Convenient Continuous Flow Synthesis of N-Methyl Secondary Amines from Alkyl Mesylates and Epoxides

Article abstract of DOI:10.1021/acs.oprd.0c00193

The first continuous flow process was developed to synthesize N-methyl secondary amines from alkyl mesylates and epoxides via a nucleophilic substitution using aqueous methylamine. A variety of N-methyl secondary amines were produced in good to excellent yields, including a number of bioactive compounds or their precursors. Up to 10.6 g (88% yield) of an N-methyl secondary amine was produced in 140 min process time. The amination procedure included an in-line workup, and the starting mesylate material was also produced in continuous flow from the corresponding alcohol. Finally, an in-line process combining the mesylate synthesis and nucleophilic substitution was developed.

Full text of DOI:10.1021/acs.oprd.0c00193

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Full Paper
Convenient Continuous Flow Synthesis of N-Methyl
Secondary Amines from Alkyl Mesylates and Epoxides
Gary Mathieu, Heena Patel, and Hélène Lebel
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.0c00193 • Publication Date (Web): 25 Aug 2020
Downloaded from pubs.acs.org on August 25, 2020
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Convenient Continuous Flow Synthesis of N-Methyl
Secondary Amines from Alkyl Mesylates and
Epoxides
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Gary Mathieu, Heena Patel and Hélène Lebel*
Department of Chemistry and Center in Green Chemistry and
Catalysis (CGCC), Université de Montréal, P.O. Box 6128, Station
Downtown, Montréal, QC H3C 3J7, Canada
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ABSTRACT. The first continuous flow process was developed to
synthesize N-methyl secondary amines from alkyl mesylates and
epoxides via a nucleophilic substitution using aqueous
methylamine. A variety of N-methyl secondary amines were produced
in good to excellent yields, including a number of bioactive
compounds, or their precursors. Up to 10.6 g (88% yield) of a N-
methyl secondary amine was produced in 140 min process time. The
amination procedure included an in-line workup, and the starting
mesylate material was also produced in continuous flow from the
corresponding alcohol. Finally, an in-line process combining the
mesylate synthesis and nucleophilic substitution was developed.
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KEYWORDS. Substitution, Methylamine, Mesylation, N-methylamino
alcohol, Betahistine, Fluoxetine.
INTRODUCTION. Nitrogen-containing molecules are an important class
of compounds1 as they are ubiquitous components of biologically
active molecules.2 Among them, N-methyl secondary amines3 are found
in many important drugs, such as fluoxetine (Prozac),4 duloxetine,5
desipramine,6 betahistine7 or L-epinephrine8 (Figure 1).9
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Figure 1. N-Methyl Secondary Amine-Containing Drugs.
A number of methods have been delineated for the synthesis of N-
methyl secondary amines,10 including the reductive amination of
aldehydes and ketones,11 and the nucleophilic displacement of
halides12 or sulfonates,13 as well as the ring opening of epoxides14
with methylamine.15 In general, THF or MeOH solutions of the later
reagent were used,12,13,14 whereas exploiting the less expensive
aqueous methylamine reagent was not as common.16 In addition,
reaction times are typically in the order of 12 to 24 h. Due to
the low boiling point of methylamine, it is often required to
perform the reaction under pressure in a sealed tube.
Alternatively, a continuous flow process would be a powerful
alternative, as shown in the synthesis of fluoxetine, whereby an
alkyl iodide was converted into a N-methyl secondary amine.17,18
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Many advantages would be associated with the development of a
general method combining the use of the aqueous methylamine reagent
with the displacement of mesylates derived from alcohols. Not only
would such a process take advantages of an inexpensive source of
methylamine, but alcohols are also readily available and versatile
reagents.
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Continuous flow is a technique that provides several advantages
over traditional batch chemistry.19 First, safety is significantly
improved, namely due to the small reactor size. Mixing, heat and
mass transfers are also positively affected by the small diameter
of the tubing. As a result, the reaction rate is often improved,
and the reaction time is typically shorter in continuous flow vs
batch process, thus avoiding by-product formation. In addition,
the use of gaseous reagents is impressively simplified (with the
use of a back-pressure regulator), allowing the development of
novel synthetic processes. In 2018, our group has reported a novel
procedure capitalizing on a continuous flow process for the
amination of halides using aqueous ammonia and hydroxylamine to
produce primary ammonium salts and alkylated hydroxylamines in
high yields (Scheme 1).20 The process was extended to ring openings
of epoxides20 and the absence of headspace in the continuous flow
microreactor,21 combined with the use of water solution of the
amine,22 appeared as key elements to avoid polyalkylation
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reactions. Other aqueous solution of amine, for instance
methylamine, may be suitable for such amination reactions.
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Scheme 1. Continuous Flow Amination of Halides.
