Preparation of dibenzo[ e, g ]isoindol-1-ones via Scholl-type oxidative cyclization reactions

Article abstract of DOI:10.1021/jo501185f

A flexible synthesis of dibenzo[e,g]isoindol-1-ones has been developed. Dibenzo[e,g]isoindol-1-ones represent simplified benzenoid analogues of biological indolo[2,3-a]pyrrolo[3,4-c]carbazol-5-ones (indolocarbazoles), compounds that have demonstrated a wide range of biological activity. The synthesis of the title compounds involved tetramic acid sulfonates. Different aryl groups were introduced at C4 of the heterocyclic ring via Suzuki-Miyaura cross-coupling reactions. Finally, mild Scholl-type oxidative cyclizations mediated by phenyliodine(III) bis(trifluoroacetate) (PIFA) converted some of the latter compounds into the corresponding dibenzo[e,g]isoindol-1-ones. A systematic study of the oxidative cyclization revealed the following reactivity trend: 3,4-dimethoxyphenyl 蠑 3-methoxyphenyl > 3,4,5-trimethoxyphenyl > 4-methoxyphenyl ≈ phenyl. Overall, the oxidative cyclization required at least two methoxy groups distributed in the aromatic rings, at least one of which had to be located para to the site of the cyclization.

Full text of DOI:10.1021/jo501185f

Article
pubs.acs.org/joc
Open Access on 08/19/2015
Preparation of Dibenzo[e,g]isoindol-1-ones via Scholl-Type Oxidative
Cyclization Reactions
Amy A. van Loon, Maeve K. Holton, Catherine R. Downey, Taryn M. White, Carly E. Rolph,
Stephen R. Bruening, Guanqun Li, Katherine M. Delaney, Sarah J. Pelkey, and Erin T. Pelkey*
Department of Chemistry, Hobart and William Smith Colleges, Geneva, New York 14456, United States
S
* Supporting Information
ABSTRACT: A flexible synthesis of dibenzo[e,g]isoindol-1-
ones has been developed. Dibenzo[e,g]isoindol-1-ones represent
simplified benzenoid analogues of biological indolo[2,3-a]-
pyrrolo[3,4-c]carbazol-5-ones (indolocarbazoles), compounds
that have demonstrated a wide range of biological activity. The
synthesis of the title compounds involved tetramic acid
sulfonates. Different aryl groups were introduced at C4 of the
heterocyclic ring via Suzuki−Miyaura cross-coupling reactions. Finally, mild Scholl-type oxidative cyclizations mediated by
phenyliodine(III) bis(trifluoroacetate) (PIFA) converted some of the latter compounds into the corresponding dibenzo[e,g]-
isoindol-1-ones. A systematic study of the oxidative cyclization revealed the following reactivity trend: 3,4-dimethoxyphenyl ≫ 3-
methoxyphenyl > 3,4,5-trimethoxyphenyl > 4-methoxyphenyl ≈ phenyl. Overall, the oxidative cyclization required at least two
methoxy groups distributed in the aromatic rings, at least one of which had to be located para to the site of the cyclization.
one 7,13 and none of these reports included an example of 7
that is N-unsubstituted. Dibenzo[e,g]isoindolones, in which
both indole rings have been replaced with simple benzene rings,
are potentially a new class of indolocarbazole analogues.
Given our interest in the chemistry of 3,4-diaryl-3-pyrrolin-2-
ones,14 along with the diverse biological activity associated with
polycyclic-fused isoindol-1-ones, we decided to investigate the
conversion of B into A (Scheme 1) via an intramolecular
INTRODUCTION
Polycyclic-fused isoindol-1-ones have demonstrated promising
utility as heterocyclic scaffolds in the search for enzyme
inhibitors (Figure 1). A prominent member of this structural
■
Scheme 1. Synthetic Approaches to Fused Isoindol-1-ones
Figure 1. Polycyclic-fused isoindol-1-ones.
Scholl-type oxidative cyclization.15 In contrast, most known
literature methods to A involve reduction of the corresponding
maleimides C;4d,e this reduction often proves to be unselective
in cases of nonsymmetrical substrates.16 There are several
possible methods available for completing oxidative cyclizations
to phenanthrenes and fused phenanthrenes; these methods
include oxidative photocyclization,17 transition metal-mediated
oxidative cyclization,18−21 and oxidative cyclization using
nonmetal reagents.22−25 We chose to focus our attention on
the latter given the mildness of the reagents and ease of use.
Kita pioneered an array of different oxidative transformations
class is the natural product staurosporinone (1),1
a
submicromolar inhibitor of protein kinase C (PKC) first
isolated in 1986.2,3 The impressive biological activity inspired
several total syntheses of 14 and the investigation into
analogues5 that retain the indolo[2,3-a]pyrrolo[3,4-c]carbazol-
5-one (indolocarbazole) backbone of 1. For example, the
indolocarbazole analogue Go 6976 (2) is a selective PKC
̈
inhibitor6 and HIV-1 antagonist.7 Several heterocyclic fused
isoindol-1-ones,8 ring-modified analogues of 1, have also been
prepared and their biological activity evaluated (e.g., 3,9 4,10
and 511). The synthesis of benzo[a]pyrrolo[3,4-c]carbazole-1-
ones (e.g., 6) was also reported in 2008.12 Interestingly, only a
small number of reports in the literature have described the
preparation of the simpler ring system, dibenzo[e,g]isoindol-1-
Received: May 27, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo501185f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
involving electron-rich arenes that used the hypervalent iodine
reagent, phenyliodine(III) bis(trifluoroacetate) (PIFA).26
PIFA-mediated cyclizations leading to phenanthrenes and
attempted to form the tetramic acids 10 by treatment of 9 with
sodium tert-butoxide as we had done previously (9: Ar3 =
Ph).14b Unexpectedly, the attempted cyclocondensations of
methoxyaryl-substituted acetamides 9 (b Ar3 = 4′-methox-
yphenyl; c Ar3 = 3′-methoxyphenyl; d Ar3 = 3′,4′-
dimethoxyphenyl) with sodium tert-butoxide failed to produce
the corresponding tetramic acids 10. Fortunately, the use of
potassium tert-butoxide29 gave methoxyaryl-substituted tetra-
mic acids 10 in moderate yields. Treatment of 10 with triflic
anhydride led to the corresponding triflates 11; in some of the
runs, purification of 11 led to the loss of the Boc protecting
group and the formation of unprotected lactams 12.30 Triflates
12 were also obtained by treatment of purified 11 with TFA in
CH2Cl2 (the yields of these reactions leading to 12 are reported
in Table 1). We subsequently found substrates 11c/12c to be
capricious in the subsequent cross-coupling reactions, so we
prepared the alternate cross-coupling substrate, tosylate 13c, by
treatment of 10c with tosyl chloride and triethylamine.31
We briefly investigated an alternative synthesis of 12 that
avoided the use of the Boc protecting group altogether.
Cyclization of unprotected acetamides 8 with potassium tert-
butoxide gave the corresponding N-unsubstituted 3-aryltetr-
amic acids in isolated yields that were very low (<10%); we
believe the low yields observed were due to the difficulty in
purifying these unprotected tetramic acids and this strategy was
not pursued further.32
́
fused phenanthrenes were subsequently reported by Domi-
nguez24 and others.25 By exploring the PIFA-mediated
oxidative cyclization of 3,4-diaryl-3-pyrrolin-2-ones, we set out
to synthesize new dibenzo[e,g]isoindol-1-one analogues of
indolocarbazoles and related biologically active heterocyclic
scaffolds including congeners containing either symmetrical or
unsymmetrical substitution patterns in the phenanthrene rings
or heterocyclic variants.
Our synthetic plan involved extending our synthesis of 3,4-
diaryl-3-pyrrolin-2-ones from 3-aryltetramic acid triflates
(Scheme 2).14b,c Our strategy allows for easy access to 3-
Scheme 2. Synthetic Plan to Dibenzo[e,g]isoindol-1-ones
pyrrolin-2-ones with different aryl groups at the 3- and 4-
positions. The choice of arylacetic acid starting material leads to
different aryl groups at the 3-positions (in blue), while different
aryl groups can be introduced at the 4-position (in red) via
Suzuki−Miyaura cross-coupling reactions with commercially
available arylboronic acids. With a small library of 3,4-diaryl-3-
pyrrolin-2-ones in hand, we explored their subsequent
intramolecular Scholl-type oxidative cyclizations into dibenzo-
[e,g]isoindol-1-ones.
We next examined Suzuki−Miyaura cross-coupling reactions
of tetramic acid sulfonates 11−13. Cross-coupling reactions of
all three types of substrates with methoxy-substituted
arylboronic acids gave the corresponding 3,4-diaryl-3-pyrrolin-
2-ones 14 and 15, respectively, in good to excellent yields in
many cases (Table 2). As expected, we did observe higher
yields using protected triflates 11 compared to unprotected
triflates 12 (e.g., entry 5 vs entry 16), but we favored the use of
unprotected triflates as it saves one synthetic operation per
substrate. Inexplicably, cross-coupling reactions of either triflate
11c, unprotected triflate 12c, or tosylate 13c (substrates with a
3-methoxyphenyl group) suffered from low yields or gave
intractable mixtures. Nonetheless, this strategy still allowed for
the preparation of a small library of methoxy-substituted 3,4-
diaryl-3-pyrrolin-2-ones for our oxidative cyclization study.
We chose to start exploring intramolecular Scholl-type
oxidative cyclizations of bis(3′,4′-dimethoxyphenyl)-3-pyrro-
lin-2-ones 14dd and 15dd (Scheme 3) using PIFA.24−26
Satisfyingly, on our first attempt, treatment of 14dd with PIFA
and BF3·Et2O at −40 °C for 30 min led to the formation of
dibenzo[e,g]isoindol-1-one 16dd in 55% yield. The reaction
proceeded with loss of the Boc protecting group. We next tried
the cyclization with N-unprotected lactam substrate 15dd and
obtained 16dd in 93% yield. Since the yield was excellent for
the free lactam, we subsequently used N-unprotected 3-
pyrrolin-2-ones in all of the subsequent oxidative cyclization
reactions. Evidence for the cyclization could readily be seen in
the 1H NMR, which showed a significant downfield shift of the
arene protons (δ6.8−7.0 in 15dd to δ7.2−8.7 in 16dd) and
methylene protons (δ4.32 in 15dd to δ4.67 in 16dd). We used
this type of analysis to diagnose crude reaction mixtures
involving the oxidative cyclizations.
