Suzuki-Miyaura arylations of tetramic acid sulfonates: Evaluation of lactam protection, sulfonate esters, and sterics

Article abstract of DOI:10.1002/jhet.96

(Chemical Equation Presented) The synthesis of 3,4-diaryl-3-pyrrolin-2-ones and 4-aryl-3-pyrrolin-2-ones using Suzuki-Miyaura cross-coupling reactions of tetramic acid sulfonates with arylboronic acids has been studied. The effect that sulfonate ester, st

Full text of DOI:10.1002/jhet.96

May 2009
Suzuki–Miyaura Arylations of Tetramic Acid Sulfonates:
Evaluation of Lactam Protection, Sulfonate Esters, and Sterics
447
Sarah J. P. Yoon-Miller, Kathryn M. Dorward,
Kimberly P. White, and Erin T. Pelkey*
Department of Chemistry, Hobart and William Smith Colleges, Geneva, New York 14456
*E-mail: pelkey@hws.edu
Received September 30, 2008
DOI 10.1002/jhet.96
Published online 26 May 2009 in Wiley InterScience (www.interscience.wiley.com).
The synthesis of 3,4-diaryl-3-pyrrolin-2-ones and 4-aryl-3-pyrrolin-2-ones using Suzuki–Miyaura
cross-coupling reactions of tetramic acid sulfonates with arylboronic acids has been studied. The effect
that sulfonate ester, sterics, and lactam protection has on the cross-coupling reaction was evaluated. As
expected, triflates were better cross-coupling partners than the corresponding tosylates. The yields were
only partially affected by the incorporation of aryl groups at the 3-position. Importantly, tetramic acid
triflates (and to a lesser extent tosylates) lacking a lactam protecting group were still competent
substrates.
J. Heterocyclic Chem., 46, 447 (2009).
of C-4 aryl analogs [16]. A four component Ugi reaction
provided access to 3,4-diaryl-3-pyrrolin-2-ones and 4-
aryl-3-pyrrolin-2-ones, but this route was not amenable
to the preparation of 5-unsubstituted derivatives [17,18].
Given their importance as drug candidates and build-
ing blocks, we initiated a program aimed at developing
novel synthetic approaches to aryl-substituted 3-pyrro-
lin-2-ones that were amenable to the synthesis of new
substitution patterns that allowed for the preparation of
analogs. We recently reported our progress toward
developing methodologies to 1 using Suzuki–Miyaura
cross-coupling reactions of tetramic sulfonates 3a [11a]
and 4b [11b] (Fig. 1). These methods have the potential
to be useful in the synthesis of analogs given the late-
stage introduction of C-4 aryl groups. The utility of
INTRODUCTION
3,4-Diaryl-3-pyrrolin-2-ones 1a and 4-aryl-3-pyrrolin-
2-ones 1b are important synthetic targets given their
range of biological activity and utility as precursors to
other compounds. 3,4-Diaryl-3-pyrrolin-2-ones have
been investigated as inhibitors of cyclooxygenase-II
(COX-II) [1], vascular endothelial growth factor recep-
tor (VEGF-R) [2], and protein kinase C (PKC) [3]. 3,4-
Diaryl-3-pyrrolin-2-ones have been used as building
blocks for the preparation of the PKC inhibitor stauro-
sporinone [4] and N-protected staurosporinones [5],
whereas 4-aryl-3-pyrrolin-2-ones have been used as
intermediates in the synthesis of 4-arylpyrrolidinones [6]
(e.g., antidepressant rolipram) [7], c-aminobutyric acids
[8] (e.g., antispastic agent baclofen) [9], and b-arylpyr-
roles [10]. Before our involvement in this field [11,12],
nearly all of the known methods to aryl-substituted 3-
pyrrolin-2-ones 1 involved linear sequences that culmi-
nated in aldol-like cyclocondensations of a-amidoke-
tones 2 [1,2,4,5,10a,13] (Fig. 1). An alternate method
that has been explored to prepare 3,4-diaryl-3-pyrrolin-
2-ones 1a involves reducing the corresponding malei-
mides with borane [3a], but these reactions have proven
to be nonselective [14]. Alternate methods used to syn-
thesize 4-aryl-3-pyrrolin-2-ones 1b include treatment of
4-bromo-2-butenoates with amines [6,8,15] and ring
expansion of cyclobutanones [10b]. These literature
methods all incorporate the C-4 aryl groups early in the
sequence making them less applicable to the synthesis
our synthetic methodology was demonstrated by prepar-
R
ing the N-unsubstituted lactam analog of VioxxV from
3a and the 4-arylpyrrolidinone precursor to baclofen
from 4b.
