Organic Syntheses, Vol. 79, pp. 186-195
Checked by Audra M. Dalton and Rick L. Danheiser.
1. Procedure
2. Notes
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%).
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.
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.
All toxic materials were disposed of in accordance with "Prudent Practices in the
Laboratory"; National Academy Press; Washington, DC, 1995.
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.
Copyright © 1921-2002, Organic Syntheses, Inc. All Rights Reserved