RESULTS AND DISCUSSION
■
We prepared methoxyaryl-substituted tetramic acids by
extending our previously reported synthetic strategy to a 3-
phenyltetramic acid (Table 1).14c Freshly prepared ethyl
glycinate free amine was coupled with arylacetic acids in the
presence of DCC/DMAP giving amidoesters 8 as white
powders after trituration. Next, treatment of 8 with Boc2O/
DMAP27 gave the Boc-protected acetamides 9.28 We next
Table 1. Synthesis of Tetramic Acid Triflates
yields (%)
A brief exploration of the reaction conditions of the oxidative
cyclization with 15dd was conducted (Table 3). Extending the
reaction time (entry 1 vs entry 2) slightly increased the yield
(93 to 96%). The yield decreased slightly (96 to 90%) when the
reaction was run at +4 °C compared to −40 °C (entry 2 vs
Ar3
8
9
10
11
12
13
b Ar3 = 4-methoxyphenyl
c Ar3 = 3-methoxyphenyl
d Ar3 = 3,4-dimethoxyphenyl
80
77
75
87
87
81
79
60
65
72
30
64
90
98
84
−
60
−
B
dx.doi.org/10.1021/jo501185f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Table 2. Synthesis of 3,4-Diaryl-3-pyrrolin-2-ones
Table 3. Oxidative Cyclization of 15cc
a
b
d
entry
substrate
product
yield (%)
temp
time
(h)
16:15
c
yield
(%)
a
b
entry oxidant
additive
(°C)
(ratio)
1
11b
11c
13c
13c
11d
12c
12d
12b
12c
12d
12b
12c
12d
12b
12c
12d
12b
12c
12d
14bb
14cc
14cc
14dc
14dd
15ac
15ad
15bb
15bc
15bd
15cb
84
c
1
2
3
4
5
6
7
8
PIFA
PIFA
PIFA
PIFA
none
DDQ
BF3·Et2O
BF3·Et2O
BF3·Et2O
none
−40
−40
+4
0.5
4
100:0
100:0
100:0
90:10
0:100
50:50
80:20
0:100
93
96
90
75
0
2
45
c
3
25
c
12
4
4
72
−40
−40
rt
5
96
39
74
55
BF3·Et2O
TFA
4
6
4
22
38
0
7
m-CPBA TFA
none TFA
rt
4
8
c
rt
4
9
61
a
10
11
12
13
14
15
16
17
18
19
49
PIFA = phenyliodine(III) bis(trifluoroacetate); m-CPBA = meta-
chloroperbenzoic acid; DDQ = 1,2-dichloro-5,6-dicyanobenzoqui-
c
44
b
c
1
d
e
none. TFA = trifluoroacetic acid. 16:15 ratio was estimated by H
NMR analysis methylene of proton integrations (δ4.67 and δ4.32,
15cc
NR
15cd
15db
15dc
15dd
15eb
15ec
15ed
45
69
25
80
57
59
49
d
respectively). Yield refers to isolated yields of pure products after
trituration and/or column chromatography; ND = not determined.
different 3,4-diaryl-3-pyrrolin-2-one substrates 15 (Table 4).
The substrates in vertical columns differ by the C3-aryl group
(4-methoxyphenyl; 3-methoxyphenyl; 3,4-dimethoxyphenyl)
and the substrates in horizontal rows differ by the C4-aryl
group (phenyl; 4-methoxyphenyl; 3-methoxyphenyl; 3,4-
dimethoxyphenyl; 3,4,5-trimethoxyphenyl). All of the oxidative
cyclization reactions were run at −40 °C (acetonitrile/CO2
bath) for 4 h, and then the solvent was removed, and the
resulting crude reaction mixtures were analyzed by 1H NMR. It
was convenient to estimate the conversion of starting material
15 to product 16 by examining the relative integrations
(rounded to the nearest 10%) of the respective methylene
protons (∼δ4.3 in 15 vs ∼δ4.7 in 16). All substrates containing
one 3,4-dimethoxyphenyl group gave conversions between 60
and 90%, whereas the substrate containing two 3,4-dimethox-
yphenyl groups (15dd) gave complete conversion. Substrates
lacking a 3,4-dimethoxyphenyl group led to conversions under
50% with the exception of the substrate containing two 3-
methoxyphenyl groups which gave 70% conversion. Finally,
substrates containing just one methoxy group or no methoxy
groups located para to the site of cyclization gave 0%
conversion (16cb also gave 0% conversion). The following
relative reactivity trend can be deduced from this data: 3,4-
dimethoxyphenyl ≫ 3-methoxyphenyl > 3,4,5-trimethoxyphen-
yl > 4-methoxyphenyl ≈ phenyl. In addition, we did not
observe any regioisomeric cyclization products in cases where
more than one regioisomer was possible (although we can
definitively rule out their existence).
a
The product number is comprised first of the letter for Ar4 and
second of letter for Ar3; 15ac: Ar4 = phenyl and Ar3 = 3-
b
methoxyphenyl. Yield refers to isolated yields of pure products
c
after column chromatography. Reaction conditions: Ar4−B(OH)2,
d
Pd(dppf)Cl2, Cs2CO3, THF. 15cc was obtained by treatment of 14cc
e
with TFA. NR = not run.
Scheme 3. Preliminary Oxidative Cyclization Results
entry 3). Although the yields in entries 1−3 are effectively the
same given the scale of these reactions (0.20−1.00 mmol), we
chose the 4 h reaction time to make further comparisons. The
use of either DDQ22 (entry 6) or m-CPBA23 (entry 7) as the
oxidant and TFA as the acid led to the incomplete conversion
of the starting material after 4 h at room temperature. The
oxidative cyclization requires an oxidant as reactions run with
just BF3·Et2O (entry 5) or TFA (entry 8) and no oxidant led to
the recovery of only starting material. Interestingly, a reaction
run with just PIFA and no BF3·Et2O led to the cyclized product
in 75% yield (entry 4). Kita and co-workers observed a much
more significant difference in yield (91% with PIFA, BF3·Et2O
vs 25% with PIFA) in a similar comparative set of oxidative
cyclization reactions leading to a dibenzo[a,c]cycloheptene.26b
We next examined the effect that methoxy-substitution had
on the Scholl-type oxidative cyclization by comparing 15
We attempted to purify the crude reaction mixtures that
contained greater than 50% conversion. Pure samples of
dibenzo[e,g]isoindol-1-ones 16, as demonstrated by 1H and 13
C
NMR, could be obtained by trituration of the crude reaction
mixtures with ethanol. This process worked in the cases where
yields are given in Table 4. Although our methodology is
limited in scope to electron-rich substrates at this point, we
were able to obtain seven analytically pure dibenzo[e,g]-
C
dx.doi.org/10.1021/jo501185f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Table 4. Oxidative Cyclizations
a
b
3-(4′-Methoxyphenyl)-4-phenyl-1H-pyrrol-2(5H)-one (15ab) starting material was available from a previous study17d Reported ratios of 16:15
c
1
were ascertained by H NMR analysis of methylene proton integrations Yields refer to isolated yields of analytically pure products obtained after
trituration with EtOH
were used without further purification. 1H NMR and 13C NMR
isoindol-1-ones from these experiments, which demonstrates its
chemical shifts are reported in parts per million (δ) using the solvent’s
potential for exploring this novel heterocyclic scaffold.
residual proton or carbon signal (CDCl3: δH 7.26 ppm, δC 77.3 ppm;
DMSO-d6: δH 2.50 ppm, δC 39.5 ppm) as an internal reference. Flash
chromatography was performed with silica gel (230−400 mesh), and
CONCLUSION
■
thin-layer chromatography (TLC) was performed with glass-backed
silica gel plates and visualized with UV (254 nm). IR spectra were
measured utilizing an infrared spectrometer fitted with an ATR
sampler (attenuated total reflectance). High resolution mass spectra
(HRMS) were obtained using a double-focusing magnetic sector
(DFS) mass spectrometer for electron impact ionization (EI) and a
Fourier transfer ion cyclotron resonance (FTICR) mass spectrometer
for electrospray ionization (ESI). All yields are for materials obtained
after chromatography, trituration, or recrystallization unless otherwise
noted.
We have developed a flexible synthesis of 3,4-diaryl-3-pyrrolin-
2-ones from 3-aryltetramic acids, which allowed for the
preparation of a small library of methoxyphenyl-substituted
analogues (symmetrical and unsymmetrical). This library of
compounds was subjected to PIFA-mediated oxidative
cyclization reactions leading to the corresponding dibenzo-
[e,g]isoindol-1-ones (phenanthrene-fused 3-pyrrolin-2-ones).
The oxidative cyclization reaction worked better with substrates
containing 3,4-dimethoxyphenyl groups and 3-methoxyphenyl
groups compared to substrates containing 4-methoxyphenyl
groups. This work should allow for further exploration into the
synthesis of simplified analogues of indolocarbazoles including
the further exploration of the biological activity of this class of
molecules.
General Method A for Preparation of Amidoesters 8. A
solution of the free amine of ethyl glycinate was generated using a
modified procedure.33 A mixture of ethyl glycinate hydrochloride (6.28
g, 45.0 mmol) in deionized water (100 mL) was treated with
potassium carbonate (12.4 g, 90.0 mmol). The mixture was extracted
with CH2Cl2 (5 × 50 mL). The organic layer was dried over sodium
sulfate and used directly in the next reaction. Next, following a
modified procedure,34 the previously obtained solution of ethyl
glycinate in CH2Cl2 was combined with an arylacetic acid (30.0 mmol)
and then treated with DMAP (0.367 g, 3.0 mmol) followed by DCC
(7.43 g, 36.0 mmol). The reaction mixture was stirred at rt until TLC
analysis (EtOAc) showed complete consumption of the starting
material. The reaction mixture was filtered, and the solid DCU residue
was washed with CH2Cl2. Approximately half of the solvent was
EXPERIMENTAL SECTION
■
General Methods. All reactions were performed under a positive
argon atmosphere with magnetic stirring unless otherwise noted.
Tetrahydrofuran (THF) and dichloromethane (CH2Cl2) were purified
by passage through a column of alumina utilizing a PureSolv 400
solvent purification system. Unless otherwise indicated, all other
reagents and solvents were purchased from commercial sources and
D
dx.doi.org/10.1021/jo501185f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
removed in vacuo and then cooled and filtered to remove additional
DCU. The organic layer was removed in vacuo gave oils or amorphous
solids. Trituration (ether) gave the desired products as powders that
were used directly without any further purification
General Method C for the Dieckmann Cyclization to
Tetramic Acids 10. To a 0 °C stirrred solution of protected
amidoester 9 (20.0 mmol) in THF (50 mL) was added solid
potassium tert-butoxide (3.37 g, 30.0 mmol). The reaction mixture was
heated to 40 °C for 6 h and then cooled back to 0 °C. To the cooled
reaction mixture was added an aqueous solution of KHSO4 (5.45 g,
40.0 mmol in 40 mL H2O) and stirred an additional 30 min. The bulk
of the THF was removed in vacuo, and the aqueous mixture was
extracted with ethyl acetate (4 × 40 mL). The combined organic layers
were washed with brine (150 mL) and dried over sodium sulfate.
Removal of the solvent in vacuo gave a crude solid. Trituration (ether)
of the crude solid provided the desired products as powders, which
were used without further purification.
Ethyl 2-((4′-methoxyphenyl)acetamido)acetate (8b).35 White
powder (6.08 g, 24.2 mmol, 80% yield): mp 78−79 °C; Rf = 0.35 (1:1
EtOAc/petroleum ether); IR (ATR, neat) 3305, 1742, 1638, 1613
1
cm−1; H NMR (400 MHz, CDCl3) δ 7.20 (d, 2H, J = 8.8 Hz), 6.89
(d, 2H, J = 8.8 Hz), 5.91 (br s, 1H), 4.17 (q, 2 H, J = 7.2 Hz), 3.98 (d,
2H, J = 5.2 Hz), 3.80 (s, 3 H), 3.56 (s, 2H), 1.25 (t, 3 H, J = 7.2 Hz)
ppm; 13C NMR (100 MHz, CDCl3) δ 171.8, 170.1, 159.2, 130.9,
126.6, 114.7, 61.8, 55.6, 42.9, 41.7, 14.4 ppm; HRMS (EI-DFS) calcd
for C13H17NO4 251.1158, found 251.1154.
