Synthesis of N -Aryl and N -Heteroaryl γ-, δ-, and ?-Lactams Using Deprotometalation-Iodination and N -Arylation, and Properties Thereof

Article abstract of DOI:10.1055/s-0036-1590798

Xanthone, thioxanthone, fluorenone, benzophenone, 2-benzoylpyridine, dibenzofuran, and dibenzothiophene were deprotonated using a base prepared in situ from MCl ₂ ·TMEDA (M = Zn or Cd; TMEDA = N, N, N ′, N ′-tetramethylethylenediamine) and lithium 2,2,6,6-tetramethylpiperidide in a 1:3 ratio, as demonstrated by subsequent iodolysis. The different aryl halides were involved as partners in the N -arylation of pyrrolidin-2-one. In the presence of copper(I) iodide and tripotassium phosphate, and using dimethyl sulfoxide as solvent, the reactions could be performed in yields ranging from 40 to 70%. Most of the products were tested for their antimicrobial, antifungal, antioxidant, and cytotoxic (MCF-7) activity.

Full text of DOI:10.1055/s-0036-1590798

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–Q
paper
A
en
R. Amara et al.
Paper
Synthesis
Synthesis of N-Aryl and N-Heteroaryl γ-, δ-, and ε-Lactams Using
Deprotometalation–Iodination and N-Arylation, and Properties
Thereof
Rim Amaraa,b
O
O
Ι
Ghenia Bentabed-Ababsa*a
Madani Hedidia,b,1
Joseph Khouryc
O
O
O
N
1) Li-Zn base
THF, 0 °C
N
H
cat. CuI
K3PO4
DMSO, 125 °C
(65% yield)
2) I2
S
S
Haçan Awadc
S
(45% yield)
Ekhlass Nassar*d
Thierry Roisnele
Vincent Dorcete
Floris Chevallierb
Ziad Fajloun*c
Florence Mongin*b
a Laboratoire de Synthèse Organique Appliquée, Faculté des Sciences Exactes
et Appliquées, Université d’Oran 1 Ahmed Ben Bella, BP 1524 El M’Naouer,
31000 Oran, Algeria
b Chimie Organique et Interfaces, Institut des Sciences Chimiques de Rennes,
UMR 6226, CNRS-Université de Rennes 1, Bâtiment 10A, Case 1003, Campus
de Beaulieu, 35042 Rennes, France
florence.mongin@univ-rennes1.fr
c Laboratory of Applied Biotechnology, Azm Center for Research in Biotechnol-
ogy and its Applications, EDST & Faculty of Science III, Lebanese University,
Tripoli, Lebanon
d Chemistry Department, Faculty of Women for Arts, Science and Education,
Ain Shams University, Cairo, Egypt
e Centre de Diffractométrie X, Institut des Sciences Chimiques de Rennes,
UMR 6226, CNRS-Université de Rennes 1, Bâtiment 10B, Campus de
Beaulieu, 35042 Rennes Cedex, France
Received: 18.05.2017
Accepted: 22.05.2017
Published online: 19.07.2017
DOI: 10.1055/s-0036-1590798; Art ID: ss-2017-z0343-op
To regioselectively introduce substituents, deprotome-
talation has imposed itself as a powerful tool.2 If alkyllithi-
ums and hindered lithium dialkylamides have been largely
employed, alternative approaches using lithium-metal
combinations based on 2,2,6,6-tetramethylpiperidide
(TMP) have recently emerged for performing reactions with
sensitive substrates.3 The 1:1 mixture of the homometallic
amides LiTMP and Zn(TMP)2, generated from LiTMP and
ZnCl2·TMEDA (TMEDA = N,N,N′,N′-tetramethylethylenedi-
amine) in a 3:1 ratio, falls into this category.4 With LiTMP-
mediated deprotonation and in situ Zn(TMP)2-induced
transmetalation, this ‘trans-metal trapping’5 approach en-
sures both chemoselective and high-yielding reactions.6
Whereas secondary carboxamides are hardly compati-
ble with the conditions required for their palladium-cata-
lyzed N-arylation and N-heteroarylation (Goldberg reac-
tion),7 the corresponding copper-catalyzed reactions have
benefited from the development of catalyst-base systems.8
Copper(I) iodide is often used in the presence of a diamine
(e.g., trans-cyclohexane-1,2-diamines or other 1,2-eth-
ylenediamines, either N-alkylated or not) as ligand, and in
combination with either a base (K3PO4, K2CO3, or Cs2CO3) or
Abstract Xanthone, thioxanthone, fluorenone, benzophenone, 2-ben-
zoylpyridine, dibenzofuran, and dibenzothiophene were deprotonated
using a base prepared in situ from MCl2·TMEDA (M = Zn or Cd; TMEDA =
N,N,N′,N′-tetramethylethylenediamine) and lithium 2,2,6,6-tetrameth-
ylpiperidide in a 1:3 ratio, as demonstrated by subsequent iodolysis.
The different aryl halides were involved as partners in the N-arylation of
pyrrolidin-2-one. In the presence of copper(I) iodide and tripotassium
phosphate, and using dimethyl sulfoxide as solvent, the reactions could
be performed in yields ranging from 40 to 70%. Most of the products
were tested for their antimicrobial, antifungal, antioxidant, and cytotox-
ic (MCF-7) activity.
Key words C–N bond formation, deprotonative metalation, lactam,
aromatic compound, antimicrobial activity, antifungal activity
Due to their presence in molecules of biological impor-
tance or in organic materials for various applications, aro-
matic compounds and notably heterocycles are essential, as
well as the development of methods to functionalize them.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–Q

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Synthesis
CsF.7,9 Ligand-free catalysis is also possible at moderate re-
action temperatures provided that DMSO is used as sol-
vent.10
We here describe the use of the lithium-zinc combina-
tion developed in the group to access aromatic iodides, as
well as their conversion to N-arylated amides based on pyr-
rolidin-2-ones, piperidin-2-ones and hexahydro-2H-azepin-
2-ones. The antimicrobial, antifungal, antioxidant, and cy-
totoxic activities of some of the prepared compounds were
evaluated.
To subsequently access new N-aryl and N-heteroaryl
lactams, we first involved xanthone (1a), thioxanthone (2a),
fluorenone (3a), benzophenone (4a), and 2-benzoylpyri-
dine (5a) in the reaction using mixed lithium-metal bases
before interception with iodine (Table 1). Achieving the
deprotometalation of such aromatic ketones represents a
challenge due to their low compatibility toward lithium
species.11 Indeed, the method has so far been restricted to a
few carbonyl-containing five-membered12 and six-mem-
bered13 aromatic compounds.
First, xanthone (1a) was reacted with a 1:1 mixture of
LiTMP and Zn(TMP)2 amides obtained by mixing ZnCl2·TMEDA
(0.5 equiv) and LiTMP (1.5 equiv).4a Conducting the reaction
in tetrahydrofuran (THF) at 0 °C for 2 h provided, after in-
terception with iodine, the 1-iodo derivative 1b in 43%
yield; a small amount (5% yield) of 1,9-diiodoxanthone (1b′)
was also isolated (entry 1) and identified unambiguously
(Figure 1). Increasing either the amount of base to 1 equiv
of ZnCl2·TMEDA and 3 equiv of LiTMP, or the reaction tem-
perature to 20–25 °C, led to extended degradation due to
the high reactivity of the ketone. In addition, replacing Zn-
Cl2·TMEDA (0.5 equiv) by CdCl2·TMEDA3d (0.5 equiv) in the
preparation of the base did not improve this result since a
complex mixture was obtained.
Starting from thioxanthone (2a), similar behavior was
observed; using the 1:1 mixture of amides LiTMP and
Zn(TMP)2, this time obtained by mixing ZnCl2·TMEDA (1
equiv) and LiTMP (3 equiv), furnished the 1-iodo derivative
2b in 45% yield (entry 2, Figure 1).
In the case of fluorenone (3a), treatment by the base
prepared from ZnCl2·TMEDA (0.5 equiv) and LiTMP (1.5
equiv) in THF at room temperature for 2 h did not give any
iodide; instead, the hydroxy ketone 3b′ was isolated in 63%
yield (entry 3). Even if we did not observe the expected io-
dide 3b, this result is of interest because it confirms that an
aryllithium is first formed by reaction using this basic mix-
ture (Scheme 1).4 Indeed, trapping by the keto group would
have been much more sluggish had an arylzinc (or zincate)
been formed.6c By decreasing the reaction temperature to
0 °C, a complex mixture was noticed.
Table 1 Deprotometalation-Iodination of the Ketones 1a–5a
1) base prepared from
MCl2·TMEDA (x equiv)
and LiTMP (3x equiv)
O
O
Ι
1
THF, temperature, 2 h
2) I2
X
X
a
b
Entry
1
Ketone
M, x
Temperature
0 °C
Iodo ketone
Product, yield (%)a
O
O
I
1
9
1a
Zn, 0.5
1b, 43b
O
O
O
O
I
2
2a
3a
Zn, 1
0 °C
2b, 45
S
S
O
O
I
3b, –c
3b, 80
8
1
3
4
Zn, 0.5
Cd, 0.5
rt
O
O
I
5
6
4a
5a
X = CH
X = N
Cd, 0.5
Zn, 0.5 or 1
rt
rt
4b, 66d
5b, –e
Ph
Ph
X
X
a After purification by column chromatography.
b 1,9-Diiodoxanthone (1b′) was also isolated in 5% yield.
c The hydroxy ketone 3b′ was obtained instead in 63% yield (see Scheme 1).
d Using a protocol previously reported.13
e Complex mixtures were obtained under these conditions, and the ketone 5b was prepared as described recently.14
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O
O
O
Li
M(TMP)2Li
M(TMP)2
LiTMP
3a
3a
I2
3b'
O
I
O
LiO
O
HO
H2O
3b
Scheme 1 Deprotometalation of fluorenone (3a)
To obtain the 1-iodo derivative 3b, we efficiently turned
to the corresponding lithium-cadmium base generated
from CdCl2·TMEDA (0.5 equiv) and LiTMP (1.5 equiv). After
2 h contact with 3a in THF at room temperature and subse-
quent quenching with iodine, 3b was this time obtained in
80% yield (Table 1, entry 4, Figure 1). This result (no detec-
tion of the hydroxy ketone 3b′) suggests a lithium cadmate
mediated deprotonation.3d,13,15 Otherwise, if deprotolithia-
tion followed by transmetalation (Scheme 1) would rather
happen as proposed,16 the latter could be considered as be-
ing faster with cadmium compared with zinc. Unfortunate-
ly, due to the lack of studies concerning compared kinet-
ics/mechanisms of both lithium/zinc and lithium/cadmium
transmetalations,17 it is not possible to come to a conclu-
sion. Nevertheless, the superiority of the lithium-cadmium
base over the lithium-zinc one to solve chemoselectivity is-
sues is a general trend, and was for example used to convert
benzophenone (4a) into the iodide 4b (entry 5).13
Figure 1 ORTEP diagrams (50% probability) of the compounds 1b′, 2b,
3b, and 6b′
Table 2 Deprotometalation–Iodination of the Substrates 6a and 7a
1) base prepared from
ZnCl2·TMEDA (x equiv)
and LiTMP (3x equiv)
THF, rt, 2 h
2) I2
X
X
I
a
b
Entry
1
Substrate
x
Iodide/diiodide
Product, yield (%)a
6a
0.5
6b, 90b
O
O
6
4
I
I
I
2
6a
7a
1
6b′, 79
O
O
S
I
3
4
5
0.5
1
1.5
7b, 47c
7b, 66c
7b, 85
S
a After purification by column chromatography.
b 4,6-Diiododibenzofuran (6b′) was also identified in the crude.
c The remainder was recovered starting material.
