Chemoselective Synthesis of Amines from Ammonium Hydroxide and Hydroxylamine in Continuous Flow

Article abstract of DOI:10.1021/acs.joc.8b02387

The chemoselective amination of alkyl bromides and chlorides with aqueous ammonia and hydroxylamine was achieved in continuous flow to produce primary ammonium salts and hydroxylamines in high yields. An in-line workup was designed to isolate the corresponding primary amine, which was also telescoped in further reactions, such as acylation and Paal-Knorr pyrrole synthesis. Monosubstituted epoxides are also compatible with the reaction conditions.

Full text of DOI:10.1021/acs.joc.8b02387

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Note
Chemoselective Synthesis of Amines from Ammonium
Hydroxide and Hydroxylamine in Continuous Flow
Clément Audubert, Alexanne Bouchard, Gary Mathieu, and Hélène Lebel
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02387 • Publication Date (Web): 24 Oct 2018
Downloaded from http://pubs.acs.org on October 24, 2018
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Chemoselective Synthesis of Amines from Ammonium Hydroxide
and Hydroxylamine in Continuous Flow
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Clément Audubert, Alexanne Bouchard, Gary Mathieu and Hélène Lebel*
Department of Chemistry and Centre in Green Chemistry and Catalysis (CGCC), Université de
Montréal,
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P.O. Box 6128, Station Downtown, Montréal, QC, Canada, H3C 3J7
helene.lebel@umontreal.ca
Abstract. The chemoselective amination of alkyl bromides and chlorides with aqueous ammonia
and hydroxylamine was achieved in continuous flow to produce primary ammonium salts and
hydroxylamines in high yields. An in-line work-up was designed to isolate the corresponding
primary amine, which was also telescoped in further reactions, such as acylation and Paal–Knorr
pyrrole synthesis. Monosubstituted epoxides are also compatible with the reaction conditions.
Nitrogen-containing compounds are essential for the pharmaceutical, agrochemical, and food
additive industries.1 Consequently, numerous methods have been investigated over the years to
form carbon-nitrogen bonds. Among them, displacement reactions with nitrogen nucleophiles are
versatile transformations allowing the synthesis of a large variety of amine products.2
Unfortunately the simplest displacement reaction with ammonia and an electrophile is complicated
by the formation of polyalkylated by-products. To overcome this problem, ammonia equivalents
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have been developed, such as azides and phthalimides (Gabriel Synthesis).3 In these cases, an
additional step is necessary to reveal the amine moiety. The reductive amination of aldehydes and
ketones is an alternative method to efficiently prepare amines, but again it is a two-steps synthesis,
although it could be performed in a one-pot process.4 Alternatively, special techniques were
reported, such as microwave irradiation to promote the amination of alkyl halides using 7M
ammonia solution in methanol at 130 °C for 0.25 to 2.5 h.5 However, the scale up of such
techniques is often limited. Furthermore, an amination process using commercially available cheap
aqueous ammonia (and other amines such as hydroxylamine) is highly desirable. Recently, we
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delineated
the
synthesis
of
trimethylsilylmethylammonium
chloride
from
trimethylsilylmethylchloride and ammonium hydroxide in a continuous flow process (scheme 1).6
Scheme 1. Continuous-flow synthesis of TMSCH2NH2.6
Continuous flow technologies enable rapid reactions with excellent heat transfer, facilitate the
manipulation of gas, and often decrease the formation of by-products.7,8,9,10 Herein, we report a
general amination procedure in flow, applicable to various electrophiles (alkyl halides and
epoxides) with ammonia and hydroxylamine. In addition, we describe in-line processes whereby
the amination reaction was combined to an additional step.
We first investigated the amination of phenethyl bromide with ammonia under the previously
developed reaction conditions.6 Low yields were obtained with the formation of the secondary
ammonium salt (resulting from the double addition of ammonia to the bromide) as the major by-
product (Table 1, entry 1). When the concentration of the bromide was decreased to 0.25 M (thus
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increasing the number of equiv of ammonium hydroxide from 28 to 56 equiv) with a 30 min
residence time, the yield increased to 74% (entry 2). To improve the mixing, a faster flow rate was
then tested using a T-mixer; the same yield was obtained with a residence time (tR) of 10 min at
160 °C (entry 5). Finally, a 0.1 M solution of phenethyl bromide produced the desired ammonium
salt 1 in 94% yield (entry 6, 93% isolated yield, Table 2, entry 1).
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Table 1. Amination of Phenethyl Bromide with Ammonia
High yield was observed with phenethyl iodide (Table 2, entry 2). Benzyl bromides and
chlorides afforded the corresponding ammonium salts in excellent yields (entries 3–7). When the
halide was not fully soluble in methanol, a mixture of methanol/THF was used (entries 4–6). The
reaction is also compatible with heterocycles (entries 7–8). Primary and secondary chlorides and
bromides were successfully reacted, furnishing the corresponding ammonium salt in high yields
(entries 9–12). Similar yield for the synthesis of TMSCH2NH3Cl was obtained under these
conditions (entry 13). Despite the high temperature, product 14 was also isolated in high yield
(entry 14).
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Table 2. Amination of Halides with Ammonia
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An in-line neutralization of the ammonium salt was considered to free-base the amine (Scheme
2). A mixture of aqueous potassium hydroxide and sodium chloride was injected after the back-
pressure regulator, and the resulting mixture was passed through a 10 mL-PFA loop. The reaction
mixture was then combined with dichloroethane (DCE) in a Continuous Stirred Tank Reactor
(CSTR). The organic layer was separated from the aqueous waste using a Zaiput liquid-liquid
separator and evaporation of the solvent afforded the pure amine 15 in 70% yield.
