Irreversible oxy-2-azonia-cope rearrangements for the synthesis of functionalized allyl α-amino acid derivatives

Article abstract of DOI:10.1002/ejoc.201301818

A general method to synthesize functionalized allyl α-amino acid derivatives through an irreversible oxy-2-azonia-Cope rearrangement is reported. In the presence of AlCl₃, the reaction of imino ethyl glyoxalates with various β,γ-unsaturated ketones furnished the corresponding allyl α-amino acid derivatives. The key to the success of this method is the amide bond formation, which makes the rearrangement irreversible. This reaction system constitutes a new strategy for the synthesis of unusual allyl glycine derivatives, which are valuable synthetic intermediates. An efficient and operationally simple three-component version of this reaction was also performed.

Full text of DOI:10.1002/ejoc.201301818

FULL PAPER
DOI: 10.1002/ejoc.201301818
Irreversible Oxy-2-azonia-Cope Rearrangements for the Synthesis of
Functionalized Allyl α-Amino Acid Derivatives
Wenbo Mu,[a] Lijun Zhou,[a,b] Yue Zou,[b] Quanrui Wang,*[a] and Andreas Goeke*[b]
Dedicated to Professor Andrew B. Holmes
Keywords: Amino acids / Allylic compounds / Sigmatropic rearrangement / Lewis acids / Multicomponent reactions
A general method to synthesize functionalized allyl α-amino
acid derivatives through an irreversible oxy-2-azonia-Cope
rearrangement is reported. In the presence of AlCl3, the reac-
tion of imino ethyl glyoxalates with various β,γ-unsaturated
ketones furnished the corresponding allyl α-amino acid de-
rivatives. The key to the success of this method is the amide
bond formation, which makes the rearrangement irrevers-
ible. This reaction system constitutes a new strategy for the
synthesis of unusual allyl glycine derivatives, which are valu-
able synthetic intermediates. An efficient and operationally
simple three-component version of this reaction was also per-
formed.
all allylglycine systems are compatible with glycine allyl-
ation conditions. The 2-aza-Cope rearrangement consti-
tutes a highly efficient means to construct C–C bonds under
mild conditions.[9] In particular, remarkable advances have
been achieved in the development of Overman’s tandem
aza-Cope–Mannich reaction that, in turn, have provided
impressive methods for the rapid assembly of new pyrrol-
idine-containing structures.[10] However, reports of the use
of aza-Cope rearrangements to prepare amino acid deriva-
tives can only be found sporadically.[11–13] A major hurdle
to realize such a route is the problem of the inherent revers-
ibility of 2-aza-Cope rearrangements. The synthesis of acy-
clic amino acids by employing cationic aza-Cope methodol-
ogies requires a subsequent driving force to push the equi-
librium toward the desired product (see Scheme 1). A clas-
sic strategy, in this regard, is the interception of the interme-
diate iminium ion by a subsequent nucleophile-induced
ene–iminium cyclization to furnish pipecolic acid deriva-
tives A as reported by Esch et al.[11] Agami et al.[12a] and
Bennett et al.[12b] have used a 2-aza-Cope–iminium ion sol-
volysis protocol to prepare allylglycine derivatives B. Re-
cently, Waters developed a tandem 2-aza-Cope/[3+2] di-
polar cycloaddition strategy for the synthesis of quaternary
α-allylproline scaffolds C.[13] Given the interest in allyl
amino acids and the paucity of general approaches to pre-
pare them, the development of new pathways is worth ex-
amining.
Introduction
Amino acids serve as building blocks for polypeptides
and proteins, which are essential parts of all living systems
and are, therefore, fundamental resources of human life.
Unsaturated amino acids have been discovered to occur in
nature.[1] Mechanistically, they can act as conformationally
irreversible enzyme “suicide” inhibitors,[2] and, thus, show
a variety of important biological activities such as antimi-
crobial properties.[2,3] Recent progress in the field of new
chemical transformations of alkenes such as olefin metathe-
sis has provided a much broader scope for the application
of these amino acids.[4,5] The versatile reactivity of the
double bond allows for various convenient and chemoselec-
tive modifications to peptides and proteins and can be fur-
ther applied to investigate their biological activities. Specifi-
cally, allylglycine,[6] which is a non-DNA encoded α-amino
acid, and its derivatives with γ,δ-unsaturation are interest-
ing building blocks for the preparation of other amino ac-
ids, polypeptides, proteins, and natural products.[7]
To date, the allylation of glycine equivalents is a classic
method for the preparation of allylglycine derivatives and,
therefore, has become a very important carbon–carbon
bond-forming reaction in organic synthesis.[8] However, not
[a] Department of Chemistry, Fudan University,
220 Handane Road, Shanghai 200433, P. R. China
E-mail: qrwang@fudan.edu.cn
http://www.fudan.edu.cn
On the basis of our prior advancements with regard to
oxy-2-oxonia(azonia)-Cope rearrangements,[14] we, herein,
extend this concept to surmount the inherent problem of
reversibility in the allylglycine synthesis and employ an oxy-
2-azonia-Cope rearrangement strategy for the facile synthe-
[b] Givaudan Fragrances (Shanghai) Ltd,
298 Li Shi Zhen Road, Shanghai 201203, P. R. China
E-mail: andreas.goeke@givaudan.com
http://www.givaudan.com
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301818.
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W. Mu, L. Zhou, Y. Zou, Q. Wang, A. Goeke
FULL PAPER
Scheme 1. Application of the 2-azonia-Cope rearrangement in the synthesis of α-amino acid derivatives.
sis of allyl α-amino acid amides D. As shown in Scheme 1, Table 1. Optimization of reaction conditions.[a]
the generation of iminium ion 1 is critical for the rearrange-
ment and for driving further transformation processes. Our
design of the oxy-2-azonia-Cope concept is based on the
speculation that intermediate 5 might form through the nu-
cleophilic addition of the imine of glyoxalate 4 to the carb-
onyl group of β,γ-unsaturated carbonyl compound 3, which
is activated by an oxophilic Lewis acid (see Scheme 2). The
subsequent [3,3] sigmatropic rearrangement of intermediate
Entry Lewis acid
Amount of LA
[mol-%]
Time
[h]
Yield
[%][b]
5 leads to N-acyl-protected α-allylglycine derivative 6, a
process that becomes irreversible through quenching the
zwitterionic charges.
