Hanada et al.
to a large scale synthesis of secondary amines. In a typical example,
2f (1.63 g, 10 mmol) was allowed to react with 1,1,3,3-tetrameth-
yldisiloxane (3.5 mL, 4.0 equiv Si-H to 2f) in DME (10 mL) in
the presence of 1 (195 mg, 0.3 mmol) at 60 °C for 12 h. The workup
in the same manner as above was followed by treatment of the
crude product with an ethereal solution of hydrogen chloride (0.17
M, 48 mL). The ammonium salt 6f was obtained in 92% yield (1.70
g). The reaction of 6f with Na2CO3 (4 g) in THF (60 mL) at 0 °C
to room temperature for 3 h afforded the amine product 3f in 83%
yield (1.23 g).
resin by simple extraction with ether. In sharp contrast, reduction
of secondary amides with PMHS affords silylated secondary
amines; this means that the amine product is attached to the
siloxane chain through a Si-N bond. Thus, isolation of
secondary amine from the produced silicon resin requires the
fission of the Si-N bond by hydrolysis, which cannot be
accomplished by simple extraction with ether. This explains the
reason why the selective isolation of tertiary amine 4 is possible
in the reduction of 2 with PMHS. Interesting exceptions are
described in Scheme 5, where the reduction of secondary amides
having a bulky N-substituent was accomplished with PMHS;
the corresponding secondary amines are facilely isolated from
the reaction mixture by simple extraction with ether. The bulky
N-substituent would prevent the reaction of sec-C with sec-3;
this blocks production of tertiary amine 4. The secondary-amine
product should be attached to the PMHS chain; however, the
bulkiness of the N-substituent would instabilize the Si-N bonds,
which can be facilely hydrolyzed by contact with trace amounts
of moisture.
1
N-Methyl-3-phenylpropylamine (3a): 51 mg (68% yield). H
NMR (270 MHz, CDCl3): δ 1.22 (bs, 1H), 1.83 (tt, J ) 7.3, 7.9
Hz, 2H), 2.44 (s, 3H), 2.62 (t, J ) 7.3 Hz, 2H), 2.67 (t, J ) 7.9
Hz, 2H), 7.16-7.32 (m, 5H). 13C NMR (67.8 MHz, CDCl3): δ
31.7, 33.8, 36.6, 51.8, 125.7, 128.28, 128.32, 142.1. HRMS (EI):
calcd for C10H15N (M+), 149.1204; found, 149.1208.
General Procedure for Secondary Amides 2 to Tertiary
Amines 4. To a solution of 1 (6.3 mg, 0.01 mmol) in tetrahydro-
pyran (0.2 mL) was added PMHS (370 µL, Si-H ) 5.5 mmol),
and the mixture was stirred at ambient temperature for 30 min.
The initial dark-orange color of the solution gradually turned to
light orange. Then, a solution of amide (1.0 mmol) in THP (0.7
mL) was added, and the solution was stirred at 40-70 °C. The
homogeneous solution turned to gel after several hours. After it
was allowed to stand for 24 h, tetrahydropyran was removed in
vacuo (6 Torr) to form a silicone resin insoluble in common organic
solvents. The resultant resin was extracted 10 times with ether
(totally 20 mL), and the combined extracts were concentrated in
vacuo. Purification of the residue by alumina column chromatog-
raphy (ether) gave the desired tertiary amine. Decomposition of
the silicone resin by hot methanol (50 °C, 24 h) was followed by
concentration of the resulting methanol solution. The residue was
purified by alumina chromatography (ether) to give the secondary
amine formed by simple reduction of the secondary amide.
Reduction of 2c and 2n in the same manner as above gave the
corresponding secondary amine 3c and 3n. No reductive N-
alkylation product was observed.
Conclusion
In this paper, we have described selective synthetic methods
for secondary amines and tertiary amines in the hydrosilane
reduction of secondary amides catalyzed by a triruthenium
complex 1. As described above, the reaction essentially produces
a mixture of three products, and we have succeeded in the
development of practical synthesis of two of them, secondary
amines and tertiary amines, which are synthesized according
to the equation: 2RC(dO)NHR′ + 6R′′3Si-H f (RCH2)2NR′
+ 2R′′3Si-O-SiR′′3 + R′N(Si R′′3)2 + H2. In the preparation
of the secondary amines, key discoveries are application of
higher catalyst concentration than usual and use of bifunctional
hydrosilanes. In contrast, use of polymeric hydrosiloxanes as a
hydride source helps for raising the selectivity and separating
the desired tertiary amines from other reaction products. It
should be noted that both of the ruthenium-free reaction products
are isolated without further purification using chromatography
and distillation. Possible mechanisms for the reduction can be
drawn as Scheme 7. These new results provide unique and
practical reduction protocols of secondary amides in organic
synthesis. Further studies on the ruthenium-catalyzed reactions
of organic molecules with hydrosilanes are now underway.
