An expedient route to heterocycles through α-arylation of ketones and arylamides by microwave induced thermal SRN1 reactions

Article abstract of DOI:10.1039/c4ra00120f

Microwave irradiation promotes a quick aromatic nucleophilic substitution by a thermally induced electron transfer process to form new C-C bonds by the coupling of aryl radicals and enolate nucleophiles. Diverse 2-aryl-1- phenylethanones can be prepared by the direct α-arylation of acetophenone with different haloarenes. The ketone enolate anion is generated by deprotonation with tBuOK in DMSO and the reaction is carried out in a closed microwave vessel at 70-100°C for 10 min. This simple procedure also allows the synthesis of deoxybenzoin and indole heterocycle derivatives by inter- or intra-molecular ring closure reactions, with moderate to excellent substitution yields. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra00120f

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An expedient route to heterocycles through
a-arylation of ketones and arylamides by
microwave induced thermal SRN1 reactions†
Cite this: RSC Adv., 2014, 4, 17490
*
Silvia M. Soria-Castro, Daniel A. Caminos and Alicia B. Penenory
˜´˜
Microwave irradiation promotes a quick aromatic nucleophilic substitution by a thermally induced electron
transfer process to form new C–C bonds by the coupling of aryl radicals and enolate nucleophiles. Diverse
2-aryl-1-phenylethanones can be prepared by the direct a-arylation of acetophenone with different
haloarenes. The ketone enolate anion is generated by deprotonation with tBuOK in DMSO and the
reaction is carried out in a closed microwave vessel at 70–100 ꢀC for 10 min. This simple procedure also
allows the synthesis of deoxybenzoin and indole heterocycle derivatives by inter- or intra-molecular ring
closure reactions, with moderate to excellent substitution yields.
Received 6th January 2014
Accepted 25th March 2014
DOI: 10.1039/c4ra00120f
www.rsc.org/advances
good yield; yet, two or more hours of photochemical induction
or the use of chemical radical initiators are required.
Introduction
The selection of liquid ammonia as solvent requires distil-
lation prior to use, which is energy costly and entails a partic-
ular careful manipulation.8 The development of new synthetic
procedures, which implies simple and safer reaction condi-
tions, is always a challenge for organic chemists. Alternatively,
there are some examples of thermally induced SRN1 a-arylation
of different aliphatic ketone enolate anions with ArI heating at
25 ꢀC for 60 min in DMSO with moderate to good yield.9
Nevertheless, under these conditions the enolate anions from
aromatic ketones did not react.9 In addition, thermal or spon-
taneous initiated reactions need about 60 min to proceed at
room temperature. We consider that this synthetic pathway
could be improved by microwave irradiation and be applied to
heterocycles synthesis.
Radical reactions provide a powerful method to achieve new
C–C bonds in organic synthesis.1 The process that involves an
electron-transfer (ET) step to generate radical anions and
radicals, as the unimolecular radical nucleophilic substitution
or SRN1, has proven to be a versatile mechanism for replacing a
suitable leaving group by a nucleophile at the ipso position.2
This reaction affords substitution in non-activated aromatic
(ArX) compounds, with an extensive variety of nucleophiles
derived from carbon, nitrogen and oxygen to form new C–C
bonds. In addition, the SRN1 mechanism is an important route
for the synthesis of carbocycles and heterocycles by ring-
closure reactions, such as indol derivatives with interesting
pharmacological properties, and for a signicant number of
natural products.2 On the other hand, 2-phenyl acetophe-
nones, also known as deoxybenzoin, is a motif present in anti-
inammatory,3 anti-convulsant, analgesic,4 and antimicrobial
drugs.5 These aryl acetophenone structures are also suitable
precursors of other interesting compounds, such as oxazoles,
pyrazoles, indoles, and re retardants in polymeric matrixes.4,6
This deoxybenzoin (3, R ¼ Ph) and its derivatives can be easily
achieved by a-arylation of carbonyl compounds by the SRN1
reaction. For example, the reactions of non-activated haloar-
enes with enolate anions from both aliphatic and aromatic
ketones afford substitution under photo-stimulation in DMSO
or liquid ammonia as solvent (Scheme 1).7 These reactions had
In the last decade microwave-assisted organic synthesis
(MAOS) has proved an attractive heating method since this
system reduces reaction time, increases yields, and in some
cases increases selectivity in comparison with traditional oil
bath heating.10 There are a few cases of thermally induced SRN
1
reactions by microwave irradiation for the substitution of acti-
vated nitro benzyl derivatives. Thus, Vanelle et al. have reported
that SRN1 reaction of p-nitrobenzyl chloride with 2-nitropropane
anion under microwave irradiation with a domestic microwave
oven affords very good coupling yields.11
´
´
´
INFIQC, Dpto. de Quımica Organica, Facultad de Ciencias Quımicas, Universidad
´
´
Nacional de Cordoba, Ciudad Universitaria, X5000HUA Cordoba, Argentina. E-mail:
penenory@fcq.unc.edu.ar; Web: http://www.inqc.fcq.edu.ar
† Electronic supplementary information (ESI) available: Typical reaction prole
under microwave irradiation and spectra (1H and 13C NMR) for products 6 and
7. See DOI: 10.1039/c4ra00120f
Scheme 1 Photostimulated SRN1 a-arylation of ketone enolate anions.