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The use of sulfonates as leaving groups shows many advantages
over halides. Not only are they suitable electrophiles for
nucleophilic substitutions, but they are also easily prepared from
the widely available alcohols. Herein, we report a general
continuous flow process to react alkyl mesylates with aqueous
methylamine, producing N-methyl secondary amines with a 4 min
residence time. An in-line work-up has been developed and the
process is applicable to gram scale production. In addition, the
starting alkyl mesylates are also produced in continuous flow and
an in-line process, combining the mesylation and nucleophilic
substitution has been achieved.
RESULTS AND DISCUSSION. Alkyl mesylates are often prepared from
the corresponding alcohol, mesyl chloride, and an amine as a base.
In batch reactions, precipitation of the ammonium chloride salt is
typically observed. Consequently, only few examples of mesylation
processes are described in continuous flow.23 Given the need for
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alkyl mesylates as substrates in the current investigation, an
opportunity was seen to develop their preparation in flow. The
reaction of 2-phenylethanol and mesyl chloride in the presence of
various amine bases and solvents was thus investigated.24 Heating
the reactor at 40 °C was key to avoid the formation of solid and
clogging of the reactor. Whereas dichloromethane or ether could be
used as solvents at a concentration of 0.1M, only acetonitrile was
suitable at higher concentration (0.3M). Quite surprisingly, there
was no advantage using bases that form ionic liquids (such as DBU,
n-butylimidazole and tributylamine),25 as higher yields were
observed with triethylamine.24 Under the optimized reaction
conditions, with 2 reactors of 10 mL at a total flow rate of 2
mL/min, mesyltate 1 was isolated in 85% yield (Scheme 2). The
reaction was performed on 30 mmol of 2-phenylethanol to produce
5.11 g of mesylate 1 in 120 min process time. Other alkyl
mesyltates containing ether (mesylate 3 & 4), chloride (mesylate
4), thiophene (mesylate 5 & 6), pyridine (mesylate 7), alkene
(mesylate 8 & 9) and alkyne (mesylate 11) functional groups were
successfully synthesized in good to excellent yields. The reaction
conditions are also compatible with the preparation of mesylates
derived from secondary alcohols (mesylate 12, 13 & 14), and no
elimination reaction was observed. Only a few substrates could not
be prepared under these reaction conditions, primarily due to
solubility issues.26
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Scheme 2. Continuous Flow Mesylation of Primary and Secondary
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Alcools.a
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With the alkyl mesylate substrates in hand, the synthesis of N-
methyl secondary amines using aqueous methylamine in continuous
flow was investigated. At the outset, a 0.1 M solution of mesylate
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1 in methanol was used, based on the reaction conditions previously
developed with ammonia.20 The commercially available aqueous
methylamine solution has a concentration of 12.8 M and was applied
neat in the process (Table 1). Two distinct 0.5 mL injection loops27
were charged with respectively the mesylate solution and the
aqueous methylamine solution, then pumped at an equal flow rate in
the T-mixer, before being injected in the reactor. With a total
rate of 2 mL/min (1 mL/min per pump) corresponding to a residence
time of 10 min, 74% and 87% yield of the desired N-methyl ammonium
salt 15 was observed at respectively 120 °C and 140 °C (entries 1,
2). Increasing the total flow rate to 5 mL/min improved the yield
slightly at 140 °C (entry 5). Decreased or equivalent yields were
obtained when using respectively THF, MeNO2 or MeCN as solvents,
known to favor nucleophilic substitutions (entries 6–8).
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Table 1. Amination of Mesylate 1 with Aqueous Methylamine
tR
(min
)
Yield
entr [OMs] Solve
Rate
Temp
(°C)
a
y
(M)
nt (mL/min)
(%)
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2
3
0.1 MeOH
0.1 MeOH
0.1 MeOH
2.0
2.0
5.0
10 120
10 140
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87
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0.1 MeOH
0.1 MeOH
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5.0
5.0
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5.0
5.0
5.0
5.0
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0.1
THF
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0.1 MeNO2
0.1 MeCN
0.25 MeOH
0.5 MeOH
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11 0.25 MeCN
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0.5 MeCN
140 60b
13c
0.25 MeOH
120 84
Yield determined by 1H NMR using 1,1,2,2-
a
b
tetrachloroethane as an internal standard.
Isolated yield of amine 16. cNH4OH, 14 M, was
used to produce PhCH2CH2NH3OMs.
Methanol was favored as a solvent, due of its low cost, although
acetonitrile proved also suitable (entries 9–12). The yield was
not affected when the amount of methylamine was decreased by a
factor of 2.5 (from 128 equiv to 51 equiv), as N-methyl ammonium
salt 15 was produced in 94–95% yield when starting with a 0.25 M
solution of mesylate 1 in methanol or acetonitrile (entries 9 and
11). However, using a more concentrated solution (0.5 M, ~26 equiv
of MeNH2) was detrimental for the yield of the desired product, as
a result of a lower conversion (entries 10 and 12). In all cases,
no polyalkylation product was detected. Ammonium hydroxide was
also compatible with the reaction conditions, and PhCH2CH2NH3OMs
was produced in 84% yield (entry 13).