1
2
3
4
5
6
7
8
9
10
BF3–Et2O
TiCl4
La(OTf)3
Sc(OTf)3
Cu(OTf)2
SnCl4
AlCl3
AlCl3
EtAlCl2
FeCl3
100
100
100
100
100
100
100
10
3
3
16
16
3
3
1
72
3
3
n.r.
n.r.
n.r.
n.r.
10
41
87
9
9
100
100
mixtures[c]
Scheme 2. Tandem nucleophilic addition/oxy-2-azonia-Cope re-
arrangement for the formation of allylglycine amides.
[a] Reagents and conditions: β,γ-unsaturated ketone 3a (0.49 g,
5.0 mmol), oxime ether 4a (0.98 g, 7.5 mmol), and Lewis acid (LA)
in 1,2-dichloroethane (10 mL) underwent the reaction at room tem-
perature during the indicated time. [b] Isolated yields after flash
chromatography (n.r.: no reaction). [c] Complex mixtures of un-
identified products.
Results and Discussion
Our investigation commenced with an exploration of the
reaction between β,γ-unsaturated ketone 3a and glyoxalate
oxime ether 4a. The reaction was performed in 1,2-di- 41%; see Table 1, Entries 5 and 6). Gratifyingly, an excellent
chloroethane (0.5 m) in the presence of a range of typical yield of amide 6a was obtained in the presence of 1.0 equiv.
Lewis acids such as BF3–Et2O, TiCl4, La(OTf)3, and of AlCl3 at room temperature for 1 h (see Table 1, Entry 7),
Sc(OTf)3 (see Table 1, Entries 1–4), but little or no trace whereas the reaction with a catalytic amount of AlCl3
amount of the expected homoallylic amide 6a was obtained. (10 mol-%) gave a poor yield, even after a much longer re-
Further screening revealed that Cu(OTf)2 and SnCl4 could action time (see Table 1, Entry 8). Reactions with other
promote the desired process, albeit in low yields (10 and Lewis acids such as EtAlCl2 and FeCl3 proved unsuccessful
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Irreversible Oxy-2-azonia-Cope Rearrangements
(see Table 1, Entries 9 and 10). Thus, the use of 1.0 equiv. Table 2. Scope of the tandem nucleophilic addition/oxy-2-azonia-
Cope rearrangement for the formation of allylglycine amides.[a]
of AlCl3 at room temperature worked most efficiently and
was, therefore, applied as the standard conditions for the
following investigation.
Encouraged by the efficiency of this transformation, the
scope of the oxy-2-aza-Cope rearrangement to synthesize
allyl amino acids was next extended to other β,γ-unsatu-
rated ketones and imino ethyl glyoxalate substrates (see
Table 2). We first employed β,γ-unsaturated ketone 3a to
define the scope of this rearrangement with regard to the
diversity of tolerated imino ethyl glyoxalate substrates (see
Table 2, Entries 1–10). The reactions of 3a with the oxime
ether of ethyl glyoxalate 4b (see Table 2, Entry 1) as well as
with the other simple ethyl 2-(alkylimino)acetates 4c–4f (see
Table 2, Entries 2–5) rapidly proceeded in excellent yields.
The reactions with cyclopropyl and benzyl imines (see
Table 2, Entries 6 and 7) also successfully led to the desired
N-cyclopropyl and N-benzyl allylglycines, although their
yields were lower than those with the ethyl 2-(alkylimino)-
acetates.
To underline the practicality and generality of the reac-
tion, we further extended the scope of the imino ethyl gly-
oxalate substrates to those that have other functionalities
such as ether and ester groups (see Table 2, Entries 8 and
9). To our delight, both cases gave highly functionalized
allyl α-amino acid derivatives that can be further manipu-
lated. Notably, imino (–)-menthyl glyoxalate 4k resulted in
product 6k in good yield, although the diastereoselectivity
with regard to the configuration of the newly formed amino
moiety was poor (see Table 2, Entry 10; diastereomeric ratio
(dr), 1:1). The rearrangement reactions of other β,γ-unsatu-
rated ketones such as 3b–3e were also investigated. Both
substrates 3b and 3c were successfully converted into
amides 6l and 6m, respectively (see Table 2, Entries 11 and
12). The reaction of 3b, which has a phenoxy group, af-
forded a better yield than that of 3c. The reaction was fur-
ther extended to α-mono- and α-disubstituted β,γ-unsatu-
rated ketones 3d and 3e. Notably, the double bond of prod-
uct 6n exclusively has the (E) configuration (see Table 2,
Entry 13). Although β,γ-unsaturated ketone 3e is more
sterically hindered than the other substrates, its reaction
with glyoxalate oxime ether 4a occurred remarkably well to
afford the desired product 6o in a good yield after 72 h (see
Table 2, Entry 14). These reactions are highly productive
and proceed on a multigram scale to give the desired allyl
amino acids derivatives, which can be efficiently trans-
formed into more valuable allyl amino alcohols.
The yields of the oxy-2-azonia-Cope products were
slightly lower in cases where the imino ethyl glyoxalate sub-
strates were generated in situ through the condensation of
ethyl glyoxalate with the appropriate amine species followed
by the addition of the β,γ-unsaturated ketone and AlCl3.
