Addition/oxidative rearrangement of 3-furfurals and 3-furyl imines: New approaches to substituted furans and pyrroles

Article abstract of DOI:10.1021/ja710988q

Furans and pyrroles are important synthons in chemical synthesis and are commonly found in natural products, pharmaceutical agents, and materials. Introduced herein are three methods to prepare 2-substituted 3-furfurals starting from 3-furfural, 3-bromofuran, and 3-vinylfurans. Addition of a variety of organofithium, Grignard, and organozinc reagents (M-R) to 3-furfural provides 3-furyl alcohols in high yields. Treatment of these intermediates with NBS initiates a novel oxidative rearrangement that results in the installation of the R group in the 2 position of the 2-substituted 3-furfurals. Likewise, metalation of 3-bromofuran with n-BuLi and addition to benzaldehyde provides a furyl alcohol that is converted to 2-phenyl 3-furfural upon oxidative rearrangement. Enantioenriched disubstituted furans can be prepared starting with the Sharpless asymmetric dihydroxylation of 3-vinylfurans. The resulting enantioenriched diols undergo the oxidative rearrangement to furnish enantioenriched 2-substituted 3-furfurals with excellent transfer of asymmetry. This later method has been applied to the enantioselective preparation of an intermediate in Honda's synthesis of the natural product (-)-canadensolide. Mechanistic studies involving deuterium-labeled furyl alcohol suggest that the oxidative rearrangement proceeds through an unsaturated 1,4-dialdehyde intermediate. The alcohol then cyclizes onto an aldehyde, resulting in the elimination of water and rearomatization. On the basis of this proposed mechanism, we found that 3-furyl imines undergo the addition of organometallic reagents to provide furyl sulfonamides. Under the oxidative rearrangement conditions, 2-substituted 3-formyl pyrroles are formed, providing a novel route to these heterocycles. In contrast to the metalation of heterocycles, which often lead to mixtures of regioisomeric products, these new oxidative rearrangements of furyl alcohols and furyl sulfonamides generate only one regioisomer in each case.

Full text of DOI:10.1021/ja710988q

Published on Web 03/04/2008
Addition/Oxidative Rearrangement of 3-Furfurals and 3-Furyl
Imines: New Approaches to Substituted Furans and Pyrroles
Ann Rowley Kelly, Michael H. Kerrigan, and Patrick J. Walsh*
P. Roy and Diana T. Vagelos Laboratories, Department of Chemistry, UniVersity of
PennsylVania, 231 South 34th Street, Philadelphia, PennsylVania 19104-6323
Received December 10, 2007; E-mail: pwalsh@sas.upenn.edu
Abstract: Furans and pyrroles are important synthons in chemical synthesis and are commonly found in
natural products, pharmaceutical agents, and materials. Introduced herein are three methods to prepare
2-substituted 3-furfurals starting from 3-furfural, 3-bromofuran, and 3-vinylfurans. Addition of a variety of
organolithium, Grignard, and organozinc reagents (M-R) to 3-furfural provides 3-furyl alcohols in high yields.
Treatment of these intermediates with NBS initiates a novel oxidative rearrangement that results in the
installation of the R group in the 2 position of the 2-substituted 3-furfurals. Likewise, metalation of
3-bromofuran with n-BuLi and addition to benzaldehyde provides a furyl alcohol that is converted to 2-phenyl
3-furfural upon oxidative rearrangement. Enantioenriched disubstituted furans can be prepared starting
with the Sharpless asymmetric dihydroxylation of 3-vinylfurans. The resulting enantioenriched diols undergo
the oxidative rearrangement to furnish enantioenriched 2-substituted 3-furfurals with excellent transfer of
asymmetry. This later method has been applied to the enantioselective preparation of an intermediate in
Honda’s synthesis of the natural product (-)-canadensolide. Mechanistic studies involving deuterium-labeled
furyl alcohol suggest that the oxidative rearrangement proceeds through an unsaturated 1,4-dialdehyde
intermediate. The alcohol then cyclizes onto an aldehyde, resulting in the elimination of water and
rearomatization. On the basis of this proposed mechanism, we found that 3-furyl imines undergo the addition
of organometallic reagents to provide furyl sulfonamides. Under the oxidative rearrangement conditions,
2-substituted 3-formyl pyrroles are formed, providing a novel route to these heterocycles. In contrast to the
metalation of heterocycles, which often lead to mixtures of regioisomeric products, these new oxidative
rearrangements of furyl alcohols and furyl sulfonamides generate only one regioisomer in each case.
conversion into a variety of functional groups.1-6,13,15-18 The
value and utility of these heterocycles continues to stimulate
research directed toward their synthesis. Despite this effort, the
efficient and selectiVe synthesis of substituted furans and
pyrroles remains a challenge.8,19-21,3
A common method to functionalize furans begins with
metalation chemistry. Although direct lithiation of furans at C-2
is often readily achieved, halogenation followed by low-
temperature metal-halogen exchange is the standard approach
to metalate C-3.22-24 3-Furyllithiums are highly reactive, and
the lithium will migrate from the 3 to the 2 position at low
temperatures. As with most organolithiums, lithiated furans
exhibit limited functional group compatibility. As an example,
Comins and co-workers used a directed metalation to lithiate
3-furfural in the 2 position. To protect the aldehyde and direct
1. Introduction
Furans and pyrroles are important constituents of natural
products and of pharmaceutical agents.1-12 Some of the best-
selling medications are heterocycles of these types: for instance
ranitidine13 is a furan used to treat stomach ulcers, and
atorvastatin (Lipitor)14 is a pyrrole used to control high
cholesterol. Furans and pyrroles are also versatile synthetic
intermediates as a result of their high reactivity and facile
(1) Keay, B. A.; Dibble, P. W. In ComprehensiVe Heterocyclic Chemistry II;
Katrinzky, A. R., Rees, C. W., Schriven, E. F., Bird, C. W., Eds.;
Pergamon: Oxford, U.K., 1996; Vol. 2, pp 395-436.
(2) Meyers, A. I. Heterocycles in Organic Synthesis; John Wiley & Sons: New
York, 1974.
(3) Cheeseman, G. W. H.; Bird, C. W. In ComprehensiVe Heterocyclic
Chemistry: The Structure, Reactions, Synthesis and Uses of Heterocyclic
Compounds; Oxford: Pergamon Press: New York, 1984; Vol. 4.
(4) Konig, B. In Science of Synthesis; Thieme: Stuttgart, Germany, 2001; Vol.
9.
(5) Sutherland, M. D.; Rodwell, J. L. Aust. J. Chem. 1989, 42, 1995-2019.
