Synthesis of δ-lactone and amino acid frameworks utilizing the umpoled reactivity of β,γ-Alkenyl aα-iminoester

Article abstract of DOI:10.1246/bcsj.20160402

An umpolung N-alkylation reaction of β,γ-alkenyl aα- iminoesters was studied, and various tandem reactions were found utilizing this N-alkylation. A useful synthesis of δ- lactones and dienamines was developed by tandem N-alkylation/ vinylogous aldol-type reaction. The synthesis of aα- quaternary alkenyl amino esters was also developed via the tandem N-alkylation/bromination/C-alkylation. These methods using β,γ-alkenyl aα-iminoesters are operationally simple and useful, and exhibit broad substrate generality.

Full text of DOI:10.1246/bcsj.20160402

Advance Publication Cover Page
Synthesis of δ-Lactone and Amino Acid Frameworks Utilizing the Umpoled
Reactivity of β,γ-Alkenyl α-Iminoester
Mami Kawanishi, Isao Mizota, Kana Aratake, Hirotaka Tanaka,
Kenta Nakahama, and Makoto Shimizu*
Advance Publication on the web January 13, 2017
doi:10.1246/bcsj.20160402
© 2017 The Chemical Society of Japan

Synthesis of δ-Lactone and Amino Acid Frameworks Utilizing the Umpoled
Reactivity of β,γ-Alkenyl α-Iminoester
Mami Kawanishi, Isao Mizota, Kana Aratake, Hirotaka Tanaka, Kenta Nakahama, and Makoto Shimizu*
Department of Chemistry for Materials, Graduate School of Engineering, Mie University, Tsu, Mie 514-8507, Japan
E-mail: mshimizu@chem.mie-u.ac.jp, imizota@chem.mie-u.ac.jp
Makoto Shimizu
Makoto Shimizu received his PhD from Tokyo Institute of Technology (1981). After a postdoctoral work with
Professor B. M. Trost, he became an Assistant Professor of the University of Tokyo (1983), a Senior Research Associate
at Riken Institute of Physical and Chemical Research (1984), an Associate Professor of Mie University (1989), and a
Full Professor there (1999). Since 2015, he is a dean of the Graduate School of Engineering. His research interests focus
on the exploration into new C-C bond forming and/or asymmetric reactions using organometallics and application to the
synthesis of new functional materials and bioactive products.
Abstract
Nu
pAn
O
pAn
O
An umpolung N-alkylation reaction of β,γ-alkenyl
α-iminoesters was studied, and various tandem reactions were
found utilizing this N-alkylation.
N
Nu
N
OEt
OEt
R
R
A useful synthesis of
δ-lactones and dienamines was developed by tandem
N-alkylation/vinylogous aldol-type reaction. The synthesis of
α-quaternary alkenyl amino esters was also developed via the
tandem N-alkylation/bromination/C-alkylation. These methods
using β,γ-alkenyl α-iminoesters are operationally simple and
useful, and exhibit broad substrate generality.
Nu
N-Addition
(b)
(c)
(a)
(d)
(a)
pAn
1,4-Addition
(b)
N
OEt
R
O
(d)
(c)
pAn
HN
pAn
N
Nu
OEt
Nu
R
R
Nu
O
O
1,2-Addition
Carbonyl addition
Introduction
α-Imino ester has a unique reactivity due to the structure
having an ester part located next to the imino carbon. Since it
enables decreasing the LUMO energy of the imino nitrogen, it
sometimes shows an unusual type of reaction, an umpolung
reaction. Although an umpolung of the α-iminoester is difficult
due to the electronegativity of the imino group, it can lead to
the introduction of substituents into the nitrogen atom of the
amino acid frameworks.1,2 Our laboratory has developed
umpolung reactions of α-imino esters.3 In 2013, we reported
the N-alkylation of β,γ-alkynyl α-iminoesters followed by
regioselective acylation through the formation of magnesium
Scheme 1. Possible reactions to β,γ-alkenyl α-iminoester.
Results and Discussion
Initially N-alkylation reaction of the β,γ-alkenyl
α-iminoester 1a was carried out under the N-alkylation
conditions optimized for the β,γ-alkynyl α-iminoester (with 1.1
equivs of EtMgBr in THF at −78 °C to rt for 30 min), to give
the desired N-addition products 2a and 3a in 24% combined
yield (Table 1, entry 1), in which isomers 2a and 3a were likely
to be formed by α- or γ-protonation of the magnesium enolate
generated by N-ethylation at the quenching step. When the
reaction was carried out at -78 oC and -95 oC, the desired
products were obtained in similar yields together with the
recovery of the starting material (entries 3 and 4). From these
results and the ratio of E/Z geometric isomers of the starting
materials, we assumed that only a single geometric isomer of
the starting iminoester participated in the reaction, while the
other isomer was inert to the N-alkylation.
To verify our hypothesis, various substrates were
synthesized, and N-alkylation at -78 oC was carried out, in
which the geometry of the substrates was assumed from the
computational study (Table 2). As shown in Table 2, a trend
was found that as the ratio of the (E)-isomer 1 increased, the
yields of N-alkylation products 2 and 3 were improved. In
particular, when the reaction of the substrate having a mesityl
group 1e was carried out, the yield was improved up to 61%,
presumably due to the preferred formation of the E isomer in
the substrate (entry 5). These results indicate that only the
(E)-isomer participates in the reaction, while the (Z)-isomer
yne-enolates.3n
Recently
we
have
reported
the
N,N,C-trialkylation of N-p-toluoyloxyiminoesters with three
kinds of nucleophiles for construction of trialkylated amino
esters.3q
In the context to construct a new type of C-C bond
formation utilized umpolung N-addition to α-iminoester, we
focused on the β,γ-alkenyl α-iminoester as a substrate. Since
β,γ-alkenyl α-iminoester has an unsaturated olefin moiety
which tends to more readily undergo 1,4-addition reaction
compared to the alkyne moiety of β,γ-alkynyl α-iminoester, the
development of the selective N-alkylation is difficult due to
undesired side reactions caused by the reaction of the olefin
such as 1,4-addition (Scheme 1, b), 1,2-addition (c) and
carbonyl addition (d). Herein we report new types of tandem
reactions utilizing N-alkylation of β,γ-alkenyl-α-iminoester for
the syntheses of δ-lactones, dienamines and α-quaternary
alkenyl aminoesters.

does not react but isomerizes to the (E)-isomer at room
temperature, since the ratio of the diastereomers in the
recovered imino ester 1 was same as that in the starting
material. Moreover, the computational study supports our
hypothesis, in which the ratios of diastereomers are constant at
>25 oC.3o
Table 1. Optimization of N-alkylation to β,γ-alkenyl
α-iminoester.a
Et
pAn
N
To improve the yield of N-alkylated product, we focused
on suppression of the side reactions to β,γ-alkenyl α-imino ester.
When β,γ-alkenyl α-imino ester having a bulky 2,6-dimethyl
phenyl group at the terminal alkene was used to suppress a
1,4-addition reaction to conjugate imine and the reaction was
Ph
Ph
CO2Et
pAn
2a
EtMgBr (1.1 equiv)
THF, temp., 30 min
N
Et
pAn
Ph
CO2Et
N
o
1a (E/Z = 48 : 52)
carried out at -78 to 40 C, the desired N-alkylation reaction
CO2Et
proceeded selectively to provide the N-alkylated product 5a in
85% yield (Table 3, entry 1). Further improvement of the yield
was achieved by using diphenyl iminoester 4b, and the
N-adduct 5b was obtained in 92% yield (entry 2) Various
substituent patterns including 2-thienyl, 4-MeOC6H4- and
4-FC6H4 group also allowed to give the N-addition products
4c-e in good to high yields (entries 3-5).
