Generation and reaction of cyano-substituted aryllithium compounds using microreactors

Article abstract of DOI:10.1039/b919325c

We developed a microflow method for the generation and reactions of aryllithiums bearing a cyano group, including o-lithiobenzonitrile, m-lithiobenzonitrile and p-lithiobenzonitrile. The method was effective at much higher temperatures than are required for conventional macrobatch reactions, by virtue of rapid mixing, short residence time, and efficient temperature control. In addition, reactions of o-lithiobenzonitrile with carbonyl compounds followed by trapping of the resulting lithium alkoxides with electrophiles were achieved in an integrated microflow system. The Royal Society of Chemistry.

Full text of DOI:10.1039/b919325c

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Generation and reaction of cyano-substituted aryllithium compounds using
microreactors†‡
Aiichiro Nagaki, Heejin Kim, Hirotsugu Usutani, Chika Matsuo and Jun-ichi Yoshida*
Received 16th September 2009, Accepted 30th November 2009
First published as an Advance Article on the web 13th January 2010
DOI: 10.1039/b919325c
We developed a microflow method for the generation and reactions of aryllithiums bearing a cyano
group, including o-lithiobenzonitrile, m-lithiobenzonitrile and p-lithiobenzonitrile. The method was
effective at much higher temperatures than are required for conventional macrobatch reactions, by
virtue of rapid mixing, short residence time, and efficient temperature control. In addition, reactions of
o-lithiobenzonitrile with carbonyl compounds followed by trapping of the resulting lithium alkoxides
with electrophiles were achieved in an integrated microflow system.
Introduction
Results and discussion
Chemical conversions involving functionalized organometallic
compounds such as organolithium, organomagnesium, organoz-
inc and organocopper compounds are important procedures in
organic synthesis.1 These types of transformations are among the
most straightforward methods for the synthesis of complicated
organic molecules.2 Especially, organometallic compounds bear-
ing a cyano group are very important because of the activating
effect of the cyano group such as the ortho-directing effect and its
transformation into various other functional groups are advanta-
geous from a synthetic point of view.3 To generate functionalized
organometallic compounds such as arylmetallics, halogen–metal
exchange reactions involving halogen–Mg,4 halogen–Cu5 and
halogen–Zn6 have been extensively investigated, as they allow
conventional access to functionalized organometallics; such re-
actions are often essential in the use of aryl iodides. Because of the
high reactivity of halogen–Li exchange reactions, their application
in the generation of functionalized aryllithiums enables the use
of aryl bromide. However, the carbon attached to the Li center
behaves as a nucleophile that reacts strongly with cyano, nitro,
alkoxycarbonyl and other electrophilic functional groups.7–9 To
overcome this problem the reactions are often conducted at very
low temperatures, but even under these conditions it is difficult
to prepare organolithium compounds having highly reactive
functional groups.
The study focused on Br–Li exchange reactions of
bromobenzonitriles.14 Lithiation of bromobenzonitriles followed
by reaction with electrophiles in a conventional macrobatch
reactor requires very low temperatures, inthe range-78 to -100◦C,
to avoid unwanted reactions at the cyano group. To confirm
this we used a conventional macrobatch reactor to investigate
Br–Li exchange reactions of bromobenzonitriles such as
o-bromobenzonitrile (1a), m-bromobenzonitrile (1b) and
p-bromobenzonitrile (1c) (Table 1). A solution of n-BuLi in
hexane was added dropwise (1 min) to tetrahydrofuran solutions
of the bromobenzonitriles (1) in 10 mL round-bottom flasks at
-78 ◦C or 0 ◦C; this generated lithiobenzonitriles (2). The solution
was stirred for 10 min at the same temperature, methanol was
added, and the solution was stirred for a further 10 min, at which
point the yield of benzonitrile (3) was determined. The Br–Li
exchange reaction with 1a followed by protonation at -78 ◦C
achieved a high yield. The reaction at 0 ◦C afforded 3 but in only
3% yield. The reactions of m- and p-bromobenzonitirile (1b and
1c) were not as effective as with o-bromobenzonitrile (1a) affording
61% and 68% of desired product, respectively; and at 0 ◦C, as in the
case of 1a, 1b and 1c also afforded very poor yields of 3 (Table 1).