Di(3-phenylpropyl)methylamine (4a):11 72 mg (54% yield). 1H
NMR (400 MHz, CDCl3): δ 1.85 (tt, J ) 7.6, 7.9 Hz, 4H), 2.28
(s, 3H), 2.43 (t, J ) 7.6 Hz, 4H), 2.69 (t, J ) 7.9 Hz, 4H), 7.21-
7.37 (m, 10H). 13C NMR (150 MHz, CDCl3): δ 29.2, 33.8, 42.3,
57.3, 125.8, 128.4, 128.5, 142.5. HRMS (EI): calcd for C19H25N
(M+), 267.1987; found, 267.1982.
Reduction of 2a in the Presence of N-Methylbenzylamine:
Formation of N-Methyl-N-(3-phenylpropyl)benzylamine (7).26
To a solution of 1 (6.3 mg, 0.01 mmol) in tetrahydropyran (0.2
mL) was added PMHS (450 µL, Si-H ) 6.6 mmol), and the
mixture was stirred at ambient temperature for 30 min. The initial
dark-orange color of the solution gradually turned to light orange.
Then, N-methylbenzylamine (193 µL, 1.5 mmol) was added, and
the mixture was stirred for 30 min at 50 °C. After cooling the
solution to ambient temperature, a solution of N-methyl-3-phenyl-
propionamide 2a (163 mg, 1.0 mmol) in THP (0.7 mL) was added,
and the resultant solution was stirred at 70 °C. The homogeneous
solution turned to gel after several hours. After it was allowed to
stand for 24 h, tetrahydropyran was removed in vacuo (6 Torr) to
form a silicone resin insoluble in common organic solvents. The
resin was extracted 10 times with ether (totally 20 mL), then the
combined organic extracts were evaporated under a reduced
pressure. Purification of the residue by alumina column chroma-
Experimental Section
General Procedure for the Reduction of Secondary Amides
2 to Secondary Amines 3. To a solution of 1 (9.8 mg, 0.015 mmol,
3 mol % based on the amide) in 0.5 mL of dimethoxyethane was
added 1,1,3,3-tetramethyldisiloxane (3.2-4.5 equiv Si-H to 2), and
the resulting solution was stirred at room temperature for 10 min.
After 10 min, amide 2 (0.5 mmol) was added, and gas evolution
was observed. The solution was heated at 40-60 °C with stirring
for 6-12 h. After complete consumption of 2 was confirmed by
TLC analysis, the reaction mixture was filtered through a pad of
Florisil, and the filtrate was poured into an ethereal solution of
hydrogen chloride [0.1 M, 10 mL; prepared from commercially
available 1 M HCl/ether (1 mL) and ether (9 mL)]. The ammonium
salt 6 was precipitated as a white powder. Separation of the
supernatant by decantation or centrifugation followed by washing
of the residue with ether afforded 6 without contamination of
silicone or ruthenium residues. 6 was treated with excess amounts
of sodium carbonate in wet THF at 0 °C for 0.5-1 h. The solid
materials were filtered off, and the desired amine 3 was obtained
by concentration of the filtrate. This procedure can be applicable
1
tography gave the tertiary amine 7, 95 mg (40% yield). H NMR
(396 MHz, CDCl3): δ 1.86 (tt, J ) 7.9, 7.3 Hz, 2H), 2.21 (s, 3H),
2.44 (t, J ) 7.3 Hz, 2H), 2.67 (t, J ) 7.9 Hz, 2H), 3.50 (s, 2H),
7.16-7.34 (m, 10H). 13C NMR (99.5 MHz, CDCl3): δ 29.3, 33.6,
42.2, 57.0, 62.4, 125.7, 126.9, 128.25, 128.34, 128.5, 129.1, 139.3,
142.5. Treatment of the silicon resins formed with methanol at 50
(26) Hon, Y.-S.; Chang, F.-J.; Lu, L.; Lin, W.-C. Tetrahedron 1998, 54,
5233.
7558 J. Org. Chem., Vol. 72, No. 20, 2007