We were initially inspired to investigate Suzuki–
Miyaura cross-coupling reactions for the installation of
C-4 aryl groups onto tetramic acid sulfonates by the
analogous cross-coupling reactions of tetronic acid sul-
fonates 5 [19,20] and 6 [21] (Fig. 2). Interestingly, the
cross-coupling of 6a was reported to proceed in very
low yield; this was attributed to a steric effect caused by
the neighboring phenyl group [21a]. On the other hand,
we observed excellent yields in the cross-coupling reac-
tions of triflate 3a which also contains a vicinal phenyl
C
V
2009 HeteroCorporation

448
S. J. P. Yoon-Miller, K. M. Dorward, K. P. White, and E. T. Pelkey
Vol 46
Scheme 1
Figure 1. Synthetic approaches to 3,4-diaryl-3-pyrrolin-2-ones and 4-
aryl-3-pyrrolin-2-ones.
group [11a]. To better understand the limitations of our
methodology, we decided to systematically study the
effect that sterics (R3 ¼ Ph vs. R3 ¼ H), sulfonate ester
[trifluoromethanesulfonyl (OTf) vs. tosylsulfonyl (OTs)],
and lactam protecting group [tert-butoxycarbonyl (Boc)
vs. 3,4-dimethoxybenzyl (DMB)] have on the yield of
the cross-coupling reaction. We thus set out to prepare
new tetramic acid sulfonates 7 and 8 and compare their
competence as cross-coupling substrates to our known
tetramic acid sulfonates 3 and 4. Our progress to date is
reported herein.
observed with 4a). We therefore decided to investigate
cross-coupling reactions of substrates that did not con-
tain protecting groups. Thus, we treated 7a and 4a with
trifluoroacetic acid (TFA), and obtained lactams 13a and
14a, respectively.
We reported a similar procedure for the synthesis of
DMB-protected tetramic acid 15 [11a]. Treatment of 15
with either triflic anhydride or tosyl chloride in the pres-
ence of triethylamine gave 3a [11a] and new compound
8a, respectively (Scheme 2).
The next substrate that was prepared was N-unsubsti-
tuted tetramic acid tosylate 14b. Known compound 4b
was available from our previous studies by the cyclo-
condensation of Boc-glycine with Meldrum’s acid
[11b,25]. Treatment of 4b with TFA led to lactam 14b
(Scheme 3). We were not able to access 4-trifloxy-3-
pyrrolin-2-one via this route as the requisite starting ma-
terial, compound 7b, turned out to be unstable and
underwent a facile dimerization [11b].
RESULTS AND DISCUSSION
Tetramic acid sulfonate ester substrates (e.g., 3a)
[11a] were prepared from the corresponding 3-phenyl-
tetramic acids. The latter can be obtained via
Dieckmann-like cyclocondensations of the correspond-
ing N-phenylacetylglycinates [22]. Toward this end,
treatment of glycine ethyl ester (9) with phenacetyl
chloride gave known amide 10 [23] (Scheme 1). Con-
version of 10 to 11 was achieved with Boc2O and 4-
(N,N0-dimethylamino)pyridine (DMAP) [24]. 3-Phenyl-
tetramic acid 12 was then prepared by a Dieckmann
cyclocondensation of 11 mediated by sodium tert-butox-
ide. Treatment of 12 with either triflic anhydride or tosyl
chloride in the presence of triethylamine gave 7a and
4a, respectively.
With the tetramic acid sulfonate substrates in hand,
we evaluated the effect that lactam protecting group,
sulfonate leaving group, and sterics have on the yield of
Suzuki–Miyaura cross-coupling reactions. We used our
previously optimized conditions for cross-coupling reac-
tions with tetramic acid triflates [Method A: Pd(PPh3)4
and Na2CO3] [11a] and tetramic acid tosylates [Method
B: Pd(1,1-bis(diphenylphosphino)ferrocen)Cl2(Pd(dppf)
Cl2), Cs2CO3] [11b]. To simplify our study and the anal-
ysis of the products, we used 4-methoxyphenylboronic
acid. Our results are detailed later in Tables 1–3.
In some cases, the synthesis of 7a was accompanied
by the formation of small amounts of lactam 13a via a
seemingly facile Boc deprotection (this was not
Scheme 2
Figure 2. Tetramic acid sulfonates and tetronic acid sulfonates.
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May 2009
Suzuki–Miyaura Arylations of Tetramic Acid Sulfonates: Evaluation of
Lactam Protection, Sulfonate Esters, and Sterics
449
Scheme 3
Table 2
We first examined the cross-coupling reactions of 3-
phenyltetramic acid sulfonates (Table 1). The results
shown in Table 1 describe the effect that lactam protect-
ing group (R1 ¼ Boc vs. R1 ¼ DMB vs. R1 ¼ H) have
on the cross-coupling reaction. These results also show
the relative capabilities of the sulfonate leaving groups
(X ¼ OTf vs. X ¼ OTs). In the triflate series, the Boc
and DMB protecting groups were equivalent (97% vs.
95%); on the other hand in the tosylate series, the Boc
protecting group proved to be superior (40% vs. Trace).
We were pleasantly surprised to see that N-unsubstituted
triflate 13a proved to be a viable substrate providing
known 3,4-diaryl-3-pyrrolin-2-one 18a in 62% yield.
This result indicates a potential for step savings that
could be realized with this methodology during the
preparation of analogs. Unlike triflate 13a, cross-cou-
pling with the corresponding N-unsubstituted tosylate
14a failed to give product 18a. As expected, triflate
leaving groups proved to be superior to tosylate leaving
groups; in some cases, triflate leaving groups appear to
be required in the cross-coupling of unprotected
lactams.
