Efficient, simple preparation of 1,3-diamine derivatives through addition of acrylamides with secondary amines

Article abstract of DOI:10.1081/SCC-200057283

Reaction of acrylamides with secondary amines results in the formation of β-amino-propionamide through the addition reaction of N-H bond of amines across the double bond of acrylamides in the good to excellent yield. The structure of 2-methyl-3-(1-piperidinyl)-propionamide has been determined by X-ray analysis. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/SCC-200057283

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Efficient, Simple Preparation
of 1,3‐Diamine Derivatives
through Addition of
Acrylamides with Secondary
Amines
Yi Liu a , Ruimao Hua a & Xianqing Qiu a
a Department of Chemistry , Tsinghua University, Key
Laboratory of Organic Optoelectronics & Molecular
Engineering of Ministry of Education , Beijing, China
Published online: 16 Aug 2006.
To cite this article: Yi Liu , Ruimao Hua & Xianqing Qiu (2005) Efficient, Simple
Preparation of 1,3‐Diamine Derivatives through Addition of Acrylamides with
Secondary Amines, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 35:10, 1375-1380, DOI: 10.1081/
SCC-200057283
To link to this article: http://dx.doi.org/10.1081/SCC-200057283
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Synthetic Communicationsw, 35: 1375–1380, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200057283
Efficient, Simple Preparation of
1,3-Diamine Derivatives through Addition
of Acrylamides with Secondary Amines
Yi Liu, Ruimao Hua, and Xianqing Qiu
Department of Chemistry, Tsinghua University, Key Laboratory of
Organic Optoelectronics & Molecular Engineering of Ministry of
Education, Beijing, China
Abstract: Reaction of acrylamides with secondary amines results in the formation of
b-amino-propionamide through the addition reaction of N–H bond of amines across
the double bond of acrylamides in the good to excellent yield. The structure of
2-methyl-3-(1-piperidinyl)-propionamide has been determined by X-ray analysis.
Keywords: Acrylamide, addition reaction, amine, 1,3-diamine
It is known that amines are much more stable than phosphines toward oxygen
and water; therefore, investigation of the use of amino compounds as ligands
to replace phosphine ligands in the preparation of transition metal complexes
has been actively studied in recent years. For instance, 1,2-diamine
ligands have been empolyed as the effective ligands in the copper-catalyzed
amidation of aryl halides,[1] chiral 1,2- and 1,4-diamine/transition metal
complexes have shown good catalytic activity for the asymmetric reduction
of ketones.[2] The 1,3-diamines can be expected to be the potential ligands
as 1,3-diphosphine ligands used in transition-metal–catalyzed reactions.
Thus, study of the new synthetic method of the formation of 1,3-diamino
Received in Japan November 4, 2004
Address correspondence to Ruimao Hua, Department of Chemistry, Tsinghua
University, Key Laboratory of Organic Optoelectronics & Molecular Engineering of
Ministry of Education, Beijing 100084, China. E-mail: ruimao@mail.tsinghua.edu.cn
1375

1376
Y. Liu, R. Hua, and X. Qiu
compounds is one of the important and interesting subjects in organic
synthesis. For synthesizing 1,3-diamines, we have designed an efficient and
simple synthetic route as shown in Scheme 1. In this article, we report the resu-
lts of the synthesis of b-amino-propionamide that is the precursor of
1,3-diamine by the addition reaction of acrylamides with amines.
The addition reaction of E-H (E ¼ heteroatom) bond to the unsaturated
compounds such as alkynes and alkenes has been proven to be the efficient
and atom-economical reaction for synthesis of functionalized (E group–
bearing) compounds, and usually proceeds in the presence of a catalytic
amount of transition-metal complex.[3] The reported addition reactions of
N–H bond of amines to alkenes (unactivated and activated alkenes) were
catalyzed by transition metal complexes of Ru,[4] Pd,[4a,5] Rh,[4a,6] and
metal halide.[7] In our attempts to develop the addition of amines with acryl-
amides, it has been found that the addition reaction could take place smoothly
at 1208C under solvent-free conditions in the absence of a catalyst.
The addition reactions were carried out in a mixture of acrylamide or
a-methylacrylamide with an excess amount of secondary amines
(1.5 equiv.), and the reaction progress and yield were monitored and deter-
mined by GC using an internal standard. Table 1 summarizes the representa-
tive results of addition reactions. All of the starting materials are analytic
grade and used without further purification. Adducts 3a was isolated by
Kugelrohr distillation in vacuum, 3b–g were isolated by recrystallization
from a mixture of CH2Cl2 and diethyl ether after removal of the volatiles.
1
The structures of adducts were determined and confirmed by H, 13C-NMR
and GC-MS spectroscopic data.
When a mixture of acrylamide 1a (355.0 mg, 5.0 mmol) and diethylamine
2a (548.0 mg, 7.5 mmol) was stirred at 1208C for 24 h, GC and GC-MS
analyses of the reaction mixture disclosed that 3-diethylamino-propionamide
3a was formed in 88% GC yield. 3a could be isolated (GC purity: 98%) in
82% by direct distillation from the reaction mixture (entry 1). The addition
reaction of 1a with di-n-butylamine or diisobutylamine also gave the
corresponding adducts 3-di-n-butylamino-propionamide 3b and 3-di-iso-
butylamino-propionamide 3c in 90% and 78% GC yields, respectively
(entries 2 and 3).
Heterocyclic amines such as pyrrolidine 2d and piperidine 2e also
proceeded the present addition reaction. In the case of 2d, both addition
Scheme 1.

