G. Mikle, F. Bede and L. Koll aꢀ r
Tetrahedron xxx (xxxx) xxx
Fig. 1. N-Picolylcarboxamides of practical importance.
iodoalkene (Scheme 1) (See Experimental).
iii) The aminocarbonylation tolerates functional groups, for
instance 3 -hydroxy groups of 5 and 6. No elimination of
The iodoalkenes 1e6 were reacted as substrates in palladium-
catalysed aminocarbonylation reaction (Scheme 2). Amines
bearing picolyl substituents, such as primary (2-picolylamine (a), 3-
picolylamine (b) and 4-picolylamine (c) and secondary amines
b
water providing the corresponding diene or alkene, respec-
tively, has been observed.
(
ethyl-4-picolylamine (d) and di-(2-picolyl)amine (e) were used as
N-nucleophiles in DMF under atmospheric carbon monoxide in the
presence of palladium(0)-triphenylphosphine catalysts formed in
situ. These catalytic systems containing low-ligated palladium(0)
species proved to be superior to ‘preformed’ palladium(0) com-
3. Conclusions
As a summary it can be stated, that new N-picolyl-carboxamides
can be synthesised by the functionalization of chiral backbones in
moderate to excellent yields in palladium-catalysed amino-
carbonylation. The highly selective reaction is based on the avail-
ability of the corresponding iodoalkenes from enolizable ketones
such as camphor and steroidal ketones.
3 4
plexes such as Pd(PPh ) due to their higher activity and easier
chromatographic work-up of the reaction mixture. The formation
of these coordinatively highly unsaturated Pd(0) species was
investigated by cyclic voltammetry and NMR techniques [18].
The iodoalkene functionalities reacted selectively and quanti-
tatively toward the corresponding
a,
b-unsaturated carboxamides
4. Experimental
possessing chiral backbones. Under the mild reaction conditions
ꢀ
used (atmospheric CO pressure, 50 C) no side-products were
4.1. Chemicals, general procedures
observed. All of the above isolated yields (Fig. 2) were obtained
from reactions yielding the products in higher than 98% conversion.
To achieve practically complete conversion, in most cases requires
PPh , palladium(II) acetate were purchased from Sigma-Aldrich.
3
Commercial Et N, primary and secondary amines including amino
3
1
e2 h. Especially high reactivity was observed with substrate 1,
acid esters (Sigma-Aldrich) were used without further purification.
where even the secondary amine nucleophiles (d,e) required 2 h
only. Much higher difference between primary and secondary
amines have been observed with steroidal iodoalkenes. The use of
primary amines (a,b,c) resulted in full conversion in less than 2 h in
case of 2, 3, 4 and 6, and even shorter reaction times (1 h) are
necessary in case of 5. The same trends but with longer reaction
times can be observed with secondary amines (d,e): 24 h are
required to convert substrates 3,4 and 6 to the corresponding car-
boxamides (3d,e; 4d,e and 6d,e, respectively), while only 6 h are
necessary to obtain 2d,e. The most reactive steroidal substrate 5 can
be transferred to 5d and 5e, in 1 and 2 h, respectively.
Toluene and DMF were dried according to standard procedures;
THF, ethyl acetate and ethanol were used without further
purification.
The iodoalkene substrates (1 [19], 2 [20], 3 [21], 4 [22], 5 [22b]
and 6[23]) were synthesised as described before.
1
13
The H and C NMR spectra were recorded on a Bruker 500
spectrometer at 500 and 125.721 MHz, respectively. The chemical
shifts are given as
d values (ppm) and referenced to tetrame-
thylsilane. TLC analyses were carried out by using Merck TLC sheets
(Silica gel 60 F254) and chloroform, chloroform/ethyl acetate, and
chloroform/methanol mixtures were used as appropriate eluents.
(The exact ratios are given at the corresponding synthetic proced-
ures.) Mass-spectrometry data have been obtained by using a GC-
MS system consisting of a PerkinElmer AutoSystem XL gas-
chromatograph and PerkinElmer TurboMass mass spectrometer
or LC-MS system Agilent 1290 Infinity UHPLC with Zero Dead
Volume unit and Agilent 6530 QTOF mass spectrometer, eluent:
methanol (0,1 v/v % formic acid).
Regarding chemoselectivity issues, the following statements can
be done:
i) No double carbon-monoxide insertion resulting in 2-
ketocarboxamides has been observed.
ii) Furthermore, under the mild conditions used, no ketone or
alkene formation as side-reaction from the iodoalkene took
place in hydrolysis or hydrogenolysis, respectively.
4.2. General procedure for aminocarbonylation at atmospheric
pressure
An iodoalkene 1 (or 2e6) (1 mmol), palladium(II) acetate
5.6 mg, 0.025 mmol), and PPh (13.1 mg, 0.05 mmol) were dis-
(
3
solved in 10 mL DMF under argon. Triethylamine (0.5 mL) and 2-
picolylamine (a) (0.206 mL 2 mmol) (or another picolylamine N-
nucleophile 2 mmol (b-e)) were added. The atmosphere was
ꢀ
changed to CO (1 bar), and the reaction was conducted at 50 C for
Scheme 1. A general scheme for the synthesis of iodoalkenes.
the appropriate reaction time. The composition of the reaction
2
Mikle, Gábor
