Org. Synth. 2002, 79, 186
DOI: 10.15227/orgsyn.079.0186
PREPARATION OF SECONDARY AMINES FROM PRIMARY AMINES VIA 2-NITROBENZENESULFONAMIDES:
N-(4-METHOXYBENZYL)-3-PHENYLPROPYLAMINE
[
Benzenepropanamine, N-[(4-methoxyphenyl)methyl]-
]
Submitted by Wataru Kurosawa, Toshiyuki Kan, and Tohru Fukuyama
1
.
Checked by Audra M. Dalton and Rick L. Danheiser.
1. Procedure
A.
N-(4-Methoxybenzyl)-2-nitrobenzenesulfonamide
.
A 300-mL, two-necked, round-bottomed flask equipped with a
magnetic stirring bar, nitrogen gas inlet,
and a rubber septum is charged with
6.81
g (49.6 mmol) of 4-methoxybenzylamine
(Note 1),
100 mL of
dichloromethane
and
6.93
mL (49.6 mmol) of triethylamine
(Note 1). The mixture is stirred and cooled in an ice-water
bath while
10.0 g (45.1
mmol) of 2-nitrobenzenesulfonyl chloride
(Note 1) is added over a period of 5 min. After 5 min, the ice
bath is removed and the reaction mixture is allowed to warm to room temperature,
stirred for 15 min (Note 2), and then quenched with
100 mL of 1N hydrochloric acid
(HCl). The aqueous layer is extracted with two
100-mL
portions of dichloromethane
, and the combined organic
extracts are washed with
50 mL of brine,
dried over
magnesium sulfate
,
filtered, and concentrated under reduced pressure to give 14.2 g (98%)
of the crude
2-nitrobenzenesulfonamide
.
Recrystallization from 500 mL of 1:1 ethyl acetate/hexane
gives 13.00-13.15 g (90-91%) of
N-(4-Methoxybenzyl)-2-nitrobenzenesulfonamide
as white crystals (Note 3).
B.
N-(4-Methoxybenzyl)-N-(3-phenylpropyl)-2-nitrobenzenesulfonamide
.
A 200-mL, two-necked, round-bottomed flask equipped with a
magnetic stirring bar, a nitrogen gas inlet,
and a rubber septum is charged with
10.0
g (31.0 mmol) of N-(4-Methoxybenzyl)-2-nitrobenzenesulfonamide,
12.9 g (93.1 mmol) of
potassium
carbonate
(Note 4), and
40
mL of anhydrous dimethylformamide (DMF).
To the stirred mixture is added
5.19 mL
(34.1 mmol) of 3-phenylpropyl bromide
(Note 5) over a period of 5 min and the resulting mixture is
heated in a 60°C oil bath for 70 min (Note 6).
The reaction mixture is allowed to cool to room temperature, diluted with 250 mL of
water, and extracted with three
250-mL portions
of ether. The combined organic extracts are washed with brine
(100 mL), dried over
magnesium
sulfate
, filtered, and concentrated under reduced pressure to
give a pale yellow liquid. The residue is purified by column chromatography on silica
gel (Note 7) to give 13.5
g (99%) of
N-(4-Methoxybenzyl)-N-(3-phenylpropyl)-2-nitrobenzenesulfonamide
(Note 8) as a viscous pale yellow liquid.
C.
N-(4-Methoxybenzyl)-3-phenylpropylamine
.
A 100-mL, two-necked, round-bottomed flask equipped with a
magnetic stirring bar, nitrogen gas inlet,
and a rubber septum is charged with
7.82
mL (76.5 mmol) of thiophenol
(Note 9) and
20 mL
of acetonitrile
(CH3CN). The mixture is
cooled in an ice-water bath and 10.9
M aqueous potassium hydroxide solution (7.02 mL,
76.5 mmol) is added over a period of 10 min. After 5 min,
the ice-water bath is removed, and
13.5
g (30.6 mmol) of N-(4-Methoxybenzyl)-N-(3-phenylpropyl)-2-nitrobenzenesulfonamide
in
20 mL of acetonitrile
is added over 20 min. The reaction mixture is heated in a 50°C oil
bath for 40 min (Note 10). The reaction mixture is
allowed to cool to room temperature, diluted with 80 mL of water, and extracted with
three
80-mL portions of dichloromethane
.
