Suzuki-Miyaura cross-coupling approach to 3,4-diaryl-3-pyrrolin-2-ones from tetramic acid triflates

Article abstract of DOI:10.1055/s-2007-983778

A three-step approach to 4-aryl-3-phenyl-3-pyrrolin-2-ones from a readily available tetramic acid is described. The introduction of different aryl groups to the 4-position of the ring system was accomplished utilizing Suzuki-Miyaura cross-coupling reactio

Full text of DOI:10.1055/s-2007-983778

PAPER
2317
Suzuki–Miyaura Cross-Coupling Approach to 3,4-Diaryl-3-pyrrolin-2-ones
from Tetramic Acid Triflates
3
, 4-Diaryl-3-pyrr
o
a
lin-2-one
s
t
T
e
tramic Acid
rTriflatesyn M. Dorward, Nicolette J. Guthrie, Erin T. Pelkey*
Department of Chemistry, Hobart and William Smith Colleges, Geneva, NY 14456, USA
Fax +1(315)7813860; E-mail: pelkey@hws.edu
Received 23 March 2007
This article is dedicated to Professor Paul Wender in honor of his 60th birthday.
MeO2S
RO2S
Abstract: A three-step approach to 4-aryl-3-phenyl-3-pyrrolin-2-
ones from a readily available tetramic acid is described. The intro-
duction of different aryl groups to the 4-position of the ring system
was accomplished utilizing Suzuki–Miyaura cross-coupling reac-
tions of the corresponding tetramic acid triflate. This strategy was
successfully employed in the first synthesis of the NH lactam ana-
Het
O
X
logue of rofecoxib.
1 R = Me or NH2
2a X = O (rofecoxib)
2b X = N-alkyl
2c X = N-aryl
Key words: lactams, Suzuki–Miyaura cross-couplings, arylations,
3-pyrrolin-2-ones, tetramic acids
7f X = N-H
Figure 1 General structures of diaryl heterocyclics 1, 2, and 7f
3-Pyrrolin-2-ones [or 1H-pyrrol-2(5H)-ones] are an im-
portant class of nitrogen heterocycles found in a variety of
natural product classes including oligopyrrole plant pig-
ments,1 indolocarbazoles,2 steroidal alkaloids,3 and the
pukeleimides.4 Small molecule examples of 3-pyrrolin-2-
ones have demonstrated interesting biological activity as
inhibitors of platelet aggregation,5 tyrosine phosphatase,6
and cyclooxygenase-2 (COX-2).7,8 With regard to the lat-
ter, a large number of diaryl heterocyclic compounds of
general structure 1 have been investigated as selective in-
hibitors of COX-2 (Figure 1). The most notable example
is furan-2-one 2a9 also known as rofecoxib (Vioxx®).
Structurally related 3-pyrrolin-2-ones analogues of 2a
have also been investigated including N-alkyl lactam de-
rivatives 2b7 and N-aryl lactam derivatives 2c.8 To our
knowledge, the corresponding NH lactam analogue 7f has
not been previously reported. Due to their wide range of
possible applications as bioactive molecules and as build-
ing blocks for more complex materials, we have on-going
interest in developing novel, efficient syntheses of highly
functionalized 3-pyrrolin-2-ones including N-unsubstitut-
ed derivatives.10 Herein, we report our progress directed at
developing a flexible synthesis of 3,4-diaryl-3-pyrrolin-2-
ones 7.
and co-workers had utilized DMB as a lactam protecting
group in their total synthesis of the indolocarbazole natu-
ral product K-252a.14
The preparation of the tetramic acid 4a was accomplished
in three steps starting from veratrylamine (3)
(Scheme 1)14b,15 as follows: (1) an N-alkylation with ethyl
bromoacetate gave a crude secondary amine intermediate;
(2) an N-acylation of this with phenylacetyl chloride gave
a crude tertiary amide intermediate; and (3) finally an in-
tramolecular Dieckmann-type cyclocondensation gave 4a
after an acidic work-up. Compound 4a was obtained in
analytically pure form by crystallization from ethyl ace-
tate. We initially attempted to transform the enol moiety
into the corresponding vinyl halide. All of our attempts to
convert 4a into the vinyl bromide (PBr3 or CBr4/PPh3) or
vinyl chloride (POCl3) failed. Eventually, we obtained the
cross-coupling substrate enol triflate 4b upon treatment of
4a with triflic anhydride in the presence of triethylamine.
Triflate 4b proved to be a very stable entity as it remained
unchanged (by 1H NMR) even after storage at room tem-
perature for one year. In a separate study,10b we found that
a structurally similar 3-unsubstituted tetramic acid triflate
proved to be quite unstable.