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This early use of a domestic microwave oven did not allow an
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Table 1 Temperature effect on microwave-induced a-arylation of
acetophenone with phenyl halides in DMSOa
accurate control of temperature, pressure and power applied to
the sample. Today, strict reaction conditions could be set and
controlled by specic laboratory microwave devices. In conse-
quence the experiment conditions can be easily reproduced.
Recently, Vanelle et al. reported the C-alkylation of 2-nitro-
propane anion with 4-[4-(chloromethyl)phenyl]-1,2-dimethyl-5-
nitro-1H-imidazole at 140 ꢀC (DMF) or 170 ꢀC (DMSO) for 30
min in 25 mL using an accurate multimode microwave reactor
with 200 W of applied power, with 60% yield12 (Scheme 2).
In this work, we revisited the thermal initiated-SRN1 reac-
tions of ArX with enolate nucleophiles, using for rst time a
controlled microwave heating to promote the reaction. Here we
present a new method to produce the a-arylation of arylketones
and aryl acetamides induced by thermal initiation under
microwave irradiation. This methodology has also been
successfully applied to the one-pot synthesis of heterocycles.
Entry
X
Time (min)
Temp. (ꢀC)
Product 3ab (%)
Xꢁc (%)
1d
2
3
4
5
6
7
8
I
I
I
I
I
I
I
I
60
10
10
10
10
5
30
10
10
10
10
10
10
10
25
40
50
60
70
70
70
100
70
70
70
70
70
70
<1
Trace
34
<1
n.q.
n.q.
n.q.
78
70
72
45e
55e
49e
54e
58e
7
92
9f
10g
11
12
13
14
I
I
<10
<10
0
21
80
8
—
Ih
Ii
Ij
Br
14
Results and discussion
Microwave-induced reactions
k
—
Trace
4
a
Reactions heated by microwave irradiation (150 Wmax) under N2
atmosphere for 10 min. Acetophenone (1.5 mmol), tBuOK (1.55
mmol), and PhI (0.5 mmol) in 2 mL of DMSO, otherwise indicated.
The reaction between PhI (1) and the enolate anion of aceto-
phenone (2a) was taken as a model to explore the effectiveness
of microwave irradiation as heating method for thermal initia-
tion, as a simple alternative to photo-induction in liquid
ammonia or DMSO. Table 1 shows the results yielded.
b
c
Quantied by NMR with internal standard.
Determined
potentiometrically using a Ag/Ag(I) electrode. n.q.: no quantied.
d
e
Thermostatized in water bath, from ref. 9. Traces (<4%) of di-
f
g
arylation product 4a were observed. DMF as solvent. MeCN
as solvent. Without acetophenone enolate. With 10 mol% m-
dinitrobenzene. With tBuOK as nucleophile and base. PhOC(CH3)3
was quantied by NMR in 4% yield.
