Novel synthesis of enamines by iridium-catalyzed dehydrogenation of tertiary amines

Article abstract of DOI:10.1039/b304357f

A novel route to enamines is reported, the dehydrogenation of tertiary amines catalyzed by a "pincer-ligated" iridium catalyst.

Full text of DOI:10.1039/b304357f

Novel synthesis of enamines by iridium-catalyzed dehydrogenation of
tertiary amines†
Xiawei Zhang, Amy Fried, Spencer Knapp* and Alan S. Goldman*
Department of Chemistry and Chemical Biology, Rutgers-The State University of New Jersey, Piscataway,
New Jersey, 08854, USA. E-mail: agoldman@rutchem.rutgers.edu; Fax: 732-445-5312; Tel: 732-445-5232
Received (in West Lafayette, IN, USA) 23rd April 2003, Accepted 25th June 2003
First published as an Advance Article on the web 9th July 2003
A novel route to enamines is reported, the dehydrogenation
of tertiary amines catalyzed by a “pincer-ligated” iridium
catalyst.
obtained (in addition to 54% mono-dehydrogenated N,N-
diethylvinylamine).
To preclude the complicating (though potentially useful)
phenomenon of multiple dehydrogenations, N,N-di(isopropyl)-
ethylamine and N,N-dimethylethylamine were investigated as
dehydrogenation substrates. The reaction with N,N-di(iso-
propyl)ethylamine was found to reproducibly give excellent
dehydrogenation yields at 90 °C (ca. 100%). Even at ambient
Enamines are of great importance as organic synthons. They are
used extensively as nucleophiles for the selective formation of
C–C bonds by Michael reactions, as Diels–Alder dienophiles,
and in a wide range of other reactions.1 Enamines are most
commonly synthesized by the condensation reaction of secon-
dary amines with carbonyl compounds.1 This method has
several limitations including harsh reaction conditions. Other
routes that have been applied include dehydrocyanation of a-
aminonitriles,2 dehydrohalogenation of haloethylamines,3 addi-
tion of Grignard reagents to dialkylformamides,4 and hydro-
amination of alkynes.5,6 Barluenga has recently reported
palladium-catalyzed cross-coupling between secondary amines
and alkenyl bromides.7 Cyclic tertiary amines have been
reported to undergo oxidation by mercuric acetate, generally
involving the removal of a tertiary hydrogen atom.1a All of
these approaches have very significant limitations.1–7
Table 1 Dehydrogenation of tertiary amines catalyzed by 1
Entry Amine
Product
Ref.
Conditionsa
Yield (%)b
c
1
2
5 h
24 h
98
65
2 mM 1
a
3
65
3
4
3
3
12 h
0.1 M TBE
65
In recent years “pincer”-ligated transition metal complexes
3
such as (t-BuPCP)IrH2
(
t-BuPCP = h -2,6-(tBu2PCH2)2C6H3)
(1) have been found to be effective and robust catalysts for the
dehydrogenation of alkanes8 (also ethylbenzene and THF9)
either with or without the use of a sacrificial hydrogen acceptor
(an olefin, typically tert-butylethylene or norbornene). Re-
cently, Jensen has reported that 1 catalyzes dehydrogenation of
the H–N–C–H linkage of secondary amines to give imines.10
We have initiated a program to explore the potential of pincer-
ligated catalysts for the dehydrogenation of H–C–C–H linkages
of functionalized organic molecules. Herein we report on the
transfer-dehydrogenation of alkyl groups of tertiary amines to
give enamines.
0.3 M TBE
0.3 M NBE
64
25
c
c
0.3 M TBE
0.3 M NBE
25
75
a
a
5
6
36
43
11
12
A wide variety of tertiary amines were found to undergo
surprisingly facile dehydrogenation by 1 (Scheme 1). Reactions
were typically conducted at 90 °C in p-xylene solution with ca.
100 mM amine, 10 mM 1 (10% catalyst load), and 200 mM tert-
butylethylene (TBE) acceptor, until catalytic activity ceased,
unless otherwise indicated.‡ Reaction yields are moderate to
good. Results are summarized in Table 1.
Heating a solution of 1 (10 mM), triethylamine (100 mM) and
TBE (100 mM) at 90 °C for 12 h yields vinyl(diethyl)amine as
the only observable product in 65% yield‡ (further heating
yields no additional product). However, when the TBE :
triethylamine ratio is 3 : 1, a significant yield of di-
dehydrogenated product, N,N-divinylethylamine (25%), is
c
a
a
7
8
13
14
10
30
a
9
10
11
15
16
35
0.3 M TBE
0.2 M NBE
67
92
Scheme 1 Transfer-dehydrogenation of tertiary amines catalyzed by 1 (tert-
butylethylene shown as hydrogen acceptor).
110 °C
N.R.
a Conditions unless otherwise specified: 90 °C, 10 mM 1, 100 mM amine,
200 mM TBE, 24 h, p-xylene-d10 solvent. b Yields determined by 1H NMR.
c Previously unreported compound.
† Electronic supplementary information (ESI) available: detailed experi-
mental procedures and spectroscopic information. See http://www.rsc.org/
suppdata/cc/b3/b304357f/
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temperature 60% yield was obtained after 24 h. N,N-Dimethyle-
thylamine also gave clean dehydrogenation but the yield of the
corresponding vinylamine was not as high (65% at 90 °C), and
was lower still at lower temperatures.
In the dehydrogenation reactions of two amines containing
N-bound n-propyl groups, N,N-di(isopropyl)-n-propylamine
and tri-n-propylamine, (E)-1-propenylamines were formed (ca.
40% yield; Table 1, entries 5 and 6). Yields and rates were lower
than those found for the aminoethyl groups in accord with the
previously reported kinetic preference of 1 for the dehydrogena-
tion of the terminal position of n-alkanes.8d