The Br–Li exchange reactions with o-bromobenzonitrile (1a),
m-bromobenzonitrile (1b) and p-bromobenzonitrile (1c), and
subsequent reactions with methanol, were then investigated using
a microflow system consisting of two T-shaped micromixers (M1
and M2) and two microtube reactors (R1 and R2), as shown in
Fig. 1. The reactions were carried out with varying residence times
We recently demonstrated that microflow systems10,11 are ef-
fective in controlling extremely rapid reactions involving highly
unstable intermediates,12 such as organolithium compounds,13 and
report here that features of these systems are highly applicable to
the generation and reaction of unstable aryllithium compounds
bearing a cyano group.
Department of Synthetic Chemistry and Biological Chemistry, Graduate
School of Engineering, Kyoto University, Nishikyo-ku, Kyoto 615-8510,
Japan
Fig. 1 A microflow system for Br–Li exchange reactions with bromoben-
zonitriles (1) followed by reaction with electrophiles§.
† This paper is part of an Organic & Biomolecular Chemistry web theme
§ Flow rate of a solution of 1 (0.10 M in THF): 6.00 mL min-1, flow rate
of n-BuLi (0.42 M in hexane): 1.50 mL min-1, flow rate of a solution of an
electrophile (0.60 M in THF): 3.00 mL min-1.
issue on enabling technologies for organic synthesis.
‡ Electronic supplementary information (ESI) available: Further experi-
mental details and 1H and 13C NMR spectra. See DOI: 10.1039/b919325c
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Table 2 Reaction of lithiobenzonitriles (2) with electrophilesa
Table 1 Br–Li exchange reaction of bromobenzonitriles (1) followed by
reaction with methanol in a conventional macrobatch systema
bromobenzonitrile
electrophile
Me3SiCl
product
yield (%)
90
bromobenzonitrile
T/◦C
-78
conv. (%) 1
yield (%) 3
1a
Bu3SnCl
MeI
85
93
92
o-bromobenzonitrile
(1a)
97
86
0
-78
100
90
3
61
m-bromobenzonitrile
(1b)
0
-78
94
90
6
68
p-bromobenzonitrile
(1c)
PhCHO
0
99
8
a A solution of n-BuLi in hexane was added dropwise to a solution of
bromobenzonitriles (1) in THF at -78 ◦C or 0 ◦C. After stirring for 10 min
at the same temperature, methanol was added. After stirring for 10 min,
the yield of benzonitrile (3) was determined by GC.
n-HexCHO
81b
94b
Ph2CO
(tR s) in R1, and varying reaction temperature (T ◦C) in the
microflow system.
As shown in Fig. 2, the yield depended on both temperature
and residence time. We found that the reaction of 1a, 1b and 1c
was ac◦hieved in high yields at 20 ◦C (1a: 90%, 1b: 82%, 1c: 82%)
and 0 C (1a: 90%, 1b: 80%, 1c: 88%). With increased residence
time the lower yield was probably because of side reactions of the
cyano group with lithiobenzonitriles. Fig. 2 also shows that the
stabilities of m-lithiobenzonitrile (2b) and p-lithiobenzonitrile (2c)
were similar. In contrast, the stability of o-lithiobenzonitrile (2a)
was higher than that of 2b and 2c because of the ortho-directing
effect of the cyano group for the Li center of 2a. These results
demonstrate that the microflow system is a more efficient method
for the generation and reactions of lithiobenzonitriles under mild
conditions than the conventional macrobatch system.15
The reactions of various electrophiles with 2a, 2b and 2c were
investigated in the microflow system under optimized conditions.
As shown in Table 2, the reactions with chlorotrimethylsilane,
chlorotributylstannane, methyl iodide and carbonyl compounds
were effective in providing good yields of the corresponding
products.
Me3SiCl
Bu3SnCl
96
95
1b
MeI
81
81
PhCHO
Me3SiCl
85
The integration of chemical reactions is of significant research
interest because combining reactions avoids the need for isolation
of intermediate products. The easy modulation of microflow
systems aids the integration of chemical reactions. To demonstrate
the utility of the present microflow method, sequential reactions
were investigated using an integrated microflow system. As shown
in Table 2, the reaction of carbonyl compounds with 2a gave
lactone derivatives (cyclization products) after cyclization of
the nitrile group with alkoxylithium followed by hydrolysis. We
hypothesized that sequential trapping reactions for alkoxylithium
compounds generated by reaction of carbonyl compounds with 2a
could be achieved by the addition of an electrophile. The integrated
microflow system consisted of three T-shaped micromixers (M1,
M2 and M3) and three microtube reactors (R1, R2 and R3), as
shown in Fig. 3. The sequential transformations were effective in
providing good yields of the corresponding products (Table 3).
