Selective N-monomethylation of primary anilines with dimethyl carbonate in continuous flow

Article abstract of DOI:10.1016/j.tet.2017.11.068

Selective N-monomethylation of anilines has been achieved under continuous flow conditions using dimethyl carbonate as a green methylating agent in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene. Our methodology takes advantage of the expanded process windows available in the continuous flow regime to safely induce monomethylation in superheated solvents at high pressure. We propose selective N-monomethylation is achieved via an in situ protection-deprotection pathway, which is supported by the observed reactivities of several putative reaction intermediates. The robust and scalable method was applicable to a broad range of primary aniline substrates including ortho-, meta-, and para-substituted anilines, as well as electron-rich and electron-deficient anilines. The synthetic precursor of diazepam, 5-chloro-2-(methylamino)benzophenone, was selectively synthesized under our optimized conditions.

Full text of DOI:10.1016/j.tet.2017.11.068

Accepted Manuscript
Selective N-monomethylation of primary anilines with dimethyl carbonate in
continuous flow
Hyowon Seo, Anne-Catherine Bédard, Willie P. Chen, Robert W. Hicklin, Alexander
Alabugin, Timothy F. Jamison
PII:
S0040-4020(17)31234-6
10.1016/j.tet.2017.11.068
TET 29148
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 18 October 2017
Revised Date: 21 November 2017
Accepted Date: 23 November 2017
Please cite this article as: Seo H, Bédard A-C, Chen WP, Hicklin RW, Alabugin A, Jamison TF, Selective
N-monomethylation of primary anilines with dimethyl carbonate in continuous flow, Tetrahedron (2017),
doi: 10.1016/j.tet.2017.11.068.
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Selective N-monomethylation of primary
anilines with dimethyl carbonate in
continuous flow
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Hyowon Seo, Anne-Catherine Bédard, Willie P. Chen, Robert W. Hicklin, Alexander Alabugin, and Timothy F.
Jamison*
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, MA
02139, USA

1
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Tetrahedron
journal homepage: www.elsevier.com
Selective N-monomethylation of primary anilines with dimethyl carbonate in
continuous flow
Hyowon Seo, Anne-Catherine Bédard, Willie P. Chen, Robert W. Hicklin, Alexander Alabugin, and
Timothy F. Jamison*
aDepartment of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, MA 02139, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Selective N-monomethylation of anilines has been achieved under continuous flow conditions
using dimethyl carbonate as green methylating agent in the presence of 1,8-
a
Received in revised form
Accepted
Available online
diazabicyclo[5.4.0]undec-7-ene. Our methodology takes advantage of the expanded process
windows available in the continuous flow regime to safely induce monomethylation in
superheated solvents at high pressure. We propose selective N-monomethylation is achieved via
an in situ protection-deprotection pathway, which is supported by the observed reactivities of
several putative reaction intermediates. The robust and scalable method was applicable to a
broad range of primary aniline substrates including ortho-, meta-, and para-substituted anilines,
as well as electron-rich and electron-deficient anilines. The synthetic precursor of diazepam, 5-
chloro-2-(methylamino)benzophenone, was selectively synthesized under our optimized
conditions.
Keywords:
Monomethylation of anilines
Continuous flow chemistry
Green chemistry
Dimethyl carbonate
in situ Protection-deprotection
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
N-alkylanilines are ubiquitous motifs in the pharmaceutical
and agrochemical industries.1 In particular, N-methylanilines are
found in a range of biologically active compounds such as
diazepam, flobetapir, triafamone, and broflanilide (Figure 1).2 N-
alkylation reactions are common and essential transformations
for the synthesis of pharmaceuticals and fine chemicals.3
However, selective mono-N-alkylation of primary alkyl and aryl
amines remains a challenging transformation due to the greater
nucleophilicity of secondary amines compared to primary
amines.4 The synthesis of N-methylanilines is particularly
challenging and the use of classical approaches for N-alkylation
via reaction with alkyl halides or by reductive amination often
results in the formation of mixtures of secondary and tertiary
Fig. 1. Representative examples of bioactive N-monomethylanilines.
transition metal catalysts at high temperatures (200-500 ºC).7
Homogeneous N-monomethylation reactions of primary anilines
have also been developed, but require expensive ligands and
4,
5
anilines.