ꢀ
h
i
When a mixture of 1 and anion 2a was stirred at 25 C for
j
k
60 min in DMSO, the detection of only a trace of a-arylation
product 3a by GLC was reported (Table 1, entry 1).9 In view of
this preliminary result we rst tested the reaction between PhI
with acetophenone enolate anion by heating under microwave
irradiation for 10 min at different temperatures. No reaction at
the yield of substitution product 3a; however, an increase in the
reduction product was shown through the higher iodide ion
yield (Table 1, entries 7 and 8). The 1,2-diphenylethanone 3a
was stable under the reaction conditions. Aer GC-MS analysis
it did not show any by-product produced by thermal decom-
position at 70–80 ꢀC, under microwave heating for 10 min; it
was recovered in 84% isolated yield. All attempts to detect the
reduced product benzene were unsuccessful.13 Another solvents
such as DMF or MeCN were also tried without success (Table 1,
entries 9 and 10). In addition, the main reaction by-product was
the auto-condensation of acetophenone present in excess in the
basic reaction media.
ꢀ
40 C under microwave irradiation was observed; however, by
increasing the temperature to 50–60 ꢀC, the substitution
product 3a occurred in moderate yields and only traces (<4%) of
di-arylation product 4a were observed (Table 1, entries 2–4).
Following this examination, the best result in this system
was obtained at 70 ꢀC in DMSO, irradiated with microwave;
substitution product 1,2-diphenylethanone 3a was quantied in
55% yield in just 10 min, with a conversion of 78% determined
by iodide ion quantication (Table 1, entry 5). A similar result
was found at 5 min; yet the GC-MS analysis showed presence of
unreacted PhI (Table 1, entry 6). Increasing time to 30 min, or
raising temperature to 100 ꢀC did not show a substantial rise in
Comparison between microwave and oil bath heating
The same model reaction was tested using a sealed microwave
tube on a pre-heated (to accurate temperature) oil bath, and
ꢀ
aer 10 min at 70 C only 10% yield of product 3a was quanti-
ed by GC-MS. In addition, product 3a was obtained in 17%
ꢀ
yield aer 60 min at 70 C. When the reaction was performed
under microwave irradiation in an open vessel (at atmospheric
pressure), a comparable yield of 3a and unreacted PhI were
found in relation to those observed in Table 1, entry 5. Under
microwave irradiation it is possible that signicant and local-
ized overheating is produced in the solution since DMSO is a
Scheme 2 Fast thermal long distance SRN1 reaction of 4-[4-(chlor-
omethyl)-phenyl]-1, 2-dimethyl-5-nitro-1H-imidazole with 2-nitro-
propane anion.
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strongly microwave absorbing solvent. This overheated spots, conversion yields (Table 1, entry 12). These assays suggest that
will help to accelerate reaction rate in relation to conventional the reaction proceeds through an SRN1 mechanism thermally
heating.14 In addition, the pressure conditions of 1.7 atm did initiated17 with radicals and radical anions as intermediates. In
not seem to be required; however, microwave irradiation was this reaction, the source of initiating electrons could be the
needed to accelerate the reaction. This reaction effectively nucleophile itself, which transfers an electron to the PhI to
proceeds faster under microwave irradiation in an open or generate Ph radical and Iꢁ by a dissociative ET.17,18 In this case,
closed vessel; for security issues, however, the latter was adop- the increase in temperature or the direct microwave energy
ted as a standard methodology. Further research into these applied to the substrate could provide the necessary energy to
microwave induced thermal ET reactions is currently in prog- the initial ET from the nucleophile to the ArX. Alternatively, the
ress in our lab.