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Our attempts to use the lithium-zinc base as before
from 2-benzoylpyridine (5a) failed (entry 6). In a recent
communication,14 we showed it is possible to achieve its
conversion to the 3-iodo derivative 5b by using LiTMP in
the presence of ZnCl2·TMEDA, and used this protocol. These
results suggest that the zinc chelate is a more efficient in
situ trap than Zn(TMP)2 to transmetalate the generated
aryllithium.
ing the base prepared from ZnCl2·TMEDA (x equiv) and
LiTMP (3x equiv) also led, at room temperature, to either
the monometalated (x = 0.5) or the dimetalated (x = 1) de-
rivatives in good yields, as evidenced by subsequent iodoly-
sis (entries 1 and 2, Figure 1). Dibenzothiophene (7a) can
be similarly mono-19d,21 or dideprotonated21c,22 using butyl-
lithium. Surprisingly, whereas it was found possible to
achieve its monometalation using the lithium-zinc base, an
efficient dimetalation proved impossible under the condi-
tions tried (entries 3–5).
These iodides in hand, we considered their conversion
to N-arylated amides. In search of an efficient method to
achieve the C–N bond formation, we evaluated a proto-
col9a,c,d using copper(I) iodide (5 mol%) as transition metal
source, DMEDA (10 mol%) as ligand (DMEDA = N,N′-dimeth-
ylethylenediamine), K3PO4 (2 equiv) as base and dioxane as
solvent at 110 °C on different aryl halides (Table 3, Figure 2).
We next turn to deprotometalation-iodolysis sequences
starting from dibenzofuran (6a) and dibenzothiophene (7a)
in order to generate either monoiodides or diiodides (Table
2). We chose the 1:1 mixture of amides LiTMP and
Zn(TMP)2 obtained by mixing ZnCl2·TMEDA (x equiv) and
LiTMP (3 x equiv) because it has been efficiently used to ei-
ther monofunctionalize or difunctionalize depending on
the amount of base.6d,e,18
Dibenzofuran (6a) can be either mono-19 or dideproton-
ated20 by using butyllithium, in the presence or not of
TMEDA, at temperatures ranging from –75 °C to 60 °C. Us-
Table 3 N-Arylation of Pyrrolidin-2-one, Piperidin-2-one, and Hexahydro-2H-azepin-2-one with Different Aryl Halides
O
O
H
N
(1.2 equiv)
( )n
Ar
X
Ar
N
( )n
CuI (5 mol%)
DMEDA (10 mol%)
K3PO4 (2 equiv)
dioxane, 110 °C
reaction time
b
c–e
Entry
1
Ar-X
Time (h)
24
N-Arylamide
Product, yield (%)a
O
I
8b
8c, 95
N
O
I
2
3
9b
24
24
9c, 99
N
OMe
OMe
O
MeO
MeO
MeO
MeO
10b
11b
10c, 99
I
N
O
4
5
6
24
24
24
n = 1
n = 2
n = 3
11c, 85
11d, 73
11e, 99
I
N
( )n
O
7
8
12b
48
24
12c, 26b, 20c, 29d
HO
NC
I
HO
NC
N
O
13b′
13c, 89
Br
N
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Table 3 (continued)
Entry
Ar-X
Time (h)
48
N-Arylamide
Product, yield (%)a
O
14b′
14c, 30
Br
N
O
10
15b
72
24
15c, 45
I
N
O
11
12
16b
16b′
X = I
X = Br
16c, 93
16c, 99
X
N
S
S
O
13
14
15
48
48
24
n = 1
n = 2
n = 3
17c, 84
17d, 93
17e, 65
17b
18b
19b
I
N
O
( )n
O
S
O
16
17
18
n = 1
n = 2
n = 3
18c, 88
18d, 81
18e, 53
I
48
N
S
( )n
O
19
20
21
24
48
48
n = 1
n = 2
n = 3
19c, 66
19d, 15
19e, 50
N
N
S
I
N
S
( )n
a After purification by column chromatography.
b A similar result was obtained by using K3PO4 (3 equiv) (reaction time: 72 h).
c Using DMSO instead of dioxane (48 h at 125 °C).
d Using CuI (10 mol%) and DMSO instead of dioxane (48 h at 125 °C).
The method works well with phenyl iodides provided
that it is not substituted by a strong electron-donating
group (entries 1–7). From phenyl bromides, these condi-
tions are more suitable in the presence of electron-with-
drawing substituents compared with electron-donating
(entries 8 and 9). Whereas a moderate yield is noticed from
2-iodonaphthalene (15b, entry 10), both 2-iodo- and 2-
bromothiophene (16b and 16b′, entries 11 and 12) are con-
verted efficiently. This encouraged us to involve in the reac-
tion iodinated benzoazoles prepared by deprotometalation-
iodolysis (entries 13–21).23 The reactions proceed in correct
to high yields from 2-iodobenzofuran (17b) and 2-iodoben-
zothiophene (18b) whereas 2-iodobenzothiazole (19b) is
converted less efficiently.
Inspired by the study published by Güell and Ribas in
2014,10 and in keeping with works recently developed in
our group on azole N-arylation,24 we next compared the
previous protocol with a ligand-free one using DMSO as
solvent. For this purpose, we employed 1-iodo-9-thioxan-
thone (2b) as substrate in the reaction with pyrrolidin-2-
one, and demonstrated the superiority of the second proto-
col to arylate the lactam (Table 4).
These optimized conditions in hand, we first involved in
the reaction the different aryl iodides b synthesized by
deprotometalation-iodolysis. The expected N-functional-
ized lactams were obtained in yields ranging from 40 to 70%
(Table 5, Figure 3).
Unfortunately, the double C–N bond formation per-
formed on the aryl diiodide 6b′ proved less obvious
(Scheme 2, Figure 3). Double functionalization did not take
place at all, the monoamides either deiodinated (6c, 55%
yield) or not (6c′, detected) being the only reaction prod-
ucts. Reacting 6c′ under the same reaction conditions also
failed, only leading to loss of iodine.
This disappointing result led us to consider a more com-
mon substrate, 1,4-diiodobenzene (8b′), to attempt the
same reaction. Even if more successful, the expected di-
amide 8c′′ was isolated in a moderate 30% yield together
with the iodinated amide 8c′ (7% yield). As already noticed
for 4-iodophenol (12b) in Table 3 using similar conditions
(entry 7, footnotes c and d), these results show that an elec-
tron-donating group (here, the introduced amide) tends to
inhibit the reaction.
Because many pharmaceuticals are pyrrolidinone deriv-
atives, e.g. cotinine (used to treat depression, Alzheimer’s
disease, post-traumatic stress disorder and schizophre-
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Figure 2 ORTEP diagrams (50% probability) of the compounds 10c, 11c, 11e, 16c, 17c–e, 18d,e, and 19d
Figure 3 ORTEP diagrams (50% probability) of compounds 1c, 2c, 3c, 5c, and 8c′′
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–Q

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O
N
H
(4 equiv)
6c
+
CuI (20 mol%)
K3PO4 (4 equiv)
O
O
55%
O
I
I
I
N
DMSO, 125 °C, 48 h
6b'
6c'
(<10%)
O
O
O
N
H
(4 equiv)
I
I
I
N
N
N
CuI (20 mol%)
K3PO4 (4 equiv)
O
DMSO, 125 °C, 48 h
8b'
8c'
7%
8c"
30%
Scheme 2 C–N Bond formation from diiodides
nia),25 doxapram (a respiratory stimulant),26 and piracetam
(a cyclic derivative of γ-aminobutyric acid mainly used to
treat myoclonus),27 some of the synthesized compounds
were evaluated for their biological properties.
Table 4 Comparison of Both Protocols for the N-Arylation of Pyrroli-
din-2-one with 1-Iodo-9-thioxanthone (2b)
O
O
I
O
O
N
The compounds 1c, 2c, 3c, 4c, 5c, 6c, 7c, 8c, 8c′′, 10c,
11c–e, 13c, 15c, 16c, 17c–e, 18c–e, and 19c–e were
screened for their antimicrobial activity against bacteria
and for their antifungal activity. An effect on the microbial
growth of strains of bacteria was only noticed in the case of
4c, 6c, 7c, and 8c′′. 1-(2-Benzoylphenyl)pyrrolidin-2-one
(4c) has no significant inhibition effect on L. monocyto-
genes; it inhibits E. coli, P. aeruginosa, and C. dubliniensis at
the same power while it strongly inhibits S. aureus and E.
faecium compared to the positive control. 1-(Dibenzofuran-
4-yl)pyrrolidin-2-one (6c) inhibits S. aureus, but above all C.
albicans. The behavior of 1-(dibenzothiophen-4-yl)piperi-
din-2-one (7c) and 1,1′-(1,4-phenylene)bispyrrolidin-2-one
(8c′′) is even more interesting since both selectively inhibit
C. albicans with a strength comparable to that of nystatin
(Table 6).
H
N
(2 equiv)
CuI (x mol%)
DMEDA (y mol%)
K3PO4 (2 equiv)
solvent, temperature
reaction time
S
S
2b
2c
Entry
CuI
(mol%)
DMEDA
(mol%)
Solvent
Temp
(°C)
Time
(h)
Yield
(%)a
1
2
3
4
5
10
10
–
dioxane
dioxane
DMSO
110
110
125
125
24
10
32
62
65
5
72
24
24
5
10
–
DMSO
a After purification by column chromatography.
As shown in Table 7, various compounds showed an av-
erage antioxidant activity around 40–50%. A study was also
carried out in order to investigate the cytotoxic potential of
the derivatives 8c, 10c, 11c, 12c, 13c, and 16c (Table 8). The
antiproliferative activity of the derivatives was determined
using breast cancer cell line MCF-7, which is an invasive dif-
ferentiated mammary epithelial breast cancer cell line used
worldwide to screen and compare the antiproliferative ac-
tivity of new molecules vs standard anticancer compounds.