(6) Shipman, M. Contemp. Org. Synth. 1995, 2, 1-17.
(7) Raczko, J.; Jurczak, J. Stud. Nat. Prod. Chem. 1995, 16, 639-685.
(8) Bellur, E.; Langer, P. Tetrahedron Lett. 2006, 47, 2151-2154.
(9) Zdero, C.; Bohlmann, F.; King, R. M. Phytochemistry 1991, 30, 1591-
1595.
(15) Brown, R. C. D. Angew. Chem., Int. Ed. 2005, 44, 850-852.
(16) Lee, H.-K.; Chan, K.-F.; Hui, C.-W.; Yim, H.-K.; Wu, X.-W.; Wong, H.
N. C. Pure Appl. Chem. 2005, 77, 139-143.
(17) 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.
(18) Lipshutz, B. H. Chem. ReV. 1986, 86, 795-820.
(10) Anderson, W. K.; Milowsky, A. S. J. Med. Chem. 1986, 29, 2241-2249.
(11) Walsh, C. T.; Garneau-Tsodikova, S.; Howard-Jones, A. R. Nat. Prod. Rep.
2006, 23, 517-531.
(19) Mross, G.; Holtz, E.; Langer, P. J. Org. Chem. 2006, 71, 8045-8049.
(20) Kirsch, S. F. Org. Biomol. Chem. 2006, 4, 2076-2080.
(21) Minetto, G.; Raveglia, L. F.; Taddei, M. Org. Lett. 2004, 6, 389-392.
(22) Williams, D. H.; Faulkner, D. J. Tetrahedron 1996, 52, 4245-4256.
(23) Lee, G. C. M.; Holmes, J. M.; Harcourt, D. A.; Garst, M. E. J. Org. Chem.
1992, 57, 3126-3131.
(12) Hoffmann, H.; Lindel, T. Synthesis 2003, 1753-1783.
(13) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4 ed.; Blackwell Science
Ltd.: Malden, MA, 2000.
(14) Lea, A. P.; Mctavish, D. Drugs 1997, 53, 828-847.
(24) Carpenter, A. J.; Chadwick, D. J. Tetrahedron 1985, 41, 3803-3812.
9
10.1021/ja710988q CCC: $40.75 © 2008 American Chemical Society
J. AM. CHEM. SOC. 2008, 130, 4097-4104
4097

A R T I C L E S
Kelly et al.
Scheme 1. Synthesis of 2-Substituted 3-Furfurals Using LiTMDA
to Form the Directing Group.
furals. Beginning with commercially available 3-furfural, the
addition of an organometallic reagent generates a furyl alcohol.
Oxidative rearrangement of the furyl alcohol with NBS provides
the desired 2-substituted 3-furfurals without contamination by
other isomers. In this fashion, a variety of substituents can be
easily installed at the 2 position. We have extended our oxidative
rearrangement to the generation of enantioenriched 2-substituted
3-furfurals and to the formation of 2-substituted 3-formyl
pyrroles.
Scheme 2. (A) Achmatowicz Reaction and (B) Our Proposed
Oxidative Rearrangement of 3-Furyl Alcohols.
2. Experimental Section
General methods are listed in the Supporting Information.
General Procedure A. Synthesis of Furyl Alcohols from
3-Furfural. 1-Furan-3-yl-propan-1-ol (2a). Under a nitrogen
atmosphere, a dry 25 mL flask was charged with 3-furfural (84
µL, 1.0 mmol) and THF (1.0 mL) and cooled to 0 °C. A solution
of ethylmagnesium bromide (0.5 mL, 3.0 M in ether, 1.5 mmol)
was added dropwise. The reaction mixture was stirred at 0 °C
for 3 h and quenched with saturated aqueous NH4Cl. The
organic and aqueous layers were separated, and the aqueous
layer was extracted with Et2O (3 × 10 mL). The combined
organic layers were dried over MgSO4 and filtered. The filtrate
was concentrated in vacuo, and the residue was chromato-
graphed on silica gel (10% EtOAc in hexanes) to afford the
title compound as a colorless oil in 98% yield (123 mg, 0.98
mmol). The 1H and 13C{1H} NMR data for this compound were
identical to previously reported literature data.30
the metalation in this process, lithiated trimethylethylene diamine
(LiTMDA) was generated, added to 3-furfural, and the resulting
adduct metalated with n-BuLi (Scheme 1). The lithiated furan
was then treated with methyl iodide to generate 2-methyl
3-furfural in 83% yield after hydrolysis of the directing group.25
This furan alkylation is limited to alkyl halides that will undergo
SN2 substitution over elimination with this bulky organolithium.
We have found that D2O is also a suitable electrophile for
preparing the 2-deutero 3-furfural, as outlined below.
Metalation processes, however, can be difficult to control,
resulting in lower selectivity, reduced yields, and challenging
separations of the desired furan from the unwanted regioiso-
mers. Also, the selectivity of such metalations depends on the
metalating reagent and the electrophile.23 Given the limitations
of these methods to generate functionalized heteroaromatics,
alternative strategies to prepare these valuable compounds are
desirable.
Our approach to the synthesis of substituted furans was
inspired by the Achmatowicz reaction (part A of Scheme 2).26,27
This process, which entails the conversion of 2-furyl alcohols
to pyranones under oxidative conditions has been widely utilized
in the synthesis of natural products and the preparation of diverse
libraries of heterocyclic compounds.28,29 The mechanism of this
oxidative transformation is believed to involve ring-opening to
generate an unsaturated 1,4-dicarbonyl intermediate that then
cyclizes to the pyranone product. On the basis of this mecha-
nism, we anticipated that 3-furyl alcohols would undergo related
oxidative rearrangement to provide furanosidic aldehydes, which
could eliminate and rearomatize to provide 2-substituted 3-fur-
furals (part B of Scheme 2).
Synthesis of Furan-3-yl-phenyl-methanol from 3-Bromo-
furan (2e). Under a nitrogen atmosphere, n-BuLi (0.4 mL, 2.5
M in hexanes, 1.0 mmol) was added dropwise to a stirred
solution of 3-bromofuran (108 µL, 1.2 mmol) in dry THF (1
mL) at -78 °C. After 15 min, benzaldehyde (101 µL, 1.0 mmol)
was added to the solution. The reaction mixture was stirred at
-78 °C until completion by TLC and quenched with saturated
aqueous NH4Cl. The organic and aqueous layers were separated,
and the aqueous layer was extracted with Et2O (3 × 10 mL).
