Ultrasound-promoted intramolecular direct arylation in a capillary flow microreactor

Article abstract of DOI:10.1016/j.ultsonch.2011.07.008

An intramolecular direct arylation of various aryl bromides was performed using ultrasonic irradiation and a continuous flow capillary microreactor. The present procedure provided a higher functional group tolerance, ligand-free, milder reaction condition

Full text of DOI:10.1016/j.ultsonch.2011.07.008

Ultrasonics Sonochemistry 19 (2012) 250–256
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Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultsonch
Ultrasound-promoted intramolecular direct arylation in a capillary flow
microreactor
⇑
Lei Zhang, Mei Geng, Peng Teng, Dan Zhao, Xi Lu, Jian-Xin Li
State Key Lab of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An intramolecular direct arylation of various aryl bromides was performed using ultrasonic irradiation
and a continuous flow capillary microreactor. The present procedure provided a higher functional group
tolerance, ligand-free, milder reaction conditions and a shorter reaction time for the direct arylation com-
pared with the conventional methods. The ultrasonic irritation not only greatly promoted the conversion
and selectivity of the direct arylation, but also solved the clogging problem of the microreactor for solid-
forming reaction and made the reaction run smoothly.
Received 23 March 2011
Accepted 20 July 2011
Available online 26 July 2011
Keywords:
Direct arylation
Ultrasound irradiation
Microreactor
Ó 2011 Elsevier B.V. All rights reserved.
Palladium-catalyzed
Synthesis
1. Introduction
traditional stirred-batch reactors, such as increased surface-to-vol-
ume ratios, excellent mass- and heat-transfer capabilities, better
Biaryl structural motif is observed in a variety of compounds,
from natural bioactive products such as vancomycin and schizan-
drin [1,2] to some important synthetic compounds like BINOL
and BINAP [3,4]. An arsenal of well-know catalytic methods includ-
ing the Suzuki–Miyaura, Negishi and Stille couplings has been
developed to build aryl-aryl bonds [5], however, all these
important reactions require the preparation of pre-activated orga-
nometallic reagents such as boronic acids, organo-magnesium, -tin
or -zinc derivatives that always associated with additional reaction
steps, wastes, solvents, purifications and time. Direct arylation as a
greener and effective alternative to these commonly employed
cross-coupling reactions has attracted considerable interest in re-
cent years [6,7], in which the aryl–heteroaryl or aryl–aryl bonds
formation of heteroaromatic compounds and simple electron-rich
arenes such as pyrroles, indoles, thiophenes and phenols with aryl
halides has significantly been developed [6,8–10]. However, in
spite of their advantages, these reactions usually need complex
catalyst systems (complex ligands) and additives (e.g. silver salts),
or often suffer from drawbacks such as longer reaction times, high-
er temperatures (120–150 °C) that significantly limit their scope
and functional group tolerance [11–13]. So there is still a need
for general protocols on the construction of aryl–aryl bonds with
a high yield, excellent selectivity and high functional group toler-
ance under mild reaction conditions.
reaction yields and so on, all of which would be expected to
promote highly effective chemical reactions [14–16]. However,
one main drawback of microreactors is a clogging problem of the
small reactor channels when solid-forming reactions are per-
formed [17]. The easy solution to this problem is highly desirable.
It is well known that ultrasound irradiation has been recognized as
an efficient technique in organic synthesis to accelerate the reac-
tion, improve yield, shorten reaction time and increase selectivity
[18–20].
As part of our continuing work directed toward developing rea-
sonable reaction conditions for aryl–aryl bond formation that are
environmentally benign and efficient [21], a methodology study
on palladium-catalyzed intramolecular direct arylation reactions
using a continuous flow capillary microreactor under ultrasound
irradiation was performed. Herein, we report a ligand-free and effi-
cient procedure for the intramolecular direct arylation of aryl bro-
mides under ultrasonic irradiation and mild conditions in the
capillary microreactor. The current reactions possessed a broad
substrate scope and high functional group tolerance in good to
excellent yields. Furthermore, ultrasonic irradiation solved the
clogging problem in microreactor. The microreactor was assem-
bled simply from syringes, a conventional capillary, a mixing unit,
syringe pumps and a ultrasonic cleaner, all of which are cheap and
commercially available (Fig. 1).
Microreactor technology has received a great deal of attention
for years. It has been shown to afford numerous advantages over
2. Results and discussion
⇑
In order to obtain appropriate reaction conditions, an optimi-
zation of the reaction conditions was conducted using a batch
Corresponding author. Tel./fax: +86 25 83686419.
E-mail address: lijxnju@nju.edu.cn (J.-X. Li).
