Continuous flow nucleophilic aromatic substitution with dimethylamine generated in situ by decomposition of DMF

Article abstract of DOI:10.1021/jo400390t

A safe, practical, and scalable continuous flow protocol for the in situ generation of dimethylamine from DMF followed by nucleophilic aromatic substitution of a broad range of aromatic and heteroaromatic halides is reported.

Full text of DOI:10.1021/jo400390t

Note
pubs.acs.org/joc
Continuous Flow Nucleophilic Aromatic Substitution with
Dimethylamine Generated in Situ by Decomposition of DMF
Trine P. Petersen,†,‡ Anders Foller Larsen,† Andreas Ritzen,*,‡ and Trond Ulven*,†
́
†Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark
‡Discovery Chemistry & DMPK, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark
S
* Supporting Information
ABSTRACT: A safe, practical, and scalable continuous flow
protocol for the in situ generation of dimethylamine from
DMF followed by nucleophilic aromatic substitution of a
broad range of aromatic and heteroaromatic halides is
reported.
ryldimethylamines can be prepared by nucleophilic
aromatic substitution (SNAr) of aryl or heteroaryl halides
to form N,N-dimethyl-3-nitropyridin-2-amine (Table 1). The
substrate and the additive were dissolved in DMF and allowed
A
with dimethylamine. However, because of the volatile nature of
this reagent and the high temperatures or long reaction times
often required,1 outgassing from open flask reactors or pressure
build-up under sealed-tube conditions can be problematic.
Rather than using a premade solution, dimethylamine can be
Table 1. Effect of Additives on Decomposition of DMF
produced in situ from thermal decomposition of DMF,2
a
ab
,
bc
,
additive
batch (%)
flow (%)
process that can be catalyzed by acids or bases.3 Substitution of
aryl halides using this method often involves refluxing the
substrate in DMF for several hours or days.4 Although the
reaction rate can be improved by microwave-assisted heating in
a sealed tube,5 the pressure build-up poses a serious safety
concern and complicates scale-up. We envisaged that
continuous flow chemistry would overcome this problem
while maintaining the advantages of sealed-tube microwave
technology, including fast and efficient heat transfer and safe
heating above the boiling point of the solvent with no
outgassing of the generated dimethylamine.6 The small volume
of a flow reactor and the fact that the system is inherently open
to the environment virtually eliminates any risk of explosion
due to excessive pressure build-up. A flow process can
furthermore be scaled up without reoptimizing the reaction
conditions simply by running the system for a longer period of
time.6a,b,d Herein, we report our findings resulting in the
development of a safe, convenient, scalable, and versatile
method for the conversion of aryl halides to aryldimethyl-
amines using DMF and aqueous ammonia as the only solvents/
reagents required.
PTSA (0.05 M)
5 (93)
5 (95)
29 (71)
11 (87)
AcOH (0.05 M)
NH4Cl (0.05 M)
K2CO3 (aq, 0.25 M)
10 (89)
45 (26)
76 (0)
32 (66)
d
precipitation
93 (7)
e
NH3 (aq, 2.5 M)
a
Microwave-assisted heating (150 °C, 30 min). Yields were
determined by HPLC. Flow rate: 0.500 mL/min, volume: 10 mL,
b
residence time: 20 min., temperature: 240 °C. Yields were determined
c
by LC−MS. The amount of remaining 2-chloro-3-nitropyrindine is
d
e
shown in parentheses. 0.5 M K2CO3 (aq) and DMF (1:1). 12.4 M
NH3 (aq) and DMF (1:4).
to react at 150 °C for 30 min using microwave heating. The
results of this study (Table 1) showed that basic additives were
superior to acidic ones as promoters of DMF decomposition.
Of these, ammonia was clearly the most efficient, with the
ammonia adduct as the only side product. This side reaction
might only pose a problem for the more reactive substrates, as
it has been shown previously that ammonia does not react with
4,7-dichlorophenanthroline.7
Transferred to a continuous flow system, the additives
produced essentially the same ranking, with ammonia being by
Inspired by our previous finding that aqueous ammonia
efficiently promotes DMF decomposition,7 we launched a pilot
study using sealed-tube microwave conditions to investigate the
effect of various acid and base additives on the rate of
nucleophilic aromatic substitution of 2-chloro-3-nitropyridine
Received: February 22, 2013
Published: March 19, 2013
© 2013 American Chemical Society
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Note
far the most efficient (Table 1). No trace of reaction with
ammonia was observed under flow conditions, indicating a
significantly better reaction control compared to the micro-
wave-assisted batch synthesis.