The reaction conditions were probed with various alkyl mesylates
to produce the corresponding N-methyl secondary amine, after a
basic work-up (Scheme 3). The reaction was performed on 90 mmol of
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mesylate 1 to produce 10.6 g of N-methyl amine 16 in 140 min
process time. A variety of aryl derivatives containing an ether
linkage, a bromide, a chloride, and an alcohol were successfully
reacted to afford the desired N-methyl secondary amines 17–23 in
excellent yields. Of note, amine 22 is a precursor in the synthesis
of fluoxetine and was prepared in very good yields. The mesylate
precursor was synthesized at low temperature by the chemoselective
mesylation of the diol (see Sup. Info for details). Giving that
the mesylation is tolerant with alcohol functional groups (the
reaction is run in methanol), it was not necessary to protect the
secondary alcohol, for the primary mesylate to undergo the
nucleophilic substitution with methylamine, producing amine 22.
Thiophene and oxazole were found compatible with the reaction
conditions and N-methyl secondary amines 24–26 were isolated in
excellent yields. Good yields were observed for the synthesis of
thiazole-containing amine 27 and betahistine 28 in acetonitrile.
The substrates of these two products are susceptible to
degradation, via ipso attack of the methylamine for mesylate S6
and polymerization for mesylate 7. The N-methyl amine derived from
nopol (29) was produced in 56% yield: it was necessary to treat
the free amine with HCl to isolate the amine•HCl salt. N-Methyl
amines 30 and 31 derived from secondary mesylates 13 and 14 were
synthesized in good yields. It was, however, necessary to use 128
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equiv of MeNH2 (mesylate concentration of 0.1 M) and a small amount
of elimination by-product was observed.
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Scheme 3. Continuous Flow Amination of Alkyl Mesylates with Aqueous
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Methylamine.a,b
One of the advantages of continuous flow synthesis is the
possibility of developing a fully automated process that includes
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the in-situ work-up and purification of the product. Such a process
was elaborated for the preparation of N-methyl amine 16 (Scheme 4,
Figure 2). Two Vapourtec R-series were connected to the same
computer to control four different pumps for the complete
automatization of the process. After the formation of N-methyl
ammonium salt 15, a mixture of aqueous KOH/NaCl was added after
the back-pressure regulator, and the combined streams passed
through a 10 mL PFA reactor. Dichloromethane was added next, and
the reaction mixture was then passed through a homemade column
magnetic stirrer. The organic layer was separated from the aqueous
with a gravity liquid-liquid separator.28 The organic layer was
pumped through a drying column (4Å MS/Celite) to afford the desired
N-methyl amine 16 in 70% yield.
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Scheme 4. In-Line Workup to Synthesize N-Methyl Amine 16.
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Figure 2. Reactor setup for the automated in-line work-up to
synthesize
methylamine
16:
1. Reagent bottles; 2. Stainless steel reactors; 3. Back pressure
regulator (BPR); 4. PFA reactor; 5. Homemade column magnetic
stirrer; 6. Gravity liquid-liquid separator; 7. Syrris Pump; 8.
Drying column; 9. Collecting flask.
An in-line process to perform the mesylation reaction, followed
by the nucleophilic substitution was then developed (Scheme 5).
Scheme 5. In-line Process to Synthesize N-Methyl Amine 16 from 2-
Phenylethanol.
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Acetonitrile was used as solvent and the concentration was
decreased to 0.1 M for the alcohol to achieve a reasonably good
conversion in the nucleophilic substitution. The desired N-methyl
amine 16 was isolated in 60%. Side reactions between the
trialkylammonium salt and methylamine may explain the slightly
lower yield obtained in comparison with the 2-step process.
Other suitable electrophiles for nucleophilic substitution
include epoxides. Using the same reaction conditions as the alkyl
mesylates, the corresponding N-methylamino alcohol was produced in
good to excellent yields (Scheme 6). The reaction was compatible
with terminal and disubstituted epoxides.
Scheme 6. Epoxide Ring Opening with Aqueous Methylamine.a
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CONCLUSION. In conclusion, a highly efficient continuous flow
process to synthesize N-methyl secondary amines and substituted N-
methylamino alcohol from alkyl mesylates and epoxides in good to
excellent yields was developed. This process features good
functional group compatibility, the use of inexpensive aqueous
methylamine and a very short reaction time. An in-line work-up was
also developed, thus a fully automated process is also possible.
In addition, it is possible to combine, both the mesylation step
and the nucleophilic substitution in one in-line process.
Considering the importance of N-methyl secondary amines in
biologically active products, this process will be of interest for
industrial researchers.
EXPERIMENTAL SECTION.
