α(δ')-Michael addition of alkyl amines to dimethyl (E)-hex-2- en-4-ynedioate: Synthesis of α,β-dehydroamino acid derivatives

Article abstract of DOI:10.3390/molecules18032611

The direct nucleophilic addition of alkyl amines to the α(δ')-carbon atom of dimethyl (E)-hex-2-en-4-ynedioate to generate α,β-dehydroamino acid derivatives is reported. Herein, we have studied the reactivity of various primary and secondary alkyl amines

Full text of DOI:10.3390/molecules18032611

Molecules 2013, 18, 2611-2622; doi:10.3390/molecules18032611
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
α(δ')-Michael Addition of Alkyl Amines to Dimethyl (E)-hex-2-
en-4-ynedioate: Synthesis of α,β-Dehydroamino Acid Derivatives
Arjun S. Chavan, Jie-Cheng Deng and Shih-Ching Chuang *
Department of Applied Chemistry, National Chiao Tung University, Hsinchu 30010, Taiwan
*
Author to whom correspondence should be addressed; E-Mail: jscchuang@faculty.nctu.edu.tw;
Tel.: +886-3-571-2121 (ext. 56508); +886-3-573-1858; Fax: +886-3-572-3764.
Received: 31 December 2012; in revised form: 7 February 2013 / Accepted: 20 February 2013 /
Published: 27 February 2013
Abstract: The direct nucleophilic addition of alkyl amines to the α(δ')-carbon atom of
dimethyl (E)-hex-2-en-4-ynedioate to generate α,β-dehydroamino acid derivatives is
reported. Herein, we have studied the reactivity of various primary and secondary alkyl
amines in the α-selective nucleophilic conjugate addition to conjugated dimethyl (E)-hex-
2-en-4-ynedioate. The reaction with primary alkyl amines gives only the (2E,4E)-stereoisomer,
while that with secondary alkyl amines gives the (2E,4E) and (2Z,4E)-stereoisomers of
dimethyl (2-alkylamino)-muconic ester.
Keywords: α-Michael addition; conjugated enyne; dehydroamino acids
1
. Introduction
The Michael addition reaction, the regioselective 1,4-addition of nucleophiles to activated olefins, is
one of the versatile methods used for C–C, C–N bond formation, and has found wide application in organic
synthesis [1–10]. On the other hand, the anti-Michael or α-Michael addition reaction, the nucleophilic
addition to the α-carbon of an activated olefinic compound, is also known in the literature [11–13]. The
regioselectivity of the reactions can be reversed by the substitution of highly electron withdrawing
groups at the β-position of the Michael acceptors [14,15]. The use of phosphine bases [16–18],
palladium catalysts [19] and organometallic reagents [20,21] are also well-known for the reversal of
regioselectivity from β-carbon to α-carbon of the Michael acceptors. The theoretical and mechanical
aspects of change in regioselectivity of Michael addition reaction were extensively studied by various
groups [22–24]. Earlier, Trost et al. observed the phosphine-mediated α-addition of nitrogen nucleophiles

Molecules 2013, 18
2612
to conjugated alkynoates and used it to prepare various α,β-dehydroamino acid derivatives [25]. It
occurs through the zwitterionic carbenoid species formation by the attack of phosphine on the β-carbon
of the allenoate substrates. In the case of the activated enyne substrate 2, our group has reported the
α-addition of phosphine and subsequent reactions of the resulting 1,3-dipolar species with various
electrophilic substrates [26,27]. Although we observed the exclusive α-addition of phosphine to enyne
2
through product analysis, we still speculated about the possibility of nucleophilic addition to
β-carbon of enyne 2 with other nucleophiles. In continuation of our interest in studying the reactivity
of enyne 2, herein we have shown the direct nucleophilic addition of alkyl amines to the α(δ')-carbon
of enyne 2 to generate the corresponding α,β-dehydroamino acid derivatives, which are important
building blocks in protein and peptide chemistry [28–30].
First, we have prepared the required propiolate dimer 2 in quantitative yield by base-catalyzed
dimerization of methyl propiolate (1) under mild reaction conditions, according to a literature procedure
(
Scheme 1) [31]. Recently, Pu and co-workers have shown the regio- and stereoselective addition of
dibenzyl amine to propiolate dimer 2 to give exclusively the (2E,4E)-stereoisomer in quantitative
yields [32]. After our success with a three-component reaction of dimer 2 with phosphines and aldehydes,
we next expanded our investigation of the reaction scope of alkylamines with 2 under various reaction
conditions for the regio- and chemoselective addition. Our results have shown that the produced
stereoisomers are highly dependent on the degrees of substitution of the alkyl amines—primary alkyl
amine gives only the (2E,4E)-stereoisomer, while secondary alkyl amines give the (2E,4E) and
(
2Z,4E)-stereoisomers of dimethyl (2-alkylamino)-muconic ester. All these investigated alkyl amines
react with enyne 2 through α(δ')-selective nucleophilic conjugate addition.
Scheme 1. Preparation of propiolate dimer 2.
Reagents and Conditions: (i) 1% DABCO, DCM (0.5 M), 0 °C, <5 min.
2
. Results and Discussion
For the reaction condition optimization study, we selected the primary amine n-octylamine and the
secondary amine piperidine as nucleophilic partners. When we treated n-octylamine with propiolate
dimer 2 in 1:1 molar ratio under different solvent conditions (Table 1, entry 1–6), the reaction in THF
at room temperature gave stereoisomer (2E,4E)-4 in higher yield (82%, Table 1, entry 1). Here we
expected the β-addition of the nucleophile to conjugated enyne 2, in a normal Michael addition pattern
in the absence of phosphine ligand. However, this enyne diester 2 undergoes a direct nucleophilic
addition to the α(δ')-carbon with no use of phosphine ligand. The unusual reactivity of this enyne
diester 2 is due to the difference in electropositivity of its α(') and β(')-carbons [26].
This reaction is highly regio-, chemo- and stereoselective with primary alkyl amines. In the case of
secondary amines, however, this reaction is regio- and chemoselective, but it does not show
stereoselectivity since it gives (2E,4E) and (2Z,4E) stereoisomers 4 in a molar ratio range of 4:1 to 7:1
with different solvents (Table 1, entry 7–12). Our results with secondary alkyl amines are in great