1c
Bu3SnCl
MeI
93
90
87
PhCHO
a Bromobenzonitriles (1a–1c) in THF (0.10 M), n-BuLi in hexane (0.42 M),
and an electrophile in THF (0.60 M) were reacted in the microflow system
under the following optimized conditions: 1a: 20 ◦C (residence time: 0.01
s), 1b: 0 ◦C (residence time: 0.01 s), 1c: 0 ◦C (residence time: 0.01 s). The
yield was determined by GC. b Isolated yield.
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Table 3 Reaction of o-lithiobenzonitrile (2a) with carbonyl compounds
followed by reaction with electrophilesa
carbonyl
compound
electrophile
AcCl
product
yield (%)
97
PhCHO
b
Me2SO4
83
75
51
66
n-HexCHO
MeO2CCl
b
Me2SO4
b
Ph2CO
Me2SO4
a The reaction was conducted under the following optimized conditions:
temperature: 20 ◦C, residence time of R1: 0.01 s, residence time of R2: 2.3 s
(See the supporting information for details). b 3 eq of HMPA was added
to a solution of Me2SO4.
Fig.
2
Effects of reaction temperature and residence time in
R1 on the yield of benzonitrile in Br–Li exchange reactions
involving o-bromobenzonitrile (1a), m-bromobenzonitrile (1b), and
p-bromobenzonitrile (1c) with n-BuLi in a microflow system.
Fig. 3 An integrated microflow system for reaction of o-lithiobenzonitrile
with carbonyl compounds followed by reaction with electrophiles¶.
Experimental
General
Conclusions
GC analysis was performed on a SHIMADZU GC-2014 gas
chromatograph equipped with a flame ionization detector using a
fused silica capillary column (column, CBPI; 0.25 mm ¥ 25 m).
1H and 13C NMR spectra were recorded on Varian MERCURY
plus-400 (1H 400 MHz, 13C 100 MHz) spectrometer with Me4Si
or CDCl3 as a standard in CDCl3 unless otherwise noted. EI
In conclusion, we have developed an effective method for the
generation and reactions of cyano-substituted aryllithium through
use of a microflow system involving a short residence time in
combination with rapid mixing and efficient temperature control.
In addition, sequential transformations were achieved in an
integrated microflow system through generation and reactions
of o-lithiobenzonitrile followed by trapping reactions with elec-
trophiles. The method provides a new dimension in functionalized
organolithium chemistry, and its application to the synthesis of
various aromatic compounds is in progress.
¶ Flow rate of a solution of 1a (0.10 M in THF): 6.00 mL min-1, flow
rate of n-BuLi (0.42 M in hexane): 1.20 mL min-1, flow rate of a solution
of carbonyl compound (0.22 M in hexane): 3.00 mL min-1, flow rate of a
solution of an electrophile (0.90 M in THF): 2.00 mL min-1.
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mass spectra were recorded on JMS-SX102A spectrometer. Gel
permeation chromatography (GPC) was carried out on Japan
Analytical Industry LC-908. THF was purchased from Kanto
Chemical Co., Inc. as a dry solvent and used without further
purification. Hexane was purchased from Wako, distilled before
use, and stored over molecular sieves 4A. o-Bromobenzonitrile
(1a), m-bromobenzonitrile (1b), p-bromobenzonitrile (1c), n-
BuLi, methanol, chlorotrimethylsilane, chlorotributylstannane,
iodomethane, benzaldehyde, n-heptanal, benzophenone, acetyl
chloride, dimethyl sulfate, HMPA were commercially available
and used without further purification. Stainless steel (SUS304)
T-shaped micromixers having inner diameter of 250 mm or
500 mm were manufactured by Sanko Seiki Co., Inc. Stainless
steel (SUS316) microtube reactors having inner diameter of 250,
500 and 1000 mm were purchased from GL Sciences. Micromixers
and microtube reactors were connected with stainless steel fittings
(GL Sciences, 1/16 OUW). The microflow system was dipped in a
cooling bath to control the temperature. Solutions were introduced
to a microflow system using syringe pumps, Harvard Model 11,
equipped with gastight syringes purchased from SGE.
