Synthesis of benzo-fused heterocycles by intramolecular α-arylation of ketone enolate anions

Article abstract of DOI:10.1021/jo202012n

A two-step synthesis of six-, seven-, eight-, and nine-member benzo-fused heterocycles in good to excellent yields is reported. The synthetic strategy involves the generation of a new intramolecular α-aryl ketone bond by the photostimulated S_RN1 reaction of ketone enolate anions linked to a pendant haloarene as the key step. On the other hand, an intramolecular C _Ar-C_Ar coupling led to the formation of five- and six-member benzo-fused heterocycles (9H-carbazole and phenanthridine) when an aromatic amide anion is competitively formed.

Full text of DOI:10.1021/jo202012n

Article
pubs.acs.org/joc
Synthesis of Benzo-fused Heterocycles by Intramolecular α-Arylation
of Ketone Enolate Anions
Javier F. Guastavino and Roberto A. Rossi*
INFIQC, Departamento de Química Organ
́ ́
ica, Facultad de Ciencias Químicas, Universidad Nacional de Cordoba, X5000HUA
Cordoba, Argentina
́
S
* Supporting Information
ABSTRACT: A two-step synthesis of six-, seven-, eight-, and
nine-member benzo-fused heterocycles in good to excellent
yields is reported. The synthetic strategy involves the
generation of a new intramolecular α-aryl ketone bond by
the photostimulated SRN1 reaction of ketone enolate anions
linked to a pendant haloarene as the key step. On the other
hand, an intramolecular CAr−CAr coupling led to the formation
of five- and six-member benzo-fused heterocycles (9H-
carbazole and phenanthridine) when an aromatic amide
anion is competitively formed.
to form a bond between an arene and a carbon next to a
carbonyl moiety (Cα) has encouraged the employ of heavy
metal compounds, such as organolead,6 organobismuth7 and
organocadmium8 derivatives. However, their use is restricted
since a stoichiometric amount is employed; they are also
prepared through time-consuming procedures, often involving
toxic and expensive materials. Furthermore, many of the
procedures to form a new α-aryl ketone bond do not utilize a
carbonyl compound but a less readily available derivative such
as silyl enol ethers,9 enol acetates10 and α-halo ketones.11
Other methods also reported include the reaction of an
enolate anion with a derivative of benzyne12,13 and the
nucleophilic aromatic substitution reaction of a stabilized
enolate anion with aryl halides having electron-withdrawing
groups.14,15 However, these reactions have serious limitations
due to the employ of drastic reaction conditions, limited
substrate scope, moderated regioselectivity and rearrangement
possibility.16
INTRODUCTION
■
The α-arylated carbonyl compounds are versatile synthetic
building blocks and the structural unit of a variety of bioactive
natural products and therapeutic agents. In particular, dibenzo-
[b,f ]oxepinones (1a),1 dibenzo[b,f ]thiepinones (1b),1a,b,f
dibenzo[b,f ]azepinones (1c)1b,f,2 and 5H-benzo[e]pyrrolo[1,2-
a]azepinone (2)3 are key elements for a number of biologically
active molecules. For example, Bermoprofen (3)4 is a
nonsteroid antiinflammatory agent of clinical use and
oxcarbazepine (4)5 (Trileptal) is a widely prescribed drug for
the treatment of epilepsy (Figure 1).
In the past decade particularly, the design, development and
application of transition metal-catalyzed reactions for the
formation of α-aryl carbonyl compounds has also been
employed.17 Some of these methods are attractive and
successful.18 However, in many cases, they still pose problems
due to the use of hazardous reagents, additives, and expensive,
sensitive reagents.
Photochemical reactions offer a mild and environmentally
benign alternative access to α-arylated ketones in a simple way.
Photoinduced SN1 reaction has demonstrated to be useful in
many cases; however, this reaction shows limited substrate
scope.19 A more straightforward method involves the aromatic
unimolecular radical nucleophilic substitution or SRN1 reac-
Figure 1. Examples of biologically active α-arylated carbonyl
compounds.
Due to the importance of α-arylated carbonyl compounds,
numerous methods are being implemented in their formation;
the development of new methodologies for their synthesis is
also a particularly active research area. The lack of general paths
Received: October 7, 2011
Published: December 5, 2011
© 2011 American Chemical Society
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tion,20 in which an aryl halide reacts with an electron donor to
produce finally an aryl radical that subsequently combines with
a nucleophile. This reaction affords the possibility of achieving
the nucleophilic substitution to electronically neutral aryl
halides, as well as those bearing electron-donating or
withdrawing substituents.
Scheme 1. Synthetic Strategy for the Synthesis of Benzo-
fused Heterocycles
The scope of the SRN1 reaction has increased considerably. It
is nowadays a particularly valuable tool in synthetic chemistry.
Several nucleophiles can be used to form new C−C or C−
heteroatom bonds in good yields; it is also compatible with
many substituents. When a substrate has both the leaving group
and the nucleophilic center, the intramolecular radical-
nucleophile coupling affords a variety of carbocyclic and
heterocyclic systems fused to benzene.
The intramolecular SRN1 has been successfully applied to the
synthesis of natural products and to a variety of heterocyclic
systems.21 The first report on intramolecular SRN1 reaction
involves the synthesis of cephalotaxinone.22 The key step of the
synthetic strategy requires intramolecular nucleophilic aromatic
substitution of an enolate anion onto an unactivated aromatic
ring. The best yield of cephalotaxinone (94%) was obtained by
irradiation of precursor in liquid ammonia with excess t-BuOK.
A similar strategy is followed in the synthesis of the alkaloids:
eupolauramine,23 ( )-tortuosamine24 and rugulovasine, an
Ergot-type alkaloid.25
Scheme 2. Preparation of 1-(2-Halobenzyl)-2-acetylpyrrole
7a−c
irradiation 7a−c‑ afforded 5H-benzo[e]pyrrolo[1,2-a]azepin-
11(10H)-one 8a in 38%, 31% and 45% yields respectively,
together with a low amount of 3-acetyl-5H-pyrrolo[2,1-
a]isoindole 9 (entries 1, 5 and 8, Table 1, eq 1). It was
Other interesting heterocyclic compounds including sub-
stituted 9H-carbazoles,26 phenanthridines and benzophenan-
thridines,27 carbolines,28 bractazonine alkaloid,29 aporphine and
homoaporphine alkaloids,30 and azaheterocycles31 were ob-
tained in a similar approach exploiting the bidentate behavior of
the anions of aromatic amides and alcohols.
Table 1. Photostimulated Reactions of 1-(2-Halobenzyl)-2-
a
acetylpyrrole 7a−c Anions
Moreover, carbanions derived from amides,32 2-methylqui-
nazolinones33 and 2-alkyl-2-oxazolines34 took part as nucleo-
philes in intramolecular coupling with aromatic and hetero-
aromatic radicals, giving five- and six-membered carbocyclic
rings in moderate to high yields.
substrate
time
(h)
t-BuOK
product
X−
d
b
c
entry
1
(%)
solvent
(equiv)
(%)
%
e
f
f
7a, X = I
(---)
NH3(liq.)
2
2
8a (38) , 9
g
2
7a (90)
7a (34)
7a (---)
DMSO
DMSO
DMSO
2
2
2
5
8a (---)
8a (3)
<5
8
Cyclization of enolate anions with aromatic radicals by
intramolecular SRN1 reaction is expected to be extremely fast,35
even in the formation of medium-size ring heterocycles.
Semmelhack and co-workers reported that simple alkyl ketone
enolate anions cyclize to give six-, seven-, eight-, and ten-
membered carbocyclic rings.36
Our main goal was to develop an efficient application of the
intramolecular SRN1 reaction and to demonstrate the synthetic
potential of this reaction in the synthesis of medium-size benzo-
fused heterocycles. We studied a new synthetic strategy that
involved, first, the construction of compounds like 7 having
both the leaving group and the precursor of ketone carbanion
tethered by a functional group Z as bridge formed by reaction
of Y in 5 with A in 6. In a second phase, the strategy includes
the formation of new α-aryl ketone bond as a key step by an
intramolecular SRN1 reaction, giving the Z-heterocycles 8
(Scheme 1).
h
3
2
i
4
4.5
8a (84), 9
(11)
82
f
5
7b, X = Br
(---)
DMSO
4
4
8a (31), 9
70
g
6
7b (97)
7b (37)
DMSO
DMSO
NH3(liq.)
4
4
2
4
4
4
8a (---)
8a (12)
<5
8
j
7
8
7c, X = Cl
(26)
8a (45), 9
(3)
78
9
7c (22)
NH3(liq.)
NH3(liq.)
2
6
5
8a (44), 9
76
76
(3)
10
7c (---)
6.5
8a (47), 9
(5)
a
Reactions were performed in DMSO (4 mL) or in NH3(l) (150 mL),
with substrates 7a−c (0.25 mmol). Irradiation was conducted in a
photochemical reactor equipped with two HPI-T 400 W lamps
b
c
(cooled with air and water). Substrate recovered. Yields were
d
determined by GC (internal standard method). Halide anions were
determined potentiometrically. Isolated yield. Not quantified.
Reactions were performed in the dark. p-DNB (40 mol %) was
added. Reaction was performed with 0.5 equiv of FeCl2 and 3 equiv of
e
f
g
h
RESULTS AND DISCUSSION
■
i
To establish the feasibility of our proposal, 1-(2-halobenzyl)-2-
acetylpyrrole 7a−c were chosen as substrate models for the
study of the reaction mechanism. They were prepared from
commercially available 2-halobenzyl chloride (5a−c) and 2-
acetylpyrrole (6a) as shown in Scheme 2. Several variations of
the approach depicted in Scheme 2 were tested.
j
pinacolone in the dark. p-DNB (30 mol %) was added.
observed that similar substitution outcomes are obtained in
both DMSO and liquid ammonia. Complete conversion of 7c
was accomplished by extending the reaction time and
increasing the amount of base; however, the yields of 8a did
not improve (entries 9 and 10, Table 1).The reaction did not
When 7a−c were treated with an excess of t-BuOK in liquid
ammonia or DMSO, anions 7a−c‑ were formed. Under
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acid−base reaction gives the more stable tautomer 9 and radical
dianion 10 (Scheme 3).41
To extend the studies of the intramolecular α-arylation
reaction and to delineate the scope of the intramolecular SRN
1
reactions in the cyclization of enolate anions with aromatic
radicals, new compounds like 7 were synthesized. Tables 2 and
3 display the results of the photostimulated intramolecular α-
arylation reactions in liquid ammonia.
