S. Laval et al. / Tetrahedron 70 (2014) 975e983
981
malononitriles 1v and 1w gave the corresponding spirocycles in
good yields. Indeed, 2-azaspiro-[3,4]-octane 3v and 5-azaspiro-
[2,3]-hexane 3w were isolated as their hydrochloride salts in 80%
and 70% yields, respectively (Table 6, entries 6 and 7). The re-
the described method can constitute an alternative to conventional
aluminum and boron hydrides as well as hydrogenation.
4. Experimental section
4.1. General
duction of a,b-unsaturated malononitrile 1x did not give the ex-
pected azetidine 3x (Table 6, entry 8). The reduction was complete
but analysis of the crude mixture showed the degradation of 1x. In
this case, the presence of the double bond forces a 90ꢀ angle be-
tween the two nitrile functions that renders the cyclization
difficult.
These reaction conditions were finally applied for the reduction
of adiponitrile 1y. After acidic treatment and concentration under
vacuum, analysis of the crude solid showed a mixture of azepane 3y
and 6-aminohexanenitrile 2y as their hydrochloride salts with a 1H
NMR ratio of 7:13 (Table 6, entry 9). The formation of seven-
membered ring seems less favorable than four-, five-, and six-
membered rings.
Tetramethyldisiloxane, 97% (TMDS) and anhydrous toluene
were purchased from Acros; polymethylhydrosiloxane (PMHS,
n¼40) and methylcyclohexane, 99%þ from SigmaeAldrich; and
titanium(IV) isopropoxide, 95% (Ti(Oi-Pr)4) from Alfa Aesar. The
nitrile compounds were also supplied from Acros, SigmaeAldrich
and Alfa Aesar. 2-(bis(2-hydroxyethyl)amino)acetonitrile 1l was
provided by MINAKEM company. All reagents and reactants were
used without further purification. NMR spectra were recorded on
a Bruker DRX 300 and DRX 400. Chemical shifts are given in parts
per million (ppm) using tetramethylsilane as the external standard
for 1H and 13C NMR spectra. Accurate mass measurements were
performed with an electromagnetic device with a double focusing
(BE) THERMOQUEST Finnigan MAT 95 XL using the technique of
‘peak matching’. 1H NMR, 13C NMR, and mass spectra were com-
pared with literature data.
2.5. Mechanism
At present, no detailed mechanistic study has been undertaken
yet. In the literature, titanocene and titanium alkoxide catalysts
have already been reported for the hydrosilylation of ketones,37
esters,16a,38 lactones,38c,39 imines,40 pyridines,41 phosphine ox-
ides,25 and amides.42 It is supposed that the reaction is performed
by a titanium(III) hydride species, which has never been charac-
terized.41,43 Recently, mechanistic highlights have been published
by Lemaire et al. for the reduction of phosphine oxides to phos-
phines using a TMDSeTi(Oi-Pr)4 reducing system.23d It was dem-
onstrated, in the reaction medium, the presence of Ti(III) species
under the form of Ti(III)/Ti(IV) cluster rather than a titanium
hydride-like complex. This result suggests a mechanism via a single
electron transfer (SET) between the hydrosiloxane and the tita-
nium(IV) that generates a silyl-radical, which then reduces the
phosphine oxide. In the present case, the characteristic deep blue
color of the reaction medium suggests a similar mechanism. We
assume that the oxido-reduction between the hydrosiloxane and
the titanium catalyst takes place via a single electron transfer (SET),
which then induces a first reduction of the nitrile into N-silyl-imine,
which is in turn reduced into N,N-disilyl-amine. The weak NeSi
bond,44 is finally easily hydrolyzed in the presence of acidic water
under mild conditions to give the corresponding amine as hydro-
chloride salt.45 The formation of an imine intermediate is in ac-
cordance with the presence of secondary amines 3m and 3n and
the formation of saturated N-heterocycles by reduction of dinitriles.
Nevertheless, mechanistic studies are still underway in the
laboratory.