Often, lab-scale syntheses of N-methylanilines
require multistep sequences involving the incorporation and
removal of protecting groups or the installation and exhaustive
reduction of a carbamate.6 The difficulty associated with the
selective N-monomethylation of primary anilines is often
reflected in the price of N-methylanilines versus their primary
aniline analogs. A 50- to 100-fold increase in the price per gram
is not unusual for this seemingly simple functionalization.
The development of robust and selective methods for the
selective N-monomethylation of primary anilines would greatly
simplify the synthesis of N-methylanilines and several
approaches have been reported. On the industrial scale, N-
monomethylation of primary anilines is accomplished via
reaction with methanol in the vapor phase using heterogeneous
Scheme 1. Schematic diagram of continuous flow system for the
selective N-monomethylation of anilines.

2
Tetrahedron
ACCEPTED MANUSCRIPT
transition metal catalysts.8
Dimethylcarbonate (DMC) is an inexpensive and green
mixer. The combined reagent stream was then transported
through a high temperature coiled tube reactor (10 mL, stainless
steel, 0.03” i.d.), which was equipped with a back pressure
regulator (100 psi) to help control the release of the CO2
produced in the reactor. Preliminary studies identified 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) as the optimal base for
the reaction and all optimization studies were performed using
methylating reagent9 that is commonly utilized in the methylation
of carboxylic acids, arylacetonitriles, phenols, indoles, and
benzimidazoles.10 DMC has been employed in the selective N-
monomethylation of primary anilines in the presence of zeolite
catalysts.11 However, these reactions employ DMC in solvent
quantities and require the use of an autoclave in order to heat the
reaction past the boiling point of DMC (b.p. = 90 °C) and to
accommodate the stoichiometric amount of CO2 generated in the
reaction. These challenges have limited the widespread
application of DMC as a reagent for the selective N-
monomethylation of primary anilines.
DBU (Entries
1 – 7). However, other bases, such as
triethylamine, were found to be competent in the reaction, albeit
lower yielding (Entry 8). The continuous N-monomethlyation of
1a was found to be highly temperature dependent. When the
reaction was performed at 90 °C (the boiling point of DMC), no
N-methyl aniline (3a) was observed during a 12 minute residence
time (Entry 1). Increasing the reaction temperature to 150 °C
showed trace conversion to carbamate 4 but no formation of 3a
(Entry 2). Further heating to 200 °C resulted in increased
formation of carbamate 4 and some formation of the desired N-
methylaniline 3a (Entry 3). Best results were obtained at 250 °C,
providing N-methylaniline 3a in 88% yield with 12% of
carbamate 4 and no overalkylation byproduct 5 (Entry 4). It was
found that 12 minutes was an optimal residence time, as
increasing or decreasing residence time resulted in decreased
yields of 3a (Entries 5 – 7). At a residence time of 20 minutes,
trace amounts N,N-dimethylaniline 5 were observed (Entry 7).
Under optimized conditions (12 minutes, 250 °C), a throughput
of 3.7 g/h of 3a was achieved.
Continuous flow systems are an attractive platform for the
selective N-monomethlyation of anilines using DMC. The ability
to incorporate back pressure regulators (BPR) and the small
volume of the flow reactor enables reactions to be safely operated
at temperatures and pressures which would be inaccessible in
traditional batch systems without specialized equipment (e.g.,
autoclave).12 Furthermore, gaseous byproducts can be safely
contained in the pressurized continuous flow system and then
undergo controlled separation from the liquid phase upon passing
through the back pressure regulator.13 Herein, we report the
development of an efficient and selective N-monomethylation of
primary anilines with environmentally benign DMC in a
commercially available Vapourtec E-series continuous flow
system (Scheme 1).