None of the compounds synthesized can compete with the
reference standard doxorubicin.
lactams. Whereas 4c shows promising activity as antimi-
crobial and antifungal, compounds 6c and, above all, 7c and
8c′′ exhibit interesting selective antifungal activity against
C. albicans.
All reactions were performed under an argon atmosphere. THF was
distilled over Na/benzophenone. Column chromatography separa-
tions were achieved on silica gel (40–63 μm). Melting points were
measured on a Kofler apparatus. IR spectra were taken on a Perkin-
Elmer Spectrum 100 spectrophotometer. 1H and 13C NMR spectra
were recorded on a Bruker Avance III spectrometer at 300 MHz and
75 MHz, respectively, 1H NMR spectra relative to the solvent residual
peak and 13C NMR spectra are relative to the central peak of the sol-
vent signal.28 The structure of the new compounds was confirmed ei-
ther by X-ray diffraction or through microanalysis.
Thus, by combining deprotometalation-iodination of ar-
omatic ketones with N-arylation of cyclic amides, we could
access a large range of N-aryl and N-heteroaryl γ-, δ-, and ε-
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Table 5 N-Arylation of Pyrrolidin-2-one with Different Aryl Monoiodides
O
I
N
O
N
(2 equiv)
Y
Y
H
CuI (10 mol%)
K3PO4 (2 equiv)
DMSO, 125 °C
reaction time
X
X
b
c
Entry
1
Ar-I
Time (h)
N-Arylamide
Product, yield (%)a
O
O
I
O
O
N
1b
24
24
1c, 70
O
O
O
I
N
O
2
3b
3c, 62
O
I
O
N
3
4
4b
5b
X = CH
X = N
24
72
X = CH
X = N
4c, 56
5c, 40
O
Ph
Ph
X
X
5
6
6b
7b
48
48
6c, 50
7c, 54
O
S
O
O
N
N
O
S
I
I
a After purification by column chromatography.
Table 6 Antimicrobial and Antifungal Activity of Compounds 4c, 6c, 7c, and 8c′′a
Escherichia
coli
Compound
Amount (μg)
dissolved in DMSO
Pseudomonas
aeruginosa
Staphylococcus
aureus
Enterococcus
faecium
Listeria
monocytogenes
Candida
dubliniensis
Candida
albicans
4cb
500
150
150
150
–
8
0
8
0
10
4
9
0
±
0
8
–
–
14
14
15
0
6cc
7cc
0
0
0
0
0
–
8c′′c
DMSO
0
0
0
0
0
–
0
0
0
0
0
0
Reference compound
28
28
18
24
30
10
13
Ceftazidime (30 μg)
Vancomycin (30 μg)
Ampicillin (25 μg) Nystatin (416 Ul)
a The diameters of zones of inhibition are given in mm.
b 10 μL/well.
c 30 μL/well.
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Table 7 Antioxidant Activity of Compounds 1c, 2c, 3c, 4c, 5c, 6c, 7c,
8c, 8c′′, 10c, 11c–e, 13c, 15c, 16c, 17c–e, 18c–e, and 19c–e
Crystallography: The samples were studied with graphite monochro-
matized Mo-Kα radiation (λ = 0.71073 Å). For compounds 1b′, 2b,
10c, 11c, 16c, 17c–e, 18d,e, and 19d, the X-ray diffraction data were
collected at T = 150 K using an APEXII Bruker-AXS diffractometer. The
structure was solved by direct methods using the SIR97 program,29
and then refined with full-matrix least-square methods based on F2
(SHELX-97)30 with the aid of the WINGX program.31 All non-hydrogen
atoms were refined with anisotropic atomic displacement parame-
ters. H atoms were finally included in their calculated positions. For
3b, 6b′, 11e, 1c, 2c, 3c, 5c, and 8c′′, the X-ray diffraction data were
collected using a D8 VENTURE Bruker AXS diffractometer at the tem-
perature given in the crystal data. The structure was solved by dual-
space algorithm using the SHELXT program,32 and then refined with
full-matrix least-square methods based on F2 (SHELXL-2014).33 All
non-hydrogen atoms were refined with anisotropic atomic displace-
ment parameters. H atoms were finally included in their calculated
positions. The molecular diagrams were generated by ORTEP-3 (ver-
sion 2.02).34
Compound
RSA (%)a at t = 0 min
RSA (%)a at t = 30 min
1c
2c
49
53
72
54
58
63
60
44
53
12
47
46
42
41.5
45
43.5
48
50
45.5
44
40
41
47
51
42
52
52
50
54
61
64
61
51
53
50
55
46
42
49
47
49
53
55
46
47
41
42.5
49
53
42
3c
4c
5c
6c
7c
8c
8c′′
10c
11c
11d
11e
13c
15c
16c
17c
17d
17e
18c
18d
18e
19c
19d
19e
1-Iodo-9-xanthone (1b) and 1,8-Diiodo-9-xanthone (1b′); Typical
Procedure
To a stirred, cooled (0 °C) solution of 2,2,6,6-tetramethylpiperidine
(0.25 mL, 1.5 mmol) in THF (2–3 mL) were successively added ca. 1.6
M BuLi in hexanes (1.5 mmol) and, after 5 min, ZnCl2·TMEDA35 (0.13
g, 0.50 mmol). The mixture was stirred for 15 min at 0 °C before intro-
duction of xanthone (1a, 0.20 g, 1.0 mmol). After 2 h at this tempera-
ture, a solution of I2 (0.38 g, 1.5 mmol) in THF (4 mL) was added. The
mixture was stirred overnight before the addition of aq sat. Na2S2O3
soln (4 mL). The mixture was extracted with EtOAc (3 × 20 mL) and
the combined organic layers were dried (MgSO4), filtered, and con-
centrated under reduced pressure. Purification by chromatography
(silica gel, heptane/CH2Cl2 100:0 to 80:20) afforded the products.
1-Iodo-9-xanthone (1b)
Pale yellow powder; yield: 0.14 g (43%) ; mp 176 °C (Lit.36 172–173.5
°C).
IR (ATR): 663, 752, 777, 849, 903, 931, 1108, 1147, 1161, 1234, 1255,
1297, 1328, 1346, 1421, 1443, 1466, 1554, 1590, 1612, 1661, 3065
cm–1
.
a Percentage of the radical scavenger activity.
1H NMR (CDCl3): δ = 7.27 (dd, J = 8.4, 7.8 Hz, 1 H), 7.36 (ddd, J = 8.1,
7.2, 0.9 Hz, 1 H), 7.41 (dm, J = 9.0 Hz, 1 H), 7.48 (dd, J = 8.4, 1.2 Hz, 1
H), 7.70 (ddd, J = 8.7, 7.2, 1.8 Hz, 1 H), 8.00 (dd, J = 7.6, 1.1 Hz, 1 H),
8.31 (ddd, J = 8.1, 1.8, 0.5 Hz, 1 H).
13C NMR (CDCl3): δ = 91.3 (C), 117.7 (CH), 119.1 (CH), 120.1 (C), 121.3
(C), 124.3 (CH), 127.3 (CH), 134.7 (CH), 135.0 (CH), 138.6 (CH), 154.9
(C), 156.8 (C), 175.4 (C).
Table 8 Cytotoxic Activity on MCF-7 of the Compounds 8c, 10c, 11c,
12c, 13c, and 16c
These data are similar to those reported previously.36
a
Compound
IC50 (μg mL–1
)
8c
12.7
12.4
12.2
11.9
15.7
13.0
3.5
1,8-Diiodo-9-xanthone (1b′)
10c
Yellow powder; yield: 22 mg (5%); mp 252 °C.
IR (ATR): 658, 777, 804, 868, 906, 1159, 1276, 1354, 1448, 1578, 1659,
11c
2927 cm–1
.
12c
1H NMR (CDCl3): δ = 7.26 (dd, J = 8.1, 7.8 Hz, 2 H), 7.42 (dd, J = 8.3, 1.1
Hz, 2 H), 8.01 (dd, J = 7.5, 1.2 Hz, 2 H).
13C NMR (CDCl3): δ = 92.1 (C), 118.7 (CH), 120.3 (C), 124.8 (C), 134.6
13c
16c
doxorubicin
(CH), 138.9 (CH), 155.6 (C).
a IC50 is defined as the concentration which results in a 50% decrease in the
cell number as compared with that of the control structures in the absence
of an inhibitor.
Crystal data for 1b′: 2(C13H6I2O2), M = 895.96, triclinic, P -1, a =
8.2003(2), b = 10.2204(2), c = 15.1904(3) Å, α = 86.8230(10), β =
74.5930(10), γ = 75.9650(10)°, V = 1190.67(4) Å3, Z = 2, d = 2.499 g
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cm–3, μ = 5.267 mm–1. A final refinement on F2 with 5418 unique in-
tensities and 307 parameters converged at ωR(F2) = 0.0725 (R(F) =
0.0402) for 4325 observed reflections with I > 2σ(I). CCDC 1544822.
1H NMR (CDCl3): δ = 7.15 (dd, J = 8.1, 7.5 Hz, 1 H), 7.33 (ddd, J = 10.2,
7.5, 4.8 Hz, 1 H), 7.49–7.56 (m, 3 H), 7.68–7.74 (m, 2 H).
13C NMR (CDCl3): δ = 91.6 (C), 120.1 (CH), 120.2 (CH), 124.7 (CH),
129.8 (CH), 134.0 (C), 134.1 (C), 135.0 (CH), 135.1 (CH), 140.6 (CH),
142.0 (C), 147.2 (C), 191.8 (C).
1-Iodo-9-thioxanthone (2b)37
These data are as described previously.14
Following the typical procedure for 1b using 2,2,6,6-tetrameth-
ylpiperidine (0.25 mL, 1.5 mmol) in THF (2–3 mL) with ca. 1.6 M BuLi
in hexanes (1.5 mmol) and then ZnCl2·TMEDA35 (0.13 g, 0.50 mmol)
and 9-thioxanthone (2a, 0.11 g, 0.50 mmol), and finally I2 (0.38 g, 1.5
mmol) in THF (4 mL). Purification by chromatography (silica gel, hep-
tane/CH2Cl2 100:0 to 80:20) afforded 2b (75 mg, 45%) as a greenish
powder; mp 156–158 °C.
Crystal data for 3b: C13H7IO, M = 306.09, T = 150 K, monoclinic, P21, a =
7.5211(7), b = 18.9683(18), c = 7.6189(7) Å, β = 108.620(3)°, V =
1030.04(17) Å3, Z = 4, d = 1.974 g cm–3, μ = 3.074 mm–1. A final refine-
ment on F2 with 2426 unique intensities and 272 parameters con-
verged at ωR(F2) = 0.0597 (R(F) = 0.0248) for 2370 observed reflec-
tions with I > 2σ(I). CCDC 1544826.
IR (ATR): 664, 711, 745, 777, 923, 1080, 1159, 1241, 1300, 1425, 1537,
1573, 1589, 1641, 3062 cm–1
.
4-Iododibenzofuran (6b)
1H NMR (CDCl3): δ = 7.10 (t, J = 7.8 Hz, 1 H), 7.41–7.47 (m, 2 H), 7.52–
7.60 (m, 2 H), 8.14 (dd, J = 7.5, 1.2 Hz, 1 H), 8.47 (dm, J = 8.1 Hz, 1 H).