The combined organic layers were dried over MgSO4 and
filtered. The filtrate was concentrated in vacuo, and the residue
was purified by column chromatography on deactivated silica
gel (10% EtOAc in hexanes) to afford the title compound as a
1
colorless oil in 90% yield (157 mg, 0.90 mmol). The H and
13C{1H} NMR data for this compound were identical to
previously reported literature data.31
General Procedure B: Oxidative Rearrangement of Furyl
Alcohols. 2-Ethyl-furan-3-carboxaldehyde (3a). A 10 mL
flask was charged with 1-furan-3-yl-propan-1-ol (126 mg, 1.0
mmol), THF (4 mL), and H2O (1 mL). NBS (178 mg, 1.0 mmol)
was added to the mixture in two portions (10 min apart) at
ambient temperature. The reaction mixture initially turned
yellow and later faded to near colorless. The reaction progress
was monitored by TLC, and the formation of a new, nonpolar,
UV active spot was observed. Upon completion (approximately
4 h), the reaction mixture was treated with 1M HCl(aq) (1 mL,
1 mmol). After stirring for 10 min, the reaction mixture was
extracted with Et2O (3 × 10 mL). The combined organic layers
were washed with brine, dried over MgSO4, and filtered. The
filtrate was concentrated in vacuo, and the residue was chro-
Herein, we disclose a novel oxidative rearrangement that
enables the selective preparation of diverse 2-substituted 3-fur-
(25) Comins, D. L.; Killpack, M. O. J. Org. Chem. 1987, 52, 104-109.
(26) Achmatowicz, O.; Bukowski, P.; Szechner, B.; Zwierzchowska, Z.;
Zamojski, A. Tetrahedron 1971, 27, 1973-1996.
(27) Lefebvre, Y. Tetrahedron Lett. 1972, 133-136.
(28) Guo, H.; O’Doherty, G. A. Org. Lett. 2005, 7, 3921-3924.
(29) Couladouros, E. A.; Georgiadis, M. P. J. Org. Chem. 1986, 51, 2725-
2727.
(30) Kitamura, T.; Kiawakami, Y.; Imagawa, T.; Kawanisi, M. Synth. Commun.
1977, 7, 521-528.
(31) Pawlicki, M.; Latos-Grazynski, L.; Szterenberg, L. J. Org. Chem. 2002,
67, 5644-5653.
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4098 J. AM. CHEM. SOC. VOL. 130, NO. 12, 2008

3-Furfurals and 3-Furyl Imines
A R T I C L E S
matographed on silica gel (5% Et2O in pentane) to afford the
title compound as a yellow oil in 71% yield (88 mg, 0.71mmol).
1H NMR (CDCl3, 500 MHz): δ 9.96 (s, 1H), 7.31 (d, J ) 1.9
Hz, 1H), 6.68 (d, J ) 1.9 Hz, 1H), 2.97 (quartet, J ) 7.8 Hz,
2H), 1.30 (t, J ) 7.5 Hz, 3H); 13C{1H} NMR (CDCl3,125
MHz): δ 184.8, 145.0, 142.1, 121.9, 108.1, 20.6, and 12.8; IR
(neat) 3123, 2979, 2878, 2743, 1683, and 1575 cm-1. HRMS-
CI m/z 124.0522 [M+; Calcd for C7H8O2: 124.0524].
layers were washed with KOH (2 N), dried over MgSO4,
filtered, and the filtrate was concentrated. Column chromatog-
raphy on silica gel (10-33% EtOAc in hexanes) afforded the
diol product in 86% yield (961 mg, 5.22 mmol) as a clear
20
viscous liquid. [R]D ) -3.98° (c ) 2.79, CHCl3, 98% ee);
1H NMR (CDCl3, 500 MHz): δ 7.46 (s, 1H), 7.43 (s, 1H), 6.42
(s, 1H), 4.46 (dd, J ) 3.2, 5.9 Hz, 1H), 3.70 (d, J ) 6.2 Hz,
1H), 2.50 (s, 1H), 2.33 (s, 1H), 1.39 (m, 6H), 0.90 (t, J ) 7.1
Hz, 3H); 13C{1H} NMR (CDCl3,125 MHz): δ 143, 140.4,
126.1, 108.9, 75.2, 70.5, 32.8, 20.0, 22.8, and 14.2; IR (neat)
3391, 2957, 2934, 2873, 1503, and 1467 cm-1. HRMS-CI m/z
167.1064 [(M-OH)+; Calcd for C10H15O2-: 167.1072].
(R)-2-(1-Hydroxy-pentyl)-3-furfural (9). General Procedure
B was applied to the diol using (1R, 2R)-1-furan-3-yl-hexane-
1,2-diol (585 mg, 3.18 mmol), THF (12 mL), DI H2O (3 mL),
and NBS (283 mg, 1.59 mmol, in two portions 10 min apart).
The yellow solution was stirred for 5 h, quenched with water
(10 mL), extracted with Et2O (3 × 10 mL), dried over MgSO4,
filtered, and the filtrate was concentrated under reduced pressure.
The resulting residue was subject to column chromatography
on silica gel (5-20% EtOAc in hexanes), affording the title
compound in 68% yield (394 mg, 2.16 mmol). [R]D20 ) -31.09°
(c ) 2.04, CHCl3, >99% ee); 1H NMR (CDCl3, 500 MHz): δ
10.01 (s, 1H), 7.37 (d, J ) 2.0 Hz, 1H), 6.78 (d, J ) 2.0 Hz,
1H), 4.96 (t, J ) 6.9 Hz, 1H), 3.65 (s, 1H), 1.89 (m, 2H), 1.35
(m, 4H), 0.92 (t, J ) 7.1 Hz, 3H); 13C{1H} NMR (CDCl3, 125
MHz): δ 187.1, 165.4, 142.1, 122.7, 110.0, 68.4, 36.1, 27.6,
General Procedure C: One-Pot Addition/Oxidative Rear-
rangement with 3-Furfural. 2-Ethyl-furan-3-carboxaldehyde
(3a). Under a nitrogen atmosphere, a dry 25 mL flask was
charged with 3-furfural (87 µL, 1.0 mmol) and dry THF (1.0
mL) and cooled to 0 °C. A solution of ethylmagnesium
bromide (0.5 mL, 3.0 M in ether, 1.5 mmol) was added
dropwise. The reaction mixture was stirred at 0 °C for 3 h. When
the addition reaction was completed by TLC, HCl(aq) (1.5 mL,
1M, 1.5 mmol) was added. THF (7 mL), water (0.5 mL), and
NBS (178 mg, 1.0 mmol, in two portions) were then added
sequentially at ambient temperature. When the rearrangement
was completed by TLC, the reaction mixture was quenched
with saturated aqueous NH4Cl and extracted with Et2O (3 ×
10 mL). The combined organic layers were washed with brine,
dried over MgSO4, and filtered. The filtrate was concentrated
in vacuo, and the residue was chromatographed on silica gel
(5% Et2O in pentane) to afford the title compound as a yellow
oil in 70% yield (86 mg, 0.70 mmol). The spectral data for
this compound were the same as those reported in General Pro-
cedure B.