1350-4177/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.ultsonch.2011.07.008

L. Zhang et al. / Ultrasonics Sonochemistry 19 (2012) 250–256
251
Fig. 1. Microreactor system.
reactor. It is reported that N,N-dimethylacetamide (DMA) is supe-
rior to other solvents such as N,N-dimethylformamide (DMF), tol-
uene, dioxanes and acetonitrile for direct arylation reactions
[11,13,22], therefore, as an initial screen, reactions of 2-iodoben-
zyl phenyl ether (1) as a substrate with 5 mol% Pd(OAc)2 and two
equiv. of different bases were performed under nitrogen atmo-
sphere at 100 °C for 24 h (Table 1). In pure DMA and inorganic
base such as K2CO3, Cs2CO3 and KOAc, substrate 1 provided intra-
molecular coupling product 20a, however, both conversions and
selectivity (ratio of 20a versus deiodination product 20b) were
poor. While organic bases such as 4-dimethylamiopryidine
(DMAP) and 1,4-diazabicyclo[2.2.2]octane (DABCO) were ineffec-
tive. When a co-solvents (DMA:water) was employed for the
reactions, the conversion was greatly increased. For the bases,
K2CO3 and Cs2CO3 gave an improved conversion, while, NaOAc
gave an inferior result. Meaningfully, in the present of KOAc
and a 10:1 mixture of DMA and water, the conversion was in-
creased up to 90%, however, the reaction selectivity was almost
unchanged (Table 1, entry 1 vs. 6, 2 vs. 7, and 5 vs. 9). Fortu-
nately, with changing the substrate 1 to 2-bromobenzyl phenyl
ether (2), the selectivity was improved more than twice, from
14:1 to 32:1 (Table 1, entry 9 and 10), however, the conversion
became to be in a moderate level.
resulted in a lower conversion. It might be reasoned that by per-
forming the reaction in the presence of water, the solubility of
the inorganic components was increased, but too much water re-
duced the solubility of the organic components. The present 10:1
ratio might be the optimal point to balance the solubilities of both
organic and inorganic components. In all co-solvent reactions, 0.05
equiv. of tetrabutylammonium bromide (TBAB) was added in order
to prevent the generation of palladium black and make the cata-
lytic system more stable [23].
Based on the above findings, a continuous flow capillary mic-
roreactor was employed under the optimal conditions obtained
from the batch reaction. When taking 2-iodobenzyl phenyl ether
(1) to run the intramolecular direct coupling in the microreactor
at 90 °C, as time went by the precipitate formed during the reac-
tion was adsorbed on the wall of capillary and increasingly accu-
mulated, and finally the microreactor was clogged. Due to the
short reaction time caused by clogging issue (less than 2 h), the
reaction in the microreactor only gave a 8.7% conversion and the
selectivity was quite lower (7:1). As sonication enables the rapid
dispersion of solids and benefits reactions which are the effects
arise from cavitation [18,24], this gave us a clue to exposing the
capillary coil to ultrasound irradiation, and might solve clogging
problem of the microreactor. Fortunately, as ultrasound irradiation
was applied, the blockage in the microreactor was easily removed
and the coupling reaction smoothly proceeded. During our experi-
ments, this kind of effect of ultrasound was also reported by other
group for an amination reaction very recently [25]. Furthermore, as
expected, a more than 98% conversion (89.3% isolated yield) was
In order to optimize the ratio of DMA and water, the effects of
different ratios on the conversion and selectivity were investi-
gated. As show in Fig. 2, there was a narrow window around a
10:1 ratio of DMA and water in which the highest conversion
(90.1%) could be obtained, and any deviation from this ratio
Table 1
Optimization of reaction conditions in batch reactor.
.
Entry
Substrate
Base
Solvent
Conversion (%)a
20a:20ba
1
2
3
4
1
1
1
1
1
1
1
1
1
2
3
K2CO3
Cs2CO3
DMAP
DABCO
KOAc
K2CO3
Cs2CO3
NaOAc
KOAc
DMA
DMA
DMA
DMA
51.5
54.4
Trace
Trace
66.1
77.7
72.1
58.8
90.1
70.3
Trace
16:1
18:1
–
–
5
DMA
15:1
15:1
18:1
8:1
14:1
32:1
–
6b
7b
8b
9b
10b
11b
DMA/H2O (10:1)
DMA/H2O (10:1)
DMA/H2O (10:1)
DMA/H2O (10:1)
DMA/H2O (10:1)
DMA/H2O (10:1)
KOAc
KOAc
Reaction conditions: 2-halobenzyl phenyl ether (0.5 mmol), Pd(OAc)2 and base were dissolved in each solvent (5.0 mL) and heated to 100 °C under nitrogen atmosphere for
24 h.
a
Determined by 1H NMR.
b
5 mol% TBAB was added.

252
L. Zhang et al. / Ultrasonics Sonochemistry 19 (2012) 250–256
ether tether could be replaced by amine and amide, and afford
the same high yields (entry 14, 15). Poly fused N-heterocycles
could be prepared in moderate to good results (entry 11-13 and
17). Five membered O-heterocycles was also obtained in 97% yield
(entry 18). Moreover, a high regioselectivity was observed in cases
where direct arylation occurred at two chemically different arene
positions, in this case, arylation arose at the more sterically acces-
sible position (entry 2 and 4). With meta-nitro and -t-butyl substi-
tutes, only one product was observed from 1H NMR (entry 2 and 4).