100 cm)) was used. A solution of bromobenzonitriles (0.10 M) in
THF (flow rate: 6.0 mL min-1) and a solution of n-BuLi (0.42 M)
in hexane (flow rate: 1.5 mL min-1) were introduced to M1 (f =
250 mm). The resulting solution was passed through R1 and was
mixed with a solution of electrophile (0.60 M) in THF (flow rate:
3.0 mL min-1) in M2 (f = 500 mm). The resulting solution was
passed through R2 (f = 1000 mm, L = 50 cm). After a steady state
was reached, the product solution was collected for 30 s while being
quenched with H2O (or 1 M HCl aqueous solution when carbonyl
compound was used as an electrophile). The reaction mixture was
analyzed by GC. The reactions of o-bromobenzonitrile (1a) were
◦
carried out at 20 C. The reactions of m-bromobenzonitrile (1b)
and p-bromobenzonitrile (1c) were carried out at 0 ◦C.
2-Trimethylsilylbenzonitrile. The product was obtained in
90% yield (GC tR 15.8 min) when o-bromobenzonitrile and
chlorotrimethylsilane were used for the reaction. The spectral data
were identical to those reported in the literature.16
2-Tributylstannylbenzonitrile. The product was obtained in
85% yield (GC tR 26.7 min) when o-bromobenzonitrile and
chlorotributylstannane were used for the reaction. The spectral
data were identical to those reported in the literature.17
Typical procedure for the Br–Li exchange reaction of
bromobenzonitriles followed by reaction with methanol in a
macrobatch system
2-Methylbenzonitrile. The product was obtained in 93% yield
t
(GC R 11.8 min) when o-bromobenzonitrile and methyl iodide
were used for the reaction. The spectral data were identical to
those of commercially available compound.
A solution of n-BuLi (0.42 M, 0.75 mL) in hexane was added
dropwise to a solution of bromobenzonitriles (0.10 M, 3.0 mL) in
THF in a 20 mL round bottom glass flask at regular pace with
3-Phenylphthalide. The product was obtained in 98% yield
◦
magnetic stirring for 1.0 min at T C. The mixture was stirred for
t
(GC R 24.2 min) when o-bromobenzonitrile and benzaldehyde
10 min, and a solution of methanol (0.60 M, 1.5 mL) in THF was
added. After stirring for 10 min, a cooling bath was removed. The
mixture was analyzed by GC.
were used for the reaction. The spectral data were identical to
those reported in the literature.18
3-Hexylphthalide. The product was obtained when o-
bromobenzonitrile and n-heptanal were used for the reaction.
After extraction, the crude product was purified by silica gel
chromatography (hexane–AcOEt = 5 : 1) to afford 52.9 mg of 3-
hexylphthalide (81% yield). The spectral data were identical to
those reported in the literature.18
Typical procedure for the Br–Li exchange reaction of
bromobenzonitriles followed by reaction with methanol in
microflow systems
A microflow system consisting of two T-shaped micromixers
(M1 and M2), two microtube reactors (R1 and R2) and three
tube pre-cooling units (P1 (inner diameter f = 1000 mm, length
L = 100 cm), P2 (f = 1000 mm, L = 50 cm) and P3 (f = 1000 mm,
L = 100 cm)) was used. A solution of bromobenzonitrile (0.10 M)
in THF (flow rate: 6.0 mL min-1) and a solution of n-BuLi (0.42
M) in hexane (flow rate: 1.5 mL min-1) were introduced to M1
(f = 250 mm) by syringe pumps. The resulting solution was passed
through R1 and was mixed with a solution of methanol (0.60 M) in
THF (flow rate: 3.0 mL min-1) in M2 (f = 500 mm). The resulting
solution was passed through R2 (f = 1000 mm, L = 50 cm). After
a steady state was reached, the product solution was collected for
30 s while being quenched with H2O. The reaction mixture was
analyzed by GC.
3,3-Diphenyl-1(3H)-isobenzofuranone. The product was ob-
tained when o-bromobenzonitrile and benzophenone were used
for the reaction. After extraction, the crude product was purified
by silica gel chromatography (hexane–AcOEt = 3 : 1) to afford
81.3 mg of 3,3diphenyl-1(3H)-isobenzofuranone (94% yield). The
spectral data were identical to those reported in the literature.19
3-Trimethylsilylbenzonitrile. The product was obtained in
t
96% yield (GC R 16.3 min) when m-bromobenzonitrile and
chlorotrimethylsilane were used for the reaction. After extraction,
the crude product was purified by silica gel chromatography
1
(hexane–AcOEt = 50 : 1): H NMR (400 MHz, CDCl3) d 0.28
(s, 9H), 7.41–7.46 (m, 1H), 7.59–7.64 (m, 1H), 7.69–7.74 (m, 1H),
7.75–7.79 ppm (m, 1H); 13C NMR (100 MHz, CDCl3) d -1.8,
111.7, 118.8, 128.0, 131.8, 136.5, 137.1, 142.1 ppm; HRMS (EI)
m/z calcd for C10H13NSi: 175.0817, found: 175.0817.