22.6, and 14.1; IR (film) 3418, 2958, 2863, and 1682 cm-1
.
HRMS-CI m/z 182.0943 [M+; Calcd for C10H14O3: 182.0943].
Synthesis of (R)-1-(3-Hydroxymethyl-furan-2-yl)-pentan-
1-ol. Under a nitrogen atmosphere at room temperature, NaBH4
was added to a solution of (R)-2-(1-hydroxy-pentyl)-3-furfural
(88.6 mg, 0.486 mmol) dissolved in 2-propanol (2 mL, HPLC
grade). After stirring for 15 min, the reaction was quenched
with H2O (3 mL) and Et2O was added (5 mL). The reaction
was extracted with Et2O (3 × 10 mL), dried over MgSO4,
filtered, and concentrated under reduced pressure. This material
was taken on to the next reaction without purification.
Synthesis of 3-Hex-1-enyl-furan (7). Under a nitrogen
atmosphere, PdCl2(dppf)‚CH2Cl2 (51 mg, 0.063 mmol), (E)-
hexen-1-ylboronic acid (400 mg, 3.13 mmol), 3-bromofuran
(277 µL, 3.13 mmol), and tert-butylamine (986 µL, 9.38 mmol)
were added to a dry 25 mL round-bottom flask, followed by
2-propanol (10 mL) and water (5 mL). A reflux condenser was
attached, and the resulting deep-red solution was refluxed for
4.5 h under N2 (oil bath ≈ 90 °C). After cooling to room
temperature, water (10 mL) was added. Following extraction
with Et2O (3 × 10 mL), the combined organic layers were
washed with HCl(aq) (2 mL, 2M), brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. Column
chromatography on silica gel (0-2.5% EtOAc in hexanes)
afforded the title compound in 80% (1.90 g, 11.4 mmol) as a
clear liquid. 1H NMR (CDCl3, 500 MHz): δ 7.36 (s, 2H) 6.52
(s, 1H), 6.24 (d, J ) 15.8 Hz, 1H), 5.96 (dt, J ) 15.8, 6.9 Hz,
1H) 2.17 (dt, J ) 6.9 Hz, 6.6 Hz, 2H) 1.40 (m, 4H), 0.94 (t, J
) 7.0 Hz, 3H); 13C{1H} NMR (CDCl3, 125 MHz): δ 143.5,
139.5, 131.1, 124.8, 119.4, 107.8, 32.8, 31.7, 22.5, and 14.5;
IR (neat) 2958, 2927, 2873, 2859, 1508, and 1466 cm-1. HRMS-
CI m/z 150.1038 [M+; Calcd for C9H10O3: 150.1045].
For purposes of characterization, the crude material was run
though a plug of silica gel (50% EtOAc in hexanes) to afford
20
1
the diol in 95% yield. [R]D ) 24.03° (c ) 3.77, CHCl3); H
NMR (CDCl3, 500 MHz): δ 7.31 (d, J ) 1.8 Hz, 1H), 6.36 (d,
J ) 1.7 Hz, 1H), 4.78 (t, J ) 7.0 Hz, 1H), 4.57 (s, 2H), 2.67(s,
1H), 2.38 (s, 1H), 1.90 (m, 2H), 1.39-1.25 (m, 4H), 0.92 (t, J
) 7.1 Hz, 3H); 13C{1H} NMR (CDCl3, 125 MHz): δ 153.4,
141.2, 120.8, 111.5, 67.3, 56.7, 35.7, 27.9, 22.7, and 14.2; IR
(film) 3335, 2967, 2933, 2873, 1512, and 1467 cm-1. HRMS-
ESI m/z 207.0994 [(M+Na)+; Calcd for C10H16O3Na: 207.0997].
1
The H NMR spectrum and the IR for this compound match
those of Honda and co-workers.32 The 13C NMR was not
previously reported.
General Procedure D: Sharpless Asymmetric Dihydroxy-
lation of trans-3-Vinylfurans. (1R, 2R)-1-Furan-3-yl-hexane-
1,2-diol (8). In a 100 mL flask, the AD-mix-â (8.47 g) was
dissolved in tert-butanol (30 mL) and DI H2O (30 mL) at room
temperature followed by the addition of methanesulfonamide
(575 mg, 6.05 mmol). After dissolution, the orange solution
was cooled to 0 °C and 3-hex-1-enyl-furan (908 mg, 6.05 mmol)
was added. After 16 h of stirring at 0 °C, sodium sulfite (9.075
g) was added, and the reaction mixture was warmed to ambient
temperature and stirred for 1 h. The reaction mixture was
extracted with CH2Cl2 (3 × 20 mL), and the combined organic
Synthesis of (R)-1-[3-(tert-Butyl-dimethyl-silanyloxy-
methyl)-furan-2-yl]-pentan-1-ol (10). The crude diol (R)-1-
(3-hydroxymethyl-furan-2-yl)-pentan-1-ol (0.486 mmol), TBSCl
(73.2 mg, 0.486 mmol), and imidazole (66.2 mg, 0.972 mmol)
were dissolved in CH2Cl2 (2 mL) and stirred for 8 h at room
temperature under a nitrogen atmosphere. The reaction mixture
was quenched with aqueous saturated NH4Cl and was extracted
with Et2O (15 mL × 3). The combined organic layers were
(32) Honda, T.; Kobayashi, Y.; Tsubuki, M. Tetrahedron 1993, 49, 1211-1222.
9
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A R T I C L E S
Kelly et al.