The combined organic extracts are washed with brine (80
mL), dried over
magnesium sulfate
,
filtered, and concentrated under reduced pressure. The residue is purified by column
chromatography on silica (Note 11) to give 7.81 g of the desired amine and its hydrochloride salt. This
oil is dissolved in
120 mL of dichloromethane
and washed with two
80-mL portions of 1
M aqueous sodium hydroxide
solution,
40
mL of brine, dried over
magnesium
sulfate
, filtered, and concentrated under reduced pressure.
Bulb-to-bulb distillation (0.25 mm, oven temperature 150°C) provides 6.98-7.08 g (89-91%) of
N-(4-Methoxybenzyl)-3-phenylpropylamine
as a colorless oil (Notes 12, 13).
2. Notes
1.
4-Methoxybenzylamine
,
triethylamine
, and
2-nitrobenzenesulfonyl chloride were purchased
by the submitters from Tokyo Kasei Kogyo Co.
The checkers
obtained
4-methoxybenzylamine and 2-nitrobenzenesulfonyl
chloride from Alfa Aesar
and
triethylamine from Mallinckrodt Inc.
.
2.
All reactions were monitored by TLC analysis on
Merck
silica gel 60 F254 plates, which were visualized by a
254-nm
UV lamp and stained with an ethanolic solution of
phosphomolybdic
acid
. TLC analysis showed clean formation of the
2-nitrobenzenesulfonamide
(
hexane : ethyl acetate
3 : 2, R
f = 0.33).
3.
Yield is based on
2-nitrobenzenesulfonyl
chloride
. The crude product was practically pure as judged by
1H NMR analysis and may be used for the next step without purification.
The recrystallized compound exhibits the following properties:
mp 123°C;
1H
NMR (400 MHz, CDCl
3) δ: 3.76 (s, 3 H), 4.25 (d,
2 H, J = 6.2), 5.63 (br, t, 1 H, J = 6.2), 6.75 (d, 2 H,
J = 8.5), 7.13 (d, 2 H, J = 8.5), 7.63-8.03 (m, 4 H)
;
13C NMR (100
MHz, CDCl
3) δ: 47.4, 55.3, 114.0,
125.2, 127.7, 129.2, 131.1, 132.7,
133.3, 134.0, 159.3
; IR (thin film) cm
−1: 3312, 2941,
1543, 1511, 1363, 1337, 1243,
1160
; MS m/z: 322,
134, 121
. Anal. Calcd for C
14H
14N
2O
5S:
C, 52.17; H, 4.38; N, 8.69. Found: C, 52.05; H, 4.46; N, 8.74.
4.
The checkers obtained anhydrous DMF from EM Sciences.
Potassium carbonate (powder, K2CO3) was purchased
from Aldrich Chemical Company, Inc.
If granular K
2CO
3
is used in place of powder, the reaction requires a longer time (5.5 hr) and proceeds
in lower yield (
81%).
5.
3-phenylpropyl bromide
was purchased from Tokyo Kasei Kogyo Co. or Alfa Aesar.
6.
TLC analysis showed clean formation of the alkylated sulfonamide
(
hexane :
ethyl acetate 1 : 1, R
f
= 0.71).
7.
Column chromatography was performed on
150
g of silica gel (100-210 µm, Kanto Chemical Co., Inc.
or Silacycle, Inc.
). The product was eluted with
300 mL of 10%
ethyl acetate-hexane
,
300 mL of 25%
ethyl
acetate-hexane
, and
1.8
L of 40%
ethyl acetate-hexane
,
and 300-mL fractions were collected.
8.
The product exhibits the following properties:
1H NMR (400 MHz, CDCl
3) δ:
1.70 (dt, 2 H, J = 7.7, 7.7), 2.44 (t, 2 H, J = 7.7), 3.23
(t, 2 H, J = 7.7), 3.79 (s, 3 H), 4.44 (s, 2 H),
6.81 (d, 2 H, J = 8.7), 6.99 (d, 2 H, J = 8.7), 7.14-7.25
(m, 5 H), 7.58-7.92 (m, 4 H)
;
13C NMR (100 MHz, CDCl
3) δ:
29.0, 32.6, 46.4, 50.7, 55.2,
114.0, 124.1, 125.9, 127.5, 128.2,
128.3, 129.7, 130.7, 131.6, 133.3,
133.6, 140.9, 147.8, 159.5
;
IR (neat) cm
−1: 2934,
1543, 1513, 1372, 1346, 1250,
1211
; MS m/z 440,
150, 122
. Anal. Calcd for C
23H
24N
2O
5S:
C, 62.71; H, 5.49; N, 6.36. Found: C, 62.76; H, 5.47; N, 6.31.