Molecules 2013, 18
2613
contrast to those of Pu’s study with dibenzylamine since we have observed two stereoisomers.
Initially, we suspected the existence of β-addition product. With careful analyses by NOE experiments,
we concluded that the isolated two stereoisomers are the result of α(δ')-addition and have (2E,4E) and
(
2Z,4E) configurations. The results obtained are summarized in Table 1. We found that the reaction
carried out in THF at room temperature condition gave excellent yield for the α(δ')-addition of nitrogen
nucleophiles to enyne 2, compared to other solvent conditions.
a
Table 1. Optimization of reaction conditions .
R1
NH
R2
O
O
OMe
R1
R2
O



O
N
O

MeO
R2
N
OMe

'
OMe
3
MeO
'
MeO

'
E
E
+
E
Z

'
R1
O
4
2
(2E,4E)-4
(2Z,4E)-
b
Reaction
Yields of 4 (%)
Entry
Amine
Solvent
conditions (2E,4E) (2Z,4E)
1
2
3
4
5
6
7
8
9
n-Octylamine
n-Octylamine
THF
THF
rt
82
81
52
49
46
65
64
54
68
00
00
00
00
00
00
16
14
11
60 °C
n-Octylamine Benzene
n-Octylamine Toluene
rt
rt
n-Octylamine
DCM
rt
n-Octylamine MeCN
rt
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
THF
THF
rt
60 °C
rt
Benzene
Toluene
DCM
1
1
1
0
1
2
rt
60 (68) 08 (09)
58 (63) 12 (13)
48 (51) 08 (09)
rt
MeCN
rt
a
All reactions are carried out with 100 mg (0.595 mmol) of enyne 2 and 77 mg (0.595 mmol) of
b
n-octylamine or 51 mg (0.595 mmol) of piperidine in 10 mL THF at r.t. for 2 h. Yields were determined
spectroscopically by adding mesitylene as an internal standard. Yields in parentheses are based on conversion
of starting material.
Later, we used the optimized reaction conditions for studying the reactivity of propiolate dimer 2
with other primary amines 3a–i. All the primary amines gave the α(δ')-addition products 4a–i as a
(
2E,4E) stereoisomer exclusively (Table 2). Aside from tert-butylamine (3g), all other primary amines
yielded the α(δ')-addition products in moderate to good yields (60–82%). The formation of
1
13
α(δ')-addition products were confirmed by infrared (IR), H- and C-NMR spectroscopic methods and
1
further supported by high resolution mass spectrometric analysis (HRMS). The H-NMR spectra of the
products show doublets for the β- and -proton due to their couplings with the adjacent -proton with
coupling constants of around 12 and 15 Hz, respectively. The -proton shows a doublet of doublet
splitting due to its coupling with the β- and -protons, and appears in a relatively downfield shift
region. The large coupling constants, ~15 Hz, between the - and -protons indicate the trans-
1
13
configuration of the C=C double bond. In the case of piperidine, H, C and nuclear overhauser
enhancement (NOE) NMR experiment confirm the formation of α(δ')-addition products (2E,4E) and
(
2Z,4E) as a stereoisomeric mixture (compound 4m). In the NOE experiment of the (2E,4E)-4m