3a
Entry
T /oC
-78 to rt
-78 to 0
-78
Yieldb /%
2a : 3a
RSMc /%
1
2
3
4
24
31
33
25
83 : 17
71 : 29
67 : 33
76 : 24
0
0
50
66
-95
a The reaction was carried out according to the general procedure.
b Isolated yield.
c Recovery of the starting material.
pAn = p-MeOC6H4.
Table 2. N-Alkylation at -78 oC for various substrates.a
Et
Et
pAn
N
N
Ph
Ph
CO2R
pAn
2
3
EtMgBr (1.1 equiv)
THF, -78 oC, 30 min
N
pAn
Ph
CO2R
1
CO2R
Entry
R
iPr
1 (E : Z)
Yieldb /%
21 (2b+3b)
25 (2c+3c)
33 (2a+3a)
34 (2d+3d)
61 (3e)
2 : 3
RSMc /% (E : Z)
47 (33 : 67)
50 (40 : 60)
50 (48 : 52)
51 (58 : 42)
27 (67 : 32)
1
2
3
4
5
1b (33 : 67)
1c (40 : 60)
1a (48 : 52)
1d (58 : 42)
1e (67 : 32)
67 : 33
68 : 32
67 : 33
79 : 21
64 : 36
Bn
Et
Me
Mes
a The reaction was carried out according to the general procedure.
b Isolated yield.
c Recovery of the starting material.
Table 3. Scope of substrates.a
pAn
Et
pAn
R2
N
R2
N
EtMgBr (1.1 equiv)
THF, -78 to 40 oC, 30 min
R1
CO2Et
R1
CO2Et
4
5
Entry
R1
R2
4
Yieldb /%
5
dr
1
2
3
4
5
2,6-Me2C6H3
Ph
2-thienyl
2-thienyl
2-thienyl
H
4a (E/Z = 55 : 45)
4b (E/Z = 89 : 11)
4c (dr = 90 : 10)
85 (5a)
92 (5b)
83 (5c)
81 (5d)
75 (5e)
-
Ph
-
2-thienyl
4-MeOC6H4
4-FC6H4
-
4d (dr = 57 : 21 : 16 : 6)
4e (dr = 84 : 16)
84 : 16c
87 : 13c
a The reaction was carried out according to the general procedure.
b Isolated yield.
c Olefin geometry of the product was not determined.

Under these optimized conditions, the scope of Grignard
reagents was examined (Scheme 2). Linear primary alkyl
Grignard reagents provided the desired N-adducts 5b,f in
excellent yields, while a branched alkyl Grignard reagent
afforded the desired product 5g in good yield. Moreover,
Grignard reagents with functional group such as cyclic acetals,
terminal alkene, and halogen, were also effective in this
reaction (5h-j). In most cases nucleophilic addition to the
ethoxycarbonyl group occurred as the side reaction, which
resulted in low yields of the desired products.
pAn
Ph
R
pAn
RMgBr (1.1 equiv)
N
Ph
N
THF, -78 to 40 oC, 30 min
Ph
CO2Et
Ph
CO2Et
4b (E/Z = 89 : 11)
5
pAn
pAn
pAn
7
Ph
N
Ph
N
Ph
N
Ph
CO2Et
Ph
CO2Et
Ph
Cl
CO2Et
5b 91%
5f 92%
5g 68%
Gratifyingly, we found that when benzaldehyde was used
as an electrophile, a tandem N-alkylation/vinylogous aldol-type
reaction proceeded regioselectively to give the δ-lactone 7a in
77% yield together with the N-alkylated product 5b in 22%
yield (Table 4, entry 1). Aldol reactions using the enolates
prepared via the 1,4-addition of organometallic reagents to
α,β-unsaturated carbonyl compounds are useful in organic
synthesis to promote three-component coupling reactions,
which can build complex molecules.4 The vinylogous
aldol-type reactions5 reported so far used allenic esters as the
starting materials.6d The directed vinylogous aldol-type
reaction6 using the enolate prepared in situ is effective in terms
of the atom economy as compared to the Mukaiyama
vinylogous aldol-type reaction,7 although its regioselectivity6e,f
was affected by steric factors of the substrates, and it was
required to use excess amounts of bulky Lewis acids.6a,b,g
α-Amino-δ-lactones are important precursors to biologically
active compounds such as pyrano[3,4-b]indol-1(9H)-ones
known as an anticancer agent.8 Therefore, we next investigated
the tandem N-alkylation/vinylogous aldol-type reaction in the
presence of an electrophile, and after various examinations of
vinylogous aldol-type reaction conditions, the optimized
reaction conditions were found to be use of 5.0 equivalents of
aldehyde at reflux for 1.5 h. On the other hand, although the
N-alkylation followed by hydrolysis of the resulting enamine
provided a simple N-alkylated product as a byproduct, we
hypothesized the retro-aldol reaction of the aldol product via
α-addition might occur to provide this N-alkylated product.
Thus, we examined the ester moiety of the substrates, the
addition of a Lewis acid to increase aldehyde reactivity, and the
effect of a Lewis base on the retro-aldol reaction in order to
increase the γ-adduct. However, the yield of δ-lactone 7a did
not increase (entries 2-6). We cannot completely rule out our
hypothesis because these results suggest that the magnesium
α-aldolate may be stabilized by a strong chelation between the
magnesium and the nitrogen atoms.
Then the scope of substrates, Grignard reagents, and
aldehydes was examined under the optimized reaction
conditions (Scheme 3). The use of primary Grignard reagents
such as isobutyl, homoallyl, chlorobutyl, and 1,3-dioxanylethyl
promoted the N-alkylation reaction followed by cyclization to
give the desired δ-lactones in moderate to good yields (7b-e).
Aromatic and heteroaromatic aldehydes afforded the desired
products 7f-h in moderate to high yields. An α,β-unsaturated
aldehyde, cinnamaldehyde, gave the product 7i in 79% yield.
A proposed reaction mechanism is shown in Scheme 4.
After isomerization of the Z-4 isomer to the more reactive
E-isomer 4 at room temperature, N-alkylation of Grignard
reagent proceeds to form the enolate intermediate A, which is
protonated at the γ-position to provide the product 6, while
protonation at the α-position leads to the product 5. On the
other hand, the vinylogous aldol-type reaction of the enolate
intermediate A with aldehydes followed by the cyclization
leads to the lactone 7 via the intermediate B, while addition to
aldehyde at the α-position forms the product C which would
give back to the 5 via retro-aldol reaction.
O
O
pAn
pAn
pAn
2
Ph
N
Ph
N
Ph
N
Ph
CO2Et
Ph
CO2Et
Ph
CO2Et
5h 96%
5i 77%
5j 54%
a The reaction was carried out according to the general procedure.
b Yields refer to pure isolated compounds.
Scheme 2. Scope of Grignard reagents for N-alkylation.a,b
Table 4. N-Alkylation at -78 oC for various substrates.a
pAn
N
O
Et
O
1. EtMgBr (1.1 equiv), THF
-78 to 40 oC, 30 min
pAn
Ph
N
Ph
Ph
7a
Ph
2. PhCHO (5.0 equiv)
Additive (x equiv)
reflux, 1.5 h
Ph
CO2Et
4b (E/Z = 89 : 11)
5b
Entry
Additive /x eq
Yieldb /%
7a
77
0
15
40
47
72
5b
1
None
22
25
68
29
32
26
2c
3c
4d
5e
6e
BF3・OEt2 /5.0
Ti(OiPr)4 /5.0
DMSO /1.0
DMSO /1.0
Et3N /1.0
a The reaction was carried out according to the general procedure.
b Isolated yield.
c A mixture of the aldehyde and the additive was added.
d The additive was added before the addition of the aldehyde.
e The additive was added after the addition of the aldehyde.
pAn
N
O
pAn
R3MgBr (1.1 equiv)
R4CHO (5.0 equiv)
reflux, 1.5 h
R2
N
R3
O
THF, -78 to 40 oC, 30 min
R1
CO2Et
R4
R1 R2
4
7
pAn
O
pAn
N
O
pAn
N
O
pAn
O
N
N
2
O
O
O
O
Ph
Ph
Ph
O
O
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Cl
7b 51%(35%)
7c 74%(22%)
7d 55%(12%)
pAn
7e 51%(30%)
pAn
N
O
O
pAn
N
O
O
O
pAn
O
O
N
N
Et
Et
Et
O
Et
N
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
OMe
Cl
7f 58%(29%)
7g 56%(37%)
7h 81%(5%)
7i 79%(0%)
a The reaction was carried out according to the general procedure.
b Yields refer to pure isolated compounds, and yields of
N-adduct are in the parentheses.