slightly excess of tBuOꢁ anion could also act as the electron
donor in an entrainment reaction.19 This later statement was
conrmed by the reaction between PhI and tBuOK in the
absence of acetophenone, which gave 80% of Iꢁ anions aer 10
min of microwave irradiation (Table 1, entry 13). As in the above
reactions, benzene could not be detected aer microwave irra-
diation. In addition only a low amount of the substitution
product with the tBuOꢁ anion was observed (4%), according to
the low reactivity of the alkoxide anions toward aryl radicals
attributed to their very positive oxidation standard potentials,
being hard nucleophiles.2,20
Reaction mechanism
To evaluate the mechanism involved in this reaction, some
experiments were performed. First we checked the presence of
radical intermediates in the reaction by using 1-(allyloxy)-2-
iodobenzene (5) as radical clock (Scheme 3).15 To reduce the
base promoted isomerization of the double bond in 5, the
reaction was conducted at 60 C.16 Thus, the reaction of 5 with
the enolate anion of acetophenone in a ratio 1 : 3, aer 10
ꢀ
ꢀ
minutes under microwave irradiation at 60 C, gave 29% and
Additionally, PhBr was unreactive toward the anion of ace-
tophenone aer 10 min of microwave irradiation at 70 ꢀC, with
low conversion (<5%) and traces of the substitution product 3a
(Table 1, entries 14). Similar results were observed at 100 or
16% of the cyclized (6) and straightforward (7) substitution
products, respectively. This result clearly indicates that aryl
radicals are reactive intermediates in the microwave reaction.15
Formation of product 6 must involve the intermediacy of the
2-(allyloxy)phenyl radical and its 5-exo ring closure followed by
addition to the enolate anion 2a. On the other hand, direct
coupling between the 2-(allyloxy)phenyl radical and the anion
2a followed by ET and isomerization of the double bond affords
product 7. Isomerization of 5 prior to ET step would also
account for the formation of product 7, but would not allow
5-exo cyclization to yield derivative 6 aer coupling with the
nucleophile. In fact, when the reaction between 5 and anion 2a
was performed at 80 ꢀC, the only product obtained was 7 in 45%
yield. Moreover, PhI showed to be thermally stable under the
reaction conditions. Aer 10 min of microwave irradiation of PhI
in DMSO, either benzene or iodide ion was not detected, (Table
1, entry 11). This fact allows discarding a homolytic rupture of
the CAr–I bond as the radical initiation process. Furthermore,
when the reaction between PhI and the enolate anion of
acetophenone was conducted in the presence of 10 mol% of
m-dinitrobenzene, which is a strong electron acceptor inhibit-
ing the ET step,2 a 14% yield of product was obtained with 21%
ꢀ
140 C.
Furthermore, the reactivity of dihalobenzenes toward the
anion of acetophenone was studied under microwave induc-
tion and the results compared with the photoinduced reac-
tions in order to get further insights into the mechanism. The
microwave-irradiated reactions of ortho-haloiodobenzenes
(8a and b; X ¼ I, Br) with anion 2a gave mono-substitution
with retention of halide (9a and b) and mono-substitution
with reduction of the second halide (3a), the later only
observed for X ¼ I (Scheme 4). The reaction of the para-diio-
dobenzene (8c) with anion 2a afforded both the p-iodo
substituted derivative (9c) and the mono-substituted reduced
product 3a with only trace of the p-disubstituted derivative
observed by GC-MS. Similar results were previously obtained
in the photoinduced reactions of 8a and b with anion 2a.21
The agreement between the reactions performed under
photochemical and microwave irradiation strongly supports
that both reactions proceed by the same SRN1 mechanism as
follows. Aer the initial ET, the radical anion of the substrate
(8a and bcꢁ) fragments into iodide anion and radical 10a
and b. The radical anions 9a and bcꢁ formed by the
coupling of radical 10a and b with anion 2a can afford the
Scheme 4 Microwave-induced reaction of acetophenone anion (2a)
with ortho-haloiodobenzene (8a and b) and para-diiodobenzene (8c)
in DMSO.
Scheme 3 1-(Allyloxy)-2-iodobenzene as radical clock.
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Table 2 Microwave-induced substitution reactions of ArX by the
mono-substituted products 9a and b aer inter-ET to the
substrate (Scheme 5, pathway a) or can fragment at the C–
halogen bond to give radical 11 (Scheme 5, pathway b). The
unpaired spin distribution in the most stable radical anion
intermediate (9a and bcꢁ) is localized in the benzoyl moiety
(p-system), which is separated from the ortho-halophenyl
moiety by a sp3 carbon atom; the intra-ET is favored only when
X ¼ I to afford radical 11 aer C–X fragmentation.
enolate anion of acetophenone in DMSOa
Entry
1
ArX
Product 3
% Yieldb
55 (53)c
Finally, disubstitution was not observed, even with the ortho-
diiodobenzene (8a). This can be attributed to the low excess of
the acetophenone anion present in the reaction media, since
di-substitution was previously observed for the ketone enolate
anion under photostimulation in liquid ammonia.22 An unfa-
vorable coupling reaction due to steric constraints can also be
responsible. On the other hand, trace of disubstitution was
detected by GC-MS for the reaction of para-diiodobenzene (8c)
in the presence of 3 equivalents of anion 2a, under both
microwave and photo-induced reactions.