Also, the reaction could be performed more efficiently as a
[a] Reagents and conditions: β,γ-unsaturated ketones 3a–3e
(5.0 mmol), imino ethyl glyoxalates 4a–4k (7.5 mmol), and AlCl3
(5.0 mmol) in 1,2-dichloroethane (10 mL) were combined at r.t. for
one-pot domino process by adding anhydrous MgSO4 as a the time indicated. [b] Isolated yields after flash chromatography.
water scavenger for the imine formation (see Scheme 3).
This transformation constitutes a preparatively useful three-
component condensation/oxy-2-azonia-Cope rearrange-
ment reaction sequence to give allylglycines.
Finally, to demonstrate the synthetic utility of our meth-
odology, allylglycine amides 6a and 6d were conveniently
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W. Mu, L. Zhou, Y. Zou, Q. Wang, A. Goeke
FULL PAPER
and is reported in parentheses. The abbreviations used are s (sing-
let), d (doublet), t (triplet), q (quartet), m (multiplet), dd (double
doublet), and br. s (broad singlet). IR spectra were recorded with
a Bruker Tensor 27 and a Jasco FT/IR-4100. High resolution MS
were obtained with a Bruker micrOTOF II spectrometer (ESI-MS).
All new compounds were characterized by using 1H and 13C NMR,
IR, and HRMS analyses.
General Procedure for the Oxy-2-aza-Cope Rearrangement Synthe-
sis to Give Functionalized Allyl α-Amino Acid Derivatives: A three-
necked flask that was flushed with argon was charged with alumi-
num chloride (0.67 g, 5.0 mmol) and 1,2-dichloroethane (5.0 mL),
and the mixture was stirred for 10 min. A solution of β,γ-unsatu-
rated carbonyl compound 3[15] (5.0 mmol), imine ester 4[16]
(7.5 mmol), and 1,2-dichloroethane (5.0 mL) was then added drop-
wise at room temperature under argon. After completion of the
addition, the mixture was stirred at room temperature for the corre-
sponding time (see Table 2). The reaction was monitored by GC
analysis of reaction aliquots that were quenched with a solution of
saturated aqueous NaHCO3. The reaction mixture was quenched
with saturated aqueous NaHCO3 solution (20 mL). The organic
phase was separated, and the aqueous layer was extracted with
methyl tert-butyl ether (MTBE, 3ϫ 20 mL). The combined organic
layers were washed with brine (20 mL) and dried with MgSO4, and
the solvents were evaporated in vacuo. The residue was purified by
column chromatography on silica gel (EtOAc/hexane, 1:10) to yield
compound 6.
Scheme 3. A three-component condensation/oxy-2-aza-Cope re-
arrangement to give allylglycine 6d.
reduced by treatment with LiAlH4 in tetrahydrofuran
(THF), which led to free amino alcohols 7a and 7d in high
yields (see Scheme 4).
Scheme 4. Reduction of allylglycine amides to give amino alcohols.
Ethyl (E)-2-(N-Methoxyacetamido)-4-methylpent-4-enoate (6a):
Using the general procedure, β,γ-unsaturated ketone 3a (0.49 g,
5.0 mmol), imine ester 4a (0.98 g, 7.5 mmol), and aluminum chlor-
ide (0.67 g, 5.0 mmol) in 1,2-dichloroethane (10 mL) were com-
Conclusions
bined at r.t. for 1 h to give 6a (1.00 g, 87% yield) as a colorless
1
In summary, we have developed a general method to syn- liquid. H NMR (300 MHz, CDCl3): δ = 5.16 (t, J = 7.4 Hz, 1 H),
4.85 (s, 1 H), 4.80 (s, 1 H), 4.20 (q, J = 7.1 Hz, 2 H), 3.78 (s, 3 H),
2.69 (d, J = 7.4 Hz, 2 H), 2.19 (s, 3 H), 1.77 (s, 3 H), 1.28 (t, J =
7.1 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 174.6 (s), 170.1
(s), 141.1 (s), 113.2 (t), 63.9 (q), 61.4 (t), 58.5 (d), 35.7 (t), 22.2 (q),
thesize functionalized allyl α-amino acid derivatives by
using an irreversible oxy-2-azonia-Cope rearrangement
strategy. In the presence of AlCl3, the reaction of imino
ethyl glyoxalates with various β,γ-unsaturated ketones af-
fords allyl α-amino acid derivatives. These results provide a
reliable protocol for the synthesis of allylglycine derivatives,
which are valuable synthetic intermediates that can be easily
converted into useful synthetic building blocks such as
amino alcohols. In addition, the reaction can also be per-
formed as an efficient and operationally simple three-com-
ponent process.
20.3 (q), 14.1 (q) ppm. IR (neat): ν = 2981, 2940, 1739, 1679, 1444,
˜
1372, 1293, 1262, 1223, 1184, 1026 cm–1. HRMS (ESI): calcd. for
C11H19NO4Na+ [M + Na]+ 252.1212; found 252.1224.