Molecules 2013, 18
2614
stereoisomer, we observed enhancement in - and β-proton signals with about 3.0% and 2.8%
respectively when we irradiated the β- and -protons individually. Similarly, in case of the (2Z,4E)-4m
stereoisomer, the observed enhancements in the - and β-proton signals are about 2.6% and 2.2%,
respectively. Later, we have carried out the reactions of secondary amines 3j–n under similar reaction
conditions, observing identical results with the formation of (2E,4E) and (2Z,4E) stereoisomers 4j–n in
3
:1 to 4:1 ratio (Table 3). The purification of primary alkyl amine products were carried out on silica
gel column with hexanes/ethyl acetate mixtures as an eluent, but, in case of secondary alkyl amine
products, the better separation of (2E,4E) and (2Z,4E) stereoisomers were achieved using 5% (v/v)
triethylamine/hexanes on a neutralized silica gel column.
a
Table 2. Reaction of enyne 2 with primary alkyl amines .
O
R -NH
3
O
OMe
1
2
O
MeO
OMe
MeO
NH-R1
THF, r.t.
E
E
O
2
(2E,4E)-4
b
Entry
R1
Product (2E,4E)
Yield (%)
1
2
3
4
n-Hexyl-3a
n-Octyl-3b
n-Decyl-3c
n-Dodecyl-3d
Benzyl-3e
67
82
73
73
c
c
5
73 (75)
6
7
8
9
iso-Propyl-3f
tert-Butyl-3g
Allyl-3h
60 (64)
25 (58)
68
Ethanol-3i
78 (80)
a
All reactions are carried out with 200 mg (1.19 mmol) of enyne 2 and 1.19 mmol of amine in 10 mL THF at
b
r.t. for 2 h. Yields were determined spectroscopically by adding mesitylene as an internal standard. Yields in
c
parentheses are based on conversion of starting materials. Reference [32].

Molecules 2013, 18
2615
a
Table 3. Reaction of enyne 2 with secondary alkyl amines .
R1
NH
O
O
OMe
R1
R2
O
R2
O
N
O
3
MeO
R1
+
OMe
OMe
MeO
N
MeO
THF, r.t.
E
E
E
Z
R2
2
O
(
2E,4E)-4
(2Z,4E)-4
Ratio of
(2E,4E)/
2Z,4E)
Yield
Minor Product
Yield
Entry
R
1
R
2
Major Product (2E,4E)
b
b
(
%)
(2Z,4E)
(%)
(
Diethyl
1
53 (58)
59 (62)
56
14 (15)
16 (17)
18
3.8:1
3.7:1
3.1:1
3
j
2
3
Dipropyl 3k
Pyrrolidine
3
l
Piperidine
4
5
64
58
16
18
4:1
3
m
Morpholine
3.2:1
3
n
a
All reactions are carried out with 500 mg (2.98 mmol) of enyne 2 and 2.98 mmol of amines in 20 mL THF
b
at r.t. for 2 h. Yields were determined spectroscopically by adding mesitylene as an internal standard. Yields
in parentheses are based on conversion of starting materials.
The possible mechanism for the formation of (2E,4E) and (2Z,4E)-stereoisomers is depicted in
Scheme 2. Initially, amine hydrogen coordinates to the carbonyl group of alkynyl end and then
nitrogen attacks the α(')-carbon in antiperiplanar fashion to form the five membered-ring structure II.
Later, proton transfer takes place to give the kinetic (2Z,4E)-stereoisomer product III. In the case of
reactions with primary amines (R = H), the intramolecularly hydrogen-bonded intermediate IV exists
2
as a resonance structure that can undergo C-C bond rotation to give intermediate VI. After resonance
takes place again, the thermodynamically favored product (2E,4E)-stereoisomer forms. However, in
the case of reactions with secondary amines, the steric hindrance makes the resonance structure IX
higher in energy. Therefore, its isomerization to the thermodynamic product XI is relatively disfavored
and slow.