It is noteworthy that the quinolone core was successfully embed-
ded in coupling product 38 (entry 17) and the current reaction pro-
vided a novel way to prepare the quinolone derivatives that
possess various bioactivities [26].
Fig. 2. Effects of the ratio of DMA to water on the conversion and selectivity.
Conventional intramolecular direct arylation usually needed a
higher temperature (above 120 oC), complex ligands, additives
(e.g. expensive silver salts or pivalic acid), inert atmosphere and
a long reaction time (more than 8 h) [11–13,22,27], these condi-
tions were greatly meliorated in the current reaction procedure.
obtained when 2-iodobenzyl phenyl ether 1 as starting material
run for 6 h at 90 °C (Table 2, entry 3), while batch reaction afforded
90% conversion for 24 h at 100 °C. However, the reaction selectivity
improved very little by comparison with that of batch reaction. It is
reported that for the intramolecular direct arylation, despite the
fact that aryl iodides provide greater reactivity in cross-coupling
reactions, aryl bromides afford better outcomes than aryl iodides
[17], thus, a bromide of the substrate (2) was employed for the
reaction to improve both conversion and selectivity. As expected,
compared with batch reaction, the selectivity and conversion im-
proved dramatically from 32:1 to 44:1 and 70% to 97%, respectively
(Table 1, entry 10 vs. Table 2, entry 6). While, batch reaction under
irradiation afforded 56% conversion and 32:1 selectivity. The re-
sults confirmed that a combination use of microreactor and ultra-
sound greatly benefited the reaction.
With this optimal reaction conditions, the scope of the current
procedure was examined. Taking the reaction superiority and
cheap price into account, aryl bromides were used as substrates.
The efficiency and functional tolerance of this procedure have been
fully demonstrated by synthesizing a number of functionalized
coupling products which bearing substitutes such as nitro, alde-
hyde, ketone, ester, phenyl, methyl, methoxy, as well as protecting
group tosyl and Bco. The results were outlined in Table 3. Interest-
ingly, the electronic nature of the substituents seemed to have lit-
tle effect on the product yields. Meaningfully, chloro substituents
remained intact under the reaction conditions, which provided a
useful handle for further cross-coupling reactions (entry 7). The
3. Conclusion
In conclusion, we have described a mild and efficient intramo-
lecular direct arylation of aryl bromides in a continuous flow cap-
illary microreactor with assistance of ultrasonic irradiation. The
intramolecular direct arylation was achieved with high selectivity,
ligand-free, low temperature, broad substrate scope and compati-
ble to complex chemical structures such as quinolone core. Fur-
thermore, ultrasound irradiation not only greatly improved the
reaction conversion and selectivity, but also solved the clogging
problem of microreactor for solid-forming reactions and made
the reaction run smoothly. Further research on aryl chloride intra-
molecilar coupling and other solid-forming reactions in the mic-
roreactor under ultrasound irradiation is underway in our lab.
4. Experimental
4.1. Reagents and apparatus
All reagents and solvents were used as supplied without further
purification. For the batch reaction, all the experiments were
conducted in a 10 mL round-bottomed flask with a magnetic stir-
rer. Syringe pump was TS2-60 supplied by Nanjing Xinzhonghui
Table 2
Optimization of reaction conditions in the microreactor under ultrasound irradiation.
.
Entry
X
RT
Conversion (%)
20a:20ba
1
2
3
4
5
6
X = I
X = I
X = I
X = Br
X = Br
X = Br
X = Cl
X = Br
X = Br
2
4
6
2
4
6
6
6
6
68.9
71.6
98.4 (89.3)
41.9
67.6
96.7 (92.1)
Trace
44.8
18:1
20:1
17:1
42:1
50:1
44:1
–
7
8b
9c
20:1
34:1
56.1
RT: reaction time (hour). Conversion was determined by 1H NMR and the isolated yield is shown in parentheses.
a
Determined by 1HNMR.
Batch reaction without ultrasound.
Ultrasound-assisted batch reaction.
b
c

L. Zhang et al. / Ultrasonics Sonochemistry 19 (2012) 250–256
253
Table 3
Biaryl formation in microreactor under ultrasound irradiation.
Entry
1
Substrate
RT
6
Product
Isolate yield
93.2
2
6
90.2
3
4
5
6
6
6
94.5
88.6
89.5
2
6
3
92.0
7
8
6
6
92.8
89.7
9
6
6
92.3
93.4
10
11
12
3
3
84.4
77.0
(continued on next page)

254
L. Zhang et al. / Ultrasonics Sonochemistry 19 (2012) 250–256
Table 3 (continued)
Entry
13
Substrate
RT
3
Product
Isolate yield
95.9
14
3
90.6
15
16
17
6
6
3
96.0
91.3
76.6
18
6
97.3
RT: Reaction time (hour).