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Scheme 2. In-line Work-up and One-pot Reactions
One of the advantages of continuous flow syntheses is the ability to telescope a series of
reactions. In this vein, the stream of amine solution 15 (without isolation) was further reacted in an
acylation and a Paal–Knorr pyrrole synthesis. Pyrrole 16 was isolated in 59% yield, whereas the
addition of 4-nitrobenzoyl chloride afforded amide 17 in 75% yield (Scheme 2).
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Monosubstituted epoxides are compatible with the reaction conditions: it underwent a ring
opening reaction with ammonium hydroxide, affording the corresponding amino alcohol 18 in high
yields (Eq 1).
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The reaction was then tested with another nucleophile, hydroxylamine, also known to afford
multiple products with halides.11 Typically N-alkylhydroxylamines are prepared by reduction of
oximes in mild conditions12 or by reduction of a nitro group.13,14 The reaction of commercially
available 50% hydroxylamine solution with phenethyl bromide in continuous flow afforded the
corresponding N-alkylhydroxylammonium salt. To separate the desired product from the remaining
hydroxylamine, the resulting salt was treated with a saturated aqueous solution of sodium
bicarbonate, affording the corresponding N-alkylhydroxylamine (Table 3). The optimal
temperature for the amination of alkyl bromide was 100 °C, as lower yields resulting from
overreaction was observed at higher temperature. Furthermore, decreasing the number of equiv of
hydroxylamine also afforded lower yields of the desired product. Under the optimal reaction
conditions with a residence time of 10 min, N-alkylhydroxylamine 19 was isolated from phenethyl
bromide and iodide in 97% and 88% yields respectively (Table 3, entries 1, 2). Various benzyl
chlorides and bromides were successfully reacted producing the desired N-alkylhydroxylamine
with good to excellent yields (entries 3-8).
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Table 3. Amination of Halides with Hydroxylamine
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The reaction is compatible with various functional groups, including heterocycles and nitro
groups (entries 7, 8). Alkylhydroxylamines 25 and 26 were also isolated in moderate to good yields
(entries 9, 10).
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In conclusion, the amination of alkyl halides and monosubstituted epoxides with nucleophilic
amine derivatives in continuous flow produced the corresponding amine products in good to high
yields. The process is fast and safe and can be easily combined with in-line purification or further
derivatization.
Experimental Section.
General Information. Analytical thin-layer chromatography (TLC) was performed using 0.25 mm
silica gel 60-F plates. Visualization of the developed chromatogram was performed by UV
absorbance, cerium ammonium molybdate, aqueous potassium permanganate or ninhydrin. Flash
chromatography was performed using silica gel (230−400 mesh) with the indicated solvent system.
Infrared spectra are reported in reciprocal centimeters (cm−1). Only the most important and
1
relevant frequencies are reported. H NMR spectra were recorded in CDCl3, unless otherwise
1
noted. Chemical shifts for H NMR spectra were recorded in parts per million with the solvent
resonance as the reference CDCl3 (δ = 7.26 ppm), DMSO-d6 (δ = 2.50 ppm) and D2O (δ = 4.79
ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet,
q = quartet, qn = quintet, m = multiplet and br = broad), coupling constant in Hz and integration.
Chemical shifts for 13C{1H} NMR spectra are recorded in parts per million using the central peak
of CDCl3 (δ = 77.16 ppm) or DMSO-d6 (39.52 ppm) as the reference. All 13C NMR spectra were
obtained with complete proton decoupling. When ambiguous, proton and carbon assignments were
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established through COSY, HSQC, and/or DEPT experiments. All NMR yields were determined
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using quantitative H NMR spectra using maleic acid as an internal standard with a 10-sec
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relaxation time. High resolution mass spectra analysis was performed by the Centre régional de
spectroscopie de masse de l'Université de Montréal.
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General Procedure A for the Amination of Alkyl Halides with Ammonia. Amination reactions
were performed in a Vapourtec R-series continuous flow system equipped with two high
temperature tube reactors (10 mL, stainless steel, 1.00 mm i.d). A stock solution of the halide (0.100
or 0.250 M in MeOH) was prepared in a 100 mL volumetric flask. The solution of the halide (0.100
M, 5.00-20.0 mL, 0.500-2.00 mmol) and saturated ammonium hydroxide (14.0 M, 5.00-20.0 mL,
70.0-280 mmol) were pumped at equal flow rates (1.00 or 2.00 mL/min) and directed into two
successive 10 mL-stainless steel reactor heated at 160 °C, after being combined with a T-mixer.
Upon exiting the second flow reactor, the combined reaction stream passed a back-pressure
regulator (350 psi) before being collected into a flask. The solvent was evaporated and the residue
was dried under high vacuum. If necessary, the product was triturated in AcOEt/Hexanes (3/7, 10
mL/1 mmol) for 30 min, filtered, and washed (2 x 10 mL AcOEt/Hexanes [3:7]) to afford the
ammonium salt product.