Scheme 3. Tandem N-alkylation/vinylogous aldol-type
reaction.a,b

R3
pAn
R2
N
Table 5. Tandem reaction of β,γ-alkenyl α-iminoesters bearing
a silyl group.a
R3
pAn
O
ꢀ-protonation
H
R2
N
R1
CO2Et
pAn
R2
R3MgBr
OEt
N
6
R1
Et
R1
pAn
N
R1
CO2Et
1. EtMgBr (1.1 equiv), THF
-78 to 40 oC, 30 min
R3
pAn
pAn
MgBr
R2
N
R3
ꢁ-protonation
(E)-4
R1
N
A
CO2Et
R1
CO2Et
ꢀ-addition
ꢁ-addition
8
R4CHO
2. R3CHO (5.0 equiv)
reflux, 1.5 h
> 25 °C
pAn
5
R2
CO2Et
R3 pAn
N
R3 pAn
N
R2
R2
5
R2
N
R1
R4
CO2Et
4f: R1 = Ph, R2 = SiMe2Ph, dr = 81 : 19
4g: R1 = 2-thienyl, R2 = SiMe2Ph, dr = 91 : 9
R1
CO2Et
Retro aldol
R1
CO2Et
HO
O
MgBr
R4
(Z)-4
B
C
R3
Yieldb/%
dr
87:13
93:7
pAn
N
O
Entry
4
O
R3
8
5
- EtOMgBr
R4
1
2
3
4f Ph
4g Ph
4f (E)-PhCH=CH
61 (8a)
49 (8b)
71 (8c)
14 (5q)
4 (5r)
trace
R1
R2
7
64:36
Scheme 4. Proposed reaction mechanism.
a The reaction was carried out according to the general procedure.
b Isolated yield.
Furthermore tandem reaction of β,γ-alkenyl
a
α-iminoester having a silyl group at the terminal alkene moiety
was investigated, and the results are shown in Table 5.
Interestingly, Peterson olefination rather than intramolecular
cyclization proceeded after the vinylogous aldol-type reaction
to afford the dienamines 8 in moderated yields (entries 1 and 2).
The use of cinnamaldehyde provided the trienamine product in
71% yield (entry 3). The geometry of these products prefers to
be trans form caused by the syn-elimination of the silanolate on
the basic Perterson olefination.
Since the tandem N-alkylation/vinylogous aldol-type
reaction starting from β,γ-alkenyl α-iminoester was developed
utilizing γ-addition of the magnesium dienolate, we next
focused on the selective α-addition of dienolate to synthesize
the α quaternary alkenyl amino acid derivatives. Quaternary
α-amino acids are an interesting class of nonproteinogenic
acids and also powerful enzyme inhibitors,9 and β,γ-alkenyl
α-iminoesters are known as an important α-amino acid
frameworks for the bioactive compounds widely existing in the
natural compounds.10 It is highly required to synthesize the
compounds that can introduce various nucleophiles freely on
the imino nitrogen. As α-adducts were not obtained presumably
due to the retro-aldol reaction when aldehydes were used as
mentioned above, various types of electrophiles were examined
such as iodomethane, allyl bromide and acetyl chloride for the
tandem N-alkylation/α-addition reaction as shown in Scheme 5.
However the desired α-adducts were not obtained at all.
Et
Ph
pAn
Et
Ph
pAn
MeI (5.0 equiv)
0 oC to rt, 1 h
N
N
N
Ph
Ph
CO2Et Ph
not obtained
pAn
CO2Et
Me
Me
Et
Ph
pAn
Ph
pAn
N
Et
Ph
Br
EtMgBr (1.1 equiv)
(5.0 equiv)
N
CO2Et
Ph
CO2Et
Ph
CO2Et THF, -78 to 40 o
30 min
C
0 oC to rt, 1 h
4b (E/Z = 89 : 11)
not obtained
pAn
Et
Ph
Et
Ph
pAn
AcCl (5.0 equiv)
40 oC, 30 min
N
N
Ph
CO2Et Ph
not obtained
CO2Et
Ac
Ac
Scheme 5. Tandem N-alkylation/electrophilic addition
reactions.
Table
6.
Optimization
of
tandem
pAn
N-alkylation/oxidation/1,2-addition.a
Et
Ph
N
1. EtMgBr (1.2 equiv), THF
pAn
-78 to 40 oC, 30 min
Ph
CO2Et
Ph
N
R
2. oxidant (x equiv)
0 oC, 15 min
9
Ph
CO2Et
4b (E/Z = 89 : 11)
5b
3. R-M (y equiv)
0 oC, 15 min
Entry
Oxidant/x eq
R-M/y eq
Yieldb/%
We next examined a further alternative synthesis of
9
5b
39
5
10
4
10
9
0
43
42
0
0
0
α-quatenary alkenyl amino esters utilizing
N-alkylation/oxidation/nucleophilic addition
a
sequential
to
1
2
3
4
5
6
7
8
9
NBS/1.2
NBS/1.5
NBS/2.0
NCS/1.5
NIS/1.5
EtMgBr/1.2
EtMgBr/1.2
EtMgBr/1.2
EtMgBr/1.2
EtMgBr/1.2
32 (9a)
68 (9a)
52 (9a)
66 (9a)
56 (9a)
61 (9a)
57 (9a)
48 (9a)
20 (9a)
0 (9b)
β,γ-alkenyl-α-imino ester 4b. As an initial reaction, the
iminoester 4b first reacted with 1.2 equivs of EtMgBr in THF
o
at -78 to 40 C for 30 min followed by bromination with 1.2
o
equivs of NBS at 0 C for 15 min and treatment with another
DBDMH/0.75 EtMgBr/1.2
o
1.2 equivs of EtMgBr at 0 C for 15 min. The desired product
BPO/1.5
NBS/1.5
NBS/1.5
NBS/1.5
NBS/1.5
NBS/1.5
EtMgBr/1.2
Et2Zn/1.2
Et2AlCl/1.2
nBuLi/1.2
EtZnI/1.2
EtZnI/1.2
9a was obtained in 32% yield (Table 6, entry 1). A series of
reaction conditions including the amount of oxidants and
second nucleophiles were examined in detail, and the results
are summarized in Table 6. Regarding the amounts of oxidants
(entries 1-3), it was found that the use of 1.5 equivs of NBS
was the most efficient to give the desired product 9a in 68%
yield (entry 2). Other oxidants such as NCS, NIS, DBDMH and
BPO also provided the products in moderate to good yields
(entries 4-7). Examination of the second nucleophile showed
that the desired product 9 was obtained in a maximum 90%
yield when 2.0 equivs of EtZnI were used at 0 oC to room
temperature for 1 h (entry 12).
10
11c
12c
80 (9a)
90 (9a)
a The reaction was carried out according to the general procedure.
b Isolated yield.
c Reaction was carried out at 0 oC to rt for 1 h.
DBDMH = 1,3-dibromo-5,5-dimethylhydantoin.