Cyclization precursor 2′-(2-chlorophenyl)acetophenone 7d
was prepared from (2-chlorophenyl)boronic acid (5d) and 2-
bromoacetophenone (6b) via a Suzuki−Miyaura coupling with
occur in the dark (entries 2 and 6, Table 1), and inhibition was
observed when anions 7a−b‑ were irradiated in the presence of
p-dinitrobenzene (p-DNB), a strong electron-acceptor (entries
3 and 7, Table 1).
The modest yields of the desired product and low mass
balance could be ascribed to the sensitiveness of the starting
materials to irradiation.37 This obstacle was overcome easily by
using FeCl2 salt as an alternative method to initiate SRN
1
reactions.38
When 7a was treated with 5 equiv of t-BuOK, 3 equiv of
pinacolone (as electron-donor, entrainment reagent) and 0.5
equiv of FeCl2 in DMSO, 8a was obtained in 84% yield
together with 11% of 9, after 4.5 h of reaction (entry 4, Table
1).
The partial inhibition of the reaction in the presence of p-
DNB and the lack of cyclization products in dark conditions
provide evidence that the present cyclization could proceed via
the SRN1 mechanism. In addition, the fact that a similar ratio
between 8a and 9 is obtained from the reactions of 7a−c (I, Br,
Cl), under different conditions (entries 4, 8, 9, and 10, Table
1), indicates that all these reactions occur by the same
mechanism.
biphenyl-2-yl-di-t-butylphosphine (JohnPhos) as ligand (eq
2).42
The best overall yield of the photostimulated cyclization of
7d was obtained using excess of t-BuOK and pinacolone
enolate ion as electron-donor. Under these reaction conditions,
ketone 7d affords excellent yield of the more stable tautomer
phenanthren-9-ol (8d) (entry 1, Table 2, eq 3).
In view of the results discussed above the mechanism
sketched in Scheme 3 is proposed. The initiation step of the
chain process is presumed to occur by iron or photoassisted
intermolecular electron transfer (ET) to 7a−c‑ yielding the
radical dianion 10.39,40 Fragmentation of the C-X bond of 10
gives the distonic radical anion 11 and X− ion. The
intermediate radical anion 11, via an intramolecular radical-
carbanion coupling, yields the conjugated radical anion 12. An
ET from 12 to 7a−c‑ affords the product 8a and the radical
dianion 10, which propagates the reaction (Scheme 3). The
intermediate distonic radical anion 11 can also couple with the
pyrrole moiety to give the radical anion 13, that by an ET and
Having demonstrated the efficiency of the methodology for
the preparation of six and seven-membered cycles, halophenyl
ether and thioether ketones 7e−f were prepared to study their
potential use as substrates to afford oxygen and sulfur
heterocycles. These similar substrates were synthesized from
the commercially available 2-bromoacetophenone 6b with 2-
bromophenol43 (5e) and 2-chlorobenzenethiol44 (5f) respec-
tively by CuI catalyzed reactions as shown in Scheme 4.
Scheme 3. Proposed Reaction Mechanism
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a
Table 2. Photostimulated Reactions of Ketone Enolate Anions 7d−f‑ in Liquid Ammonia
a
Reactions were performed in NH3(l) (250 mL), with substrates 7b−l (0.15−0.25 mmol) and t-BuOK as base. Irradiation was conducted in a
b
c
1
photochemical reactor equipped with two HPI-T 400 W lamps (cooled with air and water). Substrate recovered. Yields were determined by H
NMR (internal standard method). Halide anions were determined potentiometrically. Not determined. Reactions were performed in the dark. p-
d
e
f
g
DNB (30 mol %) was added.
Shorter reaction time led to an incomplete conversion of 7e
(entries 2 and 3, Table 2). Cyclization of 7e−f did not occur in
the dark, and the starting material was completely recovered
(entries 5 and 8, Table 2). Partial inhibition was observed when
the photoassisted cyclization of 7e was performed in presence
of p-DNB (entry 6, Table 2). The fact that 7e−f behaved like
7a−c could indicate that all these reactions occur by the same
mechanism.
Scheme 4. Synthesis of Ketones 7e−f
Attempts to synthesize the heterocycle 8e from 2′-(2-
chlorophenoxy)acetophenone 7e by the benzyne mechanism
were unsuccessful.45 Recently, 8e was synthesized in five steps
from 2-phenoxybenzoic acid in 58% overall yields.1e
Having established suitable conditions for the cyclization
reaction, the enolate anions of the 2′-(2-bromophenoxy)-
acetophenone 7e and 2′-((2-chlorophenyl)thio)acetophenone
7f were irradiated with pinacolone enolate ion as entrainment
reagent in liquid ammonia. These experiments afforded the ring
closure products dibenzo[b,f ]oxepin-10(11H)-one 8e and
dibenzo[b,f ]thiepin-10(11H)-one 8f in 99 and 85% yields,
respectively (entries 4 and 7, Table 2, eq 4).
The analogous photocyclization reaction to afford a seven-
member benzo-fused N-heterocycle was then examined. N-(2-
(2-methyl-1,3-dioxolan-2-yl)phenyl)-2-chloro aniline (7h) was
obtained from 2-chloroaniline (5g) and 2-(2-bromophenyl)-2-
methyl-1,3-dioxolane (6c) by Pd(0) catalyzed reaction as
shown in Scheme 5.46 The hydrolysis of 7h with dilute sulfuric
acid gave the desired ketone N-(2-chlorophenyl)-2′-amino-
acetophenone (7g). On the other hand, methylation of 7h
followed by hydrolysis with dilute sulfuric acid afford N-methyl-
N-(2-chlorophenyl)-2′-aminoacetophenone (7i) (Scheme 5).
In the photoinitiated reaction of the anion 7g‑ in liquid
ammonia as solvent, 1-acetyl-9H-carbazole 8g was formed in
71% yield; none of the expected seven-membered heterocycles
could be detected (entry 1, Table 3, eq 5). Complete
conversion of 7g was accomplished by extending the reaction
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Scheme 5. Preparation of the Ketones 7g−i
time, affording the ring closure product 8g in 86% isolated yield
(entry 2).
The regiochemistry in this reaction could be explained
considering that the acidic hydrogen of the N−H group of the
diarylamine should be more acidic that the hydrogen of the
acetyl group in 7g.47 In this reaction, the distonic radical anion
14 (formed by ET to 7g‑ and fragmentation of the C−Cl bond)
via an intramolecular CAr−CAr coupling yields the conjugated
radical anion 15. An ET from 15 to 7g‑ affords the intermediate
16, which ultimately gives the tautomer more stable 8g
(Scheme 6).26 A nonchain process initiated by an intra-
a
Table 3. Photostimulated Reactions of Ketone Enolate Anions 7g−l‑ in Liquid Ammonia
a
Reactions were performed in NH3(l) (250 mL), with substrates 7b−l (0.15−0.25 mmol) and t-BuOK as base. Irradiation was conducted in a
b
c
1
photochemical reactor equipped with two HPI-T 400 W lamps (cooled with air and water). Substrate recovered. Yields were determined by H
NMR (internal standard method). Halide anions were determined potentiometrically. Isolated yield. Not determined
d
e
f
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none 6e with 2-iodobenzyl chloride 5a in CH3CN as solvent.
The methylation of 7j gave the ketone N-methyl-N-(2-
iodobenzyl)-2′-aminoacetophenone 7k as shown in Scheme 7.
Scheme 6. Possible Reaction Mechanism to Formation of
Carbazole 8g
Scheme 7. Preparation of the Ketones 7j−l
molecular ET of the amide anion to the haloarene is possible,
and an intramolecular radical−radical coupling cannot be ruled
out.
The protection of the carbonyl group in 7g increased the rate
of formation of the carbazole. When treated with 2.5 equiv of t-
BuOK in liquid ammonia, diarylamine 7h gave 1-(2-methyl-1,3-
dioxolan-2-yl)-9H-carbazole 8h in 92% yield after only 0.5 h of
irradiation (entry 3, Table 3, eq 6).
Similarly, N-methyl-N-(2-chlorophenethyl)-2′-aminoacetophe-
none 7l was obtained by alkylation of 6e with 1-(2-
bromoethyl)-2-chlorobenzene 5e followed by methylation
(Scheme 7).
In the photostimulated reaction of 7j in liquid ammonia and
in the presence of 3 equiv of t-BuOK, 4-acetylphenanthridine 8j
was achieved in 51% isolated yield and none of the desired
eight-member heterocycle was detected (entry 6, Table 3,
Scheme 8).
Scheme 8. Photostimulated Reactions of Ketone 7j−l
As expected, the intramolecular radical-enolate anion
coupling to afford seven-membered N-heterocycle by intra-
molecular α-arylation reaction occurred when the N−H group
in 7g was substituted. The acid−base reaction of 7i with t-
BuOK in excess in liquid ammonia gave ketone enolate anion
7i‑. When 7i‑ was irradiated in the presence of 3.6 equiv of
pinacolone enolate anion, the expected 5-methyl-5H-dibenzo-
[b,f ]azepin-10(11H)-one 8i was obtained in 41% yield (entry
4, Table 3). By increasing the reaction time, complete
conversion was reached and the desired product 8i was formed
in 73% yield (entry 5, eq 7).
Interestingly, 7j shows a similar behavior to 7g, which only
afford the product of the nucleophilic substitution via the
bidentate anion of the aromatic amine.27
When the ketone 7k was treated with 3 equiv of t-BuOK and
irradiated for 2 h in liquid ammonia, the expected eight-
member heterocycle 5-methyl-5,6-dihydrodibenzo[b,f ]azocin-
12(11H)-one 8k was obtained in 78% isolated yield (entry 7,
Table 3, Scheme 8). In addition, the cyclization of ketone 7l
was slower than of 7k and only 23% of the desired nine-
member ring was obtained after 4 h of irradiation (entry 8).
Complete conversion was achieved when 7l was irradiated for 5
h in the presence of 7 equiv of t-BuOK and 2.5 equiv of
pinacolone enolate ion (entrainment reagent). Under this
reaction condition, the nine-member ring 5-methyl-6,7-
dihydro-5H-dibenzo[b,f ]azonin-13(12H)-one 8l was obtained
in 69% yield (entry 9).
Of particular interest is the observation that by a simply
modification of the starting material under similar condition,
the regiospecificity of the reaction can be changed by the
formation of valuable molecules such as the carbazoles48 and
dibenzo[b,f ]azepinones.1b,f,2
CONCLUSIONS
Due to the efficiency of the methodology for the preparation
of five-, six- and seven-membered benzo-fused carbo- and N-,
O-, S-heterocycles, other substrates like 7 were prepared to
establish their feasibility to form eight- and nine-membered
benzo-fused N-heterocycles.