Substrate
R1
R2
Product
Yield (%)a
4b
4a
14b
14a
Boc
Boc
H
H
Ph
H
16b
16a
18b
18a
74
40
55
0
H
Ph
a Yields reported are for isolated, chromatographed materials.
describe the effects of sterics (R2 ¼ Ph vs. R2 ¼ H) on
the cross-coupling reactions. With Boc-protected tetra-
mic acid tosylates 4, the addition of a vicinal phenyl
group lowered the yield (74% vs. 40%) although it did
not shut down the reaction as was observed with the 3-
phenyltetronic acid tosylate [21a]. Somewhat unexpect-
edly with N-unsubstituted tetramic acid tosylates 14, the
neighboring phenyl group precluded the reaction (55%
vs. 0%). When further analyzing the importance of lac-
tam protection, the yield was only partially diminished
going from N-Boc tosylate 4b to N-unsubstituted tosyl-
ate 14b (74% vs. 55%).
Finally, we investigated the reactions of tetramic acid
sulfonates with 4-methoxyphenylboronic acid and 2-
methoxyphenylboronic acid (Table 3). The results
shown in Table 3 describe the effects of sterics of the
arylboronic acids on the cross-coupling reactions. With
3-phenyltetramic acid sulfonates 4a and 7a, the
Next, we examined the cross-coupling reactions of
tetramic acid tosylates 4 and 14 with 4-methoxyphenyl-
boronic acid using Method B (Table 2). We used tosy-
lates in this study as 3-unsubstituted triflates (R2 ¼ H)
were not available. The results shown in Table 2
Table 1
Substrate
X
R1
Methodsa
Product
Yield (%)b
7a
3a
13a
4a
8a
14a
OTf
OTf
OTf
OTs
OTs
OTs
Boc
DMB
H
A
A
A
B
B
B
16a
17a
18a
16a
17a
18a
97
95
62
40
trace
0
Boc
DMB
H
a Methods A ¼ Pd(PPh3)4, Na2CO3, THF/H2O; B ¼ Pd(dppf)Cl2, Cs2CO3, THF/H2O.
b Yields reported are for isolated, chromatographed materials.
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450
S. J. P. Yoon-Miller, K. M. Dorward, K. P. White, and E. T. Pelkey
Vol 46
Table 3
Substrate
X
R2
Ar
Product
Yield (%)a
7ab
7ab
4ac
4ac
4bc
4bc
OTf
OTf
OTs
OTs
OTs
OTs
Ph
Ph
Ph
Ph
H
4-MeOC6H4
2-MeOC6H4
4-MeOC6H4
2-MeOC6H4
4-MeOC6H4
2-MeOC6H4
16a
19a
16a
19a
16b
19b
97
61
40
33
74
74
H
a Yields reported are for isolated, chromatographed materials.
b Method A.
c Method B.
wise noted. Tetrahydrofuran (THF) and CH2Cl2 were purified
by passage through a column of alumina using a PureSolv 400
solvent purification system. Et3N was distilled fresh from cal-
cium hydride immediately before use. Unless otherwise indi-
cated, all other reagents and solvents were purchased from
commercial sources and were used without further purification.
Petroleum ether (PE) refers to the fraction with boiling point
reactions with 4-methoxyphenylboronic acid were higher
yielding than the reactions with 2-methoxyphenylbor-
onic acid, although the effect was muted with tosylate
4a. With the 3-unsubstituted tetramic acid tosylate 4b,
no difference in yield was observed; consequently, the
steric effect appears to arise from the vicinal phenyl
group (R2 ¼ Ph) and not from the steric differences of
the arylboronic acids.
35–60ꢀC. 4-Methoxyphenylboronic acid and 2-methoxyphenyl-
R
boronic acid were purchased from AldrichV and used as pro-
1
vided. H NMR and 13C NMR chemical shifts are reported in
In conclusion, the Suzuki–Miyaura cross-coupling of
tetramic acid sulfonates has proven to be a versatile
methodology for the preparation of 3,4-diaryl-3-pyrro-
lin-2-ones and 4-aryl-3-pyrrolin-2-ones. This synthetic
methodology provides facile access to C-4 analogs. The
effect that sulfonate ester, sterics, and lactam protection
has on the cross-coupling reaction was studied system-
atically. In all cases, triflates were better cross-coupling
partners than the corresponding tosylates. The reactions
still proceeded with vicinal phenyl groups, although the
yield was partially diminished. We were pleased to find
that tetramic acid triflates (and to a lesser extent tetra-
parts per million (d) using the solvents residual proton or car-
bon signal (CDCl3: dH 7.24 ppm, dC 77.3 ppm; d6-DMSO:
dH 2.50 ppm, dC 39.5 ppm) as an internal reference. Flash
chromatography was performed with silica gel (230–400
mesh), and thin-layer chromatography (TLC) was performed
with glass-backed silica gel plates and visualized with UV
(254 nm). IR spectra were measured using a Perkin–Elmer
Spectrum 100 with ATR sampler (attenuated total reflectance).
Known tetramic acid derivatives 3a [11a], 4b [11b], and 15
Scheme 4
mic acid tosylates) lacking
a
lactam protecting
group proved to be competent substrates [26]. The latter
result has the potential to improve the step economy
[27] associated with preparing analogs via Suzuki–
Miyaura cross-coupling reactions of lactams. Each ana-
log can be prepared in one step using N-unsubstituted
lactam (route #2), while two steps per analog are
required with the corresponding N-substituted lactam
(route #1) (Scheme 4).
