2-Phenallyl as a versatile protecting group for the asymmetric one-pot three-component synthesis of propargylamines

Article abstract of DOI:10.1039/b507810e

2-Phenallyl was found to be a versatile protecting group of primary amines for the asymmetric one-pot three-component synthesis of propargylamines which leads to enantiomeric excess of up to 96%; it can be easily removed with a palladium(0)-catalyzed ally

Full text of DOI:10.1039/b507810e

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2-Phenallyl as a versatile protecting group for the asymmetric one-pot
three-component synthesis of propargylamines{
Nina Gommermann and Paul Knochel*
Received (in Cambridge, UK) 3rd June 2005, Accepted 5th July 2005
First published as an Advance Article on the web 26th July 2005
DOI: 10.1039/b507810e
2-Phenallyl was found to be a versatile protecting group of
primary amines for the asymmetric one-pot three-component
synthesis of propargylamines which leads to enantiomeric
excess of up to 96%; it can be easily removed with a
palladium(0)-catalyzed allylic substitution using 1,3-dimethyl-
barbituric acid as a nucleophile.
Scheme 2 Influence of the steric demand in the allyl protecting group.
Protecting groups play an important role in synthetic organic
synthesis.1 The allyl group is widely used for the protection of
bis(phenallyl)amine8 3 provides the propargylamine 2d in 96% ee,
alcohols, amines and carboxylic acids. Allyl groups are stable
which exhibits still a synthetically useful level of selectivity
under both acidic and basic conditions, but can easily be removed
(see Scheme 2).
by palladium-catalyzed substitution reactions with various nucleo-
philes.2 Recently, we3 and others4 have reported a three-
Furthermore, the bis(phenallyl)amine is easily prepared from
commercially available starting materials using standard protocols.
component asymmetric reaction of a terminal alkyne, an aldehyde
and a secondary amine using copper(I) bromide/Quinap5 as the
Thus, allylic bromination9 of a-methylstyrene using NBS at 160 uC
furnished the substituted allyl bromide in 70% yield. Nucleophilic
catalytic system leading to enantiomerically enriched propargyla-
substitution with potassium phthalimide in DMF followed by
mines (Scheme 1).
reductive cleavage with hydrazine in MeOH yielded the primary
allylamine in 66% yield over two steps.10 Condensation with
protecting groups. While dibenzylamine leads to the highest
2-phenallyl bromide led to bis(phenallyl)amine 3 in 70% yield.
In the course of our studies, we have investigated various amine
enantioselectivity (Scheme 2, 1a, 98% ee), the removal of this
In order to examine the scope of this new protecting group in
group was not possible under mild conditions. Hydrogenation of
the three-component reaction, several aldehydes 4 and alkynes 5
the dibenzyl protected propargylamines under standard condi-
tions6 led to the reduction of the triple bond. Oxidative methods
were reacted with 3 in the presence of CuBr/Quinap leading to
bis(phenallyl)-protected propargylamines
Table 1).
2 (Scheme 3 and
like CAN- or DDQ-oxidations also failed to remove chemoselec-
tively the benzyl group. Extensive decomposition of the starting
propargylamine was observed. The allyl group itself can be used as
a protecting group during the propargylamine synthesis, but lower
% ee are obtained.7 To increase the enantioselectivity of this
reaction, we have investigated the influence of the steric hindrance
of the allylic amine. The use of diallylamine in a test reaction led to
the desired amine 1b in only 90% ee compared to 98% ee obtained
by the reaction with dibenzylamine (product 1a). Increasing the
steric hindrance by the use of bis(methallyl)amine led to the
corresponding product 1c in 92% ee. Finally, the use of
With trimethylsilylacetylene (5a), branched and unbranched
aliphatic aldehydes lead to the corresponding propargylamines 2a–
f in good yields and enantioselectivities (entries 1–6, Table 1). The
selectivity increases with the steric demand of the aldehyde.