13C NMR (CDCl3): δ = 94.8 (C), 125.5 (CH), 126.7 (CH), 126.8 (CH),
127.7 (C), 129.6 (C), 130.2 (CH), 131.8 (CH), 132.3 (CH), 135.0 (C),
138.7 (C), 141.8 (CH), 179.5 (C).
Following the typical procedure for 1b using 2,2,6,6-tetrameth-
ylpiperidine (0.25 mL, 1.5 mmol) in THF (2–3 mL) with ca. 1.6 M BuLi
in hexanes (1.5 mmol) and then ZnCl2·TMEDA35 (0.13 g, 0.50 mmol)
with addition of dibenzofuran (6a, 0.17 g, 1.0 mmol) and stirring at rt
for 2 h; finally I2 (0.38 g, 1.5 mmol) in THF (4 mL) was added. Purifica-
tion by chromatography (silica gel, heptane) afforded 6b (0.26 g, 90%)
as a pale yellow powder; mp 72 °C (Lit.40 71–72 °C).
Crystal data for 2b: C13H7IOS, M = 338.15, monoclinic, C2/c, a =
13.5793(4), b = 8.3628(3), c = 19.5623(6) Å, β = 101.6770(10)°, V =
2175.54(12) Å3, Z = 8, d = 2.065 g cm–3, μ = 3.107 mm–1. A final refine-
ment on F2 with 2491 unique intensities and 145 parameters con-
verged at ωR(F2) = 0.0537 (R(F) = 0.0249) for 2207 observed reflec-
tions with I > 2σ(I). CCDC 1544824.
IR (ATR): 704, 722, 744, 785, 842, 851, 1022, 1100, 1192, 1303, 1382,
1432, 1444, 1470, 1539, 1570, 1788, 3048 cm–1
.
1H NMR (CDCl3): δ = 7.09 (t, J = 7.7 Hz, 1 H), 7.36 (td, J = 7.5, 0.9 Hz, 1
H), 7.49 (ddd, J = 8.1, 7.2, 1.2 Hz, 1 H), 7.65 (d, J = 8.1 Hz, 1 H), 7.81 (dd,
J = 7.8, 1.2 Hz, 1 H), 7.86–7.92 (m, 2 H).
9′-Hydroxy-1,9′-bifluoren-9-one (3b′)
13C NMR (CDCl3): δ = 75.5 (C), 112.2 (CH), 120.6 (CH), 121.2 (CH),
123.3 (CH), 124.5 (CH), 124.6 (C), 124.7 (C), 127.8 (CH), 136.0 (CH),
155.8 (C), 156.5 (C).
Following the typical procedure for 1b using 2,2,6,6-tetrameth-
ylpiperidine (0.25 mL, 1.5 mmol) in THF (2–3 mL) with ca. 1.6 M BuLi
in hexanes (1.5 mmol) and then ZnCl2·TMEDA35 (0.13 g, 0.50 mmol)
with addition of 9-fluorenone (3a, 0.18 g, 1.0 mmol) at 0–10 °C and
stirring at rt for 2 h; finally I2 (0.38 g, 1.5 mmol) in THF (4 mL) was
added. Purification by chromatography (silica gel, heptane–CH2Cl2
80:20) afforded 3b′ (0.11 g, 63%) as a beige powder; mp 222–224 °C
(Lit.38 222–224 °C).
These data are similar to those reported previously.41
4,6-Diiododibenzofuran (6b′)
Following the typical procedure using 2,2,6,6-tetramethylpiperidine
(0.50 mL, 3.0 mmol) in THF (4 mL) with ca. 1.6 M BuLi in hexanes (3.0
mmol) and then ZnCl2·TMEDA35 (0.26 g, 1.0 mmol) and then dibenzo-
furan (6a, 0.17 g, 1.0 mmol) and stirring at rt for 2 h; finally I2 (0.76 g,
3.0 mmol) in THF (7 mL) was added. Purification by chromatography
(silica gel, heptane) afforded 6b′ (0.33 g, 79%) as a pale yellow pow-
der; mp 155 °C (Lit.42 160 °C).
IR (ATR): 686, 728, 753, 771, 803, 909, 958, 1066, 1102, 1139, 1195,
1265, 1284, 1427, 1451, 1469, 1572, 1592, 1607, 1683, 2245, 3060,
3302 cm–1
.
1H NMR (CDCl3): δ = 6.47 (dd, J = 8.1, 0.9 Hz, 1 H), 7.11 (dd, J = 8.1, 7.5
Hz, 1 H), 7.28 (td, J = 7.5, 0.9 Hz, 2 H), 7.33–7.42 (m, 4 H), 7.47–7.57
(m, 4 H), 7.70 (d, J = 7.2 Hz, 2 H), 7.78 (d, J = 7.2 Hz, 1 H), 7.94 (s, 1 H).
13C NMR (CDCl3): δ = 85.5 (C), 119.9 (CH), 120.3 (2 CH), 120.3 (CH),
124.7 (2 CH), 125.3 (CH), 128.4 (CH), 128.4 (2 CH), 129.2 (2 CH), 129.6
(CH), 132.1 (C), 133.4 (C), 135.5 (CH), 136.0 (CH), 139.9 (2 C), 144.3
(C), 146.8 (C), 148.8 (C), 149.5 (2 C), 198.2 (C).
IR (ATR): 663, 672, 724, 749, 763, 853, 1024, 1051, 1174, 1403, 1413,
1458, 1570, 2852, 2922, 2953, 3061 cm–1
.
1H NMR (CDCl3): δ = 7.12 (t, J = 7.8 Hz, 2 H), 7.83–7.89 (m, 4 H).
13C NMR (CDCl3): δ = 75.7 (2 C), 121.1 (2 CH), 124.9 (2 CH), 125.0 (2
C), 136.7 (2 CH), 156.2 (2 C).
These data are similar to those reported previously.43
These data are as described previously.14
Crystal data for 6b′: C12H6I2O, M = 419.97, T = 150 K, monoclinic, P21,
a = 4.6869(8), b = 13.973(3), c = 17.703(3) Å, β = 92.702(7)°, V =
1158.1(4) Å3, Z = 4, d = 2.409 g cm–3, μ = 5.400 mm–1. A final refine-
ment on F2 with 4835 unique intensities and 266 parameters con-
verged at ωR(F2) = 0.1172 (R(F) = 0.0477) for 4447 observed reflec-
tions with I > 2σ(I). CCDC 1544830.
1-Iodo-9-fluorenone (3b)
Following the typical procedure for 1b using 2,2,6,6-tetrameth-
ylpiperidine (0.25 mL, 1.5 mmol) in THF (2–3 mL) with ca. 1.6 M BuLi
in hexanes (1.5 mmol) and then CdCl2·TMEDA13 (0.15 g, 0.50 mmol)
with addition of 9-fluorenone (3a, 0.18 g, 1.0 mmol) at 0–10 °C and
stirring at rt for 2 h; finally I2 (0.38 g, 1.5 mmol) in THF (4 mL) was
added. Purification by chromatography (silica gel, heptane) afforded
3b (0.24 g, 80%) as a yellow powder; mp 148 °C (Lit.39 144–145 °C).
4-Iododibenzothiophene (7b)
Following the typical procedure for 1b using 2,2,6,6-tetrameth-
ylpiperidine (0.75 mL, 4.5 mmol) in THF (5 mL) with ca. 1.6 M BuLi in
hexanes (4.5 mmol) and then ZnCl2·TMEDA35 (0.39 g, 1.5 mmol) with
addition of dibenzothiophene (7a, 0.18 g, 1.0 mmol) and stirring at rt
for 2 h; finally I2 (1.1 g, 4.5 mmol) in THF (10 mL). Workup used aq
IR (ATR): 733, 747, 784, 792, 918, 1056, 1085, 1126, 1149, 1186, 1257,
1281, 1295, 1437, 1563, 1588, 1606, 1715, 3048 cm–1
.
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sat. Na2S2O3 (10 mL) soln. Purification by chromatography (silica gel,
heptane) afforded 7b (0.26 g, 85%) as a pale yellow powder; mp 95–96
°C.
Crystal data for 10c: C11H13NO2, M = 191.22, monoclinic, P21/c, a =
9.5486(8), b = 7.4520(8), c = 13.6565(14) Å, β = 103.073(3)°, V =
946.56(16) Å3, Z = 4, d = 1.342 g cm–3, μ = 0.093 mm–1. A final refine-
ment on F2 with 2162 unique intensities and 128 parameters con-
verged at ωR(F2) = 0.1097 (R(F) = 0.0414) for 1834 observed reflec-
tions with I > 2σ(I). CCDC 1544832.
IR (ATR): 703, 729, 745, 785, 1010, 1022, 1100, 1302, 1382, 1432,
1539, 1789, 3047 cm–1
.
1H NMR (CDCl3): δ = 7.18 (t, J = 7.8 Hz, 1 H), 7.47–7.50 (m, 2 H), 7.81
(dd, J = 7.5, 0.9 Hz, 1 H), 7.86–7.89 (m, 1 H), 8.06–8.09 (m, 1 H), 8.13
(dd, J = 7.8, 0.9 Hz, 1 H).
1-(4-Methoxyphenyl)pyrrolidin-2-one (11c)
Following GP1 using 4-iodoanisole (11b, 2.3 g) and pyrrolidin-2-one
(1.0 g) with reaction time 24 h; chromatography (silica gel, hex-
ane/EtOAc 40:60) gave 11c (1.6 g, 85%) as a white powder; mp 119–
120 °C (Lit.48 113–114 °C).
1H NMR (CDCl3): δ = 2.13 (quint, J = 7.7 Hz, 2 H), 2.57 (t, J = 8.0 Hz, 2
H), 3.78 (s, 3 H), 3.81 (t, J = 6.9 Hz, 2 H), 6.89 (m, 2 H), 7.48 (m, 2 H).
13C NMR (CDCl3): δ = 88.3 (C), 121.2 (CH), 122.5 (CH), 122.9 (CH),
124.8 (CH), 125.8 (CH), 127.3 (CH), 135.8 (C), 136.0 (CH), 136.7 (C),
138.8 (C), 146.3 (C).
These data are similar to those reported previously.44
N-Aryl Lactams 8c–10c, 11c–e, 12c–16c, 17c–g, 18c–e, 19c–e; Gener-
al Procedure 1 (GP1)
13C NMR (CDCl3): δ = 18.1 (CH2), 32.6 (CH2), 49.3 (CH2), 55.5 (CH3),
114.1 (2 CH), 121.9 (2 CH), 132.6 (C), 156.6 (C), 174.0 (C).
A mixture of CuI (0.10 g, 0.50 mmol), lactam (12 mmol), K3PO4 (4.4 g,
20 mmol), halide (10 mmol), and DMEDA (0.11 mL, 1.0 mmol) in di-
oxane (5 mL) was degassed and heated under argon at 110 °C. After
filtration over Celite (washing using EtOAc) and removal of the sol-
vents, the crude product was purified by chromatography (silica gel).