Ethyl
(E)-2-(N-Ethoxyacetamido)-4-methylpent-4-enoate
(6b):
Using the general procedure, β,γ-unsaturated ketone 3a (0.49 g,
5.0 mmol), imine ester 4b (1.09 g, 7.5 mmol), and aluminum chlor-
ide (0.67 g, 5.0 mmol) in 1,2-dichloroethane (10 mL) were com-
bined at r.t. for 1 h to give 6b (1.00 g, 82% yield) as a colorless
1
liquid. H NMR (300 MHz, CDCl3): δ = 5.13 (t, J = 7.4 Hz, 1 H),
4.84 (s, 1 H), 4.79 (s, 1 H), 4.19 (q, J = 6.9 Hz, 2 H), 4.03–3.92 (m,
2 H), 2.67 (d, J = 7.4 Hz, 2 H), 2.17 (s, 3 H), 1.77 (s, 3 H), 1.27 (t,
J = 8.2 Hz, 3 H), 1.24 (t, J = 8.2 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 174.3 (s), 170.2 (s), 141.1 (s), 113.2 (t), 71.9
(t), 61.41 (t), 58.6 (d), 35.8 (t), 22.2 (q), 20.4 (q), 14.1 (q), 13.4
Experimental Section
General Methods: All reactions were performed under argon and
employed solvents and reagents without further purification from
commercial suppliers. Solvents for extraction and chromatography
were technical grade and used without further purification. Flash
chromatography was performed with Tsingdao Haiyang Chemical
silica gel (200Ϯ300 mesh) and silica gel Merck grade (60 Å). Un-
less otherwise noted, a mixture of hexane/EtOAc (10:1) was used
as the eluent. The NMR spectroscopic data were recorded with an
AW 300 MHz Bruker spectrometer. The chemical shifts for 1H
NMR spectroscopic data are reported in δ (ppm) and referenced to
the residual proton signal of the deuterated solvent. The coupling
constants are expressed in Hertz. The 13C NMR spectroscopic data
were referenced to the carbon signals of the deuterated solvent, and
the classification of the carbon atoms (i.e., C, CH, CH2, or CH3)
was determined by recording DEPT-90 and DEPT-135 experiments
(q) ppm. IR (neat): ν = 2982, 1742, 1721, 1680, 1599, 1445, 1372,
˜
1266, 1195, 1050 cm–1. HRMS (ESI): calcd. for C12H21NO4Na+ [M
+ Na]+ 266.1368; found 266.1380.
Ethyl (E)-4-Methyl-2-(N-propylacetamido)pent-4-enoate (6c): Using
the general procedure, β,γ-unsaturated ketone 3a (0.49 g,
5.0 mmol), imine ester 4c (1.07 g, 7.5 mmol), and aluminum chlor-
ide (0.67 g, 5.0 mmol) in 1,2-dichloroethane (10 mL) were com-
bined at r.t. for 1 h to give 6c (0.99 g, 82% yield) as a colorless
liquid. 1H NMR (300 MHz, CDCl3. mixture of rotamers): δ = 4.81
(s, 1 H), 4.74 (s, 1 H), 4.60 (dd, J = 9.9, 5.1 Hz, 1 H), 4.49–3.80
(m, 2 H), 3.40–2.98 (m, 2 H), 2.74–2.39 (m, 2 H), 2.11 (s, 3 H),
1.77 (s, 3 H), 1.62 (q, J = 7.0 Hz, 2 H), 1.25 (t, J = 7.1 Hz, 3 H),
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Irreversible Oxy-2-azonia-Cope Rearrangements
0.93 (t, J = 7.4 Hz, 3 H) ppm. Data for major rotamer: 13C NMR (75 MHz, CDCl3): δ = 173.4 (s), 171.7 (s), 142.3 (s), 113.1 (t), 61.1
(75 MHz, CDCl3): δ = 171.2 (s), 170.7 (s), 141.6 (s), 113.2 (t), 61.0 (t), 58.4 (d), 36.8 (t), 30.8 (d), 22.6 (q), 22.0 (q), 14.0 (q), 9.5 (q),
(t), 56.9 (d), 50.3 (t), 36.9 (t), 22.7 (t), 22.4 (q), 21.5 (q), 14.1 (q),
9.3 (q) ppm. IR (neat): ν = 2981, 1736, 1656, 1387, 1314, 1291,
˜
11.4 (q) ppm. IR (neat): ν = 2970, 1736, 1721, 1645, 1416, 1367,
1259, 1219, 1030 cm–1. HRMS (ESI): calcd. for C13H21NO3Na+ [M
+ Na]+ 262.1419; found 262.1436.
˜
1292, 1226, 1200, 1028 cm–1. HRMS (ESI): calcd. for
C13H23NO3Na+ [M + Na]+ 264.1576; found 264.1577.
Ethyl (E)-2-(N-Benzylacetamido)-4-methylpent-4-enoate (6h): Using
Ethyl (E)-2-(N-Butylacetamido)-4-methylpent-4-enoate (6d): Using the general procedure, β,γ-unsaturated ketone 3a (0.49 g,
the general procedure, β,γ-unsaturated ketone 3a (0.49 g,
5.0 mmol), imine ester 4d (1.18 g, 7.5 mmol), and aluminum chlor-
ide (0.67 g, 5.0 mmol) in 1,2-dichloroethane (10 mL) were com-
bined at r.t. for 3 h to give 6d (1.03 g, 81% yield) as a colorless
liquid. 1H NMR (300 MHz, CDCl3, mixture of rotamers): δ = 4.82
(s, 1 H), 4.74 (s, 1 H), 4.62 (dd, J = 9.9, 5.1 Hz, 1 H), 4.27–4.07
5.0 mmol), imine ester 4h (1.43 g, 7.5 mmol), and aluminum chlor-
ide (0.67 g, 5.0 mmol) in 1,2-dichloroethane (10 mL) were com-
bined at r.t. for 2 h to give 6h (0.41 g, 28% yield) as a colorless
liquid. 1H NMR (300 MHz, CDCl3, mixture of rotamers): δ =
7.48–7.09 (m, 5 H), 5.03–4.60 (m, 4 H), 4.59–4.36 (m, 1 H), 4.21–
3.88 (m, 2 H), 2.81–2.59 (m, 1 H), 2.59–2.37 (m, 1 H), 2.09 (s, 3
(m, 2 H), 3.42–3.02 (m, 2 H), 2.74–2.53 (m, 2 H), 2.11 (s, 3 H), H), 1.70 (s, 3 H), 1.22 (t, J = 7.1 Hz, 3 H) ppm. Data for major
1.77 (s, 3 H), 1.63–1.52 (m, 2 H), 1.37–1.23 (m, 2 H), 1.25 (t, J = rotamer: 13C NMR (75 MHz, CDCl3): δ = 171.7 (s), 170.9 (s), 141.6
7.1 Hz, 3 H), 0.95 (t, J = 7.3 Hz, 3 H) ppm. Data for major rot-
(s), 136.9 (s), 128.6 (d), 127.5 (d), 126.7 (d), 113.4 (t), 61.1 (t), 56.4
amer: 13C NMR (75 MHz, CDCl3): δ = 171.3 (s), 170.7 (s), 141.7 (d), 51.4 (t), 37.3 (t), 22.4 (q), 22.1 (q), 14.0 (q) ppm. IR (neat): ν
˜
(s), 113.2 (t), 61.1 (t), 56.9 (d), 48.4 (t), 36.9 (t), 31.5 (t), 22.5 (q),
= 2980, 1734, 1650, 1496, 1409, 1366, 1226, 1098, 1028 cm–1.