Valeraldehyde (4a) leads to the product 2a with 84% ee (entry 1),
isovaleraldehyde (4b) gives 2b with 90% ee (entry 2) and
2-ethylbutyraldehyde (4d) produces the highest selectivity leading
to 2d with 96% ee (entry 4). Aldehydes bearing a cyclic substituent
like cyclopropyl- and cyclohexylcarbaldehyde afford the desired
propargylamines 2e–f in 79–82% yield and 84 and 92% ee,
respectively (entries 5–6). The functionalized dihydrocinnamalde-
hyde 4g also leads to the desired product 2g in good yield
but somewhat lower enantioselectivity (75% ee, entry 7).
Phenylcinnamaldehyde 4h also participates in the reaction leading
to propargylamine 2h with 81% ee (entry 8). Benzaldehyde (4i)
Scheme 1 Asymmetric three-component synthesis of propargylamines.
Department Chemie und Biochemie, Ludwig-Maximilians-Universita¨t
Mu¨nchen, Butenandstr. 5-13, Haus F, D-81377 Mu¨nchen, Germany.
E-mail: Paul.Knochel@cup.uni-muenchen.de;
Fax: 0049-(0)89-2180-77680; Tel: 0049-(0)89-2180-77681
{ Electronic supplementary information (ESI) available: Experimental
section. See http://dx.doi.org/10.1039/b507810e
Scheme 3 Asymmetric three-component synthesis of bis(phenallyl)-
protected propargylamines.
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Table 1 Asymmetric three-component synthesis of bis(phenallyl)-protected propargylamines
Nr.
Aldehyde 4
Alkyne 5
Propargylamine 2
Yielda(%)
eeb(%)
R1CHO
1
2
3
4
5
6
4a: R1: n-Bu
4b: R1: i-Bu
4c: R1: i-Pr
4d: R1: s-Pent
4e: R1: c-Pr
4f: R1: c-Hex
5a: R2: TMS
2a: R1: n-Bu; R2: TMS
2b: R1: i-Bu; R2: TMS
2c: R1: i-Pr; R2: TMS
2d: R1: s-Pent; R2: TMS
2e: R1: c-Pr; R2: TMS
2f: R1: c-Hex; R2: TMS
86
67
79
67
79
82
84
90
86
96
84
92
5a
5a
5a
5a
5a
7
8
9
10
11
12
a
4g
4h: R1: (C6H5)2CLCH
5a
5a
5a
2g: R1: (CH2)2(2-F-4-Br-C6H3); R2: TMS
2h: R1: (C6H5)2CLCH; R2: TMS
2i: R1: Ph; R2: TMS
75
83
67
58
82
71
75
81
34
84
68
70
4i: R1: Ph
4j: R1: 3-benzothiophene
4f
4d
5a
2j: R1: 3-benzothiophene; R2: TMS
2k: R1: c-Hex; R2: n-Bu
5b: R2: n-Bu
5c: R2: Ph
b
2l: R1 s-Pent; R2: Ph
Isolated yield of analytically pure product. Enantiomeric excess determined by HPLC using Chiracel OD-H column (n-heptane : i-PrOH).
forcing conditions (heating to 60 uC) to achieve full deprotection.
In contrast, the bis(phenallyl) groups could be removed efficiently
in CH2Cl2 at room temperature leading to the corresponding
primary propargylamines 6 (Scheme 4, Table 2).
Various propargylamines 2 can be converted to the correspond-
Scheme 4 Deprotection leading to primary amines 6.
ing primary amines 6. Thus, the propargylamines 2d–e can be
leads to the product 2i with only 34% ee (entry 9), whereas
3-benzothiophenaldehyde (4j) gives the desired propargylamine 2j
in 84% ee (entry 10). Likewise, other alkynes can be reacted, but
the selectivities are lower. Therefore, reaction of 1-hexyne (5b) with
cyclohexanecarbaldehyde (4g) and bis(phenallyl)amine (3) leads to
the propargylamine 2k in 82% yield and 68% ee (entry 11).
transformed to the amines 6a and 6b in 66–75% yield (entries 1–2,
Table 2). Interestingly, the allyl-substituted propargylamine 2h
derived from phenylcinnamaldehyde undergoes a selective cleavage
of the phenallyl groups leading to the product 6c in 83% yield
(entry 3).