Crystal data for 11c: C11H13NO2, M = 191.22, orthorhombic, Pcab, a =
6.4531(9), b = 7.2771(11), c = 40.841(6) Å, V = 1917.9(5) Å3, Z = 8, d =
1.325 g cm–3, μ = 0.091 mm–1. A final refinement on F2 with 2206
unique intensities and 128 parameters converged at ωR(F2) = 0.1947
(R(F) = 0.0887) for 1434 observed reflections with I > 2σ(I). CCDC
1544827.
1-Phenylpyrrolidin-2-one (8c)
Following GP1 using iodobenzene (8b, 1.1 mL) and pyrrolidin-2-one
(1.0 g) with reaction time 24 h; chromatography (silica gel, hex-
ane/EtOAc 50:50) gave 8c (1.5 g, 95%) as a white powder; mp 67–68
°C (Lit.45 68–69 °C).
1H NMR (CDCl3): δ = 2.16 (quint, J = 7.6 Hz, 2 H), 2.61 (t, J = 8.1 Hz, 2
H), 3.86 (t, J = 7.1 Hz, 2 H), 7.14 (tt, J = 7.6, 1.2 Hz, 1 H), 7.34–7.40 (m,
2 H), 7.59–7.63 (m, 2 H).
1-(4-Methoxyphenyl)piperidin-2-one (11d)
Following GP1 using 4-iodoanisole (11b, 2.3 g) and piperidin-2-one
(1.2 g) with reaction time 24 h; chromatography (silica gel, hep-
tane/EtOAc 40:60) gave 11d (1.5 g, 73%) as a pale yellow powder; mp
72 °C.
1H NMR (CDCl3): δ = 1.92 (quint, J = 3.2 Hz, 4 H), 2.51–2.57 (m, 2 H),
3.56–3.61 (m, 2 H), 3.79 (s, 3 H), 6.90 (d, J = 9.0 Hz, 2 H), 7.14 (d, J = 9.0
Hz, 2 H).
13C NMR (CDCl3): δ = 18.2 (CH2), 32.9 (CH2), 48.9 (CH2), 120.1 (2 CH),
124.6 (CH), 128.9 (2 CH), 139.5 (C), 174.4 (C).
13C NMR (CDCl3): δ = 21.1 (CH2), 23.1 (CH2), 32.4 (CH2), 51.6 (CH2),
55.0 (CH3), 114.0 (2 CH), 127.0 (2 CH), 135.9 (C), 157.6 (C), 169.7 (C).
The spectral data are analogous to those described previously.49
1-(2-Methoxyphenyl)pyrrolidin-2-one (9c)
Following GP1 using 2-iodoanisole (9b, 2.3 g) and pyrrolidin-2-one
(1.0 g) with reaction time 24 h; chromatography (silica gel, hex-
ane/EtOAc 40:60) gave 9c (1.9 g, 99%) as a pale yellow oil.
1-(4-Methoxyphenyl)hexahydro-2H-azepin-2-one (11e)50
Following GP1 using 4-iodoanisole (11b, 2.3 g) and hexahydro-2H-az-
epin-2-one (1.4 g) with reaction time 24 h; chromatography (silica
gel, heptane/EtOAc 40:60) gave 11e (2.2 g, 99%) as a pale yellow pow-
der; mp 66 °C.
1H NMR (CDCl3): δ = 1.76–1.85 (m, 6 H), 2.67–2.70 (m, 2 H), 3.69–3.72
(m, 2 H), 3.78 (s, 3 H), 6.88 (d, J = 9.0 Hz, 2 H), 7.11 (d, J = 9.0 Hz, 2 H).
13C NMR (CDCl3): δ = 23.2 (CH2), 28.5 (CH2), 29.5 (CH2), 37.2 (CH2),
53.0 (CH2), 55.1 (CH3), 114.0 (2 CH), 127.0 (2 CH), 137.2 (C), 157.5 (C),
175.6 (C).
1H NMR (CDCl3): δ = 2.17 (quint, J = 7.6 Hz, 2 H), 2.55 (t, J = 8.1 Hz, 2
H), 3.74 (t, J = 7.1 Hz, 2 H), 3.82 (s, 3 H), 6.93–7.00 (m, 2 H), 7.21–7.29
(m, 2 H).
13C NMR (CDCl3): δ = 19.0 (CH2), 31.2 (CH2), 50.1 (CH2), 55.6 (CH3),
112.0 (CH), 120.9 (CH), 127.1 (C), 128.7 (CH), 128.8 (CH), 154.8 (C),
175.5 (C).
The spectral data are analogous to those described previously.46
1-(3-Methoxyphenyl)pyrrolidin-2-one (10c)
Crystal data for 11e: C13H17NO2, M = 219.27, monoclinic, P21/c, a =
6.0345(3), b = 19.2831(7), c = 10.1665(4) Å, β = 105.317(2)°, V =
1140.99(8) Å3, Z = 4, d = 1.276 g cm–3, μ = 0.086 mm–1. A final refine-
ment on F2 with 2618 unique intensities and 147 parameters con-
verged at ωR(F2) = 0.0986 (R(F) = 0.0387) for 2269 observed reflec-
tions with I > 2σ(I). CCDC 1544833.
Following GP1 using 3-iodoanisole (10b, 2.3 g) and pyrrolidin-2-one
(1.0 g) with reaction time 24 h; chromatography (silica gel, hex-
ane/EtOAc 50:50) gave 10c (1.9 g, 99%) as a pale yellow powder; mp
62–63 °C (Lit.47 56 °C).
1H NMR (CDCl3): δ = 2.12 (quint, J = 7.7 Hz, 2 H), 2.59 (t, J = 8.1 Hz, 2
H), 3.80 (s, 3 H), 3.82 (t, J = 6.9 Hz, 2 H), 6.68 (ddd, J = 8.1, 2.4, 0.9 Hz, 1
H), 7.10 (dt, J = 8.1, 0.9 Hz, 1 H), 7.24 (t, J = 8.1 Hz, 1 H), 7.33 (t, J = 2.3
Hz, 1 H).
1-(4-Hydroxyphenyl)pyrrolidin-2-one (12c)
Following GP1 using 4-iodophenol (12b, 2.2 g) and pyrrolidin-2-one
(1.0 g) with reaction time 48 h; chromatography (silica gel, hex-
ane/EtOAc 40:60) gave 12c (0.46 g, 26%) as a whitish powder; mp 168
°C (Lit.51 167 °C).
13C NMR (CDCl3): δ = 18.0 (CH2), 33.0 (CH2), 48.9 (CH2), 55.4 (CH3),
106.0 (CH), 110.0 (CH), 112.0 (CH), 129.5 (CH), 140.6 (C), 159.9 (C),
174.4 (C).
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1H NMR (CDCl3): δ = 2.16 (quint, J = 7.6 Hz, 2 H), 2.61 (t, J = 8.1 Hz, 2
H), 3.82 (t, J = 7.1 Hz, 2 H), 6.19 (br s, 1 H), 6.78 (d, J = 9.0 Hz, 2 H), 7.32
(d, J = 9.0 Hz, 2 H).
on F2 with 1732 unique intensities and 100 parameters converged at
ωR(F2) = 0.1199 (R(F) = 0.0435) for 1379 observed reflections with I >
2σ(I). CCDC 1544834.
13C NMR (CDCl3): δ = 18.2 (CH2), 32.5 (CH2), 49.9 (CH2), 115.9 (2 CH),
122.9 (2 CH), 132.0 (C), 153.7 (C), 173.9 (C).
1-(Benzofuran-2-yl)pyrrolidin-2-one (17c)
These data are analogous to those described previously.51
Following GP1 using 2-iodobenzofuran (17b, 2.4 g) and pyrrolidin-2-
one (1.0 g) with reaction time 48 h; chromatography (silica gel, hep-
tane/EtOAc 40:60) gave 17c (1.7 g, 84%) as a white powder; mp 138
°C.
1-(4-Cyanophenyl)pyrrolidin-2-one (13c)52
Following GP1 using 4-bromobenzonitrile (13b′, 1.8 g) and pyrroli-
din-2-one (1.0 g) with reaction time 24 h; chromatography (silica gel,
hexane/EtOAc 70:30) gave 13c (1.7 g, 89%) as a white powder; mp
115–116 °C.
IR (ATR): 748, 772, 931, 984, 1007, 1029, 1091, 1220, 1308, 1334,
1407, 1455, 1589, 1703, 2911, 3332 cm–1
.
1H NMR (CDCl3): δ = 2.24 (quint, J = 7.6 Hz, 2 H), 2.63 (t, J = 8.0 Hz, 2
H), 4.08 (t, J = 7.2 Hz, 2 H), 6.85 (d, J = 0.9 Hz, 1 H), 7.14–7.24 (m, 2 H),
7.36–7.40 (m, 1 H), 7.47–7.51 (m, 1 H).
13C NMR (CDCl3): δ = 18.4 (CH2), 31.9 (CH2), 46.8 (CH2), 90.2 (CH),
110.5 (CH), 120.5 (CH), 122.8 (CH), 123.4 (CH), 129.5 (C), 148.9 (C),
150.0 (C), 172.9 (C).
IR (ATR): 748, 772, 984, 1007, 1029, 1091, 1220, 1257, 1308, 1334,
1407, 1455, 1589, 1703, 2911, 3332 cm–1
.
1H NMR (CDCl3): δ = 2.19 (quint, J = 7.6 Hz, 2 H), 2.63 (t, J = 8.1 Hz, 2
H), 3.86 (t, J = 7.1 Hz, 2 H), 7.61 (d, J = 9.0 Hz, 2 H), 7.77 (d, J = 9.0 Hz, 2
H).
Crystal data for 17c: C12H11NO2, M = 201.22, triclinic, P-1, a =
7.0061(4), b = 10.3157(7), c = 14.2592(9) Å, α = 70.602(3), β =
86.907(3), γ = 86.026(3)°, V = 969.19(11) Å3, Z = 4, d = 1.379 g cm–3, μ =
0.095 mm–1. A final refinement on F2 with 4400 unique intensities
and 271 parameters converged at ωR(F2) = 0.1157 (R(F) = 0.0469) for
2847 observed reflections with I > 2σ(I). CCDC 1544835.
13C NMR (CDCl3): δ = 17.8 (CH2), 32.9 (CH2), 48.3 (CH2), 107.0 (C),
119.0 (C), 119.3 (2 CH), 133.0 (2 CH), 143.2 (C), 175.0 (C).
1-(4-tert-Butylphenyl)pyrrolidin-2-one (14c)53
Following GP1 using 1-bromo-4-(tert-butyl)benzene (14b′, 2.1 g) and
pyrrolidin-2-one (1.0 g) with reaction time 48 h; chromatography
(silica gel, hexane/EtOAc 50:50) gave 14c (0.65 g, 30%) as a pale yel-
low oil.