The optimal temperature and concentration for ammonia-
promoted generation of dimethylamine was investigated using
the system outlined in Scheme 1. A solution of 2-chloro-3-
Although efficient for these aryl halides, the harsh conditions
of this one-step method was found to decompose more
sensitive substrates and cause side reactions when using
reactants carrying functional groups such as nitriles (entry
14). A two-step procedure was therefore developed (Scheme 2)
Scheme 2. Two-Step Method for DMF Decomposition and
SNAr
Scheme 1. One-Step Method for DMF Decomposition and
SNAr
nitropyridine (1.0 M in DMF) was loaded into a 1.043 mL
injection loop and injected into a stream of DMF (0.167 mL/
min). This stream was mixed with a stream of pure DMF or
aqueous ammonia (12.4 M) in DMF (1:4 or 1:9 v/v at 0.167
mL/min) and passed through a heated tube reactor (10 mL,
residence time: 30 min). The system was pressurized to 25 bar
to prevent boiling and outgassing. Full conversion was observed
at a temperature of 250 °C using ammonia concentrations
down to 1.24 M (Table 2).
where the dimethylamine generation and the nucleophilic
substitution were performed in separate reactors to allow
independent variation of temperatures and reaction times.
Aqueous ammonia in DMF (1:9 v/v) was pumped at a flow
rate of 0.250 mL/min through a stainless steel reactor at 240
°C (residence time: 40 min) to preform the dimethylamine
after which it was mixed with a solution of the electrophile
(0.25 or 0.50 M in DMF). The mixture was passed through a
PFA reactor at 30−50 °C (residence time: 20 min), where the
substitution took place. In most cases, 30 °C was sufficient to
effect the substitution reaction. Using this two-step procedure,
nitriles (entries 15−16) and ethyl esters (entry 17)
incompatible with the harsh conditions of the one-step
procedure were tolerated, and good to excellent results were
obtained for a range of electron-deficient aryl and heteroaryl
fluorides and chlorides (entries 18−22). Notably, some
substituted 1-halo-2-nitrobenzenes that decomposed with the
one-step method (e.g., entries 14 and 22) gave excellent yields
using the milder two-step method (entries 15 and 23). On the
other hand, the chloropyrimidine substitution benefited from
the high temperature of the one-step method (entry 3),
whereas no conversion to product was observed with the two-
step method (entry 4). For relatively undemanding substrates
(e.g., entries 9 and 10), both methods resulted in good to
excellent yields.
To demonstrate the postulated advantages of flow chemistry
in scale-up, i.e., no safety issues due to pressure build-up, and
no boiling or outgassing, a solution of 4-chloro-6-methylpyr-
imidin-2-amine (0.50 M in DMF, 135 mL) was subjected to the
one-step method. Apart from the modification that the reactant
solution was fed directly through the pump into the system
instead of being loaded into an injection loop, no conditions
were changed or optimized to run this reaction on a 129 times
larger scale (Scheme 3). The synthesis yielded 8.8 g (83%)
corresponding to a space time yield of 65 g h−1 L−1 of N4,N4,6-
trimethylpyrimidine-2,4-diamine after semiautomatic flash
chromatography, which is consistent with the yield observed
when the synthesis was performed on small scale (entry 3,
Table 3).
Table 2. Optimization of DMF Decomposition under Flow
Conditions
a
b
temp (°C)
NH3 conc (M)
yield (%)
150
150
200
250
250
0
20
69
2.48
2.48
2.48
1.24
80
100
100
a
b
12.4 M NH3 (aq) mixed with DMF (1:4 or 1:9). Determined by
reaction with 2-chloro-3-nitrophyridine, analyzed by LC−MS.
Having identified optimal conditions for the test reaction, we
proceeded with exploring the general scope of the method.