2-Phenylethan-1-ammonium bromide (1). The title compound was prepared from (2-bro-
moethyl)benzene (1.00 mmol, 0.100 M in MeOH) according to the general procedure A, with a
residence time of 10 min. The desired ammonium salt was obtained as a white solid (188 mg, 93%)
after trituration. mp 248–250 °C (lit. 256–259 °C);15 1H NMR (400 MHz, DMSO) δ 7.79 (s (br),
13
3H), 7.35–7.31 (m, 2H), 7.26–7.23 (m, 3H), 3.04 (t, J = 8.4, 2H), 2.88 (t, J = 8.7, 2H); C{1H}
NMR (75 MHz, DMSO) δ 137.3, 128.6, 128.6, 126.7, 39.9, 32.9; IR (neat) 2989, 1593, 1496, 1461,
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1390, 1257, 1135, 1012, 934, 904, 779, 744, 693, 591, 494; HRMS (ESI +) calcd. for C8H12N [M]+:
122.0964; found 122.0968 (ESI -) calcd. for Br [M]-: 78.9194; found: 78.9204.
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2-Phenylethan-1-ammonium iodide (2). The title compound was prepared from (2-
iodoethyl)benzene (0.500 mmol, 0.100 M in MeOH) according to the general procedure A, with a
residence time of 10 min. The desired ammonium salt was obtained as a white solid (113 mg, 91%)
after trituration. mp 262–265 °C (lit. 267 °C);16 1H NMR (400 MHz, DMSO) δ 7.73 (s (br), 3H),
13
7.35–7.22 (m, 5H), 3.04 (t, J = 8.8 Hz, 2H), 2.88 (t, J = 8.8 Hz, 2H); C{1H} NMR (75 MHz,
DMSO) δ 137.3, 128.6, 128.6, 126.7, 39.9, 32.9; IR (neat) 2989, 1593, 1496, 1461, 1390, 1257,
1135, 1012, 934, 904, 779, 744,693, 591, 494; HRMS (ESI +) calcd. for C8H12N [M]+: 122.0964;
found: 122.0965 (ESI -) calcd. for I [M]-: 126.9050, found: 126.9062.
(2-Bromophenyl)methanammonium bromide (3). The title compound was prepared from 1-
bromo-2-(bromomethyl)benzene (0.500 mmol, 0.100 M in MeOH) according to the general
procedure A, with a residence time of 10 min. The desired ammonium salt was obtained as a white
solid (240 mg, 90%) after trituration. mp 159–161 °C; 1H NMR (400 MHz, D2O) δ 7.74 (dd, J =
13
8.0, 1.1 Hz, 1H), 7.54–7.44 (m, 2H), 7.40–7.35 (m, 1H), 4.35 (s, 2H); C{1H} NMR (75 MHz,
DMSO) δ 133.2, 131.9, 131.2, 131.1, 128.4, 123.8, 43.2; IR (neat) 2886, 1493, 1434, 1026, 757,
657, 450, 427, 408; HRMS (ESI +) calcd. for C7H9BrN [M]+: 185.9912; found: 185.9917 (ESI -)
calcd. for Br [M]-: 78.9189; found: 78.9193.
(4-Cyanophenyl)methanammonium bromide (4). The title compound was prepared from 4-
(bromomethyl)benzonitrile (0.200 mmol, 0.100 M in MeOH:THF (5:1)) according to the general
procedure A, with a residence time of 10 min. The desired ammonium salt was obtained as a white
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solid (38.4 mg, 90 %). mp 220–223 °C; 1H NMR (400 MHz, DMSO) δ 8.25 (s (br), 3H), 7.92 (d,
J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 4.15 (s, 2H); 13C{1H} NMR (75 MHz, DMSO) δ 139.5,
132.5, 129.8, 118.5, 111.2, 41.7; IR (neat) 2977, 2880, 2031, 1991, 1589, 1460, 1378, 1215, 1101,
960, 874, 522; HRMS (ESI +) calcd. for C8H9N2 [M]+: 133.0766; found: 133.0761.
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(3,5-Dichlorophenyl)methanammonium chloride (5). The title compound was prepared from
1,3-dichloro-5-(chloromethyl)benzene (2.00 mmol, 0.100 M in MeOH) according to the general
procedure A, with a residence time of 10 min. The desired ammonium salt was obtained as a white
solid (288 mg, 91%) after trituration. mp 240–242 °C (lit. 267–269 °C);17 1H NMR (400 MHz,
DMSO) δ 8.32 (s (br), 3H), 7.64 (s, 3H), 4.04 (s, 2H); 13C{1H} NMR (75 MHz, DMSO) δ 138.8,
134.4, 128.4, 128.3, 41.4; IR (neat) 2924, 1573, 1524, 1431, 1209, 1100, 904, 879, 858, 836, 795,
667, 433; HRMS (ESI +) calcd. for C7H8Cl2N [M]+: 176.0028; found: 176.0021.
Naphthalen-1-ylmethanammonium chloride (6).18 The title compound was prepared from 1-
(chloromethyl)naphthalene (2.25 mmol, 0.100 M in MeOH:THF (1:1)) according to the general
procedure A, with a residence time of 10 min. The desired ammonium salt was obtained as a white
solid (353 mg, 81%) after trituration. mp 243–245 °C (lit. 249–250 °C);19 1H NMR (400 MHz,
DMSO) δ 8.26 (s (br), 3H) 8.14 (d, J = 7.8 Hz, 1H), 7.97 (t, J = 9.6 Hz, 2H), 7.66–7.52 (m, 4H)
4.49 (s, 2H); 13C{1H} NMR (75 MHz, DMSO) δ 133.2, 130.7, 130.0, 129.0, 128.6, 127.3, 126.7,
126.2, 125.4, 123.5, 38.8; IR (neat) 2887, 1572, 1493, 1403, 1140, 917, 858, 797, 772, 667, 434,
409; HRMS (ESI +) calcd. for C11H12N [M]+: 158.0964; found: 158.0956.