R1
pAn
Ph
R1
O
2. NBS (1.5 equiv)
0 oC, 15 min
R1
pAn
p
pAn
Ph
Br
An
Ph
pAn
Ph
N
Mg
1. R1MgBr (1.2 equiv)
Ph
N
R1MgBr
-78 o
N
N
N
OEt
O
Ph
THF, -78 to 40 oC, 30 min
3. R2ZnI (2.0 equiv)
0 oC to r.t., 1 h
Ph
CO2Et
R2
9
C
Ph
Ph
CO2Et
Ph
CO2Et
OEt
R1MgBr
MgBr
(E)
4b (E/Z = 89 : 11)
dienolate D
Et
Ph
pAn
Et
Ph
pAn
Et
Ph
pAn
Et
Ph
pAn
N
N
N
N
pAn
pAn
Ph
Ph
CO2Et
> 25 o
C
Ph
Ph
CO2Et Ph
CO2Et Ph
3
CO2Et
7
Ph
N
N
NBS
Ph
CO2Et
9c 59%c
Et
pAn
9d 27%
Ph
CO2Et
9a 90%
9b 31%
Et
pAn
Et
pAn
(Z)
(E)
Ph
N
Ph
N
Ph
N
Et
Ph
pAn
N
Ph
CO2Et
Ph
CO2Et Ph
CO2Et
pAn
Ph
R1
O
CO2Et
N
pAn
Ph
R1
OEt
pAn
Ph
R1
EtO2C
Ph
N
N
9e 50%
Et
pAn
9f 49%
9g 0%
9h 58%
MgBr
O
Br
N
Ph
CO2Et
Ph
CO2Et
pAn
pAn
pAn
Br
5
2
N
Ph
N
Ph
Ph 3N
Ph
N
O
Ph
CO2Et
Ph
CO2Et Ph
CO2Et Ph
CO2Et
Et
9j 62%
Et
Et
9l 54%
iminium salt E
9i 48%d
9k 56%
pAn
Ph
R1
R2ZnX
N
pAn
7
pAn
pAn
Ph
Ph
CO2Et
R2
Ph
N
Ph
N
Ph
N
pAn
Ph
N
1,2-adduct
pAn
Ph
CO2Et
Ph
CO2Et
Ph
CO2Et
Et
Et
9p 0%
Et
9n 86%
Ph
CO2Et
Et
9o 77%
R1
R2CuMgX2
Ph
N
9m 63%
CO2Et
R2
1,4-adduct
a The reaction was carried out according to the general procedure.
b Yields refer to pure isolated compounds.
c nOctMgBr was used instead of Zn reagent.
Scheme 8 Plausible mechanism.
d Tetraallyltin was used instead of Zn reagent.
nHex, Oct, and Bu groups) gave the desired products 9j-n in
good to high yields. When homoallyl Grignard reagent was
used, the corresponding product 9o was also obtained in good
yield. Secondary alkyl Grignard reagent (isopropyl group) did
not afford the N-alkylated product 9p at all presumably due to
the steric hindrance.
n
i
Scheme 6. Scope of first and second nucleophiles.a,b
Et
Ph
pAn
N
pAn
Ph
1. EtMgBr (1.2 equiv), THF
-78 to 40 oC, 30 min
Regioselective 1,4-addition reaction for the iminium salt11
formed in situ was next investigated (Scheme 7). The use of
organocopper reagent for the second nucleophile gave the
desired 1,4-adduct 10 in 23% yield. It was also found that when
the β,γ-alkenyl α-iminoester 4h having an ethylthio group at the
terminal alkene was used as the substrate, the enamine product
11 was obtained in 18% yield via the 1,4-addition for iminium
salt followed by the elimination of ethylthio group albeit in low
yield.
N
Ph
CO2Et
Et
2. NBS (1.5 equiv)
0 oC, 15 min
Ph
CO2Et
10 23%
4b (E/Z = 89 : 11)
9a 45%
3. EtMgBr (1.2 equiv)
CuCN (1.2 equiv)
0 oC, 15 min
1. EtMgBr (1.2 equiv), THF
-78 to 40 oC, 30 min
pAn
Et
pAn
N
SEt
N
A proposed reaction mechanism is shown in Scheme 8.
The inert (Z)-iminoester isomerizes into its reactive
(E)-iminoester by heating above room temperature. The
N-alkylation proceeds with the Grignard reagent to give the
magnesium dienolate D through formation of a five-membered
intermediate composed of the imino nitrogen, the carbonyl
oxygen, and the magnesium atom. The enolate D is brominated
with NBS to give an iminium salt as the intermediate E, which
reacts with the second nucleophile to give the alkenyl amino
ester and the enamined through 1,2-addition or 1,4-addition
respectively.
2. NBS (1.5 equiv)
0 oC, 15 min
Ph
CO2Et
Ph
CO2Et
4h (dr = 76 : 24)
11 18%
3. EtMgBr (1.2 equiv)
CuCN (1.2 equiv)
0 oC, 15 min
Scheme 7. Tandem N-alkylation/oxidation/1,4-addition
reaction.
Regarding the sope of second nucleophiles, organozinc
reagents was evaluated under the optimized conditions
(Scheme 6). In the case of the bulky substituents such as
isopropyl and the cyclohexyl group, the desired products 9e
and 9f were obtained in moderate yields, while the introduction
of butyl and isobutyl groups decreased the yield (9b,d).
Aromatic zinc reagents did not appear to be effective in this
reaction (9g). The use of the zinc reagent having a functional
group allowed the desired product in good yield (9h). On the
other hand, the use of n-octyl Grignard reagent and tetraallyltin
was also effective in this reaction to afford the desired product
9c and 9i in moderate yields.
Conclusion
We have developed a one-pot synthesis of δ-lactones and
dienamines using umpolung N-alkylation of β,γ-alkenyl
α-iminoester followed by vinylogous aldol-type reaction. This
method shows a unique reactivity for the cyclization or
Peterson olefination in good to high yields. Moreover, we also
show the synthesis of α-quaternary alkenyl aminoesters
utilizing
a β,γ-alkenyl α-iminoester via an intermediary
iminium salt formed by the bromination of the aminoester
enolate in high yields.
Use of the Grignard reagent as a first nucleophile was
next examined. Primary alkyl Grignard reagents (Et, nPr, nBu,

Experimental
solution (1.1 equiv). After stirring for 5 min at -78 oC, the
mixture was warmed to 40 C immediately and stirred for 20
o
General Aspects. Infrared spectra were determined on a
JASCO FT/ IR-460 plus spectrometer. H NMR and 13C NMR
min. After the consumption of the substrate was confirmed by
1
o
spectra were recorded with a JEOL ECX-400P JEOL A-500
spectrometer using tetramethylsilane as an internal standard.
Mass spectra were recorded on a JEOL MS-700D spectrometer.
Tetrahydrofuran (THF) was distilled from benzophenone ketyl
immediately before use. Purification of products was
performed by column chromatography on silica gel (Kanto
Silica Gel 60N) and/or preparative TLC on silica gel (Merck
Kiesel Gel GF254). β,γ-Alkenyl α-iminoesters 1a-e, 4a-h were
prepared according to the reported procedure and
characterization data of compounds 1-8 has already been
reported.3o
General procedure for the N-alkylation to β,γ-alkenyl
iminoester (Table 1, 2 and 3, Scheme 2). Under an argon
atmosphere, a suspension of β,γ-Alkenyl α-iminoester 1 or 4
(0.15 mmol) in THF (2.0 mL) was stirred at -78 C for 5 min,
and to it was added Grignard reagent in THF solution (1.1
TLC, the mixture was cooled to 0 C and stirred for 5 min and
to it was added NBS (1.5 equiv). After stirring for 15 min, to it
was added RZnI in THF solution (2.0 equiv), which was
prepared according to the literature,12 slowly and the mixture
was warmed to room temperature and stirred for 1 h. The
reaction was quenched with sat. NaHCO3 aq. (3.0 mL), and the
whole mixture was extracted with ethyl acetate (10 mL x 3).
The combined extracts were washed with brine, dried over
anhydrous Na2SO4, and concentrated in vacuo. The crude
product was purified by silica gel chromatography
(n-hexane/ethyl acetate = 10 / 1) to give the desired compound
9.
