Regiocontrolled synthesis of pyrrole-2-carboxaldehydes and 3-pyrrolin-2-ones from pyrrole Weinreb amides

Article abstract of DOI:10.1021/jo061043m

A regiocontrolled synthesis of 3,4-disubstituted pyrrole-2-carboxaldehydes was completed in two steps from acyclic starting materials. A Barton-Zard pyrrole synthesis between N-methoxy-N-methyl-2-isocyanoacetamide and α-nitroalkenes or β-nitroacetates provided N-methoxy-N-methyl pyrrole-2-carboxamides (pyrrole Weinreb amides), which were converted into the corresponding pyrrole-2-carboxaldehydes by treatment with lithium aluminum hydride. A regioselective oxidation of the pyrrole-2-carboxaldehydes gave the corresponding 3,4-disubstituted 3-pyrrolin-2-ones.

Full text of DOI:10.1021/jo061043m

SCHEME 1. Selected Routes to 3-Pyrrolin-2-ones
Regiocontrolled Synthesis of
Pyrrole-2-carboxaldehydes and 3-Pyrrolin-2-ones
from Pyrrole Weinreb Amides
Aaron R. Coffin, Michael A. Roussell, Elina Tserlin, and
Erin T. Pelkey*
Department of Chemistry, Hobart and William Smith Colleges,
300 Pulteney St., GeneVa, New York 14456
pelkey@hws.edu
bazoles.7 5-Unsubstituted 3,4-diaryl-3-pyrrolin-2-ones have been
synthesized and evaluated as COX-II inhibitors.8 Furthermore,
simple N-substituted 3-pyrrolin-2-ones have served as precursors
to 2-silyloxypyrroles,9 compounds that have been exploited for
the preparation of complex nitrogen heterocycles.10
ReceiVed May 22, 2006
Notable synthetic routes to 5-unsubstituted 3,4-disubstituted
3-pyrrolin-2-ones include intramolecular condensation reac-
tions,11,12 reductive cyclization of cyanoesters13 (not shown),
oxidation of a pyrrole moiety,14 and reduction of a maleimide
moiety15 (Scheme 1). The first two strategies operate under
complete regiocontrol but often require multiple steps and/or
complex starting materials to prepare the acyclic substrates. The
A regiocontrolled synthesis of 3,4-disubstituted pyrrole-2-
carboxaldehydes was completed in two steps from acyclic
starting materials. A Barton-Zard pyrrole synthesis between
N-methoxy-N-methyl-2-isocyanoacetamide and R-nitroalk-
enes or â-nitroacetates provided N-methoxy-N-methyl pyr-
role-2-carboxamides (pyrrole Weinreb amides), which were
converted into the corresponding pyrrole-2-carboxaldehydes
by treatment with lithium aluminum hydride. A regioselective
oxidation of the pyrrole-2-carboxaldehydes gave the corre-
sponding 3,4-disubstituted 3-pyrrolin-2-ones.
(6) (a) Woydziak, Z. R.; Boiadjiev, S. E.; Norona, W. S.; McDonagh,
A. F.; Lightner, D. A. J. Org. Chem. 2005, 70, 8417-8423. (b) Tu, B.;
Ghosh, B.; Lightner, D. A. Tetrahedron 2004, 60, 9017-9029. (c) Chen,
Q.; Wang, T.; Zhang, Y.; Wang, Q.; Ma, J. Synth. Commun. 2002, 32,
1031-1040. (d) Jacobi, P. A.; DeSimone, R. W.; Ghosh, I.; Guo, J.; Leung,
S. H.; Pippin, D. J. Org. Chem. 2000, 65, 8478-8489.
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B. Tetrahedron Lett. 2004, 45, 2347-2349. (b) Wood, J. L.; Stoltz, B. M.;
Dietrich, H.-J.; Pflum, D. A.; Petsch, D. T. J. Am. Chem. Soc. 1997, 119,
9641-9651.