HRMS (ESI): calcd. for C17H23NO3Na+ [M + Na]+ 312.1576;
found 312.1574.
21.6 (q), 20.2 (t), 14.1 (q), 13.7 (q) ppm. IR (neat): ν = 2960, 2874,
˜
1736, 1645, 1417, 1367, 1292, 1224, 1199, 1028 cm–1. HRMS (ESI):
calcd. for C14H25NO3Na+ [M + Na]+ 278.1732; found 278.1743.
Ethyl (E)-2-[N-(3-Methoxypropyl)acetamido]-4-methylpent-4-enoate
Ethyl (E)-2-(N-Isobutylacetamido)-4-methylpent-4-enoate (6e): (6i): Using the general procedure, β,γ-unsaturated ketone 3a
Using the general procedure, β,γ-unsaturated ketone 3a (0.49 g,
5.0 mmol), imine ester 4e (1.18 g, 7.5 mmol), and aluminum chlor-
ide (0.67 g, 5.0 mmol) in 1,2-dichloroethane (10 mL) were com-
bined at r.t. for 1 h to give 6e (0.78 g, 61% yield) as a colorless
liquid. 1H NMR (300 MHz, CDCl3, mixture of rotamers): δ = 4.83
(s, 1 H), 4.74 (s, 1 H), 4.27–4.09 (m, 2 H), 4.02 (dd, J = 9.2, 5.2 Hz,
1 H), 3.08 (dd, J = 15.0, 8.2 Hz, 1 H), 2.95 (dd, J = 15.0, 6.4 Hz,
(0.49 g, 5.0 mmol), imine ester 4i (1.30 g, 7.5 mmol), and aluminum
chloride (0.67 g, 5.0 mmol) in 1,2-dichloroethane (10 mL) were
combined at r.t. for 3 h to give 6i (0.92 g, 68% yield) as a colorless
liquid. 1H NMR (300 MHz, CDCl3, mixture of rotamers): δ = 4.82
(s, 1 H), 4.74 (s, 1 H), 4.48 (dd, J = 9.8, 5.1 Hz, 1 H), 4.28–4.07
(m, 2 H), 3.55–3.39 (m, 3 H), 3.35 (s, 3 H), 3.29–3.16 (m, 1 H),
2.81–2.56 (m, 2 H), 2.12 (s, 3 H), 1.90–1.79 (m, 2 H), 1.78 (s, 3 H),
1 H), 2.83–2.60 (m, 2 H), 2.09 (s, 3 H), 1.96–1.87 (m, 1 H), 1.78 (s, 1.25 (t, J = 7.2 Hz, 3 H) ppm. Data for major rotamer: 13C NMR
3 H), 1.25 (t, J = 7.1 Hz, 3 H), 1.00 (d, J = 9.0 Hz, 3 H), 0.96 (d, J
= 9.0 Hz, 3 H) ppm. Data for major rotamer: 13C NMR (75 MHz,
CDCl3): δ = 170.9 (s), 170.5 (s), 142.0 (s), 113.5 (t), 61.0 (t), 58.6
(d), 57.7 (t), 36.7 (t), 28.0 (d), 22.5 (q), 21.9 (q), 20.3 (q), 20.1 (q),
(75 MHz, CDCl3): δ = 171.2 (s), 170.9 (s), 141.7 (s), 113.3 (t), 69.3
(t), 61.1 (t), 58.6 (q), 57.3 (d), 45.8 (t), 36.7 (t), 29.4 (t), 22.4 (q),
21.4 (q), 14.1 (q) ppm. IR (neat): ν = 2979, 2932, 1736, 1645, 1444,
˜
1368, 1223, 1197, 1115, 1027 cm–1. HRMS (ESI): calcd. for
C14H25NO4Na+ [M + Na]+ 294.1681; found 294.1688.
14.1 (q) ppm. IR (neat): ν = 2962, 1736, 1644, 1471, 1436, 1331,
˜
1293, 1225, 1201, 1149, 1084, 1028 cm–1. HRMS (ESI): calcd. for
C14H25NO3Na+ [M + Na]+ 278.1732; found 278.1735.