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General Information. Commercially available reagents were used
without further purification, unless noted. Analytical thin-layer
chromatography was performed using 0.25 mm silica gel 60-F plates.
Visualization of the developed chromatogram was performed by UV
absorbance, cerium ammonium molybdate or aqueous potassium
permanganate. Flash chromatography was performed using silica gel
(230−400 mesh) with the indicated solvent system. Infrared spectra
are reported in wavenumbers (cm-1). Only the most important and
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1
relevant frequencies are reported. Chemical shifts for H NMR
spectra were recorded in parts per million with the solvent
resonance as the reference CDCl3 (δ = 7.26 ppm) or D2O (δ = 4.79
ppm). Data are reported as follows: chemical shift, multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, qn = quintet,
sext = sextuplet, m = multiplet, and br = broad), coupling
13
constants in hertz, and integration. Chemical shifts for C{1H}
NMR spectra are recorded in parts per million using the central
peak of CDCl3 (δ = 77.16 ppm) as the reference. All 13C NMR spectra
were obtained with complete proton decoupling. When ambiguous,
proton and carbon assignments were established through COSY, HSQC,
and/or DEPT experiments. All NMR yields were determined using
quantitative 1H NMR spectra using 1,1,2,2-tetrachloroethane as an
internal standard with a 10s relaxation time. High-resolution mass
spectra analysis was performed by the Centre Régional de
Spectroscopie de Masse de l’Université de Montréal. Continuous
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flow experiments were run on the Vapourtec® R-Series flow system
(R2+ pump and R4 heating module) using a 2 mL injection loop, a 10
mL stainless steel or PFA reactor coil (1/16 OD x 0.04 ID tubing)
and a spring back-pressure regulator.
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General Continuous Flow Procedure for the Preparation of Alkyl
Mesylates (Scheme 2). NB. The continuous flow system was flushed
with anhydrous acetonitrile prior to running the reaction. A
solution of the alcohol (3.00 mmol) and NEt3 (460 µL, 3.30 mmol)
in anhydrous MeCN (0.3M), and a solution of mesyl chloride (255
µL, 3.30 mmol) in anhydrous MeCN (0.33 M) were independently
prepared in two 10 mL volumetric flasks. These stock solutions (5
mL, 1.50 mmol of alcohol; 1.65 mmol of NEt3 and 5 mL, 1.65 mmol
MsCl) were pumped using the bottle reagent mode at 1 mL/min (total
flow rate is 2 mL/min), combined in a T-mixer and injected into
two successive 10 mL PFA reactors heated at 40 °C. Upon exiting
the second flow reactor, the combined reactor stream passed a back-
pressure regulator (50 psi) before being collected into a 100 mL
opened flask (process time: 20 min). After all reagents were
pumped, the system was purged with MeCN until collection volume
was reached (Vcollection = 24 mL). Sat. aq. NaHCO3 was added, followed
by EtOAc. The two layers were separated, and the organic layer was
washed with brine, then dried over Na2SO4. The solvent was removed
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under reduced pressure and the residue was passed through a pad of
silica gel to afford the corresponding pure mesylate.
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Phenethyl methanesulfonate (1). The title compound was prepared
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according to the general procedure from 2-phenylethanol (180 L,
1.50 mmol or 3.60 mL, 30 mmol) and was obtained as a light-yellow
liquid (255 mg or 5.11 g, 85%) after purification by flash
chromatography on silica gel using hexane/EtOAc (7:3). Spectral
data matched those reported in the literature.29 Rf 0.28
(hexane/EtOAc 7:3); 1H NMR (400 MHz, CDCl3)  7.37–7.33 (m, 2H),
7.30–7.25 (m, 3H), 4.42 (t, J = 6.8 Hz, 2H), 3.06 (d, J = 6.8 Hz,
2H), 2.83 (s, 3H); 13C NMR (100 MHz, CDCl3)  136.3, 128.9, 128.6,
126.9, 70.4, 37.1, 35.5.
3-Phenylpropyl methanesulfonate (2). The title compound was
prepared according to the general procedure from 3-phenyl-1-
propanol (204 L, 1.50 mmol) and was obtained as a light-yellow
liquid (257 mg, 80%) after purification by flash chromatography on
silica gel using Hexane/EtOAc (7:3). Spectral data matched those
1
reported in the literature.29 Rf 0.36 (Hexane/EtOAc 7:3); H NMR
(400 MHz, CDCl3)  7.32-7.29 (m, 2H), 7.23-7.19 (m, 3H), 4.22 (t,
J = 8 Hz, 2H), 2.98 (s, 3H), 2.75 (t, J = 8 Hz, 2H), 2.11 (q, J =
8 Hz, 2H); 13C NMR (125 MHz, CDCl3)  140.3, 128.6, 128.5, 126.3,
69.2, 37.3, 31.6, 30.7.