Thus, various substrates were subjected to the reaction
conditions of this one-step method comprising generation of
dimethylamine and further nucleophilic substitution in the
same reactor (Scheme 1). A solution of the substrate (0.25−1.0
M in DMF depending on solubility, see Table 3) was injected
as described above (1.24 M ammonia in DMF, 30 min
residence time at 240 °C). For convenience, 240 °C was
chosen as the reactor temperature, as the stabilization time
required for 250 °C (the maximum system temperature) was
significantly longer. The output stream was collected and the
product was isolated by aqueous workup and flash chromatog-
raphy, unless otherwise stated (Table 3). Good to excellent
yields for dimethylamine substitution of 2- and 4-chloropyr-
idines, chloropyrimidines, and chloro- and bromoquinolines
(entries 1−3 and 5−7) were obtained under these conditions.
Electron-deficient chloro- and fluorobenzenes (entries 8 and 9)
as well as 2-chloro- or bromoazoles (entries 11−13) were also
excellent substrates for this procedure.
In conclusion, we have developed a flow protocol for the in
situ formation of dimethylamine from DMF to be used in the
substitution of activated aromatic and heteroaromatic halides.
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Table 3. Scope of One-step (A) and Two-Step (B) Method for DMF Decomposition and SNAr
a
b
c
Concentration of reagent in injection loop. Low yield due to difficulties isolating the product. Products pure after aqueous workup, i.e., no
d
e
column chromatography. Estimated by dividing the product peak area by the total peak area in the UV trace of LC−MS. Temperature of second
reactor: 50 °C. Flow rate of each stream: 0.500 mL/min.
f
decomposition of DMF, allowing a broader scope and resulting
in good to excellent yields for a number of electrophiles.
Notably, the reaction is safely and easily scaled up to give high
yields with no additional optimization.
Scheme 3. Scale-up
EXPERIMENTAL SECTION
■
General Methods. UPLC-MS was performed with PDA detector
(operating at 254 nm), ELS detector and TQ-MS equipped with
APPI-source operating in positive-ion mode. High-resolution mass
spectra were recorded using APPI ionization.
The synthesis is easy to perform, makes use of inexpensive
reagents, is scalable, and benefits from the improved safety
profile of the continuous flow reaction. The temperature of the
substitution reaction can be varied independently of the
Effect of Additives in Microwave Experiments. A microwave
vial was charged with 2-chloro-3-nitropyridine (0.079 g, 0.5 mmol)
and one of the following additives: p-toluenesulfonic acid (9.5 mg, 0.05
mmol) in DMF (1 mL), AcOH (3.0 mg, 0.05 mmol) in DMF (1 mL),
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NH4Cl (2.7 mg, 0.05 mmol) in DMF (1 mL), K2CO3 (35 mg, 0.25
mmol) in DMF (0.5 mL) and water (0.5 mL), or aqueous NH3 (12.4
M, 0.2 mL) mixed with DMF (0.8 mL). The vial was flushed with
argon, sealed with a cap, and left to react in a microwave reactor for 30
min at 150 °C. The results are shown in Table 1.
Effect of Additives in Flow Experiments. The system was
configured as shown in Scheme 2. The additive (p-toluenesulfonic
acid, AcOH, NH4Cl, K2CO3 (aq) or NH3 (aq), see Table 1) was
dissolved in DMF and pumped through a high temperature stainless
steel reactor (flow rate: 0.500 mL/min, volume: 10 mL, residence
time: 20 min, temperature: 240 °C). The stream from the first reactor
was mixed with a stream of 2-chloro-3-nitropyridine in DMF (1.043
mL, 1.0 mmol, 1.0 M, flow rate: 0.500 mL/min) and the mixture was
passed through a second reactor (volume: 10 mL, residence time: 10
min, temperature: 50 °C) followed by a back pressure regulator (25
bar). The results are shown in Table 1.
Effect of Temperature. The system was configured as shown in
Scheme 1. 2-Chloro-3-nitropyridine (1.585 g, 10.00 mmol) was
dissolved in DMF (10.0 mL) and NH3 (aq, 12.4 M, 2.0 mL) was
dissolved in DMF (8.0 mL). 1.043 mL of each solution were pumped
through separate pumps at 0.167 mL/min each (total flow rate: 0.333
mL/min), mixed in a T-piece and passed through a high temperature
stainless steel reactor (10 mL; temperature: 150, 200, or 250 °C;
residence time: 30 min) followed by a back pressure regulator (25
bar). The results are presented in Table 2.