Typical procedure for the Br–Li exchange reaction of
bromobenzonitriles followed by reaction with electrophiles in
microflow systems
3-Tributylstannylbenzonitrile. The product was obtained in
t
A microflow system consisting of two T-shaped micromixers (M1
and M2), two microtube reactors (R1 and R2) and three tube
pre-cooling units (P1 (inner diameter f = 1000 mm, length L =
100 cm), P2 (f = 1000 mm, L = 50 cm) and P3 (f = 1000 mm, L =
95% yield (GC R 27.8 min) when m-bromobenzonitrile and
chlorotributylstannane were used for the reaction. After extrac-
tion, the crude product was purified by silica gel chromatography
(hexane–AcOEt = 20 : 1): 1H NMR (400 MHz, CDCl3) d 0.88 (t,
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J = 7.4 Hz, 9H), 0.98–1.18 (m, 6H), 1.32 (sext, J = 7.3 Hz, 6H),
1.40–1.62 (m, 6H), 7.34–7.42 (m, 1H), 7.53–7.78 ppm (m, 3H);
13C NMR (100 MHz, CDCl3) d 9.5, 13.4, 27.1, 28.8, 112.0, 119.1,
127.9, 131.2, 139.4, 140.3, 143.9 ppm; HRMS (EI) m/z calcd for
C19H31NSn: 393.1478, found: 393.1479.
acetate (83% yield): 1H NMR (400 MHz, CDCl3) d 3.19 (s, 3H),
7.10 (s, 1H), 7.29–7.43 (m, 6H), 7.55–7.68 ppm (m, 3H); 13C NMR
(100 MHz, CDCl3) d 20.9, 74.8, 111.2, 117.2, 127.1, 127.2, 128.2,
128.5, 128.7, 133.0, 133.3, 138.1, 143.8, 169.5 ppm; HRMS (EI)
m/z calcd for C16H13NO2: 251.0946, found: 251.0945.
3-Methylbenzonitrile. The product was obtained in 81% yield
(GC R 12.2 min) when m-bromobenzonitrile and methyl iodide
2-(Methoxy(phenyl)methyl)benzonitrile. After extraction, the
crude product was purified by silica gel chromatogra-
t
were used for the reaction. The spectral data were identical to
those of commercially available compound.
phy (hexane–AcOEt
=
10 : 1) to afford 62.7 mg of 2-
(methoxy(phenyl)methyl)benzonitrile (93% yield): 1H NMR
(400 MHz, CDCl3) d 3.43 (s, 3H), 5.64 (s, 1H), 7.26–7.39 (m, 4H),
7.42–7.46 (m, 2H), 7.55–7.65 ppm (m, 3H); 13C NMR (100 MHz,
CDCl3) d 57.3, 82.6, 111.3, 117.7, 126.9, 127.0, 127.9, 128.1,
128.6, 132.8, 133.1, 139.8, 146.0 ppm; HRMS (EI) m/z calcd for
C15H13NO: 223.0997, found: 223.1002.
3-(Hydroxyphenylmethyl)benzonitrile. The product was ob-
tained in 81% yield (GC tR 24.6 min) when m-bromobenzonitrile
and benzaldehyde were used for the reaction. The spectral data
were identical to those reported in the literature.20
4-Trimethylsilylbenzonitrile. The product was obtained in
85% yield (GC tR 16.4 min) when p-bromobenzonitrile and
chlorotrimethylsilane were used for the reaction. The spectral data
were identical to those reported in the literature.21
1-(2-Cyanophenyl)heptyl ethyl carbonate. After extraction, the
crude product was purified by silica gel chromatography (hexane–
AcOEt = 5 : 1) to afford 62.1 mg of 1-(2-cyanophenyl)heptyl ethyl
1
carbonate (75% yield): H NMR (400 MHz, CDCl3) d 0.87 (t, J
4-Tributylstannylbenzonitrile. The product was obtained in
93% yield (GC tR 28.3 min) when p-bromobenzonitrile and
chlorotributylstannane were used for the reaction. The spectral
data were identical to those reported in the literature.22
= 6.8 Hz, 3H), 1.20–1.38 (m, 7H), 1.38–1.50 (m, 1H), 1.79–1.90
(m, 1H), 1.93–2.05 (m, 1H), 3.76 (s, 3H), 5.84–5.90 (m, 1H), 7.40
(td, J = 7.8, 1.2 Hz, 1H), 7.50–7.55 (m, 1H), 7.57–7.63 (m, 1H),
7.63–7.67 ppm (m, 1H); 13C NMR (100 MHz, CDCl3) d 13.9, 22.4,
25.1, 28.7, 31.5, 36.1, 54.9, 77.6, 110.9, 117.0, 126.3, 128.3, 132.8,
133.1, 144.3, 154.9 ppm; HRMS (EI) m/z calcd for C16H21NO3:
275.1521, found: 275.1524.