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2-(Benzo[d][1,3]dioxol-5-yl)ethyl methanesulfonate (3).The title
compound was prepared according to the general procedure from 2-
(benzo[d][1,3]dioxol-5-yl)ethan-1-ol (249 mg, 1.50 mmol) and was
obtained as a yellow liquid (293 mg, 80%) after purification by
flash chromatography on silica gel using hexane/EtOAc (7:3).
Spectral data matched those reported in the literature.29 Rf 0.5
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(hexane/EtOAc 6:4); 1H NMR (400 MHz, CDCl3)  6.76–6.66 (m, 3H),
5.92 (s, 2H), 4.35 (t, J = 6.8 Hz, 2H), 2.95 (t, J = 6.8 Hz, 2H),
2.89 (s, 3H); 13C NMR (100 MHz, CDCl3)  147.9, 146.7, 130.0, 122.1,
109.4, 108.5, 101.1, 70.5, 37.4, 35.4.
2-(4-Chlorophenoxy)ethyl methanesulfonate (4).The title compound
was prepared according to the general procedure from 2-(4-
chlorophenoxy)ethan-1-ol (259 mg, 1.5 0mmol) and was obtained as
a white crystalline solid (271 mg, 72%) after purification by flash
chromatography on silica gel using hexane/EtOAc (7:3). Rf 0.29
(hexane/EtOAc 7:3); mp 76–77 °C; 1H NMR (400 MHz, CDCl3)  7.25–
7.23 (m, 2H), 6.83–6.81(m, 2H), 4.55–4.53 (m, 2H), 4.21–4.19 (m,
2H), 2.07 (s, 3H); 13C NMR (100 MHz, CDCl3)  156.7, 129.6, 126.6,
115.9, 67.8, 66.2, 37.8; FTIR (neat) 1595, 1489, 1452, 1343, 1243,
1169, 1030, 968, 811, 527; HRMS (ESI+) m/z [M + Na]+ calcd for
C9H11ClO4S 272.9958 found 272.9957.
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2-(Thiophen-2-yl)ethyl methanesulfonate (5). The title compound
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was prepared according to the general procedure from 2-
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thiopheneethanol (167 L, 1.50 mmol), and was obtained as a light-
yellow liquid (282 mg, 90%) after purification by flash
chromatography on silica gel using hexane/EtOAc (7:3). Spectral
data matched those reported in the literature.30 Rf 0.28
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(hexane/EtOAc 8:2). 1H NMR (400 MHz, CDCl3)  7.19–7.17 (m, 1H),
6.96–6.94 (m, 1H), 6.91–6.90 (m, 1H), 4.39 (t, J = 6.5 Hz, 2H),
3.25 (t, J = 6.5 Hz, 2H), 2.90 (s, 3H); 13C NMR (125 MHz, CDCl3) 
138.2, 127.1, 126.2, 124.5, 69.9, 37.2, 29.7.
2-(Thiophen-3-yl)ethyl methanesulfonate (6). The title compound was prepared
according to the general procedure from 3-thiopheneethanol (166
L, 1.50 mmol) and was obtained as a light-orange liquid (282 mg,
91%) after purification by flash chromatography on silica gel using
hexane/EtOAc (7:3). Rf 0.28 (hexane/EtOAc 7:3); 1H NMR (400 MHz,
CDCl3)  7.29–7.27 (m, 1H), 7.08–7.07 (m, 1H), 6.99–6.97 (m, 1H),
4.39 (t, J = 6.8 Hz, 2H), 3.97 (t, J = 6.8 Hz, 2H), 2.86 (s, 3H);
13C NMR (100 MHz, CDCl3)  136.5, 128.1, 126.0, 122.3, 69.8, 37.1,
30.0; FTIR (neat) 2931, 1439, 1380, 1247, 1116, 1034, 849, 821,
689; HRMS (ESI+) m/z [M + Na]+ calcd for C7H10O3S2 228.9963 found
228.9963.
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2-(Pyridin-2-yl)ethyl methanesulfonate (7). The title compound
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was prepared according to the general procedure from 2-
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pyridineethanol (169 L, 1.50 mmol) and was obtained as an orange
liquid (302 mg, 100%) after purification by flash chromatography
on silica gel using hexane/EtOAc (5:5). Spectral data matched those
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reported in the literature.30 Rf 0.20 (hexane/EtOAc 5:5); H NMR
(400 MHz, CDCl3)  8.50–8.49 (m, 1H), 7.60–7.56 (m, 1H), 7.18–7.11
(m, 2H), 4.62–4.58 (m, 2H), 3.18–3.14 (m, 2H), 2.84 (s, 3H); 13C
NMR (100 MHz, CDCl3)  156.5, 149.4, 136.6, 123.9, 122.1, 69.1,
37.4, 36.1.