■
The present paper reports our studies on photostimulated
intramolecular SRN1 reactions using acetyl enolate anions as
nucleophiles. The intramolecular radical-acetyl enolate anion
coupling affords a new α-aryl ketone bond as the key step in the
synthesis of six-, seven, eight and nine-member benzo-fused N-,
O-, S-heterocycles.
N-(2-Iodobenzyl)-2′-aminoacetophenone 7j was prepared by
benzylation of the commercially available 2′-aminoacetophe-
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stirred at rt and 2-iodobenzyl chloride (0.3961 g, 1.57 mmol) was
added in portions. The reaction was carried out at this temperature
until the electrophile had been consumed as judged by GC analysis (3
h approximately). Each individual reaction was not optimized in terms
of temperature, quantity of catalyst or reaction time. The mixture was
diluted with water and CH2Cl2. The phases were separated and the
aqueous phase was extracted with CH2Cl2 (4 × 20 mL). The
combined organic phase was dried (MgSO4), filtered, and the solvent
removed in vacuo to provide the crude product as a light-colored solid.
7a was purified by column chromatography on silica gel eluting with a
petroleum ether/diethyl ether gradient (90:10→70:30) and 79%
9H-carbazole and phenanthridine were selectively formed via
an intramolecular CAr−CAr coupling when the Z-bridge group
in the compounds like 7 has nitrogen capable of forming an
aromatic amide anion.
Considering the good yields and the value of the molecules
obtained, the slow cost, availability and/or simplicity of the
starting material, and the short time and mild reaction
conditions, this methodology could be a valuable alternative
to access to cyclic α-arylated ketones in a simple approach.
1
(0.4047 g, 1.24 mmol) was isolated as white crystals. H NMR (400
EXPERIMENTAL SECTION
General Considerations. Gas chromatographic analyses were
performed using a gas chromatograph with a flame ionization detector,
and equipped with the following columns: 25 m x 0.20 mm x 0.25 μm
■
MHz, CDCl3) δ 7.84 (d, J = 7.8 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.05
(m, 1H), 6.94 (t, J = 7.5 Hz, 1H), 6.84 (m, 1H), 6.46 (d, J = 7.6 Hz,
1H), 6.23 (m, 1H), 5.56 (s, 2H), 2.42 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 188.3 (C), 140.7 (C), 139.3 (CH), 130.4 (CH), 130.3
(CH), 128.9 (CH), 128.5 (CH), 127.1 (CH), 120.2 (CH), 108.8 (C),
1
column and 15 m × 0.25 mm × 0.25 μm column. H NMR (400.16
MHz), 13C NMR (100.63 MHz) spectra were obtained in acetone-d6,
DMSO-d6 and CDCl3 as solvents. Coupling constants are given in Hz
and chemical shifts are reported in δ values in ppm. Data are reported
as followed: chemical shift, multiplicity (s = singlet, s br = broad
singlet, d = doublet, t = triplet, dd = double doublet, dt = double
triplet, ddd = double double doublet, m = multiplet), coupling
constants (Hz), and integration. Gas Chromatographic/Mass Spec-
trometer analyses were carried out on a GC/MS spectrometer
equipped with a 30 m × 0.25 mm × 0.25 μm column. Irradiation was
conducted in a reactor equipped with two 400-W lamps49 (cooled with
water). Potentiometric titration of halide ions where performed in a
pHmeter using an Ag/Ag+ electrode. Melting points were performed
with an electrical instrument. The high resolution mass (HRMS) of
pure products were recorded on equipment, operated with an ESI
source operated in (positive/negative) mode, using nitrogen as
nebulizing and drying gas and sodium formiate 10 mM as internal
calibrate instrument.
1
97.4 (C), 57.7 (CH2), 27.2 (CH3). H−1H COSY NMR (CDCl3)
δH/δH 6.94/7.84, 6.94/7.20, 6.84/7.05, 6.46/7.20, 6.23/7.05, 6.23/
6.84. 1H−13C HSQC NMR (CDCl3) δH/δC δ 7.84/139.3, 7.20/128.5,
7.05/120.2, 6.94/128.9, 6.84/130.3, 6.46/127.1, 6.23/108.8, 5.56/57.7,
2.42/27.2. GC-MS (m/z): 326 (M+ + 1, 1); 325 (M+, 77); 217 (38);
199 (15); 198 (M+ − 127, 100); 183 (18); 182 (6); 156 (27); 155
(12); 154 (19); 128 (5); 127 (9); 91 (7); 90 (34); 89 (22); 77 (9); 63
(8); 51 (5). mp 100.3−101.5 °C. HRMS: calcd for C13H13NOI
326.0036; found [MH]+ 326.0047.
1-(2-Bromobenzyl)-2-acetylpyrrole (7b). 1H NMR (400 MHz,
CDCl3) δ 7.55 (d, J = 7.8 Hz, 1H), 7.16 (t, J = 7.4 Hz, 1H), 7.10 (t, J =
7.5 Hz, 1H), 7.04 (m, 1H), 6.87 (m, 1H), 6.53 (d, J = 7.6 Hz, 1H),
6.22 (m, 1H), 5.64 (s, 2H), 2.42 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 188.4 (C), 137.9 (C), 132.7 (CH), 130.5 (CH), 128.8
(CH), 127.8 (CH), 127.7 (CH), 122.4 (C), 120.4 (CH), 108.9 (CH),
52.9 (CH2), 27.3 (CH3). 1H−1H COSY NMR (CDCl3) δH/ δH 7.10/
7.55, 6.87/7.04, 6.53/7.16, 6.22/7.04, 6.22/6.87. 1H−13C HSQC
NMR (CDCl3) δH/ δC 7.55/132.7, 7.16/127.7, 7.10/128.8, 7.04/
120.4, 6.87/130.5, 6.53/127.7, 6.22/108.9, 5.65/52.9, 2.42/27.3. GC-
MS (m/z): 279 (M+ + 1, 3); 278 (M+, 1); 277 (4); 264 (4); 199 (12);
198 (M+ − 79, 100); 183 (14); 171 (30); 169 (46); 156 (23); 155
(12); 154 (13); 127 (8); 91 (5); 90 (26); 89 (20); 77 (6); 63 (9); 51
(5). mp 80−81 °C. (lit.3b,c 80−81 °C).
Materials. Iodomethane, 2-iodobenzyl chloride, 2-bromobenzyl
chloride, 2-chlorobenzyl chloride, 1-(2-bromoethyl)-2-chlorobenzene,
2-acetylpyrrole, (2-chlorophenyl)boronic acid, 2-bromoacetophenone,
2-bromophenol, 2-chlorobenzenethiol, 2-chloroaniline, 2′-aminoaceto-
phenone, N1,N2-dimethylethan-1,2-diamine, tetrabutylammonium bro-
mide (TBAB), 2-naphthoic acid, t-BuOK, NaOH, Cs2CO3, NaH, y
CuI were commercially available and used as received from the
supplier. DMSO was stored under molecular sieves (4 Å).
Tetrahydrofuran (THF) and toluene was distilled from Na−
benzophenone and stored under N2 atmosphere. All solvents were
analytical grade and used as received from the supplier. Silica gel
(0.063−0.200 mm) was used in column chromatography, and 1, 2 and
4 mm silica gel (60 PF254) plates were employed in radial thin-layer
chromatography purification.
Experimental Procedures and Characterization Data for the
Starting Materials. The starting materials were synthesized by
utilizing standard synthetic organic methods according to literature
procedures: compounds 1-(2-halobenzyl)-2-acetylpyrrole 7a−c,50 2′-
(2-chlorophenyl)acetophenone (7d),42 2′-(2-bromophenoxy)-
acetophenone (7e),43 2′-((2-chlorophenyl)thio)acetophenone (7f).44
Synthesis of 1-(2-Halobenzyl)-2-acetylpyrrole (7a−
c). Method A. From the anion of the 2-acetylpyrrole 6a− in organic
solvent. A flame-dried Schlenk tube under nitrogen atmosphere was
charged with sodium hydride in mineral oil (60%, 0.088 g, 2.2 mmol),
2-acetylpyrrole (0.20 g, 1.84 mmol) and 5 mL of DMSO. The mixture
was stirred at room temperature for 75 min and then a solution of 2-
iodobenzyl chloride (0.53 g, 2.12 mmol) in dry diethyl ether was
added. The reaction was stirred for 22 h and then diluted with water
and CH2Cl2. The aqueous phase was extracted with CH2Cl2 (4 × 20
mL). The resulting solution was dried over anhydrous magnesium
sulfate, filtered, and concentrated. The crude product was purified by
column chromatography on silica gel affording 1-(2-iodobenzyl)-2-
acetylpyrrole 7a in 74% yield (0.442 g, 1.36 mmol).
1-(2-Chlorobenzyl)-2-acetylpyrrole (7c). 1H NMR (400 MHz,
CDCl3) δ 7.37 (d, J = 7.8 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.12
(t, J = 7.4 Hz, 1H), 7.04 (m, 1H), 6.89 (m, 1H), 6.61 (d, J = 7.5 Hz,
1H), 6.22 (m, 1H), 5.68 (s, 2H), 2.43 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 188.3 (C), 136.2 (C), 132.5 (C), 130.6 (CH), 130.5 (C),
129.3 (CH), 128.5 (CH), 127.7 (CH), 127.1 (CH), 120.3 (CH),
108.7 (CH), 50.3 (CH2), 27.2 (CH3). 1H−1H COSY NMR (CDCl3)
δH/δH 7.18/7.37, 7.12/7.18, 6.89/7.04, 6.61/7.12, 6.2/7.04, 6.22/6.89.
1H−13C HSQC NMR (CDCl3) δH/δC 7.37/129.3, 7.18/128.5, 7.12/
127.1, 7.04/120.3, 6.89/130.6, 6.61/127.7, 6.22/108.7, 5.68/50.3,
2.43/27.2. GC-MS (m/z): 235 (M+ + 2,4); 233 (M+, 13); 220 (4);
218 (11); 199 (13); 198 (M+ − 35, 83); 190 (14); 183 (9); 156 (14);
154 (7); 127 (37); 126 (8); 125 (100); 99 (8); 90 (7); 89 (23); 63
(8); 51 (5). Mp 69−70 °C. HRMS: calcd for C13H13ClNO 234.0680;
found [MH]+ 234.0687.
