1028
PRACTICAL SYNTHETIC PROCEDURES
A Large-Scale Low-Cost Access to the Lithium 2,2,6,6-Tetramethylpiperidide
Precursor
L
arge-Scale Prepa
e
rationof 2,
t
l
etramet
e
hylpiperidi
f
ne Kampmann,a Georg Stuhlmüller,a Roger Simon,b Fabrice Cottet,b Frédéric Leroux,b
Manfred Schlosser*b
a
Clariant Acetyl Building Blocks, 86368 Gersthofen, Germany
Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale, BCh, 1015 Lausanne,
b
PSP
Switzerland
Fax +41(21)6939365; E-mail: manfred.schlosser@epfl.ch
Received 15 June 2004
No45
Abstract: Wolff–Kishner–Huang reduction of the cheap 2,2,6,6-tetramethyl-4-piperidinone (2) provides the expensive 2,2,6,6-tetrameth-
ylpiperidine (1), the precursor to lithium 2,2,6,6-tetramethylpiperidide, in high yield. As specified in the detailed protocol, the reaction can
be conveniently carried out on a >10 mol laboratory scale.
Key words : continuous reaction, hydrazone dediazotation, lithium 2,2,6,6-tetramethylpiperidide, 2,2,6,6-tetramethylpiperidine, Wolff–
Kishner reduction
Procedure
O
O
NNH2
KOH
N2H4
NH3
∆T
N
H
N
H
N
H
3
1
2
Scheme 1
In the past three decades, lithium 2,2,6,6-tetramethylpipe- ment should amplify the use of LITMP as a strong, though
ridide (LITMP)1–5 has become one of the most popular re- non-organometallic and poorly nucleophilic base, and, at
agents. LITMP, being far more basic than lithium the same time, promote the use of 2,2,6,6-tetramethylpip-
diisopropylamide (LIDA) or any other metal dialkyl- eridine (1) in other fields, for example as a key intermedi-
amide from the outset, can still have its proton affinity ate on the route to 2,2,6,6-tetramethylpiperidin-1-oxyl
boosted by the simultaneous addition of N,N,N¢,N¢¢,N¢¢- (‘TEMPO’), a mild oxidant.10–15
pentamethyldiethylenetriamine (PMDTA) and potassium
Previously 2,2,6,6-tetramethylpiperidine (1) was made
primarily from triacetoneamine (2) by reduction with tin,
tert-butoxide (‘Faigl mix’).6
Unstable in ethereal solvents at ambient temperature,7 zinc and sodium amalgam or by catalytic hydrogenation.
LITMP is commonly prepared just prior to use by the re- One published protocol16 does employ the Wolff–Kishner
action between 2,2,6,6-tetramethylpiperidine (1) and bu- method but, as it operates discontinuously, it is restricted
tyllithium in tetrahydrofuran. This diffusion-controlled to a <50 g scale.
process occurs instantaneously even at –75 °C or –100 °C.
To proceed in this way has, nevertheless, a pecuniary
2,2,6,6-Tetramethylpiperidine
drawback. The retail price of 2,2,6,6-tetramethylpiperi-
dine (approx. 350 €/mol) is too high for a throw-away
product. On the other hand, 2,2,6,6-tetramethyl-4-piperi-
dinone (‘triacetoneamine’, 2) is quite inexpensive (ap-
prox. 20 €/mol) as it can be easily made by 1,4-addition
of ammonia to 2,6-dimethyl-2,5-heptadien-4-one (‘phor-
Hydrazine hydrate (1.0 L, 1.0 kg, 21 mol) was added over a period
of 30 min to liquid triacetoneamine (mp 34–38 °C; 2.0 kg, 13 mol).
Due to a moderately exothermal reaction, the temperature rose tem-
porarily to 90 °C. The viscous, though homogeneous brown mix-
ture was thermostatted in a 60 °C bath and transferred dropwise, at
a rate of 2.5 g per min, by means of a pump (model ProMinent Elec-
one’, 3).8 As we demonstrate below, 2,2,6,6-tetrameth- tronic A2001) into a solution of KOH (48 g, 0.85 mol) in diethylene
glycol (0.25 L) and paraffin oil (60 mL) kept at 210 °C ( 10 °C) in
a polyethylene glycol bath (see Figure 1). The 2,2,6,6-tetrameth-
ylpiperidine formed and the released H2O were continuously re-
moved by distillation through a 50 cm long Vigreux column and
ylpiperidine (1) can indeed be readily prepared from
triacetoneamine (2) by Wolff–Kishner–Huang reduction9
on a kg-scale in excellent yield (Scheme 1). This achieve-
collected in a separation funnel until the reaction was terminated.
SYNTHESIS 2005, No. 6, pp 1028–1029
Advanced online publication: 21.10.2004
DOI: 10.1055/s-2004-834856; Art ID: T06604SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
4
Distillation of the organic layer afforded 2,2,6,6-tetramethylpiperi-
20
20
dine as a colorless liquid; bp 155–157 °C; nD 1.4454 [Lit.16 nD
1.4455]; d420 0.837; yield: 1.51 kg (83%).