General Method A. A solution of the electrophile (3.0 mL, 0.50 or
1.00 M in DMF) was loaded into a sample loop (1.043 mL). The
solution was injected into a DMF stream pumped at 0.167 mL/min
and mixed with a stream of aqueous NH3/DMF (12.4 M of aqueous
NH3 mixed with DMF (1:9); flow rate: 0.167 mL/min). The mixture
was passed through a high temperature stainless steel reactor (10 mL,
240 °C, residence time: 30 min) followed by a cooling element (1 m)
and a back pressure regulator (25 bar). Unless otherwise stated, the
collected product was diluted with brine (100 mL) and the product
was extracted with EtOAc (3 × 100 mL). The combined organic
phases were then dried over MgSO4 and concentrated, and the residue
was purified by column chromatography (CombiFlash Rf, 24 g silica,
eluent: heptane/EtOAc).
General Method B. Aqueous NH3/DMF (12.4 M aqueous NH3
mixed with DMF (1:9)) was pumped (0.250 mL/min) through a
stainless steel reactor (10 mL, 240 °C, residence time: 40 min)
followed by a cooling element (1 m). A solution of the electrophile
(3.0 mL, 0.25 or 0.50 M in DMF) was loaded into a sample loop
(1.043 mL). The solution was injected into a DMF stream (0.250 mL/
min) and mixed with the aqueous NH3/DMF stream exiting the
stainless steel reactor. The mixture was passed through a PFA reactor
(10 mL, 30 or 50 °C, residence time: 20 min) followed by a back
pressure regulator (25 bar). Unless otherwise stated, the collected
product was diluted with brine (100 mL) and the product extracted
with EtOAc (3 × 100 mL). The combined organic phases were dried
over MgSO4 and concentrated, and the residue was purified by column
chromatography (CombiFlash Rf, 24 g silica, eluent: heptane/EtOAc).
N,N-Dimethyl-3-nitropyridin-2-amine (Table 3, Entry 1). The
title compound was prepared from 2-chloro-3-nitropyridine (475.6
mg, 3.000 mmol) according to method A. The collected solution was
diluted with EtOAc (100 mL), washed with water (3 × 200 mL), dried
over MgSO4, and filtered and the solvent evaporated. The product was
purified by column chromatography (CombiFlash Rf, 24 g silica,
eluent: pentane/EtOAc). The solvent was evaporated by heating the
eluted solution to 90 °C (ambient pressure) to yield 102.2 mg (59%)
of the title compound. NMR data agree with those of Kodimuthali et
al.2d and Rasala et al.8
NMR (151 MHz, CDCl3) δ 154.5, 149.2, 106.7, 39.2. H NMR data
agree with those of Kodimuthali et al.2d
N4,N4,6-Trimethylpyrimidine-2,4-diamine (Table 3, Entries 3
and 4). The title compound was prepared from 2-amino-4-chloro-6-
methylpyrimidine (222.0 mg, 1.546 mmol) according to method A.
The collected product was diluted with saturated aqueous K2CO3 (100
mL) and extracted with EtOAc (3 × 100 mL). The organic phases
were collected, dried over MgSO4, and concentrated. The residue was
purified by column chromatography: A 24 g silica column was flushed
with 10% triethylamine in EtOAc and washed with EtOAc before the
chromatography. Eluent EtOAc/2% triethylamine in EtOAc: yield 60.4
1
mg (74%); white crystalline solid; mp 159−168 °C dec; H NMR
(600 MHz, CDCl3) δ 5.70 (s, 1H), 4.99 (s, 2H), 2.98 (s, 6H), 2.16 (s,
3H); 13C NMR (151 MHz, CDCl3) δ 165.1, 163.7, 162.3, 92.6, 37.0,
23.8; HRMS calcd for C7H13N4 (M + H) 153.1135, found 153.1137.
Attempted preparation of the title compound from 2-amino-4-chloro-
6-methylpyrimidine (222.3 mg, 1.548 mmol) according to method B
was unsuccessful, and no product or remaining starting material could
be identified by LC−MS analysis of the reaction mixture.