Pyrrole-2-carboxaldehydes and 3-pyrrolin-2-ones (1H-pyrrol-
2(5H)-ones) are important heterocyclic building blocks utilized
in the preparation of a wide array of biologically active
compounds. Highly functionalized pyrrole-2-carboxaldehydes
have been employed as key intermediates in the synthesis of
oligopyrrole macrocycles,1,2 linear oligopyrroles,3 porphobili-
nogen analogues,4 and kinase inhibitors.5 The condensation of
pyrrole-2-carboxaldehydes with 3-pyrrolin-2-ones provides dipyr-
rinones,6 useful materials for the preparation of oligopyrrole
plant pigments. Substituted 3-pyrrolin-2-ones have also been
utilized as starting materials for the preparation of indolocar-
(8) (a) Bai, A. P.; Guo, Z. R.; Hu, W. H.; Shen, F.; Cheng, G. F. Chin.
Chem. Lett. 2001, 12, 775-778. (b) Bosch, J.; Roca, T.; Catena, J.-L.;
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(9) Casiraghi, G.; Rassu, G. Synthesis 1995, 607-626.
(10) Recent examples of the use of 2-silyloxypyrroles in synthesis: (a)
Brimble, M. A.; Burgess, C.; Halim, R.; Petersson, M.; Ray, J. Tetrahedron
2004, 60, 5751-5758. (b) DeGoey, D. A.; Chen, H.-J.; Flosi, W. J.;
Grampovnik, D. J.; Yeung, C. M.; Klein, L. L.; Kempf, D. J. J. Org. Chem.
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Yeleswarapu, K. R. Tetrahedron 2004, 60, 3987-3997. (b) References 6c,
8a, and 8b.
(1) (a) Barbe, J. M.; Burdet, F.; Espinosa, E.; Gros, C. P.; Guilard, R. J.
Porphyrins Phthalocyanines 2003, 7, 365-374. (b) Paolesse, R.; Pandey,
R. K.; Forsythe, T. P.; Jacquinod, L.; Gerzevske, K. R.; Nurco, D. J.; Senge,
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(2) Notably, pyrrole-2-carboxaldehydes were utilized as building blocks
in the total synthesis of chlorophyll a: Woodward, R. B.; Ayer, W. A.;
Beaton, J. M.; Bickelhaupt, F.; Bonnett, R.; Buchschacher, P.; Closs, G.
L.; Dutler, H.; Hannah, J.; Hauck, F. P.; Itoˆ, S.; Langemann, A.; Le Goff,
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Tetrahedron 1990, 46, 7599-7659.
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(b) De Leon, C. Y.; Ganem, B. Tetrahedron 1997, 53, 7731-7752.
(5) (a) Lin, N.-H.; Xia, P.; Kovar, P.; Park, C.; Chen, Z.; Zhang, H.;
Rosenberg, S. H.; Sham, H. L. Bioorg. Med. Chem. Lett. 2006, 16, 421-
426. (b) Sun, L.; Tran, N.; Liang, C.; Tang, F.; Rice, A.; Schreck, R.; Waltz,
K.; Shawver, L. K.; McMahon, G.; Tang, C. J. Med. Chem. 1999, 42, 5120-
5130.
(12) Intramolecular condensation approaches to indolocarbazoles: (a)
Trost, B. M.; Krische, M. J.; Berl, V.; Grenzer, E. M. Org. Lett. 2002, 4,
2005-2008. (b) Kobayashi, Y.; Fujimoto, T.; Fukuyama, T. J. Am. Chem.