Ethyl
2-ethyl-2-[ethyl(4-methoxyphenyl)amino]-4,4-diphenylbut-3
-enoate (9a). Yield 90%; Yellow oil; 1H NMR (400 MHz,
CDCl3) δ 0.85 (dd, J = 7.1, 7.1 Hz, 3H), 0.95 (dd, J = 7.2, 7.2
Hz, 3H), 1.14 (dd, J = 7.3, 7.3 Hz, 3H), 1.67-1.80 (m, 2H), 2.92
(dq, J = 7.2, 13.6 Hz, 1H), 3.24 (dq, J = 7.2, 13.6 Hz, 1H),
3.73-3.93 (m, 5H including singlet at 3.75 ppm, 3H), 6.61 (s,
1H), 6.70-6.80 (m, 4H), 7.06-7.32 (m, 10H); 13C NMR (100
MHz, CDCl3) δ 8.9, 14.1, 14.7, 30.7, 44.3, 55.3, 60.4, 70.3,
113.3, 126.9, 127.0, 127.2, 127.5, 127.6, 128.0, 129.7, 131.2,
139.5, 139.6, 141.5, 143.7, 155.8, 173.6; IR(neat) 2975, 1722,
1509, 1463, 1443, 1377, 1284, 1245, 1220, 1118, 1074, 1037,
832, 760, 701 cm-1; HRMS(EI):Calcd for C29H33NO3(M)+
443.2460, found 443.2455.
o
o
equiv) slowly. After 5 min, the mixture was warmed to 40 C
immediately and was stirred for 25 min. The reaction was
quenched with sat. NaHCO3 aq. (3.0 mL), and the whole
mixture was extracted with ethyl acetate (10 mL x 3). The
combined extracts were washed with brine, dried over
anhydrous Na2SO4, and concentrated in vacuo. The crude
product was purified by silica gel chromatography
(n-hexane/ethyl acetate = 5 / 1) to give the desired compounds
2, 3, and 5.
General
procedure
for
the
tandem
N-alkylation/vinylgous aldol-type reaction (Table 4, Scheme
3). Under an argon atmosphere, a suspension of β,γ-Alkenyl
α-iminoester 4 (0.10 mmol) in THF (2.0 mL) was stirred at -78
oC for 5 min, and to it was added Grignard reagent in THF
solution (1.1 equiv). After stirring for 5 min at -78 oC, the
Ethyl
2-(2,2-diphenylvinyl)-2-[ethyl(4-methoxyphenyl)amino]hexa
noate (9b). Yield 31%; Yellow oil; 1H NMR (400 MHz,
CDCl3) δ 0.84 (t, J = 6.9 Hz, 3H), 0.86 (dd, J = 6.7, 6.7 Hz,
3H), 1.13 (dd, J = 7.1, 7.1 Hz, 3H), 1.19-1.29 (m, 3H), 1.59 (dt,
J = 6.9, 15.1 Hz, 1H), 1.67-1.79 (m, 2H), 2.92 (dq, J = 6.7, 14.0
Hz, 1H), 3.24 (dq, J = 6.7, 14.0 Hz, 1H), 3.66-3.79 (m, 4H,
including singlet at 3.74 ppm, 3H), 3.87 (dq, J = 7.1, 10.8 Hz,
1H), 6.63 (s, 1H), 6.72-6.79 (m, 4H), 7.06-7.32 (m, 10H); 13C
NMR (100 MHz, CDCl3) δ 14.0, 14.7, 23.2, 26.5, 37.6, 44.2,
55.2, 60.3, 69.8, 113.2, 126.9, 127.0, 127.2, 127.4, 127.5, 128.0,
129.7, 131.6, 139.5, 139.6, 141.2, 143.6, 155.7, 173.5; IR(neat)
2959, 2931, 1722, 1507, 1465, 1443, 1377, 1282, 1244, 1181,
1125, 1074, 1035, 759, 701 cm-1; HRMS(EI): Calcd for
C31H37NO3(M)+ 471.2773, found 471.2780.
o
mixture was warmed to 40 C immediately and stirred for 25
min. After the consumption of substrate was confirmed by TLC,
the reaction mixture was heated to reflux and to it was added an
aldehyde (5.0 equiv) and was stirred for 1.5 h. The reaction was
quenched with sat. NaHCO3 aq. (3.0 mL), and the whole
mixture was extracted with ethyl acetate (10 mL x 3). The
combined extracts were washed with brine, dried over
anhydrous Na2SO4, and concentrated in vacuo. The crude
product was purified by silica gel chromatography
(n-hexane/ethyl acetate = 5 / 1) to give the desired compounds
7 and 5.
Ethyl
General
procedure
for
the
tandem
2-(2,2-diphenylvinyl)-2-[ethyl(4-methoxyphenyl)amino]deca
noate (9c). Yield 59%; Yellow oil; 1H NMR (400 MHz,
CDCl3) δ 0.85 (t, J = 6.8 Hz, 3H), 0.86 (dd, J = 7.0, 6.8 Hz,
3H), 1.12-1.27 (m, 15H, including dd at 1.13 ppm, J = 7.2, 7.3
Hz, 3H), 1.58-1.69 (m, 2H), 2.91 (dq, J = 6.8, 13.8 Hz, 1H),
3.23 (dq, J = 7.0, 13.8 Hz, 1H), 3.72-3.80 (m, 4H, including
singlet at 3.76 ppm, 3H), 3.88 (dq, J =7.2, 10.8 Hz, 1H), 6.62 (s,
1H), 6.72-6.78 (m, 4H), 7.05-7.07 (m, 2H), 7.15-7.32 (m, 8H);
13C NMR (100 MHz, CDCl3) δ 14.1, 14.7, 22.6, 24.4, 29.3,
29.5, 30.1, 31.8, 37.9, 44.2, 55.3, 60.4, 69.9, 113.3, 126.9,
127.0, 127.2, 127.4, 127.6, 127.8, 128.0, 129.8, 131.7, 139.5,
139.6, 141.2, 143.7, 155.7, 173.6; IR(neat) 3055, 2927, 2856,
1723, 1509, 1445, 1375, 1285, 1243, 1180, 1125, 1074, 1037,
762, 700 cm-1; HRMS(EI): Calcd for C35H45NO3(M)+ 527.3399,
found 527.3422.
N-alkylation/γ-addition/peterson olefination (Table 5).
Under an argon atmosphere, a suspension of β,γ-Alkenyl
α-iminoester 4 (0.10 mmol) in THF (2.0 mL) was stirred at -78
oC for 5 min, and to it was added EtMgBr in THF solution (1.1
equiv). After stirring for 5 min at -78 oC, the mixture was
o
warmed to 40 C immediately and stirred for 25 min. After the
consumption of substrate was confirmed by TLC, the mixture
was heated to reflux and to it was added an aldehyde (5.0
equiv), and was stirred for 1.5 h. The reaction was quenched
with sat. NaHCO3 aq. (3.0 mL), and the whole mixture was
extracted with ethyl acetate (10 mL x 3). The combined
extracts were washed with brine, dried over anhydrous Na2SO4,
and concentrated in vacuo. The crude product was purified by
silica gel chromatography (n-hexane/ethyl acetate = 9 / 1) to
give the desired compounds 8 and 5.
Ethyl
General
procedure
for
the
tandem
2-(2,2-diphenylvinyl)-2-[ethyl(4-methoxyphenyl)amino]-4-m
ethylpentanoate (9d). Yield 27%; Red oil; 1H NMR (400 MHz,
CDCl3) δ 0.79 (dd, J = 6.9, 6.9 Hz, 3H), 0.84 (d, J = 6.4 Hz,
3H), 0.87 (d, J = 6.4 Hz, 3H), 1.17 (dd, J = 7.2, 7.2 Hz, 3H),
1.56 (dd, J = 6.4, 13.7 Hz, 1H), 1.76 (dd, J = 6.4, 13.7 Hz, 1H),
N-alkylation/bromination/1,2-addition (Table 6, Scheme 6).
