 20% acetone
in CHCl3 as the eluent, to give 48 in 70% yield as a colorless
oil: 1H NMR (400 MHz, CDCl3) δ 1.51 (s, 3H), 2.05-2.17
(m, 1H), 2.34-2.41 (m, 1H), 2.44 (tt, 1H, J ) 9.6 and 1.6 Hz),
2.59-2.70 (m, 2H), 2.85-2.94 (m, 1H), 3.03-3.11 (m, 1H), 3.86
(s, 3H), 3.88 (s, 3H), 4.24-4.32 (m, 1H), and 6.57 (s, 2H). The
spectral data of this compound are identical with those
reported in the literature.45
N-[2-(3,4-Dim et h oxyp h en yl)et h yl]-C,C,C-t r iflu or o-N-
(5-m eth ylfu r a n -2-yl)m eth a n esu lfon a m id e (49). To a solu-
tion of 47 (0.15 g, 0.5 mmol) in 5 mL of CH2Cl2 at -78 °C was
added pyridine (0.2 mL, 2.7 mmol) and then 0.2 mL (1.1 mmol)
of triflic anhydride (Tf2O). The crude reaction mixture was
allowed to warm to room temperature over 30 min and was
stirred at 25 °C for an additional 10 min. Water was added
and the organic layer was separated. The aqueous layer was
extracted with chloroform and the organic phase was washed
with water and brine, dried over MgSO4, filtered, and concen-
trated under reduced pressure. The crude mixture was purified
by flash chromatography on silica gel, using 20% Et2O in
hexane as the eluent, to give furan 49 in 90% yield (0.19 g) as
a colorless oil: IR (neat) 1614, 1465, 1401, 1228, 1189, 1142,
and 1029 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.28 (s, 3H), 2.85
(dd, 2H, J ) 8.3 Hz), 3.85 (s, 3H), 3.86 (s, 3H), 3.89 (dd, 2H, J
) 8.3 Hz), 5.99 (dd, 1H, J ) 3.2 and 1.3 Hz), and 6.17 (d, 1H,
J ) 3.2 Hz), 6.67 (d, 1H, J ) 1.9 Hz), 6.70 (dd, 1H, J ) 7.9
and 1.9 Hz), and 6.79 (d, 1H, J ) 7.9 Hz); 13C NMR (100 MHz,
CDCl3) δ 13.9, 35.0, 54.1, 56.0, 107.5, 109.6, 111.5, 112.1, 120.1
(q, J ) 322.5 Hz), 121.0, 129.4, 140.2, 148.1, 149.2, and 151.9.
Anal. Calcd for C16H18F3NO5S: C, 48.85; H, 4.61; N, 3.56.
Found: C, 48.55; H, 4.76; N, 3.68.
N-F u r a n -2-ylp yr r olid in on e (41). Using the general pro-
cedure for Cu(I)-catalyzed C-N cross-couplings described
above, 2-bromofuran and 2-pyrrolidinone afforded 0.14 g (82%)
of 41: mp 65-66 °C; IR (film) 1706, 1593, 1516, and 1419 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 2.00-2.17 (m, 2H), 2.40-2.53
(m, 2H), 3.76-3.88 (m, 2H), 6.26-6.37 (m, 2H), and 6.99-7.07
(m, 1H); 13C NMR (CDCl3, 75 MHz) δ 17.9, 31.1, 46.5, 94.1,
111.2, 135.3, 146.3, and 171.9. Anal. Calcd for C8H9NO2: C,
63.56; H, 6.00; N, 9.27. Found: C, 63.61; H, 5.99; N, 9.27.
P en t-4-en oic Acid F u r a n -2-yla m id e (42). Using the
general procedure for Cu(I)-catalyzed C-N cross-couplings
described above, 2-bromofuran and 4-pentenamide (2.4 equiv)
afforded 0.07 g (43%) of pent-4-enoic acid furan-2-ylamide (42)
as a pale yellow oil: IR (film) 1652, 1558, 1235, and 1145 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 2.42-2.50 (m, 4H), 5.03 (d, 1H,
J ) 10.4 Hz), 5.09 (d, 1H, J ) 17.6 Hz), 5.73-5.92 (m, 1H),
6.29 (d, 1H, J ) 3.2 Hz), 6.24-6.40 (m, 1H), 6.97-7.06 (m,
1H), and 8.19 (br s, 1H); 13C NMR (CDCl3, 75 MHz) δ 29.4,
35.9, 95.6, 111.6, 116.1, 135.5, 136.8, 145.4, and 169.3; HRMS
calcd for C9H11NO2 165.0790, found 165.0803.