Soc. 1999, 121, 6501-6502. (c) Eils, S.; Winterfeldt, E. Synthesis 1999,
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54, 6909-6918. (b) Bishop, J. E.; Nagy, J. O.; O’Connell, J. F.; Rapoport,
H. J. Am. Chem. Soc. 1991, 113, 8024-8025.
(14) For the oxidation of R-unsubstituted pyrroles: (a) Xie, M.; Lightner,
D. A. Tetrahedron 1993, 49, 2185-2200. (b) Bonnett, R.; Buckley, D. G.;
Hamzetash, D. J. Chem. Soc., Perkin Trans. 1 1981, 322-325. (c) Bocchi,
V.; Chierici, L.; Gardini, G. P.; Mondelli, R. Tetrahedron 1970, 26, 4073-
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1998, 63, 6053-6058. (b) Link, J. T.; Raghavan, S.; Gallant, M.;
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Tetrahedron Lett. 1993, 34, 8361-8364.
10.1021/jo061043m CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/26/2006
6678
J. Org. Chem. 2006, 71, 6678-6681

SCHEME 2. Retrosynthetic Approach
SCHEME 3. Preparation of Isocyanide 7a
latter two strategies are well suited to the preparation of sym-
metrical substrates with respect to the substitution pattern at
the 3- and 4-positions (R1 ) R2), but both require a regio-
selective transformation in the event of nonsymmetrical sub-
strates (R1 * R2) and this often proves to be dependent on steric
and/or electronic factors. In the case of a reported total syn-
thesis of the indolocarbazole natural product staurosporine, a
regioselective reduction of a maleimide moiety proved to be
problematic.15bc Similarly, the synthesis of pyrrole-2-carboxal-
dehydes utilizing either a Vilsmeier-Haack formylation16 or
metalation17 often lead to mixtures of products when nonsym-
metrical pyrrole substrates are involved.18
We envisioned a new regiocontrolled route to 5-unsubstituted
3,4-disubstituted pyrrole-2-carboxaldehydes 2 and 3-pyrrolin-
2-ones 3 starting from the corresponding pyrrole Weinreb
amides 1 (Scheme 2).19 First, compounds 1 could be converted
to pyrrole-2-carboxaldehydes 2 by reduction of the Weinreb
amide.20 Second, a precedented regiospecific oxidation21 of the
formyl group of 2 followed by hydrolysis of the intermediate
formate esters would lead to the desired 3-pyrrolin-2-ones 3.
The requisite pyrrole Weinreb amides 1 could be obtained by
utilizing the Barton-Zard pyrrole synthesis,22,23 a cyclocon-
densation reaction between an R-nitroalkene or â-nitroacetate
and an activated isocyanide. This reaction has received much
attention for the preparation of 3,4-disubstituted pyrrole-2-
carboxylates suitable for the preparation of porphyrins and
related macrocyclic pyrrole-containing materials,23ab although
it has not been utilized for the synthesis of pyrrole Weinreb
amides.24 Overall, this synthetic route to pyrrole-2-carboxalde-
hydes and 3-pyrrolin-2-ones is attractive as a result of the
flexibility afforded by incorporating readily available starting
a Reagents and conditions: (a) MeONHMe, DCC, CH2Cl2, 0 °C f rt
(78%); (b) HCO2H, 80 °C; (c) HCO2Et, Et3N, ∆ (65%, two steps); (d)
POCl3, Et3N, THF (70%).
materials that include nitroalkanes25 and aldehydes (Henry
reactions of which give R-nitroalkenes26 or â-nitroacetates22a
)
along with known isocyanide 7.27 Notably, related syntheses
of 3-pyrrolin-2-ones have been reported28 that involve the
regioselective introduction of oxygen onto R-tosylpyrroles.
The synthesis of known isocyanide 727 was achieved in four
steps from Boc-glycine (4) utilizing a procedure that differed
from the literature29 (Scheme 3). DCC coupling of 4 with freshly
distilled N,O-dimethylhydroxylamine gave 5 in 78% yield.
Removal of the Boc group and formylation gave 6 in 65% yield
(two steps) after a modified workup. Finally, dehydration of
the formamide 6 with phosphorus oxychloride gave the desired
isocyanide 7 in 70% yield, which represents an improvement
over the literature yield of 50% for the same transformation.27b
The yield for this dehydration reaction appears to be dependent
on the purity of the formamide substrate, and thus an extra
workup step of the crude formamide 6 proved to be beneficial.