The increased ratio of 4 to 3a at lower temperature and shorter
residence time is consistent with formation of 4 as the initial
product of the reaction (Scheme 2). N-methylaniline 3a could
then be formed by an in situ thermal decarboxylation of 4,
analogous to a solvent-free thermal tert-butyloxycarbonyl (Boc)
deprotection.14 Based on these observations, we propose that the
reaction sequence begins by reaction of aniline 1a with DMC to
form carbamate 6, followed by methylation of the carbamate via
reaction with a second equivalent of DMC in the presence of
2. Results/Discussion
Initial optimization studies on the continuous N-
monomethlyation of primary anilines with DMC were performed
using 4-chloroaniline (1a) as a model substrate (Table 1). In a
Vapourtec E-series continuous flow platform, a stream of 1a in
N-methyl-2-pyrrolidone (NMP) was mixed with streams of DMC
(3 equiv) in NMP and base (1.5 equiv) in NMP using a cross
Table 1. Optimization of selective N-monomethylation of 4-chlroaniline.a
Entry
Base
DBU
DBU
DBU
DBU
DBU
DBU
DBU
TEA
Temp (ºC)
90
tR (min)
12
Yield 3a (%)b
Yield 4 (%)b
Yield 5 (%)b
1
2
3
4
5
6
7
8
0
0
trace
63
12
17
7
0
0
150
12
0
200
12
26
88
55
61
68
15
0
250
12
0
250
5
0
250
16
0
250
20
15
<5
250
12
30
0
aReactions were carried out using a Vapourtec E-series flow chemistry system. Reaction conditions: 1a (20 mmol, 2 M in NMP), DMC
(60 mmol, 6 M in NMP), base (30 mmol, 3 M in NMP) were introduced to a 10 mL stainless steel reactor tubing at a flow rate for the
b
designated residence time. The system was equilibrated for 1.5 time the residence time. Calculated by GC analysis using methyl
benzoate as an internal standard.

3
3. Conclusion
DBU to form 4. Carbamate 4 then undergoes a thermal
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decarboxylation to provide N-methylaniline 3a. In support of this
reaction pathway, we found that 4 decomposes to form 3a at 250
°C and 6 reacts with DMC and DBU to form 3a. These results
suggest that anilines preferentially react with DMC to form
In conclusion, the selective N-monomethlyation of primary
anilines has been accomplished using a commercial continuous
flow platform. The reaction employs DMC as an inexpensive and
environmentally friendly methylating reagent and relies on an in
situ protection/deprotection strategy to achieve excellent
selectivity for monomethylation. The continuous flow system
enables safe and robust N-monomethlyation of anilines at high
temperature with a throughput of 3.7 g/h. Aniline substitution is
generally tolerated in the reaction and selective N-
monomethlyation can be achieved with both electron-rich and
electron-deficient anilines. This methodology was successfully
employed to produce an intermediate in the synthesis of
diazepam in good yield at low cost.
4. Experimental Section
4.1. General
Commercially available reagents were used without additional
purification. Analytical thin-layer chromatography (TLC) was
performed on 0.2 mm coated silica gel (EM 60 F254) plates.
Visualization was accomplished with UV light (254 nm) and
exposure to potassium permanganate solution followed by
heating. Column chromatography was carried out on a Biotage
Isolera flash chromatography system using Ultra-Sil columns
(silica gel, average particle size 25 ꢀm spherical). Proton nuclear
magnetic resonance (1H NMR) spectra and carbon nuclear
magnetic resonance (13C NMR) spectra were obtained on a
Bruker 400 MHz NMR instrument (400 and 101 MHz,
respectively). Chemical shifts for proton are reported in parts per
million (ppm) downfield from tetramethylsilane (δ = 0.00 ppm)
and are referenced to residual protium in CDCl3 (7.26 ppm).
Chemical shifts for carbon are reported in ppm downfield from
tetramethylsilane (δ = 0.00 ppm) and are referenced to residual
carbon in CDCl3 (77.0 ppm). The following designations are used
to describe multiplicities: s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet), br (broad). IR spectra were obtained on
an Agilent Cary 630 FT-IR spectrometer equipped with an ATR
(attenuated total reflectance) accessory. The following
designations are used to describe intensities: s (strong), m
Scheme 2. Proposed pathway of selective N-monomethylation of
anilines.
carbamates under our reaction conditions and methylation
predominantly occurs by reaction of DMC with a carbamate.
We next explored the scope of our selective N-
monomethlyation reaction with a variety of aniline substrates
(Table 2). It was found that substitution was generally tolerated
at the para- (3a – 3f), meta- (3g and 3h), and ortho-positions (3i –
3l). However, sterically hindered anilines such as 2,5-
dimethylaniline did not undergo methylation under our reaction
conditions. It was also found that both electron-deficient (3a, 3b,
3i, 3k and 3l) and electron-rich (3c, 3d, 3e, 3h, and 3j) substrates
were tolerated under the conditions. N-methylaniline 3l has been
employed as a starting point in several syntheses of diazepam but
is significantly more expensive than the corresponding primary
aniline.2a,15 Under our optimized continuous flow conditions, 3l
was readily generated in a good yield without the formation of
any overalkylation byproducts.