1-Ben zyl-5-h ydr oxy-5-m eth ylpyr r olidin -2-on e (50). This
lactam was prepared from lactone 45 and benzylamine by
using a procedure similar to that employed for 46. Pyrrolidi-
none 50 was obtained as a colorless oil in 67% yield: IR (neat)
1-[2-(3,4-Dim et h oxyp h en yl)et h yl]-5-h yd r oxy-5-m et h -
ylp yr r olid in -2-on e (46). A solution of 3,4-dimethoxyphen-
ethylamine (1.0 g, 5.6 mmol) in water (0.5 mL) was added to
R-angelica lactone 45 (0.5 g, 5.1 mmol) and the mixture was
stirred at room temperature for 1 h. The solution was
concentrated under reduced pressure, and the resulting resi-
due was purified by flash chromatography on silica gel, using
20% acetone in CHCl3 as the eluent. The major product 46
was obtained as a yellow oil in 80% yield: 1H NMR (300 MHz,
CDCl3) δ 1.39 (s, 3H), 1.95-2.13 (m, 2H), 2.20-2.38 (m, 1H),
2.40-2.56 (m, 1H), 2.67-2.95 (m, 3H), 3.50-3.29 (m, 2H), 3.81
(s, 3H), 3.83 (s, 3H), and 6.68-6.80 (m, 3H). The spectral data
of this compound are identical with those reported in the
literature.44
4-Oxop en ta n oic Acid 2-(3,4-Dim eth oxyp h en eth yl)-
a m id e (47). To a solution of lactone 45 (0.5 g, 5.1 mmol) in
10 mL of THF at 0 °C was added 3,4-dimethoxyphenethyl-
amine (1.0 g, 5.6 mmol) dropwise. The reaction mixture was
allowed to warm to room temperature and was stirred for 2
h. The solvent was removed under reduced pressure and the
residue was purified on silica gel, using 20% acetone in CHCl3
as the eluent. The major product was obtained as a yellow solid
in 98% yield: mp 83-85 °C; 1H NMR (400 MHz, CDCl3) δ 2.18
(s, 3H), 2.35 (t, 2H, J ) 6.4 Hz), 2.72 (t, 2H, J ) 7.0 Hz), 2.75
(t, 2H, J ) 6.4 Hz), 3.40 (dt, 2H, J ) 7.0 and 5.8 Hz), 3.85 (s,
1
1666, 1413, 1356, 1200, and 1098 cm-1; H NMR (300 MHz,
CDCl3) δ 1.33 (s, 3H), 2.16-2.06 (m, 2H), 2.40-2.31 (m, 1H),
2.64-2.50 (m, 1H), 4.00 (br s, 1H), 4.31 (d, 1H, J ) 15.3 Hz),
4.60 (d, 1H, J ) 15.3 Hz), and 7.29-7.18 (m, 5H); 13C NMR
(75 MHz, CDCl3) δδ 27.2, 29.3, 35.1, 42.5, 90.7, 127.4, 127.9,
128.7, 138.7, and 175.6; HRMS calcd for C12H15NO2 205.1103,
found 205.1099.
N -Be n zyl-4-m e t h yl-N -(5-m e t h ylfu r a n -2-yl)b e n ze n e -
su lfon a m id e (51). To a solution of 46 (0.1 g, 0.5 mmol) in 5
mL of CH2Cl2 at -78 °C was added pyridine (0.4 mL, 4.9 mmol)
and 0.36 g (1.1 mmol) of p-toluenesulfonic anhydride ((p-tol)2O)
The reaction mixture was allowed to warm to room temper-
ature over 30 min and was stirred for an additional 30 min.
Water was added and the organic layer was separated. The
aqueous layer was extracted with chloroform and the organic
phase was washed with water and brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude
residue was purified by flash chromatography on silica gel,
using 50% Et2O in hexane as the eluent, to give 0.04 g of furan
51 in 23% yield as a white solid: mp 91-92 °C; IR (neat) 1562,
1350, 1165, 1088, and 1016 cm-1; 1H NMR (400 MHz, CDCl3)
δ 2.14 (s, 3H), 2.45 (s, 3H), 4.61 (s, 2H), 5.81 (dd, 1H, J ) 3.2
and 1.0 Hz), 5.85 (d, 1H, J ) 3.2 Hz), 7.20-7.33 (m, 7H), and
7.64-7.70 (m, 2H); 13C NMR (100 MHz, CDCl3) δδ 13.9, 21.8,
54.1, 107.1, 108.7, 127.9, 128.0, 128.5, 128.7, 129.7, 135.9,
(43) Padwa, A.; Dimitroff, M.; Waterson, A. G.; Wu, T. J . Org. Chem.