The synthesis of pyrrole Weinreb amides 1 was simulta-
neously investigated with both â-nitroacetates 8 and R-nitro-
alkenes 9. The cyclocondensation reaction between isocyanide
7 and 8 or 9 in the presence of DBU led to the corresponding
pyrrole Weinreb amides 1 in good yields when the reaction
conditions were kept mild (0 °C f rt) (Table 1). With
nonsymmetrical pyrroles 1b and 1c, the expected regiochemistry
was confirmed by their subsequent conversion to the corre-
sponding known pyrrole-2-carboxaldehydes 2b and 2c and
known 3-pyrrolin-2-ones 3b and 3c, respectively.
(16) de Groot, J. A.; Gorter-La Roy, G. M.; van Koeveringe, J. A.;
Lugtenburg, J. Org. Prep. Proc. Int. 1981, 13, 97-101.
(17) (a) Katritzky, A. R.; Kunihiko, A. Org. Prep. Proc. Int. 1988, 20,
585-590. (b) Brittain, J. M.; Jones, R. A.; Arques, J. S.; Saliente, T. A.
Synth. Commun. 1982, 12, 231-248.
The pyrrole Weinreb amides 1 were then converted into the
corresponding known pyrrole-2-carboxaldehyes 2 by reduction
with lithium aluminum hydride30 in THF (Table 2). The yields
obtained were moderate, and no major byproducts were isolated.
(18) Examples of formylations that give mixtures of regioisomeric
formylpyrroles: (a) Balasubramanian, T.; Strachan, J.-P.; Boyle, P. D.;
Lindsey, J. S. J. Org. Chem. 2000, 65, 7919-7929 (compound 4). (b)
Reference 2 (compound 24); (c) Reference 4b (compound 29).
(19) This work was initially communicated in part at two conferences:
(a) Roussell, M. A.; Pelkey, E. T. Abstracts of Papers, 224th National
Meeting of the American Chemical Society, Boston, MA.; American
Chemical Society: Washington, DC, 2002; CHED 200. (b) Tserlin, E.;
Pelkey, E. T. Abstracts of Papers, 224th National Meeting of the American
Chemical Society, Boston, MA.; American Chemical Society: Washington,
DC, 2002; CHED 215. (c) Coffin, A. R.; Pelkey, E. T. Abstract of Papers,
47th Undergraduate Research Symposium-ACS Rochester Section, Geneva,
NY.; American Chemical Society: Washington, DC, 2002.
(20) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-3818.
(21) Pichon-Santander, C.; Scott, I. A. Tetrahedron Lett. 2000, 41, 2825-
2829. See also: Hwang, K.-O.; Lightner, D. A. Tetrahedron 1994, 50,
1955-1966.
(22) (a) Barton, D. H. R.; Kervagoret, J.; Zard, S. Z. Tetrahedron 1990,
46, 7587-7598. (b) Ono, N.; Kawamura, H.; Bougauchi, M.; Maruyama,
K. Tetrahedron 1990, 46, 7483-7496.
(24) Examples of pyrrole Weinreb amides in the literature prepared from
the corresponding pyrrole-2-carboxylic acids: (a) Ruiz, J.; Sotomayor, N.;
Lete, E. Org. Lett. 2003, 5, 1115-1117. (b) Banwell, M.; Smith, J. Synth.
Commun. 2001, 31, 2011-2019.
(25) (a) Ballini, R.; Barboni, L.; Giarlo, G. J. Org. Chem. 2004, 69,
6907-6908. (b) Rosini, G.; Ballini, R. Synthesis 1988, 833-847. (c)
Kornblum, N.; Larson, H. O.; Blackwood, R. K.; Mooberry, D. D.; Oliveto,
E. P.; Graham, G. E. J. Am. Chem. Soc. 1956, 78, 1497-1501.
(26) (a) Ballini, R.; Castagnani, R.; Petrini, M. J. Org. Chem. 1992, 57,
2160-2162. (b) Robertson, D. N. J. Org. Chem. 1960, 25, 47-50.