(medium),
w
(weak), br (broad). High-resolution mass
spectrometry data were acquired in the Department of Chemistry
Instrumentation Facility, Massachusetts Institute of Technology
on a Bruker Daltonics APEXIV 4.7 Tesla FT-ICR Mass
Spectrometer. Gas chromatography (GC) was performed on an
Agilent 5870 GC (HP-5 column) with a flame ionization
detector.
Table 2. Substrate scope.a
4.2. General procedure for the selective N-monomethylation of
anilines in continuous flow.
Selective N-monomethlyation reactions were performed in a
Vapourtec E-series continuous flow system equipped with a high
temperature tube reactor (10 mL, stainless steel, 0.03” i.d., Figure
2) and a membrane back pressure regulator (Zaiput). Stock
solutions of aniline (20 mmol, 1.0 equiv, 2 M), DMC (5.05 mL,
60 mmol, 3.0 equiv, 6 M), and DBU (4.47 mL, 30 mmol, 1.5
equiv, 3 M) were prepared in oven-dried 10 mL volumetric flasks
using NMP as the solvent. The solutions were transferred to
screw-thread vials with septum caps and reagents were pumped
directly from the vials. After the high temperature coiled tube
reactor was heated to 250 ºC, peristaltic pumps (Vapourtec V-3)
were used to pump the reactant solutions into the system (0.277
mL/min each for a 12 min residence time). The solutions were
mixed with a cross-mixer (0.4’’ i.d.), passed though the high
temperature coiled tube reactor. Upon exiting the reactor, the
aIsolated yield of the N-monomethylaniline.

4
Tetrahedron
777 (w), 731 (w), 702 (w). HRMS (m/z) [M+H]+ calcd for C11H18N,
reaction stream was passed through a short segment of stainless
ACCEPTED MANUSCRIPT
164.1434; found, 164.1435.
steel tubing to enable the reaction to cool and then exited the
system by passage through the back pressure regulator (Note:
PFA fittings should not be used at the exit of the reactor as they
will deform due to the high temperature of the reaction stream
and cause leaks in the system. Stainless steel connectors and
tubing (12”) were used in our system.). After the flow system
was equilibrated for 18 minutes, the product stream was collected
for 5 min (2.77 mmol of aniline). The crude mixture was
dissolved in ethyl acetate and washed with brine. The combined
organic layers were dried over magnesium sulfate, filtered, and
concentrated under reduced pressure. The residue was purified by
column chromatography (Biotage 25 g Ultra-sil, 3–15% ethyl
4.2.5. N-methyl-[1,1'-biphenyl]-4-amine (3e)
323 mg (64%); yellow solid; H NMR (400 MHz, CDCl3) δ 7.55
(d, J = 7.0 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.40 (t, J = 7.6 Hz, 2H),
7.27 (t, J = 7.4 Hz, 1H), 6.79 (d, J = 7.6 Hz, 2H), 3.42 (br s, 1H),
2.91 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 147.5, 141.1, 131.4,
128.6, 128.0, 126.4, 126.2, 113.6, 31.4. The 1H and 13C NMR spectra
are in agreement with those reported in the literature.18
1
4.2.6. 4-iodo-N-methylaniline (3f)
490 mg (76%); yellow oil; H NMR (400 MHz, CDCl3) δ 7.50 –
1
7.40 (m, 2H), 6.47 – 6.44 (m, 2H), 3.37 (br s, 1H), 2.81 (s, 3H). 13C
NMR (101 MHz, CDCl3) δ 137.8, 115.2, 31.0. IR (neat, cm-1) 3418
(m), 3182 (w), 2984 (w), 2922 (w), 2879 (m), 2811 (m), 2571 (w),
2384 (w), 2295 (w), 2118 (w), 1869 (w), 1590 (w), 1494 (s), 1430
(w), 1389 (m), 1314 (s), 1293 (m), 1257 (s), 1180 (s), 1154 (m),
1111 (w), 1067 (w), 1051 (m), 993 (m), 807 (s), 751 (m), 692 (m).
HRMS (m/z) [M+H]+ calcd for C7H9IN, 233.9774; found, 233.9782.