Scientific Equipment Co., Ltd.; syringe was SGE supplied by Beijing
Huadr Science and Technology Co., Ltd.; capillary was purchased
from Yongnian Ruipu Chromatogram Equipment Co., Ltd.; 1H
NMR and 13C NMR were determined in CDCl3 on a Brucker 300
or 500 MHz spectrometer at room temperature, tetramethylsilane
(TMS) served as an internal standard. EI-MS was taken on a
QP2010 GC–MS instrument (Shimadzu, Japan), ESI-MS and high
resolution MS (HRMS) were carried out on a LTQ Orbitrap XL
(The Thermo Scientific, USA). Sonication was performed in Kun-
shan SB-3200DT ultrasonic cleaner with the frequency of 40 kHz
and an output power of 150 W.
ethyl acetate/hexanes mixtures. Products were characterized by
1H NMR and MS (EI or ESI).
4.3. Typical procedure for the synthesis of substrate 16 (Table 3, entry
13)
To a mixture of 2-halobenzoic acid (1 equiv.), DCC (1.2 equiv.),
DMAP (0.1 equiv.) and dichloromethane (0.25 M) was added a
solution of monomethylaniline (1.5 equiv.) in dichloromethane
(0.25 M) in ice-water bath. When reaction complete, the mixture
was filtered and washed with ether. Remove solvent under re-
duced pressure. The residues were then purified via silica gel col-
umn chromatography using ethyl acetate/hexanes mixtures to
give substrate 16. Products were characterized by 1H NMR and
EI-MS.
4.2. General procedure for the synthesis of substrates 1–14, 15, 17, and
19 (Table 3, entry1–8, 12, 14, 15, 16)
The appropriate phenol or heterocycle compounds or sulfamide
(1.2 equiv.), K2CO3 (or KOH for 12, 13, 14, and 15) (2 equiv.) and
DMF (or DMSO for 12, 13, 14, and 15) (0.5 M) were placed in a
round bottom flask equipped with a magnetic stir bar. Addition
of the appropriate 2-halobenzylbromide (or 4-nitroflorobenzene
for 19) (1 equiv.) was followed by heating (60 °C) of the reaction
overnight. The reaction was allowed to cool and was diluted with
water and extracted with Et2O. The combined organic phase was
washed by brine, dried over anhydrous Na2SO4, filtered and the
volatiles were evaporated under reduced pressure. The residues
were then purified via silica gel column chromatography using
4.4. General procedure for intramolecular direct arylation in the
microreactor with assistance of ultrasonic irradiation
A stock solution of the 2-halobenzyl phenyl ether (0.5 mmol)
and TBAB (0.05 equiv.) in DMA (2.5 mL) was prepared and taken
up in a SGE gas-tight syringe. A second stock solution containing
Pd(OAc)2 (5 mol%) and KOAc (2.0 equiv.) in H2O (0.45 mL) and
DMA (2.05 mL) was also prepared and taken up in a second SGE
gas-tight syringe. The syringes were placed on a TS2-60 syringe
pump which was set at different flow rates to meet different

L. Zhang et al. / Ultrasonics Sonochemistry 19 (2012) 250–256
255
reaction times (Reaction time was calculated according to the fol-
lowing equation: time (h) Â flow rate ( L/h) = volume of microre-
actor ( L)). The two reactant streams were mixed in a 1:1 ratio
through a micro static mixing Tee, and then delivered into a
500 cm capillary coil with an inner diameter of 530 m (Fig. 1).
The capillary coil was located in the maximum energy area in
the ultrasonic generator and heated to 90 °C. The output from
the reactor was quenched with Et2O/H2O immediately. The result-
ing mixture was extracted with Et2O or EtOAc (3 Â 8 mL) and the
combined organic phase was washed with brine, dried over anhy-
drous Na2SO4, and then the solvent was removed under reduced
pressure. The residues were then purified via silica gel column
chromatography using ethyl acetate/hexanes mixtures. Products
were characterized by NMR, MS and HRMS (EI or ESI).
4.5.2. Coupling products 22–39
l
The structures of known coupling products 23, 25, 27, 28, 32,
33, 35, 36 and 39 were elucidated by comparison the spectral data
with those reported in the literatures [11,13,27,30,31,33].
l
l
4.5.2.1. Compound 22. White solid; 1H NMR (300 MHz, CDCl3) d
7.70 (d, J = 7.6 Hz, 1H), 7.63 (dd, J = 7.7, 1.5 Hz, 1H), 7.38 (td,
J = 7.6, 1.5 Hz, 1H), 7.31–7.26 (m, 2H), 7.19 (d, J = 7.4 Hz, 1H),
7.02 (t, J = 7.7 Hz, 1H), 5.07 (s, 2H), 1.43 (s, 9H); 13C NMR
(75 MHz, CDCl3) d 153.61, 139.03, 131.80, 130.83, 128.35, 127.33,
126.71, 124.37, 123.96, 122.53, 121.68, 121.65, 67.60, 34.82,
29.80(3); EI-MS m/z (rel. int.,%): 238 (37), 223 (100), 195 (22),
165 (22); HRMS (ESI): calculated for C17H18O + H = 239.1436,
found: 239.1480.