(27) (a) Kim, S. W.; Bauer, S. M.; Armstrong, R. W. Tetrahedron Lett.
1998, 39, 6993-6996. (b) Sawamura, M.; Nakayama, Y.; Kato, T.; Ito, Y.
J. Org. Chem. 1995, 60, 1727-1732.
(28) (a) Kakiuchi, T.; Kinoshita, H.; Inomata, K. Synlett 1999, 901-
904. (b) Kohori, K.; Hashimoto, M.; Kinoshita, H.; Inomata, K. Bull. Chem.
Soc. Jpn. 1994, 67, 3088-3093. (c) see also refs 6a, 6b.
(29) With regard to the reported syntheses of isocyanide 7: (a) Reference
27a utilized Boc-glycine but offered very little experimental details and no
yields. (b) Reference 27b utilized Cbz-glycine.
(23) Recent applications of the Barton-Zard pyrrole synthesis: (a)
Okujima, T.; Komobuchi, N.; Uno, H.; Ono, N. Heterocycles 2006, 67,
255-267. (b) Cillo, C. M.; Lash, T. D. Tetrahedron 2005, 61, 11615-
11627. (c) Larionov, O. V.; de Meijere, A. Angew. Chem., Int. Ed. 2005,
44, 5664-5667. (d) Reference 6a.
(30) Kolhatkar, R. B.; Ghorai, S. K.; George, C.; Reith, M. E. A.; Dutta,
A. K. J. Med. Chem. 2003, 46, 2205-2215.
J. Org. Chem, Vol. 71, No. 17, 2006 6679

metrical pyrrole-2-carboxaldehydes and 3-pyrrolin-2-ones with
respect to substituents located in the â-positions, and this might
prove useful for the preparation of oligopyrroles and related
compounds. Furthermore, by taking advantage of the chemistry
associated with the Weinreb amide functionality,33 1 could prove
to be useful precursors to 2-ketopyrroles.
TABLE 1. Preparation of Pyrrole Weinreb Amides 1
Experimental Section
General Method. Synthesis of Pyrrole Weinreb Amides 1
from R-Nitroalkenes 9. To a 0 °C stirred solution of isocyanide 7
(0.51 g, 4.0 mmol) and DBU (0.84 mL, 5.6 mmol) in THF (10
mL) was added a solution of R-nitroalkene 9 (5.6 mmol) in THF
(10 mL) dropwise via syringe. The reaction mixture was stirred at
0 °C for 30 min and then at room temperature for 4 h. The solvent
was then removed in vacuo, and the crude material obtained was
purified by flash chromatography (ethyl acetate/petroleum ether
gradient).
substrate
R1
Me
Me
Et
R2
Me
Me
Me
Me
Et
Et
-[CH2]4-
Ph
product
(%)
8a
9a
8b
9b
8c
9c
9d
9e
1a
1a
1b
1b
1c
1c
1d
1e
89
89
95
92
85
90
84
71
Et
Me
Me
-[CH2]4-
Ph
N-Methoxy-N-methyl-3,4-diphenylpyrrole-2-carboxamide (1e).
The product was obtained as a white amorphous solid (71% yield).
Recrystallization (ethyl acetate) gave the analytical sample as white
prisms: mp 137-140 °C; Rf ) 0.16 (1:2 ethyl acetate/petroleum
ether); IR (film) 3470, 3220, 3025, 2990, 1610, 1470, 1425, 1380,
1265, 1070, 1020, 965, 940, 895, 860 cm-1; 1H NMR (CDCl3, 300
MHz) δ 10.01 (br s, 1 H), 7.03-7.26 (m, 10 H), 7.06 (d, 1 H, J )
3.0 Hz), 3.59 (s, 3 H), 2.98 (s, 3 H) ppm; 13C NMR (CDCl3, 75
MHz) δ 162.4, 135.5, 135.1, 130.5, 128.7, 128.33, 128.26, 127.5,
126.9, 126.1, 125.5, 121.6, 119.9, 61.0, 35.2 ppm; MS m/z 276,
275 (M+ - OMe), 246 (M+ - NMeOMe), 245, 217, 216, 190,
189. Anal. Calcd for C19H18N2O2: C, 74.49; H, 5.92; N, 9.14.
Found: C, 74.25; H, 5.92; N, 9.14.