9.
Thiophenol
and
potassium hydroxide were purchased
by the submitters from Tokyo Kasei Kogyo Co. and by the checkers
from Aldrich Chemical Company, Inc. and Mallinckrodt
Inc.
, respectively.
10.
TLC analysis showed clean formation of the deprotected amine
(
methanol:dichloromethane
10 : 90, R
f = 0.52).
11.
Column chromatography was performed on
150
g of silica gel (100-210 µm, Kanto Chemical Co., Inc.
or Silacycle, Inc.
). The product was eluted with
70 mL of dichloromethane
,
900 mL of 2%
methanol-dichloromethane
,
and
1.8 L of 2.5:2.5:95 isopropylamine-methanol-dichloromethane
(300-mL fractions).
12.
The product exhibits the following properties:
1H NMR (400 MHz, CDCl
3) δ:
1.83 (dt, 2 H, J = 7.8, 7.8), 2.65 (m, 4 H), 3.71
(s, 2 H), 3.79 (s, 3 H), 6.84-7.28 (m, 9 H)
;
13C NMR (100
MHz, CDCl
3) δ: 31.6, 33.6, 48.7,
53.4, 55.1, 113.8, 125.8, 128.3,
129.2, 132.6, 142.1, 158.5
;
IR (neat) cm
−1:
3302,
2931, 1511, 1246
; MS m/z 255, 150, 121
.
Anal. Calcd for C
17H
21NO: C, 79.96; H, 8.29; N, 5.49. Found:
C, 79.76; H, 8.40; N, 5.41.
13.
The amine can be transformed to the
hydrochloride
salt by bubbling a stream of
hydrogen chloride gas into a solution
of 7.81 g of the amine in
methanol
at 0°C. Recrystallization from
2-propanol
gives
N-(4-methoxybenzyl)-3-phenylpropylamine
hydrochloride
(
7.92 g,
88%) as white crystals. The product exhibits the following
properties:
mp 206°C;
1H NMR (400 MHz, CDCl
3)
δ: 2.14 (dt, 2 H, J = 7.4, 7.7), 2.62 (t, 2 H, J = 7.4),
2.73 (t, 2 H, J = 7.7), 3.74 (s, 3 H), 3.91 (s, 2
H), 6.87 (d, 2 H, J = 8.6), 7.10-7.24 (m, 5 H), 7.45
(d, 2 H, J = 8.6), 9.80 (br, s, 1 H)
;
13C NMR (100 MHz, CDCl
3) δ:
27.0, 32.5, 44.9, 49.8, 55.1,
114.2, 121.8, 126.1, 128.2, 128.4,
131.8, 139.7, 160.2
; IR (thin film) cm
−1: 2938, 2789,
1518, 1252
; MS
m/z 255, 150, 121
. Anal. Calcd for
C
17H
22ClNO: C, 69.97; H, 7.60; N, 4.80. Found: C, 69.85; H,
7.58; N, 4.86.
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
Conversion of primary amines to the corresponding secondary amines appears to be
deceptively simple.
2 Alkylation of primary amines with alkyl
halides or sulfonates frequently leads to the formation of the undesired tertiary
amines and/or quaternary ammonium salts. Reductive alkylation with aldehydes or ketones
using
sodium cyanoborohydride (NaBH
3CN) often produces
tertiary amines to a varying extent unless the desired secondary amine is sterically
hindered. Reduction of N-monoalkyl amides with such strong reducing agents as
lithium aluminum hydride (LiAlH4),
diisobutylaluminum hydride (DIBAL),
or
borane seems to be the most reliable procedure. To circumvent
these problems, the Mitsunobu alkylations of toluenesulfonamides
3
and trifluoroacetamides
4 have recently
been reported. However, because of the relatively harsh deprotection conditions, these
methods do not appear to be suitable for the preparation of the base-sensitive secondary
amines. The present procedure describes the simple and general transformation of primary
amines to the corresponding secondary amines using the
2-nitrobenzenesulfonamide
protecting group that can be applied to the synthesis of a wide range of secondary
amines (Scheme 1).
5
A related procedure using 2,4-dinitrobenzenesulfonamides that requires even milder
deprotection conditions (HSCH
2CO
2H, Et
3N, CH
2Cl
2,
room temperature) has recently been reported.