1H NMR (CDCl3): δ = 1.31 (s, 9 H), 2.15 (quint, J = 7.5 Hz, 2 H), 2.60 (t,
J = 8.1 Hz, 2 H), 3.85 (t, J = 7.1 Hz, 2 H), 7.38 (d, J = 9.0 Hz, 2 H), 7.51 (d,
J = 9.0 Hz, 1 H).
1-(Benzofuran-2-yl)piperidin-2-one (17d)
Following GP1 using 2-iodobenzofuran (17b, 2.4 g) and piperidin-2-
one (1.2 g) with reaction time 48 h; chromatography (silica gel, hep-
tane/EtOAc 60:40) gave 17d (2.0 g, 93%) as a white powder; mp 114–
115 °C.
13C NMR (CDCl3): δ = 18.3 (CH2), 29.8 (CH2), 31.5 (3 CH3), 32.8 (C), 49.0
(CH2), 120.0 (2 CH), 125.8 (2 CH), 136.9 (C), 147.6 (C), 174.2 (C).
IR (ATR): 754, 774, 932, 985, 1008, 1092, 1182, 1221, 1335, 1408,
1455, 1489, 1567, 1591, 1668, 1704, 2955 cm–1
.
1H NMR (CDCl3): δ = 1.87–1.98 (m, 4 H), 2.61 (t, J = 6.0 Hz, 2 H), 3.92
(t, J = 6.0 Hz, 2 H), 6.87 (d, J = 0.9 Hz, 1 H), 7.17–7.23 (m, 2 H), 7.35–
7.40 (m, 1 H), 7.48–7.54 (m, 1 H).
13C NMR (CDCl3): δ = 20.7 (CH2), 22.8 (CH2), 33.3 (CH2), 47.9 (CH2),
95.0 (CH), 110.5 (CH), 120.7 (CH), 123.0 (CH), 123.1 (CH), 129.2 (C),
150.2 (C), 150.3 (C), 169.1 (C).
1-(2-Naphthyl)pyrrolidin-2-one (15c)
Following GP1 using 2-iodonaphthalene (15b, 2.5 g) and pyrrolidin-2-
one (1.0 g) with reaction time 72 h; chromatography (silica gel, hex-
ane/EtOAc 50:50) gave 15c (0.95 g, 45%) as a yellow powder; mp 120
°C (Lit.54 125 °C).
1H NMR (CDCl3): δ = 2.27 (quint, J = 7.5 Hz, 2 H), 2.68 (t, J = 8.1 Hz, 2
H), 3.81 (t, J = 6.9 Hz, 2 H), 7.36 (dd, J = 7.2, 1.2 Hz, 1 H), 7.45–7.56 (m,
3 H), 7.74–7.90 (m, 3 H).
13C NMR (CDCl3): δ = 19.1 (CH2), 31.4 (CH2), 51.7 (CH2), 122.6 (CH),
124.5 (CH), 125.5 (CH), 126.2 (CH), 126.6 (CH), 128.2 (CH), 128.4 (CH),
129.5 (C), 134.4 (C), 135.4 (C), 175.3 (C).
Crystal data for 17d: C13H13NO2, M = 215.24, monoclinic, P21/n, a =
6.2043(6), b = 13.6566(11), c = 12.3273(9) Å, β = 95.109(3)°, V =
1040.34(15) Å3, Z = 4, d = 1.374 g cm–3, μ = 0.093 mm–1. A final refine-
ment on F2 with 2374 unique intensities and 145 parameters con-
verged at ωR(F2) = 0.1113 (R(F) = 0.0437) for 1943 observed reflec-
tions with I > 2σ(I). CCDC 1544855.
1-(2-Thienyl)pyrrolidin-2-one (16c)
1-(Benzofuran-2-yl)hexahydro-2H-azepin-2-one (17e)
Following GP1 using 2-iodothiophene (16b, 1.1 mL) [or 2-bromothio-
phene (16b′, 0.97 mL)] and pyrrolidin-2-one (1.0 g) with reaction
time 24 h; chromatography (silica gel, hexane/EtOAc 50:50) gave 16c
[1.6 g, 93% (or 99%)] as a whitish powder; mp 118–119 °C (Lit.9d 116–
117 °C).
1H NMR (CDCl3): δ = 2.22 (quint, J = 7.7 Hz, 2 H), 2.59 (t, J = 8.3 Hz, 2
H), 3.86 (t, J = 7.2 Hz, 2 H), 6.51 (dd, J = 3.6, 1.5 Hz, 1 H), 6.84–6.92 (m,
2 H).
Following GP1 using 2-iodobenzofuran (17b, 2.4 g) and hexahydro-
2H-azepin-2-one (1.4 g) with reaction time 24 h; chromatography
(silica gel, heptane/EtOAc 60:40) gave 17e (1.5 g, 65%) as a white
powder; mp 76 °C.
IR (ATR): 746, 786, 806, 945, 970, 983, 1148, 1165, 1187, 1247, 1352,
1364, 1401, 1437, 1454, 1571, 1678, 2858, 2931 cm–1
.
1H NMR (CDCl3): δ = 1.81–1.91 (m, 6 H), 2.73–2.77 (m, 2 H), 3.96–3.99
(m, 2 H), 6.73 (d, J = 0.9 Hz, 1 H), 7.17–7.23 (m, 2 H), 7.34–7.41 (m, 1
H), 7.46–7.53 (m, 1 H).
13C NMR (CDCl3): δ = 23.6 (CH2), 28.8 (CH2), 29.7 (CH2), 38.0 (CH2),
49.1 (CH2), 95.5 (CH), 110.6 (CH), 120.7 (CH), 123.1 (CH), 123.2 (CH),
129.3 (C), 150.4 (C), 150.5 (C), 174.9 (C).
13C NMR (CDCl3): δ = 17.9 (CH2), 31.3 (CH2), 48.8 (CH2), 110.6 (CH),
118.0 (CH), 123.8 (CH), 140.5 (C), 172.1 (C).
Crystal data for 16c: C8H9NOS, M = 167.22, monoclinic, P21/n, a =
7.6305(14), b = 8.928(2), c = 11.712(2) Å, β = 107.493(10)°, V =
761.0(3) Å3, Z = 4, d = 1.46 g cm–3, μ = 0.358 mm–1. A final refinement
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Crystal data for 17e: C14H15NO2, M = 229.27, monoclinic, C2/c, a =
15.2276(19), b = 10.4953(13), c = 14.7612(19) Å, β = 108.973(4)°, V =
2230.9(5) Å3, Z = 8, d = 1.365 g cm–3, μ = 0.091 mm–1. A final refine-
ment on F2 with 2496 unique intensities and 154 parameters con-
verged at ωR(F2) = 0.1127 (R(F) = 0.0465) for 1881 observed reflec-
tions with I > 2σ(I). CCDC 1544836.
unique intensities and 154 parameters converged at ωR(F2) = 0.0788
(R(F) = 0.0355) for 2294 observed reflections with I > 2σ(I). CCDC
1544838.
1-(Benzothiazol-2-yl)pyrrolidin-2-one (19c)
Following GP1 using 2-iodobenzothiazole (19b, 2.5 g) and pyrrolidin-
2-one (1.0 g) with reaction time 24 h; chromatography (silica gel,
heptane/EtOAc 60:40) gave 19c (1.4 g, 66%) as a white powder; mp
180 °C.
1H NMR (CDCl3): δ = 2.30 (quint, J = 8.4 Hz, 2 H), 2.75 (t, J = 8.1 Hz, 2
H), 4.29 (t, J = 7.2 Hz, 2 H), 7.31 (ddd, J = 7.8, 7.2, 1.2 Hz, 1 H), 7.44
(ddd, J = 8.1, 7.5, 1.5 Hz, 1 H), 7.80–7.87 (m, 2 H).
13C NMR (CDCl3): δ = 18.1 (CH2), 31.9 (CH2), 48.2 (CH2), 121.3 (CH),
121.4 (CH), 124.0 (CH), 126.1 (CH), 132.3 (C), 148.5 (C), 157.1 (C),
174.3 (C).
1-(Benzothiophen-2-yl)pyrrolidin-2-one (18c)
Following GP1 using 2-iodobenzothiophene (18b, 2.6 g) and pyrroli-
din-2-one (1.0 g) with reaction time 48 h; chromatography (silica gel,
heptane/EtOAc 40:60) gave 18c (1.9 g, 88%) as a white powder; mp
210 °C.
1H NMR (CDCl3): δ = 2.23 (quint, J = 7.7 Hz, 2 H), 2.64 (t, J = 8.1 Hz, 2
H), 3.91 (t, J = 7.2 Hz, 2 H), 6.65 (d, J = 0.6 Hz, 1 H), 7.22–7.35 (m, 2 H),
7.63 (dm, J = 7.8 Hz, 1 H), 7.76 (dm, J = 7.8 Hz, 1 H).
13C NMR (CDCl3): δ = 17.8 (CH2), 31.5 (CH2), 48.8 (CH2), 106.1 (CH),
122.0 (CH), 122.2 (CH), 123.3 (CH), 124.5 (CH), 135.6 (C), 137.0 (C),
140.4 (C), 172.9 (C).
The spectral data are analogous to those described previously.56
1-(Benzothiazol-2-yl)piperidin-2-one (19d)
The spectral data are analogous to those described previously.55
Following GP1 using 2-iodobenzothiazole (19b, 2.5 g) and piperidin-
2-one (1.2 g) with reaction time 48 h; chromatography (silica gel,
heptane/EtOAc 70:30) gave 19d (0.35 g, 15%) as a beige powder; mp
143 °C.
1H NMR (CDCl3): δ = 1.92–2.06 (m, 4 H), 2.72 (t, J = 6.8 Hz, 2 H), 4.28
(t, J = 6.2 Hz, 2 H), 7.30 (td, J = 7.6, 1.2 Hz, 1 H), 7.42 (td, J = 7.8, 1.4 Hz,
1 H), 7.82 (t, J = 7.7 Hz, 2 H).
1-(Benzothiophen-2-yl)piperidin-2-one (18d)
Following GP1 using 2-iodobenzothiophene (18b, 2.6 g) and piperi-
din-2-one (1.2 g) with reaction time 48 h; chromatography (silica gel,
heptane/EtOAc 60:40) gave 18d (1.9 g, 81%) as a yellow powder; mp
180 °C.
IR (ATR): 728, 741, 799, 1167, 1238, 1266, 1296, 1353, 1410, 1437,
13C NMR (CDCl3): δ = 20.3 (CH2), 22.8 (CH2), 33.2 (CH2), 48.7 (CH2),
121.2 (CH), 121.4 (CH), 124.0 (CH), 126.0 (CH), 133.5 (C), 148.2 (C),
159.4 (C), 170.5 (C).
1485, 1515, 1637, 2953, 3053 cm–1
.
1H NMR (CDCl3): δ = 1.86–1.95 (m, 2 H), 1.99–2.08 (m, 2 H), 2.66 (t, J =
6.6 Hz, 2 H), 3.88 (t, J = 6.3 Hz, 2 H), 6.81 (s, 1 H), 7.25 (td, J = 7.2, 1.5
Hz, 1 H), 7.31 (td, J = 7.2, 1.2 Hz, 1 H), 7.65 (dm, J = 7.2 Hz, 1 H), 7.76
(dm, J = 7.8 Hz, 1 H).