Under an argon atmosphere, a suspension of β,γ-Alkenyl
α-iminoester 4 (0.10 mmol) in THF (2.0 mL) was stirred at -78
oC for 5 min, and to it was added Grignard reagent in THF

1.86-2.01 (m, 1H), 2.85 (dq, J = 6.9, 13.3 Hz, 1H), 3.18 (dq, J
= 6.9, 13.3 Hz, 1H), 3.76 (s, 3H), 3.82 (dq, J = 7.2, 11.0 Hz,
1H), 3.92 (dq, J = 7.2, 11.0 Hz, 1H), 6.71 (s, 3H), 6.73 (s, 1H),
7.10-7.35 (m, 11H); 13C NMR (100 MHz, CDCl3) δ 14.1, 14.3,
23.7, 24.3, 25.0, 44.0, 46.3, 55.3, 60.4, 69.4, 113.1, 126.8,
127.0, 127.2, 127.5, 128.0, 128.1, 129.8, 131.4, 139.3, 139.7,
141.3, 143.8, 155.8, 173.8; IR(neat) 2957, 2868, 1719, 1508,
1465, 1443, 1385, 1289, 1244, 1214, 1181, 1128, 1035, 758,
701 cm-1; HRMS(EI): Calcd for C31H37NO3(M)+ 471.2773,
found 471.2778.
127.1, 127.2, 127.6, 128.0, 128.5, 129.8, 131.5, 134.1, 139.3,
141.7, 143.6, 156.3, 172.9; IR(neat) 3443, 2975, 2360, 1722,
1643, 1507, 1443, 1375, 1286, 1243, 1119, 1034, 833, 757,
700, 576 cm-1; HRMS(EI): Calcd for C30H33NO3(M)+ 455.2460,
found 455.2471.
Ethyl
2-ethyl-2-[(4-methoxyphenyl)(propyl)amino]-4,4-diphenylb
1
ut-3-enoate (9j). Yield 62%; Yellow oil; H NMR (400 MHz,
CDCl3) δ 0.86 (dd, J = 7.5, 7.6 Hz, 3H), 0.99 (dd, J = 7.1, 7.3
Hz, 3H), 1.12 (dd, J = 7.2, 7.3 Hz, 3H), 1.12-1.29 (m, 2H),
1.66-1.80 (m, 2H), 2.88 (dq, J = 7.1, 7.4 Hz, 1H), 3.14 (dq, J =
7.1, 7.4 Hz, 1H), 3.66 (dq, J = 7.2, 10.8 Hz, 1H), 3.74-3.83 (m,
4H including singlet at 3.76 ppm, 3H), 6.50 (s, 1H), 6.72-6.76
(m, 2H), 6.84-6.88 (m, 2H), 7.06-7.32 (m, 10H); 13C NMR
(100 MHz, CDCl3) δ 8.8, 11.6, 14.0, 22.3, 30.5, 52.7, 55.3,
60.2, 70.1, 113.3, 126.9, 127.0, 127.2, 127.6, 128.0, 128.2,
129.8, 131.7, 139.4, 140.1, 141.3, 143.7, 156.2, 173.4; IR(neat)
2960, 2872, 1722, 1508, 1463, 1443, 1286, 1245, 1220, 1181,
1106, 1074, 1037, 758, 700 cm-1; HRMS(EI): Calcd for
C30H35NO3(M)+ 457.2617, found 457.2607.
Ethyl
2-[ethyl(4-methoxyphenyl)amino]-2-isopropyl-4,4-diphenyl
but-3-enoate (9e). Yield 50%; Yellow oil; 1H NMR (400 MHz,
CDCl3) δ 0.83 (dd, J = 7.0, 7.0 Hz, 3H), 1.08-1.16 (m, 9H),
2.39 (sep, J = 6.7 Hz, 1H), 2.86 (dq, J = 7.0, 13.1 Hz, 1H), 3.10
(dq, J = 7.0, 13.1 Hz, 1H), 3.20 (dq, J = 7.2, 10.5 Hz, 1H), 3.67
(dq, J = 7.2, 10.5 Hz, 1H), 3.80 (s, 3H), 5.98 (s, 1H), 6.79-6.82
(m, 2H), 6.86-6.88 (m, 2H), 7.05-7.07 (m, 2H), 7.15-7.33 (m,
8H); 13C NMR (100 MHz, CDCl3) δ 14.0, 14.7, 19.2, 20.4, 34.5,
45.4, 55.4, 60.0, 73.8, 113.3, 126.7, 126.8, 127.4, 127.4, 127.9,
128.8, 129.8, 130.2, 139.6, 140.4, 140.9, 145.0, 156.4, 173.0;
IR(neat) 2966, 2931, 1719, 1684, 1652, 1558, 1540, 1507, 1457,
1383, 1242, 1035, 842, 763, 701 cm-1; HRMS(EI): Calcd for
C30H35NO3(M)+ 457.2617, found 457.2630.
Ethyl
2-[butyl(4-methoxyphenyl)amino]-2-ethyl-4,4-diphenylbut-
1
3-enoate (9k). Yield 56%; Yellow oil; H NMR (400 MHz,
CDCl3) δ 0.85 (t, J = 7.1 Hz, 3H), 0.98 (t, J = 7.3 Hz, 3H), 1.12
(dd, J = 7.1, 7.1 Hz, 3H), 1.16-1.40 (m, 4H), 1.73 (q, J = 7.3 Hz,
2H), 2.89 (dt, J = 6.8, 13.5 Hz, 1H), 3.15-3.22 (m, 1H), 3.68
(dq, J = 7.1, 11.0 Hz, 1H), 3.72-3.83 (m, 4H including singlet
at 3.75 ppm, 3H), 6.51 (s, 1H), 6.71-6.76 (m, 2H), 6.83-6.87 (m,
2H), 7.07-7.09 (m, 2H), 7.15-7.32 (m, 8H); 13C NMR (100
MHz, CDCl3) δ 8.8, 14.0, 14.1, 20.3, 30.5, 31.4, 50.6, 55.3,
60.2, 70.1, 113.3, 126.9, 127.0, 127.2, 127.5, 128.0, 128.0,
129.8, 131.6, 139.4, 140.1, 141.3, 143.7, 156.1, 173.3; IR(neat)
2957, 2933, 1723, 1509, 1464, 1443, 1288, 1245, 1217, 1181,
1115, 1038, 758, 701 cm-1; HRMS (EI): Calcd for
C31H37NO3(M)+ 471.2773, found 471.2756.
Ethyl
2-cyclohexyl-2-[ethyl(4-methoxyphenyl)amino]-4,4-diphenyl
but-3-enoate (9f). Yield 49%; Yellow oil; 1H NMR (500 MHz,
CDCl3) δ 0.80 (dd, J = 6.8, 6.8 Hz, 3H), 1.09-1.28 (m, 8H,
including doublet at 1.11 ppm, J = 7.0, 7.0 Hz, 3H), 1.62-1.65
(m, 1H), 1.73-1.78 (m, 2H), 1.99-2.03 (m, 1H), 2.10-2.12 (m,
1H), 2.29-2.33 (m, 1H), 2.85 (dq, J = 6.8, 13.3 Hz, 1H), 3.04
(dq, J = 6.8, 13.3 Hz, 1H), 3.13-3.22 (m, 1H), 3.72 (dq, J = 7.0,
10.7 Hz, 1H), 3.80 (s, 3H), 5.98 (s, 1H), 6.79-6.85 (m, 4H),
7.05-7.33 (m, 10H); 13C NMR (125 MHz, CDCl3) δ 14.0, 14.5,
26.7, 27.0, 27.2, 28.9, 31.0, 44.9, 45.0, 55.4, 60.0, 73.6, 113.2,
126.7, 126.8, 127.4, 127.9, 129.5, 129.8, 130.2, 139.7, 140.2,
140.3, 145.0, 156.3, 173.0; IR(neat) 2926, 2853, 1721, 1509,
1445, 1241, 1213, 1179, 1036, 835, 756, 700 cm-1; HRMS(EI):
Calcd for C33H39NO3(M)+ 497.2930, found 497.2933.