4-(3-(4-(Chloromethyl)phenyl)-1,2,4-oxadiazol-5-yl)benzenammonium chloride (7). The title
compound was prepared from 5-(4-(chloromethyl)phenyl)-3-(4-chlorophenyl)-1,2,4-oxadiazole
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(0.200 mmol, 0.100 M in MeOH:THF (1:1)) according to the general procedure A, with a residence
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time of 5 min. The desired ammonium salt was obtained as an orange solid (63 mg, 97 %). mp
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215–218 °C; H NMR (300 MHz, DMSO) δ 8.24 (d, J = 8.4 Hz, 2H), 8.11 (d, J = 8.4 Hz, 2H),
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7.94 (s (br), 3H), 7.77 (d, J = 8.4 Hz, 2H), 7.70, (d, J = 8.4 Hz, 2H), 4.14 (s, 2H); 13C{1H} NMR
(75 MHz, DMSO) δ 175.8, 168.0, 140.1, 136.9, 130.4, 130.0, 129.4, 128.6, 125.4, 123.6, 42.4; IR
(neat) 2964, 2170, 2043, 1991, 1596, 1466, 1409, 1094, 835, 758; HRMS (ESI +) calcd. for
C15H13ClN3O [M]+: 286.0742; found: 286.0734.
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Pyridin-4-ylmethanammonium chloride (8). The title compound was prepared from 4-
(chloromethyl)pyridine hydrochloride (0.500 mmol, 0.100 M in MeOH) according to the general
procedure A, with a residence time of 10 min. The desired ammonium salt was obtained as a white
solid (123 mg, 85%) after trituration. mp 188–190 °C; 1H NMR (300 MHz, D2O) δ 8.61 (d, J = 6.1
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Hz, 2H), 7.52 (d, J = 6.1 Hz, 2H), 4.29 (s, 2H); C{1H} NMR (75 MHz, D2O) δ 149.2, 143.0,
123.6, 41.7; IR (neat) 2824, 1610, 1524, 1392, 1223, 1125, 987, 837, 797, 590, 505; HRMS (ESI
+) calcd. for C6H9N2 [M]+: 109.0760; found: 109.0764.
Propan-1-ammonium bromide (9). The title compound was prepared from 1-bromopropane
(0.500 mmol, 0.250 M in MeOH) according to the general procedure A, with a residence time of
10 min. The desired ammonium salt was obtained as a white solid (69 mg, 98%). mp 157–160 °C
(lit. 169–172 °C);20 1H NMR (400 MHz, D2O) δ 2.99 (t, J = 7.4 Hz, 2H), 1.70 (sex, J = 7.4 Hz,
2H), 1.00 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (75 MHz, D2O) δ 41.1, 20.2, 10.1; IR (neat) 2966,
1499, 1393, 988, 753, 446; HRMS (ESI +) calcd. for C3H10N [M]+: 60.08078; found 60.0810 (ESI
-) calcd. for Br [M]-: 78.9194; found: 78.9185.
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Butan-1-ammonium chloride (10). The title compound was prepared from 1-chlorobutane (0.500
mmol, 0.250 M in MeOH) according to the general procedure A, with a residence time of 10 min.
The desired ammonium salt was obtained as a white solid (106 mg, 97%). mp 205-207 °C (lit. 208-
209 °C);21 1H NMR (400 MHz, D2O) δ 2.95 (t, J = 7.5 Hz , 2H), 1.59 (qn, J = 7.6 Hz , 2H), 1.34
(sex, J = 7.5 Hz, 2H) 0.89 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (75 MHz, D2O) δ 39.3, 28.8, 19.0,
12.9; IR (neat) 2959, 2929, 2871, 1602, 1510, 1399, 1161, 1075, 1025, 914, 741, 479, 434; HRMS
(ESI+) calcd. for C4H12N [M]+: 74.0964; found: 74.0966.
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Cyclohexylmethanammonium bromide (11). The title compound was prepared from
(bromomethyl)cyclohexane (1.00 mmol, 0.100 M in MeOH) according to the general procedure A,
with a residence time of 5 min. The desired ammonium salt was obtained as a white solid (166 mg,
86%) after trituration. mp 262–265 °C; 1H NMR (400 MHz, DMSO) δ 7.66 (s (br), 3H), 2.63 (d, J
13
= 6.9 Hz, 2H), 1.73–1.48 (m, 6H), 1.22–1.07 (m, 3H), 0.95–0.86 (m, 2H); C{1H} NMR (75 MHz,
DMSO) δ 44.3, 35.4, 29.7, 25.6, 25.0; IR (neat) 2920, 2850, 1597, 1503, 1393, 990, 470; HRMS
(ESI +) calcd. for C11H12N [M]+: 158.0964; found: 158.0956; (ESI -) calcd. for Br [M]-: 78.9194;
found: 78.9203.
Propan-2-ammonium bromide (12). The title compound was prepared from 2-bromopropane
(5.00 mmol, 0.250 M in MeOH) according to the general procedure A, with a residence time of 5
min. The desired ammonium salt was obtained as a yellowish solid (600 mg, 86%). mp > 230 °C;
1H NMR (400 MHz, D2O) δ 3.53 (sep, J = 6.6 Hz, 1H) 1.32 (d, J = 6.6 Hz, 6H); 13C{1H} NMR
(75 MHz, D2O) δ 44.1, 19.8; IR (neat) 2977, 1620, 1504, 1396, 1213; HRMS (ESI +) calcd. for
C3H10N [M]+: 60.0808; found: 60.0800; (ESI -) calcd. for Br [M]-: 78.9189, found: 78.9185.