1998, 63, 3986.
(44) Collado, M. I.; Manteca, I.; Sotomayor, M.; Villa, M.; Lete, E.
J . Org. Chem. 1997, 62, 2080.
(45) Padwa, A.; Waterson, A. G. J . Org. Chem. 2000, 65, 235.
2616 J . Org. Chem., Vol. 68, No. 7, 2003

Synthesis of 2-Amido Substituted Furans
136.2, 143.3, 144.0, and 150.4. Anal. Calcd for C19H19NO3S:
C, 66.84; H, 5.61; N, 4.10. Found: C, 66.93; H, 5.62; N, 4.14.
The minor compound isolated from the chromatographic
separation was identified as 1-benzyl-5-methylene-pyrrolidin-
2-one (52): 1H NMR (400 MHz, CDCl3) δ 2.52-2.65 (m, 2H),
2.67-2.80 (m, 2H), 4.12 (d, 1H, J ) 1.8 Hz), 4.19 (d, 1H, J )
1.8 Hz), 4.68 (s, 2H), and 7.20-7.39 (m, 5H). The spectral data
of this compound are identical with those reported in the
literature.46
N-Ben zyl-2-(2-oxo-cycloh exyl)a ceta m id e (53). To a so-
lution of (2-oxo-cyclohexyl)acetic acid (1.1 g, 7.3 mmol) in
CH2Cl2 (70 mL) was added benzylamine (0.9 mL, 8.0 mmol)
and 1.5 g (8.0 mmol) of 1-[3-(dimethylamino)propyl]-3-ethyl-
carbodiimide hydrochloride (EDCI). The mixture was stirred
at room temperature for 3 h and partitioned between water
and chloroform. The organic layer was separated, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
crude product was purified by flash chromatography on silica
gel, using 10% acetone in CHCl3 as the eluent. Keto amide 53
was obtained as a white solid in 80% yield: mp 110-112 °C;
IR (KBr) 1694, 1637, 1547, 1453, and 1413 cm-1; 1H NMR (400
MHz, CDCl3) δ 1.29 (qd, 1H, J ) 9.7 and 3.8 Hz), 1.46-1.60
(m, 1H), 1.65 (qt, 1H, J ) 13.0 and 9.7 Hz), 1.75-1.84 (m, 1H),
2.01 (dd, 1H, J ) 14.6 and 5.4 Hz), 2.05-2.14 (m, 2H), 2.31
(d, 1H, J ) 5.7 Hz), 2.21-2.34 (m, 1H), 2.58 (dd, 1H, J ) 14.6
and 7.3 Hz), 2.82-2.92 (m 1H), 4.27-4.39 (m, 2H), 6.53 (br s,
1H), and 7.16-7.30 (m, 5H); 13C NMR (100 MHz, CDCl3) δ
25.3, 28.0, 34.4, 36.6, 42.0, 43.4, 47.7, 127.3, 127.6, 128.6, 138.5,
171.9, and 212.6. Anal. Calcd for C15H19NO2: C, 73.44; H, 7.81;
N, 5.71. Found: C, 73.41; H, 7.85; N, 5.71.
N-Ben zyl-C,C,C-tr iflu or o-N-(4,5,6,7-tetr a h yd r oben zo-
fu r a n -2-yl)m eth a n esu lfon a m id e (54). To a solution of keto
amide 53 (0.2 g, 0.8 mmol) in freshly distilled CH2Cl2 (10 mL)
were added pyridine (0.7 mL, 8.2 mmol) and Tf2O (0.3 mL,
1.7 mmol). The reaction mixture was stirred at room temper-
ature for 12 h and was then quenched by the addition of water.