Preparation of 1,3-Diamine Derivatives
1377
Table 1. Addition reaction of acrylamide with secondary aminea
Yield
(%)b
Entry
1
R
Amine
Adduct 3
H 1a
Et2NH 2a
82 (88)
79 (90)
2
3
1a
1a
n-Bu2NH 2b
iso-Bu2NH 2c
60 (78)
4
5
1a
91
92
CH3 1b
2d
6
7
8
1a
1b
1a
60 (84)
60 (80)
(,5)
2e
aThe reactions were carried out at 120 8C for 24 h by using 5.0 mmol of 1 and
7.5 mmol of 2 in the absence of solvent.
bIsolated yield based on the amount of 1 used; the figure in parenthesis of GC yield.

1378
Y. Liu, R. Hua, and X. Qiu
reactions of 2d with 1a or with a-methylacrylamide 1b produced the adducts
3-(1-pyrrolidinyl)-propionamide 3d and 2-methyl-3-(1-pyrrolidinyl)-propio-
namide 3e in very high yields (entries 4 and 5). Similarly, the adducts of
3-(1-piperidinyl)-propionamide 3f and 2-methyl-3-(1-piperidinyl)-propiona-
mide 3g were obtained in good yields from the reactions of 1a, 1b with piper-
idine (entries 6 and 7). Furthermore, the structure of 3g was unambiguously
confirmed by X-ray diffraction analysis, and the molecular structure of 3g is
shown in Figure 1. Crystals for X-ray diffraction analysis were obtained by
recrystallization from a mixture of CH2Cl2 and diethyl ether at 210 8C.
Crystal data for 3g: colorless plate crystals, monoclinic, space group P21/c,
3
˚
˚
˚
˚
a ¼ 17.144 (2) A, b ¼ 6.2109 (10) A, c ¼ 9.8210 (18) A, V ¼ 1034.5 (3) A ,
Z ¼ 4,
D
(calcd.) ¼ 1.093 g/cm3,
fw ¼ 170.25, R1 ¼
0.0865,
wR2 ¼ 0.1205, GOF ¼ 1.055.
In addition, the present addition reaction could be slightly accelerated by
adding a base. For example, in the presence of Bu3N (1.0 mmol), the reaction
of 1b with piperidine afforded 3g in 86% GC yield.
In contrast to aliphatic amines 2a–e, under the same conditions, aromatic
amines displayed very low reactivity. For example, the reaction of 1a with
N-methylaniline 2f gave only small amount of the corresponding adduct 3h
(,5%). In this case, some unidentified products were formed (entry 8).
Furthermore, the addition reactions of acrylamides with primary amines
(e.g., benzylamine, n-propylamine, and cyclohexylamine) have also been
investigated. However, these addition reactions produced a mixture of
adducts 3 and 4 as shown in Scheme 2. Adduct 4 arose from the double
addition reaction of one equivalent of primary amine with two equivalent of
acrylamide. Attempts to improve the selectivity of adduct 3 by using a
greater excess of primary amines (3.0–5.0 equiv.) was not successful.
In summary, we has described here the addition reaction of acryl-
amides with secondary amines in the absence of a catalyst to give
3-amino-propionamides in good to excellent yields. 3-Amino-propionamides
have been designed as the intermediates for the synthesis of 1,3-diamines,
which are expected to be potentially useful ligands in the preparation of
Figure 1. Molecular structure of adduct 3g. Hydrogen atoms are omitted for clarity.

Preparation of 1,3-Diamine Derivatives
1379
Scheme 2.
transition-metal complex catalysts. The synthesis of 1,3-diamine ligands
including the new chiral 1,3-diamine ligands (by resolution of 1,3-diamines,
R ¼ alkyl, as shown in Scheme 1) is now in progress.
ACKNOWLEDGMENT
Financial support from Tsinghua University for scientific research is grate-
fully acknowledged.
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