Diethyl
Ethyl
2-ethyl-2-[hexyl(4-methoxyphenyl)amino]-4,4-diphenylbut-
3-enoate (9l). Yield 54%; Yellow oil; 1H NMR (400 MHz,
CDCl3) δ 0.86 (t, J = 6.9 Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H), 1.12
(dd, J = 7.2, 7.2 Hz, 3H), 1.19-1.36 (m, 8H), 1.73 (q, J = 7.4 Hz,
2H), 2.85-2.92 (m, 1H), 3.13-3.20 (m, 1H), 3.68 (dq, J = 7.2,
10.8 Hz, 1H), 3.74-3.84 (m, 4H, including singlet at 3.76 ppm,
3H), 6.51 (s, 1H), 6.70-6.76 (m, 2H), 6.82-6.87 (m, 2H),
7.06-7.09 (m, 2H), 7.15-7.32 (m, 8H); 13C NMR (100 MHz,
CDCl3) δ 8.8, 14.0, 22.7, 26.9, 29.2, 30.5, 31.8, 50.8, 55.3, 60.3,
70.2, 113.3, 126.9, 127.0, 127.2, 127.6, 128.0, 129.8, 131.6,
139.4, 140.1, 141.3, 143.8, 156.1, 173.4; IR(neat) 2955, 2930,
2856, 1723, 1508, 1465, 1443, 1288, 1245, 1181, 1115, 1038,
758, 700 cm-1; HRMS (EI): Calcd for C33H41NO3(M)+
499.3086, found 499.3065.
2-(2,2-diphenylvinyl)-2-[ethyl(4-methoxyphenyl)amino]hexa
1
nedioate (9h). Yield 58%; Yellow oil; H NMR (400 MHz,
CDCl3) δ 0.87 (dd, J = 7.0, 7.0 Hz, 3H), 1.13 (t, J = 7.2 Hz,
3H), 1.21 (dd, J = 7.2, 7.2 Hz, 3H), 1.60-1.76 (m, 3H),
1.91-2.04 (m, 1H), 2.16 (t, J = 7.1 Hz, 2H), 2.95 (dq, J = 7.0,
13.6 Hz, 1H), 3.30 (dq, J = 7.0, 13.6 Hz, 1H), 3.67 (dq, J = 7.2,
10.9 Hz, 1H), 3.77 (s, 3H), 3.80 (dq, J = 7.2, 10.9 Hz, 1H), 4.09
(q, J = 7.2 Hz, 2H), 6.47 (s, 1H), 6.73-6.77 (m, 2H), 6.84-6.87
(m, 2H), 7.09-7.33 (m, 10H); 13C NMR (100 MHz, CDCl3) δ
14.0, 14.2, 15.0, 19.9, 34.7, 37.0, 45.1, 55.3, 60.2, 60.4, 69.7,
113.4, 127.0, 127.2, 127.2, 127.6, 128.0, 128.8, 129.9, 131.3,
139.3, 139.5, 141.8, 143.5, 156.5, 173.0, 173.4; IR(neat) 2977,
2935, 1728, 1508, 1464, 1443, 1374, 1288, 1245, 1181, 1094,
1035, 834, 758, 702 cm-1; HRMS(EI): Calcd for
C33H39NO5(M)+ 529.2828, found 529.2814.
Ethyl
2-ethyl-2-[(4-methoxyphenyl)(octyl)amino]-4,4-diphenylbut
1
-3-enoate (9m). Yield 63%; Yellow oil; H NMR (400 MHz,
CDCl3) δ 0.87 (dd, J = 6.8, 6.8 Hz, 3H), 0.98 (dd, J = 7.4, 7.4
Hz, 3H), 1.12 (dd, J = 7.1, 7.1 Hz, 3H), 1.13-1.28 (m, 12H),
1.73 (dq, J = 7.4, 14.7 Hz, 2H), 2.88 (dq, J = 6.8, 6.9 Hz, 1H),
3.17 (dq, J = 6.8, 6.9 Hz, 1H), 3.68 (dq, J = 7.1, 11.0 Hz, 1H),
3.73-3.84 (m, 4H, including singlet at 3.76 ppm, 3H), 6.52 (s,
1H), 6.72-6.76 (m, 2H), 6.82-6.87 (m, 2H), 7.06-7.09 (m, 2H),
7.15-7.32 (m, 8H); 13C NMR (100 MHz, CDCl3) δ 8.8, 14.0,
14.1, 22.6, 27.2, 29.2, 29.3, 29.5, 30.5, 31.8, 50.8, 55.3, 60.2,
70.2, 113.3, 126.9, 127.0, 127.2, 127.6, 127.8, 128.0, 129.8,
131.6, 139.4, 140.1, 141.3, 143.8, 156.1, 173.4; IR(neat) 2955,
2927, 2854, 1723, 1509, 1464, 1443, 1245, 1221, 1181, 1115,
1038, 760, 701 cm-1; HRMS (EI): Calcd for C35H45NO3(M)+
527.3399, found 527.3403.
Ethyl
2-(2,2-diphenylvinyl)-2-[ethyl(4-methoxyphenyl)amino]pent
1
-4-enoate (9i). Yield 48%; Yellow oil; H NMR (400 MHz,
CDCl3) δ 0.86 (dd, J = 6.9, 6.9 Hz, 3H), 1.13 (t, J = 7.1 Hz,
3H), 2.44 (dd, J = 7.7, 14.1 Hz, 1H), 2.55 (dd, J = 6.3, 14.1 Hz,
1H), 2.97 (dq, J = 6.9, 13.4 Hz, 1H), 3.29 (dq, J = 6.9, 13.4
Hz, 1H), 3.71 (dq, J = 7.1, 10.8 Hz, 1H), 3.76 (s, 3H), 3.80 (dq,
J = 7.1, 10.8 Hz, 1H), 4.99-5.07 (m, 2H), 5.96 (dddd, J = 6.3,
7.7, 10.9, 18.1, 1H), 6.49 (s, 1H), 6.73-6.75 (m, 2H), 6.83-6.85
(m, 2H), 7.09-7.34 (m, 10H); 13C NMR (100 MHz, CDCl3) δ
14.0, 14.8, 42.4, 44.7, 55.3, 60.4, 69.8, 113.3, 117.8, 127.0,

1
Ethyl
enoate (11). Yield 18%; Yellow oil; (dr = 75 : 25); H NMR
2-ethyl-2-[isobutyl(4-methoxyphenyl)amino]-4,4-diphenylb
ut-3-enoate (9n). Yield 86%; Yellow oil; 1H NMR (400 MHz,
CDCl3) δ 0.82 (d, J = 6.4 Hz, 3H), 1.05-1.08 (m, 9H),
1.33-1.43 (m, 1H), 1.61 (dq, J = 7.2, 14.4 Hz, 1H), 1.79 (dq, J
= 7.2, 14.4 Hz, 1H), 2.93 (dd, J = 4.8, 13.0 Hz, 1H), 3.02 (dd, J
= 9.4, 13.0 Hz, 1H), 3.45 (dq, J = 7.2, 10.9 Hz, 1H), 3.58 (dq, J
= 7.2, 10.9 Hz, 1H), 3.77 (s, 3H), 6.26 (s, 1H), 6.75- 6.79 (m,
2H), 7.03-7.07 (m, 2H), 7.11-7.34 (m, 10H); 13C NMR (100
MHz, CDCl3) δ 8.4, 13.9, 20.6, 20.8, 27.0, 29.9, 55.3, 60.0,
60.4, 70.0, 113.5, 127.0, 127.1, 127.6, 128.1, 130.2, 130.3,
132.7, 139.0, 140.3, 140.9, 143.7, 157.3, 172.7; IR(neat) 2953,
2867, 1722, 1508, 1465, 1443, 1246, 1222, 1180, 1108, 1093,
1038, 836, 758, 701 cm-1; HRMS (EI): Calcd for
C31H37NO3(M)+ 471.2773, found 471.2775.