Scheme 3. Optimization of the Oxidative Rearrangement
(Table 1).
dried over MgSO4, filtered, and the filtrate was concentrated
under reduced pressure. Column chromatography on silica gel
(5-10% EtOAc in hexanes) afforded the title compound in 78%
20
yield (113.1 mg, 0.379 mmol). [R]D ) 9.65° (c ) 2.07,
1
CHCl3); H NMR (CDCl3, 500 MHz): δ 7.28 (d, J ) 1.6 Hz,
1H), 6.29 (d, J ) 1.7 Hz, 1H), 4.76 (dd, J1 ) 6.7, 4.8 Hz, 1H),
4.64 (s, 2H), 2.85 (d, J ) 4.7 Hz, 1H), 1.88 (m, 2H), 1.44-
1.26 (m, 4H), 0.93 (m, 12H), 0.13 (s, 6H); 13C{1H} NMR
(CDCl3, 125 MHz): δ 153.3, 140.7, 120.6 111.2, 67.4, 57.8,
35.7, 27.9, 26.1, 22.8, 18,5, 14.2, -5.08, and -5.10; IR (film)
3412, 2956, 2931, 2856, and 1471 cm-1. HRMS-ESI m/z
321.1876 [(M+Na)+; Calcd for C16H30O3SiNa: 321.1862]. The
1H NMR spectrum, IR, and optical rotation for this compound
match those of Honda and co-workers.32 The 13C NMR was
not previously reported.
Table 1. Optimization of the Oxidative Rearrangement with NBS
entry
equiv of NBS
workup
yield (%)
1
2
3
4
5
6
7
8
9
1.1
2.0
1.1
1.1
1.1
1.1
1.1
1.5
1.1
1.0
KI, Na2S2O3,NaHCO3
KI, Na2S2O3, NaHCO3
KI
Na2S2O3
NaHCO3
KI, 1M HCl
Na2S2O3, 1M HCl
1M HCl
1M HCl
1M HCl
50
42
30
51
29
25
68
70
71
70
N-(1-Furan-3-yl-propyl)-4-methyl-benzene-sulfonamide
(12a). This compound was prepared according to General
Procedure A using N-furan-3-ylmethylene-4-methyl-benzene-
sulfonamide (249 mg, 1.0 mmol), THF (1 mL), and ethyl
magnesium bromide (0.5 mL, 3.0 M in ether). The product was
chromatographed on silica gel (10% EtOAc in hexanes) to afford
the title compound as a colorless oil in 94% yield (262 mg,
10
Scheme 4. Our Two-step Method for the Synthesis of
2-Substituted 3-Furfurals (Table 2).
1
0.94 mmol). H NMR (CDCl3, 500 MHz): δ 7.0 (d, 2H, J )
8.1 Hz), 7.26 (m, 3H), 7.10 (s, 1H), 6.10 (s, 1H), 4.30 (m, 1H),
4.23 (q, 1H, J ) 7.0 Hz), 2.44 (s, 3H), 1.75 (m, 2H), and 0.85
(t, 3H, J ) 7.4 Hz); 13C{1H} NMR (CDCl3, 125 MHz): δ 143.3,
143.2, 139.5, 137.9, 129.4, 127.0, 125.8, 108.3, 51.5, 29.3, 21.5,
and 10.1; IR (neat) 3356, 3260, 2923, 1599, 1527, and 1157
cm-1. HRMS-CI m/z 280.1007 [MH+; Calcd for C14H18NO3S:
280.1007].
Use of Br2 in acetone led to consumption of the starting material
with the formation of multiple products. Fortunately, higher
yields were obtained with NBS, and we focused our efforts on
optimization with this reagent.
2-Ethyl-1-(toluene-4-sulfonyl)-1H-pyrrole-3-carbalde-
hyde (13a). This compound was prepared by General Procedure
B using N-(1-furan-3-yl-propyl)-4-methyl-benzene-sulfonamide
(278 mg, 1.0 mmol), NBS (178 mg, 1.0 mmol), THF (4 mL),
and H2O (1 mL). After the usual workup, the crude product
was purified by column chromatography on deactivated silica
gel (0-10% EtOAc in hexanes) to afford the title compound
The conditions for optimization of the oxidative rearrange-
ment are shown in Table 1. Initially we employed 1.1 or 2.0
equiv of NBS in a 4:1 THF/water mixture at room temperature
(entries 1 and 2). Under these conditions, the yellow/orange
solution became colorless over the 4 h reaction course. Upon
consumption of the starting material, the reaction was quenched
with successive washings with KI, Na2S2O3, and NaHCO3,
which is a common workup procedure for Achmatowitz
reactions.29 The yield ranged from 42 to 50% (Table 1, entries
1 and 2). With 1.1 equiv of NBS, alternative workup conditions
were examined including evaluating each component of the
previous workup individually: KI (entry 3), Na2S2O3 (entry 4),
or NaHCO3 (entry 5). The yields from these workups were also
low. We speculated that basic workup conditions inhibited loss
of water and rearomatization of the furanosidic aldehyde;
therefore, we examined the affect of acid on the workup. In
most cases, acidic workup conditions resulted in increased yields
(entries 6-10). When an excess of NBS was used, bromine
incorporation into the product was occasionally observed.
Further optimization was then performed with 1.0 equiv of NBS
(entry 10).
1
as a yellow oil in 67% yield (186 mg, 0.67 mmol). H NMR
(CDCl3, 500 MHz): δ 9.92 (s, 1H), 7.75 (d, 2H, J ) 5.5 Hz),
7.35 (m, 3H), 6.67 (d, 1H J ) 4.0 Hz), 3.10 (q, 2H, J ) 10.0
Hz), 2.47 (s, 3H), and 1.20 (t, J ) 10.0 Hz, 3H); 13C{1H} NMR
(CDCl3, 125 MHz): δ 187.1, 147.1, 146.9, 136.8, 131.5, 128.5,
125.4, 123.7, 110.0, 22.2, 19.3, and 16.5; IR (neat) 2976, 1724,
1596, 1493, and 1164 cm-1. HRMS-CI m/z 277.0760 [M+;
Calcd for C14H15NO3S: 277.0773].
3. Results and Discussion
3.1. Development and Optimization of the Oxidative
Rearrangement. Our synthesis of 2-substituted 3-furfurals (3)
begins with the addition of an organometallic reagent to
commercially available 3-furfural (1). This addition proved to
be straightforward, furnishing the furyl alcohols in high yields.
The oxidative rearrangement of the resulting furyl alcohols,
however, required significant optimization. Utilizing 1-furyl-
1-propanol (2a) to optimize the oxidation (Scheme 3), we
screened various oxidants, oxidant equivalents, and workup
procedures. When mCPBA, monoperphthalic acid, MMPP,
TBHP, and NIS were used, no reaction was observed. Oxidative
rearrangement with Br2 in THF/H2O and with NCS led to low
isolated yields of the desired rearranged products (15-20%).