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(Trimethylsilyl)methanammonium chloride (13). The title compound was prepared from
(chloromethyl)trimethylsilane (2.50 mmol, 0.100 M in MeOH) according to the general procedure
A, with a residence time of 10 min. The desired ammonium salt was obtained as a white solid (254
mg, 73% yield). mp 240-242 °C (lit. 240–241 °C);22 1H NMR (300 MHz, D2O) δ 2.45 (s, 2H), 0.17
(s, 9H); 13C{1H} NMR (75 MHz, D2O) δ 28.4, -3.9.
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2-(Phenylsulfonyl)ethan-1-ammonium chloride (14). The title compound was prepared from 2-
chloroethyl phenyl sulfone (0.500 mmol, 0.100 M in MeOH) according to the general procedure
A, with a residence time of 10 min. The desired ammonium salt was obtained as a white solid (90
mg, 81%) after trituration. mp 155–158 °C (lit. 155–155.5 °C);23 1H NMR (400 MHz, DMSO) δ
8.25 (s (br), 3H), 7.94 (d, J = 7.8 Hz, 2H), 7.81 (t, J = 7.5 Hz, 1H), 7.71 (t, J = 7.8 Hz, 2H), 3.72
(t, J = 7.6 Hz, 2H), 2.99 (t, J = 7.6 Hz, 2H); 13C{1H} NMR (75 MHz, DMSO) δ 138.0, 134.5,
129.8, 50.0, 33.1; IR (neat) 2833, 1562, 1447, 1400, 1298, 1144, 1084, 827, 803, 750, 689, 533;
HRMS (ESI+) calcd. for C8H12NO2S [M]+: 186.0583; found: 186.0583.
2-Phenylethan-1-amine (15).24 The reaction was performed in a Vapourtec R-series continuous
flow system equipped with a high temperature tube reactor (10 mL, stainless steel, 1.00 mm i.d).
A stock solution of 2-bromoethylbenzene (0.100 M in MeOH) was prepared in a 25 mL volumetric
flask. The solution of the halide (0.100 M, 10.00 mL, 1.00 mmol) and saturated ammonium
hydroxide (14.0 M, 10.00 mL, 140.0 mmol) were pumped at equal flow rates (0.5 mL/min) and
directed into a 10 mL stainless steel reactor heated at 160 °C, after being combined with a T-mixer.
Upon exiting the second flow reactor, the combined reaction stream passed a back-pressure
regulator (350 psi). A continuous stream of KOH/NaCl 2M was injected at 0.5 mL/min after the
BPR in a 10 mL PFA reactor. The reaction was combined in a magnetic CSTR with a stream of
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DCE (0.5 mL/min), then passed by a 50 cm PFA tubing. The organic layer was then separated
using a Zaiput liquid-liquid separator. A solution of free amine was collected in a round bottom
flask and the solvent was evaporated to afford the amine as a colorless liquid (85.1 mg, 70 %). 1H
NMR (400 MHz, CDCl3) δ 7.33–7.26 (m, 2H), 7.23–7.17 (m, 3H), 2.95 (t, J = 6.9 Hz, 2H), 2.73
(t, J = 6.9 Hz, 2H), 1.26 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 140.0, 129.0, 128.6, 126.3,
43.8, 40.3.
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2,5-Dimethyl-1-phenethyl-1H-pyrrole (16).25 The reaction was performed in a Vapourtec R-
series continuous flow system equipped with a high temperature tube reactor (10 mL, stainless
steel, 1.00 mm i.d). A stock solution of 2-bromoethylbenzene (0.100 M in MeOH) was prepared in
a 500 mL volumetric flask. The solution of the halide (0.100 M, 5.00 mL, 0.500 mmol) and
saturated ammonium hydroxide (14.0 M, 5.00 mL, 70.0 mmol) were pumped at equal flow rates
(0.5 mL/min) and directed into a 10 mL-stainless steel reactor heated at 160 °C, after being
combined with a T-mixer. Upon exiting the second flow reactor, the combined reaction stream
passed a back-pressure regulator (350 psi). A continuous stream of KOH/NaCl 2M was injected at
0.5 mL/min after the BPR in a 10 mL PFA reactor. The reaction was combined in a magnetic CSTR
with a stream of DCE (0.5 mL/min). The organic layer was separated using a Zaiput liquid-liquid
separator and collected in a round bottom flask. To this solution was added acetonylacetone (70
µL, 0.60 mmol, 1.2 equiv) and the reaction was heated at reflux during 1 h. The reaction was
quenched with aq. NH4Cl (25 mL), then the layers were separated. The aqueous layer was extracted
with DCM (2 x 20 mL). The combined organic layers were washed with brine and dried over
MgSO4. The solvent was removed under reduced pressure, affording the desired pyrrole (58.9 mg,
0.295 mmol, 59%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 7.36–7.26 (m, 3H), 7.18–7.11 (m,
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CDCl3) δ 138.7, 129.0, 128.7, 127.5, 126.7, 105.3, 45.4, 37.7, 12.5.