We envisioned that 3-phenyltetramic acid 4a would pro-
vide convenient access to 4-aryl-3-phenyl-3-pyrrolin-2-
ones 5 through palladium-catalyzed cross-coupling reac-
tions at the 4-position. Similar chemistry has been inves-
tigated with maleimides,11 furan-2-ones,12 and
coumarins.13 We chose to incorporate the dimethoxyben-
zyl (DMB) protecting group due to its relative ease of re-
moval late in the synthesis under acidic conditions. Wood
1. BrCH2CO2Et, Et3N, THF
NH2
R
Ph
2. PhCH2COCl, Et3N, CH2Cl2
3. NaOt-Bu, THF
4
3
MeO
MeO
O
(28–50% overall yield)
N
DMB
3
4a R = OH
4b R = OTf
Tf2O, Et3N, CH2Cl2 (95%)
SYNTHESIS 2007, No. 15, pp 2317–2322
Advanced online publication: 12.07.2007
x
x.
x
x
.
2
0
0
7
(DMB = 3,4-dimethoxybenzyl)
DOI: 10.1055/s-2007-983778; Art ID: C02007SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

2318
K. M. Dorward et al.
PAPER
With triflate 4b in hand, we investigated the Suzuki– With the optimized reaction conditions, we explored the
Miyaura cross-coupling reaction with arylboronic acids 5 generality of the cross-coupling reaction with additional
(Table 1). Our initial conditions included 1.1 equivalents arylboronic acid substrates 5 (Table 2). In each case, the
of the boronic acid 5, 10 mol% of tetrakis(triphenylphos- expected 4-aryl-3-pyrrolin-2-ones 6 were obtained in
phine)palladium(0), Na2CO3 as the base, and THF as the good yields with electron-rich (5a and 5e), electron-neu-
solvent. Initially with boronic acid 5a, these conditions tral (5b), electron-poor (5c), and heterocyclic (5d) boron-
proved to be fairly successful (Table 1, entry 1). A brief ic acids. Removal of the DMB protecting group was then
13
survey of different bases including Cs2CO3,16 K3PO4,
realized upon treatment of 6 with trifluoroacetic acid in
KOAc17 showed sodium carbonate to be superior. We also the presence of the cation scavenger, veratrole.14b This re-
explored a different palladium catalyst, PdCl2(dppf),16 action proved to be somewhat sluggish and often required
and observed no change in yield (Table 1, entries 2 and 3). long reaction times (in some runs, heating to reflux as
We then switched to using 1.5 equivalents of the boronic well) in order to push the reactions to completion. Never-
acid substrates 5 in order to obtain more consistent results. theless, the ‘free’ lactams 7 were obtained in good yields
A survey of different solvents found our initial choice of in all cases with the exception of the furan analogue 7d
THF to give the best yields (Table 1, entry 6). Important- (Table 2, entry 4). We steered away from pursuing the
ly, we were able to maintain the high yield after dropping DMB removal under oxidative conditions19 due to the
the catalyst to 5 mol% (Table 1, entry 10). Notably, a possibility of oxidizing the 3-pyrrolin-2-ones to the corre-
cross-coupling reaction with a structurally related tetronic sponding maleimides20 although we did not investigate
acid tosylate substrate containing a phenyl group at the 3- this directly.
position proved to be very low yielding.18 It seems that the
higher reactivity offered by the triflate might be required
Table 2 Preparation of 3,4-Diaryl-3-pyrrolin-2-ones 7a
for cross-coupling reactions involving sterically congest-
ed (vicinal-aryl) substrates.
TFA
Ar
Ph
Ar
Ph
veratrole
CH2Cl2
Ar-B(OH)2
5
Table 1 Survey of Suzuki–Miyaura Reaction Conditions with 4ba
4b
O
O
N
N
H
MeO
DMB
MeO
6
7
Yield 6 (%)b Yield 7 (%)b
TfO
Entry
Ar
Substrate
B(OH)2
5a
1
2
3
4
5
4-OMeC6H4
Ph
a
b
c
95
91
90
80
89
84
72
64
30
62
O
O
N
N
DMB
DMB
4b
6a
4-FC6H4
2-furyl
Entry
5a (equiv) Pd cat.
Base
Solvent
Yield
(%)b
d
e
(mol%)
4-SMeC6H4
1
2
1.1
1.1
1.1
1.1
1.1
1.5
1.5
1.5
1.5
1.5
10
10
10c
10
10
10
10
10
10
5
Na2CO3
Cs2CO3
Cs2CO3
K3PO4
THF
85
72
71
23
56
94
88
66
22
95
a Conditions: 1.5 equiv 5, 5 mol% Pd catalyst, 2.2 equiv Na2CO3,
THF–H2O, 40 min at r.t., then 1–6 h at reflux.