EXPERIMENTAL
General remarks. All reactions were performed under a
positive argon atmosphere with magnetic stirring unless other-
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May 2009
Suzuki–Miyaura Arylations of Tetramic Acid Sulfonates: Evaluation of
Lactam Protection, Sulfonate Esters, and Sterics
451
[11a] were prepared using our previously published
procedures.
was added neat Et3N (0.626 g, 0.860 mL, 6.18 mmol) fol-
lowed by neat trifluoromethanesulfonic anhydride (Tf2O; 1.44
g, 0.860 mL, 5.11 mmol) dropwise via syringe. The reaction
mixture was stirred at ꢂ15ꢀC for 2.5 h at which point TLC
showed complete conversion of the starting material 12. The
reaction mixture first turned green on the addition of Tf2O,
and then turned into a clear yellow solution after 5 min. The
reaction mixture was poured onto an aqueous solution of
KHSO4 (1.27 g, 9.33 mmol in 75 mL H2O) and the aqueous
layer was extracted with CH2Cl2 (3 ꢁ 30 mL). The combined
organic layers were washed with an aqueous solution of so-
dium bicarbonate (1% w/v, 100 mL), brine (100 mL), and
dried over sodium sulfate. Removal of the solvent in vacuo
gave a crude yellow solid (1.36 g). Purification by flash col-
umn chromatography (gradient: 1:15 to 1:11 EtOAc/PE) gave
the titled compound 7a as an analytically pure yellow solid
(1.07 g, 2.63 mmol, 57% yield): mp 94–96ꢀC; Rf ¼ 0.34 (1:8
EtOAc/PE); IR (ATR, neat) 2980, 1772, 1693, 1449, 1424,
1371, 1328, 1311, 1293, 1247, 1223, 1211, 1151, 1133, 1096,
Ethyl 2-(20-phenylacetamido)acetate (10) [23]. A modifi-
cation of a known procedure to the corresponding methyl ester
was followed [28]. To a 0ꢀC stirred solution of glycine ethyl
ester hydrochloride (9) (10.0 g, 104 mmol) in CH2Cl2
(155 mL) was added ice-cooled, neat Et3N (21.0 g, 28.9 mL,
208 mmol) followed by a solution of phenylacetyl chloride
(16.1 g, 13.8 mL, 104 mmol) in CH2Cl2 (45 mL) dropwise via
addition funnel. The cloudy yellow reaction mixture was
stirred at 0ꢀC for 2 h and then at rt for 2 h. The organic layer
was then washed with H2O (250 mL), brine (250 mL), and
dried over sodium sulfate. Removal of the solvent in vacuo
gave a crude yellow oil that solidified on standing. Trituration
(ether) gave the known titled compound 10 as a yellow amor-
phous solid (15.6 g, 70.5 mmol, 68% yield): mp 77–79ꢀC (lit.
1
[23b] mp 79–82ꢀC); H NMR (CDCl3, 300 MHz) d 7.24–7.38
(m, 5H), 5.91 (br s, 1H), 4.15 (q, 3H, J ¼ 7.1 Hz), 3.97 (d,
2H, J ¼ 5.1 Hz), 3.61 (s, 2H), 1.22 (t, 4H, J ¼ 3.6 Hz) ppm;
13C NMR (CDCl3, 75 MHz) d 171.4, 170.0, 134.7, 129.7,
129.3, 127.7, 61.8, 43.7, 41.7, 14.4 ppm.
969, 922, 902, 847, 820, 783, 764, 735, 696, 670 cmꢂ1 1H
;
NMR (CDCl3, 300 MHz) d 7.62–7.65 (m, 2H), 7.41–7.44 (m,
3H), 4.59 (s, 2H), 1.57 (s, 9H) ppm; 13C NMR (CDCl3, 75
MHz) d 164.6, 154.9, 149.2, 130.2, 129.1, 129.0, 126.2, 124.6,
118.5 (q, J ¼ 320 Hz), 84.6, 47.8, 28.3 ppm; Anal. calcd for
C16H16F3NO6S: C, 47.17; H, 3.96; N, 3.44. Found: C, 47.13;
H, 3.89; N, 3.39.
Ethyl 2-(N-(tert-butoxycarbonyl)-20-phenylacetamido)-
acetate (11). To a rt stirred solution of 10 (15.6 g, 70.6
mmol) in CH3CN (170 mL) was added DMAP (0.862 g, 7.06
mmol) followed by a solution of Boc2O (16.9 g, 79.0 mmol)
in CH3CN (80 mL). The brown reaction mixture was stirred at
rt for 3 h. The solvent was then concentrated in vacuo to give
a brown oil that was taken up in ether (50 mL) and washed
with an aqueous solution of HCl (1M, 40 mL), brine (40 mL),
and dried over sodium sulfate. Removal of the solvent in
vacuo gave the title compound 11 as a brown oil, which was
used directly without further purification (21.0 g, 65.3 mmol,
tert-Butyl 2,5-dihydro-2-oxo-3-phenyl-4-(tosyloxy)-1H-
pyrrole-1-carboxylate (4a). To a rt stirred solution of 12
(1.00 g, 3.65 mmol) in CH2Cl2 (40 mL) was added TsCl
(0.730 g, 3.83 mmol) followed by neat Et3N (0.443 g, 0.608
mL, 4.38 mmol) dropwise via syringe. The reaction mixture
was stirred at rt for 1 h at which point TLC showed complete
conversion of the starting material 12. The reaction mixture
was poured onto an aqueous solution of KHSO4 (0.992 g, 7.30
mmol in 50 mL H2O) and the aqueous layer was extracted
with CH2Cl2 (3 ꢁ 40 mL). The combined organic layers were
washed with an aqueous solution of sodium bicarbonate (1%
w/v, 150 mL), brine (150 mL), and dried over sodium sulfate.