Molecules 2013, 18
Scheme 2. Proposed mechanism for regio- and chemoselective addition of amine to enyne 2.
2616
R2
R
1
O
R2
N H
R
1
R1
H
O
MeO
O
N
H+
transfer
R
2
anti-periplanar
opening
O
O
N
O
MeO
MeO
2
OMe
H
OMe
OMe
kinetic product III
2Z,4E)
I
II
(
R1
R1
N
H
N
MeO
MeO
H
O
O
H
C-C
O
O
when
= H
primary
amine
O
O
rotation
O
O
R
2
H
MeO
MeO
H
MeO
MeO
N
MeO
MeO
N
H
OMe
H
OMe
H
VI
R1
R1
IV
V
(2E,4E) VII
III
R
1
R
1
R2
MeO
O
MeO
when
R2  H
secondary
amine
R
N
2
C-C
rotation
O
O
O
O
O
N
R
1
O
O
R1
N
MeO
MeO
N
R
H
OMe
H
OMe
H
H
R2
XI
2
VIII
IX
less favored
X
(2E,4E)
thermodynamic product
3. Experimental
3.1. General
All reactions were performed under nitrogen. Anhydrous THF, benzene, and toluene were distilled
over sodium/benzophenone under argon. Anhydrous DCM and MeCN were distilled over CaH under
argon. The chemical shifts in the H (300 MHz) and C-NMR (75 MHz) spectra are referenced to
TMS or CHCl . NMR, FT-IR and mass data were recorded with Bruker DRX-300, Digilab Excalibur
HE series FTS 3100 and Varian 901-MS spectrometers, respectively.
2
1
13
3
3
.2. General Experimental Procedure for Reactions with Primary Alkyl Amines
A solution of dimer 2 (0.20 g, 1.19 mmol) in anhydrous benzene (10 mL × 4 times) was distilled
from a Dean-Stark apparatus to remove the moisture residue as an azeotropic mixture. Then, 10 mL of
anhydrous THF was added at room temperature followed by the addition of the appropriate amine 3a–i
(
1.19 mmol, 1 equiv.). Then, the resulting reaction mixture was stirred for 2 h at room temperature.
After completion of the reaction (TLC monitoring), the solvent was removed under vacuum and the
crude product was subjected to silica gel chromatography. Elution of the column with hexanes/ethyl
acetate mixture gives the yellow colored products.
(
2E,4E)-Dimethyl-2-(hexylamino)hexa-2,4-dienedioate (2E,4E-4a). R
f
= 0.39 (3:1 hexanes/ethyl acetate),
1
Yellow solid. mp: 34–36 °C; H-NMR (CDCl
3
) δ 0.88–0.92 (m, 3H), 1.26–1.43(m, 6H), 1.57–1.67
(
m, 2H), 3.02 (dd, J = 6.9, 12.4 Hz, 2H), 3.73 (s, 3H), 3.92 (s, 3H), 4.91 (s, 1H), 5.46 (d, J = 12.1 Hz,
1
3
1
2
1
H), 5.72 (d, J = 14.9 Hz, 1H), 8.23 (dd, J = 12.1, 14.9 Hz, 1H) ppm; C-NMR (CDCl
3
) δ 13.9, 22.5,
–
1
6.7, 28.3, 31.4, 43.3, 51.1, 52.8, 102.0, 115.3, 139.2, 142.7, 164.6, 168.4; FT-IR (KBr) (cm ) 1602,
+
+
4
710, 1735, 2859, 2931, 2954; HRMS (EI ), calcd for C14H23NO (M ) 269.1627 found 269.1629.