Ethyl 2-((3′-methoxyphenyl)acetamido)acetate (8c).35 White
powder (5.03 g, 20.0 mmol, 77% yield): mp 48−50 °C; Rf = 0.33 (1:1
EtOAc/petroleum ether); IR (ATR, neat) 3255, 1741, 1675, 1650
cm−1; 1H NMR (400 MHz, CDCl3) δ 7.26−7.30 (m, 1H), 6.83−6.89
(m, 3H), 5.94 (br s, 1H), 4.18 (q, 2H, J = 7.2 Hz), 3.99 (d, 2H, J = 5.2
Hz), 3.81 (s, 3H), 3.60 (s, 2H), 1.26 (t, 3H, J = 7.2 Hz) ppm; 13C
NMR (100 MHz, CDCl3) δ 171.2, 170.0, 160.3, 136.1, 130.4, 122.0,
115.3, 113.4, 61.8, 55.5, 43.9, 41.7, 14.4 ppm; HRMS (EI-DFS) calcd
for C13H17NO4 251.1158, found 251.1153.
1-(tert-Butoxycarbonyl)-4-hydroxy-3-(4′-methoxyphenyl)-
1H-pyrrol-2(5H)-one (10b). White powder (3.49 g, 11.4 mmol, 79%
yield): mp 223−225 (dec) °C (lit.36 mp ∼250 °C (dec)); Rf = 0.13
(1:10 MeOH/EtOAc); IR (ATR, neat) 3362, 1743, 1677, 1638, 1610
1
cm−1; H NMR (400 MHz, DMSO-d6) δ 7.83 (d, 2H, J = 9.0 Hz),
6.90 (d, 2H, J = 9.0 Hz), 4.19 (s, 2H), 3.74 (s, 3H), 1.47 (s, 9H) ppm
(note: hydroxy proton was not observed); 13C NMR (100 MHz,
DMSO-d6) δ 168.24, 168.21, 157.4, 149.0, 128.2, 123.6, 113.3, 103.2,
81.0, 55.0, 47.9, 27.8 ppm; HRMS (EI-DFS) calcd for C16H19NO5
305.1263, found 305.1259.
1-(tert-Butoxycarbonyl)-4-hydroxy-3-(3′-methoxyphenyl)-
1H-pyrrol-2(5H)-one (10c). White powder (0.993 g, 3.25 mmol,
60% yield): mp 111−114 °C; Rf = 0.54 (1:10 MeOH/EtOAc); IR
(ATR, neat) 1739, 1667, 1642, 1607 cm−1; 1H NMR (400 MHz,
DMSO-d6) δ 12.45 (br s, 1H), 7.45−7.50 (m, 2H), 7.26 (t, 1H, J = 8.0
Hz), 6.79 (ddd, 1H, J = 1.2, 2.4, 8.0 Hz), 4.26 (s, 2H), 3.74 (s, 3H),
1.48 (s, 9H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 169.7, 167.9,
158.8, 149.0, 132.4, 128.8, 119.5, 112.6, 111.6, 103.2, 81.1, 54.9, 47.8,
27.8 ppm; HRMS (EI-DFS) calcd for C16H19NO5 305.1263, found
305.1256.
Ethyl 2-((3′,4′-dimethoxyphenyl)acetamido)acetate (8d).35
White powder (5.36 g, 21.3 mmol, 75% yield): mp 74−76 °C; Rf =
0.32 (2:1 EtOAc/petroleum ether); IR (ATR, neat) 3284, 1747, 1655,
1610 cm−1; 1H NMR (400 MHz, CDCl3) δ (400 MHz, CDCl3) 6.80−
6.84 (m, 3H), 5.98 (br s, 1H), 4.17 (q, 2H, J = 7.4 Hz), 3.99 (d, 2H, J
= 5.2 Hz), 3.88 (s, 3H), 3.87 (s, 3H), 3.56 (s, 2H), 1.25 (t, 3H, J = 7.4
Hz) ppm; 13C NMR (100 MHz, CDCl3) δ (100 MHz, CDCl3) 171.7,
170.1, 149.5, 148.6, 127.1, 121.9, 112.7, 111.7, 61.8, 56.2 (2), 43.3,
41.7, 14.4 ppm; HRMS (EI-DFS) calcd for C14H19NO5 281.1263,
found 281.1250.
General Method B for Preparation of N-Boc Amidoesters 9.
Modification of a literature procedure was followed.27 To a rt stirred
solution of suitable amidoester 8 (50.0 mmol) and DMAP (0.611 g,
5.00 mmol) in THF (50 mL) was added a solution of Boc2O (13.1 g,
60.0 mmol) in THF (50 mL) dropwise via addition funnel. The
reaction mixture was heated to 40 °C for 2 h and the solvent was
removed in vacuo. The resulting oil was taken up in ether (100 mL),
and the organic solution was washed with an aqueous solution of HCl
(50 mL, 1.0 M) followed by brine (50 mL) and then dried over
sodium sulfate. Removal of the solvent in vacuo gave the desired
compounds as oils that were used directly without further purification.
Ethyl 2-(N-(tert-butoxycarbonyl)-2-(4′-methoxyphenyl)-
acetamido)acetate (9b). Yellow oil (10.6 g, 30.2 mmol, 87%
yield): Rf = 0.46 (1:4 EtOAc/petroleum ether); IR (ATR, neat) 1736,
1691, 1612 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.17 (d, 2H, J = 8.8
Hz), 6.85 (d, 2H, J = 8.8 Hz), 4.44 (s, 2H), 4.23 (s, 2H), 4.18 (q, 2H, J
= 7.2 Hz), 3.78 (s, 3H), 1.49 (s, 9H), 1.25 (t, 3H, J = 7.2 Hz) ppm;
13C NMR (100 MHz, CDCl3) δ 174.4, 169.2, 158.7, 152.4, 130.9,
1-(tert-Butoxycarbonyl)-4-hydroxy-3-(3′,4′-dimethoxyphen-
yl)-1H-pyrrol-2(5H)-one (10d). Pale yellow powder (3.62 g, 10.8
mmol, 65% yield): mp 124−125 °C; Rf = 0.33 (15:85 MeOH/
EtOAc); IR (ATR, neat) 1758, 1621, 1602 cm−1; 1H NMR (400 MHz,
DMSO-d6) δ 12.27 (br s, 1H), 7.54 (d, 1H, J = 2.0 Hz), 7.45 (dd, 1H,
J = 2.0, 8.8 Hz), 6.94 (d, 1H, J = 8.4 Hz), 4.24 (s, 2H), 3.75 (s, 3H),
3.73 (s, 3H), 1.48 (s, 9H) ppm; 13C NMR (100 MHz, DMSO-d6) δ
168.2, 168.1, 149.0, 148.0, 147.2, 123.9, 119.7, 111.4, 110.8, 103.2,
81.0, 55.4, 55.3, 47.8, 27.8 ppm; HRMS (EI-DFS) calcd for
C17H21NO6 335.1369, found 335.1371.
General Method D for the Preparation of Tetramic Acid
Triflates 11. To a −15 °C stirred solution of tetramic acid 10 (10.0
mmol) in CH2Cl2 (50 mL) was added neat Et3N (2.1 mL, 15 mmol)
followed by neat trifluoromethanesulfonic anhydride (2.0 mL, 12
mmol) dropwise via syringe. The reaction mixture was allowed to
slowly warm to room temperature over the course of 2 h. To the
reaction mixture was added an aqueous solution of KHSO4 (2.72 g,
20.0 mmol in 50 mL H2O) dropwise via additional funnel and stirred
an additional 30 min. The reaction mixture was then transferred to a
separatory funnel and extracted with CH2Cl2 (4 × 50 mL). The
combined organic layers were washed with brine (200 mL) and dried
over sodium sulfate. Removal of the solvent in vacuo gave a crude oil
or solid. The crude triflates were often taken on directly in the next
step (Boc deprotection), or purification by flash chromatography
(EtOAc/petroleum ether gradient) gave the title compounds as
amorphous solids.
127.1, 114.0, 84.2, 61.5, 55.5, 45.8, 43.5, 28.1, 14.4 ppm; HRMS (EI-
DFS) calcd for C18H25NO6 351.1682, found 351.1675.
Ethyl 2-(N-(tert-butoxycarbonyl)-2-(3′-methoxyphenyl)-
acetamido)acetate (9c). Colorless oil (1.83 g, 5.21 mmol, 87%
yield): Rf = 0.48 (1:4 EtOAc/petroleum ether); IR (ATR, neat) 1736,
1692, 1601 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.22 (t, 1H, J = 7.4
Hz), 6.78−6.85 (m, 3H), 4.45 (s, 2H), 4.28 (s, 2H), 4.19 (q, 2H, J =
7.4 Hz), 3.79 (s, 3H), 1.48 (s, 9H), 1.26 (s, 3H) ppm; 13C NMR (100
MHz, CDCl3) δ 173.9, 169.2, 159.8, 152.4, 136.5, 129.5, 122.2, 115.4,
112.8, 84.3, 61.5, 55.5, 45.9, 44.4, 28.1, 14.5 ppm; HRMS (EI-DFS)
calcd for C18H25NO6 351.1682, found 351.1688.
Ethyl 2-(N-(tert-butoxycarbonyl)-2-(3′,4′-dimethoxyphenyl)-
acetamido)acetate (9d). Yellow oil (5.50 g, 14.4 mmol, 81% yield):
Rf = 0.24 (1:4 EtOAc/petroleum ether); IR (ATR, neat) 1736, 1690,
1608 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.81 (s, 3H), 4.44 (s, 2H),
4.25 (s, 2H), 4.17 (q, 2H, J = 7.2 Hz), 3.86 (s, 3H), 3.85 (s, 3H), 1.48
(s, 9H), 1.25 (t, 3H, J = 7.2 Hz) ppm; 13C NMR (100 MHz, CDCl3) δ
174.3, 169.2, 152.4, 148.9, 148.2, 127.6, 122.0, 113.1, 111.3, 84.2, 61.5,
56.2, 56.1, 45.9, 43.8, 28.1, 14.5 ppm; HRMS (ESI-DFS) calcd for
C19H27NO7·Na−Boc 304.1155, found 304.1155.
1-(tert-Butoxycarbonyl)-3-(4′-methoxyphenyl)-4-(((trifluoro-
methyl)sulfonyl)oxy)-1H-pyrrol-2(5H)-one (11b). Tan amor-
phous solid (1.02 g, 2.33 mmol, 72% yield); trituration (EtOH)
gave the analytical sample as a white powder: mp 123−124 °C; Rf =
0.33 (1:8 EtOAc/petroleum ether); IR (ATR, neat) 1774, 1701, 1686,
1
1610 cm−1; H NMR (400 MHz, CDCl3) δ 7.67 (d, 2H, J = 8.8 Hz),
6.96 (d, 2H, J = 8.8 Hz), 4.57 (s, 2H), 3.84 (s, 3H), 1.58 (s, 9H) ppm;
13C NMR (100 MHz, CDCl3) δ 165.0, 161.0, 153.5, 149.2, 130.5,
124.0, 118.7, 118.5 (q, J = 319 Hz), 114.4, 84.5, 55.6, 47.7, 28.3 ppm;
HRMS (ESI-FTICR) calcd for C17H18F3NO7S·Na 460.0648, found
460.0648.