4.2.7. 3-bromo-N-methylaniline (3g)
1
490 mg (96%); yellow oil; H NMR (400 MHz, CDCl3) δ 7.03 (t,
J = 8.0 Hz, 1H), 6.85 – 6.82 (m, 1H), 6.77 (t, J = 2.0 Hz, 1H), 6.57 –
6.54 (m, 1H), 4.07 (br s, 1H), 2.82 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 150.0, 130.4, 123.3, 120.4, 115.2, 111.6, 30.8. The 1H and
13C NMR spectra are in agreement with those reported in the
literature.17
4.2.8. 3-methoxy-N-methylaniline (3h)
1
183 mg (48%); yellow oil; H NMR (400 MHz, CDCl3) δ 7.11 (t,
J = 8.1 Hz, 1H), 6.34 – 6.28 (m, 2H), 6.23 (q, J = 2.3 Hz, 1H), 4.07
(br s, 1H), 3.79 (s, 3H), 2.84 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
1
160.8, 149.9, 130.0, 106.2, 103.2, 99.0, 55.1, 31.2. The H NMR
spectra is in agreement with that reported in the literature. 19
4.2.9. 2-(methylamino)benzonitrile (3i)
1
70 mg (19%); yellow solid; H NMR (400 MHz, CDCl3) δ 7.42
(dt, J = 7.5, 1.9 Hz, 2H), 6.76 (td, J = 7.2, 6.7 Hz, 2H), 4.17 (br s,
acetate in hexanes) to afford the desired product.
1H), 2.95 (d, J = 2.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 151.0
1
134.3, 132.8, 117.6, 116.0, 109.7, 95.2, 30.6. The H and 13C NMR
spectra are in agreement with those reported in the literature.17
Fig. 2. Photographs of E-series flow platform.
4.2.1. 4-chloro-N-methylaniline (3a)
4.2.10. N-methyl-2-(1H-pyrrol-1-yl)aniline (3j)
119 mg (25%); clear oil; 1H NMR (400 MHz, CDCl3) δ 7.30 (td, J
= 7.8, 1.6 Hz, 1H), 7.17 (dd, J = 7.6, 1.6 Hz, 1H), 6.92 – 6.77 (m,
4H), 6.35 (t, J = 2.1 Hz, 2H), 5.20 (br s, 1H), 2.77 (s, 3H). 13C NMR
(101 MHz, CDCl3) δ 144.5, 128.9, 127.3, 126.9, 121.9, 116.5, 110.8,
109.3, 30.3. IR (neat, cm-1) 3422 (m), 2918 (m), 2880 (m), 2817 (m),
1741 (w), 1606 (m), 1586 (m), 1516 (s), 1484 (m), 1317 (s), 1291
(m), 1265 (w), 1247 (w), 1168 (m), 1117 (w), 1094 (m), 1065 (m),
1038 (w), 1013 (m), 923 (m), 842 (w), 801 (w), 722 (s). HRMS
(m/z) [M+H]+ calcd for C11H13N2, 173.1073; found, 173.1069.
1
307 mg (79%); yellow oil; H NMR (400 MHz, CDCl3) δ 7.20 –
7.07 (m, 2H), 6.62 – 6.50 (m, 2H), 3.85 (br s, 1H), 2.82 (s, 3H). 13C
NMR (101 MHz, CDCl3) δ 147.6, 129.0, 122.0, 113.6, 30.9. 1H
NMR spectra is in agreement with that reported in the literature.16
4.2.2. N-methyl-4-(trifluoromethyl)aniline (3b)
1
359 mg (74%); clear oil; H NMR (400 MHz, CDCl3) δ 7.43 (d, J
= 8.4 Hz, 2H), 6.68 (d, J = 8.0 Hz, 2H), 4.36 (br s, 1H), 2.88 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 150.7, 126.6 (q, J = 3.9 Hz), 126.2,
4.2.11. (2-(methylamino)phenyl)(phenyl)methanone
(3k)
1
123.5, 112.2, 30.8. The H NMR spectra is in agreement with that
215 mg (37%); yellow solid; 1H NMR (400 MHz, CDCl3) δ 7.65 –
7.57 (m, 2H), 7.55 – 7.48 (m, 2H), 7.48 – 7.40 (m, 3H), 6.91 (d, J =
8.4 Hz, 1H), 6.64 (t, J = 7.6 Hz, 1H), 2.99 (s, 3H). 13C NMR (101