THF
b Isolated yields of 6 and 7 after column chromatography.
3
THF
4
THF
We next turned our attention to the preparation of the ro-
fecoxib analogue 7f (Scheme 2). Oxidation of thioether 6e
to the corresponding the methyl sulfone 6f was achieved
in 81% yield by treatment with m-chloroperoxybenzoic
acid (MCPBA). Removal of the DMB group then gave the
desired rofecoxib analogue 7f in 47% yield. Interestingly,
using our initial DMB deprotection procedure (concentra-
tion of the volatiles followed by chromatography), 7f was
apparently obtained as the corresponding TFA salt
(7f·TFA) based on CHN analysis. We did not observe
TFA salts in our previous synthesis of 3-unsubstituted 4-
aryl-3-pyrrolin-2-ones,10a nor did we observe it with other
substrates here. Nevertheless, this was subsequently
avoided by doing a basic work-up (aq NaHCO3) of the
crude material obtained after removal of TFA.
5
KOAc
dioxane
THF
6
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
7
dioxane
toluene
DMF
THF
8
9
10
a Conditions: 1.1 or 1.5 equiv 5a, 5 or 10 mol% Pd(PPh3)4 catalyst,
2.2 equiv base, solvent/H2O, 40 min at r.t., then 1–6 h at reflux.
b Isolated yields of 6a after column chromatography.
c 10 mol% PdCl2(dppf); dppf = bis(diphenylphosphino)ferrocene.
Synthesis 2007, No. 15, 2317–2322 © Thieme Stuttgart · New York

PAPER
3,4-Diaryl-3-pyrrolin-2-ones from Tetramic Acid Triflates
2319
The crude yellow oil was taken up in CH2Cl2 (100 mL) and the so-
lution was cooled to 0 °C and charged with Et3N (5.53 g, 54.7
mmol) followed by the dropwise addition of phenylacetyl chloride
(7.58 g, 49.0 mmol). The mixture was stirred at 0 °C for 2 h and then
at r.t. for 15 h. The mixture was washed with an aq solutions of HCl
(1.0 M, 100 mL), NaHCO3 (saturated, 100 mL), and brine (100
mL). The organic layer was dried (Na2SO4) and then the solvent was
removed in vacuo to give crude intermediate ethyl 2-[N-(3¢,4¢-
dimethoxybenzyl)-2¢¢-phenylacetamido]acetate as an impure yel-
low oil (16.1 g). The last step involved a base-induced cyclization
leading to the title tetramic acid.14b,15b The crude oil was taken up in
THF (200 mL) and cooled to 0 °C. The resulting mixture was
charged with t-BuONa (4.99 g, 52.0 mmol) and the mixture was
stirred at 0 °C for 4 h then at r.t. for 2 h. The solvent was then re-
moved in vacuo giving a yellow oil. The crude oil was taken up in
enough EtOAc (~80 mL) to dissolve all of the material and aq HCl
was added (50 mL). The aqueous layer was separated and further
extracted with EtOAc (4 × 50 mL). The combined organic layers
were dried (Na2SO4) and then partially concentrated by rotary evap-
oration until crystallization was observed. Repeated cycles of filtra-
tion and concentration gave the title compound 4a as an analytically
pure white powder [5.36 g, 28% yield from veratrylamine (3)]; mp
187–189.5 °C. In nine other runs through this sequence where the
material was not all taken forward, yields ranging from 31–50%
were obtained based on 3.
MeO2S
1. MCPBA, CH2Cl2
2. TFA, CH2Cl2, veratrole
6e
O
N
R
6f R = DMB
7f R = H
(81% yield)
(47% yield)
Scheme 2
In summary, we have developed a short synthetic se-
quence to 4-aryl-3-phenyl-3-pyrrolin-2ones 7 starting
from tetramic acid 4a. The utility of the methodology was
demonstrated through the preparation of the lactam ana-
logue 7f of rofecoxib (2a). We next plan to explore the use
of 3-pyrrolin-2-ones 6 as building blocks to 3,4-diarylpyr-
roles by reduction21 of the lactam and to 2,3,4-triarylpyr-
roles by conversion of the lactam to the triflate22 and
subsequent cross-coupling. The latter would allow for a
controlled, step-wise introduction of aryl groups onto the
pyrrole nucleus23 which could prove useful to the prepara-
tion of complex pyrrole natural products (i.e.,
lamellarins24).