Removal of the solvent in vacuo gave the titled compound 4a
as a yellow amorphous solid (1.44 g, 3.35 mmol, 92% yield).
Recrystallization (CH2Cl2) gave the analytical sample as yel-
low crystals: mp 137–140ꢀC; Rf ¼ 0.76 (1:2 EtOAc/PE); IR
(ATR, neat) 1770, 1450, 1377, 1335, 1314, 1287, 1192, 1159,
1
93% yield): H NMR (CDCl3, 300 MHz) d 7.19–7.29 (m, 5H),
4.43 (s, 2H), 4.28 (s, 2H), 4.16 (q, 2H, J ¼ 7.2 Hz), 1.46 (s,
9H), 1.24 (t, 3H, J ¼ 7.2 Hz) ppm; 13C NMR (CDCl3, 75
MHz) d 174.1, 169.2, 152.4, 135.1, 129.9, 128.6, 127.1, 84.3,
61.5, 45.9, 44.4, 28.1, 14.5 ppm.
tert-Butyl 2,5-dihydro-4-hydroxy-2-oxo-3-phenyl-1H-
pyrrole-1-carboxylate (12). To a 0ꢀC stirred solution of 11
(15.1 g, 47.1 mmol) in THF (200 mL) was added sodium tert-
butoxide (5.43 g, 47.1 mmol). The cloudy rust-colored reaction
mixture was stirred at 0ꢀC for 2 h and then at rt overnight. An
aqueous solution of KHSO4 (12.8 g, 94.0 mmol in 200 mL
H2O) was added to the reaction mixture and allowed to stir for
20 min. The THF was then removed in vacuo, and the remain-
ing aqueous layer was extracted with ethyl acetate (EtOAc) (3
ꢁ 80 mL). The combined organic layers were then washed
with brine (200 mL) and dried over sodium sulfate. Removal
of the solvent in vacuo gave a crude yellow solid. Trituration
(EtOAc) gave the titled compound 12 as white crystals (7.04
g, 25.6 mmol, 55% yield): mp 134–135ꢀC; IR (ATR, neat)
3141, 1745, 1718, 1663, 1639, 1408, 1350, 1313, 1257, 1155,
1103, 1073, 980, 898, 851, 780, 754, 742, 721, 694, 665
1091, 977, 898, 781, 761, 697, 664 cmꢂ1 1H NMR (CDCl3,
;
300 MHz) d 7.60 (d, 2H, J ¼ 8.4 Hz), 7.35–7.39 (m, 2H),
7.21–7.25 (m, 3H), 7.11 (d, 2H, J ¼ 9.0 Hz), 4.58 (s, 1H),
2.35 (s, 3H), 1.57 (s, 9H) ppm; 13C NMR (CDCl3, 75 MHz) d
165.7, 156.6, 149.0, 147.5, 131.1, 129.9, 128.7, 128.6, 128.2,
128.0, 127.0, 122.5, 83.7, 48.2, 28.1, 21.7 ppm; Anal. calcd
for C22H23NO6S: C, 61.52; H, 5.40; N, 3.26. Found: C, 61.13;
H, 5.46; N, 3.31.
2,5-Dihydro-2-oxo-3-phenyl-4-(trifluoromethylsulfonoxy)-
1H-pyrrole (13a). To a rt stirred solution of 7a (1.50 g, 3.68
mmol) in CH2Cl2 (10 mL) was added TFA (10 mL). The reac-
tion mixture was stirred at rt for 5 min at which point TLC
showed complete conversion of the starting material 7a. Re-
moval of the solvent in vacuo gave a crude brown oil that was
taken up in CHCl3 (20 mL) and washed with a saturated aque-
ous solution of sodium bicarbonate (20 mL). The aqueous
layer was extracted with CHCl3 (3 ꢁ 20 mL) and the com-
bined organic layers were then washed with brine (50 mL) and
cmꢂ1 1H NMR (CDCl3, 300 MHz) d 12.39 (br s, 1H), 7.84
;
(d, 2H, J ¼ 7.2 Hz), 7.35 (t, 2H, J ¼ 7.5 Hz), 7.20 (t, 1H, J ¼
7.5), 4.27 (s, 2H), 1.48 (s, 9H) ppm; 13C NMR (CDCl3, 75
MHz) d 169.4, 168.0, 149.0, 131.1, 127.9, 127.0, 126.2, 103.5,
81.1, 47.9, 27.8 ppm; Anal. calcd for C15H17NO4: C, 65.44; H,
6.22; N, 5.09. Found: C, 65.23; H, 6.22; N, 5.00.