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4-nitro-N-phenethylbenzamide (17).26 The reaction was performed in a Vapourtec R-series
continuous flow system equipped with a high temperature tube reactor (10 mL, stainless steel, 1.00
mm i.d). A stock solution of 2-bromoethylbenzene (0.100 M in MeOH) was prepared in a 500 mL
volumetric flask. The solution of the halide (0.100 M, 5.00 mL, 0.500 mmol) and saturated
ammonium hydroxide (14.0 M, 5.00 mL, 70.0 mmol) were pumped at equal flow rates (0.5
mL/min) and directed into a 10 mL-stainless steel reactor heated at 160 °C, after being combined
with a Y-mixer. Upon exiting the second flow reactor, the combined reaction stream passed a back-
pressure regulator (350 psi). A continuous stream of KOH/NaCl 2M was injected at 0.5 mL/min
after the BPR in a 10 mL PFA reactor. The reaction was combined in a magnetic CSTR with a
stream of DCE (0.5 mL/min). The organic layer was separated using a Zaiput liquid-liquid
separator and collected in a round bottom flask. To this solution was added was added triethylamine
(174 µL, 1.25 mmol, 2.50 equiv), 4-(dimethylamino)pyridine (6 mg, 0.05 mmol, 0.1 equiv) and 4-
nitrobenzoyl chloride (118 µL, 1.25 mmol, 2.50 equiv) and the reaction was stirred 1 h at 25 °C.
The reaction was quenched with aq NH4Cl (25 mL), then the layers were separated. The aqueous
layer was extracted with DCM (2 x 20 mL). The combined organic layers were washed with brine
and dried over MgSO4. The solvent was removed under reduced pressure. The crude mixture was
purified by flash chromatography on silica gel using 80/20 to 70/30 Hexanes/AcOEt. The desired
compound (102 mg, 0.377 mmol, 75%) was obtained as a white solid. 1H NMR (300 MHz, CDCl3)
δ 8.38-8.16 (m, 2H), 7.97–7.75 (m, 2H), 7.45–7.30 (m, 2H), 7.30–7.20 (m, 3H), 6.37 (s (br), 1H),
3.75 (app. q, J = 6.9 Hz, 2H), 2.96 (t, J = 6.9 Hz, 2H); 13C{1H} NMR (75 MHz, CDCl3) δ 165.6,
149.6, 140.3, 138.6, 128.9, 128.9, 128.1, 126.9, 123.9, 41.5, 35.6.
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1-Amino-3-(4-methoxyphenyl)propan-2-ol (18). The ring opening reaction was performed in a
Vapourtec R-series continuous flow system equipped with two high temperature tube reactors (10
mL, stainless steel, 1.00 mm i.d). A solution of 2-(4-methoxybenzyl)oxirane (5.00 mL, 0.500
mmol, 0.100 M in MeOH) and saturated ammonium hydroxide (14.0 M, 5.00 mL, 70.0 mmol)
were pumped at equal flow rates (2.00 mL/min) and directed into two successive 10 mL-stainless
steel reactor heated at 160 °C, after being combined with a T-mixer. Upon exiting the second flow
reactor, the combined reaction stream passed a back-pressure regulator (350 psi) before being
collected into a flask. The solvent was evaporated and the residue was dried under high vacuum.
The title amino alcohol was isolated (87.9 mg, 97%) as a colorless oil which crystalize over time.
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mp 182-183 °C; H NMR (500 MHz, DMSO) δ 7.15–7.08 (m, 2H), 6.85–6.79 (m, 2H), 3.71 (s,
3H), 3.55–3.47 (m, 1H), 2.61 (dd, J = 13.6, 5.8 Hz, 1H), 2.54 (dd, J = 12.6, 6.0 Hz, 1H), 2.43–2.35
(m, 1H).; 13C{1H} NMR (125 MHz, DMSO) δ 157.4, 131.4, 130.2, 113.4, 73.1, 54.9, 47.0, 40.0;
IR (neat) 3255, 2931, 2835, 1655, 1610, 1509, 1462, 1243, 1107, 1082, 1031, 811; HRMS (ESI-
TOF) m/z: [M+Na]+ Calcd for C10H15NaNO2 205.0976; Found 205.0875.
General Procedure B for the Amination of Alkyl Halides with Hydroxylamine. Amination
reactions were performed in a Vapourtec R-series continuous flow system equipped with two high
temperature tube reactors (10 ml, stainless steel, 1 mm i.d). A solution of halide (0.10 M in MeOH)
was prepared in a 25 ml volumetric flask. The solution of halide (0.10 M, 1.0 mmol, 10 ml) and
hydroxylamine in water (15 M, 150 mmol, 10 ml) were pumped with two separate pumps at equal
flow (1 ml/min) and directed into two successive 10 ml stainless steel reactors heated at 100 °C,
after being combined with a T-mixer. After exiting the second flow reactor, the combined reaction
stream passed through a back-pressure regulator (350 psi) before being collected. The collected
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mixture was then treated with NaHCO3 (15 mL) and extracted with EtOAc (3 x 15 mL). The
combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. Purification
by flash chromatography furnish the desired product.
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N-Phenethylhydroxylamine (19).13 The title compound was prepared from (2-
bromoethyl)benzene (1.00 mmol, 0.100 M in MeOH) according to the general procedure B, with a
residence time of 10 min. The desired N-alkylhydroxylamine was obtained as a white solid (137
mg, >99%) after purification by flash chromatography using Hexanes/EtOAc 8:2 then 0:100. Rf
0.26 (Hexane/EtOAc 4:6); mp 83-85 °C (lit. 85 °C);13 1H NMR (500 MHz, CDCl3) δ 7.32-7.29 (m,
2H), 7.23–7.20 (m, 3H), 5.67 (s (br), 2H), 3.19 (t, J = 7.1 Hz, 2H), 2.88 (t, J = 7.1 Hz, 2H); 13C{1H}
NMR (125 MHz, CDCl3) δ 139.4, 129.0, 128.7, 126.5, 55.1, 33.5; FTIR (neat) 3262, 2906, 2828,
1634, 1012, 695, 459, 436, 421; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C8H12NO 138.0913,
found 138.0917.