IR (ATR, neat): 3011, 2836, 2428 (br), 1660, 1587, 1512, 1497,
1455, 1442, 1421, 1382, 1332, 1315, 1299, 1283, 1240, 1215, 1159,
1132, 1021, 973, 959, 887, 856, 805, 781, 763, 743, 734, 695, 672,
657 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 11.66 (br s, 1 H), 8.01 (d,
J = 7.5 Hz, 2 H), 7.33 (dd, J = 7.5, 7.5 Hz, 2 H), 7.16 (t, J = 7.5 Hz,
1 H), 6.91 (d, J = 8.1 Hz, 1 H), 6.86 (d, J = 1.8 Hz, 1 H), 6.75 (dd,
J = 1.8, 8.1 Hz, 1 H), 4.47 (s, 2 H), 3.82 (s, 2 H), 3.73 (s, 6 H).
13C NMR (75 MHz, DMSO-d6): d = 171.0, 167.0, 148.8, 148.0,
132.4, 130.4, 127.7, 126.7, 125.6, 119.8, 111.9, 111.6, 102.9, 55.5,
55.4, 48.6, 44.3.
All reactions were performed under a positive argon atmosphere
with magnetic stirring unless otherwise noted. Anhyd THF, CH2Cl2,
and toluene were obtained by passage through a column of alumina
utilizing a PureSolv 400 solvent purification system. Anhyd diox-
ane and DMF were purchased from commercial sources. Et3N was
distilled fresh from CaH2 immediately prior to use. Petroleum ether
used refers to the fraction boiling in the range 35–60 °C. Unless oth-
erwise indicated, all other reagents and solvents were purchased
from commercial sources and were used without further purifica-
tion. 1H NMR and 13C NMR were run at 300 MHz and 75 MHz, re-
spectively, utilizing an Oxford multinuclear Fourier transform
instrument. Chemical shifts are reported in parts per million (d) us-
ing the solvent’s residual proton or carbon signal (CDCl3: dH = 7.24,
dC = 77.3; DMSO-d6: dH = 2.50, dC = 39.5) as an internal reference.
Flash chromatography was performed with silica gel (230–400
mesh) and TLC was performed utilizing glass-backed silica gel
plates and visualized utilizing UV (254 nm). IR spectra were mea-
sured utilizing a PerkinElmer Spectrum 100 with ATR sampler (at-
tenuated total reflectance). All yields are for chromatographed or
crystallized, isolated materials.
Anal. Calcd for C19H19NO4: C, 70.14; H, 5.89; N, 4.31. Found: C,
70.03; H, 5.88; N, 4.29.
1-(3¢,4¢-Dimethoxybenzyl)-3-phenyl-4-trifluoromethane-
sulfonyl-1H-pyrrol-2(5H)-one (4b)
To a stirred solution of tetramic acid 4a (3.16 g, 9.73 mmol) and
Et3N (1.31 g, 12.9 mmol) in CH2Cl2 (20 mL) at –15 °C was added
neat trifluoromethanesulfonic anhydride dropwise via syringe. The
mixture was stirred at –15 °C for 1 h and then poured into an aq so-
lution of HCl (1.0 M, 50 mL), and H2O (50 mL) was added. The
aqueous layer was separated and extracted with CH2Cl2 (3 × 35
mL). The combined organic layers were washed with aq NaHCO3
(1% w/v, 100 mL), brine (100 mL), and dried (Na2SO4). Removal
of the solvent in vacuo gave a crude orange-brown oil. Trituration
with PE (10 mL) gave the desired product 4b as a tan powder (4.20
g, 95%); mp 85–86.5 °C; Rf = 0.20 (EtOAc–PE, 1:4).
1-(3¢,4¢-Dimethoxybenzyl)-4-hydroxy-3-phenyl-1H-pyrrol-
2(5H)-one (4a)
A three-step reaction sequence was utilized to prepare the title prod-
uct with intermediates taken on directly without purification. To a
0 °C stirred solution of veratrylamine (3; 10.0 g, 59.8 mmol) and
Et3N (6.35 g, 62.8 mmol) in THF (50 mL), was added a solution of
ethyl bromoacetate (9.99 g, 59.8 mmol) in THF (50 mL) dropwise
via addition funnel. The mixture was stirred at 0 °C for 2 h and then
at r.t. for 16 h. The mixture was filtered through sintered glass and
the solid was washed with Et2O (2 × 20 mL). The combined organic
layers were concentrated in vacuo giving known ethyl 2-(3¢,4¢-
dimethoxybenzylamino)acetate25 as an impure yellow oil (11.3 g).