E
dx.doi.org/10.1021/jo501185f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1-(tert-Butoxycarbonyl)-3-(3′-methoxyphenyl)-4-(((trifluoro-
methyl)sulfonyl)oxy)-1H-pyrrol-2(5H)-one (11c). Yellow amor-
phous solid (0.424 g, 0.969 mmol, 30% yield): mp 84−86 °C; Rf =
0.50 (1:5 EtOAc/petroleum ether); IR (ATR, neat) 1774, 1703, 1687,
were washed with aqueous solution of NaHCO3 (1% w/v, 100 mL),
brine (100 mL), and dried over sodium sulfate. Removal of the solvent
in vacuo gave an oily solid. Purification by flash chromatography
(CH2Cl2/petroleum ether gradient) gave the desired product as a
white amorphous solid (0.36 g, 0.78 mmol, 60% yield): mp 138−141
°C; Rf = 0.50 (5:95 EtOAc/CH2Cl2); IR (ATR, neat) 1771, 1698,
1678, 1607 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.62 (d, 2H, J = 8.4
Hz), 7.14 (t, 1H, J = 8.0 Hz), 7.13 (d, 2H, J = 8.0 Hz), 6.98−7.01 (m,
1H), 6.91−6.93 (m, 1H), 6.81 (ddd, 1H, J = 1.0, 2.4, 8.0 Hz), 4.59 (s,
2H), 3.73 (s, 3H), 2.37 (s, 3H), 1.58 (s, 9H) ppm; 13C NMR (100
MHz, CDCl3) δ 166.0, 159.4, 156.9, 149.3, 146.9, 131.4, 130.2, 129.3,
128.50, 128.45, 122.7, 121.4, 115.4, 113.7, 84.1, 55.4, 48.6, 28.4, 22.0
ppm; HRMS (EI-DFS) calcd for C23H25NO7S 459.1352, found
459.1367.
General Method F for the Suzuki−Miyaura Cross-Coupling.
To a rt stirred solution of triflate 11 or 12 (2.00 mmol) in THF (20
mL) was added an arylboronic acid (3.00 mmol), and the solution was
stirred until the boronic acid completely dissolved. To this solution
was added Pd(PPh3)4 (0.100 mmol) followed by an aqueous solution
of sodium carbonate (0.466 g, 4.40 mmol in 2 mL H2O). The reaction
mixture was stirred at rt for 30 min and then heated to reflux until
TLC (1:1 EtOAc/petroleum ether) showed complete consumption of
the starting material (typically 4−16 h). The reaction mixture was
allowed to cool and then was filtered through a short plug of Celite
with the aid of ethyl acetate. Removal of the solvent in vacuo gave a
crude oil or solid. Flash chromatography (EtOAc/petroleum ether
gradient) gave the title compounds as amorphous solids.
1
1607 cm−1; H NMR (400 MHz, CDCl3) δ 7.35 (t, 1H, J = 8.2 Hz),
7.23−7.25 (m, 2H), 6.97 (ddd, 1H, J = 1.2, 2.4, 8.2 Hz), 4.59 (s, 2H),
3.82 (s, 3H), 1.59 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ
164.6, 159.9, 154.9, 149.1, 130.0, 127.3, 124.4, 121.4, 118.3 (q, J = 319
Hz), 116.6, 114.0, 84.7, 55.6, 47.8, 28.3 ppm; HRMS (ESI-FTICR)
calcd for C17H18F3NO7S·Na 460.0648, found 460.0648.
1-(tert-Butoxycarbonyl)-3-(3′,4′-dimethoxyphenyl)-4-(((tri-
fluoromethyl)sulfonyl)oxy)-1H-pyrrol-2(5H)-one (11d). White
powder after trituration with EtOH (1.78 g, 3.80 mmol, 64% yield);
trituration (EtOH) gave the analytical sample as a white powder: mp
103−105 °C; Rf = 0.20 (1:6 EtOAc/petroleum ether); IR (ATR, neat)
1
1788, 1706, 1677, 1601 cm−1; H NMR (400 MHz, CDCl3) δ 7.35
(dd, 1H, J = 2.0, 8.4 Hz), 7.32 (d, 1H, J = 2.0 Hz), 6.92 (d, 1H, J = 8.4
Hz), 4.56 (s, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 1.58 (s, 9H) ppm; 13C
NMR (100 MHz, CDCl3) δ 165.0, 153.5, 150.6, 149.11, 149.10, 123.9,
122.4, 118.9, 118.5 (q, J = 319 Hz), 111.7, 111.3, 84.6, 56.16, 56.15,
47.6, 28.3 ppm; HRMS (ESI-FTICR) calcd for C18H20F3NO8S·Na
490.0754, found 490.0754.
General Method E for the Conversion of 11 into 12. To a rt
stirred solution of triflate 11 (5.00 mmol) in CH2Cl2 (10 mL) was
added TFA (10 mL). The reaction mixture was stirred until TLC (1:1
EtOAc/petroleum ether) showed consumption of the starting
material. The solvent was removed in vacuo, and the crude product
was taken up in CH2Cl2 (20 mL), and the organic solution was washed
with brine (20 mL) and dried over sodium sulfate. Removal of the
solvent in vacuo followed by trituration (EtOH) or flash
chromatography (EtOAc/petroleum ether gradient) gave the desired
products as powders or amorphous solids.
3-(4′-Methoxyphenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-1H-
pyrrol-2(5H)-one (12b). Tan amorphous solid (1.48 g, 4.39 mmol,
90% yield): reaction time = 6 h; mp 111−113 °C; Rf = 0.38 (1:1
EtOAc/petroleum ether); IR (ATR, neat) 3202, 1693, 1613 cm−1; 1H
NMR (400 MHz, CDCl3) δ 8.72 (br s, 1H), 7.64 (d, 2H, J = 9.2 Hz),
7.05 (d, 2H, J = 9.2 Hz), 4.32 (d, 2H, J = 1.2 Hz), 3.80 (s, 3H) ppm;
13C NMR (100 MHz, CDCl3) δ 168.3, 159.9, 154.2, 129.8, 122.7,
General Method G for the Suzuki−Miyaura Cross-Coupling.
The same as Method F with triflate 11 or triflate 12 or tosylate 13c
and Pd(dppf)Cl2 (0.100 mmol) as the palladium catalyst and cesium
carbonate (4.40 mmol in 2 mL H2O) as the base.
General Method H for the Conversion of 14 into 15. To a rt
stirred solution of 3-pyrrolin-2-ones 14 (1.00 mmol) in CH2Cl2 (5
mL) was added TFA (5 mL). The reaction mixture was stirred until
TLC (1:1 EtOAc/petroleum ether) showed consumption of the
starting material (typically 1−6 h). The solvent was removed in vacuo,
and the crude product was taken up in CH2Cl2 (20 mL), and the
organic solution was washed with brine (20 mL) and dried over
sodium sulfate. Removal of the solvent in vacuo followed by trituration
(cold EtOH) or flash chromatography (EtOAc/petroleum ether
gradient) gave the desired products as powders or amorphous solids.
1-(tert-Butoxycarbonyl)-3,4-bis(4′-methoxyphenyl)-1H-pyr-
rol-2(5H)-one (14bb). Yellow amorphous solid (Method F: 0.152 g,
0.384 mmol, 84% yield): mp 145−147 °C; Rf = 0.42 (1:2 EtOAc/
petroleum ether); IR (ATR, neat) 1771, 1723, 1699, 1639, 1604 cm−1;
1H NMR (400 MHz, CDCl3) δ 7.300 (d, 2H, J = 8.8 Hz), 7.295 (d,
119.5, 117.7 (q, J = 319 Hz), 114.0, 55.2, 44.4 ppm; HRMS (EI-DFS)
calcd for C12H10F3NO5S 337.0232, found 337.0222.
3-(3′-Methoxyphenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-1H-
pyrrol-2(5H)-one (12c). Yellow powder (1.06 g, 3.14 mmol, 98%
yield): reaction time = 1 h; mp 108−110 °C; Rf = 0.39 (1:1 EtOAc/
1
petroleum ether); IR (ATR, neat) 3208, 1686, 1608 cm−1; H NMR
(400 MHz, CDCl3) δ 8.78 (br s, 1H), 7.41 (t, 1H, J = 8.4 Hz), 7.20−
7.23 (m, 2H), 7.03 (ddd, 1H, J = 1.2, 2.4, 8.4 Hz), 4.35 (d, 2H, J = 1.2
Hz), 3.77 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 168.0, 159.0,
155.7, 129.7, 128.4, 123.0, 122.5, 120.6, 117.7 (q, J = 319 Hz), 114.9,
113.9, 55.1, 44.5 ppm; HRMS (EI-DFS) calcd for C12H10F3NO5S
337.0232, found 337.0237.
3-(3′,4′-Dimethoxyphenyl)-4-(((trifluoromethyl)sulfonyl)-
oxy)-1H-pyrrol-2(5H)-one (12d). Off-white powder (0.662 g, 1.80
mmol, 84% yield): reaction time = 18 h; mp 141−143 °C; Rf = 0.29
(1:1 EtOAc/petroleum ether); IR (ATR, neat) 3202, 1696, 1603
cm−1; 1H NMR (400 MHz, CDCl3) δ 8.76 (br s, 1H), 7.29−7.33 (m,
2H), 7.08 (d, 1H, J = 8.4 Hz), 4.31 (d, 2H, J = 0.8 Hz), 3.80 (s, 3H),
3.75 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 168.3, 154.2, 149.6,
148.3, 122.7, 121.5, 119.6, 117.7 (q, J = 319 Hz), 111.6, 111.5, 55.5,
55.3, 44.3 ppm; HRMS (ESI-FTICR) calcd for C13H12F3NO6S·Na
390.0230, found 390.0229.
1-(tert-Butoxycarbonyl)-3-(3′-methoxyphenyl)-4-(tosyloxy)-
1H-pyrrol-2(5H)-one (13c). To a rt stirred mixture of 10c (0.40 g,
1.3 mmol) and toluenesulfonyl chloride (0.27 g, 1.4 mmol) in CH2Cl2
(50 mL) was added triethylamine (0.22 mL, 1.6 mmol) dropwise via
syringe. The reaction mixture was stirred at rt for 30 min by which
time TLC showed consumption of 10c. The reaction mixture was
combined with an aqueous solution of KHSO4 (1.0 M, 50 mL), and
the organic layer was separated. The aqueous layer was further
extracted with CH2Cl2 (2 × 50 mL). The combined organic layers
2H, J = 8.8 Hz), 6.89 (d, 2H, J = 8.8 Hz), 6.82 (d, 2H, J = 8.8 Hz),
4.62 (s, 2H), 3.82 (s, 3H), 3.81 (s, 3H), 1.59 (s, 9H) ppm; 13C NMR
(100 MHz, CDCl3) δ 169.2, 161.1, 159.8, 150.5, 148.4, 131.2, 130.3,
129.6, 125.0, 123.9, 114.4, 114.3, 83.2, 55.6, 55.5, 50.9, 28.5 ppm;
HRMS (EI-DFS) calcd for C23H25NO5 395.1733, found 395.1739.