3,7-Dimethyloct-6-en-1-yl methanesulfonate (8). The title
compound was prepared according to the general procedure from(+/-)
citronellol (274 L, 1.50 mmol) and was obtained as a colorless
liquid (264 mg, 75%) after purification by flash chromatography on
silica gel using hexane/EtOAc (7:3). Spectral data matched those
reported in the literature.31 Rf 0.4 (hexane/EtOAc 8:2);1H NMR (400
MHz, CDCl3)  5.07–5.04 (m, 1H), 4.29–4.19 (m, 2H), 2.98 (s, 3H),
2.01–1.91 (m, 2H), 1.82–1.74 (m, 1H), 1.69 (s, 3H), 1.62–1.48 (m
+ s, 5H), 1.38–1.29 (m, 1H), 1.23-1.14 (m, 1H), 0.91 (d, J = 6.4
Hz, 3H); 13C NMR (100 MHz, CDCl3)  131.6, 124.3, 68.6, 37.4, 36.9,
35.9, 29.0, 25.8, 25.3, 19.2, 15.7.
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2-((1R,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-en-2-yl)ethyl
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methanesulfonate (9).The title compound was prepared according to
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the general procedure from(1R)-(-)-nopol (258 L, 1.50 mmol) and
was obtained as a light-yellow liquid (279 mg, 76%) after
purification by flash chromatography on silica gel using
hexane/EtOAc (7:3). Spectral data matched those reported in the
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literature.32 Rf 0.28 (hexane/EtOAc 7:3); 1H NMR (400 MHz, CDCl3) 
5.33 (s, 1H), 4.21-4.17 (m, 2H), 2.97 (s, 3H), 2.41–2.33 (m, 3H),
2.27–2.15 (m, 2H), 2.07–2.01 (m, 2H), 1.26 (s, 3H), 1.13 (d, J =
8.8 Hz, 1H), 0.81 (s, 3H); 13C NMR (125 MHz, CDCl3)  142.6, 120.0,
68.0, 45.6, 40.6, 38.1, 37.5, 36.4, 31.6, 31.4, 26.3, 21.2.
Cyclohexylmethyl methanesulfonate (10). The title compound was
prepared according to the general procedure fromcyclohexylmethyl
alcohol(185 L, 1.50 mmol), and was obtained as a colorless liquid
(262 mg, 91%) after purification by flash chromatography on silica
gel using hexane/EtOAc (8:2). Rf 0.35 (hexane/EtOAc 8:2); 1H NMR
(400 MHz, CDCl3)  3.97 (d, J = 6 Hz, 2H), 2.95 (s, 3H), 1.72–1.66
(m, 6H), 1.24–1.11 (m, 3H), 1.01–0.95 (m, 2H); 13C NMR (100 MHz,
CDCl3)  75.0, 37.4, 37.1, 29.1, 26.1, 25.4; FTIR (neat) 2925,
2853, 1450, 1347, 1170, 967, 936, 830, 519; HRMS (ESI+) m/z [M +
Na]+ calcd for C8H16O3S 215.01512 found 215.0711.
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Prop-2-yn-1-yl methanesulfonate (11). The title compound was
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prepared according to the general procedure frompropargyl alcohol
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(87.3 L, 1.50 mmol) and was obtained as a colorless liquid (291
mg, 95%) after purification by flash chromatography on silica gel
using hexane/EtOAc (7:3). Spectral data matched those reported in
the literature.33 Rf 0.21 (hexane/EtOAc 8:2); 1H NMR (400 MHz,
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CDCl3)  4.82 (d, J = 2.4 Hz, 2H), 3.10 (s, 3H), 2.70 (s, 1H); 13C
NMR (100 MHz, CDCl3)  78.0, 75.8, 75.3, 39.0.
1,3-Diphenylpropan-2-yl methanesulfonate (12). The title
compound was prepared according to the general procedure from1,3-
diphenylpropan-2-ol (318 mg, 1.50 mmol) and was obtained as a white
solid (327 mg, 75%) after purification by flash chromatography on
silica gel using hexane/EtOAc (7:3). Rf 0.53 (hexane/EtOAc 7:3);
mp 76 °C; 1H NMR (300 MHz, CDCl3)  7.36–7.22 (m, 10H), 4.91 (qn,
J = 6.6 Hz, 1H), 3.01 (d, J = 6.6 Hz, 4H), 2.17 (s, 3H); 13C NMR
(75 MHz, CDCl3)  136.7, 129.8, 128.8, 127.2, 86.1, 41.2, 37.2;
FTIR (neat) 3030, 2932, 1603, 1495, 1365, 1169, 970, 894, 689;
HRMS (ESI+) m/z [M + Na]+ calcd for C16H18O3S 313.0868 found
313.0872.
