A facile method for the stereoselective preparation of (1E,3E)-4-substituted-1-amino-1,3-dienes via 1,4-elimination

Article abstract of DOI:10.1016/j.tetlet.2007.06.140

The 1,4-elimination reaction of 1-amino-4-methoxy-(2Z)-alkenes is shown to proceed with high (1E,3E)-stereoselectivities to afford the corresponding 4-substituted-1-amino-1,3-dienes in good yield. The scope and stereochemical features of the synthetic met

Full text of DOI:10.1016/j.tetlet.2007.06.140

Tetrahedron Letters 48 (2007) 6163–6166
A facile method for the stereoselective preparation of
(1E,3E)-4-substituted-1-amino-1,3-dienes via 1,4-elimination
Eiji Tayama* and Sayaka Sugai
Graduate School of Science and Technology, Niigata University, Niigata 950-2181, Japan
Received 7 May 2007; revised 25 June 2007; accepted 26 June 2007
Available online 4 July 2007
Abstract—The 1,4-elimination reaction of 1-amino-4-methoxy-(2Z)-alkenes is shown to proceed with high (1E,3E)-stereoselectivities
to afford the corresponding 4-substituted-1-amino-1,3-dienes in good yield. The scope and stereochemical features of the synthetic
method are described.
Ó 2007 Elsevier Ltd. All rights reserved.
1-Amino-1,3-dienes (1,3-dienamines or 1,3-dienamides)
are very useful building blocks, which work as active
diene components in the Diels–Alder reaction to afford
nitrogen-containing fused-ring compounds.1 The reac-
tive 1,3-dienamines are usually prepared by condensa-
tion of a,b- or b,c-unsaturated aldehydes or ketones
with secondary amines.2 The analogue, 1,3-dienamides,
which are less reactive and easily handled, are prepared
by N-acylation and isomerization of the N-acyliminium
ions.3 Overman has reported another preparative
method of 1,3-dienamides from 2,4-dienoic acids via
Scheme 1. Application of 1,4-elimination for 1-amino derivatives.
the Curtius rearrangement.4 However, the stereoselec-
tive preparative methods of 4-substituted-1-amino-1,
(oct-1,3-dien-1-yl)aniline (2a) was obtained in 96% yield
3-dienes has been limited. Recently, we reported an effi-
with high stereoselectivity [(1E,3E):(1Z,3E) = 96:4].7,8
cient and stereoselective synthetic method of 1,3-dienyl
1
The stereochemistry of 2a was assigned by H NMR
ethers (1-alkoxy-1,3-dienes) via the 1,4-elimination reac-
[J1H–2H = 13.4 Hz and J3H–4H = 15.0 Hz for (1E,3E),
tion (Scheme 1, Eq. 1).5 With that method, we extended
and J1H–2H = 8.4 Hz and J3H–4H = 15.3 Hz for
the 1,4-elimination reaction to 1-amino analogues,
(1Z,3E)]. Equally high (1E,3E)-stereoselectivity was
which would afford the corresponding 1-amino-1,3-
observed in the reaction in THF (entry 2). To define
dienes (Eq. 2). We now wish to report that treatment
the scope and limitation of the present 1,3-dienamine
of 1-amino-4-methoxy-(2Z)-alkenes (1) with organic
forming reaction, we prepared a series of substrates
bases affords the 1,3-dienamines or dienamides in high
1b–i and carried out their reactions with n-butyllithium.
(1E,3E)-stereoselectivities.
The corresponding 1,3-dienemines 2b–d were obtained
with good yield and excellent (1E,3E)-stereoselectivities
(entries 3–5). However, the reaction of more electron-
rich substrates such as N-(4-methylphenyl)-(1e) or
N-(4-methoxyphenyl)-derivatives (1f) gave 2e [(1E,3E):
First, we carried out the reaction of (2Z)-N-(4-meth-
oxyoct-2-en-1-yl)-N-methylaniline (1a)6 with n-butyl-
lithium in diethyl ether (Table 1, entry 1). The
corresponding 1,4-elimination product, N-methyl-N-
(1Z,3E) = 89:11] or 2f [(1E,3E):(1Z,3E) = 74:26] with
lower stereoselectivities (entries 6,7). The reaction of
the 4-cyclohexyl derivative (1g) also afforded 2g
Keywords: 1,4-Elimination; 1-Amino-1,3-dienes; Dienamines; Dien-
[(1E,3E):(1Z,3E) = 87:13] with lower selectivity (entry
8). However, the reaction of 4-phenyl derivative (1h)
or N-methyl-N-(1-phenyethyl) derivative (1i) as an
amides; Diels–Alder reaction.
*
Corresponding author. Tel./fax: +81 25 262 7741; e-mail: tayama@
gs.niigata-u.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.140