1-(tert-Butoxycarbonyl)-3,4-bis(3′-methoxyphenyl)-1H-pyr-
rol-2(5H)-one (14cc). Yellow amorphous solid (from 11c, Method
G: 88 mg, 0.22 mmol, 45% yield; from 13c, Method G: 0.11 g, 0.28
mmol, 25% yield): mp 70−75 °C; Rf = 0.20 (1:4 EtOAc/petroleum
1
ether); IR (ATR, neat) 1758, 1727, 1637 cm−1; H NMR (400 MHz,
CDCl3) δ 7.21−7.27 (m, 2H), 6.82−6.93 (m, 6H), 4.66 (s, 2H), 3.73
(s, 3H), 3.61 (s, 3H), 1.60 (s, 9H) ppm; 13C NMR (100 MHz,
CDCl3) δ 168.6, 159.9, 159.8, 150.2, 149.7, 133.5, 132.59, 132.57,
130.1, 129.8, 122.2, 120.3, 116.4, 114.92, 114.85, 113.3, 83.4, 55.5,
55.4, 51.1, 28.4 ppm; HRMS (EI-DFS) calcd for C23H25NO5
395.1733, found 395.1737.
1-(tert-Butoxycarbonyl)-3-(3′,4′-dimethoxyphenyl)-4-(3″-
methoxyphenyl)-1H-pyrrol-2(5H)-one (14dc). Tan amorphous
solid (from 13c, Method G: 0.180 g, 0.423 mmol, 72% yield): mp
147−149 °C; Rf = 0.16 (1:3 EtOAc/petroleum ether); IR (ATR, neat)
1724, 1707, 1630 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.29 (t, 1H, J
= 8.4 Hz), 6.99 (dd, 1H, J = 2.0, 8.4 Hz), 6.80−6.93 (m, 5H), 4.68 (s,
2H), 3.89 (s, 3H), 3.76 (s, 3H), 3.51 (s, 3H), 1.60 (s, 9H) ppm; 13C
NMR (100 MHz, CDCl3) δ 168.8, 160.1, 151.0, 150.5, 149.4, 148.9,
F
dx.doi.org/10.1021/jo501185f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
133.3, 130.9, 130.0, 124.7, 122.3, 120.9, 115.0, 114.7, 111.4, 111.1,
83.4, 56.2, 55.7, 55.6, 50.8, 28.5 ppm; HRMS (EI-DFS) calcd for
C24H27NO6 425.1838, found 425.1848.
115.2, 114.3, 113.3, 55.5, 55.4, 48.3 ppm; HRMS (ESI-FTICR) calcd
for C18H17NO3·Na 318.1101, found 318.1101.
3,4-Bis(3′-methoxyphenyl)-1H-pyrrol-2(5H)-one (15cc). Trit-
uration (EtOH) gave the title product as a yellow powder (Method H:
48 mg, 0.16 mmol, 95% yield): mp 118−121 °C; Rf = 0.13 (1:1
EtOAc/petroleum ether); IR (ATR, neat) 3212, 1671 cm−1; 1H NMR
(400 MHz, CDCl3) δ 8.31 (br s, 1H), 7.22−7.31 (m, 2H), 6.82−6.94
(m, 6H), 4.48 (s, 2H), 3.75 (s, 3H), 3.63 (s, 3H) ppm; 13C NMR (100
MHz, CDCl3) δ 176.1, 160.0, 159.9, 152.5, 133.6, 132.2, 131.9, 130.2,
130.0, 122.1, 120.3, 116.1, 115.0, 114.8, 113.4, 55.5, 55.4, 49.7 ppm;
HRMS (EI-DFS) calcd for C18H17NO3 295.1208, found 295.1220.
3-(3′,4′-Dimethoxyphenyl)-4-(3″-methoxyphenyl)-1H-pyr-
rol-2(5H)-one (15cd). Light orange amorphous solid (Method F:
0.122 g, 0.375 mmol, 45% yield): mp 173−175 °C; Rf = 0.59 (1:10
1-(tert-Butoxycarbonyl)-3,4-bis(3′,4′-dimethoxyphenyl)-1H-
pyrrol-2(5H)-one (14dd). Yellow amorphous solid (Method F:
0.188 g, 0.412 mmol, 96% yield): mp 165 °C (dec); Rf = 0.32 (1:1
EtOAc/petroleum ether); IR (ATR, neat) 1783, 1727, 1708, 1602
cm−1; 1H NMR (400 MHz, DMSO-d6) δ 6.81−6.99 (m, 6H), 4.66 (s,
2H), 3.891 (s, 3H), 3.886 (s, 3H), 3.79 (s, 3H), 3.57 (s, 3H), 1.60 (s,
9H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 169.1, 150.9, 150.5,
149.3, 149.2, 148.9, 148.7, 130.5, 125.0, 124.2, 122.7, 121.0, 112.3,
111.5, 111.17, 111.15, 83.4, 56.21, 56.20, 56.18, 55.8, 50.8, 28.5 ppm;
HRMS (EI-DFS) calcd for C25H29NO7 455.1944, found 455.1937.
3-(3′-Methoxyphenyl)-4-phenyl-1H-pyrrol-2(5H)-one (15ac).
White amorphous solid (Method F: 0.15 g, 0.57 mmol, 39% yield):
mp 171−174 °C; Rf = 0.31 (1:1 EtOAc/petroleum ether); IR (ATR,
neat) 3161, 1684 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 8.52 (br s,
1H), 7.33 (s, 5H), 7.25 (t, 1H, J = 8.0 Hz), 6.87−6.91 (m, 1H), 6.81−
6.84 (m, 2H), 4.35 (d, 2H, J = 1.2 Hz), 3.67 (s, 3H) ppm; 13C NMR
(100 MHz, DMSO-d6) δ 172.2, 158.9, 150.6, 133.6, 133.3, 131.5,
129.2, 129.0, 128.6, 127.5, 121.5, 114.9, 113.1, 54.9, 47.5 ppm; HRMS
(EI-DFS) calcd for C17H15NO2 265.1103, found 265.1101.
1
MeOH/EtOAc solvent); IR (ATR, neat) 3178, 1685, 1604 cm−1; H
NMR (400 MHz, DMSO-d6) δ 8.48 (br s, 1H), 7.23−7.27 (m, 1H),
6.86−6.95 (m, 6H), 4.31 (d, 2H, J = 1.2 Hz), 3.75 (s, 3H), 3.65 (s,
3H), 3.58 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 172.5,
159.2, 149.2, 148.5, 148.2, 134.9, 131.4, 129.7, 124.5, 121.9, 119.9,
114.3, 113.1, 113.0, 111.5, 55.4, 55.3, 54.9, 47.5 ppm; HRMS (EI-
DFS) calcd for C19H19NO4 325.1314, found 325.1310.
4-(3″,4″-Dimethoxyphenyl)-3-(4′-methoxyphenyl)-1H-pyr-
rol-2(5H)-one (15db). Off-white amorphous solid (Method F: 0.270
g, 0.830 mmol, 69% yield); recrystallization (CH2Cl2/petroleum
ether) gave the analytical sample as white crystals: mp 160−162 °C; Rf
= 0.48 (1:10 MeOH/EtOAc); IR (ATR, neat) 3173, 1671, 1607 cm−1;
1H NMR (400 MHz, DMSO-d6) δ 8.38 (br s, 1H), 7.23 (d, 2H, J = 8.4
Hz), 6.87−6.95 (m, 5H), 4.32 (s, 2H), 3.76 (s, 3H), 3.74 (s, 3H), 3.50
(s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 172.9, 158.7, 149.4,
149.2, 148.3, 130.7, 129.9, 125.8, 124.8, 120.3, 113.7, 111.6, 110.0,
55.5, 55.10, 55.07, 47.3 ppm; HRMS (EI-DFS) calcd for C19H19NO4
325.1314, found 325.1318.
4-(3″,4″-Dimethoxyphenyl)-3-(3′-methoxyphenyl)-1H-pyr-
rol-2(5H)-one (15dc). Tan amorphous solid (Method F: 22 mg,
0.068 mmol, 25% yield): mp 160−164 °C; Rf = 0.40 (EtOAc); IR
(ATR, neat) 3163, 1676 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 8.41
(br s, 1H), 7.29 (t, 1H, J = 8.0 Hz), 6.82−6.95 (m, 6H), 4.35 (d, 2H, J
= 0.8 Hz), 3.74 (s, 3H), 3.70 (s, 3H), 3.48 (s, 3H) ppm; 13C NMR
(100 MHz, DMSO-d6) δ 172.6, 159.1, 150.3, 149.6, 148.2, 134.2,
130.2, 129.3, 125.4, 121.7, 120.4, 115.1, 113.0, 111.5, 111.0, 55.5, 55.0
(2), 47.3 ppm; HRMS (EI-DFS) calcd for C19H19NO4 325.1314,
found 325.1319.
3-(3′,4′-Dimethoxyphenyl)-4-phenyl-1H-pyrrol-2(5H)-one
(15ad). Off-white amorphous solid (Method F: 0.17 g, 0.58 mmol,
74% yield): mp 135−137 °C; Rf = 0.61 (1:9 MeOH/EtOAc); IR
(ATR, neat) 3159, 1676 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 8.48
(br s, 1H), 7.35 (s, 5H), 6.88−6.94 (m, 2H), 6.84 (d, 1H, J = 1.6 Hz),
4.32 (d, 2H, J = 0.8 Hz), 3.75 (s, 3H), 3.56 (s, 3H) ppm; 13C NMR
(100 MHz, DMSO-d6) δ 172.5, 149.4, 148.4, 148.1, 133.7, 131.2,
128.8, 128.6, 127.6, 124.4, 121.9, 112.9, 111.5, 55.4, 55.2, 47.5 ppm;
HRMS (EI-DFS) calcd for C18H17NO3 295.1208, found 295.1219.
3,4-Bis(4′-methoxyphenyl)-1H-pyrrol-2(5H)-one (15bb).37
White amorphous solid (Method F: 0.240 g, 0.813 mmol, 55%
yield): mp 223−227 °C (lit.14d mp 213-216 °C); Rf = 0.55 (1:9
1
MeOH/EtOAc); IR (ATR, neat) 3174, 1672, 1626, 1602 cm−1; H
NMR (400 MHz, DMSO-d6) δ 8.36 (br s, 1H), 7.28 (d, 2H, J = 9.2
Hz), 7.22 (d, 2H, J = 9.2 Hz), 6.92 (d, 2H, J = 9.2 Hz), 6.89 (d, 2H, J
= 9.2 Hz), 4.29 (s, 2H), 3.76 (s, 3H), 3.74 (s, 3H) ppm; 13C NMR
(100 MHz, DMSO-d6) δ 172.9, 159.7, 158.7, 148.9, 130.5, 129.6,
128.9, 125.8, 124.7, 1140.0, 113.7, 55.2, 55.0, 47.3 ppm; HRMS (EI-
DFS) calcd for C18H17NO3 295.1208, found 295.1200.
3-(3′-Methoxyphenyl)-4-(4″-methoxyphenyl)-1H-pyrrol-
2(5H)-one (15bc). Yellow amorphous powder (Method G: 0.268 g,
0.907 mmol, 61% yield): mp 150−154 °C; Rf = 0.47 (EtOAc); IR
(ATR, neat) 3168, 1682, 1607 cm−1; 1H NMR (400 MHz, DMSO-d6)
δ 8.41 (br s, 1H), 7.27 (d, 2H, J = 9.0 Hz), 7.24−7.28 (m, 1H), 6.89
(d, 2H, J = 9.0 Hz), 6.81−6.92 (m, 3H), 4.32 (d, 2H, J = 0.8 Hz), 3.74
(s, 3H), 3.69 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 172.6,
159.8, 159.0, 150.1, 134.1, 130.0, 129.3, 129.0, 125.4, 121.6, 115.0,
114.0, 113.0, 55.2, 54.9, 47.3 ppm; HRMS (ESI-FTICR) calcd for
C18H17NO3·Na 318.1101, found 318.1100.