Using norbornene (NBE) instead of TBE as a hydrogen
acceptor was found to give higher yields in some cases. For
example, dehydrogenation of triethylamine gave ca. 100%
conversion with 75% yield of di-dehydrogenated product, N,N-
divinylethylamine.
mM) and N,N-di(isopropyl)(ethyl-d5)amine (296 mM), and kh/
kd was found to be 6. Thus electron transfer from the amine is
apparently not rate-determining. Analogous isotope-effect stud-
ies are presently being conducted with alkanes which will be
used for purposes of comparison.
In summary, we report the first catalytic synthesis of
enamines from tertiary amines. The tertiary amines show
surprisingly high reactivity and, fortuitously, the presence of the
catalyst prevents decomposition of the enamine products.
Studies regarding the scope of applicability of this reaction, as
well as the mechanism and the origin of the surprisingly high
reactivity, are presently underway.
We thank the Division of Chemical Sciences, Office of Basic
Energy Sciences, Office of Energy Research, US Department of
Energy for support of this research.
It is noteworthy that N,N-di(isopropyl)vinylamine, N,N-
divinylethylamine, N,N-diisopropyl-1-(E)-propenylamine, and
N,N-di-(E)-1-propenylpropylamine are all previously unre-
ported compounds.
Notes and references
‡ All reactions gave no spectroscopically observable materials other than
1
the product noted. Products were characterized by H NMR and, in some
All of the enamine products noted above degraded (usually
within several hours) after being isolated from the catalyst (via
vacuum transfer of enamine and solvent); this observation is
consistent with the known instability of simple enamines.1,3
Remarkably, however, we find that the products are stable for
extended periods in the original catalyst-containing solutions.§
Presumably, the catalyst inhibits chain decomposition reac-
tions. This property may substantially contribute to the utility of
the present method for generating and exploiting enamines.
N-Methylpyrrolidine was dehydrogenated to N-methylpyr-
role in modest yield. However N-methylpiperidine was surpris-
ingly resistant to dehydrogenation. In accord with the lack of
reactivity of the six-membered heterocycle, N-ethylpiperidine
showed dehydrogenation exclusively at the ethyl group (see
Table 1, entries 8–11).
The apparently high reactivity of the acyclic amine sub-
strates, as indicated by the good product yields, was confirmed
in a competition experiment between N,N-di(isopropyl)ethyla-
mine (60 mM) and cyclooctane (600 mM).‡ (Cyclooctane is a
substrate frequently used in alkane dehydrogenation studies
because of its anomalously low enthalpy of dehydrogenation.)
The ratio of cyclooctene to vinylamine remained roughly
constant (1 : 2.0), even from the earliest reaction times,
indicating that the observed product ratio reflects reaction
kinetics, not thermodynamics.¶ Dehydrogenation of the ami-
noethyl group was thus found to be 20 times more rapid than
dehydrogenation of cyclooctane on a per mol basis; on a per C–
C bond basis the ratio is therefore 160.
Competition experiments between varying N,N-di(alkyl)-
ethylamines reveal that reactivity is dependent upon the
ancillary N-alkyl group as follows: isopropyl > ethyl > methyl
in the ratio 140 : 7 : 1. This seems in discord with expectations
based on steric or electronic factors, at least if the reaction is
assumed to proceed via an oxidative-addition/b-hydrogen
elimination mechanism.11 In particular, although oxidative
addition is expected to be favored by a less electron-rich
substrate, the more electron-rich, more highly substituted, N,N-
di(alkyl)ethylamines apparently favor dehydrogenation. Very
likely, this trend is closely tied to the high reactivity found for
tertiary amines, in general, relative to alkanes.
We considered that the unusually high reactivity of the
tertiary amines, and the more highly substituted amines in
particular, might be attributed to a mechanism involving
electron transfer (oxidation of the amine). In this context we
conducted the following isotope-effect experiments.
iPr2N(C2D5) was synthesized (from the reaction of iPr2NH and
C2D5I17). In a competitive catalytic reaction 1 (10.2 mM), TBE
(250 mM), N,N-di(isopropyl)ethylamine (30.7 mM) and N,N-
di(isopropyl)(ethyl-d5)amine (61.4 mM), were reacted; kh/kd
was found to be 7. A stoichiometric competition reaction gave
the same value (within experimental error): (PCP)Ir(H)(Ph)
(32.8 mM) was reacted with N,N-di(isopropyl)ethylamine (95
cases, GC-MS. All yields were determined by 1H NMR. Removal of
volatiles from the catalyst by vacuum transfer was conducted in some cases
to facilitate characterization. Detailed experimental procedures and spectro-
scopic information are given as ESI.†
§ For example a solution of N,N-di(isopropyl)vinylamine was found to be
stable for 2 months in the catalyst-containing solution (even after
evacuating unreacted TBE, thus indicating that the presence of TBE is not
responsible for the unusual stability of the enamines).
¶ Cyclooctane dehydrogenation is thermodynamically more favorable (DH
=
24 kcal mol21 18) than dehydrogenation of an aminoethyl group
(estimated DH = 26.1 kcal mol21 1d).
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