4.5.2.2. Compound 24. Pale yellow solid; 1H NMR (300 MHz, CDCl3)
d 7.95 (dd, J = 7.8, 1.5 Hz, 1H), 7.81 (dd, J = 8.2, 1.5 Hz, 1H), 7.70 (d,
J = 7.4 Hz, 1H), 7.46–7.35 (m, 2H), 7.24–7.18 (m, 1H), 7.13 (t,
J = 8.0 Hz, 1H), 5.26 (s, 2H); 13C NMR (75 MHz, CDCl3) d 154.67,
146.11, 136.73, 135.13, 135.08, 134.29 (s), 133.09, 133.84,
131.90, 131.00, 128.58, 127.35, 83.61, 83.19, 82.76, 75.13; MS
4.5. Experimental data for compounds
4.5.1. Substrates 1–19
The structures of the known compounds 1–3, 5–7, 9, 10, 14–18
and 21 were identified by comparison the spectral data with those
reported in the literatures [11–13,28–33].
(ESI):
228.05
(M + H);
HRMS
(ESI):
calculated
for
C
13H9NO3 + H = 228.0661, found: 228.0648.
4.5.1.1. Compound 4. White solid; Yield: 88.1%; 1H NMR (300 MHz,
CDCl3) d 7.62–7.59 (m, 2H), 7.38 (m, 2H), 7.24–7.13 (m, 2H), 6.99–
6.88 (m, 2H), 5.20 (s, 2H), 1.44 (s, 9H); EI-MS m/z (rel. int.,%): 318
(12), 169 (100).
4.5.2.3. Compound 26. White solid; 1H NMR (300 MHz, CDCl3) d
7.95 (d, J = 2.2 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.68–7.57 (m, 2H),
7.49–7.29 (m, 6H), 7.19 (d, J = 7.0 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H),
5.17 (s, 2H); 13C NMR (75 MHz, CDCl3) d 154.30, 140.92, 135.30,
131.40, 129.98, 128.74, 128.45, 128.22, 127.77, 126.90, 126.84,
124.67, 123.04, 121.99, 117.66, 77.41, 76.99, 76.56, 68.52; EI-MS
m/z (rel. int.,%): 258 (100), 257 (85), 228 (17), 229 (14), 215 (6);
4.5.1.2. Compound 8. White solid; Yield: 96.8%; 1H NMR (300 MHz,
CDCl3) d 7.67–7.58 (m, 2H), 7.55 (dd, J = 7.9, 1.2 Hz, 1H), 7.48–7.29
(m, 6H), 7.29–7.21 (m, 1H), 7.16 (dd, J = 7.7, 1.6 Hz, 1H), 7.13–7.07
(m, 1H), 7.06–7.03 (m, J = 9.6, 1.2 Hz, 1H), 5.13 (s, 2H); EI-MS m/z
(rel. int.,%): 338 (33), 259, (28), 169 (100).
HRMS (ESI): calculated for
259.1101.
C19H14O + H = 259.1123, found:
4.5.2.4. Compound 29. White solid; 1H NMR (300 MHz, CDCl3) d
9.95 (s, 1H), 7.89 (d, J = 1.7 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.50–
7.30 (m, 3H), 7.19 (d, J = 7.6 Hz, 1H), 5.30 (s, 2H), 3.98 (s, 3H);
4.5.1.3. Compound 11. White solid; Yield: 95.6%; 1H NMR
(300 MHz, CDCl3) d 9.85 (s, 1H), 7.59 (dd, J = 7.9, 1.1 Hz, 1H), 7.53
(d, J = 7.7 Hz, 1H), 7.45 (d, J = 1.8 Hz, 1H), 7.41 (dd, J = 8.2, 1.9 Hz,
1H), 7.33 (td, J = 7.6, 1.1 Hz, 1H), 7.19 (td, J = 7.8, 1.6 Hz, 1H), 6.96
(d, J = 8.2 Hz, 1H), 5.30 (s, 2H), 3.97 (s, 3H); EI-MS m/z (rel.
int.,%): 320 (11), 169 (100).
13C NMR (75 MHz, CDCl3)
d 190.79, 149.62, 149.08, 130.79,
130.42, 130.16, 128.65, 128.48, 124.61, 123.21, 122.22, 119.96,
109.58, 68.87, 56.04; MS (ESI): 241.05 (M + H); HRMS (ESI): calcu-
lated for C15H12O3 + H = 241.0865, found: 241.0847.