13C NMR (CDCl3): δ = 20.5 (CH2), 23.2 (CH2), 33.2 (CH2), 49.6 (CH2),
107.0 (CH), 121.7 (CH), 122.2 (CH), 123.4 (CH), 124.3 (CH), 136.6 (C),
136.8 (C), 143.5 (C), 168.6 (C).
The spectral data are analogous to those described previously.55
Crystal data for 19d: 2(C13H12NOS), M = 460.59, tetragonal, P-4 21/c,
a = 14.2662(9), c = 21.0404(18) Å, V = 4282.2(5) Å3, Z = 8, d = 1.429
g cm–3, μ = 0.277 mm–1. A final refinement on F2 with 4894 unique
intensities and 289 parameters converged at ωR(F2) = 0.2382 (R(F) =
0.1) for 3133 observed reflections with I > 2σ(I). CCDC 1544839.
Crystal data for 18d: C13H13NOS, M = 231.30, monoclinic, P21/n, a =
6.2311(4), b = 13.6241(8), c = 12.9733(7) Å, β = 97.711(2)°, V =
1091.39(11) Å3, Z = 4, d = 1.408 g cm–3, μ = 0.272 mm–1. A final refine-
ment on F2 with 2493 unique intensities and 145 parameters con-
verged at ωR(F2) = 0.1091 (R(F) = 0.0438) for 1983 observed reflec-
tions with I > 2σ(I). CCDC 1544837.
1-(Benzothiazol-2-yl)hexahydro-2H-azepin-2-one (19e)
Following GP1 using 2-iodobenzothiazole (19b, 2.5 g) and hexahydro-
2H-azepin-2-one (1.4 g) with reaction time 48 h; chromatography
(silica gel, heptane/EtOAc 60:40) gave 19e (1.2 g, 50%) as a pale yellow
powder; mp 130 °C.
1H NMR (CDCl3): δ = 1.83–1.90 (m, 6 H), 2.85–2.89 (m, 2 H), 4.57–4.61
(m, 2 H), 7.29 (ddd, J = 8.4, 7.4, 1.4 Hz, 1 H), 7.42 (ddd, J = 8.1, 6.9, 1.2
Hz, 1 H), 7.78–7.83 (m, 2 H).
13C NMR (CDCl3): δ = 23.5 (CH2), 28.0 (CH2), 29.4 (CH2), 37.9 (CH2),
47.8 (CH2), 121.0 (CH), 121.1 (CH), 123.7 (CH), 125.9 (CH), 133.6 (C),
147.9 (C), 159.7 (C), 175.6 (C).
1-(Benzothiophen-2-yl)hexahydro-2H-azepin-2-one (18e)
Following GP1 using 2-iodobenzothiophene (18b, 2.6 g) and hexahy-
dro-2H-azepin-2-one (1.4 g) with reaction time 48 h; chromatogra-
phy (silica gel, heptane/EtOAc 70:30) gave 18e (1.3 g, 53%) as a white
powder; mp 143 °C.
IR (ATR): 744, 793, 979, 1195, 1217, 1242, 1267, 1303, 1397, 1439,
The spectral data are analogous to those described previously.55
1522, 1659, 2857, 2930 cm–1
.
1H NMR (CDCl3): δ = 1.81–1.92 (m, 6 H), 2.78–2.82 (m, 2 H), 4.00–4.03
(m, 2 H), 6.87 (d, J = 0.3 Hz, 1 H), 7.24 (td, J = 7.5, 1.3 Hz, 1 H), 7.31 (td,
J = 7.5, 1.3 Hz, 1 H), 7.64 (dm, J = 7.2 Hz, 1 H), 7.74 (dm, J = 7.5 Hz, 1 H).
13C NMR (CDCl3): δ = 23.4 (CH2), 27.5 (CH2), 29.3 (CH2), 37.6 (CH2),
51.4 (CH2), 109.0 (CH), 121.7 (CH), 122.3 (CH), 123.4 (CH), 124.3 (CH),
136.7 (C), 136.9 (C), 144.5 (C), 174.4 (C).
N-Arylated Pyrrolidin-2-ones 1c–7c; General Procedure 2 (GP2)
A mixture of CuI (19 mg, 0.10 mmol), K3PO4 (0.42 g, 2.0 mmol), pyrro-
lidin-2-one (0.17 g, 2.0 mmol), and iodide (1.0 mmol) in DMSO (2 mL)
was degassed and stirred under argon at 125 °C. After cooling to rt,
the mixture was filtered over Celite. H2O (25 mL) was added to the fil-
trate and it was extracted with Et2O (3 ×10 mL). The combined ex-
tracts were dried (Na2SO4), the solvent was removed, and the residue
was purified by chromatography (silica gel).
Crystal data for 18e: C14H15NOS, M = 245.33, orthorhombic, Pbn21, a =
6.2621(7), b = 9.9132(10), c = 19.3294(15) Å, V = 1199.9(2) Å3, Z = 4,
d = 1.358 g cm–3, μ = 0.252 mm–1. A final refinement on F2 with 2458
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1-(9-Oxo-9H-xanthen-1-yl)pyrrolidin-2-one (1c)
Crystal data for 3c: 2(C17H10NO2), M = 520.52, monoclinic, P21/c, a =
7.0380(3), b = 22.3046(13), c = 16.6958(9) Å, β = 104.886(2)°, V =
2532.9(2) Å3, Z = 4, d = 1.365 g cm–3, μ = 0.090 mm–1. A final refine-
ment on F2 with 5301 unique intensities and 331 parameters con-
verged at ωR(F2) = 0.3050 (R(F) = 0.1373) for 4131 observed reflec-
tions with I > 2σ(I). CCDC 1544828.
Following GP2 using 1-iodo-9-xanthone (1b, 0.32 g) with reaction
time 24 h; chromatography (silica gel, EtOAc) gave 1c (0.20 g, 70%) as
a yellow powder; mp 236 °C.
IR (ATR): 671, 727, 767, 797, 925, 1139, 1233, 1252, 1306, 1333, 1351,
1416, 1438, 1470, 1604, 1615, 1653, 1683, 2974 cm–1
.
1H NMR (CDCl3): δ = 2.33 (br s, 2 H), 2.68 (br s, 2 H), 3.82 (br s, 2 H),
7.19 (dd, J = 7.8, 1.2 Hz, 1 H), 7.35 (ddd, J = 8.1, 7.2, 1.2 Hz, 1 H), 7.45
(dd, J = 8.4, 0.6 Hz, 1 H), 7.51 (dd, J = 8.7, 1.2 Hz, 1 H), 7.70 (ddd, J = 8.4,
7.2, 1.5 Hz, 1 H), 7.72 (dd, J = 8.4, 7.5 Hz, 1 H), 8.24 (dd, J = 8.0, 1.4 Hz,
1 H).
13C NMR (CDCl3): δ = 19.4 (CH2), 31.6 (CH2), 51.5 (CH2), 117.7 (CH),
118.4 (C), 118.8 (CH), 122.6 (C), 124.2 (CH), 125.1 (CH), 126.8 (CH),
134.6 (CH), 134.9 (CH), 138.8 (C), 155.3 (C), 157.9 (C), 176.3 (C), 176.3
(C).
1-(2-Benzoylphenyl)pyrrolidin-2-one (4c)
Following GP2 using 2-iodobenzophenone (4b, 0.31 g) with reaction
time 24 h; chromatography (silica gel, EtOAc/heptane 80:20) gave 4c
(0.15 g, 56%) as a yellow oil.
IR (ATR): 701, 756, 921, 1137, 1236, 1316, 1397, 1454, 1484, 1599,
1664, 1698, 2961 cm–1
.
1H NMR (CDCl3): δ = 1.88 (quint, J = 7.4 Hz, 2 H), 2.21 (t, J = 8.0 Hz, 2
H), 3.77 (t, J = 6.9 Hz, 2 H), 7.29 (dd, J = 8.0, 0.7 Hz, 1 H), 7.34 (td, J =
7.8, 1.2 Hz, 1 H), 7.40–7.47 (m, 2 H), 7.49–7.58 (m, 3 H), 7.78–7.83 (m,
2 H).
13C NMR (CDCl3): δ = 18.7 (CH2), 31.4 (CH2), 50.8 (CH2), 125.4 (CH),
126.5 (CH), 128.3 (2 CH), 129.9 (2 CH), 130.2 (CH), 131.7 (CH), 132.9
(CH), 135.7 (C), 137.4 (C), 137.5 (C), 174.6 (C), 195.9 (C).
Crystal data for 1c: C17H13NO3, M = 279.28, T = 295 K, orthorhombic,
Pna21, a = 18.9134(17), b = 5.5288(5), c = 12.5988(9) Å, V =
1317.44(19) Å3, Z = 4, d = 1.408 g cm–3, μ = 0.097 mm–1. A final refine-
ment on F2 with 2959 unique intensities and 190 parameters con-
verged at ωR(F2) = 0.1398 (R(F) = 0.0628) for 2150 observed reflec-
tions with I > 2σ(I). CCDC 1544823.
The spectral data are analogous to those described previously.57
1-(9-Thioxo-9H-xanthen-1-yl)pyrrolidin-2-one (2c)
1-(2-Benzoyl-3-pyridyl)pyrrolidin-2-one (5c)
Following GP2 using 2-benzoyl-3-iodopyridine14 (5b, 0.31 g) with re-
action time 72 h; chromatography (silica gel, EtOAc/heptane 60:40)
gave 5c (0.11 g, 40%) as a pale yellow powder; mp 132 °C.
Following GP2 using 1-iodo-9-thioxanthone (2b, 0.34 g) with reaction
time 24 h; chromatography (silica gel, EtOAc) gave 2c (0.19 g, 65%) as
a yellow powder; mp 192 °C.
IR (ATR): 673, 728, 755, 791, 918, 1079, 1122, 1160, 1249, 1308, 1409,
IR (ATR): 664, 693, 711, 781, 804, 815, 920, 946, 1022, 1066, 1151,
1225, 1241, 1296, 1315, 1328, 1397, 1457, 1666, 1692, 2888, 2923,
1449, 1591, 1641, 1691, 2975 cm–1
.
2968, 3063 cm–1
.
1H NMR (CDCl3): δ = 2.33 (quint, J = 7.5 Hz, 2 H), 2.64 (t, J = 8.1 Hz, 2
H), 3.90 (t, J = 6.8 Hz, 2 H), 7.26 (dd, J = 6.9, 1.8 Hz, 1 H), 7.44 (ddd, J =
8.4, 6.9, 1.5 Hz, 1 H), 7.49–7.63 (m, 4 H), 8.40 (ddd, J = 8.7, 1.5, 0.6 Hz,
1 H).
13C NMR (CDCl3): δ = 19.4 (CH2), 31.9 (CH2), 51.6 (CH2), 125.4 (CH),
126.0 (C), 126.3 (CH), 122.6 (CH), 127.4 (CH), 129.9 (CH), 131.3 (C),
132.1 (CH), 132.3 (CH), 135.7 (C), 139.5 (C), 140.5 (C), 175.8 (C), 180.8
(C).