The organic layer was separated and the aqueous layer was
extracted with chloroform. The organic phase was washed with
water and brine, dried over MgSO4, filtered, and concentrated
under reduced pressure. The crude residue was purified by
flash chromatography on silica gel, using 20% Et2O in hexane
as the eluent. Furan 54 was isolated as the major product in
93% yield (0.27 g) as a colorless oil: IR (neat) 1570, 1406, 1221,
1145, and 1029 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.58-1.65
(m, 2H), 1.70-1.77 (m, 2H), 2.21-2.26 (m, 2H), 2.41-2.46 (m,
2H), 4.77 (s, 2H), 5.79 (s, 1H), and 7.18-7.30 (m, 5H); 13C NMR
(100 MHz, CDCl3) δ 21.9, 22.8, 23.0, 56.4, 109.9, 118.5, 120.2
(q, J ) 323.6 Hz), 128.7, 128.8, 129.0, 134.5, 139.3, and 150.5;
HRMS calcd for C16H16F3NO3S 359.0803, found 359.0793.
N-Ben zyl-2,2,2-tr iflu or o-N-(4,5,6,7-tetr a h yd r oben zofu -
r a n -2-yl)a ceta m id e (55). To a solution of ketoamide 53 (0.1
g, 0.4 mmol) in freshly distilled CH2Cl2 (4.0 mL) was added
0.3 mL (4.1 mmol) of pyridine and trifluoroacetic anhydride
(TFAA) (0.1 mL, 0.9 mmol). The reaction mixture was stirred
at room temperature for 6 h and the reaction was quenched
by the addition of water. The organic layer was separated and
the aqueous layer was extracted with chloroform. The organic
phase was washed with water and brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude
residue was purified by flash chromatography on silica gel,
using 20% Et2O in hexane as the eluent. Furan 55 was isolated
as the major product in 77% yield (0.1 g) as a colorless oil: IR
1
(neat) 1716, 1577, 1210, and 1161 cm-1; H NMR (400 MHz,
CDCl3) δ 1.66-1.90 (m, 4H), 2.30-2.39 (m, 2H), 2.49-2.58 (m,
2H), 4.83 (s, 2H), 5.81 (s, 1H), and 7.24-7.38 (m, 5H); 13C NMR
(100 MHz, CDCl3) δ 21.9, 22.9, 23.0, 54.0, 108.2, 116.3 (q, J )
286.8 Hz), 118.2, 128.2, 128.7, 128.9, 135.4, 141.4, 149.8, and
157.9 (q, J ) 35.5 Hz); HRMS calcd for C17H16F3NO2 323.1133,
found 323.1138.
4-Ben zyla m in o-6,7-d ih yd r on a p h th o[1,2-c]fu r a n -1,3-d i-
on e (56). A solution of furan 54 (0.1 g, 0.3 mmol) and maleic
anhydride (0.3 g, 2.8 mmol) in toluene (3 mL) was heated at
120 °C in a sealed tube for 24 h. The reaction mixture was
allowed to cool to room temperature and the solvent was
removed under reduced pressure. The crude product was
purified by flash chromatography on silica gel, using 20% Et2O
in hexane as the eluent. The major product 56 was obtained
as a red-orange solid in 19% yield: mp 203-205 °C; IR (KBr)
1807, 1754, 1309, and 1204 cm-1; 1H NMR (400 MHz, CDCl3)
δ 2.30-2.36 (m, 2H), 2.79 (t, 2H, J ) 7.6 Hz), 4.52 (d, 2H, J )
6.0 Hz), 6.17 (dt, 1H, J ) 9.8 and 4.4 Hz), 6.55 (t, 1H, J ) 5.4
Hz), 6.67 (br s, 1H), 7.20 (d, 1H, J ) 9.8 Hz), and 7.29-7.40
(m, 5H); 13C NMR (100 MHz, CDCl3) δ 22.9, 28.9, 46.9, 107.7,
116.6, 122.0, 123.8, 124.1, 127.2, 128.0, 129.2, 131.4, 137.4,
146.6, 148.4, 163.8, and 165.3; HRMS calcd for C19H15NO3
305.1052, found 305.1050.
Ack n ow led gm en t. This research was supported by
the National Science Foundation (grant CHE-0132651).
We thank Tianhua Wu for some experimental as-
sistance. We also wish to acknowledge the NSF (CHE
9974864) and the NIH (S10-RR13673) for shared in-
strumentation grants.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for new compounds lacking elemental analyses. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(46) J acobi, P. A.; Brielmann, H. L.; Hauck, S. I. J . Org. Chem. 1996,
61, 5013.
J O026757L
J . Org. Chem, Vol. 68, No. 7, 2003 2617