Ethyl (E)-2-[N-(3-Ethoxy-3-oxopropyl)acetamido]-4-methylpent-4-
enoate (6j): Using the general procedure, β,γ-unsaturated ketone 3a
(0.49 g, 5.0 mmol), imine ester 4j (1.51 g, 7.5 mmol), and aluminum
chloride (0.67 g, 5.0 mmol) in 1,2-dichloroethane (10 mL) were
combined at r.t. for 2 h to give 6j (0.60 g, 40% yield) as a colorless
liquid. 1H NMR (300 MHz, CDCl3, mixture of rotamers): δ = 4.83
Ethyl (E)-2-(N-Hexylacetamido)-4-methylpent-4-enoate (6f): Using
the general procedure, β,γ-unsaturated ketone 3a (0.49 g,
5.0 mmol), imine ester 4f (1.39 g, 7.5 mmol), and aluminum chlor-
ide (0.67 g, 5.0 mmol) in 1,2-dichloroethane (10 mL) were com-
bined at r.t. for 1 h to give 6f (0.99 g, 70% yield) as a colorless (s, 1 H), 4.74 (s, 1 H), 4.62 (dd, J = 9.8, 5.0 Hz, 1 H), 4.21–4.11
liquid. 1H NMR (300 MHz, CDCl3, mixture of rotamers): δ = 4.81
(s, 1 H), 4.73 (s, 1 H), 4.63 (dd, J = 9.9, 5.1 Hz, 1 H), 4.27–4.05
(m, 4 H), 3.78–3.41 (m, 2 H), 2.78–2.61 (m, 4 H), 2.15 (s, 3 H),
1.77 (s, 3 H), 1.29 (t, J = 6.8 Hz, 3 H), 1.24 (t, J = 6.8 Hz, 3
(m, 2 H), 3.43–3.00 (m, 2 H), 2.74–2.53 (m, 2 H), 2.11 (s, 3 H), H) ppm. Data for major rotamer: 13C NMR (75 MHz, CDCl3): δ
1.77 (s, 3 H), 1.68–1.47 (m, 2 H), 1.41–1.17 (m, 9 H), 0.90 (t, J = = 171.2 (s), 171.0 (s), 170.7 (s), 141.6 (s), 113.4 (t), 61.2 (t), 60.8
6.5 Hz, 3 H) ppm. Data for major rotamer: 13C NMR (75 MHz,
(t), 57.4 (d), 43.8 (t), 36.7 (t), 34.4 (t), 22.3 (q), 21.6 (q), 14.1 (q),
CDCl3): δ = 171.2 (s), 170.6 (s), 141.6 (s), 113.1 (t), 61.0 (t), 56.9 14.1 (q) ppm. IR (neat): ν = 2981, 1731, 1650, 1444, 1376, 1185,
˜
(d), 48.6 (t), 36.9 (t), 31.4 (t), 29.4 (t), 26.7 (t), 22.6 (t), 22.4 (q), 1097, 1023 cm–1. HRMS (ESI): calcd. for C15H25NO5Na+ [M +
21.5 (q), 14.1 (q), 13.9 (q) ppm. IR (neat): ν = 2931, 2858, 1737,
Na]+ 322.1630; found 322.1643.
˜
1647, 1416, 1368, 1335, 1294, 1261, 1195, 1095, 1028 cm–1. HRMS
(ESI): calcd. for C16H29NO3Na+ [M + Na]+ 306.2045; found
306.2045.
2-Isopropyl-5-methylcyclohexyl (E)-(1R,2S,5R)-2-(N-Methoxyacet-
amido)-4-methylpent-4-enoate (6k): Using the general procedure,
β,γ-unsaturated ketone 3a (0.49 g, 5.0 mmol), imine ester 4k
(1.81 g, 7.5 mmol), and aluminum chloride (0.67 g, 5.0 mmol) in
1,2-dichloroethane (10 mL) were combined at r.t. for 2 h to give 6k
(1.05 g, 62% yield, dr 1:1) as a colorless liquid. 1H NMR
(300 MHz, CDCl3, mixture of two diastereomers): δ = 5.15 (t, J =
7.6 Hz, 1 H), 4.85 (s, 1 H), 4.80 (s, 1 H), 4.77–4.61 (m, 1 H), 3.78
(s, 3 H), 2.67 (d, J = 7.6 Hz, 2 H), 2.18 (s, 3 H), 2.07–1.80 (m, 2
H), 1.77 (s, 3 H), 1.72–1.60 (m, 2 H), 1.58–1.34 (m, 2 H), 1.13–0.84
(m, 9 H), 0.74 (dd, J = 6.9, 3.1 Hz, 3 H) ppm. 13C NMR (75 MHz,
Ethyl (E)-2-(N-Cyclopropylacetamido)-4-methylpent-4-enoate (6g):
Using the general procedure, β,γ-unsaturated ketone 3a (0.49 g,
5.0 mmol), imine ester 4g (1.06 g, 7.5 mmol), and aluminum chlor-
ide (0.67 g, 5.0 mmol) in 1,2-dichloroethane (10 mL) were com-
bined at r.t. for 3 h to give 6g (0.49 g, 41% yield) as a colorless
1
liquid. H NMR (300 MHz, CDCl3): δ = 4.82 (s, 1 H), 4.75 (s, 1
H), 4.63 (dd, J = 11.0, 4.2 Hz, 1 H), 4.14 (q, J = 7.1 Hz, 2 H),
2.89–2.80 (m, 1 H), 2.78–2.61 (m, 2 H), 2.21 (s, 3 H), 1.77 (s, 3 H),
1.24 (t, J = 7.1 Hz, 3 H), 0.90–0.83 (m, 4 H) ppm. 13C NMR CDCl3, mixture of two diastereomers): δ = 174.8 (s), 169.6 (s),
Eur. J. Org. Chem. 2014, 2379–2385
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2383

W. Mu, L. Zhou, Y. Zou, Q. Wang, A. Goeke
FULL PAPER
141.2 (s), 113.3 (t), 113.1 (t), 75.8 (d), 75.7 (d), 64.1 (q), 63.9 (q),
58.8 (q), 46.9 (d), 46.9 (d), 40.6 (t), 40.6 (t), 35.8 (t), 35.8 (t), 34.1
(t), 31.4 (d), 26.0 (d), 25.8 (d), 23.2 (t), 23.1 (t), 22.3 (d), 22.2 (d),
21.9 (d), 20.8 (q), 20.8 (q), 20.3 (q), 20.3 (q), 16.1 (q), 16.0 (q) ppm.
1371, 1257, 1227, 1029 cm–1. HRMS (ESI): calcd. for
C13H23NO4Na+ [M + Na]+ 280.1525; found 280.1516.