4.5.1.4. Compound 12. White solid; Yield: 96.0%; 1H NMR
4.5.2.5. Compound 30. White solid; 1H NMR (300 MHz, CDCl3) d
7.89 (dd, J = 7.7, 1.6 Hz, 1H), 7.75 (dd, J = 7.8, 1.6 Hz, 1H), 7.68 (d,
J = 7.4 Hz, 1H), 7.39 (td, J = 7.5, 1.1 Hz, 1H), 7.32 (td, J = 7.4,
1.2 Hz, 1H), 7.18 (d, J = 7.3 Hz, 1H), 7.08 (t, J = 7.8 Hz, 1H), 5.20 (s,
2H), 3.92 (s, 3H); 13C NMR (75 MHz, CDCl3) d 166.27, 154.48,
134.84, 133.30, 131.13, 129.22, 128.50, 128.06, 127.16, 124.60,
124.52, 124.12, 122.13, 121.20, 68.56, 52.03; MS (ESI): 241.05
(300 MHz, CDCl3)
d 7.87 (dd, J = 7.8, 1.6 Hz, 1H), 7.81 (d,
J = 7.7 Hz, 1H), 7.57 (dd, J = 8.0, 1.0 Hz, 1H), 7.53–7.43 (m, 1H),
7.38 (td, J = 7.6, 1.0 Hz, 1H), 7.19 (td, J = 8.0, 1.6 Hz, 1H), 7.02 (dd,
J = 11.6, 4.3 Hz, 2H), 5.22 (s, 2H), 3.93 (s, 3H); EI-MS m/z (rel.
int.,%): 320 (3), 209 (56), 169 (100).
4.5.1.5. Compound 13. White solid; Yield: 83.9%; 1H NMR
(300 MHz, CDCl3) d 8.03–7.85 (m, 2H), 7.60 (dd, J = 7.9, 1.1 Hz,
1H), 7.52 (d, J = 7.7 Hz, 1H), 7.34 (td, J = 7.5, 1.1 Hz, 1H), 7.21 (td,
J = 7.8, 1.7 Hz, 1H), 7.10–6.95 (m, 2H), 5.20 (s, 2H), 2.56 (s, 3H);
EI-MS m/z (rel. int.,%): 304 (12), 169 (100).
(M + H); HRMS (ESI): calculated for
found: 241.0848.
C15H12O3 + H = 241.0865,
4.5.2.6. Compound 31. White solid; 1H NMR (300 MHz, CDCl3) d
8.40 (d, J = 2.1 Hz, 1H), 7.85 (dd, J = 8.5, 2.1 Hz, 1H), 7.81 (d,
J = 7.7 Hz, 1H), 7.42 (t, J = 7.1 Hz, 1H), 7.33 (td, J = 7.4, 1.1 Hz, 1H),
7.17 (d, J = 7.4 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H), 5.20 (s, 2H), 2.62
(s, 3H); 13C NMR (75 MHz, CDCl3) d 196.68, 158.64, 131.38,
130.59, 130.07, 128.90, 128.61, 128.22, 124.58, 123.74, 122.44,
122.10, 117.25, 68.48, 26.31; MS (ESI): 225.05 (M + H); HRMS
(ESI): calculated for C15H12O2 + H = 225.0916, found: 225.0894.
4.5.1.6. Compound 19. White solid; Yield: 95.7%; 1H NMR
(300 MHz, CDCl3) d 7.60 (d, J = 7.9 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H),
7.37–7.29 (m, 2H), 7.25–7.15 (m, 2H), 6.98–6.91 (m, 2H), 5.15 (s,
6H), 4.38 (s, 6H), 1.44 (s, 26H); MS (ESI): 392 (M + H).
4.5.1.7. Compound 20. Pale yellow solid; Yield: 81.5%; 1H NMR
4.5.2.7. Compound 34. Pale solid; 1H NMR (300 MHz, CDCl3) d 7.77
(d, J = 7.6 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H),
7.41 (t, J = 7.6 Hz, 1H), 7.30 (dd, J = 11.3, 4.4 Hz, 2H), 7.20 (t,
J = 6.9 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 5.05 (s, 2H), 2.57 (s, 3H);
(300 MHz, CDCl3)
d 7.63 (dd, J = 7.4, 1.8 Hz, 1H), 7.41 (d,
J = 7.8 Hz, 1H), 7.25–7.11 (m, 2H), 6.81 (dd, J = 7.2, 2.1 Hz, 1H),
6.31 (d, J = 2.1 Hz, 1H), 6.24 (d, J = 7.7 Hz, 1H), 6.01 (d, J = 2.1 Hz,
1H), 5.24 (s, 2H), 3.94 (s, 3H), 3.71 (s, 3H); MS (ESI): 374 (M + H).