Likewise the phenyl-substituted amine 2i was subjected to the
deprotection procedure and furnished the benzylamine 6d in 77%
yield (entry 4). Finally, deprotection also takes place with the
phenylacetylene-substituted amine 2l leading to 6e in very good
yield (90%, entry 5).
Reaction of 2-ethylbutyraldehyde (4d) with amine
3 and
phenylacetylene (5c) gives the propargylamine 2l in 71% yield
and 70% ee (entry 12).
For the product 1b derived from diallylamine, both allyl groups
are readily removed by Guibe´’s method.2a We have observed that
the more sterically hindered methallyl group (1c) needs more
In summary, we have developed an efficient protecting group
for the synthesis of chiral primary propargylamines.
Table 2 Removal of the phenallyl groups leading to primary amines 6
Nr.
Propargylamine 2
Primary amine 6
Yielda(%)
ee(%)
1
2
3
4
5
a
2d: R1: s-Pent; R2: TMS
2e: R1: c-Pr; R2: TMS
2h: R1: (C6H5)2CLCH; R2: TMS
2i: R1: Ph; R2: TMS
6a: R1: s-Pent; R2: TMS
6b: R1: c-Pr; R2: TMS
6c: R1: (C6H5)2CLCH; R2: TMS
6d: R1: Ph; R2: TMS
66
75
83
77
90
96
84
81
34
70
2l: R1: s-Pent; R2: Ph
6e: R1: s-Pent; R2: Ph
Isolated yield of analytically pure product.
4176 | Chem. Commun., 2005, 4175–4177
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Bis(phenallyl)amine is easily prepared and leads to good enantio-
selectivities (up to 96% ee) in the one-pot three-component
synthesis of propargylamines. Furthermore, it can be removed
using a Pd0-catalyzed allylic substitution with dimethylbarbituric
acid leading to chiral primary propargylamines in good yields. This
new protecting group should find numerous applications for the
preparation of sensitive amines since the deprotection occurs under
very mild conditions.
We thank the Fonds der Chemischen Industrie and Merck
Research Laboratories (MSD) for financial support. We thank the
DFG (SPP 1118 ‘‘Sekunda¨re Wechselwirkungen als
Steuerungsprinzip zur gerichteten Funktionalisierung reaktionstra¨-
ger Substrate’’) for a fellowship for N. G. and Chemetall GmbH
(Frankfurt) and BASF AG (Ludwigshafen) for generous gifts of
chemicals.
8 During the preparation of this manuscript, the 2-phenallyl group was
described first by Barluenga, using tert-butyllithium for deprotection:
J. Barluenga, F. J. Fanana´s, R. Sanz, C. Marcos and J. M. Ignacio,
Chem. Commun., 2005, 933.
9 For the preparation of [1-(bromomethyl)vinyl]benzene, see: S. F. Reed,
J. Org. Chem., 1965, 30, 3258.
10 (a) For the preparation of phenallylamine, see: N. De Kimpe and
D. De Smaele, Tetrahedron, 1995, 51, 6465; (b) I. A. McDonald,
J. M. Lacoste, P. Bey, M. G. Palfreyman and M. Zreika, J. Med. Chem.,
1985, 28, 186.
Notes and references
1 P. J. Kocienski, Protective Groups, Thieme, Stuttgart, 3rd edn., 2003.
2 (a) For the deprotection using 1,3-dimethylbarbituric acid, see: F. Garro-
Helion, A. Merzouk and F. Guibe´, J. Org. Chem., 1993, 58, 6109; (b) for
the deprotection using thiosalicylic acid, see: S. Lemaire-Audoire,
M. Savignac and J. P. Geneˆt, Tetrahedron Lett., 1995, 36, 1267;
S. Lemaire-Audoire, M. Savignac, C. Dupuis and J. P. Geneˆt, Bull. Soc.
Chim. Fr., 1995, 132, 1157; (c) for the deprotection using sulfinic acids,
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