IR (ATR, neat): 3007, 2909, 2837, 1694, 1593, 1516, 1498, 1449,
1420, 1334, 1314, 1252, 1239, 1222, 1192, 1168, 1131, 1103, 1027,
985, 959, 941, 918, 900, 842, 804, 782, 762, 753, 701, 663 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.72–7.76 (m, 2 H), 7.36–7.47 (m,
3 H), 6.82 (s, 1 H), 6.79–6.82 (m, 2 H), 4.63 (s, 2 H), 4.12 (s, 2 H),
3.86 (s, 3 H), 3.85 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 167.1, 153.2, 149.7, 149.2, 129.9,
129.0, 128.8, 127.3, 124.1, 120.9 (2C), 118.5 (q, J = 319 Hz),
111.55, 111.48, 56.3, 56.2, 48.7, 46.3.
1H NMR (300 MHz, CDCl3): d = 6.77–6.95 (m, 3 H), 4.12 (q,
J = 7.2 Hz, 2 H), 3.85 (s, 3 H), 3.83 (s, 3 H), 3.71 (s, 2 H), 3.50 (s,
2 H), 3.36 (s, 1 H), 1.20–1.26 (m, 3 H).
Anal. Calcd for C20H18F3NO6S: C, 52.51; H, 3.97; N, 3.06; S, 7.01.
Found: C, 52.37; H, 3.93; N, 3.05; S, 6.86.
Synthesis 2007, No. 15, 2317–2322 © Thieme Stuttgart · New York

2320
K. M. Dorward et al.
PAPER
Suzuki Cross-Coupling Reaction Leading to 3,4-Diaryl-3-pyr-
rolin-2-ones 6; General Procedure A
Hz), 129.5 (d, J = 3 Hz), 128.8, 128.5, 121.0, 116.0 (d, J = 21 Hz),
111.9, 111.4, 56.3, 56.2, 52.2, 46.6.
To a stirred solution of triflate 4b (0.328 mmol) and an arylboronic
acid 5 (0.492 mmol) in THF (15 mL) at r.t., was added Pd(PPh3)4
(0.0164 mmol) followed by an aq solution of Na2CO3 (0.076 g, 0.72
mmol, 2 mL of H2O). The mixture was stirred at r.t. for 40 min and
then heated to reflux for 1–6 h until TLC showed complete conver-
sion of the starting material 4b. The mixture was filtered through a
short plug of Celite with the aid of CH2Cl2 and the bulk of the sol-
vent was removed in vacuo. The crude material was taken up in
CH2Cl2 (30 mL) and washed with H2O (30 mL). The aqueous layer
was back-extracted with CH2Cl2 (3 × 30 mL). The combined organ-
ic layers were washed with brine (100 mL) and dried (Na2SO4). Re-
moval of the solvent gave a crude solid. The desired products 6 were
obtained after purification by flash chromatography [gradient:
EtOAc–PE, 1:4 to 1:2).
Anal. Calcd for C25H22FNO3: C, 74.43; H, 5.50; N, 3.47. Found: C,
74.39; H, 5.49; N, 3.46.
1-(3¢,4¢-Dimethoxybenzyl)-4-(furan-2¢¢-yl)-3-phenyl-1H-pyrrol-
2(5H)-one (6d)
The title product 6d was obtained utilizing general procedure A;
yield: 80%; yellow solid; mp 101–104 °C; Rf = 0.41 (EtOAc–PE,
1:1).
IR (ATR, neat): 3107, 2933, 2835, 1669, 1592, 1514, 1482, 1451,
1405, 1352, 1307, 1259, 1232, 1136, 1077, 1026, 963, 938, 883,
848, 807, 781, 765, 734, 696, 658 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.32–7.54 (m, 6 H), 6.80–6.89 (m,
3 H), 6.47 (d, J = 3.5 Hz, 1 H), 6.33 (dd, J = 1.7, 3.5 Hz, 1 H), 4.65
(s, 2 H), 4.21 (s, 2 H), 3.86 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 170.8, 149.6, 148.9, 148.5, 143.6,
137.3, 132.2, 130.1, 129.7, 128.7, 128.6, 120.9, 112.2, 111.7, 111.4,
111.3, 56.3, 56.2, 50.1, 46.6 (missing one aromatic).
13C NMR (75 MHz, DMSO-d6): d = 169.5, 148.8, 148.1, 147.7,
144.7, 136.9, 132.1, 129.9, 129.5, 128.2, 128.1, 128.0, 120.0, 112.2,
111.9, 111.8, 111.7, 55.5, 55.4, 49.6, 45.3.