Molecules 2013, 18
2617
(
2E,4E)-Dimethyl-2-(octylamino)hexa-2,4-dienedioate (2E,4E-4b). R = 0.33 (4:1 hexanes/ethyl acetate),
f
1
Yellow solid. mp: 44–46 °C; H-NMR (CDCl
3
) δ 0.86–0.91 (m, 3H), 1.28–1.40 (m, 10H), 1.57–1.64
(
m, 2H), 3.01 (dd, J = 6.9, 12.4 Hz, 2H), 3.72 (s, 3H), 3.91 (s, 3H), 4.95 (t, J = 4.8 Hz, 1H), 5.46 (d,
1
3
J = 12.1 Hz, 1H), 5.72 (d, J = 14.9 Hz, 1H), 8.23 (dd, J = 12.1, 14.9 Hz, 1H); C-NMR (CDCl ) δ
3
1
3.9, 22.4, 26.9, 28.1, 29.1, 29.3, 31.6, 43.1, 50.8, 52.5, 101.7, 114.9, 139.1, 142.6, 164.3, 168.2;
–
1
+
+
FT-IR (KBr) (cm ) 1603, 1713, 1737, 2856, 2928; HRMS (EI ), calcd for C16
found 297.1945.
4
H27NO (M ) 297.1940
(
2E,4E)-Dimethyl-2-(decylamino)hexa-2,4-dienedioate (2E,4E-4c). R = 0.30 (5:1 hexanes/ethyl acetate),
f
1
Yellow solid. mp: 52–54 °C; H-NMR (CDCl
3
) δ 0.86–0.90 (m, 3H), 1.27–1.36 (m, 14H), 1.57–1.66
(
m, 2H), 3.01 (dd, J = 6.8, 12.4 Hz, 2H), 3.72 (s, 3H), 3.90 (s, 3H), 4.98 (t, J = 4.9 Hz, 1H), 5.45 (d,
13
J = 12.1 Hz, 1H), 5.71 (d, J =14.9 Hz, 1H), 8.23 (dd, J = 12.1, 14.9 Hz, 1H); C-NMR (75.5 MHz,
CDCl ) δ 13.9, 22.4, 26.9, 28.1, 29.1, 29.3, 31.6, 43.1, 50.8, 52.5, 101.7, 114.9, 139.1, 142.6, 164.3,
3
–
1
+
+
1
3
68.2; FT-IR (KBr) (cm ) 1602, 1711, 1736, 2855, 2927; HRMS (EI ), calcd for C H NO (M )
18 31 4
25.2253 found 325.2252.
(
2E,4E)-Dimethyl-2-(dodecylamino)hexa-2,4-dienedioate (2E,4E-4d). R
f
= 0.35 (5:1 hexanes/ethyl
1
acetate), Yellow solid. mp: 63–65 °C; H-NMR (CDCl
3
) δ 0.86–0.90 (m, 3H), 1.26–1.33 (m, 18H),
1
.57–1.64 (m, 2H), 3.01 (dd, J = 6.7, 12.4 Hz, 2H), 3.72 (s, 3H), 3.91 (s, 3H), 4.96 (t, J = 4.7 Hz, 1H), 5.45
1
3
(
d, J = 12.1 Hz, 1H), 5.71 (d, J =14.9 Hz, 1H), 8.23 (dd, J = 12.1, 14.9 Hz, 1H); C-NMR (CDCl
3
) δ
1
1
3.9, 22.5, 27.0, 28.2, 29.1, 29.2, 29.35, 29.41, 29.46, 29.48, 31.7, 43.2, 50.9, 52.6, 101.8, 115.0,
–
1
+
39.1, 142.7, 164.4, 168.3; FT-IR (KBr) (cm ) 1602, 1714, 1736, 2854, 2926; HRMS (EI ), calcd for
+
C
20
H35NO
4
(M ) 353.2566 found 353.2558.
(
2E,4E)-Dimethyl-2-(isopropylamino)hexa-2,4-dienedioate (2E,4E-4f). R
f
= 0.33 (4:1 hexanes/ethyl
1
acetate), Yellow sticky liquid; H-NMR (CDCl
3
) δ 1.21 (d, J = 6.3 Hz, 6H), 3.46–3.57 (m, 1H), 3.72
(
s, 3H), 3.91 (s, 3H), 4.86 (d, J = 7.1 Hz, 1H), 5.47 (d, J = 12.1 Hz, 1H), 5.70 (d, J = 14.9 Hz, 1H),
1
3
8
1
2
3
.23 (dd, J = 12.1, 14.9 Hz, 1H); C-NMR (CDCl ) δ 21.7, 43.7, 51.0, 52.7, 101.9, 114.7, 138.1,
–
1
+
+
42.8, 164.6, 168.3; FT-IR (KBr) (cm ) 1600, 1712, 2953; HRMS (EI ), calcd for C11
27.1158 found 227.1156.
4
H17NO (M )
(
2E,4E)-Dimethyl-2-(tert-butylamino)hexa-2,4-dienedioate (2E,4E-4g). R = 0.32 (4:1 hexanes/ethyl
f
1
acetate), Yellow sticky liquid; H-NMR (CDCl
3
) δ 1.36 (s, 9H), 3.72 (s, 3H), 3.91 (s, 3H), 4.92
1
3
(
s, 1H), 5.68 (d, J = 1.5 Hz, 1H), 5.73 (s, 1H), 8.14 (dd, J = 11.8, 15.1 Hz, 1H); C-NMR (CDCl
3
) δ
–
1
2
2
8.7, 51.0, 51.2, 52.8, 103.7, 114.7, 137.9, 143.0, 165.4, 168.4; FT-IR (KBr) (cm ) 1598, 1711, 1734,
+
+
4
954, 2978; HRMS (EI ), calcd for C12H19NO (M ) 241.1314 found 241.1311.
(
2E,4E)-Dimethyl-2-(allylamino)hexa-2,4-dienedioate (2E,4E-4h). R
f
= 0.37 (3:1 hexanes/ethyl acetate),
1
Yellow solid. mp: 38–40 °C; H-NMR (CDCl
3
) δ 3.67–3.69 (m, 2H), 3.72 (s, 3H), 3.92 (s, 3H), 5.14
(
s, 1H), 5.20–5.29 (m, 2H), 5.49 (d, J = 12.0 Hz, 1H), 5.72 (d, J = 15.0 Hz, 1H), 5.80–5.93 (m, 1H),
13
8
1
.22 (dd, J = 12.1, 14.9 Hz, 1H); C-NMR (CDCl
3
) δ 45.6, 51.1, 52.7, 102.9, 115.8, 117.2, 132.7,
–
1
+
38.6, 142.4, 164.3, 168.2; FT-IR (KBr) (cm ) 1600, 1713, 1734, 2850, 2952, 3082; HRMS (EI ),
+
calcd for C11
H15NO
4
(M ) 225.1001 found 225.0997.