2
3
4
5
46
54
57
19
Scope of the microwave induced a-arylation reaction
We subsequently studied the reactivity of different aryl halides
to determine the scope of the microwave a-arylation reaction;
results are found in Table 2. In general, the reaction of aryl
iodides bearing electron-donor and -acceptor substituent gave
the substitution product in moderate to good yields (46–57%,
Table 2, entries 1–4). Using 4-iodobenzonitrile, anion 2a was
mono-arylated in 46% yield. The a-arylation of 4-iodobenzoni-
trile has not been previously reported under photoinduced SRN1
conditions.2 Furthermore, attempts to a-arylation of anion 2a by
Pd-catalysis failed; instead of the desired product, b-enami-
nones were obtained by condensation of the acetophenone with
the nitrile moiety of the substrate.23 On the other hand, it is
known that the fragmentation rates of the radical anions of
nitro-substituted aryl halides determined electrochemically24 or
by pulse radiolysis25 are slow and range from 10ꢁ3 to 102 sꢁ1. As
a consequence such substrates have not been suitable for
electrochemical or photoinduced SRN1 reactions.2 In this
context, it should be noted that under microwave irradiation
19% of the nitro derivate is obtained (Table 2, entry 5). Never-
theless, a classical aromatic nucleophilic substitution cannot be
disregarded. In addition, 1-iodonaphtalene, 1-bromonaphta-
lene, 2-bromonaphtalene and 2-iodopyridine, by reaction with
anion 2a gave substitution products in moderate yield (Table 2,
entries 6–9).
6
59
7
8
55
35
44
9
a
Reactions heated to 70 ꢀC by microwave irradiation (150 Wmax) under
N2 atmosphere for 10 min. Acetophenone (1.5 mmol), tBuOK (1.55
mmol), and ArX (0.5 mmol) in 2 mL of DMSO, otherwise indicated.
b
c
Quantied by NMR with internal standard. Isolated yield from a
preparative scale reaction: acetophenone (7.5 mmol), tBuOK (7.75
mmol), and PhI (2.5 mmol) in 10 mL of DMSO.
Besides, p-substituted acetophenone enolate anions (2j–m)
were also investigated as nucleophiles in the reaction with PhI
(Table 3). As expected for an ET-initiated reaction, the presence
of an electron donor group such as CH3 in anion 2j afforded
comparable yield of substitution product relative to anion 2a
(Table 3, entries 1 and 2). The amino group is also deprotonated
in the reaction media and the yield of a-arylation decreased
(Table 3, entry 3). On the other hand the presence of electron
withdrawing groups such as Cl and NO2 in the enolate anion
Scheme 5 Propagation steps for the SRN1 mechanism of the reaction
of acetophenone anion (2a) with ortho-haloiodobenzene (8a and b) in
DMSO.
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Table 3 Microwave-induced substitution reactions of PhI by ketone
enolate anions in DMSOa
Entry
1
Anion
Product
%Yieldb
55 (53)c
Scheme 6 “One-pot” synthesis of 2-phenylindole (15).
2
3
4
5
40
34
0
strongly inhibits or avoids ET pathways (Table 3, entries 4 and
5). The formation of 3a in the a-arylation of anion 2m supports
the participation of 3mcꢁ as intermediate (Table 3, entry 5).
In addition, we have performed some experiments using the
enolate anion of cyclohexanone as nucleophile under micro-
wave irradiation to compare with the thermal induced reaction
previously reported.9 To our surprise at 70 C only 10% of the
ꢀ
a-arylated product, 2-phenylcyclohexanone (12) was observed
and most IPh remained unreacted (Table 3, entry 6). The yield of
ꢀ
12 was not improved by increasing the temperature to 100 C,
except for the ketone condensation product. Further attempts
to reproduce the previous reported results9 were unsuccessful.
In our hands, IPh did not react with the enolate anion of
14d
10
ꢀ
cyclohexanone in DMSO aer 60 min heating at 25 C.