1-(3¢,4¢-Dimethoxybenzyl)-4-(4¢¢-methoxyphenyl)-3-phenyl-1H-
pyrrol-2(5H)-one (6a)
The title product 6a was obtained utilizing general procedure A;
yield: 95%; yellow solid; mp 163–164.5 °C; Rf = 0.36 (EtOAc–PE,
1:1).
IR (ATR, neat): 2961, 2915, 1676, 1635, 1604, 1590, 1573, 1510,
1471, 1452, 1422, 1393, 1364, 1312, 1299, 1250, 1231, 1194, 1175,
1142, 1106, 1042, 1016, 950, 936, 919, 845, 828, 809, 789, 765,
754, 741, 730, 714, 701, 669, 655 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.39–7.44 (m, 2 H), 7.28–7.37 (m,
3 H), 7.16 (d, J = 6.9 Hz, 2 H), 6.87 (s, 1 H), 6.81–6.90 (m, 2 H),
6.73 (d, J = 6.9 Hz, 2 H), 4.67 (s, 2 H), 4.13 (s, 2 H), 3.86 (s, 6 H),
3.75 (s, 3 H).
1-(3¢,4¢-Dimethoxybenzyl)-4-[4¢¢-(methylthio)phenyl]-3-phenyl-
4-1H-pyrrol-2(5H)-one (6e)
The title product 6e was obtained utilizing general procedure A;
yield: 89%; yellow solid; mp 63–67 °C; Rf = 0.51 (EtOAc–PE, 1:1).
IR (ATR, neat): 2921, 1672, 1592, 1513, 1451, 1420, 1400, 1361,
1259, 1232, 1138, 1095, 1025, 959, 817, 785, 766, 744, 697 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.40–7.43 (m, 2 H), 7.30–7.37 (m,
3 H), 7.13 (AB system, d, J = 8.9 Hz, 2 H), 7.06 (AB system, d,
J = 8.9 Hz, 2 H), 6.81–6.90 (m, 3 H), 4.67 (s, 2 H), 4.13 (s, 2 H),
3.862 (s, 3 H), 3.858 (s, 3 H), 2.43 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 171.0, 149.6, 148.9, 147.2, 140.7,
132.4, 132.1, 130.2, 129.8, 129.7, 128.8, 128.4, 128.1, 126.0, 121.0,
111.8, 111.3, 56.3, 56.2, 52.0, 46.6, 15.4.
13C NMR (75 MHz, CDCl3): d = 171.2, 160.5, 149.5, 148.8, 147.5,
132.7, 131.0, 130.3, 129.8, 129.2, 128.7, 128.2, 125.7, 120.9, 114.2,
111.8, 111.3, 56.3, 56.2, 55.5, 52.1, 46.5.
Anal. Calcd for C26H25NO4: C, 75.16; H, 6.06; N, 3.37. Found: C,
74.91; H, 6.04; N, 3.33.
1-(3¢,4¢-Dimethoxybenzyl)-3,4-diphenyl-1H-pyrrol-2(5H)-one
(6b)
Anal. Calcd for C26H25NO3S: C, 72.36; H, 5.84; N, 3.25. Found: C,
71.65; H, 5.85; N, 3.20.
The title product 6b was obtained utilizing general procedure A;
yield: 91%; yellow solid; mp 55–58 °C; Rf = 0.39 (EtOAc–PE, 1:1).
IR (ATR, neat): 2932, 1674, 1591, 1512, 1446, 1403, 1359, 1258,
1232, 1138, 1072, 1025, 959, 916, 845, 810, 786, 763, 694, 672
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.40–7.44 (m, 2 H), 7.28–7.36 (m,
3 H), 7.20–7.26 (m, 5 H), 6.80–6.90 (m, 3 H), 4.68 (s, 2 H), 4.16 (s,
2 H), 3.86 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 170.9, 149.6, 148.9, 147.9, 133.4,
132.6, 132.2, 130.2, 129.8, 129.4, 128.9, 128.7, 128.4, 127.8, 121.0,
111.8, 111.4, 56.3, 56.2, 52.2, 46.6.
Removal of the DMB Protecting Group Leading to 3,4-Diaryl-
3-pyrrolin-2-ones 7; General Procedure B
A modification of a literature procedure was utilized.14b A mixture
of the DMB-protected 3-pyrrolin-2-one 6 (0.200 mmol) and vera-
trole (2.00 mmol) was charged with TFA (10 mL). The mixture was
stirred for 40 min at r.t. and then heated to reflux for 6–16 h until
TLC showed complete conversion of the starting material 6. The
mixture was poured into a sat. aq solution of NaHCO3 (100 mL).