Molecules 2013, 18
2618
(
2E,4E)-Dimethyl-2-(2-hydroxyethylamino)hexa-2,4-dienedioate (2E,4E-4i). R = 0.18 (1:1 hexanes/ethyl
f
1
acetate), Yellow sticky liquid; H-NMR (CDCl
3
) δ 3.22 (q, J = 5.3 Hz, 2H), 3.73 (s, 3H), 3.86 (t,
J = 5.2 Hz, 2H), 3.91 (s, 3H), 5.30 (s, 1H), 5.50 (d, J = 12.0 Hz, 1H), 5.70 (d, J = 15.0 Hz, 1H), 8.23
1
3
(
dd, J = 12.0, 15.0 Hz, 1H); C-NMR (CDCl ) δ 45.3, 51.3, 52.8, 60.0, 102.6, 115.7, 139.3, 142.6,
3
–
1
+
+
1
5
64.4, 168.6; FT-IR (KBr) (cm ) 1600, 1712, 2953; HRMS (EI ), calcd for C10H15NO (M ) 229.0950
found 229.0946.
.3. General Experimental Procedure for Reactions with Secondary Alkyl Amines
A solution of dimer 2 (0.50 g, 2.98 mmol) in anhydrous benzene (20 mL × 3 times) was distilled
3
from a Dean-Stark apparatus to remove the moisture residue as an azeotropic mixture. Then,
anhydrous THF (10 mL) was added at room temperature, followed by the addition of the appropriate
amine 3j–n (2.98 mmol, 1 equiv.) Then, the resulting reaction mixture was stirred for 2 h at room
temperature. After completion of the reaction (TLC monitoring), the solvent was removed under
vacuum and the crude product was subjected to 5% triethylamine-neutralized silica gel chromatography
to separate both the isomeric products. Elution of the column with hexanes/ethyl acetate mixture gives
the corresponding yellow colored products.
(
2E,4E)-Dimethyl-2-(diethylamino)hexa-2,4-dienedioate (2E,4E-4j). R = 0.21 (4:1 hexanes/ethyl acetate),
f
1
Yellow sticky liquid; H-NMR (CDCl
3
) δ 1.15 (t, J = 6.9 Hz, 6H), 3.15 (q, J = 6.9 Hz, 4H), 3.68
(
s, 3H), 3.91 (s, 3H), 5.21 (d, J = 12.0 Hz, 1H), 5.56 (d, J = 14.4 Hz, 1H), 7.24 (dd, J = 12.0, 14.7 Hz,
1
3
1
3
H); C-NMR (CDCl ) δ 12.9, 44.9, 51.1, 52.7, 97.2, 110.1, 143.0, 148.8, 166.0, 168.6; FT-IR (KBr)
–
1
+
+
(
cm ) 1438, 1577, 1719, 2873, 2954, 2972; HRMS (EI ), calcd for C12
41.1316.
4
H19NO (M ) 241.1314 found
2
(
2Z,4E)-Dimethyl-2-(diethylamino)hexa-2,4-dienedioate (2Z,4E-4j). R
f
value = 0.47 (4:1 hexanes/ethyl
1
acetate), Yellow sticky liquid; H-NMR (CDCl
3
) δ 1.07 (t, J = 7.1 Hz, 6H), 3.14 (q, J = 7.1 Hz, 4H), 3.74
(
s, 3H), 3.78 (s, 3H), 5.91 (d, J = 15.3 Hz, 1H), 6.34 (d, J = 12.0 Hz, 1H), 7.69 (dd, J = 11.7, 15.3 Hz,
1
3
1
3
H); C-NMR (CDCl ) δ 13.8, 47.5, 51.6, 52.2, 120.2, 120.9, 140.2, 144.7, 166.7, 167.7; FT-IR (KBr)
–
1
+
+
(
cm ) 1436, 1578, 1725, 2872, 2954, 2972; HRMS (EI ), calcd for C12
41.1315.
4
H19NO (M ) 241.1314 found
2
(
2E,4E)-Dimethyl-2-(dipropylamino)hexa-2,4-dienedioate (2E,4E-4k). R = 0.44 (4:1 hexanes/ethyl
f
1
acetate), Yellow sticky liquid; H-NMR (CDCl
3
) δ 0.87 (t, J = 7.5 Hz, 6H), 1.51–1.64 (m, 4H), 3.02
(
t, J = 7.5 Hz, 4H), 3.67 (s, 3H), 3.89 (s, 3H), 5.15 (d, J = 12.0 Hz, 1H), 5.40 (d, J = 14.7 Hz, 1H), 7.21
1
3
(
dd, J = 12.0, 14.7 Hz, 1H); C-NMR (CDCl
3
) δ 11.4, 20.9, 51.1, 52.7, 52.9, 97.4, 111.1, 143.1, 149.3,
–
1
+
1
66.1, 168.7; FT-IR (KBr) (cm ) 1458, 1522, 1725, 2857, 2926, 2956; HRMS (EI ), calcd for
+
C H NO (M ) 269.1627 found 269.1628.
1
4
23
4
(
2Z,4E)-Dimethyl-2-(dipropylamino)hexa-2,4-dienedioate (2Z,4E-4k). R = 0.56 (4:1 hexanes/ethyl
f
1
acetate), Yellow sticky liquid; H-NMR (CDCl
3
) δ 0.80 (t, J = 7.5 Hz, 6H), 1.37–1.49 (m, 4H), 3.00
(
(
t, J = 7.3 Hz, 4H), 3.67 (s, 3H), 3.71 (s, 3H), 5.82 (d, J = 15.3 Hz, 1H), 6.16 (d, J = 12.0 Hz, 1H), 7.60
1
3
dd, J = 12.0, 15.3 Hz, 1H); C-NMR (CDCl ) δ 11.5, 21.9, 51.6, 52.3, 55.4, 118.1, 120.3, 140.4,
3