As it has been well established, the photoinduced SRN1
reaction provides a good alternative to the synthesis of hetero-
cycles.2 Therefore, two different approaches were explored to
achieve target compounds under microwave irradiation: (1)
6
a
Reactions heated to 70 ꢀC by microwave irradiation (150 Wmax) under
intramolecular SRN1 reaction and (2) intermolecular SRN
1
N2 atmosphere for 10 min. Ketone (1.5 mmol), tBuOK (1.55 mmol), and
PhI (0.5 mmol) in 2 mL of DMSO. Quantied by NMR with internal
standard. Isolated yield from a preparative scale reaction. Together
with 7% of 3a.
b
reaction, followed by a polar ring closure reaction. Initially, the
synthesis of indolinone derivatives was performed by intra-
molecular cyclization of N-(2-halophenyl)phenylacetamides (13)
under microwave irradiation (Table 4). Thus, the reaction of the
iodo derivative 13a in the presence of tBuOK gave 90% yield of
the cyclized compound 1-methyl-3-phenylindolin-2-one (14)
and 10% of the reduced product N-methyl-N,2-diphenylaceta-
mide at 70 ꢀC in DMSO (Table 4, entry 1). Quantitative yield was
achieved by increasing temperature to 100 ꢀC (Table 4, entry 2).
The bromo derivative 13b, afforded 80% of substitution at
100 ꢀC, while the chloro derivative 13c required increasing
temperature to 130 ꢀC to observe only 14% of product 14 (Table
4, entries 3–6). The reactivity order I > Br > Cl is according to the
reduction potential of the aryl halides and with the average
fragmentation rate constant for their radical anion intermedi-
ates.2 Finally, this methodology was extended to the “one-pot”
synthesis of indole derivatives (15) by two consecutives reac-
tions, an intermolecular nucleophilic substitution of ortho-iodo
aniline with the enolate anion 2a induced by microwave irra-
diation followed by a condensation. The best isolated yield
(49%) of indole 15 was obtained at 100 ꢀC (Scheme 6). This
result agrees with that found in the previous examples in Table
2, for intermolecular process.
c
d
Table 4 Synthesis of 1-methyl-3-phenylindolin-2-one (14) by intra-
molecular cyclization of N-(2-halophenyl)phenylacetamides by
microwave heating
Entry
Substrate 13
X
Temp. ꢀC
Product 14 yielda %
1
2
3
4
5
6
13a
13b
13c
I
70
100
70
100
100
130
90b
100
30
80
0
Br
Cl
Conclusions
14
a
b
The use of modern microwave heating devices proves valuable
in the ne chemist and pharmaceutical chemistry offering a
Quantied by GC by the internal standard method. Together with
10% N-methyl-N,2-diphenylacetamide.
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faster and safer synthetic methodology. In this report new C–C with a 5% phenylpolysiloxane phase column. HRMS spectra
bonds were obtained by a-arylation of aromatic ketones and were recorded on a GCT Premie orthogonal acceleration time-of-
acetamides by a thermally induced SRN1 reaction by microwave ight (oa-TOF) GC mass spectrometer. Ionization was
irradiation at moderate temperatures. This is the rst report of achieved by electronic impact (70 eV) and detection set up
microwave-induced SRN1 reaction in the aromatic system. The positive mode.
initiation step is proposed to take place by a microwave-induced
thermal ET.
Representative experimental procedure
By comparison with the photoinduced procedures, the main
disadvantage of the microwave-initiated reaction is the The reactions were carried out in a 10 mL CEM Discover
competitive reduction observed for intermolecular process, microwave glass vessel, lled with nitrogen and with a magnetic
consequently the best substitution yields is about 60%. On the stirrer. The tube was dried under vacuum, lled with nitrogen,
other hand, the microwave-induced reaction shows as many and then charged with dried DMSO (2 mL) and degassed. Next,
advantages as simplicity, short times (10 min of microwave for the a-arylation of the haloarene, tBuOK (179 mg, 1.55
irradiation compared with 120 min of photoirradiation), mmol), acetophenone (1.5 mmol), and aryl halide (0.5 mmol)
compatibility with substituents like NO2, CN, F, Br, and a better were added to the degassed solvent under nitrogen. For the
performance in intramolecular reactions.