4.2. General procedure for the reduction of nitriles: 4-
bromophenylacetonitrile 1a
To a nitrogen purged screw-caped vial containing 1a (1.0 g,
5.1 mmol, 1.0 equiv) in 6.0 mL of toluene were added TMDS (900
mL,
5.1 mmol, 1.0 equiv) or PMHS (610 L, 10.2 mmol, 2.0 equiv) and
m
Ti(Oi-Pr)4 (1.5 mL, 5.1 mmol, 1.0 equiv) at rt. The mixture was then
heated at 60 ꢀC for 24 h (the colorless solution turned into black and
the conversion of the substrate can be followed up by TLC and/or 1H
NMR). After cooling to rt, the clear solution was acidified using
aqueous 1 M HCl (7.7 mL, 1.5 equiv) and the crude mixture was
concentrated under reduced pressure. The resulting solid was fil-
tered, washed with pentane (3ꢁ50 mL), and dissolved in ethanol.
The filtrate was finally concentrated under reduced pressure
affording the amine 2a as a hydrochloride salt. 1H NMR (300 MHz,
MeOD)
d
2.94 (t, 2H, J¼7.1 Hz, CH2CH2NH2), 3.17 (t, 2H, J¼7.1 Hz,
CH2CH2NH2), 7.22 (d, 2H, J¼8.1 Hz, 2ꢁCHAr), 7.49 (d, 2H, J¼8.1 Hz,
2ꢁCHAr). 13C NMR (100 MHz, MeOD)
137.2. MS (CI, NH3) m/z¼200 (MH)þ.
d 33.9, 41.6, 122.0, 131.8, 133.0,
4.3. Procedure for the synthesis of 2-[(2-aminoethyl)-(2-
hydroxyethyl)-amino]-ethanol 2l from 2-(bis(2-hydroxyethyl)
amino)acetonitrile 1l
3. Conclusion
PMHS (2.2 mL, 36.9 mmol, 5.3 equiv) and Ti(Oi-Pr)4 (4.2 mL,
14.0 mmol, 2.0 equiv) were added to a solution of 1l (1.0 g,
7.0 mmol, 1.0 equiv) in 10.0 mL of anhydrous toluene. The mixture
was heated at 60 ꢀC for 24 h (the solution turned into deep purple
and the conversion of the substrate can be followed up by 1H NMR).
After cooling, the clear solution was diluted in toluene (40 mL) and
hydrolyzed with aqueous 3 M NaOH (20 mL) at rt for 4 h. The
aqueous layer was then extracted with toluene (3ꢁ30 mL), neu-
tralized (aqueous 1 M HCl) and concentrated under vacuum. The
resulting solid was washed with a solution of MeOH:/NH4OH
25 wt % (95:5) to solubilize the product. The filtrate was then
concentrated and purified by flash column chromatography on
silica gel (MeOH/NH4OH 25 wt %, 95:5) (Rf¼0.23) to afford the free-
amine 2l as a clear oil in 37% yield. 1H NMR (300 MHz, CDCl3),
We report herein two efficient systems, TMDSeTi(Oi-Pr)4 and
PMHSeTi(Oi-Pr)4, for the reduction of aromatic and aliphatic ni-
triles into the corresponding primary amines. In contrast to the
reduction of phosphine oxides, PMHS is suitable for the reduction
of nitriles and the reaction is faster than in the case of TMDS. Fur-
thermore, these two systems are able to reduce dinitriles into the
corresponding saturated N-heterocycles. The reduction led, in one
step, to azepane, piperidine, pyrrolidine, and azetidine derivatives
through an intramolecular reductive alkylation reaction.
The advantages of the used systems lie on the choice of the
reagents and the reaction workup. In fact, both components of the
system are relatively inexpensive, commercially available in multi-
kilogram lots, stable, and relatively innocuous. The mild acidic
workup process actually offers a practical method for preparation
of various amines as their hydrochloride salts without further pu-
rification using chromatography or distillation. For these reasons,
d
2.57e2.64 (m, 6H, N(CH2)3), 2.84 (m, 2H, CH2NH2), 3.61 (m, 4H,
2ꢁCH2OH), 4.09 (br s, 4H, 2ꢁOH and NH2). 13C NMR (100 MHz,
CDCl3)
d
39.9, 55.9, 57.5, 59.9. MS (CI, NH3) m/z¼149 (MH)þ, 132
(MHþꢂNH3)þ.