Molecules 2013, 18
2619
–
1
+
1
45.6, 166.8, 167.7; FT-IR (KBr) (cm ) 1434, 1577, 1603, 1718, 2875, 2961; HRMS (EI ), calcd for
+
C
14 4
H23NO (M ) 269.1627 found 269.1626.
(
2E,4E)-Dimethyl-2-(pyrrolidin-1-yl)hexa-2,4-dienedioate (2E,4E-4l). R
f
= 0.31 (4:1 hexanes/ethyl
1
acetate), Yellow solid. mp: 102–104 °C; H-NMR (CDCl ) δ 1.90–1.95 (m, 4H), 3.21–3.25 (m, 4H),
3
3
1
.67 (s, 3H), 3.90 (s, 3H), 5.14 (d, J = 12.0 Hz, 1H), 5.56 (d, J = 14.7 Hz, 1H), 7.342 (dd, J = 12.0,
1
3
3
4.7 Hz, 1H); C-NMR (CDCl ) δ 25.3, 48.7, 51.1, 52.8, 98.1, 111.1, 142.9, 146.7, 165.5, 168.3;
–
1
+
+
FT-IR (KBr) (cm ) 1438, 1569, 1697, 1733, 2867, 2952; HRMS (EI ), calcd for C H NO (M )
1
2
17
4
2
39.1158 found 239.1167.
(
2Z,4E)-Dimethyl-2-(pyrrolidin-1-yl)hexa-2,4-dienedioate (2Z,4E-4l). R
f
= 0.44 (4:1 hexanes/ethyl
1
acetate), Yellow solid. mp: 61–63 °C; H-NMR (CDCl ) δ 1.88–1.92 (m, 4H), 3.51–3.55 (m, 4H), 3.69
3
(
s, 3H), 3.79 (s, 3H), 5.56 (d, J = 12.9 Hz, 1H), 5.25 (d, J = 14.7 Hz, 1H), 7.82 (dd, J = 12.9, 14.4 Hz,
1
3
1
3
H); C-NMR (CDCl ) δ 25.7, 51.3, 52.2, 52.6, 101.8, 114.7, 141.8, 142.3, 166.8, 168.7; FT-IR (KBr)
–
1
+
+
(
cm ) 1452, 1575, 1704, 1728,2873, 2952; HRMS (EI ), calcd for C H NO (M ) 239.1158 found
12 17 4
2
39.1157.
(
2E,4E)-Dimethyl-2-(piperidin-1-yl)hexa-2,4-dienedioate (2E,4E-4m). R
f
= 0.44 (3:1 hexanes/ethyl
1
acetate), Yellow solid. mp: 68–70 °C; H-NMR (CDCl
3
) δ 1.61 (m, 6H), 3.03–3.05 (m, 4H), 3.69
(
s, 3H), 3.90 (s, 3H), 5.41 (d, J = 11.7 Hz, 1H), 5.65 (d, J = 14.7 Hz, 1H), 7.68 (dd, J = 12.0, 14.7 Hz,
13
1
3
H); C-NMR (CDCl ) δ 23.6, 24.9, 48.8, 50.7, 52.3, 100.8, 113.1, 142.2, 149.6, 165.7, 167.8; FT-IR
–
1
+
+
(
KBr) (cm ) 1437, 1576, 1606, 1706, 1735, 2855, 2947; HRMS (EI ), calcd for C13
53.1314 found 253.1321.
4
H19NO (M )
2
(
2Z,4E)-Dimethyl-2-(piperidin-1-yl)hexa-2,4-dienedioate (2Z,4E-4m). R
f
= 0.56 (3:1 hexanes/ethyl
1
acetate), Yellow solid. mp: 38–40 °C; H-NMR (CDCl
3
) δ 1.62 (bs, 6H), 3.15–3.17 (m, 4H), 3.74
(
s, 3H), 3.79 (s, 3H), 5.84 (d, J = 15.0 Hz, 1H), 6.08 (d, J = 12.3 Hz, 1H), 7.67 (dd, J = 12.0, 15.0 Hz,
13
1
3
H); C-NMR (CDCl ) δ 24.1, 26.6, 51.6, 52.5, 53.1, 114.3, 119.6, 140.5, 146.1, 166.9, 167.9; FT-IR
–
1
+
+
(
KBr) (cm ) 1435, 1578, 1605, 1716, 2854, 2945; HRMS (EI ), calcd for C13
4