tert-Butyl 2,5-dihydro-2-oxo-3-phenyl-4-(trifluoromethyl-
sulfonoxy)-1H-pyrrole-1-carboxylate (7a). To a ꢂ15ꢀC stir-
red solution of 12 (1.21 g, 4.65 mmol) in CH2Cl2 (30 mL)
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452
S. J. P. Yoon-Miller, K. M. Dorward, K. P. White, and E. T. Pelkey
Vol 46
dried over sodium sulfate. Removal of the solvent in vacuo
gave the titled compound 13a as a yellow amorphous solid
(1.10 g, 3.58 mmol, 97% yield). Recrystallization (EtOH) gave
the analytical sample as yellow crystals: mp 117–119ꢀC; Rf ¼
0.33 (1:2 EtOAc/PE); IR (ATR, neat) 3072, 1699, 1420, 1333,
1211, 1170, 1134, 1025, 958, 919, 825, 781, 766, 735, 694,
13C NMR (CDCl3, 75 MHz) d 168.3, 154.8, 149.6, 149.0,
146.5, 131.4, 130.0, 129.4, 128.8, 128.6, 128.4, 128.2, 122.5,
120.9, 111.5, 111.4, 56.2, 49.4, 46.1, 21.9 ppm; Anal. calcd
for C26H25NO6S: C, 65.12; H, 5.25; N, 2.92. Found: C, 65.05;
H, 5.37; N, 2.92.
2,5-Dihydro-2-oxo-4-(tosyloxy)-1H-pyrrole (14b). To
a
1
681 cmꢂ1; H NMR (CDCl3, 300 MHz) d 8.78 (s, 1H), 7.61–
0ꢀC stirred solution of known tosylate 4b [11b] (0.600 g, 1.70
mmol) in CH2Cl2 (8.6 mL) was added TFA (8.6 mL) dropwise
via syringe. The reaction mixture was stirred for 0.5 h. Re-
moval of the solvent in vacuo gave a crude product that was
taken up in CHCl3 (25 mL) and washed with an aqueous solu-
tion of sodium bicarbonate (5% w/v, 2 ꢁ 25 mL), brine
(25 mL), and dried over sodium sulfate. Removal of the sol-
vent in vacuo gave the titled compound 14b as a white amor-
phous solid (0.355 g, 1.40 mmol, 83% yield): mp 151–153ꢀC;
IR (ATR, neat) 3102, 1693, 1631, 1596, 1386, 1360, 1325,
1216, 1196, 1184, 1161, 1092, 980, 921, 877, 818, 803, 782,
7.64 (m, 2H), 7.46–7.49 (m, 3H), 4.36 (d, 2H, J ¼ 1.2 Hz)
ppm; 13C NMR (CDCl3, 75 MHz) d 168.1, 155.6, 129.3,
128.5, 128.4, 127.2, 123.3, 117.7 (q, J ¼ 320 Hz), 44.5 ppm;
Anal. calcd for C11H8F3NO4S: C, 43.00; H, 2.62; N, 4.56.
Found: C, 42.91; H, 2.59; N, 4.58.
2,5-Dihydro-2-oxo-3-phenyl-4-(tosyloxy)-1H-pyrrole (14a). To
a rt stirred solution of 4a (1.00 g, 2.33 mmol) in CH2Cl2 (20
mL) was added TFA (20 mL). The reaction mixture was
stirred at rt for 5 min at which point TLC showed complete
conversion of the starting material 4a. Removal of the solvent
in vacuo gave a crude brown oil that was taken up in CHCl3
(20 mL) and washed with a saturated aqueous solution of so-
dium bicarbonate (20 mL). The aqueous layer was extracted
with CHCl3 (3 ꢁ 25 mL) and the combined organic layers
were then washed with a saturated aqueous solution of sodium
bicarbonate (200 mL), brine (200 mL), and dried over sodium
sulfate. Removal of the solvent in vacuo gave titled compound
14a as a yellow amorphous solid (0.750 g, 2.28 mmol, 98%
yield). Recrystallization (CH2Cl2) gave the analytical sample
as light yellow crystals: mp 159–161ꢀC; Rf ¼ 0.21 (1:1
EtOAc/PE); IR (ATR, neat) 3071, 1686, 1593, 1497, 1451,
1360, 1306, 1236, 1204, 1182, 1172, 1088, 1039, 960, 813,
704, 667 cmꢂ1 1H NMR (CDCl3, 300 MHz) d 8.03 (s, 1H),
;
7.96 (d, 2H, J ¼ 8.4 Hz), 7.54 (d, 2H, J ¼ 8.1 Hz), 5.62 (d,
1H, J ¼ 1.5 Hz), 3.93 (t, 2H, J ¼ 1.2 Hz), 2.45 (s, 3H) ppm;
13C NMR (CDCl3, 75 MHz) d 170.8, 163.3, 146.9, 130.6,
130.4, 128.5, 107.4, 46.2, 21.2 ppm; Anal. calcd for
C11H11NO4S: C, 52.16; H, 4.38; N, 5.53; S, 12.66. Found: C,
52.10; H, 4.30; N, 5.47; S, 12.71.