N-Phenethylhydroxylamine (19).13 The title compound was prepared from (2-iodoethyl)benzene
(1.00 mmol, 0.100 M in MeOH) according to the general procedure B, with a residence time of 10
min. The desired N-alkylhydroxylamine was obtained as a white solid (121 mg, 88%) after
purification by flash chromatography using Hexanes/EtOAc 8:2 then 0:100. Rf 0.26
(Hexane/EtOAc 4:6); mp 83–85 °C (lit. 85 °C);13 1H NMR (500 MHz, CDCl3) δ 7.32–7.29 (m,
2H), 7.23–7.20 (m, 3H), 5.67 (s (br), 2H), 3.19 (t, J = 7.1 Hz, 2H), 2.88 (t, J = 7.1 Hz, 2H); 13C{1H}
NMR (125 MHz, CDCl3) δ 139.4, 129., 128.7, 126.5, 55.1, 33.5; FTIR (neat) 3262, 2906, 2828,
1634, 1012, 695, 459, 436, 421; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C8H12NO 138.0913,
found 138.0917.
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N-Benzylhydroxylamine (20).27 The title compound was prepared from (chloromethyl)benzene
(1.00 mmol, 0.1 M in MeOH) according to the general procedure B, with a residence time of 10
min. The desired N-alkylhydroxylamine was obtained as an off-white solid (79.6 mg, 65%) after
purification by flash chromatography using hexane/EtOAc 5:5 then 0:100. Rf 0.37 Hexane/EtOAc
5:5); mp 55–56 °C (lit. 54–56 °C);28 1H NMR (500 MHz, CDCl3) δ 7.36–7.28 (m, 5H), 5.9 (s (br),
2H), 3.99 (s, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 137.1, 129.3, 128.7, 127.8, 58.4; FTIR
(neat): 3257, 2911, 2864, 2359, 1454, 1018, 746, 696, 491; HRMS (ESI-TOF) m/z: [M+H]+ calcd
for C7H10NO 124.0756; found 124.0755.
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N-Benzylhydroxylamine (20).27 The title compound was prepared from (bromomethyl)benzene
(1.00 mmol, 0.1 M in MeOH) according to the general procedure B, with a residence time of 10
min. The desired N-alkylhydroxylamine was obtained as an off-white solid (94 mg, 76%) after
purification by flash chromatography using hexane/EtOAc 5:5 then 0:100. Rf 0.37 Hexane/EtOAc
5:5); mp 55–56 °C (lit. 54–56 °C);28 1H NMR (500 MHz, CDCl3) δ 7.36–7.28 (m, 5H), 5.9 (s (br),
2H), 3.99 (s, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 137.1, 129.3, 128.7, 127.8, 58.4; FTIR
(neat): 3257, 2911, 2864, 2359, 1454, 1018, 746, 696, 491; HRMS (ESI-TOF) m/z: [M+H]+ calcd
for C7H10NO 124.0756; found 124.0755.
N-(2-Bromobenzyl)hydroxylamine (21). The title compound was prepared from 1-bromo-2-
(bromomethyl)benzene (1.00 mmol, 0.1 M in MeOH) according to the general procedure B, with
a residence time of 10 min. The desired N-alkylhydroxylamine was obtained as a white solid (173
mg, 86%) after purification by flash chromatography using Hexane/EtOAc 7:3 then 0:100. Rf 0.37
(Hexane/EtOAc 6:4); mp 79–81°C; 1H NMR (500 MHz, CDCl3) δ 7.56 (dd, J = 7.7, 1.1 Hz, 1H),
7.38 (dd, J = 7.6, 1.6 Hz, 1H), 7.28 (dt, J = 7.7, 1.6 Hz, 1H), 7.16 (dt, J = 7.6, 1.2 Hz, 1H), 5.71 (s
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(br), 2H), 4.12 (s, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 136.3, 133.1, 131.9, 129.5, 127.6,
124.6, 58.1; FTIR (neat): 3260, 2921, 1470, 1439, 1024, 749; HRMS (ESI-TOF) m/z: [M+H]+
calcd for C7H9BrNO 201.9862, found 201.9869.
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N-((perfluorophenyl)methyl)hydroxylamine (22). The title compound was prepared from 1-
(bromomethyl)-2,3,4,5,6-pentafluorobenzene (1.00 mmol, 0.1 M in MeOH) according to the
general procedure B, with a residence time of 10 min. The desired N-alkylhydroxylamine was
obtained as a white solid (206 mg, 97%) after purification by flash chromatography using
Hexane/EtOAc 0:100. Rf 0.37 (Hexane/EtOAc 6:4); mp 111–113 °C (lit. 110–111 °C);29 1H NMR
(500 MHz, CDCl3) δ 5.87 (s (br), 1H), 5.39 (s (br), 1H), 4.16 (s, 2H); 13C{1H} NMR (176 MHz,
CDCl3) δ 145.7 (dm, J = 248 Hz), 140.9 (dm, J = 249 Hz), 137.4 (dm, J = 250 Hz), 110.8 (td, J =
14, 3 Hz), 45.0; 19F NMR (282 MHz, CDCl3) δ -144.8–-144.9 (m), -156.1 (t, J = 21 Hz), -163.5 –
-163.7; FTIR (neat) 3268, 3252, 3186, 2904, 2361, 1505, 1123, 1020, 926; HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C7H5F5NO 214.0285; found 214.0295.