Multigram Scale Oxy-2-aza-Cope Rearrangement Leading to Ethyl
(E)-2-(N-Methoxyacetamido)-4-methylpent-4-enoate (6a): A three-
necked flask that was flushed with argon was charged with alumin-
ium chloride (6.7 g, 50 mmol) and 1,2-dichloroethane (50 mL), and
the mixture was stirred for 10 min. A solution of β,γ-unsaturated
carbonyl compound 3a (4.9 g, 50 mmol) and imine ester 4a (9.8 g,
75 mmol) in 1,2-dichloroethane (50 mL) was added dropwise at
room temperature under argon. After completion of the addition,
the mixture was stirred at room temperature for 1 h. The reaction
mixture was quenched with saturated aqueous NaHCO3 solution
(200 mL). The organic phase was separated, and the aqueous layer
was extracted with MTBE (3ϫ150 mL). The combined organic lay-
ers were washed with brine (100 mL) and dried with MgSO4, and
the solvents were evaporated in vacuo. The residue was purified by
column chromatography on silica gel (EtOAc/hexane, 1:10) to give
6a (8.1 g, 70% yield) as a colorless liquid.
IR (neat): ν = 2955, 2870, 1736, 1682, 1454, 1370, 1180, 1037, 982,
˜
895, 732, 646 cm–1. HRMS (ESI): calcd. for C19H33NO4Na+ [M +
Na]+ 362.2307; found 362.2292.
Ethyl (E)-2-(N-Methoxy-2-phenoxyacetamido)-4-methylpent-4-eno-
ate (6l): Using the general procedure, β,γ-unsaturated ketone 3b
(0.96 g, 5.0 mmol), imine ester 4a (0.98 g, 7.5 mmol), and alumi-
num chloride (0.67 g, 5.0 mmol) in 1,2-dichloroethane (10 mL)
were combined at r.t. for 2 h to give 6l (0.79 g, 49% yield) as a
1
colorless liquid. H NMR (300 MHz, CDCl3): δ = 7.40–6.89 (m, 5
H), 5.15 (dd, J = 10.1, 5.5 Hz, 1 H), 4.89 (s, 3 H), 4.84 (s, 1 H),
4.21 (q, J = 7.1 Hz, 2 H), 3.83 (s, 3 H), 2.90–2.60 (m, 2 H), 1.78 (s,
3 H), 1.28 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 172.2 (s), 169.7 (s), 158.2 (s), 140.9 (s), 129.4 (d), 121.5 (d), 114.8
(d), 113.7 (t), 65.7 (t), 64.5 (q), 61.8 (t), 59.3 (d), 35.6 (t), 22.1 (q),
14.1 (q) ppm. IR (neat): ν = 2980, 1738, 1697, 1599, 1496, 1436,
˜
Three-Component Condensation/Oxy-2-aza-Cope Rearrangement
Leading to Ethyl (E)-2-(N-Butylacetamido)-4-methylpent-4-enoate
(6d): A three-necked flask that was flushed with argon was charged
with aluminum chloride (0.67 g, 5.0 mmol), MgSO4 (2.40 g,
20 mmol), n-butylamine (0.73 g, 10 mmol), and 1,2-dichloroethane
(5.0 mL), and the mixture was stirred for 10 min. The solution of
β,γ-unsaturated carbonyl compound 3a (5.0 mmol), ethyl gly-
oxalate (1.02 g, 10 mmol), and 1,2-dichloroethane (5.0 mL) was
then added dropwise at room temperature under argon. After com-
pletion of the addition, the mixture was stirred at room tempera-
ture for 3 h. Then, the reaction mixture was quenched with satu-
rated aqueous NaHCO3 solution (20 mL). The organic phase was
separated, and the aqueous layer was extracted with MTBE
(3ϫ20 mL). The combined organic layers were washed with brine
(20 mL) and dried with MgSO4, and the solvents were evaporated
in vacuo. The residue was purified by column chromatography on
silica gel (EtOAc/hexane, 1:10) to yield compound 6d (0.93 g, 73%
yield) as a colorless liquid.
1217, 1086, 1023, 897, 752, 690 cm–1. HRMS (ESI): calcd. for
C17H23NO5Na+ [M + Na]+ 344.1474; found 344.1469.
Ethyl (E)-2-(N-Methoxyhexanamido)-4-methylpent-4-enoate (6m):
Using the general procedure, β,γ-unsaturated ketone 3c (0.77 g,
5.0 mmol), imine ester 4a (0.98 g, 7.5 mmol), and aluminum chlor-
ide (0.67 g, 5.0 mmol) in 1,2-dichloroethane (10 mL) were com-
bined at r.t. for 2 h to give 6m (0.39 g, 27% yield) as a colorless
1
liquid. H NMR (300 MHz, CDCl3): δ = 5.14 (t, J = 7.6 Hz, 1 H),
4.84 (s, 1 H), 4.79 (s, 1 H), 4.19 (q, J = 7.4 Hz, 2 H), 3.76 (s, 3 H),
2.69 (d, J = 7.6 Hz, 2 H), 2.53–2.37 (m, 2 H), 1.77 (s, 3 H), 1.71–
1.57 (m, 2 H), 1.43–1.24 (m, 4 H), 1.27 (t, J = 7.4 Hz, 3 H), 0.90
(t, J = 7.5 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 177.0
(s), 170.2 (s), 141.1 (s), 113.2 (t), 64.0 (q), 61.4 (t), 58.6 (d), 35.8
(t), 32.1 (t), 31.5 (t), 24.0 (t), 22.4 (t), 22.2 (q), 14.1 (q), 13.9
(q) ppm. IR (neat): ν = 2935, 2872, 1741, 1445, 1378, 1261, 1183,
˜
1025 cm–1. HRMS (ESI): calcd. for C15H27NO4Na+ [M + Na]+
308.1838; found 308.1839.