13C NMR (75 MHz, CDCl3)
d 141.63, 140.01, 133.59, 133.55,

256
L. Zhang et al. / Ultrasonics Sonochemistry 19 (2012) 250–256
[11] L.C. Campeau, M. Parisien, M. Leblanc, K. Fagnou, Biaryl synthesis via direct
arylation: establishment of an efficient catalyst for intramolecular processes, J.
Am. Chem. Soc. 126 (2004) 9186–9187.
[12] M. Parisien, D. Valette, K. Fagnou, Direct arylation reactions catalyzed by
Pd(OH)(2)/C: evidence for a soluble palladium catalyst, J. Org. Chem. 70 (2005)
7578–7584.
[13] L.C. Campeau, M. Parisien, A. Jean, K. Fagnou, Catalytic direct arylation with
aryl chlorides, bromides, and iodides: intramolecular studies leading to new
intermolecular reactions, J. Am. Chem. Soc. 128 (2006) 581–590.
[14] B.P. Mason, K.E. Price, J.L. Steinbacher, A.R. Bogdan, D.T. McQuade, Greener
approaches to organic synthesis using microreactor technology, Chem. Rev.
107 (2007) 2300–2318.
133.04, 127.92, 126.23, 123.45, 121.36, 120.75, 119.49, 118.72,
108.98, 101.90, 47.94, 8.94; MS (ESI): 220.05 (M + H); HRMS
(ESI): calculated for C16H13N + H = 220.1126, found: 220.1104.
4.5.2.8. Compound 37. White solid; 1H NMR (300 MHz, CDCl3) d
7.73–7.63 (m, 2H), 7.38 (t, J = 7.6 Hz, 1H), 7.30 (dd, J = 7.4, 1.2 Hz,
1H), 7.24 (d, J = 9.6 Hz, 2H), 7.16 (d, J = 6.8 Hz, 1H), 7.02 (t,
J = 7.6 Hz, 1H), 5.14 (s, 2H), 4.34 (s, 2H), 1.44 (s, 9H); 13C NMR
(75 MHz, CDCl3) d 155.82, 152.59, 131.01, 129.90, 129.26, 128.45,
127.64, 127.32, 124.53, 122.74, 122.55, 122.14, 121.75, 79.17,
68.37, 40.08, 28.36; MS (ESI): 312.15 (M + H); HRMS (ESI): calcu-
lated for C19H21NO3 + H = 312.1600, found: 312.1571.
[15] J.C. Brandt, S.C. Elmore, R.I. Robinson, T. Wirth, Safe and efficient ritter
reactions in flow, Synlett (2010) 3099–3103.
[16] P. Watts, S.J. Haswell, The application of micro reactors for organic synthesis,
Chem. Soc. Rev. 34 (2005) 235–246.
[17] S.L. Poe, M.A. Cummings, M.R. Haaf, D.T. McQuade, Solving the clogging
problem: precipitate-forming reactions in flow, Angew. Chem. Int. Ed. 45
(2006) 1544–1548.
[18] P. Cintas, J.L. Luche, Green chemistry – The sonochemical approach, Green
Chem. 1 (1999) 115–125.
[19] R. Rajagopal, D.V. Jarikote, K.V. Srinivasan, Ultrasound promoted Suzuki cross-
coupling reactions in ionic liquid at ambient conditions, Chem. Commun.
(2002) 616–617.
[20] J.T. Li, J.F. Han, J.H. Yang, T.S. Li, An efficient synthesis of 3, 4-
dihydropyrimidin-2-ones catalyzed by NH2SO3H under ultrasound
irradiation, Ultrason. Sonochem. 10 (2003) 119–122.
4.5.2.9. Compound 38. Pale solid; 1H NMR (300 MHz, CDCl3) d 7.68
(d, J = 7.3 Hz, 1H), 7.62–7.42 (m, 3H), 6.56 (s, 1H), 6.23 (s, 2H), 5.12
(s, 2H), 3.91 (s, 6H); 13C NMR (75 MHz, CDCl3) d 178.09, 162.94,
161.79, 149.55, 142.33, 137.66, 133.34, 130.71, 128.42, 122.79,
121.67, 110.54, 103.14, 94.55, 89.26, 56.01, 55.60, 54.41; MS
(ESI):
294.05
(M + H);
HRMS
(ESI):
calculated
for
C18H15NO3 + H = 294.1130, found: 294.1096.
[21] J. Jin, M.M. Cai, J.X. Li, Highly efficient suzuki coupling of aryl chlorides in a
continuous flow capillary microreactor, Synlett (2009) 2534–2538.
[22] D.E. Ames, A. Opalko, Palladium-catalyzed cyclization of 2-substituted
halogenoarenes by dehydrohalogenation, Tetrahedron 40 (1984) 1919–1925.
[23] J.H. Li, W.J. Liu, Y.X. Xie, Recyclable and reusable Pd(OAc)(2)/DABCO/PEG-400
system for Suzuki–Miyaura cross-coupling reaction, J. Org. Chem. 70 (2005)
5409–5412.