2′-(2-Chlorophenyl)acetophenone (7d). (2-Chlorophenyl)-
boronic acid (0.128 g, 0.82 mmol, 1.5 equiv), 2-bromoacetophenone
(0.995 g, 0.54 mmol), Pd(OAc)2 (0.0026 g, 2.0 mol %), KF (0.087 g,
1.5 mmol, 3 equiv), and [1,1′-biphenyl]-2-yl-di-tert-butylphosphine
(0.0068 g, 4 mol %) were sequentially added to an flame-dried Schlenk
tube. The mixture was suspended in THF (1.5 mL) and stirred for 2 h
at rt. The mixture was directly purified by column chromatography on
silica gel with a petroleum ether/diethyl ether gradient (100:0 →
90:10) to provide 2′-(2-chlorophenyl)acetophenone in 65% yield
(0.0817 g, 0.35 mmol) as a colorless oil. 1H NMR (400 MHz, CDCl3)
δ 7.73 (dd, J = 7.7, 1.1 Hz, 1H), 7.53 (td, J = 7.5, 1.4 Hz, 1H), 7.49−
7.41 (m, 2H), 7.34−7.29 (m, 2H), 7.28 (m, 1H), 7.26−7.21 (m, 1H),
2.21 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 201.4 (C), 140.0 (C),
139.4 (C), 138.2 (C), 132.5 (C), 131.1 (CH), 131.0 (CH), 130.9
(CH), 129.4 (CH), 129.0 (CH), 128.2 (CH), 128.0 (CH), 126.8
Method B. Typical phase Transfer Catalysis. A round-bottomed
flask was charged with 2-acetylpyrrole (0.221 g, 2.03 mmol, 1.27
equiv), TBAB (0.0645 g, 0.2 mmol, 10 mol %), a 50% aqueous
solution of NaOH (1 mL) and 2.5 mL of CH2Cl2. The mixture was
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1
(CH), 29.0 (CH3). H−1H COSY NMR (CDCl3) δH/δH 7.45/7.73,
with nitrogen. The 2-(2-bromophenyl)-2-methyl-1,3-dioxolane (ob-
tained from the 2-bromoacetophenone)51 (0.47 g, 1.94 mmol) was
added to the flash, followed by toluene (4 mL). The reaction was
heated with stirring to 110 °C for 24 h. The mixture was then cooled
to room temperature and partitioned between water and CH2Cl2. The
organic layer was dried over anhydrous magnesium sulfate, filtered,
and concentrated. The crude product was purified by radial thin-layer
chromatography eluting with petroleum/CH2Cl2 (90/10) to afford the
2-chloro-N-(2-(2-methyl-1,3-dioxolan-2-yl)phenyl)aniline in 79%
(0.458 g, 1.58 mmol) as a white solid, m.p 79.7−80.7. 1H NMR
(400 MHz, CDCl3) δ 7.86 (s br, 1H), 7.52 (dd, J = 7.7, 1.6 Hz, 1H),
7.38−7.32 (m, 3H), 7.24−7.19 (m, 1H), 7.14−7.10 (m, 1H), 6.94 (td,
J = 7.6, 1.1 Hz, 1H), 6.81 (td, J = 7.9, 1.5 Hz, 1H), 4.15−4.06 (m, 2H),
3.93−3.84 (m, 2H), 1.68 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
140.0 (C), 139.8 (C), 131.0 (C), 129.9 (CH), 128.7 (CH), 127.2
(CH), 126.7 (CH), 122.8 (C), 121.0 (CH), 120.6 (CH), 118.4 (CH),
7.45/7.53, 7.31/7.45, 7.28/7.53, 7.24/7.31, 7.23/7.45. H−13C HSQC
1
NMR (CDCl3) δH/ δC 7.75/128.2, 7.53/131.0, 7.45/128.0, 7.45/
129.4, 7.31/129.0, 7.31/126.8, 7.28/131.1, 7.24/130.9, 2.20/29.0. GC-
MS (m/z): 215 (M+ − 15, 2), 197 (1), 196 (13), 195 (M+ − 35, 100),
152 (27), 151 (9), 149 (6), 76 (12). HRMS: calcd for C14H12ClO
231.0571; found [MH]+ 231.0592.
Synthesis of 2′-(2-bromophenoxy)acetophenone (7e). A flame-
dried Schlenk tube was charged with molecular sieves 4 Å (0,562 g),
Cs2CO3 (4 mmol), CuI (0.1 mmol) and 2-naphthoic acid (4 mmol),
evacuated and filled with nitrogen. Toluene (1.5 mL), 2-bromophenol
(4 mmol), 2-bromoacetophenone (2 mmol) and ethyl acetate (0.1
mmol) where added via syringe. The reaction tube was purged with
nitrogen, and the mixture was heated with stirring to 100 °C for 29 h.
Upon cooling at room temperature, dichloromethane was added and
the solvent was removed by filtration. The organic phase was
concentrated, and 2-bromophenol was distilled under reduced
1
116.6 (CH), 109.3 (C), 64.3(2 CH2), 25.1 (CH3). H−1H COSY
pressure using a Kugelrohr apparatus. The 2′-(2-bromophenoxy)-
acetophenone 7e was purified by column chromatography on silica gel
with a petroleum ether/diethyl ether gradient (100:0 → 90:10) as
NMR (CDCl3) δH/δH 7.21/7.35, 7.12/7.35, 6.94/7.52, 6.94/7.21,
̈
1
6.81/7.35, 6.81/7.12, 3.88/4.10. H−13C HSQC NMR (CDCl3) δH/
δC 7.52/126.7, 7.35/129.9, 7.35/118.4, 7.35/116.6, 7.21/128.7, 7.12/
127.2, 6.95/121.0, 6.81/120.6, 4.10/64.3, 3.88/64.3, 1.68/25.1.
1H−13C HMBC NMR (CDCl3) δH/δC 7.52/139.8, 7.52/128.7,
7.52/109.3, 7.35/140.0, 7.35/131.0, 7.35/127.2, 7.35/122.8, 7.35/
120.6, 7.21/139.8, 7.21/126.7, 7.12/140.0, 7.12/131.0, 7.12/116.6,
6.94/131.0, 6.94/118.4, 6.81/122.8, 6.81/116.6, 4.10/109.3, 3.88/
109.3, 1.68/131.0, 1.68/109.3. GC-MS (m/z): 292 (M+ + 1, 4), 291
(M+ + 1, 35), 290 (M+, 12), 289 (100), 276 (21), 274 (73), 254 (27),
246 (16), 245 (11), 244 (37), 232 (14), 230 (40), 210 (62), 196 (10),
195 (46), 194 (12), 193 (12), 192 (16), 182 (12), 181 (11), 180 (31),
168 (12), 167 (46), 166 (22), 164 (23), 139 (11), 120 (56), 116 (13),
115 (27), 87 (16), 83 (31), 77 (10), 75 (12). HRMS (IE) calcd for
C16H17ClNO2 290.0942; found [MH]+ 290.0956.
1
colorless oil in 82% yield (0.465 g, 1.7 mmol). H NMR (400 MHz,
CDCl3) δ 7.87 (dd, J = 7.8, 1.8 Hz, 1H), 7.67 (dd, J = 8.0, 1.6 Hz, 1H),
7.41 (ddd, J = 8.3, 7.3, 1.8 Hz, 1H), 7.31 (ddd, J = 8.1, 7.5, 1.6 Hz,
1H), 7.17 (td, J = 7.8, 1.0 Hz, 1H), 7.10−7.06 (m, 1H), 6.98 (dd, J =
8.1, 1.5 Hz, 1H), 6.74 (dd, J = 8.3, 0.9 Hz, 1H), 2.72 (s, 3H). 13C
NMR (101 MHz, CDCl3) δ 198.8 (C), 155.9 (C), 152.6 (C), 134.1
(CH), 133.6 (CH), 130.7 (CH), 129.7 (C), 128.9 (CH), 125.7 (CH),
123.4 (CH), 120.7 (CH), 117.5 (CH), 115.0 (C), 31.8 (CH3).
1H−1H COSY NMR (CDCl3) δH/δH 7.41/7.87, 7.31/7.67, 7.17/7.86,
7.17/7.41, 7.08/7.67, 7.08/7.31, 6.98/7.31, 6.74/7.42. H−13C HSQC
1
NMR (CDCl3) δH/δC 7.85/130.7, 7.67/134.1, 7.40/133.6, 7.30/128.9,
7.16/123.4, 7.07/125.7, 6.96/120.7, 6.74/117.5, 2.72/31.8. GC-MS
(m/z): 292 (M+ + 2, 1); 290 (M+ − 1, 1); 277 (12); 275 (12); 212
(23); 211 (M+ − 79, 100); 197 (10); 196 (73); 168 (34); 139 (34);
121 (7); 119 (30); 118 (15); 106 (10); 92 (7); 91 (20); 77 (6); 76
(13); 75 (10); 65 (6); 64 (8); 63 (12); 51 (6); 50 (11).
N-Methyl-N-(2-chlorophenyl)-2′-aminoacetophenone (7i). A
mixture of N-(2-(2-methyl-1,3-dioxolan-2-yl)phenyl)-2-chloro aniline
7h (0.226 g, 0.78 mmol), t-BuOK (0.134 g, 1.19 mmol), and
iodomethane (0.227 g, 1.6 mmol) in DMSO (5 mL) was stirred at 50
°C for 3 h. The mixture was diluted with water and extracted with
CH2Cl2 (2 × 15 mL) and ethyl acetate (2 × 15 mL). The organic
extracts were dried and concentrated. The residue was dissolved in
dioxane (1 mL) in a round-bottomed flask fitted with a reflux
condenser. Water (5 mL), followed by H2SO4 concentrated (4 drops)
was added and the reaction was heated with stirring to 90 °C for 4 h.
The solution was basified with Na2CO3 and extracted. The crude
product was purified by radial thin layer chromatography with a
petroleum ether/methylene chloride gradient (90:10 → 70:30) in 61%
yield as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.38−7.34 (m,
3H), 7.19 (td, J = 7.7, 1.5 Hz, 1H), 7.06−6.98 (m, 4H), 3.25 (s, 3H),
2.42 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 203.2 (C), 148.1 (C),
147.0 (C), 134.3 (C), 131.6 (CH), 131.2 (CH), 129.2 (C), 129.0
(CH), 127.8 (CH), 125.0 (CH), 124.9 (CH), 122.2 (CH), 120.4
(CH), 42.0 (CH2), 29.1 (CH3). 1H−1H COSY NMR (CDCl3) δH/δH
2′-((2-Chlorophenyl)thio)acetophenone (7f). A flame-dried
Schlenk tube was charged with 2-bromoacetophenone (1 mmol), 2-
chlorobenzenethiol (0.5 mmol), CuI (0.05 mmol), N1,N2-dimethyle-
than-1,2-diamine (4.0 mmol) and water (6.5 mL) under nitrogen at
room temperature. The reaction mixture was heated to 120 °C for 36
h, allowed to cool to room temperature and the resulting mixture was
extracted with CH2Cl2 (4 × 5 mL). The combined organic layers were
dried over anhydrous sodium sulfate and concentrated under reduced
pressure. The 2-bromoacetophenone was distilled under reduced
pressure using a Kugelrohr apparatus. The colored residue was purified
̈
by silica gel column chromatography with a petroleum ether/diethyl
ether gradient (90:10 → 50:50) to afford the 2′-((2-chlorophenyl)
thio)acetophenone 7f in 84% yield (0.110 g, 0.42 mmol) as white
crystal. Mp 87−88.5 °C. 1H NMR (400 MHz, CDCl3) δ 7.85 (dd, J =
7.7, 1.6 Hz, 1H), 7.57 (dd, J = 7.6, 1.8 Hz, 1H), 7.52 (dd, J = 7.9, 1.4
Hz, 1H), 7.36 (td, J = 7.7, 1.8 Hz, 1H), 7.31−7.27 (m, 2H), 7.22 (td, J
= 7.5, 1.2 Hz, 1H), 6.80 (dd, J = 8.0, 1.2 Hz, 1H), 2.67 (s, 3H). 13C
NMR (101 MHz, CDCl3) δ 199.2 (C), 139.5 (C), 138.9 (C), 136.8
(CH), 134.9 (C), 132.5 (C), 132.2 (CH), 130.8 (CH), 130.4 (CH),
130.38 (CH), 128.0 (CH), 127.8 (CH), 124.9 (CH), 28.1 (CH3).