intramolecular cyclization reaction halophenylacetamide (0.5
Thus, this process allows the synthesis of 2-aryl-1-phenyl- mmol) and tBuOK (112 mg, 1.0 mmol) were added to the
etanones (3a–k and 3m) by a-arylation of the enolate anion of degassed solvent under nitrogen. Then, the reaction tube was
acetophenones (2) with different haloarenes (1a–i). In addition, heated by microwave irradiation.
this methodology provides a simple way to achieve heterocycles
as 1-methyl-3-phenylindolin-2-one (14) and 2-phenylindol (15) mode instrument equipped with
by intra- or intermolecular SRN1 reactions, respectively, in a very temperature sensor, direct pressure control system for
Microwave-induced reactions were performed in a single
a
noncontact infrared
fast reaction.
measuring the pressure of the reaction vessel contents and a
cooling system by compressed air. The sample vessels reach the
selected temperature in about 30 s (ꢃ2.5 ꢀC sꢁ1). Although, the
maximum microwave power was set at 150 W, aer the initial
heating pulse of maximum 100 W for 30 s, the average applied
power was about 1 W to keep the selected temperature (see ESI†
for irradiation details). Aer 10 min of irradiation the device
cooled the tube to 50 ꢀC with compressed air above 1 min
Experimental section
Chemicals
Potassium tert-butoxide (tBuOK), iodobenzene, bromobenzene,
cyclohexanone, acetophenone, 1-p-tolylethanone, 1-(4-amino-
phenyl)ethanone, 1-(4-nitrophenyl)ethanone, 1-(4-chloroph-
enyl)ethanone, 1-iodonaphthalene, 1-bromonaphthalene, 2-
bromonaphtalene, 2-iodopyridine, 2-iodoaniline 1,2-diiodo-
benzene, 1,4-diiodobenzene, 1,2-bromo-iodobenzene, 1,4-u-
(ꢁ0.5 C sꢁ1).
ꢀ
The average pressure in the vessel was 1.7 atm during the
reaction time. Aer completion of the reaction, the vessel was
removed from the microwave cavity and opened to the atmo-
sphere. The reaction was subsequently quenched by addition of
water (30 mL) and NH4NO3 excess, and the mixture was
extracted with methylene chloride (3 ꢂ 20 mL). The combined
organic extract was dried over anhydrous CaCl2, and the prod-
ucts were quantied by GC or NMR by the internal standard
method or isolated by silica gel chromatography from the crude
product reaction mixture. Water layer was recovered to quantify
the halide ions by potentiometric titration with an AgNO3
standard solution.
oro-iodobenzene,
1,4-cyano-iodobenzene,
1,4-methoxy-
iodobenzene, and 1,4-iodo-nitrobenzene were all high purity
commercial samples used without further purication.
DMSO absolute grade was used without further purication
˚
and stored over molecular sieves (4 A). N-Methylanilides 13a–c
were synthesized by standard procedures from the reaction
between commercial 2-haloanilines and the corresponding acyl
chloride in CH2Cl2 in the presence of pyridine.26 N-(2-iodo-
phenyl)-N-methyl-2-phenylacetamide (13a),27 N-(2-bromophenyl)-
N-methyl-2-phenylacetamide (13b),28 and N-(2-chlorophenyl)-N-
methyl-2-phenylacetamide (13c)27 present spectral data in good
agreement with the literature.
Product isolation from a preparative scale reaction
The ketone enolate anion or the anion of N-methylanilides
was generated in situ by acid–base deprotonation using tBuOK.
This reaction was performed following the representative
experimental procedure using acetophenone (7.5 mmol),
tBuOK (7.75 mmol), and PhI (2.5 mmol) in 10 mL of DMSO.