3.2. Oxidative Rearrangement Substrate Scope. To deter-
mine the substrate scope of the furan synthesis, we next
examined the addition of organolithiums, Grignard, and orga-
nozinc reagents to 3-furfural (1) (Scheme 4). The resulting furyl
alcohols were purified and isolated in high yields (83-99%,
Table 2). Although basic, highly reactive organolithium reagents
worked well in this process, more functional group tolerant
Grignard and organozinc species also provided the furyl alcohols
9
4100 J. AM. CHEM. SOC. VOL. 130, NO. 12, 2008

3-Furfurals and 3-Furyl Imines
A R T I C L E S
Table 2. Results for the Two-step and One-pot Synthesis of
Scheme 6. Synthesis of 2-Phenyl 3-Furfural.
2-Substituted 3-Furfurals
only a single purification is needed. Addition of 1.5 equiv of
the organometallic species to 3-furfural was carried out as in
Scheme 4; however, rather than workup and isolation of the
furyl alcohol, HCl (1M, 1.5 equiv) was added to neutralize the
reaction solution. Additional THF and water (4:1) were then
introduced into the reaction mixture, followed by 1 equiv of
NBS (Scheme 5). After 4 h, the reactions were quenched with
additional water and extracted with diethyl ether. As shown in
Table 2, the product yields in the one-pot transformation are
comparable to, or slightly below, those of the two-step
procedure. The one-pot method was unsuccessful with the
organozinc reagents. The pivolate protecting group was lost
under the conditions of the one-pot procedure, most likely
because of the acidic nature of the reaction mixture (entry 4).
In the case of the vinyl zinc additions (entries 10 and 11), we
speculate that the boron-containing byproducts interfered with
the NBS oxidation of the intermediate furyl alcohol.
Scheme 5. One-Pot Synthesis of 2-Substituted 3-Furfurals.
To explore the potential utility of our method, we examined
the scalability of the one-pot synthesis of 2-substituted 3-fur-
furals. Employing PhLi and 3-furfural on a 5 mmol scale, we
were pleased to discover that the reaction proceeded without
complication or loss of yield (entry 5, Table 2). To highlight
the versatility of our addition/oxidative rearrangement procedure,
we also synthesized 2-phenyl 3-furfural by the generation of
3-furyllithium from commercially available 3-bromofuran. Ad-
dition of 3-furyllithium to benzaldehyde gave the furyl alcohol
2e in 90% isolated yield (Scheme 6). The oxidative rearrange-
ment then furnished 3e in 72% yield.
3.3. Mechanistic Investigations. Several mechanisms for the
oxidative rearrangement can be envisioned. Free-radical pro-
cesses were deemed unlikely because the reaction exhibits
similar behavior in the dark and in the light. Of relevance to
our oxidative rearrangement, it is known that oxidation of 2,5-
disubstituted furans can lead to unsaturated 1,4-dicarbonyl
compounds.38-41 A possible reaction pathway for the oxidative
rearrangement begins with bromination of the furan ring of 2
as shown in Scheme 7. We propose that the resulting oxonium
ion can undergo the addition of water at the 2 position followed
by proton loss, opening of the furan ring, and generation of the
key unsaturated 1,4-dialdehyde intermediate. The π system of
this unsaturated 1,4-dialdehyde is highly electrophilic and
undergoes isomerization about the 2,3 double bond by Michael
addition of water, bond rotation, and reformation of the double
bond with concomitant elimination of water. Finally, protonation
of the carbonyl and attack of the alcohol reforms the heterocycle,
generating the furanosidic aldehyde after the proton transfer to
the solvent. This intermediate is proposed to undergo acid-
catalyzed elimination of water to form the observed 2-substituted
3-furfural (3).
in high yields. The functionalized dialkylzinc reagent Zn[(CH2)4-
OPiv]2 was prepared by Knochel’s method and underwent
addition to 3-furfural to furnish product in 83% yield.33 The
(E)-alkenylzinc reagent was generated by Oppolzer’s protocol34
via hydroboration of the terminal alkyne followed by trans-
metalation with diethylzinc. The (Z)-alkenylzinc reagent was
generated by our method35,36 involving hydroboration of a
1-bromo-1-alkyne, addition of tert-butyllithium,37 and trans-
metalation of the resulting (Z)-vinylborane with diethylzinc. In
situ generation and addition of these alkenylzinc reagents to
3-furfural proceeded in 92-93% yield, and no scrambling of
the double bond geometry was detected in either product.
With the isolated furyl alcohols in hand, the optimized
oxidation conditions (Table 1, entry 10) were utilized in the
rearrangement. The conditions proved to be tolerant of a range
of functional groups, enabling the installation of alkyl, vinyl,
allyl, aryl, and alkynyl groups at the 2 position with yields
ranging from 66 to 80% (Table 2). No bromination of the
unsaturated side chains or isomerization of the allyl (entry 8)
or vinyl (entries 10 and 11) groups were observed with 1.0 equiv
of NBS. The combined yields for the two-step addition/oxidative
rearrangement process were 63-73%.
We next set out to perform the organometallic addition/
oxidative rearrangement sequence in a one-pot tandem reaction
(Scheme 5). The advantages of the one-pot procedure are that
it is not necessary to isolate the intermediate furyl alcohol and
(33) Langer, F.; Schwink, L.; Devasagayaraj, A.; Chavant, P.-Y.; Knochel, P.
J. Org. Chem. 1996, 61, 8229-8243.
(34) Oppolzer, W.; Radinov, R. N. HelV. Chim. Acta 1992, 75, 170-173.
(35) Jeon, S.-J.; Fisher, E. L.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc.
2006, 128, 9618-9619.
(38) Piancatelli, G.; D’Auria, M.; D’Onofrio, F. Synthesis 1994, 867-889.
(39) Jurczak, J.; Pikul, S. Tetrahedron Lett. 1985, 26, 3039-3040.
(36) Salvi, L.; Jeon, S.-J.; Fisher, E. L.; Carroll, P. J.; Walsh, P. J. J. Am. Chem.
Soc. 2007, 129, 16119-16125.
(40) Fitzpatrick, J. E.; Milner, D. J.; White, P. Synth. Commun. 1982, 12, 489-
494.
(37) Campbell, J. B. J.; Molander, G. A. J. Organomet. Chem. 1978, 156, 71-
79.
(41) Burke, M. D.; Berger, E. M.; Schreiber, S. L. Science 2003, 302, 613-
618.
9
J. AM. CHEM. SOC. VOL. 130, NO. 12, 2008 4101

A R T I C L E S
Kelly et al.
Scheme 9. AD Route to Chiral Enantioenriched Furyl Alcohols.
Scheme 7. Possible Reaction Pathway for the NBS-Promoted
Oxidative Rearrangement.