[24] S. Koda, T. Kimura, T. Kondo, H. Mitome, A standard method to calibrate
sonochemical efficiency of an individual reaction system, Ultrason. Sonochem.
10 (2003) 149–156.
[25] T. Noël, J.R. Naber, R.L. Hartman, J.P. McMullen, K.F. Jensen, S.L. Buchwald,
Palladium-catalyzed amination reactions in flow: overcoming the challenges
of clogging via acoustic irradiation, Chem. Sci. 2 (2011) 287–290.
[26] G.B. Liu, J.L. Xu, C.C. He, G. Chen, Q. Xu, H.X. Xu, J.X. Li, Synthesis and evaluation
of a novel series of quinoline derivatives with immunosuppressive activity,
Bioorgan. Med. Chem. 17 (2009) 5433–5441.
[27] M. Lafrance, D. Lapointe, K. Fagnou, Mild and efficient palladium-catalyzed
intramolecular direct arylation reactions, Tetrahedron 64 (2008) 6015–6020.
[28] J. Forrester, R.V.H. Jones, L. Newton, P.N. Preston, Synthesis and reactivity of
benzylic sulfonium salts: benzylation of phenol and thiophenol under near-
neutral conditions, Tetrahedron 57 (2001) 2871–2884.
[29] B.J. Margolis, J.J. Swidorski, B.N. Rogers, An efficient assembly of
heterobenzazepine ring systems utilizing an intramolecular palladium-
catalyzed cycloamination, J. Org. Chem. 68 (2003) 644–647.
[30] Y. Antonio, M.E. Delacruz, E. Galeazzi, A. Guzman, B.L. Bray, R. Greenhouse, L.J.
Kurz, D.A. Lustig, M.L. Maddox, J.M. Muchowski, Oxidative radical cyclization
to pyrroles under reducing conditions – reductive desulfonylation of alpha-
sulfonylpyrroles with tri-n-butyltin hydride, Can. J. Chem. 72 (1994) 15–22.
[31] N. Barbero, R. SanMartin, E. Dominguez, Divergent synthesis of isoindolo 2, 1-a
indole and indolo 1, 2-a indole through copper-catalysed C- and N-arylations,
Tetrahedron Lett. 50 (2009) 2129–2131.
[32] S.R. Flanagan, D.C. Harrowven, M. Bradley, Radical cyclisation reactions with
indoles, Tetrahedron Lett. 44 (2003) 1795–1798.
[33] D.E. Ames, A. Opalko, Synthesis of dibenzofurans by palladium-catalyzed
intramolecular dehydrobromination of 2-bromophenyl phenyl ethers,
Synthesis-Stuttgart (1983) 234–235.
Acknowledgement
This work was supported by 973 Program (2007CB714504) and
National Natural Science Foundation of China (20821063,
90913023). The authors thank Dr. Yin Ding (Nanjing University,
China) for HRMS measurements.
References
[1] M.C. Kozlowski, B.J. Morgan, E.C. Linton, Total synthesis of chiral biaryl natural
products by asymmetric biaryl coupling, Chem. Soc. Rev. 38 (2009) 3193–
3207.
[2] H. Guinaudeau, M. Leboeuf, A. Cave, Aporphine alkaloids.2, J. Nat. Prod. 42
(1979) 325–360.
[3] J.M. Brunel, BINOL: a versatile chiral reagent, Chem. Rev. 105 (2005) 857–897.
[4] R. Noyori, H. Takaya, BINAP – an efficient chiral element for asymmetric
catalysis, Acc. Chem. Res. 23 (1990) 345–350.
[5] J. Hassan, M. Sevignon, C. Gozzi, E. Schulz, M. Lemaire, Aryl–aryl bond
formation one century after the discovery of the Ullmann reaction, Chem. Rev.
102 (2002) 1359–1469.
[6] T. Satoh, M. Miura, Catalytic direct arylation of heteroaromatic compounds,
Chem. Lett. 36 (2007) 200–205.
[7] D. Alberico, M.E. Scott, M. Lautens, Aryl–aryl bond formation by transition-
metal-catalyzed direct arylation, Chem. Rev. 107 (2007) 174–238.
[8] G.B. Bajracharya, O. Daugulis, Direct transition-metal-free intramolecular
arylation of phenols, Org. Lett. 10 (2008) 4625–4628.
[9] D.D. Hennings, S. Iwasa, V.H. Rawal, Anion-accelerated palladium-catalyzed
intramolecular coupling of phenols with aryl halides, J. Org. Chem. 62 (1997)
2–3.
[10] F. Bellina, R. Rossi, Recent advances in the synthesis of (hetero)aryl-substituted
heteroarenes via transition metal-catalysed direct (hetero)arylation of
heteroarene C–H bonds with aryl halides or pseudohalides, diaryliodonium
salts, and potassium aryltrifluoroborates, Tetrahedron 65 (2009) 10269–
10310.