The aqueous solution was extracted with CH2Cl2 (2 × 100 mL). The
combined organic layers were then washed with brine (100 mL) and
dried (Na2SO4). Removal of the solvent gave a crude oil. The de-
sired products 7 were obtained after purification by flash chroma-
tography (gradient: EtOAc to MeOH–EtOAc, 1:19). Analytical
samples were obtained by trituration with Et2O.
1-(3¢,4¢-Dimethoxybenzyl)-4-(4¢¢-fluorophenyl)-3-phenyl-1H-
pyrrol-2(5H)-one (6c)
The title product 6c was obtained utilizing general procedure A;
yield: 90%; white solid; mp 145–147 °C; Rf = 0.43 (EtOAc–PE,
1:1).
4-(4¢-Methoxyphenyl)-3-phenyl-1H-pyrrol-2(5H)-one (7a)
The title product 7a was obtained utilizing general procedure B;
yield: 84%; white solid; mp 193–196 °C; Rf = 0.18 (EtOAc–PE,
4:1).
IR (ATR, neat): 3062, 2921, 1673, 1603, 1509, 1456, 1418, 1402,
1363, 1283, 1265, 1236, 1215, 1180, 1152, 1123, 1097, 1074, 1033,
1003, 966, 928, 866, 841, 827, 798, 787, 766, 748, 717, 701, 676,
654 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.30–7.41 (m, 5 H), 7.16–7.22 (m,
2 H), 6.81–6.95 (m, 5 H), 4.67 (s, 2 H), 4.13 (s, 2 H), 3.86 (s, 6 H).
IR (ATR, neat): 3182, 3056, 1686, 1607, 1515, 1456, 1443, 1366,
1315, 1295, 1252, 1230, 1180, 1122, 1080, 1061, 1035, 972, 892,
833, 789, 750, 708, 674 cm–1.
13C NMR (75 MHz, CDCl3): d = 170.8, 163.2 (d, J = 250 Hz),
149.6, 148.9, 146.7, 132.6, 132.1, 130.1, 129.79, 129.77 (d, J = 8
Synthesis 2007, No. 15, 2317–2322 © Thieme Stuttgart · New York

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3,4-Diaryl-3-pyrrolin-2-ones from Tetramic Acid Triflates
2321
1H NMR (300 MHz, DMSO-d6): d = 8.41 (br s, 1 H), 7.29–7.40 (m,
3 H), 7.24–7.28 (m, 4 H), 6.87 (d, J = 9.0 Hz, 2 H), 4.33 (s, 2 H),
3.73 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 172.7, 159.8, 150.0, 132.8,
130.2, 129.4, 129.0, 128.3, 127.6, 125.5, 114.0, 55.2, 47.4.
1-(3¢,4¢-Dimethoxybenzyl)-3-phenyl-4-[4¢¢-(methylsulfonyl)phe-
nyl]-1H-pyrrol-2(5H)-one (6f)
To a stirred solution of thioether 6e (0.500 g, 1.16 mmol) in CH2Cl2
(17 mL) at 0 °C, was added MCPBA (0.600 g, 3.48 mmol) and the
mixture was allowed to warm to r.t. After stirring at r.t. for 2 h, the
mixture was washed with H2O (30 mL) and the aqueous layer was
back-extracted with CH2Cl2 (2 × 30 mL). The combined organic
layers were washed with brine (80 mL) and then dried (Na2SO4).
Removal of the solvent in vacuo gave a crude solid which was pu-
rified by flash chromatography (gradient: EtOAc–PE, 1:4 to 2:1);
yield: 81%; yellow solid; mp 64–66 °C; Rf = 0.42 (EtOAc–PE, 2:1).
Anal. Calcd for C17H15NO2: C, 76.96; H, 5.70; N, 5.28. Found: C,
76.69; H, 5.71; N, 5.26.
3,4-Diphenyl-1H-pyrrol-2(5H)-one (7b)
The known26 title product 7b was obtained utilizing general proce-
dure B; the product matched a sample (by TLC and NMR) previous-
ly prepared in our lab10a utilizing a different method; yield: 72%;
yellow solid; mp 180–181 °C (Lit.26b mp 192–193 °C; Lit.10a mp
182–183 °C); Rf = 0.37 (EtOAc).