General procedures for Suzuki–Miyaura reactions
Method A (tetramic acid triflates). To a rt stirred solution of
tetramic acid triflate (1.00 mmol) in THF (10 mL) was added
an arylboronic acid (1.50 mmol) and was allowed to dissolve
completely. To this solution was added Pd(PPh3)4 (0.050
mmol) followed by an aqueous solution of sodium carbonate
(2.2 mmol in 1 mL H2O). The reaction mixture was stirred at
rt for 40 min and then heated to reflux until TLC showed com-
plete conversion of the starting triflate (typically 1–3 h). The
reaction mixture was then filtered through a short plug of ce-
lite with the aid of EtOAc. Removal of the solvent in vacuo
gave a crude solid that was purified by flash column chroma-
tography (gradient: 1:4 to 1:1 EtOAc/PE).
Method B (tetramic acid tosylates). To a rt stirred solution
of tetramic acid tosylate (1.00 mmol) in THF (10 mL) was
added an arylboronic acid (1.50 mmol) and was allowed to
dissolve completely. To this solution was added Pd(dppf)Cl2
(0.050 mmol) followed by a solution of an aqueous solution of
cesium carbonate (3.00 mmol, 1 mL H2O). The reaction mix-
ture was stirred at rt for 40 min and then heated to reflux until
TLC showed complete conversion of the starting material (typ-
ically 12–20 h). The reaction mixture was then filtered through
a short plug of celite with the aid of EtOAc. The organic layer
was washed with a saturated aqueous solution of sodium bicar-
bonate (50 mL), brine (50 mL), and dried over sodium sulfate.
Removal of the solvent in vacuo gave a crude oil that was
purified by flash column chromatography (gradient: CH2Cl2 to
8:92 EtOAc/CH2Cl2).
1
786, 735, 703, 689 cmꢂ1; H NMR (CDCl3, 300 MHz) d 8.47
(s, 1H), 7.73–7.76 (m, 2H), 7.28–7.37 (m, 7H), 4.20 (d, 2H, J
¼ 0.9 Hz), 2.35 (s, 3H) ppm; 13C NMR (CDCl3, 75 MHz) d
169.3, 156.6, 146.6, 130.5, 130.2, 128.2, 128.1, 128.0, 127.9,
121.5, 44.9, 21.2 ppm; Anal. calcd for C17H15NO4S: C, 61.99;
H, 4.59; N, 4.25. Found: C, 62.00; H, 4.64; N, 4.29.
2,5-Dihydro-1-(30,40-dimethoxybenzyl)-2-oxo-3-phenyl-4-(tosy-
loxy)-1H-pyrrole (8a). To a rt stirred solution of known tetra-
mic acid 15 [2] (2.00 g, 6.18 mmol) in CH2Cl2 (60 mL) was
added TsCl (1.23 g, 6.46 mmol) followed by neat Et3N (0.748
g, 1.028 mL, 7.39 mmol) dropwise via syringe. The reaction
mixture was stirred at rt for 2 h at which point TLC showed
complete conversion of the starting material 15. The reaction
mixture was poured onto an aqueous solution of KHSO4 (1.99
g, 14.6 mmol in 75 mL H2O) and the aqueous layer was
extracted with CH2Cl2 (3 ꢁ 50 mL). The combined organic
layers were washed with an aqueous solution of sodium bicar-
bonate (1% w/v, 150 mL), brine (150 mL), and dried over so-
dium sulfate. Removal of the solvent in vacuo gave a crude
clear oil (2.79 g) that was purified by flash column chromatog-
raphy (gradient: 1:5 to 1:1 EtOAc/PE). Removal of the solvent
in vacuo gave the titled compound 8a as a clear oil. Tritura-
tion (MeOH) gave the analytical sample as a white solid (1.94
g, 4.05 mmol, 66% yield): mp 110–112ꢀC; Rf ¼ 0.17 (1:2
EtOAc/PE); IR (ATR, neat) 1688, 1593, 1517, 1447, 1405,
1356, 1338, 1296, 1280, 1263, 1356, 1338, 1296, 1280, 1263,
1236, 1205, 1160, 1136, 1090, 1022, 973, 956, 900, 814, 787,
tert-Butyl 2,5-dihydro-4-(40-methoxyphenyl)-2-oxo-3-
phenyl-1H-pyrrole-1-carboxylate (16a). Using triflate 7a,
Method A was followed and gave the titled compound 16a as
a light yellow amorphous solid (97% yield). Recrystallization
(EtOAc) gave the analytical sample as white crystals: mp 177–
179ꢀC; Rf ¼ 0.60 (1:2 EtOAc/PE); IR (ATR, neat) 1763,
1686, 1604, 1516, 1450, 1366, 1348, 1313, 1298, 1257, 1160,
1
766, 741, 706, 697 cmꢂ1; H NMR (CDCl3, 300 MHz) d 7.52
(d, 2H, J ¼ 8.1 Hz), 7.43–7.46 (m, 2H), 7.20–7.22 (m, 3H),
7.05 (d, 2H, J ¼ 8.7 Hz), 6.79 (d, 3H, J ¼ 12 Hz), 4.59 (s,
2H), 4.12 (s, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 2.31 (s, 3H) ppm;
1
1123, 1097, 1027, 926, 912, 851, 835, 787, 743, 700 cmꢂ1; H
NMR (CDCl3, 300 MHz) d 7.33–7.34 (m, 5H), 7.26 (d, 2H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2009
Suzuki–Miyaura Arylations of Tetramic Acid Sulfonates: Evaluation of
Lactam Protection, Sulfonate Esters, and Sterics
453
J ¼ 7.5 Hz), 6.79 (d, 2H, J ¼ 9.0 Hz), 4.64 (s, 2H), 3.79 (s,
3H), 1.58 (s, 9H) ppm; 13C NMR (CDCl3, 75 MHz) d 168.9,
161.2, 150.5, 149.3, 131.8, 130.7, 129.9, 129.7, 128.8, 128.6,
124.7, 114.4, 83.3, 55.6, 50.9, 28.4 ppm; Anal. calcd for
C22H23NO4: C, 72.31; H, 6.34; N, 3.83. Found: C, 72.10; H,
6.38; N, 3.87.