1H−1H COSY NMR (CDCl3) δH/δH 7.36/7.52, 7.29/7.58, 7.29/7.36,
1
7.19/7.36, 7.02/7.36, 7.02/7.19. H−13C HSQC NMR (CDCl3) δH/
δC 7.36/131.2, 7.36/129.0, 7.36/124.9, 7.19/127.8, 7.02/131.6, 7.02/
1
125.0, 7.02/122.2, 7.02/120.4, 3.25/42.0, 2.42/29.1. H−13C HMBC
NMR (CDCl3) δH/δC 7.36/203.2, 7.36/147.0, 7.36/131.6, 7.36/127.8,
7.19/147.0, 7.19/131.2, 7.02/134.3, 7.02/129.2, 7.02/124.9, 7.02/
122.2, 7.02/120.4, 3.25/147.0, 2.42/203.2. GC-MS (m/z): 262 (M+ +
2, 4), 261 (M+ + 1, 26), 259 (M+ − 1, 72), 246 (28), 245 (12), 244
(M+ − 15, 100), 242 (55), 209 (22), 194 (11), 181 (38), 180 (58),
166 (15), 152 (14), 140 (15), 139 (10), 138 (13), 105 (13), 77 (28),
75 (15), 51 (11).
7.22/7.85, 7.22/7.29, 6.80/7.29. H−13C HSQC NMR (CDCl3) δH/
1
δC 7.84/130.8, 7.57/136.8, 7.52/130.5, 7.36/130.38, 7.29/132.2, 7.29/
127.8, 7.22/124.9, 6.80/128.0, 2.67/28.1. GC-MS (m/z): 265 (5); 264
(39); 263 (15); 262 (M+, 100); 249 (35); 248 (13); 247 (90); 227
(14); 213 (9); 212 (66); 185 (12); 184 (65); 183 (17); 152 (19); 151
(37); 139 (37); 138 (6); 137 (38); 135 (10); 134 (7); 113 (4); 108
(14); 91 (16); 82 (6); 77 (5); 76 (6); 75 (10); 74 (6); 69 (14); 63
(9); 51 (7); 50 (8); 45 (6). HRMS (IE) calcd for C14H12OSCl
263.0292; found [MH]+ 263.0298.
N-(2-Chlorophenyl)-2′-aminoacetophenone (7g). In a round-
bottomed flask was dissolved N-(2-(2-methyl-1,3-dioxolan-2-yl)-
phenyl)-2-chloro aniline 7h (0.11 g, 0.38 mmol) in dioxane (1 mL).
Water (5 mL), followed by H2SO4 concentrated (2 drops) was added
and the reaction was heated with stirring to 90 °C for 4 h. The mixture
was then cooled to room temperature, basified with Na2CO3 and
extracted with CH2Cl2 and ethyl acetate. The N-(2-chlorophenyl)-2′-
aminoacetophenone 7g was purified by radial thin layer chromatog-
raphy eluting with petroleum/diethyl ether (90/10) in 96% yield as
N-(2-(2-Methyl-1,3-dioxolan-2-yl)phenyl)-2-chloro aniline (7h).
A flame-dried Schlenk tube was charged with 2-chloroaniline (0.29 g,
2.27 mmol), t-BuONa (0.265 g, 2.75 mmol), Pd(OAc)2 (0.010 g, 2
mmol %) and DPEphos (0.04 g, 0.075 mmol), evacuated and filled
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colorless oil. H NMR (400 MHz, CDCl3) δ 10.62 (s br, 1H), 7.84
(47), 120 (26), 118 (24) 111 (11), 106 (15), 105 (19), 104 (19), 103
(12), 91 (61), 90 (80), 89 (42), 78 (18), 77 (53), 76 (13,) 65 (19), 64
(11), 63 (21), 51 (22). HRMS (IE) calcd for C16H16INaNO 388.0169;
found [MH]+ 388.0196.
N-Methyl-N-(2-chlorophenethyl)-2′-aminoacetophenone (7l). A
mixture of 2′-aminoacetophenone (0.28 g, 2.09 mmol), K2CO3 (0.41 g,
2.96 mmol), and 1-(2-bromoethyl)-2-chlorobenzene (0.686 g, 3.12
mmol) in acetonitrile (5 mL) was stirred at 85 °C in a sealed tube for
72 h. The mixture was diluted with water and was extracted with
CH2Cl2 (3 × 15 mL) and diethyl ether (2 × 10 mL). The combined
organic phase was dried (Na2SO4), filtered, and the solvent removed in
vacuo. The 1-(2-bromoethyl)-2-chlorobenzene was distilled under
(dd, J = 8.0, 1.4 Hz, 1H), 7.49 (dd, J = 8.1, 1.3 Hz, 1H), 7.44 (dd, J =
8.0, 1.4 Hz, 1H), 7.36−7.32 (m, 1H), 7.25−7.20 (m, 2H), 7.01 (td, J =
7.8, 1.5 Hz, 1H), 6.82−6.78 (m, 1H), 2.66 (s, 3H). 13C NMR (101
MHz, CDCl3) δ 201.2 (C), 146.4 (C), 137.7 (CH), 134.4 (CH), 132.4
(CH), 130.3 (CH), 127.3 (C), 127.1 (CH), 124.1 (CH), 122.6 (CH),
120.2 (C), 117.5 (CH), 114.6 (CH), 28.1 (CH3). 1H−1H COSY
NMR (CDCl3) δH/δH 7.34/7.85, 7.22/7.49, 7.22/7.34, 7.01/7.44,
7.01/7.22, 6.80/7.84, 6.80/7.34. H−13C HSQC NMR (CDCl3) δH/
1
δC 7.84/132.4, 7.49/122.6, 7.44/130.3, 7.34/134.4, 7.22/127.1, 7.22/
114.6, 7.01/124.1, 6.80/117.5, 2.66/28.1. GC-MS (m/z): 248 (M+ +
2, 5), 247 (M+ + 1, 35), 246 (M+, 15), 245 (M+ − 1, 100), 232 (12),
230 (35), 210 (67), 196 (11), 195 (81), 182 (9), 180 (12), 168 (13),
167 (40), 166 (22), 140 (10), 139 (14), 120 (56), 83 (19). HRMS
calcd for C14H12ClNaNO 268.0500; found [MH]+ 268.0515.
reduced pressure using a Kugelrohr apparatus. The residue was
̈
dissolved in acetonitrilo (5 mL), and K2CO3 (0.55 g, 4 mmol), and
iodomethane (0.568 g, 4 mmol) were added. The mixture was stirred
at 85 °C in a sealed tube for 72 h. The solution was extracted with
CH2Cl2 (2 × 15 mL) and ethyl acetate (2 × 15 mL). The combined
organic layers were dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The residue was purified by
radial thin-layer chromatography eluting with petroleum ether
affording the N-methyl-N-(2-chlorophenethyl)-2′-aminoacetophenone
N-(2-Iodobenzyl)-2′-aminoacetophenone (7j). A mixture of 2′-
aminoacetophenone (0.350 g, 2.59 mmol), K2CO3 (0.519 g, 3.76
mmol), and 2-iodobenzyl chloride (0.323 g, 1.28 mmol) in acetonitrile
(5 mL) was stirred at 85 °C in a sealed tube for 72 h. The mixture was
diluted with water and was extracted with CH2Cl2 (3 × 15 mL) and
diethyl ether (2 × 10 mL). The combined organic phase was dried
(Na2SO4), filtered, and the solvent removed in vacuo. The residue was
purified by column chromatography (silica gel, petroleum ether/
diethyl ether (90:10)) to give N-(2-iodobenzyl)-2′-aminoacetophe-
none 7j (0.3828 g, 1.09 mmol, 85%). The solid was recrystallized in
petroleum ether as white needles crystals, m.p.: 128.3−129.3 °C
1
7l (0.072 g, 0.25 mmol, 12%) as colorless oil. H NMR (400 MHz,
CDCl3) δ 7.42−7.35 (m, 2H), 7.33−7.30 (m, 1H), 7.16−7.09 (m,
4H), 6.98 (td, J = 7.5, 0.9 Hz, 1H), 3.31−3.27 (m, 2H), 2.97−2.93 (m,
2H), 2.88 (s, 3H), 2.52 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 204.1
(C), 150.8 (C), 137.0 (C), 134.3 (C), 134.0 (C), 131.6 (CH), 130.9
(CH), 129.5 (CH), 129.3 (CH), 127.8 (CH), 126.9 (CH), 121.3
(CH), 119.0 (CH), 56.4 (CH2), 41.9 (CH3), 31.0 (CH2), 29.0
1
(petroleum ether). H NMR (400 MHz, CDCl3) δ 9.39 (s br, 1H),
7.85 (d, J = 7.8 Hz, 1H), 7.78 (dd, J = 8.1, 1.4 Hz, 1H), 7.31−7.24 (m,
3H), 6.98−6.93 (m, 1H), 6.64−6.60 (m, 1H), 6.52 (d, J = 8.5 Hz,
1H), 4.42 (d, J = 6.0 Hz, 2H), 2.62 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 201.1 (C), 150.6 (C), 140.1 (C), 139.4 (CH), 135.1 (CH),
132.7 (CH), 128.9 (CH), 128.4(CH), 128.0 (CH), 118.0 (C), 114.7
(CH), 112.2 (CH), 98.2 (C), 51.9 (CH2), 28.0 (CH3). 1H−1H COSY
NMR (CDCl3) δH/δH 6.95/7.85, 6.95/7.23, 6.63/7.78, 6.63/7.27,
1
(CH3). H−1H COSY NMR (CDCl3) δH/δH 7.12/7.38, 7.12/7.31,
6.98/7.38, 2.95/3.29. 1H−13C HSQC NMR (CDCl3) δH/δC 7.38/
129.3, 7.38/131.5, 7.31/129.5, 7.12/130.9, 7.12/127.8, 7.12/126.9,
7.12/119.0, 6.98/121.3, 3.29/56.4, 3.29/31.0, 2.95/56.4, 2.95/31.0,
2.88/41.9, 2.50/29.0. GC-MS (m/z): 164 (1), 163 (18), 162 (100),
144 (5), 134 (6), 120 (31), 119 (6), 118 (6), 91 (10), 77 (13). HRMS
(IE) calcd for C17H18ClNaNO 310.0969; found [MNa]+ 310.0978.