3-(3′,4′-Dimethoxyphenyl)-4-(4″-methoxyphenyl)-1H-pyr-
rol-2(5H)-one (15bd). Off-white amorphous solid (Method F: 0.340
g, 1.05 mmol, 49% yield); recrystallization (CH2Cl2/petroleum ether)
gave the analytical sample as white crystals: mp 169−170 °C; Rf = 0.56
(1:10 MeOH/EtOAc solvent); IR (ATR, neat) 3179, 1677, 1608
cm−1; 1H NMR (400 MHz, DMSO-d6) δ 8.37 (br s, 1H), 7.30 (d, 2H,
J = 8.8 Hz), 6.85−6.95 (m, 5H), 4.29 (d, 2H, J = 0.8 Hz), 3.76 (s, 3H),
3.74 (s, 3H), 3.60 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ
172.9, 159.7, 149.0, 148.3, 148.2, 130.0, 128.9, 125.7, 124.9, 121.9,
114.0, 112.9, 111.5, 55.4, 55.3, 55.2, 47.3 ppm; HRMS (EI-DFS) calcd
for C19H19NO4 325.1314, found 325.1316.
3-(4′-Methoxyphenyl)-4-(3″-methoxyphenyl)-1H-pyrrol-
2(5H)-one (15cb). Off-white amorphous solid (Method G: 59 mg,
0.20 mmol, 44% yield): mp 180−185 °C; Rf = 0.38 (EtOAc); IR
(ATR, neat) 3232, 1672, 1629, 1600 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.36 (d, 2H, J = 8.8 Hz), 7.22 (t, 1H, J = 8.0 Hz), 7.07 (br s,
1H), 6.90 (d, 2H, J = 8.8 Hz), 6.83−6.92 (m, 3H), 4.33 (d, 2H, J = 1.2
Hz), 3.81 (s, 3H), 3.65 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ
174.5, 159.9, 159.8, 149.4, 135.0, 132.3, 131.1, 130.0, 124.2, 120.2,
3,4-Bis(3′,4′-dimethoxyphenyl)-1H-pyrrol-2(5H)-one (15dd).
Yellow amorphous solid (Method F: 0.400 g, 1.13 mmol, 80% yield);
recrystallization (CH2Cl2/petroleum ether) gave the analytical sample
as yellow crystals: mp 149−150 °C (lit.38 mp 170−172 °C); Rf = 0.46
1
(1:10 MeOH/EtOAc); IR (ATR, neat) 3165, 1680, 1600 cm−1; H
NMR (400 MHz, DMSO-d6) δ 8.39 (br s, 1H), 6.87−6.97 (m, 6H),
4.32 (s, 2H), 3.76 (s, 3H), 3.74 (s, 3H), 3.62 (s, 3H), 3.52 (s, 3H)
ppm; 13C NMR (100 MHz, DMSO-d6) δ 172.8, 149.4, 149.2, 148.4,
148.31, 148.25, 130.0, 125.8, 125.1, 122.0, 120.4, 113.0, 111.63,
111.55, 111.1, 55.50, 55.48, 55.4, 55.1, 47.3 ppm; HRMS (ESI-
FTICR) calcd for C20H21NO5·Na 378.1312, found 378.1311.
3-(4′-Methoxyphenyl)-4-(3″,4″,5″-trimethoxyphenyl)-1H-
pyrrol-2(5H)-one (15eb). Tan amorphous solid (Method F: 0.375 g,
1.06 mmol, 57% yield): mp 160−165 °C; Rf = 0.23 (2:1 EtOAc/
1
petroleum ether); IR (ATR, neat) 3180, 1678, 1628, 1605 cm−1; H
NMR (400 MHz, DMSO-d6) δ 8.43 (br s, 1H), 7.26 (d, 2H, J = 8.8
Hz), 6.95 (d, 2H, J = 8.8 Hz), 6.63 (s, 2H), 4.35 (s, 2H), 3.76 (s, 3H),
3.65 (s, 3H), 3.57 (s, 6H) ppm; 13C NMR (100 MHz, DMSO-d6) δ
172.7, 158.8, 152.7, 149.2, 138.0, 131.0, 130.7, 128.7, 124.5, 113.6,
105.2, 60.0, 55.6, 55.1, 47.3 ppm; HRMS (EI-DFS) calcd for
C20H21NO5 355.1420, found 355.1419.
3-(3′-Methoxyphenyl)-4-(3″,4″,5″-trimethoxyphenyl)-1H-
pyrrol-2(5H)-one (15ec). Tan amorphous solid (Method F: 0.301 g,
0.847 mmol, 59% yield): mp 135−137 °C; Rf = 0.22 (2:1 EtOAc/
1
petroleum ether); IR (ATR, neat) 3187, 1683, 1605 cm−1; H NMR
(400 MHz, DMSO-d6) δ 8.46 (br s, 1H), 7.30 (t, 1H, J = 8.0 Hz),
6.84−6.92 (m, 3H), 6.62 (s, 2H), 4.38 (d, 2H, J = 0.8 Hz), 3.70 (s,
3H), 3.65 (s, 3H), 3.56 (s, 6H) ppm; 13C NMR (100 MHz, DMSO-
G
dx.doi.org/10.1021/jo501185f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
d6) δ 172.3, 159.1, 152.6, 150.3, 138.2, 134.0, 131.5, 129.3, 128.3,
121.7, 115.0, 113.1, 105.3, 60.1, 55.6, 55.0, 47.4 ppm; HRMS (EI-
DFS) calcd for C20H21NO5 355.1420, found 355.1407.
105.0, 104.5, 56.0, 55.7, 55.5, 43.9 ppm; HRMS (EI-DFS) calcd for
C19H17NO4 323.1158, found 323.1157.
2,3-Dihydro-5,6,10-trimethoxy-1H-dibenzo[e,g]isoindole-1-
one (16dc). Brown powder (16 mg, 0.049 mmol, 45% yield): mp
276−280 °C; Rf = 0.41 (EtOAc); IR (ATR, neat) 3176, 1673, 1620,
3-(3′,4′-Dimethoxyphenyl)-4-(3″,4″,5″-trimethoxyphenyl)-
1H-pyrrol-2(5H)-one (15ed). Bright orange powder (Method F:
0.180 g, 0.467 mmol, 49% yield): mp 165−167 °C; Rf = 0.16 (2:1
EtOAc/petroleum ether); IR (ATR, neat) 3178, 1677, 1624 cm−1; 1H
NMR (400 MHz, DMSO-d6) δ 8.44 (br s, 1H), 6.87−6.97 (m, 3H),
6.65 (s, 2H), 4.34 (s, 2H), 3.75 (s, 3H), 3.65 (s, 3H), 3.62 (s, 3H),
3.59 (s, 6H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 172.6, 152.7,
149.3, 148.5, 148.3, 138.0, 131.1, 128.7, 124.8, 122.0, 113.1, 111.7,
105.3, 60.0, 55.7, 55.5, 55.4, 47.4 ppm; HRMS (EI-DFS) calcd for
C21H23NO6 385.1525, found 385.1523.
General Method I for the Oxidative Cyclization to Dibenzo-
[e,g]isoindole-1-ones 16. To a −40 °C stirred solution of 15 (1.00
mmol) and PIFA (0.473 g, 1.10 mmol) in CH2Cl2 (10 mL) was added
BF3·Et2O (0.15 mL, 1.2 mmol). The reaction mixture was stirred at
−40 °C for 4 h. The solvent was then removed in vacuo giving a crude
solid. The solid was transferred to a centrifuge tube and triturated with
warm EtOH (10 mL). The mixture was centrifuged, and the solvent
was removed in vacuo, which gave the title compounds as analytically
pure powders.
1
1605 cm−1; H NMR (400 MHz, DMSO-d6) δ 8.77 (d, 1H, J = 9.6
Hz), 8.70 (d, 1H, J = 2.8 Hz), 8.62 (br s, 1H), 8.15 (s, 1H), 7.40 (s,
1H), 7.30 (dd, 1H, J = 2.8, 9.2 Hz), 4.72 (s, 2H), 4.04 (s, 3H), 3.95 (s,
3H), 3.91 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 172.2,
157.7, 150.9, 148.9, 144.4, 128.1, 126.8, 125.0, 123.7, 121.8, 120.2,
116.6, 104.5, 104.1, 103.7, 55.9, 55.7, 55.2, 44.0 ppm; HRMS (EI-
DFS) calcd for C19H17NO4 323.1158, found 323.1149.
2,3-Dihydro-5,6,9,10-tetramethoxy-1H-dibenzo[e,g]-
isoindole-1-one (16dd). Off-white powder (48.0 mg, 0.136 mmol,
96% yield): mp 257−260 °C (dec); Rf = 0.67 (1:10 MeOH/EtOAc
1
solvent); IR (ATR, neat) 3369, 1642, 1621 cm−1; H NMR (400
MHz, DMSO-d6) δ 8.69 (s, 1H), 8.59 (s, 1H), 8.07 (s, 2H), 7.36 (s,
1H), 4.67 (s, 2H), 4.07 (s, 3H), 4.05 (s, 3H), 3.95 (s, 3H), 3.91 (s,
3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 172.3, 150.5, 148.98,
148.97, 148.9, 141.5, 125.9, 124.2, 121.8, 121.7, 120.7, 104.45, 104.37,
104.3, 103.5, 56.0, 55.8, 55.6, 55.3, 43.8 ppm; HRMS (EI-DFS) calcd
for C20H19NO5 353.1263, found 353.1264.
2,3-Dihydro-9,10-dimethoxy-1H-dibenzo[e,g]isoindole-1-
one (16ad). Brown powder (29 mg, 0.099 mmol, 58% yield): mp
295−297 °C (dec); Rf = 0.49 (EtOAc solvent); IR (ATR, neat) 3201,
ASSOCIATED CONTENT
■
S
* Supporting Information
1
1672 cm−1; H NMR (400 MHz, DMSO-d6) δ 8.88 (d, 1H, J = 8.4
1
Copies of H NMR spectra and 13C NMR spectra for all
Hz), 8.74 (s, 2H), 4.74 (s, 2H), 4.04 (s, 3H), 3.93 (s, 3H), 8.23 (s,
2H), 8.04 (d, 1H, J = 8.0 Hz), 7.78 (t, 1H, J = 8.0 Hz), 7.67 (t, 1H, J =
8.0 Hz) ppm; 13C NMR (100 MHz, DMSO-d6) δ 172.1, 149.6, 149.2,
142.1, 130.8, 128.2, 126.3, 125.9, 124.8, 124.3, 123.8, 123.7, 122.3,
104.4, 103.7, 55.7, 55.4, 43.7 ppm; HRMS (EI-DFS) calcd for
C18H15NO3 293.1052, found 293.1058.
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: pelkey@hws.edu.
■
2,3-Dihydro-6,9,10-trimethoxy-1H-dibenzo[e,g]isoindole-1-
one (16bd). Brown powder (18 mg, 0.056 mmol, 45% yield): mp
255−259 °C (dec); Rf = 0.42 (EtOAc solvent); IR (ATR, neat) 3183,
Notes
The authors declare no competing financial interest.