IR (ATR, neat): 2924, 1675, 1593, 1513, 1451, 1400, 1359, 1304,
1281, 1260, 1233, 1146, 1089, 1027, 956, 837, 770, 698, 663 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.80 (AB system, d, J = 9.0 Hz, 2
H), 7.39 (AB system, d, J = 9.0 Hz, 2 H), 7.33–7.37 (m, 5 H), 6.82–
6.90 (m, 3 H), 4.69 (s, 2 H), 4.17 (s, 2 H), 3.864 (s, 3 H), 3.861 (s,
3 H), 3.02 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 170.1, 149.6, 149.0, 145.2, 140.8,
138.9, 135.6, 131.3, 129.74, 129.68, 129.1, 129.0, 128.8, 128.0,
121.0, 111.9, 111.4, 56.3, 56.2, 52.0, 46.7, 44.6.
1H NMR (300 MHz, DMSO-d6): d = 8.53 (br s, 1 H), 7.25–7.36 (m,
10 H), 4.37 (s, 2 H).
13C NMR (75 MHz, DMSO-d6): d = 172.4, 150.4, 133.3, 132.4,
131.7, 129.3, 129.0, 128.6, 128.2, 127.7, 127.5, 47.5.
4-(4¢-Fluorophenyl)-3-phenyl-1H-pyrrol-2(5H)-one (7c)
The title product 7c was obtained utilizing general procedure B;
yield: 64%; white solid; mp 204–207 °C; Rf = 0.29 (EtOAc).
4-[4¢-(Methylsulfonyl)phenyl]-1H-pyrrol-2(5H)-one (7f)
The title product 7f was obtained utilizing general procedure B;
yield: 47%; white powder; mp 197–200 °C; Rf = 0.27 (EtOAc–PE,
4:1).
IR (ATR, neat): 3184, 3060, 1682, 1603, 1512, 1493, 1442, 1408,
1363, 1343, 1226, 1162, 1105, 1059, 1015, 974, 945, 892, 837, 808,
788, 745, 715, 701, 675 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 8.53 (br s, 1 H), 7.15–7.39 (m,
9 H), 4.36 (s, 2 H).
IR (ATR, neat): 3182, 3058, 3011, 2995, 2918, 1677, 1633, 1597,
1492, 1447, 1404, 1363, 1337, 1303, 1285, 1226, 1182, 1147, 1090,
1060, 1022, 961, 918, 890, 834, 790, 770, 737, 715, 694, 664 cm–1.
13C NMR (75 MHz, DMSO-d6): d = 172.3, 162.3 (d, J = 246 Hz),
149.4, 132.2, 131.8, 129.83, 129.82 (d, J = 9 Hz), 129.3, 128.3,
127.8, 115.7 (d, J = 22 Hz), 47.5.
1H NMR (300 MHz, DMSO-d6): d = 8.69 (br s, 1 H), 7.87 (d,
J = 8.4 Hz, 2 H), 7.56 (d, J = 8.4 Hz, 2 H), 7.35–7.38 (m, 3 H),
7.26–7.30 (m, 2 H), 4.41 (s, 2 H), 3.23 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 171.9, 148.8, 140.7, 138.5,
133.9, 131.6, 129.3, 128.5, 128.4, 128.1, 127.2, 47.6, 43.2.
Anal. Calcd for C16H12FNO: C, 75.88; H, 4.78; N, 5.53. Found: C,
75.57; H, 4.87; N, 5.39.
Anal. Calcd for C17H15NO3S: C, 65.16; H, 4.82; N, 4.47. Found: C,
64.46; H, 4.82; N, 4.29.
4-(Furan-2¢-yl)-3-phenyl-1H-pyrrol-2(5H)-one (7d)
The title product 7d was obtained utilizing general procedure B;
yield: 30%; white solid; mp 203–205 °C; Rf = 0.38 (EtOAc).
IR (ATR, neat): 3174, 3112, 3059, 1680, 1599, 1494, 1482, 1444,
1359, 1230, 1202, 1098, 1021, 980, 931, 884, 786, 769, 760, 742,
698, 672 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 8.42 (br s, 1 H), 7.75 (d,
J = 1.7 Hz, 1 H), 7.36–7.46 (m, 5 H), 6.63 (dd, J = 0.8, 3.5 Hz, 1 H),
6.56 (dd, J = 1.7, 3.5 Hz, 1 H), 4.34 (d, J = 1.2 Hz, 2 H).
Acknowledgment
Financial support of this research provided by the Camille & Henry
Dreyfus Foundation, the Research Corporation, the Patchett Foun-
dation, and Hobart and William Smith Colleges is greatly apprecia-
ted.
13C NMR (75 MHz, DMSO-d6): d = 172.3, 148.0, 144.5, 138.7,
132.2, 129.4, 128.9, 127.9 (2), 112.1, 111.5, 45.3.
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Synthesis 2007, No. 15, 2317–2322 © Thieme Stuttgart · New York