Representative Procedure for Photostimulated Reactions.
Preparation of 5H-benzo[e]pyrrolo[1,2-a]azepin-11(10H)-one 8a.
The following procedure is representative of all of these reactions.
Liquid ammonia (150 mL), previously dried over Na metal, was
distilled into a 250 mL three-necked round-bottomed flask equipped
with a coldfinger condenser and a magnetic stirrer under a nitrogen
atmosphere. The base t-BuOK (2.0 equiv, 0.056 g, 0.50 mmol) was
added to the liquid ammonia, then the substrate 1-(2-iodobenzyl)-2-
acetylpyrrole 7a (1.0 equiv, 0.081 g, 0.25 mmol) was added to the
solution dissolved in 1 mL of dried ethyl ether when the reaction flask
was already being irradiated. The irradiation was conducted in a
reactor equipped with two HPI-T 400 W lamps (cooled with air and
water). The irradiation was continued for 2 h. The reaction was
quenched with ammonium nitrate and the ammonia was allowed to
evaporate. Water was added to the residue and the mixture was
extracted with CH2Cl2 (3 × 30 mL). The organic extract was dried
over anhydrous MgSO4 then filtered and the solvent was removed to
leave the crude product. 5H-Benzo[e]pyrrolo[1,2-a]azepin-11(10H)-
one 8a was separated and isolated by radial thin-layer chromatography
on silica gel. In other similar experiments, the products were quantified
by CG or NMR by using the internal standard method. The yield of
halide ions in the aqueous solution was determined potentiometrically.
Photostimulated Reaction of 1-(2-Iodobenzyl)-2-acetylpyr-
role (7a) in DMSO. The reaction was carried out in a two-necked 20
mL round-bottomed flask, equipped with a nitrogen inlet and
magnetic stirrer at room temperature. DMSO (5 mL) was dried and
deoxygenated, then t-BuOK (2.0 equiv, 0.056 g, 0.5 mmol) and
substrate 7a (1.0 equiv, 0.080 g, 0.25 mmol) were added and the
reaction mixture was irradiated for 2 h. The reaction was quenched
with water and ammonium nitrate in excess. The residue was extracted
with CH2Cl2 (4 × 20 mL) and the organic extract was washed with
water, dried with anhydrous MgSO4 and filtered. The solvent was
removed to leave the crude product. The product 8a was separated
and isolated by radial thin-layer chromatography on silica gel eluting
6.52/7.27. H−13C HSQC NMR (CDCl3) δH/δC 7.85/139.4, 7.78/
1
132.7, 7.27/135.1, 7.27/128.4, 7.27/128.0, 6.95/128.9, 6.63/114.7,
6.52/112.2, 4.42/51.9, 2.62/28.0. 1H−13C HMBC NMR (CDCl3) δH/
δC 7.85/140.1, 7.85/128.4, 7.85/98.2, 7.78/201.1, 7.78/150.6, 7.78/
135.1, 7.27/150.5, 7.27/140.1, 7.27/132.5, 7.27/128.9, 7.27/98.2,
6.95/128.0, 6.63/118.0, 6.63/112.2, 6.52/118.0, 6.52/114.7, 4.42/
150.6, 4.42/140.1, 4.42/128.0, 4.42/98.2, 2.62/201.1, 2.62/132.7,
2.62/118.0. GC-MS (m/z): 353 (M+ + 2, 2), 352 (M+ + 1, 14), 351
(M+, 100), 232 (59), 224 (40), 222 (19), 217 (58), 209 (47), 206
(13), 204 (15), 182 (28), 181 (12), 180 (54), 152 (21), 148 (20), 146
(12), 134 (46), 132 (11), 130 (20), 120 (12), 106 (13), 105 (47), 104
(11), 103 (12), 92 (11) 91 (37), 90 (94), 89 (49), 78 (18) 77 (51), 76
(18), 65 (18), 64 (13), 63 (25), 51 (25), 50 (12). HRMS (IE) calcd
for C15H15INO 352.0193; found [MH]+ 352.0211.
N-Methyl-N-(2-iodobenzyl)-2′-aminoacetophenone (7k). A mix-
ture of 1-(2-((2-iodobenzyl)amino)phenyl)ethanone (0.139 g, 0.396
mmol), K2CO3 (0.121 g, 0.87 mmol), and iodomethane (0.336 g, 2.37
mmol) in acetonitrile (5 mL) was stirred at 80 °C in a sealed tube for
72 h. The mixture was diluted with water and was extracted with
CH2Cl2 (4 × 20 mL). The organic extracts were dried and
concentrated. The residue was purified by radial thin-layer
chromatography eluting with petroleum ether/diethyl ether (90/10)
to give N-methyl-N-(2-iodobenzyl)-2′-aminoacetophenone 7k (0.133
g, 92%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.89−7.82 (m,
1H), 7.46 (dd, J = 7.6, 1.5 Hz, 1H), 7.37−7.31 (m, 1H), 7.28−7.25
(m, 2H), 7.02−6.53 (m, 3H), 4.31 (s, 2H), 2.77 (s, 3H), 2.63 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 203.2 (C), 150.8 (C), 139.6 (CH),
139.3 (C), 132.6 (C), 131.8 (CH), 129.5 (CH), 129.2 (CH), 129.0
(CH), 128.2 (CH), 120.6 (CH), 118.6 (CH), 99.4 (C), 64.2 (CH3),
42.7 (CH3), 29.5 (CH3). 1H−1H COSY NMR (CDCl3) δH/δH 6.77/
7.85, 6.77/7.46, 6.77/7.34, 6.77/7.26. H−1C HSQC NMR (CDCl3)
1
δH/δC 7.84/139.6, 7.46/129.5, 7.34/131.8, 7.26/129.2, 7.26/128.2,
6.77/129.0, 6.77/120.6, 6.77/118.6, 4.31/64.2, 2.77/42.7, 2.63/29.5.
GC-MS (m/z): 366 (M+ + 1, 10), 365 (M+, 65), 351 (6), 350 (47),
348 (16), 246 (22), 238 (16), 223 (30), 217 (53), 204 (10), 194 (49),
180 (13), 162 (15), 152 (12), 148 (100), 146 (17), 132 (15), 130
468
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The Journal of Organic Chemistry
Article
with petroleum ether/diethyl ether (90:10) and was isolated as a white
solid in 38% yield (0.019 g, 0.10 mmol).
COSY NMR (CDCl3) δH/δH 7.54/8.06, 7.27/7.54, 7.19/8.06, 7.19/
1
7.53, 7.19/7.30. H−13C HSQC NMR (CDCl3) δH/δC 8.06/130.5,
Reaction of 1-(2-Iodobenzyl)-2-acetylpyrrole Enolate Ion
(7a) Induced by FeCl2 in DMSO. The reaction was carried out in an
oven-dried Schlenk tube covered of the light at rt. DMSO (5 mL) was
dried and deoxygenated, t-BuOK (0.087 g, 0.75 mmol, 5.0 equiv),
pinacolone (0.045 g, 0.45 mmol, 3.0 equiv) and FeCl2 (0.094 g, 0.75
mmol, 0.50 equiv) were added. After 10 min substrate 7a (0.048 g,
0.15 mmol, 1.0 equiv) was added and the reaction mixture was stirred
for 4.5 h. Water and ammonium nitrate were added to the residue and
the mixture was extracted with CH2Cl2 (4 × 15 mL). The organic
extract was dried over anhydrous MgSO4 and filtered. The solvent was
removed to leave the crude products.
7.54/134.9, 7.38/121.5, 7.27/129.7, 7.27/128.5, 7.27/120.4, 7.19/
1
126.3, 7.19/123.8, 4.10/48.2. H−13C HMBC NMR (CDCl3) δH/δC
8.06/190.4, 8.06/160.2, 8.06/134.9, 7.54/160.2, 7.54/130.5, 7.38/
160.2, 7.38/123.8, 7.27/156.9, 7.27/128.5, 7.27/126.2, 7.19/126.4,
7.19/121.5, 7.19/120.4, 4.10/190.4, 4.10/156.9, 4.10/129.7, 4.10/
126.2. GC-MS (m/z): 211 (M+ + 1, 14); 210 (M+, 100); 209 (27);
182 (20); 181 (94); 165 (7); 154 (5); 153 (17); 152 (25); 151 (6); 91
(10); 89 (8); 77 (6); 76 (26); 64 (8); 63 (12); 51 (8); 50 (8).
Dibenzo[b,f ]thiepin-10(11H)-one (8f).1a,b,f Compound 8f was
obtained according to the general procedure. The benzothiepinone
was purified by radial thin-layer chromatography eluting with
petroleum ether/diethyl ether (90:10) and 0.041 g (70%, 0.18
mmol) was isolated as a yellow pale solid: mp 73.5−75.0 °C (lit.1a 72−
73 °C). 1H NMR (400 MHz, CDCl3) δ 8.20 (dd, J = 7.9, 1.5 Hz, 1H),
7.64 (dd, J = 7.7, 0.8 Hz, 1H), 7.60 (dd, J = 7.9, 0.9 Hz, 1H), 7.46−
7.40 (m, 2H), 7.36 (td, J = 7.5, 1.2 Hz, 1H), 7.33−7.29 (m, 1H), 7.20
(td, J = 7.6, 1.4 Hz, 1H), 4.37 (s, 2H). 13C NMR (101 MHz, CDCl3) δ
191.4 (C), 140.2 (C), 137.6 (C), 136.1 (C), 134.5 (C), 132.5 (CH),
131.5 (CH), 131.2 (CH), 130.9 (CH), 129.9 (CH), 129.4 (CH),
127.2 (CH), 126.8 (CH), 51.0 (CH2). 1H−1H COSY NMR (CDCl3)
5H-Benzo[e]pyrrolo[1,2-a]azepin-11(10H)-one (8a). 1H NMR
(400 MHz, CDCl3) δ 7.34−7.28 (m, 3H), 7.27−7.22 (m, 1H), 7.10
(dd, J = 4.1, 1.8 Hz, 1H), 6.94 (t, J = 2.1 Hz, 1H), 6.15 (dd, J = 4.1, 2.5
Hz, 1H), 5.24 (s, 2H), 4.07 (s, 2H). 13C NMR (101 MHz, CDCl3) δ
184.3 (C), 135.0 (C), 134.1 (C), 132.3 (C), 129.7 (CH), 129.2 (CH),
128.1 (CH), 127.7 (CH), 127.4 (CH), 118.4 (CH), 109.0 (CH), 53.6
(CH2), 49.0 (CH2). 1H−1H COSY NMR (400 MHz, CDCl3) δH/δH
7.24/7.31, 6.94/7.10, 6.15/7.10, 6.15/6.94. 1H−13C HSQC NMR
(400 MHz, CDCl3) δH/δC 7.31/129.7, 7.31/129.2, 7.31/128.1, 7.24/
127.4, 7.10/118.4, 6.94/127.7, 6.15/109.0, 5.24/53.6, 4.07/49.0.