4-Methylbenzonitrile. The product was obtained in 90% yield
t
(GC R 12.5 min) when p-bromobenzonitrile and methyl iodide
were used for the reaction. The spectral data were identical to
those of commercially available compound.
2-(1-Methoxyheptyl)benzonitrile. After extraction, the crude
product was purified by silica gel chromatography (hexane–AcOEt
= 10 : 1) to afford 35.4 mg of 2-(1-methoxyheptyl)benzonitrile
4-(Hydroxyphenylmethyl)benzonitrile. The product was ob-
tained in 93% yield (GC tR 24.7 min) when p-bromobenzonitrile
and benzaldehyde were used for the reaction. The spectral data
were identical to those reported in the literature.23
1
(51% yield): H NMR (400 MHz, CDCl3) d 0.86 (t, J = 6.8 Hz,
3H), 1.20–1.38 (m, 7H), 1.38–1.50 (m, 1H), 1.62–1.73 (m, 1H),
1.73–1.85 (m, 1H), 4.52–4.58 (m, 1H), 7.37 (td, J = 7.5, 1.6 Hz,
1H), 7.52–7.58 (m, 1H), 7.58–7.68 ppm (m, 2H); 13C NMR
(100 MHz, CDCl3) d 14.0, 22.5, 25.5, 29.0, 31.7, 37.8, 57.1, 81.4,
111.4, 117.4, 126.6, 127.8, 132.7, 133.1, 146.9 ppm; HRMS (FAB)
m/z calcd for C15H22NO: 232.1701, found: 232.1697.
Reaction of o-lithiobenzonitrile with carbonyl compounds followed
by sequential reaction with electrophiles
A microflow system consisting of three T-shaped micromixers
(M1, M2, and M3), three microtube reactors (R1, R2, and R3) and
four tube pre-cooling units (P1, P3, (inner diameter f = 1000 mm,
length L = 100 cm), P2, P4 (f = 1000 mm, L = 50 cm)) was
used. A solution of o-bromobenzonitrile (0.10 M) in THF (flow
rate: 6.0 mL min-1) and a solution of n-BuLi (0.42 M) in hexane
(flow rate: 1.5 mL min-1) were introduced to M1 (f = 250 mm).
The resulting solution was passed through R1 and was mixed with
a solution of carbonyl compound (0.22 M) in THF (flow rate:
3.0 mL min-1) in M2 (f = 500 mm). The resulting solution was
passed through R2 and was mixed with a solution of electrophile
(0.90 M) in THF (flow rate: 2.0 mL min-1) in M3 (f = 500 mm). The
resulting solution was passed through R3. After a steady state was
reached, the product solution was collected for 30 s while being
quenched with H2O. The microtube reactor R3 (f = 1000 mm,
L = 50 cm) was used for the reaction with acetyl chloride or
methyl chlorocarbonate as an electrophile. For the reaction with
dimethyl sulfate, a longer microtube reactor R3 (f = 1000 mm,
L = 2560 cm (50 cm at 0 ◦C, 10 cm at ambient temperature, and
2500 cm at 50 ◦C) was used in order to complete the reaction.
2-(Methoxydiphenylmethyl)benzonitrile. After extraction, the
crude product was purified by silica gel chromatogra-
phy (hexane–AcOEt
=
10 : 1) to afford 59.6 mg of 2-
(methoxydiphenylmethyl)benzonitrile (66% yield): 1H NMR
(400 MHz, CDCl3) d 3.10 (s, 3H), 7.28–7.39 (m, 7H), 7.45–7.51
(m, 5H), 7.63–7.67 ppm (m, 2H); 13C NMR (100 MHz, CDCl3)
d 52.2, 87.0, 111.7, 118.8, 127.2, 127.7, 128.0, 129.1, 129.3, 131.8,
135.5, 141.1, 148.9 ppm; HRMS (EI) m/z calcd for C21H17NO:
299.1310, found: 299.1313.
Notes and references
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