N-(2-nitrobenzyl)hydroxylamine (23). The title compound was prepared from 1-
(chloromethyl)-2-nitrobenzene (1 mmol, 0.1 M in MeOH) according to the general
procedure B, with a residence time of 10 min. The desired N-alkylhydroxylamine was obtained as
a pale yellow solid (118 mg, 70%) after purification by flash chromatography using Hexane/EtOAc
1
7:3 then 0:100. Rf 0.37 (Hexane/EtOAc 5:5); mp 66–67 °C; H NMR (500 MHz, CDCl3) δ 7.98
(dd, J = 8.2, 1.1 Hz, 1H), 7.62–7.55 (m, 2H), 7.47–7.44 (m, 1H), 6.28 (s (br), 1H), 4.27 (s, 2H);
13C{1H} NMR (125 MHz, CDCl3) δ 149.5, 133.3, 133.1, 132.6, 128.8, 125.0, 55.1; FTIR (neat):
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3271, 2942, 2878, 2360, 2342, 1519, 1342, 1018, 729; HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C7H9N2O3 169.0609; found 169.0616.
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N-(4-(3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl)benzyl)hydroxylamine
(24).
The
title
compound was prepared from 5-(4-(chloromethyl)phenyl)-3-(4-chlorophenyl)-1,2,4-oxadiazole (1
mmol, 0.1M in MeOH:THF (1:5)) according to the general procedure B, with a residence time of
10 min. The desired N-alkylhydroxylamine was obtained as a white solid (240 mg, 80%) after
purification by flash chromatography using Hexane/EtOAc 6:4 then 0:100. Rf 0.35 (Hexane/EtOAc
2:8); mp 165–167 °C; 1H NMR (500 MHz, DMSO) δ 8.13 (d, J = 8.5 Hz, 2H), 8.10 (d, J = 8.5 Hz,
2H), 7.67 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.5 Hz, 2H), 7.36 (s (br), 1H), 6.27 (s (br), 1H), 3.99 (s,
13
2H); C{1H} NMR (176 MHz, CDCl3) δ 176.17, 167.92, 146.21, 136.85, 129.98, 129.92, 129.37,
128.12, 125.54, 122.00, 57.33; FTIR (neat): 3267, 2359, 2342, 1636, 1414, 1368, 1355, 1014, 757;
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C15H13ClN3O2 302.0690, found 302.0696.
N-(Cyclohexylmethyl)hydroxylamine (25). The title compound was prepared from
(bromomethyl)cyclohexane (1 mmol, 0.1 M in MeOH) according to the general procedure B, with
a residence time of 20 min. The desired N-alkylhydroxylamine was obtained as a white solid (92
mg, 71%) after purification by flash chromatography using Hexane/EtOAc 8:2 then 0:100. Rf 0.32
(Hexane/EtOAc 5:5); mp 59–60 °C; 1H NMR (500 MHz, CDCl3) δ 5.91 (s (br), 2H), 2.78 (d, J =
6.5 Hz, 2H), 1.78–1.63 (m, 5H), 1.62–1.53 (m, 1H), 1.30–1.13 (m, 3H), 0.97–0.87 (m, 2H);
13C{1H} NMR (125 MHz, CDCl3) δ 60.6, 35.2, 31.3, 26.6, 25.9; FTIR (neat): 3251, 3225, 3160,
2915, 2849, 2361, 2342, 1446, 1027, 959; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C7H16NO
130.1226; found 130.1230.
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N-(2-(Phenylsulfonyl)ethyl)hydroxylamine (26). The title compound was prepared from 2-
chloroethyl phenyl sulfone (1.00 mmol, 0.100 M in MeOH) according to the general procedure B,
with a residence time of 10 min. The desired N-alkylhydroxylamine was obtained as a white solid
(100 mg, 50 %) after purification by flash chromatography using Hexane/EtOAc 7:3 then 0:100.
Rf 0.35 (Hexane/EtOAc 2:8); mp 68–70 °C (lit. 67–68 °C);12b 1H NMR (500 MHz, CDCl3) δ 7.94–
7.92 (m, 2H), 7.69–7,66 (m, 1H), 7.60–7.57 (m, 2H), 5.68 (s (br), 2H), 2.43 (t, J = 6.1 Hz, 2H),
3.33 (t, J = 6.1 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 139.3, 134.1, 129.6, 128.1, 53.2,
47.4; FTIR (neat) 3277, 1447, 1286, 1142, 1085, 1039, 734, 689, 578, 535; HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C8H12NO3S 202.0532, found 202.0527.
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Supporting Information Available: Characterization spectra (1H and 13C{1H} NMR) for all
compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgement.
This research was supported by the Natural Science and Engineering Research Council of Canada
(NSERC) under the CREATE Training Program in Continuous Flow Science, a discovery grant
from NSERC (Canada), the Canada Foundation for Innovation, the Université de Montréal and the
Centre in Green Chemistry and Catalysis (CGCC). We would like to thank Vanessa Kairouz and
Dr. James J. Mousseau for fruitful discussions.
1 Lawrence, S. A., Amines: Synthesis, Properties and Applications. Cambridge University Press:
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