TiCl4-mediated amination of propargylic esters

Article abstract of DOI:10.1016/S0040-4039(01)00012-0

The TiCl₄-mediated substitution of propargylic esters with amides afforded the corresponding α-substituted propargylic amides.

Full text of DOI:10.1016/S0040-4039(01)00012-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1655–1656
TiCl4-mediated amination of propargylic esters
R. Mahrwald* and S. Quint
Institut fu¨r Organische und Bioorganische Chemie der Humboldt Universita¨t, Hessische Straße 1-2, D-10115 Berlin, Germany
Received 9 November 2000; revised 27 December 2000; accepted 28 December 2000
Abstract—The TiCl4-mediated substitution of propargylic esters with amides afforded the corresponding a-substituted propargylic
amides. © 2001 Elsevier Science Ltd. All rights reserved.
Propargylic amines, which possess strong inhibitory
activities toward several enzymes (i.e. monoamine
oxidase B,1 aldehyde dehydrogenase2) are ideal starting
materials in the synthesis of allylamines, also having
highly potent biological activities.3 Only a few publica-
tions dealing with equimolar or multistep procedures
for preparing enantiopure a-substituted propargylic
amines have been reported.4 The shortest and most
promising route seems to be the direct Lewis acid-medi-
ated nucleophilic displacement reaction of the corre-
sponding propargylic esters.5,6 This reaction has
advantages over previous described methods (amina-
tion of propargylic triflates,7 propargylic halides8 and
allenyl halides9) with regard to chemoselectivity, reac-
tion conditions and availability of the starting products.
(p-toluenesulfonamide and acetamide) provided us with
the desired 1,3-diphenyl-a-substituted propargylic
amides 2a–2e (Scheme 1, entries 6–10, Table 1).
However, by using benzamide in these reactions, more
satisfactory results were obtained with regard to reac-
tion time, catalytic execution and yield. Carried out at
room temperature, 10 mol% of TiCl4 was sufficient
enough for obtaining the propargylic benzamides 2f–2i
(entries 11–15, Table 1).11
Since a-propargylic amines are unstable compounds,12
compounds 2f–2i seem to be very useful precursors for
the corresponding a-propargylic amines. As an exam-
ple, the benzoyl group of the amide 2f was removed by
reduction with DIBAL13 at −78°C to yield 1,3-
diphenylprop-2-ynyl-1-amine (3) (entry 16, Table 1).14
A
copper(I)-catalyzed nucleophilic substitution of
propargylic esters has already been reported, this reac-
tion is limited to the use of terminal alkynes only.10
Herein we describe preliminary results of TiCl4-medi-
ated nucleophilic displacement of propargylic esters
with amines—our direct approach to unsubstituted
propargylic amines.
Acknowledgements
This research was supported by the Deutsche
Forschungsgemeinschaft and the Fonds der Chemi-
schen Industrie.
According to our procedures previously developed for
the TiCl4-mediated nucleophilic substitution of propar-
gylic esters with alcohols, we have tried to react pri-
mary and secondary amines with propargylic esters
under the described conditions. No reactions were
observed in any experiments carried out with the 1,3-
diphenyl-a-substituted propargylic esters 1a and 1b as
starting materials. Only the use of ‘activated’ amines
Keywords: alkynes; substitution; amides; catalysis.
* Corresponding author. Tel.: +49-30-2093 8397; fax: +49-30-2093
8479; e-mail: rainer.mahrwald@rz.hu-berlin.de
Scheme 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00012-0

1656
R. Mahrwald, S. Quint / Tetrahedron Letters 42 (2001) 1655–1656
Table 1. TiCl4-mediated substitution of propargylic esters with amides
Entry
R1
R2
R3
R4
R5
Compound
Yield (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph-ꢀ
nBu-ꢀ
Ph
Ph
Ph
Ph
Ph
Ph
Ph
iBoc
Ac
Ac
Ac
Ac
–
–
–
–
–
–
–
–
–
–
–
Ph
Ph
nBu
Ph
nBu
Ph
Ph
Ph
Ph
Ph
Ph
Ph
nBu
Ph
nBu
Ph
–
–
–
–
–
–
–
–
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
2f
–
–
Ts
Ts
Ts
Ts
Ac
Bz
Bz
Bz
Bz
Bz
H
nC6H13
H
nPr
Allyl
H
H
H
H
H
41
58
38
21
19
78
43a
73
57
51
55
9
10
11
12
13
14
15
16
2f
Ph
2g
2h
2i
Ph-ꢀ
nBu-ꢀ
Ph
H
H
3
a 1a was used as starting material.
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