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E. Tayama, S. Sugai / Tetrahedron Letters 48 (2007) 6163–6166
Table 1. 1,4-Elimination reaction of 4-methoxy-(2Z)-alkenylamine derivatives (1) with n-butyllithium
Entry
R1
R2
R3
Solvent
Temp, time
Yield (%)a
(1E,3E):(1Z,3E)b
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
4-Cl-Ph
4-CF3-Ph
4-Me-Ph
4-MeO-Ph
Ph
Me
Me
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
c-Hex
Ph
a
a
b
c
d
e
f
Et2O
THF
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
0 °C, 3 h, then rt, 1 h
0 °C, 2 h
96
88c
89
79
90
86
68
93
0
96:4
97:3
95:5
95:5
98:2
89:11
74:26
87:13
—
CH2CH@CMe2
0 °C, 2 h, then rt, 1 h
0 °C, 1 h, then rt, 2 h
0 °C, 1 h, then rt, 2 h
0 °C, 1 h, then rt, 2 h
0 °C, 2 h, then rt, 1 h
0 °C, 1 h, then rt, 2 h
0 °C, 1 h, then rt, 2 h
0 °C, 1 h, then rt, 3 h
Me
Me
Me
Me
Me
Me
Me
g
h
i
Ph
10
CH(Me)Ph
n-Bu
0
—
a Isolated yield after purification by chromatography on pH-controlled silica gel (pH = 9.5). For more details, see Supplementary data.
b The ratios were determined by 1H NMR assay.
c Include 7% of (1E,3Z)-isomer.
aliphatic amine substrate9 gave a complex mixture of
unidentified products (entries 9 and 10).
Though its exact origin is unclear, the high (1E,3E)-ste-
reoselectivity of 1,4-elimination reaction of 1 may be
rationalized as a result of the precoordination of n-butyl-
lithium to the 4-ether oxygen to form complex A, which
leads to the (1E,3E)-isomer (Fig. 1). This precoordina-
tion would accelerate the (1E,3E)-stereoselective 1,4-
elimination reaction because the butyllithium is located
at the position close to the 1-proton (H1). Complex B
which leads to the (1E,3Z)-isomer would be sterically
less favorable than complex A. The formation of chelate
complex C10 would be suppressed by the steric repulsion
between the 4-methoxy and 1-bulky amino substituent.
However, the reaction of a more electron-rich substrate
such as 1f is accompanied by the 1,4-elimination via
complex C leading to lowered (1E,3E)-selectivity (Table
1, entry 7).
Scheme 2. The 1,4-elimination reaction of the 2E-isomer of 1a.
Next, we applied our 1,4-elimination reaction to the N-
tert-butoxycarbonyl (Boc) derivative 3a,11 which would
afford N-Boc-1,3-dienamide 4a (Table 2). The reaction
of 3a under the standard reaction condition (entry 1,
n-butyllithium in diethyl ether) gave 4a in lower yield
with no stereoselectivity [(1E,3E):(1E,3Z) = 59:41]. Use
of THF as a solvent (entry 2) or lithium diisopropyl-
amide (LDA) as a base (entry 3) did not show any
improvement of stereoselectivities. Interestingly how-
ever, use of lithium bis(trimethylsilyl)amide (LiHMDS)
as a base dramatically improved the stereoselectivity;
the ratio of (1E,3E):(1Z,3E) was 95:5 though the reac-
tion proceeded slowly (entry 4), while use of sodium
bis(trimethylsilyl)amide (NaHMDS) in THF gave a
complex mixture (entry 5). When the reaction was
carried out in diethyl ether–THF (4:1), the 1,4-elimina-
tion reaction proceeded smoothly to afford 4a in 71%
yield with high (1E,3E)-stereoselectivity (entry 6).12
In fact, the reaction with the 2E-isomer of 1a gave a
complex mixture of unidentified products and 2a was
hardly observed (Scheme 2); the interaction of butyl-
lithium to the ether oxygen would not be expected at
the transition state of the reaction because of the E-
geometry of the double bond. This observation suggests
that the butyllithium should be located at the position
close to the 1-proton for the 1,4-elimination reaction.
To further expand the scope of the present stereoselec-
tive preparation of N-Boc-1,3-dienamides 4, we pre-
pared a series of N-Boc derivatives 3b–f and carried
out their reactions with NaHMDS in diethyl ether–
THF (4:1). As shown in Table 3, various types of N-
Boc-1,3-dienamides 4b–f were obtained with good yield
and high (1E,3E)-stereoselectivities.
At present, no reasonable explanation can be offered for
the pronounced effect of the bases on the stereoselectiv-
ity, while the high (1E,3E)-selectivity observed may be
explained as a result of the 1,4-elimination through com-
Figure 1. Proposed mechanism of the stereoselective 1,4-elimination
reaction of 1a.