Table 3. Synthesis of Enantioenriched Furans by Asymmetric
Dihydroxylation of 3-Vinyl Furans with AD-Mix-â and Oxidative
Rearrangement (Scheme 9)
AD
Rearrangement
yield (%)
entry
R
product
yield (%)
ee (%)
product
ee (%)
1
2
3
4
5
CO2Et
5a
5b
5c
5d
5e
78
79
97
79
89
99
>99
97
99
97
6a
6b
6c
6d
6e
63
55
62
66
59
99
>99
97
88
97
CH2OBn
cyclohexyl
3-C6H4-CF3
t-Bu
performed using the conditions outlined above to furnish the
enantioenriched furan products with good conservation of ee.
Only in the case of the aryl substituted derivative was a drop
in ee observed (from 98 to 88% ee). This is most likely due to
the formation of a stabilized benzylic carbocation from the
oxidative rearrangement product.
Scheme 8. Deuterium Labeling Experiment in the Oxidative
Rearrangement.
It is noteworthy that the enantioenriched 2-substituted 3-fur-
furals 6 would be very difficult to prepare using other methods.
Selective asymmetric addition of an organometallic reagent or
enolate derivative to the 2-formyl group of 2,3-diformyl furan
would be challenging.47
To probe the mechanism of the oxidative rearrangement, we
prepared 2-deutero 3-furfural42 (1-d1) using the directed lithiation
of Comins and co-workers (Scheme 1).25 The resulting orga-
nolithium was then quenched with D2O.23,43 The deuterated
product contained 80% deuterium incorporation, as determined
3.5. Enantioselective Synthesis of a Key Intermediate in
Route to (-)-Canadensolide. With this method in hand, we
sought to demonstrate its utility in natural product synthesis.
An interesting natural product target is (-)-canadensolide, which
was isolated from Penicillium canadense by McCorkindale and
co-workers and exhibits antigerminative activity against fungi.48
Several racemic syntheses49-54 and syntheses from enantioen-
riched natural sources55-61 have been reported. With the
exception of Honda’s kinetic resolution (KR),62,32 no syntheses
based on asymmetric catalysis have appeared. Honda’s enan-
1
by integration of the H NMR spectrum. Addition of 1-hexy-
nyllithium, prepared in situ, to 2-deutero 3-furfural (1-d1) gave
the furyl alcohol 2l-d1 in 92% yield with no loss of deuterium
1
(Scheme 8, H NMR spectroscopy). The oxidation was per-
formed with 1.0 equiv of NBS in THF and H2O to generate
1
3l-d1. After rearrangement, it was determined by H and 13C-
{1H} NMR spectroscopic studies that the deuterium was situated
in the aldehydic position (80% incorporation). The outcome of
this labeling study supports the reaction pathway proposed in
Scheme 7 and the intermediacy of an unsaturated 1,4-dialdehyde
or equivalent thereof.
3.4. Synthesis of Enantioenriched 2-Substituted 3-Fur-
furals. Enantioenriched heterocycles are important building
blocks in the pharmaceutical industry, yet their synthesis is often
challenging. We envisioned a different approach to the prepara-
tion of the oxidative rearrangement precursors than organome-
tallic addition to 3-furfural (Scheme 4) or generation of
3-furyllithium (Scheme 6) that would allow enantioselective
introduction of stereogenic centers. Our strategy was to prepare
3-vinyl furans (4) and subject them to the Sharpless asymmetric
dihydroxylation (AD).44-46 A series of 3-vinyl furans were
prepared and dihydroxylated with AD-mix-â affording the
desired diols (5) in 78-97% yield with enantioselectivities
g97% (Scheme 9, Table 3). The oxidative rearrangement was
(44) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung,
J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang,
X.-L. J. Org. Chem. 1992, 57, 2768-2771.
(45) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994,
94, 2483-2547.
(46) Feng, Z.-X.; Zhou, W.-S. Tetrahedron Lett. 2003, 44, 493-495.
(47) Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757-824.
(48) McCorkindale, N. J.; Wright, J. L. C.; Brian, P. W.; Clarke, S. M.;
Hutchinson, S. A. Tetrahedron Lett. 1968, 727-730.
(49) Kato, M.; Tanaka, R.; Yoshikoshi, A. J. Chem. Soc. D 1971, 1561-
1562.
(50) Hon, Y.-S.; Hsieh, C.-H. Tetrahedron 2006, 62, 9713-9717.
(51) Tsuboi, S.; Fujita, H.; Muranaka, K.; Seko, K.; Takeda, A. Chem. Lett.
1982, 1909-1912.
(52) Sakai, T.; Yoshida, M.; Kohmoto, S.; Utaka, M.; Takeda, A. Tetrahedron
Lett. 1982, 23, 5185-5188.
(53) Lertvorachon, J.; Thebtaranonth, Y.; Thongpanchang, T.; Thongyoo, P. J.
Org. Chem. 2001, 66, 4692-4694.
(54) Kato, M.; Kageyama, M.; Tanaka, R.; Kuwahara, K.; Yoshikoshi, A. J.
Org. Chem. 1975, 40, 1932-1941.
(55) Sharma, G. V. M.; Vepachedu, S. R. Tetrahedron 1991, 47, 519-524.
(56) Sharma, G. V. M.; Krishnudu, K.; Rao, S. M. Tetrahedron: Asymmetry
1995, 6, 543-548.
(57) Al-Abed, Y.; Naz, N.; Mootoo, D.; Voelter, W. Tetrahedron Lett. 1996,
37, 8641-8642.
(58) Anderson, R. C.; Fraser-Reid, B. J. Org. Chem. 1985, 50, 4786-4790.
(59) Anderson, R. C.; Fraser-Reid, B. Tetrahedron Lett. 1978, 3233-3236.
(60) Nubbemeyer, U. Synthesis 1993, 1120-1128.
(61) Ohrui, H.; Sueda, N.; Kuzuhara, H. Nippon Kagaku Kaishi 1981, 769-
775.
(42) Gronowitz, S.; Johnson, I.; Hornfeldt, A.-B. Chem. Scr. 1975, 7, 211-
222.
(43) Denat, F.; Gaspard-Iloughmane, H.; Dubac, J. Synthesis 1992, 954-
(62) Honda, T.; Kobayashi, Y.; Tsubuki, M. Tetrahedron Lett. 1990, 31, 4891-
956.
4894.
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4102 J. AM. CHEM. SOC. VOL. 130, NO. 12, 2008

3-Furfurals and 3-Furyl Imines
A R T I C L E S
Scheme 10. Our Synthesis of Honda’s Furyl Alcohol Intermediate
in Route to (-)-Canadensolide.