1
1693, 1621, 1603 cm−1; H NMR (400 MHz, DMSO-d6) δ 8.72 (s,
1H), 8.58 (br s, 1H), 8.16−8.18 (m, 2H), 7.98 (d, 1H, J = 8.8 Hz),
7.33 (dd, 1H, J = 2.0, 8.8 Hz), 4.70 (s, 2H), 4.05 (s, 3H), 4.04 (s, 3H),
3.93 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 172.3, 159.5,
149.7, 148.8, 142.3, 132.6, 126.1, 124.1, 122.8, 121.4, 120.5, 116.4,
105.2, 104.8, 103.6, 55.9, 55.7, 55.4, 43.7 ppm; HRMS (EI-DFS) calcd
for C19H17NO4 323.1158, found 323.1154.
ACKNOWLEDGMENTS
■
Support of this work by a grant from the National Institute of
Health (R15-GM086819-01A1), Patchett Family Fund (under-
graduate summer fellowships to C.R.D. and C.E.R.), Dr.
Edward Franks (undergraduate summer fellowships to T.M.W.
and A.A.v.L.), Drs. Cohen and Cary (undergraduate summer
fellowship to M.K.H.), and the Hobart and William Smith
Colleges’ Provost Office is gratefully acknowledged. We also
thank Ivan Keresztes and Anthony Kondo and Cornell
University for mass spectrometry assistance. We thank a
referee for bringing the patent noted in ref 35 to our attention.
2,3-Dihydro-5,10-dimethoxy-1H-dibenzo[e,g]isoindole-1-
one (16cc). Brown powder (14 mg, 0.048 mmol, 45% yield): mp
275−280 °C; Rf = 0.50 (EtOAc solvent); IR (ATR, neat) 3201, 1682,
1
1615 cm−1; H NMR (400 MHz, DMSO-d6) δ 8.70−8.75 (m, 4H),
7.39−7.44 (m, 2H), 7.33 (dd, 1H, J = 2.4, 8.8 Hz), 4.74 (s, 2H), 3.95
(s, 3H), 3.91 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 171.9,
157.74, 157.69, 144.5, 127.7, 126.8, 125.7, 125.0, 124.5, 124.3, 124.2,
119.0, 117.0, 104.9, 104.1, 55.5, 55.2, 44.0 ppm; HRMS (EI-DFS)
calcd for C18H15NO3 293.1052, found 293.1065.
REFERENCES
■
2,3-Dihydro-5,9,10-trimethoxy-1H-dibenzo[e,g]isoindole-1-
one (16cd). Brown powder (21 mg, 0.065 mmol, 42% yield): mp
209−211 °C (dec); Rf = 0.40 (EtOAc solvent); IR (ATR, neat) 3218,
1654, 1622 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, 1H, J =
9.2 Hz), 8.73 (br s, 1H), 8.80 (s, 1H), 8.15 (s, 1H), 7.37−7.42 (m,
2H), 4.71 (s, 2H), 4.02 (s, 3H), 3.95 (s, 3H), 3.91 (s, 3H) ppm; 13C
NMR (100 MHz, DMSO-d6) δ 172.1, 157.6, 149.3, 148.9, 141.5,
127.2, 125.6, 125.2, 125.1, 124.2, 121.1, 118.5, 104.5, 103.9, 103.6,
55.7, 55.5, 55.3, 43.9 ppm; HRMS (EI-DFS) calcd for C19H17NO4
323.1158, found 323.1166.
2,3-Dihydro-5,6,9-trimethoxy-1H-dibenzo[e,g]isoindole-1-
one (16db). Brown powder (29 mg, 0.090 mmol, 58% yield): mp
236−239 °C (dec); Rf = 0.30 (EtOAc solvent); IR (ATR, neat) 3365,
1681, 1607 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 9.12 (d, 1H, J =
8.8 Hz), 8.56 (s, 1H), 8.16 (d, 1H, J = 3.6 Hz), 7.41 (s, 1H), 7.33 (dd,
1H, J = 2.4, 9.2 Hz), 4.69 (s, 2H), 4.07 (s, 3H), 4.01 (s, 3H), 3.97 (s,
3H) ppm; 13C NMR (100 MHz, DMSO-d6) δ 172.1, 157.9, 150.4,
149.7, 141.2, 131.0, 125.7, 124.9, 122.4, 121.9, 121.2, 116.1, 105.1,
(1) Yasuzawa, T.; Iida, T.; Yoshida, M.; Hirayama, N.; Takahashi, M.;
Shirahata, K.; Sano, H. J. Antibiot. 1986, 39, 1072−1078.
(2) (a) Nakanishi, S.; Matsuda, Y.; Iwahashi, K.; Kase, H. J. Antibiot.
1986, 39, 1066−1071. (b) Horton, P. A.; Longley, R. E.; McConnell,
O. J.; Ballas, L. M. Experentia 1994, 50, 843−845.
(3) Indolocarbazole (1) is the aglycone of staurosporine, a
nanomolar inhibitor of protein kinase C (PKC) and lead compound
in a large number of studies: Omura, S.; Sasaki, Y.; Iwai, Y.;
Takeshima, H. J. Antibiot. Chem. 1995, 48, 535−548.
(4) Selected total syntheses of staurosporinone (1): (a) Sarstedt, B.;
Winterfeldt, E. Heterocycles 1983, 20, 469−476. (b) Hughes, I.; Nolan,
W. P.; Raphael, R. A. J. Chem. Soc., Perkin Trans. 1 1990, 2475−2480.
(c) Moody, C. J.; Rahimtoola, K. F.; Porter, B.; Ross, B. C. J. Org.
Chem. 1992, 57, 2105−2214. (d) Harris, W.; Hill, C. H.; Keech, E.;
Malsher, P. Tetrahedron Lett. 1993, 34, 8361−8364. (e) Xie, G.; Lown,
J. W. Tetrahedron Lett. 1994, 35, 5555−5558. (f) Wood, J. L.; Stoltz, B.
M.; Dietrich, H.-J.; Pflum, D. A.; Petsch, D. T. J. Am. Chem. Soc. 1997,
119, 9641−9651. (g) Beccalli, E. M.; Gelmi, M. L.; Marchesini, A.
H
dx.doi.org/10.1021/jo501185f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Tetrahedron 1998, 54, 6909−6918. (h) Eils, S.; Winterfeldt, E.
Synthesis 1999, 275−281. (i) Gaudencio, S. P.; Santos, M. M. M.;
Lobo, A. M.; Prabhakar, S. Tetrahedron Lett. 2003, 44, 2577−2578.
(j) Wada, Y.; Nagasaki, H.; Tokuda, M.; Orito, K. J. Org. Chem. 2007,
72, 2008−2014. (k) Rajeshwaran, G. G.; Mohanakrishnan, A. K. Org.
Lett. 2011, 13, 1418−1421.
3765. (c) Quin, L. D.; Middlemas, E. D.; Rao, N. S.; Miller, R. W.;
McPhail, A. T. J. Am. Chem. Soc. 1982, 104, 1893−1900. (d) Smith, P.
A. S.; Friar, J. J.; Resemann, W.; Watson, A. C. J. Org. Chem. 1990, 55,
3351−3362. (e) Trost, B. M.; Krische, M. J.; Berl, V.; Grenzer, E. M.
Org. Lett. 2002, 4, 2005−2008. (f) Nikolaev, V. A.; Galkina, O. S.;
Sieler, J.; Rodina, L. L. Tetrahedron Lett. 2010, 51, 2713−2716.
(g) Chang, M.-Y.; Lee, N.-C. Synlett 2011, 1875−1881. (h) Lu, Z.;
Cui, W.; Xia, S.; Bai, Y.; Luo, F.; Zhu, G. J. Org. Chem. 2012, 77,
9871−9877. (i) Chang, M.-Y; Wu, M.-H. Tetrahedron 2013, 69, 129−
136.
(5) Selected reports of nonglycosidic indolocarbazole-based ana-
logues of (1): (a) Kleinschroth, J.; Hartenstein, J.; Rudolph, C.;
Schachtele, C. Bioorg. Med. Chem. Lett. 1995, 5, 55−60. (b) Xie, G.;
̈
Nagata, H.; Tamaoki, T.; Lown, J. W. Bioorg. Med. Chem. Lett. 1995, 5,
2841−2844. (c) Yang, S.-M.; Malaviya, R.; Wilson, L. J.; Argentieri, R.;
Chen, X.; Yang, C.; Wang, B.; Cavender, D.; Murray, W. V. Bioorg.
Med. Chem. Lett. 2007, 17, 326−331. (d) Wilson, L. J.; Yang, C.;
Murray, W. V. Tetrahedron Lett. 2007, 48, 7399−7403. (e) Wilson, L.
J.; Malaviya, R.; Yang, C.; Argentieri, R.; Wang, B.; Chen, X.; Murray,
W. V.; Cavender, D. Bioorg. Med. Chem. Lett. 2009, 19, 3333−3338.
(18) VOF3: (a) Liepa, A.; Summons, R. E. J. Chem. Soc., Chem.
Comm. 1977, 826−827. (b) Halton, B.; Maidment, A. I.; Officer, D. L.;
Warnes, J. M. Aust. J. Chem. 1984, 37, 2119−2128. (c) Comins, D. L.;
Chen, X.; Morgan, L. A. J. Org. Chem. 1997, 62, 7435−7438.
(d) Wang, K.; Wang, Q.; Huang, R. J. Org. Chem. 2007, 72, 8416−
8421. (e) Ambrosini, L. M.; Cernak, T. A.; Lambert, T. H. Tetrahedron
2010, 66, 4882−4887. (f) Leighty, M. W.; Georg, G. I. ACS Med.
Chem. Lett. 2011, 2, 313−315. (g) Pansare, S. V.; Lingampally, R.;
Dyapa, R. Eur. J. Org. Chem. 2011, 2235−2238.
(6) (a) Kleinschroth, J.; Hartenstein, J.; Rudolph, C.; Schachtele, C.
̈
Bioorg. Med. Chem. Lett. 1993, 3, 1959−1964. (b) Martiny-Baron, G.;
Kazanietz, M. G.; Mischak, H.; Blumberg, P. M.; Kochs, G.; Hug, H.;
Marme,
́
D.; Schachtele, C. J. Biol. Chem. 1993, 268, 9194−9197.
(19) FeCl3: (a) Borner, R. C.; Jackson, R. F. W. J. Chem. Soc., Chem.
Commun. 1994, 845−846. (b) Brenna, E.; Fuganti, C.; Serra, S. J.
̈
(7) Qatsha, K. A.; Rudolph, C.; Marme,
S. Proc. Natl. Acad. Sci. U. S. A. 1993, 90, 4674−4678.
́
D.; Schachtele, C.; May, W.
̈
Chem. Soc., Perkin Trans 1 1998, 901−904. (c) Wang, K.-L.; Lu, M.-Y.;
̈
(8) (a) Rotella, D. P.; Glicksman, M. A.; Prantner, J. E.; Neff, N. T.;
Hudkins, R. L. Bioorg. Med. Chem. Lett. 1995, 5, 1167−1170.