4-Phenylbutan-2-yl methanesulfonate (13).The title compound was
prepared according to the general procedure from4-phenylbutan-2-
ol (225 mg, 1.50 mmol) and was obtained as a colorless liquid (240
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mg, 70%) after purification by flash chromatography on silica gel
using hexane/EtOAc (7:3). Spectral data matched those reported in
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the literature.34 Rf 0.57 (hexane/EtOAc 7:3); H NMR (300 MHz,
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CDCl3) 7.32-7.26 (m, 2H), 7.22-7.19 (m, 3H), 4.84 (sext, J = 6.3
Hz, 1H), 2.99 (s, 3H), 2.82–2.65 (m, 2H), 2.13–1.87 (m, 2H), 1.46
(d, J = 6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3)  140.8, 128.7, 128.4,
126.3, 79.6, 38.8, 38.4, 31.5, 21.4.
1-(4-Methoxyphenoxy)propan-2-yl methanesulfonate (14). The title
compound was prepared according to the general procedure from1-
(4-methoxyphenoxy)propan-2-ol (273 mg, 1.50 mmol), and was
obtained as a white solid (281 mg, 72%) after purification by flash
chromatography on silica gel using hexane/EtOAc (7:3). Rf 0.31
(hexane/EtOAc 7:3); mp 70–71 °C; 1H NMR (500 MHz, CDCl3)  6.85–
6.81 (m, 4H), 5.05 (m, 1H), 4.04 (dd, J = 10.5, 7.5 Hz, 2H), 4.97
(dd, J = 10.5, 3.5 Hz, 2H), 3.76 (s, 3H), 3.07 (s, 3H), 1.50 (d,
J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)  154.5, 152.2, 115.6,
114.9, 77.9, 71.2, 55.8, 38.6, 18.1; FTIR (neat) 2941, 1508, 1460,
1341, 1230, 1171, 1077, 975, 743, 530; HRMS (ESI+) m/z [M + Na]+
calcd for C11H16O5S 283.0610 found 283.0610.
General Continuous Flow Procedure for the Amination of Alkyl
Mesylates with Aqueous Methylamine (Scheme 3). NB. The continuous
flow system was successively flushed with aqueous ammonia, water,
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and the reaction solvent, prior to running the reaction. A stock
solution of the alkyl mesylate (5.00 mL, 1.25 mmol, 0.25 M in MeOH
of in CH3CN) and the aqueous methylamine solution (12.8 M, 5.00
mL, 51.2 mmol) were pumped using the bottle reagent mode at 2.5
mL/min (total flow rate: 5 mL/min), combined in a T-mixer and
injected into two successive 10 mL SS reactors heated at 140 °C.
Upon exiting the second flow reactor, the combined reaction stream
passed a back-pressure regulator (300 psi) before being collected
into a 100 mL opened flask (process time:10 min). After all
reagents were pumped, the system was purged with MeOH until
collection volume was reached (Vcollection = 34 mL). The solvent and
the excess of aqueous methylamine were removed under reduced
pressure. The crude residue was treated with aq. KOH (2M) and
extracted with EtOAc (3x). The two layers were separated, and the
organic layer was washed with brine and dried over MgSO4. The
solvent was removed under reduced pressure to afford the
analytically pure N-methyl secondary amine.
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N-Methyl-2-phenylethan-1-amine (16). The title compound was
prepared according to the general procedure from phenethyl
methanesulfonate (1) (250 mg, 1.25 mmol, 0.25 M in MeOH or MeCN or
18 g, 90 mmol, 0.25 M in MeOH). The desired amine was obtained as
a pale-yellow liquid (90%, 152 mg (in MeOH); 88%, 149 mg (in MeCN);
88%, 10.6 g (in MeOH), after Kugelrohr distillation). Spectral
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data matched those reported in the literature.35 1H NMR (400 MHz,
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CDCl3)  7.31–7.26 (m, 2H), 7.22–7.19 (m, 3H), 4.0 (m, 4H), 2.44
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(s, 3H), 1.40 (s (br), 1H); 13C NMR (100 MHz, CDCl3)  140.1, 128.8,
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128.5, 126.2, 53.2, 36.4, 36.2.
N-Methyl-3-phenylpropan-1-amine (17). The title compound was
prepared according to the general procedure from 3-phenylpropyl
methanesulfonate (2) (268 mg, 1.25 mmol, 0.25 M in MeOH). The
desired amine was obtained as a pale-yellow liquid (85%, 159 mg).
Spectral data matched those reported in the literature.36 1H NMR
(400 MHz, CDCl3) 7.29-7.25 (m, 2H), 7.19-7.15 (m, 3H), 2.65 (t,
J = 7.2 Hz, 2H), 2.60 (t, J = 7.2 Hz, 2H), 2.42 (s, 3H), 1.81 (q,
13
J = 7.2 Hz, 2H), 1.11 (s (br), 1H); C NMR (100 MHz, CDCl3) 
142.3, 128.5, 128.4, 125.8, 51.7, 36.6, 33.7, 31.7.