E. Tayama, S. Sugai / Tetrahedron Letters 48 (2007) 6163–6166
6165
Table 2. Preparation of N-Boc-1,3-dienamide 4a by the stereoselective 1,4-elimination reaction
Entry
Base
Solvent
Temp, time
Yielda (%)
drb
1
2
3
4
5
6
n-BuLi
n-BuLi
LDA
LiHMDS
NaHMDS
NaHMDS
Et2O
THF
THF
THF
THF
Et2O–THF (4:1)
0 °C, 2 h
0 °C, 2 h
0 °C, 2 h
rt, 5 h, then reflux, 1 h
0 °C, 2 h, then rt, 4 h
rt, 3 h
57
58
90
70
0
59:41c
54:46c
64:36c
95:5d
—
71
94:6d
a Isolated yield.
b The ratios were determined by 1H NMR assay.
c (1E,3E):(1E,3Z).
d (1E,3E):(1Z,3E).
Table 3. Preparation of various types of N-Boc-1,3-dienamides by the
stereoselective 1,4-elimination reaction
Entry
Temp, time
Yielda (%) (1E,3E):(1Z,3E)b
Scheme 3. The 1,4-elimination reaction of the 2E-isomer of 3e.
1
2
3
4
5c
b
c
d
e
f
0 °C, 3 h, then rt, 1 h
0 °C, 4 h, then rt, 7 h
0 °C, 3 h, then rt, 1 h
rt, 3 h, then reflux, 3 h 72
À20 °C, 15 h 77
98
83
99
>98:2
>98:2
96:4
94:6
>98:2
Finally, the Diels–Alder reaction of the 4-substituted-1-
amino-1,3-dienes obtained was performed (Scheme 4).
The reactions of dienamine 2a or dienamide 4f with N-
phenylmaleimide in benzene proceeded smoothly to give
5 or 6 with good yield.
a Isolated yield.
b The ratios were determined by 1H NMR assay.
c 2.0 equiv of NaHMDS was used.
plex D as depicted in Figure 2. It is interesting to note
that a similar reaction of the (2E)-isomer of 3e afforded
a mixture (87:13) of the (1Z,3E)- and (1Z,3Z)-4e in a
70% combined yield (Scheme 3).13 Again, the mechanis-
tic origin of the (1Z)-selectivity observed here is unclear.
Further mechanistic studies are awaited.
Figure 2. Proposed mechanism of the stereoselective 1,4-elimination
reaction of 3.
Scheme 4. The Diels–Alder reaction of 4-substituted-1-amino-1,3-
dienes.