(400 MHz, CDCl3) δ 1.01 (t, J = 7.1 Hz, 3H), 1.10 (t, J = 7.1
Hz, 2.25H), 1.12 (t, J = 7.6 Hz, 0.75H), 1.66 (d, J = 7.3 Hz,
0.75H), 1.85 (d, J = 7.3 Hz, 2.25H), 2.94 (q, J = 7.2 Hz, 0.5H),
3.09 (q, J = 7.0 Hz, 1.5H), 3.73 (s, 2.25H), 3.74 (s, 0.75H),
4.10 (q, J = 7.0 Hz, 0.5H), 4.11 (q, J = 7.0 Hz, 1.5H), 5.93 (q, J
= 7.2 Hz, 0.75H), 6.25-6.33 (m, 0.75H), 6.38-6.42 (m, 1.5H),
6.67-6.70 (m, 2H), 6.94-7.00 (m, 1.25H, including singlet at
7.00 ppm, 0.75H), 7.09-7.19 (m, 4.75H, including singlet at
7.19 ppm, 0.25H); 13C NMR (125 MHz, CDCl3) δ 12.4, 14.0,
14.1, 15.5, 15.7, 45.1, 45.6, 55.6, 55.7, 60.8, 61.0, 114.1, 114.1,
114.2, 114.3, 114.9, 115.0, 115.8, 115.9, 126.0, 126.8, 126.9,
127.3, 127.6, 127.9, 128.6, 130.7, 135.2, 137.0, 137.2, 137.8,
140.2, 141.0, 151.6, 152.3, 167.8, 167.8; IR(neat) 2974, 2931,
1719, 1510, 1460, 1390, 1241, 1183, 1127, 1037, 821, 701
cm-1; HRMS(EI): Calcd for C23H27NO3(M)+ 365.1991, found
365.1991.
Ethyl
2-[but-3-en-1-yl(4-methoxyphenyl)amino]-2-ethyl-4,4-diphe
1
nylbut-3-enoate (9o). Yield 77%; Yellow oil; H NMR (400
MHz, CDCl3) δ 0.99 (t, J = 7.3 Hz, 3H), 1.12 (dd, J = 7.1, 7.1
Hz, 3H), 1.67-1.81 (m, 2H), 1.99 (q, J = 7.3 Hz, 2H), 2.98 (dt, J
= 7.4, 13.8 Hz, 1H), 3.30 (dt, J = 7.4, 13.8 Hz, 1H), 3.65 (dq, J
= 7.1, 11.0 Hz, 1H), 3.71-3.82 (m, 4H, including singlet at 3.76
ppm, 3H), 4.97-5.01 (m, 2H), 5.79-5.89 (m, 1H), 6.50 (s, 1H),
6.73-6.77 (m, 2H), 6.84-6.88 (m, 2H), 7.06- 7.08 (m, 2H),
7.15-7.32 (m, 8H); 13C NMR (100 MHz, CDCl3) δ 8.8, 14.0,
30.6, 33.6, 50.5, 55.3, 60.3, 70.1, 113.4, 115.4, 127.0, 127.1,
127.2, 127.6, 128.0, 129.8, 131.5, 137.0, 139.3, 139.7, 141.4,
143.6, 156.2, 173.3; IR(neat) 3056, 2976, 2834, 1722, 1508,
1443, 1288, 1246, 1181, 1117, 1075, 1036, 914, 758, 701 cm-1;
HRMS (EI): Calcd for C31H35NO3(M)+ 469.2617, found
469.2640.
Acknowledgement
This work was supported by Grants-in-Aid for Scientific
Research (B) and on Innovative Areas “Organic Synthesis
Based on Reaction Integration, Development of New Methods
and Creation of New Substances” from JSPS and MEXT.
Supporting Information
NMR spectra. This material is available on
http://dx.doi.org/10.1246/bcsj.***.
References
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General
procedure
for
the
tandem
N-alkylation/bromination/1,4-addition (Scheme 7). Under an
argon atmosphere, a suspension of β,γ-Alkenyl α-iminoester 4
o
(0.10 mmol) in THF (2.0 mL) was stirred at -78 C for 5 min,
and to it was added EtMgBr in THF solution (1.1 equiv). After
o
o
stirring for 5 min at -78 C, the mixture was warmed to 40 C
immediately and stirred for 20 min. After the consumption of
substrate was confirmed by TLC, the mixture was cooled to 0
oC and stirred for 5 min, and to it was added NBS (1.5 equiv).
After stirring for 15 min, to it was added copper reagent in THF
solution (1.2 equiv), which was prepared by mixing CuCN (1.2
equiv) in THF (2.0 mL) and EtMgBr in THF (1.2 equiv) at 0 oC
for 40 min, and the mixture was warmed to room temperature
and stirred for 1 h. The reaction was quenched with sat.
NaHCO3 aq. (3.0 mL), and the whole mixture was extracted
with ethyl acetate (10 mL x 3). The combined extracts were
washed with brine, dried over anhydrous Na2SO4, and
concentrated in vacuo. The crude product was purified by silica
gel chromatography (n-hexane/ethyl acetate = 10 / 1) to give
the desired compound.
2.
Ethyl
(Z)-2-[ethyl(4-methoxyphenyl)amino]-4,4-diphenylhex-2-en
oate (10). Yield 23%; Yellow oil; 1H NMR (400 MHz, CDCl3)
δ 0.64 (t, J = 7.3 Hz, 3H), 0.99 (t, J = 7.2 Hz, 3H), 1.11 (t, J =
7.1 Hz, 3H), 2.36 (q, J = 7.3 Hz, 2H), 2.94 (q, J = 7.2 Hz, 2H),
3.73 (s, 3H), 4.09 (q, J = 7.1 Hz, 2H), 6.32-6.36 (m, 2H),
6.66-6.70 (m, 2H), 7.13-7.25 (m, 10H), 7.54 (s, 1H); 13C
NMR(100 MHz, CDCl3) δ 9.9, 12.0, 14.1, 30.6, 45.8, 53.2,
55.6, 60.9, 114.1, 114 6, 126.0, 127.8, 128.4, 134.8, 141.2,
144.8, 145.8, 151.7, 167.6; IR(neat) 2933, 1717, 1684, 1653,
1559, 1541, 1509, 1457, 1376, 1242, 1036, 819, 755, 701, 562
cm-1; HRMS(EI): Calcd for C29H33NO3(M)+ 443.2460, found
443.2476.
3.
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(2Z)-2-[ethyl(4-methoxyphenyl)amino]-4-phenylhexa-2,4-di

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Graphical Abstract
<Title>
Synthesis of δ-Lactone and Amino Acid Frameworks Utilizing the Umpoled Reactivity of β,γ-Alkenyl α-Iminoester
<Authors' names>
M. Kawanishi, I. Mizota, K. Aratake, H. Tanaka, K. Nakahama, M. Shimizu
<Summary>
An umpolung N-alkylation reaction of β,γ-alkenyl α-iminoesters was studied, and various tandem reactions were found utilizing this
N-alkylation.
A novel synthesis of δ-lactones and α-quaternary alkenyl amino esters was developed by tandem
N-alkylation/vinylogous aldol-type reaction and the tandem N-alkylation/bromination/C-alkylation, which these methods are
operationally simple and useful, and exhibit broad substrate generality.
<Diagram>
Nu
N
O
O
R3
Nu
R1
R3
O
R2
N
R4
R1
R2
R3
Nu
R2
N
OR4
ꢀ-Lactone
R1
CO2R4
Nu
N-Alkylation
Quaternary Amino Acid