MHz, CDCl3) δ 199.1, 151.2, 140.1, 135.3, 135.0, 130.9, 129.0,
128.7, 128.1, 118.4, 115.2, 112.6, 30.4. The 1H and 13C NMR spectra
are in agreement with those reported in the literature. 20
reported in the literature.16
4.2.3. N,4-dimethylaniline (3c)
168 mg (50%); clear oil; 1H NMR (400 MHz, CDCl3) δ 7.03 (d, J
= 7.9 Hz, 2H), 6.56 (d, J = 8.2 Hz, 2H), 2.83 (s, 3H), 2.27 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 146.8, 129.7, 126.8, 112.9, 31.3,
20.4. The 1H and 13C NMR spectra are in agreement with those
reported in the literature.17
4.2.12. (5-chloro-2-
(methylamino)phenyl)(phenyl)methanone (3l)
4.2.4. 4-(tert-butyl)-N-methylaniline (3d)
461 mg (68%); yellow solid; 1H NMR (400 MHz, CDCl3) δ 7.63 –
7.58 (m, 2H), 7.57 – 7.52 (m, 1H), 7.51 – 7.43 (m, 3H), 7.37 (dd, J =
9.0, 2.6 Hz, 1H), 6.83 (d, J = 8.9 Hz, 1H), 2.97 (s, 3H). 13C NMR
(101 MHz, CDCl3) δ 198.1, 149.9, 139.4, 134.8, 133.9, 131.3, 129.0,
128.3, 119.6, 118.9, 113.9, 30.3. The 1H and 13C NMR spectra are in
agreement with those reported in the literature.21
1
183 mg (41%); clear oil; H NMR (400 MHz, CDCl3) δ 7.30 –
7.24 (m, 2H), 6.81 – 6.72 (m, 2H), 3.37 (br s, 1H), 2.90 – 2.81 (s,
3H), 1.29 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 146.7, 140.2,
125.9, 112.4, 33.8, 31.5, 31.1. IR (neat, cm-1) 3410 (m), 3054 (w),
2959 (m), 2900 (m), 2868 (m), 2810 (w), 1700 (w), 1617 (m), 1520
(s), 1488 (m), 1459 (m), 1392 (w), 1362 (m), 1348 (m), 1303 (m),
1262 (m), 1193 (m), 1155 (m), 1113 (w), 1058 (w), 931 (w), 819 (s),
4.3. Characterization of reaction intermediates.

5
10. (a) Selva, M.; Marques, C. A.; Tundo, P. J. Chem. Soc. [Perkin 1]
4.3.1. methyl (4-chlorophenyl)(methyl)carbamate
ACCEPTED MANUSCRIPT
1994, 0, 1323-1328. (b) Bomben, A.; Selva, M.; Tundo, P.; Valli, L.
Ind. Eng. Chem. Res. 1999, 38, 2075-2079. (c) Shieh, W.-C.; Dell, S.;
Repič, O. Org. Lett. 2001, 3, 4279-4281. (d) Shieh, W.-C.; Dell, S.;
Repič, O. J. Org. Chem. 2002, 67, 2188-2191. (e) Battilocchio, C.;
Deadman, B. J.; Nikbin, N.; Kitching, M. O.; Baxendale, I. R.; Ley, S.
V. Chem. Eur. J. 2013, 19, 7917-7930.
(4)
1H NMR (400 MHz, CDCl3) δ 7.35 – 7.28 (m, 2H), 7.22 – 7.13
(m, 2H), 3.71 (s, 3H), 3.28 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
155.9, 141.8, 129.0, 126.9, 53.0, 37.6.
4.3.2. methyl (4-chlorophenyl)carbamate (6)
11. (a) Onaka, M.; Umezono, A.; Kawai, M.; Izumi, Y. J. Chem. Soc.
Chem. Commun. 1985, 17, 1202-1203. (b) Selva, M.; Bomben, A.;
Tundo, P. J. Chem. Soc. [Perkin 1] 1997, 0, 1041-1046.
12. (a) Ley, S. V.; Fitzpatrick, D. E.; Myers, R. M.; Battilocchio, C.;
Ingham, R. J. Angew. Chem. Int. Ed. 2015, 54, 10122-10136. (b)
Cambié, D.; Bottecchia, C.; Straathof, N. J. W.; Hessel, V.; Noël, T.