1H−13C HMBC NMR δH/δC 7.31/134.1, 7.31/129.2, 7.31/128.1,
7.31/127.4, 7.24/135.0, 7.24/129.7, 7.10/132.3, 7.10/127.7, 7.10/
109.0, 6.94/132.3, 6.94/118.4, 6.94/109.0, 6.15/132.3, 6.15/127.7,
6.15/118.4, 5.24/135.0, 5.24/132.3, 5.24/128.1, 4.07/184.3, 4.07/
134.1, 4.07/129.7. GC-MS (m/z): 199 (M+ + 2, 1), 198 (M+ + 1, 14),
197 (M+, 99), 169 (33), 168 (86), 167 (13), 142 (10), 116 (20), 104
(100), 103 (32), 83 (25), 78 (45), 77 (22), 51 (10).
1
δH/δH 7.43/7.64, 7.36/7.43, 7.31/8.20, 7.20/7.64, 7.20/7.36. H−13C
HSQC NMR (CDCl3) δH/δC 8.20/131.5, 7.64/131.2, 7.60/130.8,
7.43/132.5, 7.43/129.4, 7.36/129.9, 7.31/126.8, 7.20/127.2, 4.37/51.0.
GC-MS (m/z): 228 (M+ + 2, 5); 227 (M+ + 1, 17); 226 (M+, 100);
225 (28); 198 (9); 197 (49); 195 (6); 194 (13); 193 (7); 166 (7); 165
(53); 164 (6); 153 (6); 152 (13); 121 (6); 99 (5); 98 (10); 82 (8); 77
(6); 76 (7); 69 (7); 63 (9). HRMS (IE) calcd for C14H11OS 227.0525;
found [MH]+ 227.0527.
3-Acetyl-5H-pyrrolo[2,1-a]isoindole (9). The product was sepa-
1-Acetyl-9H-carbazole (8g).52 The carbazole 8g was purified by
radial thin-layer chromatography eluting with petroleum ether/diethyl
ether (90/10) and 0.024 g (86%, 0.12 mmol) was isolated as a yellow
rated by radial thin-layer chromatography on silica gel eluting with
1
petroleum ether/diethyl ether (90:10) as a colorless solid. H NMR
(400 MHz, CDCl3) δ 7.64−7.62 (m, 1H), 7.51−7.49 (m, 1H), 7.42−
7.38 (m, 1H), 7.34−7.30 (m, 1H), 7.08 (d, J = 4.1 Hz, 1H), 6.41 (d, J
= 4.1 Hz, 1H), 5.22 (s, 2H), 2.48 (s, 3H). 1H−1H COSY NMR
(CDCl3) δH/δH 7.40/7.63, 7.32/7.50, 6.41/7.08. 1H−13C HSQC
RMN (Cl3CD): δH/δC 7.63/120.1, 7.50/123.3, 7.40/128.0, 7.32/
127.0, 7.08/121.5, 6.41/99.9, 5.22/53.9, 2.48/25.7. GC-MS (m/z):
199 (M+ + 2, 1), 198 (M+ + 1, 14), 197 (M+, 100), 183 (11), 182 (M+
− 15, 94), 155 (11), 154 (84), 153 (14), 128 (10), 127 (40), 126 (15),
77 (13).
1
pale solid: mp 136−137 °C H NMR (400 MHz, CDCl3) δ 10.57 (s
br, 1H), 8.27 (d, J = 7.6 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.94 (dd, J
= 7.7, 0.8 Hz, 1H), 7.53−7.52 (m, 1H), 7.48−7.44 (m, 1H), 7.29−7.23
(m, 2H), 2.74 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 200.3 (C),
140.0 (C), 139.0 (C), 127.9 (CH), 126.5 (CH), 126.1 (CH), 124.9
(C), 122.0 (C), 120.3 (CH), 120.1 (CH), 119.3 (C), 118.2 (CH),
1
111.3 (CH), 26.7 (CH3). H−1H COSY NMR (400 MHz, CDCl3)
δH/δH 7.46/8.08, 7.46/7.52, 7.26/8.27, 7.26/8.08, 7.26/7.94, 7.26/
1
7.46. H−13C HSQC NMR (400 MHz, CDCl3) δH/δC 8.27/126.1,
Phenanthren-9-ol (8d). Compound 8d was obtained according to
the general procedure. The phenanthren-9-ol was purified by radial
thin-layer chromatography eluting with a petroleum ether/diethyl
ether gradient (80:20→50:50) and was isolated as a light-colored solid
8.08/120.3, 7.94/127.9, 7.52/111.3, 7.46/126.6, 7.27/120.1, 7.24/
1
118.2, 2.76/26.7. H−13C HMBC NMR (400 MHz, CDCl3) δH/δC
8.27/139.0, 8.27/127.9, 8.27/122.0, 8.08/140.0, 8.08/126.1, 7.94/
200.3, 7.94/139.0, 7.94/126.1, 7.52, 7.52, 7.46/139.0, 7.46/126.1,
7.26/127.9, 7.26/124.9, 7.26/122.0, 7.26/119.3, 7.26/111.3, 2.74/
200.3, 2.74/127.9, 2.74/119.3. GC-MS (m/z): 211 (M+ + 2, 1), 210
(M+ + 1, 16), 209 (M+, 100), 195 (13), 194 (97), 166 (58), 140 (13),
139 (34), 83 (12), 69 (11).
1
(CAS 484−17−3). H NMR (400 MHz, CDCl3) δ 8.71−8.62 (m,
1H), 8.63−8.55 (m, 1H), 8.32−8.30 (m, 1H), 7.73−7.67 (m, 2H),
7.64 (ddd, J = 8.0, 7.0, 1.3 Hz, 1H), 7.57−7.45 (m, 2H), 7.01 (s, 1H),
5.43 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 149.5 (C), 132.7 (C),
131.5 (C), 127.2 (CH), 126.9 (CH), 126.7 (CH), 126.4 (CH), 125.5
(C), 124.3 (CH), 122.7 (CH), 122.6 (CH), 122.3 (CH), 106.1 (CH).
1H−1H COSY NMR (CDCl3) δH/δH 7.70/8.67, 7.64/8.31, 7.51/7.70,
1-(2-Methyl-1,3-dioxolan-2-yl)-9H-carbazole (8h). The product
was purified by radial thin-layer chromatography on silica gel eluting
with petroleum ether/diethyl ether (90:10). White solid was isolated
1
7.51/8.59. H−13C HSQC NMR (CDCl3) δH/δC 8.67/122.7, 8.59/
1
in 93% yield (0.035 g, 0.14 mmol), mp 223−225 °C. H NMR (400
122.6, 8.31/122.3, 7.70/127.2, 7.70/126.7, 7.64/126.4, 7.51/126.9,
1
7.51/124.3, 7.01/106.1. H−13C HMBC NMR (CDCl3) δH/δC 8.67/
MHz, DMSO-d6) δ 10.79 (s, 1H), 8.07 (t, J = 8.2 Hz, 2H), 7.65 (d, J =
8.1 Hz, 1H), 7.45−7.35 (m, 2H), 7.14 (t, J = 7.6 Hz, 2H), 4.13−4.04
(m, 2H), 3.78−3.70 (m, 2H), 1.76 (s, 3H). 13C NMR (101 MHz,
DMSO-d6) δ 140.0 (C), 135.7 (C), 125.5 (C), 125.4 (CH), 123.4 (C),
122.1 (CH), 121.9, 119.9 (CH), 119.8 (CH), 118.5 (CH), 118.2
(CH), 111.7 (CH), 108.2 (C), 64.1 (CH2), 26.1 (CH3). 1H−1H
COSY NMR (DMSO-d6) δH/δH 7.38/8.07, 7.38/7.65, 7.14/8.07,
126.4, 8.60/132.7, 8.60/126.9, 8.31/149.5, 8.31/131.5, 8.31/127.2,
7.70/131.5, 7.70/126.7, 7.70/124.3, 7.70/122.3, 7.70/106.1, 7.64/
122.7, 7.64/125.5, 7.51/132.7, 7.51/126.7, 7.51/122.6, 7.01/149.5,
7.01/126.7. GC-MS (m/z): 195 (M+ + 1, 8), 194 (M+, 71), 166 (49),
165 (100), 164 (13), 163 (28), 139 (10), 83 (28), 82 (33), 63 (12).
Dibenzo[b,f ]oxepin-10(11H)-one (8e).1b,e,f,2a The oxepinone 8e
was purified by column chromatography on silica gel eluting with
petroleum ether/diethyl ether (90:10) as a white solid: mp 51−53 °C
(lit.1e 48−50 °C). 1H NMR (400 MHz, CDCl3) δ 8.06 (dd, J = 7.9, 1.8
Hz, 1H), 7.54 (ddd, J = 8.3, 7.2, 1.8 Hz, 1H), 7.38 (dd, J = 8.2, 0.9 Hz,
1H), 7.32−7.23 (m, 3H), 7.21−7.17 (m, 2H), 4.10 (s, 2H). 13C NMR
(101 MHz, CDCl3) δ 190.4 (C), 160.2 (C), 156.9 (C), 134.9 (CH),
130.5 (CH), 129.7 (CH), 128.5 (CH), 126.4 (C), 126.3 (CH), 126.2
(C), 123.8 (CH), 121.5 (CH), 120.4 (CH), 48.2 (CH2). 1H−1H
1
7.14/7.38, 3.74/4.08. H−13C HSQC NMR (DMSO-d6) δH/δC 8.07/
119.9, 8.07/119.8, 7.64/111.7, 7.38/125.4, 7.38/122.1, 7.14/118.5,
1
7.14/118.2, 4.08/64.1, 3.74/64.1, 1.76/26.1. H−13C HMBC NMR
(DMSO-d6) δH/δC 8.07/140.0, 8.07/135.7, 8.07/125.5, 8.07/122.1,
7.64/121.9, 7.64/118.5, 7.38/140.0, 7.38/135.7, 7.38/119.9, 7.38/
108.2, 7.14/125.4, 7.14/123.4, 7.14/122.1, 7.14/111.7, 4.08/108.2,
4.08/64.1, 3.74/108.2, 3.74/64.1, 1.76/125.4, 1.76/108.2. GC-MS (m/
z): 254 (M+ + 1, 8), 253 (M+, 47), 238 (M+ − 15, 100), 209 (21), 194
469
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Article
(72), 166 (29), 139 (15), 97 (14), 83 (14). HRMS calcd for
C16H16NO2 254.1176; found [MH]+ 254.1200.