H19NO (M ) 253.1314
found 253.1321.
(
2E,4E)-Dimethyl-2-(morpholino)hexa-2,4-dienedioate (2E,4E-4n). R
f
= 0.20 (2:1 hexanes/ethyl acetate),
1
Yellow sticky liquid; H-NMR (CDCl
3
) δ 3.02 (t, J = 4.8 Hz, 4H), 3.70 (s, 3H), 3.76 (t, J = 4.8 Hz,
4
1
H), 3.90 (s, 3H), 5.47 (d, J = 11.7 Hz, 1H), 5.73 (d, J = 15.0 Hz, 1H), 7.36 (dd, J = 11.7, 15.3 Hz,
1
3
3
H); C-NMR (CDCl ) δ 48.4, 51.5, 52.9, 66.2, 104.6, 116.7, 141.4, 149.0, 165.6, 167.9; FT-IR (KBr)
–
1
+
+
(
cm ) 1435, 1582, 1611, 1704, 1731, 2857, 2954; HRMS (EI ), calcd for C12
5
H17NO (M ) 255.1107
found 255.1109.
(
2Z,4E)-Dimethyl-2-(morpholino)hexa-2,4-dienedioate (2Z,4E-4n). R
f
= 0.33 (2:1 hexanes/ethyl acetate),
1
Yellow solid. mp: 43–45 °C; H-NMR (CDCl ) δ 3.16 (t, J = 4.5 Hz, 4H), 3.74 (s, 3H), 3.75 (t, J = 4.5 Hz,
3
4
H), 3.78 (s, 3H), 5.94 (d, J = 15.3 Hz, 1H), 6.35 (d, J = 12.0 Hz, 1H), 7.66 (dd, J = 12.0, 15.3 Hz, 1H);
13
–1
C-NMR (CDCl
3
) δ 51.8, 51.9, 52.5, 67.4, 119.3, 122.2, 139.3, 144.8, 166.1, 167.4; FT-IR (KBr) (cm )
+
+
1435, 1583, 1605, 1717, 2851, 2954; HRMS (EI ), calcd for C H NO (M ) 255.1107 found 255.1103.
12 17 5

Molecules 2013, 18
. Conclusions
Herein we have shown the direct and exclusive α-addition of various primary and secondary alkyl
2620
4
amines to a conjugated enyne. The observed addition pattern is same as that observed with
phosphine nucleophiles, however, the reaction with primary alkyl amines gives the corresponding
(
(
2E,4E)-stereoisomer exclusively, and that with secondary alkyl amines gives a mixture of (2E,4E) and
2Z,4E)-stereoisomers. This direct nucleophilic addition to an activated enyne substrate is highly regio-
and chemoselective. The resulting α,β-dehydroamino acid derivatives may find significant applications
in protein and peptide chemistry.
Acknowledgments
We thank the National Science Council (NSC1012113M009008) for financial support and ASC
thanks NSC for post-doctoral fellowship.
Supplementary Materials
1
13
Supplementary materials include the copies of the H-NMR and C-NMR spectra for all new
compounds, which can be accessed at: http://www.mdpi.com/1420-3049/18/3/2611/s1.
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2013 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
http://creativecommons.org/licenses/by/3.0/).
(