2-(4-Bromophenyl)-N-methylethan-1-amine (18). The title compound
was prepared according to the general procedure from 4-
bromophenethyl methanesulfonate (S1) (349 mg, 1.25 mmol, 0.25 M in
MeOH or in MeCN). The crude mixture was diluted in ether and
treated with HCl (0.320 mL, 4.0 M in dioxane) to produce the
corresponding ammonium salt. A filtration afforded the desired
amine•HCl as a solid (83%, 260 mg (in MeOH); 89%, 279 mg (in
MeCN)). Spectral data matched those reported in the literature.37
mp 196–197 °C (litt. 196 °C);39 1H NMR (400 MHz, D2O)  7.57 (d, J
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= 8.2 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 3.31 (t, J = 7.2 Hz 2H),
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3.01 (t, J = 7.2 Hz, 2H), 2.72 (s, 3H). 13C NMR (100 MHz, D2O) 
135.4, 131.9, 130.7, 120.5, 49.7, 32.8, 31.1. FTIR (neat) 2935,
2779, 2712, 2451, 1591, 1481, 1445, 1073, 816; HRMS (ESI+) m/z [M
+ H]+ calcd for C9H12BrN 214.0226 found 214.0224.
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2-(Benzo[d][1,3]dioxol-5-yl)-N-methylethan-1-amine (19). The
title compound was prepared according to the general procedure
from 2-(benzo[d][1,3]dioxol-5-yl)ethyl methanesulfonate (3) (305
mg, 1.25 mmol, 0.25 M in MeOH). The desired amine was obtained as
a yellow liquid (97%, 217 mg). Spectral data matched those reported
in the literature.38 1H NMR (400 MHz, CDCl3)  6.72–6.67 (m, 2H),
6.64–6.62 (m, 1H), 5.89 (s, 2H), 2.77 (t, J = 6.4 Hz, 2H), 2.69
(t, J = 6.4 Hz, 2H), 2.40 (s, 3H), 1.14 (s (br), 1H); 13C NMR (100
MHz, CDCl3)  147.7, 145.9, 133.8, 121.5, 109.1, 108.2, 100.8,
53.4, 36.3, 35.9.
2-(4-Chlorophenoxy)-N-methylethan-1-amine (20). The title
compound was prepared according to the general procedure from 2-
(4-chlorophenoxy)ethyl methanesulfonate (4) (313 mg, 1.25 mmol,
0.25 M in MeOH:THF, 1:1). The desired amine was obtained as a
yellow liquid (90%, 209 mg). 1H NMR (400 MHz, CDCl3)  7.20 (d, J
= 9 Hz, 2H), 6.81 (d, J = 9 Hz, 2H), 4.02 (t, J = 5 Hz, 2H), 2.95
(t, J = 5 Hz, 2H), 2.49 (s, 3H), 1.51 (s (br), 1H); 13C NMR (100
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MHz, CDCl3)  157.6, 129.4, 125.7, 115.8, 67.6, 50.8, 36.5; FTIR
(neat) 2932, 1596, 1489, 1282, 1239, 1092, 1040, 821, 665; HRMS
(ESI+) m/z [M + H]+ calcd for C9H12ClNO 186.0680 found 186.0682.
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3-(Benzyloxy)-N-methylpropan-1-amine (21). The title compound
was prepared according to the general procedure from 3-
(benzyloxy)propyl methanesulfonate (S2) (305 mg, 1.25 mmol, 0.25
M in MeOH). The desired amine was obtained as a yellow liquid (89%,
199 mg). 1H NMR (300 MHz, CDCl3)  7.36–7.24 (m, 5H), 4.49 (s, 2H),
3.53 (t, J = 6.6 Hz, 2H), 2.67 (t, J = 6.6 Hz, 2H), 2.41 (s, 3H),
1.79 (q, J = 6.6 Hz, 2H), 1.32 (s (br), 1H); 13C NMR (75 MHz, CDCl3)
 138.6, 128.4, 127.6, 127.5, 72.9, 68.9, 49.5, 36.6, 30.0; FTIR
(neat) 2850, 1453, 1362, 1098, 1027, 733, 695, 610; HRMS (ESI+)
m/z [M + H]+ calcd for C11H17NO 180.1382 found 180.1378.
3-(Methylamino)-1-phenylpropan-1-ol (22). The title compound was
prepared according to the general procedure from 3-hydroxy-3-
phenylpropyl methanesulfonate (S3) (288 mg, 1.25 mmol, 0.25 M in
MeOH or in MeCN). The desired amine was obtained as a light-yellow
liquid (80%, 165 mg (in MeOH); 85%, 176 mg (in MeCN)). Spectral
data matched those reported in the literature.39 1H NMR (300 MHz,
CDCl3)  7.38–7.30 (m, 4H), 7.26–7.21 (m, 1H), 4.93 (m, 1H), 4.77
(s (br), 2H), 2.99–2.85 (m, 2H), 2.47 (s, 3H), 1.98–1.80 (m, 2H);
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