TABLE 2. Preparation of Pyrrole-2-carboxaldehydes 2 and
3-Pyrrolin-2-ones 3a
substrate
R1
Me
Et
Me
-[CH2]4-
Ph
R2
Me
Me
Et
-[CH2]4-
Ph
2 (%)b
3 (%)c
1a
1b
1c
1d
1e
84
69
65
59
72
50
73
67
56
80
General Method. Synthesis of Pyrrole-2-carboxaldehydes 2.
To a 0 °C stirred mixture of lithium aluminum hydride (57 mg,
1.5 mmol) in THF (5 mL) was added a solution of pyrrole Weinreb
amide 1 (1.0 mmol) dissolved in THF (10 mL) dropwise via
addition funnel. The reaction mixture was stirred at 0 °C for 2-4
h and monitored by TLC (1:4 ethyl acetate/petroleum ether). Upon
completion, the reaction mixture was treated with an aqueous
solution of KHSO4 (0.82 g, 6.0 mmol) in deionized water (20 mL)
dropwise via addition funnel followed by dilution with ether (20
mL). The organic layer was separated, and the aqueous layer was
extracted with ether (3 × 20 mL). The combined organic layers
were washed with aqueous citric acid (5% w/v, 50 mL), aqueous
sodium bicarbonate (saturated, 50 mL), and brine (50 mL) and dried
over sodium sulfate. Removal of the solvent in vacuo gave a crude
material that was purified by flash chromatography (ethyl acetate/
petroleum ether gradient).
a Reaction conditions: (a) LiAlH4, THF, 0 °C; (b) H2O2, NaHCO3,
MeOH, rt. b Yields of 2 are reported for isolated, chromatographed materials.
c Yields of 3 are reported for isolated, recrystallized materials.
The identity of 2 was confirmed by comparison to reported
spectral data.31 This reduction was also investigated using
DIBAL32 with 1c, but unexpectedly, none of the desired product
2c was formed. Importantly, this sequence allows for the
preparation of pyrrole-2-carboxaldehydes where the substitution
pattern can be controlled by the appropriate choice of starting
material.
Finally, oxidation of the pyrrole-2-carboxaldehydes 2 to the
corresponding known 3-pyrrolin-2-ones 3 was accomplished
utilizing hydrogen peroxide and sodium bicarbonate as described
by Scott and Pichon-Santander.21 This reaction presumably
proceeds via a Baeyer-Villiger-type oxidation of the formyl
group followed by hydrolysis of the intermediate formate ester.
Again, the identity of 3 was confirmed by comparison to
reported spectral data.31
In conclusion, we have demonstrated a novel synthetic route
to 3,4-disubstituted pyrrole-2-carboxaldehydes 2 and 3-pyrrolin-
2-ones 3 from readily available acyclic starting materials as
follows: (1) Barton-Zard pyrrole synthesis leading to pyrrole
Weinreb amides 1; (2) reduction to pyrrole-2-carboxaldehydes
2; and (3) a regioselective oxidation to 3-pyrrolin-2-ones 3.
Significantly, this work allows for the preparation of nonsym-
3,4-Diphenylpyrrole-2-carboxaldehyde (2e).34 The product was
obtained as a red amorphous solid (72% yield): mp 168-172 °C
(lit.34 mp 168-170 °C); Rf ) 0.30 (1:4 ethyl acetate/petroleum
1
ether); H NMR (d6-DMSO, 300 MHz) δ 12.40 (br s, 1 H), 9.30
(s, 1 H), 7.11-7.49 (m, 11 H) ppm; 13C NMR (d6-DMSO, 75 MHz)
δ 179.2, 134.0, 132.8, 130.4, 130.0, 128.4, 128.3, 127.8, 127.4,
126.1, 125.2, 125.0, 124.7 ppm; MS m/z 248, 247 (M+), 246, 218,
189, 165, 152, 140, 123, 115, 108.