1H NMR (CDCl3): δ = 2.14 (quint, J = 7.2 Hz, 2 H), 2.39 (t, J = 8.0 Hz, 2
H), 3.88 (t, J = 6.9 Hz, 2 H), 7.42–7.49 (m, 3 H), 7.55 (td, J = 7.4, 1.2 Hz,
1 H), 7.67 (d, J = 8.1 Hz, 1 H), 7.92–7.96 (m, 2 H), 8.53 (d, J = 4.5 Hz, 1
H).
13C NMR (CDCl3): δ = 18.8 (CH2), 31.4 (CH2), 50.2 (CH2), 125.4 (CH),
128.3 (2 CH), 130.7 (2 CH), 132.9 (CH), 133.2 (CH), 134.1 (C), 135.8
(C), 146.0 (CH), 152.4 (C), 174.6 (C), 193.1 (C).
Crystal data for 2c: C17H13NO2S, M = 295.34, T = 150 K, monoclinic,
Crystal data for 5c: C16H14N2O2, M = 266.29, T = 150 K, monoclinic,
P21/c, a = 10.8301(10), b = 8.2056(6), c = 14.9205(14) Å, β =
91.168(4)°, V = 1325.7(2) Å3, Z = 4, d = 1.334 g cm–3, μ = 0.090 mm–1. A
final refinement on F2 with 3012 unique intensities and 181 parame-
ters converged at ωR(F2) = 0.1349 (R(F) = 0.0550) for 2432 observed
reflections with I > 2σ(I). CCDC 1544829.
P21/c,
a = 13.3409(9), b = 5.4022(5), c = 18.5865(15) Å, β =
100.595(3)°, V = 1316.70(18) Å3, Z = 4, d = 1.490 g cm–3, μ = 0.249 mm–1
.
A final refinement on F2 with 2988 unique intensities and 190 param-
eters converged at ωR(F2) = 0.0889 (R(F) = 0.0394) for 2290 observed
reflections with I > 2σ(I). CCDC 1544825.
1-(9-Oxo-9H-fluoren-1-yl)pyrrolidin-2-one (3c)
1-(Dibenzofuran-4-yl)pyrrolidin-2-one (6c)
Following GP2 using 1-iodo-9-fluorenone (3b, 0.31 g) with reaction
time 24 h; chromatography (silica gel, EtOAc) gave 3c (0.16 g, 62%) as
a yellow powder; mp 124 °C.
Following GP2 using 4-iododibenzofuran (6b, 0.29 g) with reaction
time 48 h; chromatography (silica gel, heptane/EtOAc 60:40) gave 6c
(0.13 g, 50%) as a beige powder; mp 85 °C.
IR (ATR): 676, 757, 802, 911, 1148, 1188, 1239, 1308, 1398, 1455,
IR (ATR): 675, 740, 753, 832, 1019, 1192, 1250, 1265, 1299, 1318,
1484, 1591, 1607, 1700, 2973 cm–1
.
1392, 1424, 1451, 1503, 1602, 1688, 2895, 2924, 2985 cm–1
.
1H NMR (CDCl3): δ = 2.27 (quint, J = 7.4 Hz, 2 H), 2.63 (t, J = 8.0 Hz, 2
H), 3.90 (t, J = 6.9 Hz, 2 H), 7.22 (dd, J = 7.7, 1.1 Hz, 1 H), 7.29 (td, J =
7.2, 1.2 Hz, 1 H), 7.43–7.54 (m, 4 H), 7.61 (dt, J = 7.5, 1.7 Hz, 1 H).
13C NMR (CDCl3): δ = 19.3 (CH2), 31.7 (CH2), 50.4 (CH2), 119.2 (CH),
120.4 (CH), 124.4 (CH), 127.9 (C), 128.2 (CH), 129.5 (CH), 134.2 (C),
134.7 (CH), 135.7 (CH), 137.1 (C), 143.7 (C), 146.2 (C), 175.4 (C), 191.7
(C).
1H NMR (CDCl3): δ = 2.27 (quint, J = 7.6 Hz, 2 H), 2.65 (t, J = 8.0 Hz, 2
H), 4.12 (t, J = 6.9 Hz, 2 H), 7.31–7.38 (m, 2 H), 7.45 (td, J = 7.8, 1.4 Hz,
1 H), 7.57 (d, J = 8.1 Hz, 1 H), 7.67 (dd, J = 8.0, 1.1 Hz, 1 H), 7.81 (dd, J =
7.8, 1.2 Hz, 1 H), 7.93 (dd, J = 7.5, 0.6 Hz, 1 H).
13C NMR (CDCl3): δ = 19.0 (CH2), 31.5 (CH2), 49.9 (CH2), 111.8 (CH),
118.7 (CH), 120.8 (CH), 123.1 (CH), 123.1 (CH), 123.7 (C), 123.9 (CH),
124.0 (C), 126.0 (C), 127.5 (CH), 149.5 (C), 156.0 (C), 174.8 (C).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–Q

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R. Amara et al.
Paper
Synthesis
1-(Dibenzothiophen-4-yl)pyrrolidin-2-one (7c)
finement on F2 with 1315 unique intensities and 82 parameters con-
verged at ωR(F2) = 0.1134 (R(F) = 0.0425) for 1202 observed reflec-
tions with I > 2σ(I). CCDC 1544831.
Following GP2 using 4-iododibenzothiophene (7b, 0.31 g) with reac-
tion time 48 h; chromatography (silica gel, heptane/EtOAc 60:40)
gave 7c (0.14 g, 54%) as a beige powder; mp 98 °C.
1-(4-Iodophenyl)pyrrolidin-2-one (8c′)
White powder; yield: 20 mg (7%); mp 140 °C (Lit.59 140–142 °C).
IR (ATR): 704, 744, 837, 848, 888, 1067, 1120, 1206, 1229, 1243, 1270,
1305, 1410, 1443, 1466, 1569, 1606, 1682, 1729, 2901, 2972, 2988,
3675 cm–1
.
IR (ATR): 694, 735, 765, 812, 836, 1001, 1034, 1068, 1126, 1189, 1224,
1303, 1386, 1403, 1484, 1583, 1598, 1678, 2854, 2924, 2955, 3101,
1H NMR (CDCl3): δ = 2.25 (quint, J = 7.5 Hz, 2 H), 2.64 (t, J = 8.1 Hz, 2
H), 3.90 (t, J = 6.9 Hz, 2 H), 7.36–7.50 (m, 4 H), 7.79–7.83 (m, 1 H), 8.06
(dd, J = 7.8, 1.2 Hz, 1 H), 8.09–8.13 (m, 1 H).
13C NMR (CDCl3): δ = 19.4 (CH2), 31.5 (CH2), 49.8 (CH2), 120.5 (CH),
121.9 (CH), 122.8 (CH), 124.2 (CH), 124.6 (CH), 125.3 (CH), 127.2 (CH),
133.8 (C), 135.6 (C), 136.1 (C), 137.6 (C), 139.3 (C), 174.4 (C).
3349 cm–1
.
1H NMR (CDCl3): δ = 2.15 (quint, J = 7.5 Hz, 2 H), 2.59 (t, J = 8.1 Hz, 2
H), 3.81 (t, J = 7.1 Hz, 2 H), 7.37–7.42 (m, 2 H), 7.62–7.67 (s, 2 H).
13C NMR (CDCl3): δ = 18.0 (CH2), 32.8 (CH2), 48.6 (CH2), 88.0 (C), 121.6
(2 CH), 128.9 (C), 137.8 (2 CH), 174.4 (C).
The spectral data are analogous to those described previously.59
N-Iodoarylated Pyrrolidines 6c′ and 8c′; General Procedure 3 (GP3)
A mixture of CuI (38 mg, 0.20 mmol), K3PO4 (0.84 g, 4.0 mmol), pyrro-
lidin-2-one (0.34 g, 4.0 mmol), and iodide (1.0 mmol) in DMSO (2 mL)
was degassed and stirred under argon at 125 °C. After cooling to rt,
the mixture was filtered over Celite. H2O (25 mL) was added to the fil-
trate and it was extracted with Et2O (3 × 10 mL). The combined ex-
tracts were dried (Na2SO4), the solvent was removed, and the residue
was purified by chromatography (silica gel).
Funding Information
We thank the Ministère de l’Enseignement supérieur et de la Recherche
scientifique Algérien (M.H.), the Centre National de la Recherche Sci-
entifique, the Institut Universitaire de France and Rennes Métropole
(F.M.). We acknowledge FEDER founds (D8 VENTURE Bruker AXS dif-
fractometer) and Thermofisher (generous gift of 2,2,6,6-tetrameth-
ylpiperidine). This research has been partly performed as part of the
CNRS PICS project ‘Bimetallic synergy for the functionalization of het-
1-(Dibenzofuran-4-yl)pyrrolidin-2-one (6c) and 1-(6-Iododiben-
zofuran-4-yl)pyrrolidin-2-one (6c′)
eroaromatics’
)(
Following GP3 using 4,6-diiododibenzofuran (6b′, 0.42 g) with reac-
tion time 48 h; chromatography (silica gel, heptane/EtOAc 60:40)
gave 6c (0.21 g, 55%) and 6c′, which was also detected in the crude
product, and identified by NMR.
Acknowledgment
R.A., M.H., and F.M. thank Dr. William Erb and Frédéric Lassagne, and
Z.F. thanks Dr. Monzer Hamze for helpful discussions.
1-(6-Iododibenzofuran-4-yl)pyrrolidin-2-one (6c′)
1H NMR (CDCl3): δ = 2.32 (quint, J = 7.5 Hz, 2 H), 2.68 (t, J = 8.0 Hz, 2
H), 4.28 (t, J = 7.1 Hz, 2 H), 7.13 (t, J = 7.7 Hz, 1 H), 7.39 (t, J = 7.8 Hz, 1
H), 7.78 (dd, J = 7.8, 1.2 Hz, 1 H), 7.79–7.84 (m, 2 H), 7.90 (dd, J = 7.7,
1.1 Hz, 1 H).
13C NMR (CDCl3): δ = 19.3 (CH2), 31.7 (CH2), 50.0 (CH2), 75.5 (C), 118.8
(CH), 120.8 (CH), 123.8 (CH), 124.2 (CH), 124.2 (C), 124.4 (C), 124.9
(CH), 126.3 (C), 136.2 (CH), 148.4 (C), 156.4 (C), 175.1 (C).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590798.
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References
1,1′-(1,4-Phenylene)bispyrrolidin-2-one (8c′′) and 1-(4-Iodophe-
nyl)pyrrolidin-2-one (8c′)
(1) Present address: Département de Chimie, Faculté des Sciences
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–Q

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