Aer reaction and usual workup, the combined dried extract
General methods
1H and 13C NMR spectra were recorded at 400.16 and 100.62 was rst chromatographed on a silica gel short-column eluted
MHz respectively on a 400 spectrometer, and all spectra were rst with n-pentane and second with n-pentane : ethyl ether
reported in d (ppm) relative to Me4Si, with CDCl3 as solvent. Gas (90 : 10). Aer evaporation the oily residue was distilled in a
¨
chromatographic analyses were performed with a ame-ioniza- kugelrohr to separate the product 1,2-diphenylethanone (3a)
tion detector, on 30 m capillary column of a 0.32 mm ꢂ 0.25 mm from acetophenone. The substitution product 3a crystallizes
ꢀ
lm thickness, with a 5% phenylpolysiloxane phase. GC-MS at 0 C with a small amount of n-hexane: 260 mg (53%); mp
ꢀ
analyses were performed employing a 25 m ꢂ 0.2 mm ꢂ 0.33 mm 53–55 C.
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Argentina and SECyT-UNC. A.B.P. and D.A.C. are scientic
members from CONICET, S.S.C. gratefully acknowledges the
receipt of a fellowship from CONICET.
Products characterization
All the products present in Table 2 were obtained following the
general procedure, quantied by NMR or GC. Products 3a–k,
3m, 9a–c, 12, 14, and 15 are known compounds and present
spectral data as shown in the literature, in agreement with the
proposed structures. 1,2-Diphenylethanone (3a),29 4-(2-oxo-2-
phenylethyl)benzonitrile (3b),30 2-(4-methoxyphenyl)-1-phenyl-
ethanone (3c),31 2-(4-uorophenyl)-1-phenylethanone (3d),31
2-(4-nitrophenyl)-1-phenylethanone (3e),32 2-(naphthalen-1-yl)-
1-phenylethanone (3f),33 2-(naphthalen-2-yl)-1-phenylethanone
(3h),34 1-phenyl-2-(pyridin-2-yl)ethanone (3i),35 1-(4-methylph-
enyl)-2-phenylethanone (3j),36 1-(4-aminophenyl)-2-phenyletha-
none (3k),37 1-(4-chlorophenyl)-2-phenylethanone (3m),36 1-
(allyloxy)-2-iodobenzene (5),16 2-(2-iodophenyl)-1-phenyletha-
none (9a),21 2-(2-bromophenyl)-1-phenylethanone (9b),38 2-(4-
iodophenyl)-1-phenylethanone (9c),21 2-phenylcyclohexanone
(12),39 1-methyl-3-phenylindolin-2-one (14),28 and 2-phenyl-1H-
indole (15).32
Notes and references
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Following the general procedure, using tBuOK (179 mg, 0.75
mmol), acetophenone (0.75 mmol), and aryl halide 5 (0.25
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purication by radial chromatography (petroleum/ethyl ether,
8/2) provided 6 as light yellow crystals (18 mg, 29% yield).
1H NMR (400 MHz, CDCl3) d 7.94–7.92 (m, 2H), 7.57 (tt, 7.3,
1.3 Hz, 1H), 7.46 (tb, J ¼ 7.6 Hz, 2H), 7.21 (db, J ¼ 7.3 Hz, 1H),
7.14 (tb, J ¼ 7.7 Hz, 1H), 6.87 (td, J ¼ 7.4, 1 Hz, 1H), 6.81 (d, J ¼ 8
Hz, 1H), 4.66 (t, J ¼ 8.9 Hz, 1H), 4.28 (dd, J ¼ 8.9, 5.8 Hz, 1H),
3.61-3.54 (m, 1H), 3.11-2.95 (m, 2H), 2.24-2.16 (m, 1H), 2.11-2.02
(m, 1H). 13C NMR (101 MHz, CDCl3) d 199.5, 160.0, 136.8, 133.2,
130.1, 128.7, 128.4, 128.0, 124.5, 120.5, 109.7, 41.1, 35.3, 28.9.
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mmol), acetophenone (0.75 mmol), and aryl halide 5 (0.25
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1 Hz, 1H), 7.56 (tt, J ¼ 7, 1 Hz), 7.46 (tb, J ¼ 7.5 Hz, 1H), 7.27–
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a
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This work was supported by Consejo Nacional de Inves- 15 J. I. Bardagı, S. E. Vaillard and R. Rossi, Tetrahedron Lett.,
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Nacional de Promocion Cientıca y Tecnica (ANPCyT), Minis- 16 S. E. Vaillard, A. Postigo and R. A. Rossi, J. Org. Chem., 2002,
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17496 | RSC Adv., 2014, 4, 17490–17497
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RSC Adv., 2014, 4, 17490–17497 | 17497