(24). HRMS calcd for C16H15NNaO 260.1051; found [MNa]+
260.1074.
5-Methyl-5H-dibenzo[b,f ]azepin-10(11H)-one (8i).1b,f,2 Com-
pound 8i was obtained according to the general procedure. The
azepinone was purified by radial thin-layer chromatography on silica
gel eluting with petroleum ether/diethyl ether (90:10) as light yellow
crystals, mp 106.5−107.5 °C (lit.1b 102−103 °C). 1H NMR (400
MHz, CDCl3) δ 8.16 (dd, J = 7.9, 1.8 Hz, 1H), 7.51 (ddd, J = 8.7, 7.1,
1.8 Hz, 1H), 7.32−7.30 (m, 1H), 7.25−7.14 (m, 4H), 7.00−6.96 (m,
1H), 3.91 (s, 2H), 3.60 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
190.3, 149.6 (C), 148.1 (C), 133.9 (CH), 131.2 (CH), 129.2 (C),
128.6 (CH), 127.2 (CH), 125.6 (CH), 125.4 (C), 120.4 (CH), 119.7
5-Methyl-6,7-dihydro-5H-dibenzo[b,f ]azonin-13(12H)-one (8l).
Compound 8l was obtained according to the general procedure and
was purified by radial thin-layer chromatography eluting with
petroleum ether/dichloromethane (50/50) and was isolated as a
white solid, mp 121.5−123.0 °C. 1H NMR (400 MHz, CDCl3) δ 7.60
(dd, J = 7.7, 1.7 Hz, 1H), 7.46 (dd, J = 7.4, 0.8 Hz, 1H), 7.38 (ddd, J =
8.8, 7.2, 1.8 Hz, 1H), 7.27 (dt, J = 7.4, 1.9 Hz, 1H), 7.17 (td, J = 7.4,
1.3 Hz, 1H), 7.09 (d, J = 6.9 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.92−
6.88 (m, 1H), 4.24 (s, 2H), 3.25−3.22 (s, 2H), 3.17−3.12 (m, 2H),
2.95 (s, 3H).13C NMR (101 MHz, CDCl3) δ 201.7 (C), 151.9 (C),
140.0 (C), 134.5 (C), 132.8 (CH), 132.6 (CH), 131.1 (CH), 129.6
(CH), 128.8 (C), 126.8 (CH), 126.6 (CH), 119.4 (CH), 115.7 (CH),
1
(CH), 116.5 (CH), 49.1 (CH2), 40.3 (CH3). H−1H COSY NMR
(CDCl3) δH/δH 7.19/7.51, 6.98/8.16, 6.98/7.51. 1H−13C HSQC
NMR (400 MHz, CDCl3) δH/δC 8.15/131.2, 7.51/133.9, 7.31/128.6,
7.19/127.2, 7.19/125.6, 7.19/120.4, 7.19/116.5, 6.98/119.7, 3.91/49.1,
1
60.1 (CH2), 44.2 (CH2), 37.9 (CH2), 36.0 (CH3). H−1H COSY
NMR (CDCl3) δH/δH 7.38/7.62, 7.27/7.46, 7.17/7.46, 7.17/7.27,
7.08/7.17, 6.99/7.38, 6.90/7.60, 6.90/7.38, 6.90/7.08, 3.14/3.23.
1H−13C HSQC NMR (CDCl3) δH/δC 7.60/131.1, 7.46/132.8, 7.38/
132.6, 7.27/126.8, 7.17/126.6, 7.08/129.6, 6.99/115.7, 6.90/119.4,
4.24/44.2, 3.23/60.1, 3.23/37.9, 3.14/60.1, 3.14/37.9, 2.95/36.0.
1H−13C HMBC NMR (CDCl3) δH/δC 7.60/201.7, 7.60/151.9,
7.60/132.6, 7.46/140.0, 7.46/126.6, 7.46/44.2, 7.38/151.9, 7.38/
131.1, 7.27/134.5, 7.27/129.6, 7.17/140.0, 7.08/134.5, 7.08/37.9,
6.99/128.8, 6.99/119.4, 6.90/128.8, 6.90/115.7, 4.24/201.7, 4.24/
139.4, 4.24/134.5, 4.24/132.8, 3.23/37.9, 3.14/140.0, 3.14/134.5,
3.14/129.6, 3.14/60.1, 2.95/151.9, 2.95/115.7, 2.95/60.1. GC-MS (m/
z): 253 (M+ + 2, 1), 252 (M+ + 1, 17), 251 (M+, 100), 236 (12), 234
(13), 233 (11), 232 (13), 222 (12), 208 (14), 160 (14), 147 (51), 146
(44), 132 (12), 118 (11), 117 (14), 115 (15), 107 (10), 106 (13), 105
(27), 104 (39), 91 (47), 78 (16), 77 (27). HRMS calcd for
C17H17NNaO 274.1208; found [MNa]+ 274.1225.
1
3.60/40.3. H−13C HMBC NMR (400 MHz, CDCl3) δH/δC 8.16/
190.3, 8.16/149.6, 8.16/133.9, 7.51/149.6, 7.51/131.2, 7.19/190.3,
7.19/148.1, 7.19/128.6, 7.19/125.4, 7.19/119.7, 7.19/119.7, 6.98/
125.4, 6.98/116.5, 3.91/190.3, 3.91/, 3.91/148.1, 3.91/129.2, 3.91/
125.4, 3.60/149.6, 3.60/148.1, 3.60/116.5. GC-MS (m/z): 225 (M+ +
2, 1), 224 (M+ + 1, 14), 223 (M+, 100), 222 (9), 208 (31), 195 (11),
194 (53), 180 (22), 179 (13), 152 (14), 77 (10).
4-Acetylphenanthridine (8j). Compound 8j was obtained accord-
ing to the general procedure. The phenanthridine was purified by
radial thin-layer chromatography eluting with a petroleum ether/ethyl
acetate gradient (95:5→80:20) and was isolated as a light-colored
solid, mp 93.7−95.5 °C. 1H NMR (400 MHz, CDCl3) δ 9.32 (s, 1H),
8.69 (dd, J = 8.2, 1.1 Hz, 1H), 8.62 (d, J = 8.3 Hz, 1H), 8.08 (d, J = 7.9
Hz, 1H), 7.92−7.86 (m, 2H), 7.78−7.74 (m, 1H), 7.73−7.69 (m, 1H),
2.95 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 204.9 (C), 153.4 (CH),
141.7 (C), 140.9 (C), 132.2 (C), 131.3 (CH), 128.8 (CH), 127.9
(CH), 127.6 (CH), 126.6 (CH), 126.1 (C), 125.0 (CH), 124.2 (C),
122.0 (CH), 32.9 (CH3). 1H−1H COSY NMR (CDCl3) δH/δH 8.61/
ASSOCIATED CONTENT
■
1
9.32, 7.89/8.62, 7.76/8.08, 7.76/7.89, 7.71/8.69, 7.71/7.89. H−13C
S
* Supporting Information
1H NMR, 13C NMR and 2D NMR experiment. This material is
available free of charge via the Internet at http://pubs.acs.org.
HSQC NMR (CDCl3) δH/δC 9.32/153.4, 8.69/125.0, 8.62/122.0,
8.09/128.8, 7.89/131.3, 7.89/127.6, 7.76/127.9, 7.71/126.6, 2.95/32.9.
1H−13C HMBC NMR (CDCl3) δH/δC 9.32/141.7, 9.32/132.2, 9.32/
128.8, 9.32/126.1, 8.69/141.7, 8.69/132.2, 8.69/127.6, 8.62/127.9,
8.62/126.1, 8.62/124.2, 8.08/153.4, 8.08/131.3, 7.89/204.9, 7.89/
141.7, 7.89/132.27,.89/128.8, 7.89/125.0, 7.76/126.1, 7.76/122.0,
7.71/140.9, 7.71/122.0, 2.95/204.9. GC-MS (m/z): 223 (M+ + 2,
16), 222 (M+ + 1, 14), 221 (M+,100), 220 (18), 207 (23), 206 (7),
204 (75), 194 (20), 193 (16), 180 (10), 179 (39), 178 (79), 177 (24),
152 (25), 151 (53), 150 (28), 103 (12), 89 (14), 76 (19), 75 (16).
HRMS calcd for C15H12NO 222.0913; found [MH]+ 222.0921.
5-Methyl-5,6-dihydrodibenzo[b,f ]azocin-12(11H)-one (8k).
Compound 8k was purified by radial thin-layer chromatography
eluting with a petroleum ether/diethyl ether gradient (90/10: 70/30)
and 0.034 g (78%, 0.14 mmol) was isolated as a yellow pale solid, mp
108−109 °C. 1H NMR (400 MHz, CDCl3) δ 7.61 (dd, J = 7.6, 1.3 Hz,
1H), 7.44−7.40 (m, 1H), 7.30−7.21 (m, 4H), 7.12−7.10 (m, 1H),
7.04 (d, J = 8.2 Hz, 1H), 6.93−6.89 (m, 1H), 4.20 (s, 2H), 4.07 (s,
2H), 3.00 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 201.7 (C), 152.8
(C), 135.6 (C), 135.1 (C), 132.5 (CH), 131.0 (C), 130.7 (CH), 129.3
(CH), 128.6 (CH), 128.2 (CH), 127.0 (CH), 118.8 (CH), 115.0
AUTHOR INFORMATION
■
Corresponding Author
*rossi@fcq.unc.edu.ar
ACKNOWLEDGMENTS
■
This work was supported in part by the Agencia Cor
Ciencia, the Consejo Nacional de Investigaciones Cientificas y
́
doba
́
Tec
́
nicas (CONICET), SECYT, Universidad Nacional de
doba, and FONCYT, Argentina. J.F.G. gratefully acknowl-
Cor
́
edges the receipt of a fellowship from CONICET.
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