General Method. Synthesis of 3-Pyrrolin-2-ones (1H-Pyrrol-
2(5H)-ones) 3. A modification of a reported procedure was
utilized.21 To a room temperature stirred solution of pyrrole-2-
carboxaldehyde 2 (2.0 mmol) in methanol (50 mL) was added
sodium bicarbonate (1.7 g, 20 mmol) followed by hydrogen
peroxide (30% w/v, 2.3 mL, 20 mmol). The reaction mixture was
stirred for 3-7 d, and additional hydrogen peroxide was added
periodically until TLC (4:1 ethyl acetate/petroleum ether, visualiza-
(31) See Supporting Information for references regarding known pyrrole-
2-carboxaldehydes 2 and known 3-pyrrolin-2-ones 3.
(32) Davies, I. W.; Marcoux, J.-F.; Corley, E. G.; Journet, M.; Cai, D.-
W.; Palucki, M.; Wu, J.; Larsen, R. D.; Rossen, K.; Pye, P. J.; DiMichele,
L.; Dormer, P.; Reider, P. J. J. Org. Chem. 2000, 65, 8415-8420.
(33) Ruiz, J.; Ardeo, A.; Ignacio, R.; Sotamayor, N.; Lete, E. Tetrahedron
2005, 61, 3311-3324.
(34) Dannhardt, G.; Steindl, L. Arch. Pharm. (Weinheim) 1986, 319,
749-755.
6680 J. Org. Chem., Vol. 71, No. 17, 2006

tion with Ehrlich’s reagent) showed complete conversion (total
hydrogen peroxide, 30-60 mmol). The solvent was then removed
in vacuo, and the crude material obtained was treated with deionized
water (30 mL) and aqueous HCl (0.1 M, 30 mL). The aqueous
layer was extracted with CH2Cl2 (5 × 50 mL). The organic layer
was concentrated in vacuo, giving a crude material that was purified
by flash chromatography (gradient ethyl acetate/petroleum ether).
3,4-Diphenyl-1H-pyrrol-2(5H)-one (3e).35 The product was
obtained as a yellow amorphous solid (80% yield): mp 182-183
°C (lit.35 mp 192-193 °C); Rf ) 0.56 (4:1 ethyl acetate/petroleum
Acknowledgment. Support of this research by a Camille &
Henry Dreyfus start-up grant (E.T.P.), Merck/AAAS/Perkin
Foundations undergraduate summer fellowships (E.T. and
M.A.R.), a Council of Undergraduate Research summer fel-
lowship (A.R.C.), Patchett Foundation undergraduate summer
fellowship (A.R.C.), Research Corporation, and Hobart and
William Smith Colleges is greatly appreciated. This work also
benefited from helpful correspondence with Dr. A. I. Scott and
Clotilde Pichon-Santander.
1
ether); H NMR (d6-DMSO, 300 MHz) δ 8.62 (br s, 1 H), 7.33-
7.36 (m, 10 H), 4.41 (s, 2 H) ppm; 13C NMR (d6-DMSO, 75 MHz)
δ 172.4, 150.4, 133.3, 132.3, 131.7, 129.3, 129.0, 128.6, 128.1,
127.7, 127.5, 47.5 ppm; MS m/z 235 (M+), 206, 191, 178.
Supporting Information Available: General methods, experi-
mental procedures (5-7), and spectral data (1-3, 5-7). This
material is available free of charge via the Internet at http://pubs.
acs.org.
(35) Yakushijin, K.; Kozuka, M.; Furukawa, H. Chem. Pharm. Bull. 1980,
28, 2178-2184.
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