6
Protection of the primary amines was performed by treatment with
2-nitrobenzenesulfonyl
chloride
and base (
triethylamine,
pyridine, or 2,6-lutidine
) to
give N-monosubstituted 2-nitrobenzenesulfonamides in high yields (Step A). Alkylation
of N-monosubstituted 2-nitrobenzenesulfonamides (1) proceeded smoothly under either
the conditions described above (conventional) or Mitsunobu conditions
7 to give
N,N-disubstituted 2-nitrobenzenesulfonamide (2) in excellent yields. For large-scale
alkylations, conventional conditions are recommended, because of the ease of purification.
Facile deprotection of N,N-disubstituted 2-nitrobenzenesulfonamides is achieved by
treatment with thiolate nucleophile, presumably via the formation of a Meisenheimer
complex
8 (3),
giving the desired secondary amines (4) in excellent yields (Step C). Since
potassium hydroxide
is inexpensive,
the described procedure is convenient for a large-scale reaction. For a small scale
reaction, however, one of the following reported procedures is recommended: (1)
potassium carbonate
,
thiophenol
in
DMF, (2)
cesium
carbonate
,
thiophenol
in CH
3CN, (3)
lithium hydroxide
,
mercaptoacetic acid
in
DMF. Procedure (3) has the advantage that the by-product
2-nitrophenylthioacetic acid
(5) can be easily removed by partitioning between ether and an
aqueous
sodium bicarbonate
solution. Representative examples
of this protocol are summarized in Table I.
Since the 2-nitrobenzenesulfonamide group is stable under
acidic [HCl (10 eq), MeOH, 60°C, 4 hr] as well as basic [NaOH (10 eq), MeOH, 60°C,
4 hr] conditions, it can be used extensively for protection of primary and secondary
amines. Because of the mild conditions and easy procedure, the submitters believe
that the use of 2-nitrobenzenesulfonamides serves as a method of choice for the preparation
of a wide variety of secondary amines comparable to the Gabriel synthesis for primary
amines.
TABLE 1
ALKYLATION AND DEPROTECTION OF 2-NITROBENZENESULFONAMIDES
|
|
RX or ROH
|
Alkylation conditionsa
|
2b(% isolated yield)
|
Deprotection conditionsc
|
4b,d(%isolated yield)
|
|
|
|
A
|
(98)
|
TP
|
(94)
|
|
|
|
|
MA
|
(93)
|
|
|
B
|
(98)
|
TP
|
(94)
|
|
|
C
|
(91)
|
TP
|
(88)
|
|
|
C
|
(87)
|
TP
|
(93)
|
|
aA: RX (1.1 eq), K2CO3
(2 eq), DMF, 23°C, 1 hr.
|
B: RX (1.1 eq), K2CO3 (2 eq),
DMF, 60°C, 30 min.
|
C: ROH (1.3 eq), DEAD (1.3 eq), PPh3 (1.3
eq), CH2Cl2, 23°C, 1 hr.
|
bSatisfactory spectroscopic data were obtained
on all new compounds.
|
cTP: PhSH (1.2 eq), K2CO3
(3 eq), DMF, 23°C, 40 min.
|
MA: HSCH2CO2H (2 eq), LiOH (4
eq), DMF, 23 °C, 1 hr.
|
dSeparated by silica gel chromatography
after partitioning between Et2O and a dilute NaHCO3 solution.
|
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
N-(4-Methoxybenzyl)-3-phenylpropylamine:
Benzenepropanamine,
N-[(4-methoxyphenyl)methyl]- (13); (145060-50-0)
N-(4-methoxybenzyl)-2-nitrobenzenesulfonamide:
Benzenesulfonamide,
N-[(4-methoxyphenyl)methyl]-2-nitro- (13); (171414-16-7)
4-Methoxybenzylamine:
Benzylamine, p-methoxy-
(8);
Benzenemethaneamine, 4-methoxy- (9); (2393-23-9)
Triethylamine (8):
Ethanamine, N,N-diethyl-
(9); (121-44-8)
o-Nitrobenzenesulfonyl chloride:
Benzenesulfonyl
chloride, o-nitro- (8);
Benzenesulfonyl chloride, 2-nitro-
(9); (1694-92-4)
3-Phenylpropyl bromide: ALDRICH:
1-Bromo-3-phenylpropane:
Benzene, (3-bromopropyl)- (8,9); (637-59-2))
Thiophenol:
Benzenethiol (13);
(108-98-5)
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