Scale-up. 2-Amino-4-chloro-6-methylpyrimidine (10.36 g, 72.2
mmol) was dissolved in DMF to a total volume of 140 mL. This
solution (135 mL) and a solution of aqueous NH3/DMF (12.4 M
aqueous NH3 mixed with DMF (1:9)) were pumped via separate
pumps (flow rate of each pump: 0.167 mL/min). The streams were
mixed in a T-piece and continued through a high-temperature stainless
steel reactor (10 mL, 240 °C, residence time: 30 min) followed by a
cooling element (1 m) and a back-pressure regulator (25 bar). The
collected product was diluted with saturated aqueous K2CO3 (500
mL) and extracted with EtOAc (3 × 500 mL). The organic phases
were collected, dried over MgSO4, and concentrated. The residue was
purified by column chromatography (220 g silica flushed with 10%
triethylamine in EtOAc and washed with EtOAc; eluent, EtOAc/2%
triethylamine in EtOAc): yield 8.78 g (83%).
6-Ethyl-N,N,2-trimethylquinolin-4-amine (Table 3, Entry 5).
The title compound was prepared from 4-chloro-6-ethyl-2-methyl-
quinoline (617.7 mg, 3.003 mmol) according to method A. The
collected product was diluted with EtOAc (100 mL) and washed with
water (100 mL) and brine (100 mL), and the organic phase was dried
over MgSO4 and concentrated. The residue was purified by column
chromatography to yield 184.4 mg (82%) of the title compound as a
1
pale yellow oil: H NMR (600 MHz, CDCl3) δ 7.87 (d, J = 8.6 Hz,
1H), 7.77 (d, J = 0.9 Hz, 1H), 7.45 (dd, J = 8.6, 1.9 Hz, 1H), 6.63 (s,
1H), 2.96 (s, 6H), 2.79 (q, J = 7.6 Hz, 2H), 2.63 (s, 3H), 1.30 (t, J =
7.6 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 158.4, 157.6, 148.3,
140.2, 130.1, 129.2, 122.1, 121.7, 108.5, 44.2, 29.4, 25.8, 16.0; HRMS
calcd for C14H19N2 (M + H) 215.1543, found 215.1541.
N,N-Dimethylquinolin-2-amine (Table 3, Entries 6 and 7).
The title compound was prepared from 2-chloroquinoline (490.7 mg,
2.999 mmol) according to method A. The collected product was
diluted with EtOAc (100 mL) and washed with water (100 mL) and
brine (100 mL), the organic phase was dried over MgSO4 and
concentrated. The residue was purified by column chromatography to
yield 160.6 mg (89%) of the title compound. NMR data agrees with
Lundgren et al.9 Alternatively, the title compound was prepared
according to method A from 2-bromoquinoline (660.0 mg, 3.172
mmol). The collected product was diluted with EtOAc (100 mL) and
washed with water (100 mL) and brine (100 mL), and the organic
phase was dried over MgSO4 and concentrated. The residue was
purified by column chromatography to yield 146.8 mg (77%) of the
title compound.
2-Bromo-N,N-dimethyl-4-nitroaniline (Table 3, Entry 8). The
title compound was prepared from 2-bromo-1-chloro-4-nitrobenzene
(708.8 mg, 2.998 mmol) according to method A. The collected
product was diluted with EtOAc (100 mL) and washed with water
(100 mL) and brine (100 mL), and the organic phase was dried over
MgSO4 and concentrated. The residue was purified by column
N,N-Dimethylpyridin-4-amine (Table 3, Entry 2). The title
compound was prepared from 4-chloropyridine hydrochloride (225.1
mg, 1.500 mmol) according to method A. The collected solution was
diluted with brine (100 mL), extracted with EtOAc (3 × 100 mL),
dried over MgSO4, and filtered and the solvent evaporated to afford
49.4 mg (78%) of the title compound: 1H NMR (600 MHz, CDCl3) δ
8.20 (d, J = 5.8 Hz, 2H), 6.49 (d, J = 6.5 Hz, 2H), 3.00 (s, 6H); 13C
1
chromatography to yield 222.2 mg (87%) of the title compound: H
NMR (600 MHz, CDCl3) δ 8.36 (d, J = 2.7 Hz, 1H), 8.06 (dd, J = 9.0,
2.7 Hz, 1H), 6.99 (d, J = 9.0 Hz, 1H), 2.99 (s, 6H); 13C NMR (151
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1
MHz, CDCl3) δ 157.2, 141.1, 130.4, 123.9, 118.5, 114.5, 43.5. H
NMR data agree with those of Doyle et al.10
2-Bromo-N,N-dimethyl-4-nitroaniline (Table 3, Entry 18).