Table 4. Synthesis of 2-Substituted 3-Formyl Pyrroles (Scheme
11)
addition
oxidation
entry
organometallic reagent
product
yield (%)
product
yield (%)
1
2
3
4
5
6
7
EtMgBr
n-BuLi
PhLi
BrMg(2-C6H4-Me)
BrMg(1-Naphthyl)
(Allyl)MgBr
12a
12b
12c
12d
12e
12f
94
90
90
91
92
91
90
13a
13b
13c
13d
13e
13f
67
67
70
73
71
54
72
12g
13g
The addition and oxidative rearrangements of a variety of
imine substrates were examined (Scheme 11), and the results
are compiled in Table 4. Addition of alkyl (entries 1-2), aryl
(entries 3-5), allyl (entry 6), and vinyl (entry 7) organometallic
reagents to the furyl imines furnished the desired furyl amines
in high isolated yields (90-95%). The oxidative rearrangement
of the furyl sulfonamide addition products was performed with
NBS under conditions identical to those used in the rearrange-
ment of the furyl alcohols (Table 2). These reactions proceeded
smoothly to provide the pyrrole products in 54-73% yield. The
addition/oxidative rearrangement route to pyrroles from readily
available 3-furfural is a straightforward and practical method
to access these valuable heterocycles.
4. Conclusions and Outlook. We have introduced new
methods to prepare functionalized 2-substituted 3-furfurals and
2-substituted 3-formyl pyrroles. Unlike prior methods to prepare
these fundamental heterocyclic building blocks, our methods
enable the synthesis of a range of derivatives that can be isolated
free of undesired isomers. Furthermore, in many cases the addi-
tion to 3-furfural/oxidative rearrangement can be carried out in
a tandem one-pot procedure, circumventing intermediate puri-
fication.
Scheme 11. Synthesis of 2-Substituted 3-Formyl Pyrroles.
tioenriched furyl alcohol intermediate, which was prepared by
KR63 with the Sharpless-Katsuki catalyst (41%, providing
product of >95% ee)64,65 attracted our attention.62,32
To highlight our oxidative rearrangement method, we ap-
proached the synthesis of Honda’s enantioenriched furyl alcohol
intermediate (10) as outlined in Scheme 10. A Suzuki cross-
coupling66 of 3-bromofuran with 1-hexenyl-1-boronic acid
produced the trans alkene 7 in 82% yield. The Sharpless AD
was performed with AD-mix-â to afford the desired diol 8 in
87% yield with 98% ee. Subjecting the diol to our oxidative
rearrangement protocol led to the desired 2-substituted 3-furfural
intermediate 9 with no loss of ee, as determined by chiral
stationary phase HPLC (Scheme 10). From this intermediate,
reduction with NaBH4 and selective TBS protection of the
primary alcohol led to formation of the furyl alcohol 10 in 78%
yield over this two step procedure. The overall yield of our
synthesis was 38%, which compares favorably with the 22%
yield achieved by Honda. Given the improved yield and high
enantiopurity of the furyl alcohol in Scheme 10, coupled with
the scalability of the oxidative furan synthesis (Scheme 5), we
anticipate that this method will be useful in the synthesis of
other natural products.
The precursors to the oxidative furan rearrangement can be
prepared by three approaches: (1) addition of organolithium,
Grignard, and organozinc reagents to 3-furfural, (2) addition of
3-furyllithium to aldehydes, and (3) asymmetric dihydroxylation
of 3-vinylfurans. The later method enables the synthesis of
enantioenriched furan derivatives and has been applied to the
generation of an intermediate in Honda’s synthesis of the natural
product (-)-canadensolide.
3.6. Synthesis of 2-Substituted 3-Formyl Pyrroles. On the
basis of our oxidative rearrangement mechanism (Scheme 7),
we hypothesized that 3-furyl imines (11) would undergo a
similar rearrangement sequence to form pyrroles (13, Scheme
11). To activate the imine toward nucleophilic addition and serve
as a protecting group for the resulting pyrrole, we chose to
employ N-sulfonyl imines. Although deprotection of sulfona-
mides is quite difficult, the sulfonyl group is an excellent
protecting group for pyrroles67 because it not only moderates
the high reactivity of pyrroles but it is easily removed under
basic conditions.68
Our method for the synthesis of 2-substituted 3-formyl
pyrroles begins with the readily prepared sulfonyl imine of
3-furfural. Addition of organometallic reagents generates sul-
fonamides in high yields. When subjected to oxidative rear-
rangement conditions, the furyl sulfonamide undergoes pyrrole
formation. This method makes possible the generation of alkyl,
aryl, vinyl, and allyl substituted pyrroles that would be otherwise
difficult to access. Finally, our deuterium labeling studies and
the formation of pyrroles from furyl sulfonamides support a
proposed mechanism involving oxidative cleavage of the furan
ring to an unsaturated 1,4-dialdehyde intermediate. This highly
reactive intermediate is not observed but undergoes cyclization
to form the observed furan and pyrrole products.
(63) Mart´ın, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.;
Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237-6240.
(64) Kobayashi, Y.; Kusakabe, M.; Kitano, Y.; Sato, F. J. Org. Chem 1988, 53,
1586-1587.
The importance of heterocycles in natural products and
medicinal chemistry, coupled with the versatility and scalability
of our methods to prepare substituted furans and pyrroles, make
(65) Kusakabe, M.; Kitano, Y.; Kobayashi, Y.; Sato, F. J. Org. Chem 1989, 54,
2085-2091.
(66) Molander, G. A.; Bernardi, C. R. J. Org. Chem. 2002, 67, 8424-8429.
(67) Thompson, A.; Butler, R. J.; Grundy, M. N.; Laltoo, A. B. E.; Robertson,
K. N.; Cameron, T. S. J. Org. Chem. 2005, 70, 3753-3756.
(68) Kozikowski, A. P.; Chen, Y. Y. J. Org. Chem. 1981, 46, 5248-5250.
9
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A R T I C L E S
Kelly et al.
these methods potentially very useful in target and diversity-
oriented synthesis.69
Supporting Information Available: Procedures, full charac-
terization, and stereochemical assignments of new compounds
are available (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the NSF (CHE-065210) and
NIH (National Institute of General Medical Sciences, GM58101)
for partial support of this work. We are also grateful to Akzo
Nobel Polymer Chemicals for a gift of dialkylzinc reagents.
JA710988Q
(69) Schreiber, S. L. Science 2000, 287, 1964-1969.
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4104 J. AM. CHEM. SOC. VOL. 130, NO. 12, 2008