2-(Methoxyamino)-4-methylpent-4-en-1-ol (7a): To a suspension of
lithium aluminum hydride (0.14 g, 3.6 mmol) in anhydrous tetra-
hydrofuran (20 mL) in an ice bath was added a solution of ester
6a (0.69 g, 3.0 mmol) in anhydrous tetrahydrofuran (5.0 mL). The
mixture was warmed to r.t. and stirred for 3 h. The reaction mix-
ture was quenched sequentially with water (0.14 mL), 15% aqueous
NaOH solution (0.14 mL), and water (0.42 mL). After the filtration
through a small pad of MgSO4, the filtrate was concentrated under
reduced pressure. The residue was purified by flash chromatog-
raphy on silica gel (CH2Cl2/MeOH, 99:1) to afford 7a (0.38 g, 86%
Ethyl (E,E)-2-(N-Methoxyacetamido)-4-methylhex-4-enoate (6n):
Using the general procedure, β,γ-unsaturated ketone 3d (0.56 g,
5.0 mmol), imine ester 4a (0.98 g, 7.5 mmol), and aluminum chlor-
ide (0.67 g, 5.0 mmol) in 1,2-dichloroethane (10 mL) were com-
bined at r.t. for 2 h to give 6n (0.45 g, 37% yield) as a colorless
liquid. 1H NMR (300 MHz, CDCl3): δ = 5.31 (q, J = 5.7 Hz, 1 H),
5.08 (t, J = 7.2 Hz, 1 H), 4.19 (q, J = 7.1 Hz, 2 H), 3.77 (s, 3 H),
2.71–2.52 (m, 2 H), 2.16 (s, 3 H), 1.63 (s, 3 H), 1.57 (d, J = 6.1 Hz,
3 H), 1.27 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 174.4 (s), 170.4 (s), 131.1 (s), 122.3 (d), 63.7 (q), 61.3 (t), 59.0
1
yield) as a colorless oil. H NMR (300 MHz, CDCl3): δ = 4.86 (s,
(d), 37.6 (t), 20.2 (q), 15.4 (q), 14.1 (q), 13.4 (q) ppm. IR (neat): ν
˜
1 H), 4.78 (s, 1 H), 3.79–3.51 (m, 2 H), 3.55 (s, 3 H), 3.19–3.06 (m,
1 H), 2.43 (br. s, 1 H), 2.28–2.02 (m, 2 H), 1.76 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 141.9 (s), 113.3 (t), 63.1 (t), 62.5 (q),
= 2982, 2938, 1739, 1679, 1443, 1371, 1267, 1184, 1031 cm–1.
HRMS (ESI): calcd. for C12H21NO4Na+ [M + Na]+ 266.1368;
found 266.1389.
59.1 (d), 36.9 (t), 22.4 (q) ppm. IR (neat): ν = 3371, 3076, 2938,
˜
2362, 1649, 1442, 1376, 1040 cm–1. HRMS (ESI): calcd. for
C7H15NO2Na+ [M + Na]+ 168.1000; found 168.0993.
Ethyl (E)-2-(N-Methoxyacetamido)-4,5-dimethylhex-4-enoate (6o):
Using the general procedure, β,γ-unsaturated ketone 3e (0.63 g,
5.0 mmol), imine ester 4a (0.98 g, 7.5 mmol), and aluminum chlor-
ide (0.67 g, 5.0 mmol) in 1,2-dichloroethane (10 mL) were com-
bined at r.t. for 72 h to give 6o (0.91 g, 71% yield) as a colorless
2-[Butyl(ethyl)amino]-4-methylpent-4-en-1-ol (7d): To a suspension
of lithium aluminum hydride (0.27 g, 7.2 mmol) in anhydrous tetra-
hydrofuran (20 mL) in an ice bath was added a solution of the ester
6d (0.77 g, 3.0 mmol) in anhydrous tetrahydrofuran (5.0 mL). The
1
liquid. H NMR (300 MHz, CDCl3): δ = 4.87 (t, J = 7.4 Hz, 1 H),
4.19 (q, J = 7.1 Hz, 2 H), 3.74 (s, 3 H), 2.96–2.53 (m, 2 H), 2.14 reaction system was warmed to r.t. and stirred for 3 h. The reaction
(s, 3 H), 1.66 (s, 6 H), 1.64 (s, 3 H), 1.27 (t, J = 7.1 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 173.8 (s), 170.6 (s), 128.4 (s),
123.0 (s), 63.3 (q), 61.3 (t), 59.8 (d), 33.0 (t), 20.8 (q), 20.5 (q), 20.2
mixture was quenched sequentially with water (0.27 mL), 15%
aqueous NaOH solution (0.27 mL), and water (0.81 mL). After the
filtration through a small pad of MgSO4, the filtrate was concen-
(q), 18.1 (q), 14.1 (q) ppm. IR (neat): ν = 2983, 2936, 1739, 1678, trated under reduced pressure. The residue was purified by flash
˜
2384
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2379–2385

Irreversible Oxy-2-azonia-Cope Rearrangements
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(0.54 g, 90% yield) as a colorless oil. 1H NMR (300 MHz, CDCl3):
δ = 4.75 (s, 1 H), 4.69 (s, 1 H), 3.51 (br. s, 1 H), 3.51–3.41 (m, 1
H), 3.19 (t, J = 10.4 Hz, 1 H), 3.03–2.89 (m, 1 H), 2.70–2.23 (m, 5
H), 1.91–1.76 (m, 1 H), 1.73 (s, 3 H), 1.56–1.19 (m, 4 H), 1.06 (t,
J = 7.1 Hz, 3 H), 0.92 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 142.7 (s), 112.6 (t), 60.6 (t), 58.6 (d), 48.7
(t), 43.1 (t), 34.0 (t), 31.7 (t), 22.3 (q), 20.5 (t), 14.6 (q), 14.0
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˜
1456, 1410, 1375, 1226, 1094, 1039 cm–1. HRMS (ESI): calcd. for
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Supporting Information (see footnote on the first page of this arti-
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Acknowledgments
The authors thank Dr. G. Brunner for the NMR experiments and
G. Tang (Fudan University) for the high resolution mass spectrom-
etry data. The financial support from the NNSFC under grant
number 21372045 is gratefully acknowledged.
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Received: December 6, 2013
Published Online: February 6, 2014
Eur. J. Org. Chem. 2014, 2379–2385
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2385