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E. Tayama, S. Sugai / Tetrahedron Letters 48 (2007) 6163–6166
5. (a) Tayama, E.; Sugai, S.; Hara, M. Tetrahedron Lett.
2006, 47, 7533–7535; (b) Tayama, E.; Sugai, S. Synlett
2006, 849–852.
6. Prepared from N-methylaniline in four steps (71% overall
yield) [(i) propargyl bromide, K2CO3, acetonitrile, rt, then
reflux; (ii) LDA, nBuCHO, THF, À78 °C, then rt; (iii)
nBu4NI, (MeO)2SO2, benzene, 50% aq. NaOH, rt; (iv) H2
(1 atm), Lindlar cat., quinoline, benzene, rt]. For more
details, see Supplementary data.
In summary, we have demonstrated that the 1,4-elimina-
tion reaction of 1-amino-4-methoxy-(2Z)-alkenes with
n-butyllithium or NaHMDS affords the corresponding
4-substituted-1-amino-1,3-dienes with good yield and
excellent (1E,3E)-stereoselectivities. Our method is
widely applicable for the preparation of different types
of the 1,3-dienamines and 1,3-dienamides.
7. Reaction procedure: A solution of 1a (698 mg, 2.82 mmol)
in ether (12 mL) was treated with a 1.6 M hexane solution
of n-BuLi (2.6 mL, 4.2 mmol) at 0 °C and the mixture was
stirred for 3 h at 0 °C and for 1 h at room temperature.
The resulting mixture was quenched with water and
extracted with ether. The combined extracts were washed
with brine, dried over sodium sulfate, and concentrated.
The residue was purified by chromatography on pH-
controlled silica gel (hexane as eluent) to afford 2a
(582 mg, 96% yield) as a pale yellow oil.
Acknowledgment
This work was supported by a Grant-in-Aid for Scien-
tific Research on Priority Areas ‘Advanced Molecular
Transformations of Carbon Resources’ from the Minis-
try of Education, Culture, Sports, Science and Techno-
logy, Japan.
8. Condensation of N-methylaniline and trans-oct-2-en-1-nal
(benzene, reflux, 3 h) gave 1a in 57% yield as a mixture of
stereoisomers [(1E,3E):(1E,3Z) = 6:4].
Supplementary data
9. The presence of aliphatic amines might suppress the
favorable 1,4-elimination reaction. For example, the
reaction of 1a using LDA (THF, 0 °C, 2 h, then rt, 2 h),
which affords diisopropylamine after reaction, gave 2a
in lower yield and stereoselectivity [70% yield,
(1E,3E):(1Z,3E) = 84:16].
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2007.
06.140.
10. This type of intermediate has been claimed to give the
(1Z,3E)-1,3-dienyl ethers. For more details, see Ref. 5.
11. Prepared from N-Boc-aniline by the similar procedures to
those described for 1a. For more details, see Supplemen-
tary data.
References and notes
1. Oppolzer, W. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5,
Chapter 4.1.3.2, pp 331–333.
2. For review: Hickmott, P. W. Tetrahedron 1984, 40, 2989–
3051.
3. (a) Oppolzer, W.; Bieber, L.; Francotte, E. Tetrahedron
Lett. 1979, 20, 981–984; (b) Oppolzer, W.; Flaskamp, E.
Helv. Chim. Acta 1977, 60, 204–207; (c) Oppolzer, W.;
Fro¨stl, W.; Weber, H. P. Helv. Chim. Acta 1975, 58, 593–
595.
4. (a) Jessup, P. J.; Petty, C. B.; Roos, J.; Overman, L. E.
Org. Synth. 1979, 59, 1–7; (b) Overman, L. E.; Taylor, G.
F.; Petty, C. B.; Jessup, P. J. J. Org. Chem. 1978, 43, 2164–
2167.
12. Reaction procedure: A solution of 3a (147 mg, 0.416 mmol)
in ether (2.5 mL) was treated with a 0.99 M THF solution
of NaHMDS (0.63 mL, 0.62 mmol) at 0 °C. The mixture
was stirred for 3 h at room temperature and quenched
with water at 0 °C. Extractive workup and purification of
the residue by chromatography on silica gel (hexane:ethyl
acetate = 20:1 to 10:1 as eluent) gave 4a (94.8 mg, 71%
yield) as a colorless gum.
13. Assigned by 1H NMR assay. (1Z,3E)-4e: J1H–2H = 8.4 Hz,
J3H–4H = not identifiable by multiplet peaks, (1Z,3Z)-4e:
J1H–2H = 9.5 Hz, J3H–4H = 11.2 Hz. For more details, see
Supplementary data.