4-Chloroaniline (6.4 g, 50 mmol) and methyl chloroformate (5.8
mL, 75 mmol) were added to a solution of sodium carbonate (10.6 g,
100 mmol) in water (100 mL) and dichloroethane (100 mL). The
reaction mixture was stirred at 40 ºC for 3 hr. The organic layer was
separated, washed with 1 M HCl solution and brine. The organic
layer was concentrated to provide the carbamate 6 in 99% (9.2 g)
yield as a white solid.22 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J =
8.6 Hz, 2H), 7.27 (d, J = 8.6 Hz, 2H), 6.58 (br s, 1H), 3.78 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 153.9, 136.4, 129.0, 128.4, 119.9,
Chem. Rev. 2016, 116, 10276-10341. (c) Lummiss, J. A. M.; Morse, P.
D.; Beingessner, R. L.; Jamison, T. F. Chem. Rec. 2017, 17, 667-680.
13. (a) Mallia, C. J.; Baxendale, I. R. Org. Process Res. Dev. 2016, 20, 327-
360. (b) McTeague, T. A.; Jamison, T. F. Angew. Chem. Int. Ed. 2016,
55, 15072-15075. (c) Seo, H.; Katcher, M. H.; Jamison, T. F. Nat.
Chem. 2017, 9, 453-456.
1
52.4. The H NMR spectra is in agreement with that reported in the
literature.22
14. Bogdan, A. R.; Charaschanya, M.; Dombrowski, A. W.; Wang, Y.;
Djuric, S. W. Org. Lett. 2016, 18, 1732-1735.
4.4. Supporting experiments for the reaction pathway of the N-
monomethylation of anilines.
15. Adamo, A.; Beingessner, R. L.; Behnam, M.; Chen, J.; Jamison, T. F.;
Jensen, K. F.; Monbaliu, J.-C. M.; Myerson, A. S.; Revalor, E. M.;
Snead, D. R.; Stelzer, T.; Weeranoppanant, N.; Wong, S. Y.; Zhang, P.
Science 2016, 352, 61-67.
4.4.1. Formation of 3a from 4.
General procedure was followed with carbamate 4 (20 mmol, 1.0
equiv, 2 M) and DBU (30 mmol, 1.5 equiv, 3 M) with no DMC. 359
mg (92%); yellow oil.
16. Sun, N.; Wang, S.; Mo, W.; Hu, B.; Shen, Z.; Hu, X. Tetrahedron 2010,
66, 7142-7148.
17. González, I.; Mosquera, J.; Guerrero, C.; Rodríguez, R.; Cruces, J. Org.
Lett. 2009, 11, 1677-1680.
18. Cho, S.-D.; Kim, H.-K.; Yim, H.; Kim, M.-R.; Lee, J.-K.; Kim, J.-J.;
Yoon, Y.-J. Tetrahedron 2007, 63, 1345-1347.
19. Hirayama, T.; Iyoshi, S.; Taki, M.; Maeda, Y.; Yamamoto, Y. Org.
Biomol. Chem. 2007, 5, 2040-2045.
20. Aurelio, L.; Flynn, B. L.; Scammells, P. J. Org. Biomol. Chem. 2011, 9,
4886-4902.
21. Martjuga, M.; Shabashov, D.; Belyakov, S.; Liepinsh, E.; Suna, E. J.
Org. Chem. 2010, 75, 2357-2363.
4.4.2. Formation of 3a from 6.
General procedure was followed with carbamate 6 (20 mmol, 1.0
equiv, 2 M) and DMC (40 mmol, 2.0 equiv, 4 M), and DBU (30
mmol, 1.5 equiv, 3 M). 363 mg (93%); yellow oil.
Acknowledgement
This work was supported by the Defense Advanced Research
Project Agency (DARPA), Army Research Office under contract
number W911NF-16-0023. H.S. thanks Amgen Graduate Fellowship
in Synthetic Chemistry. A.C.B. thanks NSERC for a postdoctoral
fellowship. We thank the Undergraduate Research Opportunities
Program (MIT UROP) for financial support to W.P.C. and A.A. We
thank R. Beingessner for her advice and support and L. P. Kelly for
mass spectral data.
22. Zhang, J.; Zhang, L.; Sun, D. J. Pestic. Sci. 2011, 36, 252-254.
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