The title compound was prepared from 2-bromo-1-fluoro-4-nitro-
benzene (165.9 mg, 0.754 mmol) according to method B to yield 62.6
N,N-Dimethyl-2-nitro-4-(trifluoromethyl)aniline (Table 3,
Entries 9 and 10). The title compound was prepared from 1-
fluoro-2-nitro-4-(trifluoromethyl)benzene (627.7 mg, 3.002 mmol)
according to method A. The collected product was diluted with EtOAc
(100 mL) and washed with water (100 mL) and brine (100 mL), and
the organic phase was dried over MgSO4 and concentrated. The
residue was purified by column chromatography to yield 191.0 mg
1
mg (97%) without column chromatography: H NMR (600 MHz,
CDCl3) δ 8.39 (d, J = 2.7 Hz, 1H), 8.08 (dd, J = 9.0, 2.7 Hz, 1H), 6.97
(d, J = 9.0 Hz, 1H), 2.97 (s, 6H); 13C NMR (151 MHz, CDCl3) δ
1
157.2, 141.3, 130.4, 123.9, 118.4, 114.7, 43.5; H NMR data agrees
with those of Doyle et al.10
N,N-Dimethylbenzo[d]oxazol-2-amine (Table 3, Entry 19).
The title compound was prepared from 2-chlorobenzo[d]oxazole
(230.3 mg, 1.500 mmol) according to method B to yield 79.5 mg
(94%) without column chromatography. NMR data agree with those
of Cho et al.12
4-Chloro-N,N-dimethyl-2-nitroaniline (Table 3, Entry 20).
The title compound was prepared from 4-chloro-1-fluoro-2-nitro-
benzene (132.7 mg, 0.756 mmol) according to method B to yield 41.6
mg (79%). NMR data agree with those of Yang et al.14
N,N,4-Trimethyl-5-nitropyridin-2-amine (Table 3, Entry 21).
The title compound was prepared from 2-chloro-4-methyl-5-nitro-
pyridine (257.3 mg, 1.491 mmol) according to method B to yield 86.9
mg (92%): 1H NMR (600 MHz, CDCl3) δ 8.92 (s, 1H), 6.19 (s, 1H),
3.15 (s, 6H), 2.55 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 160.2,
148.1, 144.8, 135.6, 106.5, 38.3, 22.2; HRMS calcd for C8H12N3O2 (M
+ H) 182.0924, found 182.0926.
1
(78%) of the title compound as a yellow oil: H NMR (600 MHz,
CDCl3) δ 8.04 (d, J = 1.5 Hz, 1H), 7.57 (dd, J = 9.0, 2.1 Hz, 1H), 7.08
(d, J = 9.0 Hz, 1H), 2.97 (s, 6H); 13C NMR (151 MHz, CDCl3) δ
147.8 (s), 136.8 (s), 129.6 (q, J = 3.3 Hz), 124.8 (q, J = 12.3 Hz),
123.7 (q, J = 270.8 Hz), 118.4 (q, J = 34.3 Hz), 117.8 (s), 42.1 (s);
HRMS calcd for C9H10F3N2O2 (M + H) 235.0689, found 235.0690.
Alternatively, the title compound was prepared from 1-fluoro-2-nitro-
4-(trifluoromethyl)benzene (315.1 mg, 1.507 mmol) according to
method B to yield 96.5 mg (82%).