Using tosylate 4a, Method B was followed and gave the ti-
tled compound 16a as a light yellow amorphous solid (40%
yield) which gave spectral data consistent with the material
prepared from triflate 7a.
2,5-Dihydro-1-(30,40-dimethoxybenzyl)-4-(400-methoxyphenyl)-
2-oxo-3-phenyl-1H-pyrrole (17a). Using triflate 3a [11a],
Method A was followed and gave the titled compound 17a as
a yellow amorphous solid as reported previously [11a] (95%
yield).
Using tosylate 8a, Method B was followed in an attempt to
obtain the titled compound 17a; however, only a trace amount
of product was formed as seen by TLC. Flash column chroma-
tography gave only starting material 3a.
ppm; 13C NMR (CDCl3, 75 MHz) d 168.5, 157.2, 150.4,
149.8, 133.2, 131.6, 131.1, 130.5, 129.4, 128.3, 128.2, 122.1,
122.0, 111.6, 83.1, 55.5, 52.1, 28.5 ppm; Anal. calcd for
C22H23NO4: C, 72.31; H, 6.34; N, 3.83. Found: C, 72.03; H,
6.46; N, 3.81.
Using tosylate 4a, Method B was followed and gave the ti-
tled compound 19a as a yellow oil (33% yield) that gave spec-
tral data consistent with the material prepared from 7a.
2,5-Dihydro-4-(20-methoxyphenyl)-2-oxo-1H-pyrrole-1-car-
boxylate (19b). Using tosylate 4b [11b], Method B was fol-
lowed and gave the titled compound 19b as a brown amor-
phous solid (74% yield). Trituration (EtOH) gave the analyti-
cal sample as white crystals: mp 127–128ꢀC; Rf ¼ 0.33 (5:95
EtOAc/CH2Cl2); IR (ATR, neat) 1756, 1678, 1606, 1577,
1501, 1455, 1362, 1333, 1293, 1251, 1156, 1077, 1015, 876,
852, 789, 759, 730 cmꢂ1 1H NMR (CDCl3, 300 MHz) d
;
7.38–7.41 (m, 2H), 6.95–6.99 (m, 2H), 6.65 (s, 1H), 4.71 (d,
2H, J ¼ 1.5 Hz), 3.89 (s, 3H), 1.56 (s, 9H) ppm; 13C NMR
(CDCl3, 75 MHz) d 170.3, 158.9, 153.1, 150.0, 132.5, 128.4,
123.0, 121.0, 120.1, 111.8, 83.0, 55.7, 52.8 ppm; Anal. calcd
for C16H19NO4: C, 66.42; H, 6.62; N, 4.84. Found: C, 66.33;
H, 6.67; N, 4.92.
2,5-Dihydro-4-(40-methoxyphenyl)-2-oxo-3-phenyl-1H-pyrrole
(18a). Using triflate 13a, Method A was followed and gave the
titled compound 18a as a white amorphous solid (62% yield):
mp 169–174ꢀC (lit. [11a] mp 193–196ꢀC); Rf ¼ 0.28 (1:1
1
EtOAc/PE); H NMR (CDCl3, 300 MHz) d 8.42 (s, 1H), 7.29–
Acknowledgments. The authors thank Camille and Henry Drey-
fus start-up grant (E.T.P.), Research Corporation, Patchett Foun-
dation (S.J.P.Y.-M.), Dr. Edwards P. Franks (K.P.W.), and
Hobart and William Smith Colleges for the support of this
research
7.37 (m, 3H) 7.24–7.28 (m, 4H) 6.87 (d, 2H, J ¼ 8.7 Hz),
4.33 (s, 2H), 3.74 (s, 3H) ppm. The physical properties and
spectral data for 18a were consistent to that reported previ-
ously [11a].
Using tosylate 14a, Method B was followed in an attempt to
obtain 18a; however, spectroscopic and TLC assessment of the
crude material obtained on work-up failed to reveal even
reveal a trace of 18a.
REFERENCES AND NOTES
tert-Butyl 2,5-dihydro-4-(40-methoxyphenyl)-2-oxo-1H-
pyrrole-1-carboxylate (16b). Using tosylate 4b [11b],
Method B was followed and gave the titled compound 16b as
a tan amorphous solid (74% yield): mp 151–154ꢀC (lit. [11b]
´
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1
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454
S. J. P. Yoon-Miller, K. M. Dorward, K. P. White, and E. T. Pelkey
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