(b) Gingrich, D. E.; Reddy, D. R.; Iqbal, M. A.; Singh, J.; Aimone,
L. D.; Angeles, T. S.; Albom, M.; Yang, S.; Ator, M. A.; Meyer, S. L.;
Robinson, C.; Ruggeri, B. A.; Dionne, C. A.; Vaught, J. L.; Mallamo, J.;
Hudkins, R. L. J. Med. Chem. 2003, 46, 5375−5388. (c) Tao, M.; Park,
C. H.; Bihovsky, R.; Wells, G. J.; Husten, J.; Ator, M. A.; Hudkins, R.
L. Bioorg. Med. Chem. Lett. 2006, 16, 938−942. (d) Tao, M.; Park, C.
H.; Josef, K.; Hudkins, R. L. J. Heterocycl. Chem. 2009, 46, 1185−1189.
(9) Hudkins, R. L.; Diebold, J. L.; Tao, M.; Josef, K. A.; Park, C. H.;
Angeles, T. S.; Aimone, L. D.; Husten, J.; Ator, M. A.; Meyer, S. L.;
Holskin, B. P.; Durkin, J. T.; Fedorov, A. A.; Fedorov, E. V.; Almo, S.
C.; Mathiasen, J. R.; Bozyczko-Coyne, D.; Saporito, M. S.; Scott, R.
W.; Mallamo, J. P. J. Med. Chem. 2008, 51, 5680−5689.
Wang, Q.-M.; Huang, R.-Q. Tetrahedron 2008, 64, 7504−7510.
(d) Wang, K.; Lu, M.; Yu, A.; Zhu, X.; Wang, Q. J. Org. Chem. 2009,
̈
74, 935−938. (e) Mysliwiec, D.; Donnio, B.; Chmielswski, P. J.;
Heinrich, B.; Stepien, M. J. Am. Chem. Soc. 2012, 134, 4822−4833.
(f) Zhou, C.; Chen, X.; Lu, P.; Wang, Y. Tetrahedron 2012, 68, 2844−
2850.
(20) MnO2: Wang, K.; Hu, Y.; Li, Z.; Wu, M.; Liu, Z.; Su, B.; Yu, A.;
Liu, Y.; Wang, Q. Synthesis 2010, 1083−1091.
(21) Tl(OCOCF3)2: (a) Taylor, E. C.; Andrade, J. G.; McKillop, A. J.
Chem. Soc., Chem. Comm. 1977, 538−539. (b) Cragg, J. E.; Herbert, R.
B. J. Chem. Soc., Perkin Trans I 1982, 2487−2490. (c) Pansare, S. V.;
Dyapa, R. Org. Biomol. Chem. 2012, 10, 6776−6784.
(22) 2-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ): (a) Zhai, L.;
Shukla, R.; Rathore, R. Org. Lett. 2009, 11, 3474−3477. (b) Navale, T.
S.; Thakur, K.; Rathore, R. Org. Lett. 2011, 13, 1634−1637. (c) See
also references 15c and 17i.
(23) m-Chloroperbenzoic acid (m-CPBA): Wang, K.; Hu, Y.; Meng,
W.; Li, Z.; Liu, Z.; Su, B.; Yu, A.; Liu, Y.; Wang, Q. Tetrahedron 2010,
66, 9135−9140.
(24) Phenyliodine(III) bis(trifluoroacetate) (PIFA): (a) Olivera, R.;
SanMartin, R.; Pascual, S.; Herrero, M.; Domínguez, E. Tetrahedron
Lett. 1999, 40, 3479−3480. (b) Moreno, I.; Tellitu, I.; SanMartín, R.;
Badía, D.; Carrillo, L.; Domínguez, E. Tetrahedron Lett. 1999, 40,
5067−5070. (c) Moreno, I.; Tellitu, I.; SanMartin, R.; Domínguez, E.
Synlett 2001, 1161−1163. (d) Olivera, R.; SanMartin, R.; Tellitu, I.;
Domínguez, E. Tetrahedron 2002, 58, 3021−3037. (e) Churruca, F.;
SanMartin, R.; Carril, M.; Urtiaga, M. K.; Solans, X.; Tellitu, I.;
Domínguez, E. J. Org. Chem. 2005, 70, 3178−3187. (f) Churruca, F.;
SanMartin, R.; Tellitu, I.; Domínguez, E. Eur. J. Org. Chem. 2005,
2481−2490.
(25) (a) Pingaew, R.; Ruchirawat, S. Synlett 2007, 2363−2366.
(b) Niphakis, M. J.; Georg, G. I. J. Org. Chem. 2010, 75, 6019−6022.
(c) Barrett, T. N.; Braddock, D. C.; Monta, A.; Webb, M. R.; White, A.
J. P. J. Nat. Prod. 2011, 74, 1980−1984. (d) See also reference 15b.
(26) (a) Kita, Y.; Gyoten, M.; Ohtsubo, M.; Tohma, H.; Takada, T.
Chem. Commun. 1996, 1481−1482. (b) Takada, T.; Arisawa, M.;
Gyoten, M.; Hamada, R.; Tohma, R.; Kita, Y. J. Org. Chem. 1998, 63,
7698−7706. (c) Hamamoto, H.; Anilkumar, G.; Tohma, H.; Kita, Y.
Chem. Commun. 2002, 450−451.
(27) Casiraghi, G.; Rassu, G.; Spanu, P.; Pinna, L. J. Org. Chem. 1992,
57, 3760−3763.
(28) We also attempted to prepare a nitro-substituted substrate 9d
from 8d (Ar3 = 4′-nitrophenyl), but this reaction inexplicably failed;
the synthesis of 9d was not pursued further.
(10) (a) Hudkins, R. L.; Johnson, N. W. J. Heterocycl. Chem. 2001, 38,
591−597. (b) Hudkins, R. L.; Johnson, N. W.; Angeles, T. S.; Gessner,
G. W.; Mallamo, J. P. J. Med. Chem. 2007, 50, 433−441.
(11) Ma, D.-W.; Zhang, Y.-D.; Zhang, X.-R.; Wu, S.-H.; Feng-Gang,
T. Chin. J. Chem. 2001, 19, 489−492.
(12) Conchon, E.; Anizon, F.; Aboab, B.; Prudhomme, M. Synthesis
2008, 2569−2574.
(13) (a) Yakushijin, K.; Kozuka, M.; Furukawa, H. Chem. Pharm. Bull.
1980, 28, 2178−2184. (b) Lewis, F. D.; Burch, E. L. J. Photochem.
Photobiol., A 1996, 96, 19−23. (c) Klumpp, D. A.; Zhang, Y.;
O’Connor, M. J.; Esteves, P. M.; de Almeida, L. S. Org. Lett. 2007, 9,
3085−3088. (d) Kim, Y. H.; Lee, H.; Kim, Y. J.; Kim, B. T.; Heo, J.-N.
J. Org. Chem. 2008, 73, 495−501. (e) Yamashita, S.; Kurono, N.;
Senboku, H.; Tokuda, M.; Orito, K. Eur. J. Org. Chem. 2009, 1173−
1180.
(14) (a) Coffin, A. R.; Roussell, M. A.; Tserlin, E.; Pelkey, E. T. J.
Org. Chem. 2006, 71, 6678−6681. (b) Dorward, K. M.; Guthrie, N. J.;
Pelkey, E. T. Synthesis 2007, 2317−2322. (c) Yoon-Miller, S. J. P.;
Dorward, K. M.; White, K. P.; Pelkey, E. T. J. Heterocycl. Chem. 2009,
46, 447−454. (d) Greger, J. G.; Yoon-Miller, S. J. P.; Bechtold, N. R.;
Flewelling, S. A.; MacDonald, J. P.; Downey, C. R.; Cohen, E. A.;
Pelkey, E. T. J. Org. Chem. 2011, 76, 8203−8214.
(15) (a) Kovacic, P.; Jones, M. B. Chem. Rev. 1987, 87, 357−359.
(b) King, B. T.; Kroulik, J.; Robertson, C. R.; Rempala, P.; Hilton, C.
L.; Korinek, J. D.; Gortari, L. M. J. Org. Chem. 2007, 72, 2279−2288.
(c) Zhai, L.; Shukla, R.; Wadumethrige, S. H.; Rathore, R. J. Org.
Chem. 2010, 75, 4748−4760.
(16) (a) Fabre, S.; Prudhomme, M.; Sancelme, M.; Rapp, M. Bioorg.
Med. Chem. 1994, 2, 73−77. (b) Link, J. T.; Raghavan, S.; Gallant, M.;
Danishefsky, S. J.; Chou, T. C.; Ballas, L. M. J. Am. Chem. Soc. 1996,
118, 2825−2842. (c) See also reference 8c.
(17) (a) Wood, C. S.; Mallory, F. B. J. Org. Chem. 1964, 29, 3373−
3377. (b) Padwa, A.; Hartman, R. J. Am. Chem. Soc. 1966, 88, 3759−
(29) (a) Andrews, M. D.; Brewster, A. G.; Chuhan, J.; Ibbett, A. J.;
Moloney, M. G.; Watkin, D. Synthesis 1997, 305−308. (b) Ito, M.;
Okui, H.; Nakagawa, H.; Mio, S.; Iwasaki, T.; Iwabuchi, J. Heterocycles
I
dx.doi.org/10.1021/jo501185f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2002, 57, 881−894. (c) Miyazaki, H.; Ogiku, T.; Sai, H.; Moritani, Y.;
Ohtani, A.; Ohmizu, H. Chem. Pharm. Bull. 2009, 57, 979−985.
(d) Mallinger, A.; Nadal, B.; Chopin, N.; Le Gall, T. Eur. J. Org. Chem.
2010, 1142−1148.
(30) We had previously encountered a similar lability of the Boc
group in tetramic acid triflate 11 (Ar3 = Ph); see reference 14c.
(31) (a) Li, W.-R.; Lin, S. T.; Hsu, N.-M.; Chern, M.-S. J. Org. Chem.
2002, 67, 4702−4706. (b) Boukouvalas, J.; McCann, L. C. Tetrahedron
Lett. 2010, 51, 4636−4639.
(32) Le Gall and co-workers also reported a low yield in their
synthesis of 3-(4′-methoxyphenyl)tetramic acid using a different
method; see reference 29d.
(33) Erhardt, P. W.; Woo, C. M.; Gorczynski, R. J.; Anderson, W. G.
J. Med. Chem. 1982, 25, 1402−1407.
(34) Gynther, M.; Laine, K.; Ropponen, J.; Leppanen, J.; Mannila, A.;
̈
Nevalainen, T.; Savolainen, J.; Jarvinen, T.; Rautio, J. J. Med. Chem.
2008, 51, 932−936.
̈
(35) Although amidoesters 8 apparently have not been reported in
the literature, structurally related methyl esters have appeared in the
patent literature: Xiao, Z.; Deng, R.; Zeng, Q. Faming Zhuanli
Shenqing, CN 103483321, 2014. Chem. Abstr. 2014, 160, 190111.
(36) Storgaard, M.; Dorwald, F. Z.; Peschke, B.; Tanner, D. J. Org.
̈
Chem. 2009, 74, 5032−5040.
(37) 3-Pyrrolin-2-one 15bb has recently been prepared via a double
Suzuki cross-coupling of a 3,4-dibromo-3-pyrrolin-2-one: Awuah, E.;
Capretta, A. J. Org. Chem. 2011, 76, 3122−3130.
(38) Zhang, P. Y.; Wong, I. L. K.; Yan, C. S. W.; Zhang, X. Y.; Jiang,
T.; Chow, L. M. C.; Wan, S. B. J. Med. Chem. 2010, 53, 5108−5120.
J
dx.doi.org/10.1021/jo501185f | J. Org. Chem. XXXX, XXX, XXX−XXX