N,N-Dimethyl-1H-benzo[d]imidazol-2-amine (Table 3, Entry
11). The title compound was prepared from 2-chloro-1H-benzo[d]-
imidazole (229.0 mg, 1.501 mmol) according to method A. The
collected product was diluted with water (100 mL), the product
extracted with EtOAc (100 mL), and the organic phase dried over
MgSO4 and concentrated. The residue was purified by column
5-Bromo-N,N-dimethyl-2-nitroaniline (Table 3, Entries 22
and 23). Attempted preparation from 4-bromo-2-fluoro-1-nitro-
benzene (335.2 mg, 1.524 mmol) according to method A was
unsuccessful, and no product or starting material was observed by
LC−MS. Instead, the title compound was prepared from 4-bromo-2-
fluoro-1-nitrobenzene (330.3 mg, 1.501 mmol) according to method B
but with the flow rate of each pump increased to 0.500 mL/min to
yield 125.8 mg (97%) without column chromatography: yellow
1
chromatography to yield 77.4 mg (92%) of the title compound: H
NMR (600 MHz, DMSO-d6) δ 7.16 (d, J = 7.7 Hz, 1H), 7.13 (d, J =
7.6 Hz, 1H), 6.91 (t, J = 7.4 Hz, 1H), 6.84 (t, J = 7.4 Hz, 1H), 3.03 (s,
6H); 13C NMR (151 MHz, DMSO-d6) δ 156.9, 143.8, 134.4, 120.2,
118.2, 114.8, 108.7, 38.1. 1H NMR data agree with those of El-Faham
et al.11
N,N-Dimethylbenzo[d]thiazol-2-amine (Table 3, Entries 12
and 13). The title compound was prepared from 2-chlorobenzo[d]-
thiazole (256.3 mg, 1.511 mmol) according to method A. The
collected product was diluted with water (100 mL), the product
extracted with EtOAc (100 mL), and the organic phase dried over
MgSO4 and concentrated. The residue was purified by column
chromatography to yield 80.9 mg (86%) of the title compound. NMR
data agree with those of Cho et al.12 Alternatively, the title compound
was prepared from 2-bromobenzo[d]thiazole (319.4 mg, 1.492 mmol)
according to method A to yield 71.8 mg (78%).
4-(Dimethylamino)-3-nitrobenzonitrile (Table 3, Entries 14
and 15). Attempted preparation of the title compound from 4-chloro-
3-nitrobenzonitrile (273.6 mg, 1.499 mmol) according to method A
afforded a complex mixture; LC−MS showed 14% product and 86%
unidentified side products. Alternatively, the title compound was
prepared from 4-chloro-3-nitrobenzonitrile (273.5 mg, 1.498 mmol)
according to method B to yield 96.3 mg (97%). NMR data agree with
those of Brzozowski et al.13
1
crystalline solid; mp 47−49 °C; H NMR (600 MHz, CDCl3) δ 7.62
(d, J = 8.7 Hz, 1H), 7.12 (d, J = 2.0 Hz, 1H), 6.88 (dd, J = 8.7, 2.0 Hz,
1H), 2.87 (s, 6H); 13C NMR (151 MHz, CDCl3) δ 146.9, 137.5,
128.2, 128.0, 120.8, 120.5, 42.4; HRMS calcd for C8H10BrN2O2 (M +
H) 244.9920, found 244.9912.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ulven@sdu.dk, arit@lundbeck.com.
■
Notes
2-(Dimethylamino)-4-methylquinoline-3-carbonitrile (Table
3, Entry 16). The title compound was prepared from 2-chloro-4-
methylquinoline-3-carbonitrile (304.1 mg, 1.501 mmol) according to
method B to yield 75.2 mg (68%).: pale yellow crystalline solid; mp
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the Danish Agency for Science, Technology and
Innovation for financial support.
■
1
101−102 °C; H NMR (600 MHz, CDCl3) δ 7.79 − 7.76 (m, 1H),
7.71 − 7.68 (m, 1H), 7.61 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.29 (ddd, J
= 8.2, 6.8, 1.3 Hz, 1H), 3.25 (s, 6H), 2.81 (s, 3H); 13C NMR (151
MHz, CDCl3) δ 158.0, 154.6, 147.9, 132.3, 127.8, 124.3, 123.7, 121.9,
117.7, 97.9, 41.1, 17.7; HRMS calcd for C13H14N3 (M + H) 212.1182,
found 212.1176.
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