N-allylideneamines derived from acrolein: synthesis and use as acceptors of two nucleophiles

Article abstract of DOI:10.1002/ejoc.200900457

Two practical methods have been developed for the preparation of N-allylideneamines 1b,c. One involves the isomerlzation of propargylamines and the other the dehydration of acrolein. N-Allylideneamines 1b,c thus prepared, were used as efficient substrates

Full text of DOI:10.1002/ejoc.200900457

FULL PAPER
DOI: 10.1002/ejoc.200900457
N-Allylideneamines Derived from Acrolein: Synthesis and Use as Acceptors of
Two Nucleophiles
Isao Mizota,[a] Yuri Matsuda,[a] Iwao Hachiya,[a] and Makoto Shimizu*[a]
Keywords: Amines / Allylic compounds / Nucleophilic addition / Regioselectivity / Amino acids
Two practical methods have been developed for the prepara-
as efficient substrates for 1,4- and 1,2-double nucleophilic
tion of N-allylideneamines 1b,c. One involves the isomeriza- addition reactions.
tion of propargylamines and the other the dehydration of
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
acrolein. N-Allylideneamines 1b,c thus prepared were used
Germany, 2009)
Introduction
Results and Discussion
N-Allylideneamines 1 derived from acrolein are impor-
The most direct way to synthesize this particular imine
tant building blocks because they consist of three carbon involves the dehydration reactions of acrolein and primary
atoms bearing useful amino and olefin moieties for further amines (Scheme 1). However, several attempts using a vari-
functional group manipulations. Although we have already ety of dehydration conditions led to the formation of only
reported that various amino esters can be synthesized by traces of the imine.
1,4- and 1,2-double nucleophilic addition to α,β-unsatu-
rated imines and N-allylideneamines, the simplest α,β-un-
saturated imines are not readily accessible. Because imines
1 have high reactivity and are prone to polymerize even
Scheme 1. The dehydration reaction between acrolein and primary
during their preparation, their synthesis is difficult and thus
only a few reports are available for the synthesis of this type
of imine.[1] Although the use of imine 1 bearing a TBS
group at the nitrogen atom was reported by Colvin et al.
for β-lactam synthesis, it has not been used for other reac-
tions.[1d,2] The TMS-protected derivative has also been pre-
pared in situ from acrolein and used in the total synthesis
of (+/–)-sedridine. However, the formation of this particular
derivative was only confirmed by GC analysis.[1c] Another
analogous imine protected with an electron-withdrawing
group at the nitrogen atom has been reported by Davis and
Deng.[1a] Unfortunately, this imine did not work as an effec-
tive acceptor in 1,4- and 1,2-nucleophilic addition reactions
in our experiments.[3] We therefore embarked on the search
for a practical synthesis of stable N-allylideneamines 1.
Herein we report the synthesis of N-allylideneamines 1 and
their subsequent double nucleophilic addition reactions.[4]
amines.
Because there appear to be several routes to prepare N-
allylideneamine 1 besides dehydration, three approaches,
(1) the formation of trimethylsilyl-protected imine followed
by desilylation, (2) the dehydrogenation of allylamines, and
(3) the isomerization of propargylamines, were next exam-
ined (Scheme 2).
Scheme 2. Strategy for preparing N-allylideneamine.
[a] Department of Chemistry for Materials, Graduate School of
Engineering, Mie University,
Tsu, Mie 514-8507, Japan
Fax: +81-59-231-9413
E-mail: mshimizu@chem.mie-u.ac.jp
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900457.
The 3-trimethylsilylated acrolein was readily iminated to
give imine 2 in 81% yield. However, desilylation with TBAF
only led to the polymerization of the product (Scheme 3).
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I. Mizota, Y. Matsuda, I. Hachiya, M. Shimizu
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Scheme 5. Benzophenone formation.
Isomerization of propargylamines 6 was next carried out
(Table 2). Starting propargylamines 6 were readily prepared
in good yields (Scheme 6). When the diphenylmethyl deriva-
tive was used, the reaction afforded the isomerized benzo-
phenone imine (Table 2, Entry 2). With trityl and diphenyl-
ethyl groups, desired N-allylideneamines 1 were isolated in
high yields (Table 2, Entries 4–6).
Scheme 3. Imination of the 3-trimethylsilylated acrolein.
Next, the dehydrogenation of allylamines 3 was exam-
ined by using a variety of reagents; allylamines 3a–c were
prepared by simple allylation of the primary amines
(Scheme 4). The results of the dehydrogenation reactions
are shown in Table 1.
Table 2. Isomerization of propargylamines 6.
Yield
[%]
Entry
R
Temp.
Time
N-Allylideneamine
1
2
3
4
5
6
PMP
CHPh2
tBu
CCH3Ph2
CCH3Ph2
CPh3
r.t.
r.t.
40 °C
45 °C
r.t.
3 h
5 h
1 h
1 h
10 min
4 h
–
–
–
1b
1b
1c
–
–
–
86
86
78
[a]
r.t.
[a] Isomerized benzophenone imine was obtained.
Scheme 4. Preparation of allylamines 3a–c.
Table 1. Dehydrogenation of allylamines.
Entry
R
Solvent
Oxidant
Conditions Yield [%]
1
2
3
4
5
6
PMP
PMP
PMP
CHPh2
CHPh2
CPh3
CH2Cl2
CH3CN
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
MnO2
MnO2
DDQ
MnO2
SeO2
r.t., 12 h
reflux, 9 h
r.t., 12 h
reflux, 8 h
r.t., 1 d
–
–
–
Scheme 6. Preparation of propargylamines 6.
[a]
–
–
–
A facile isomerization mechanism is described below.
Propargylamines 6 are deprotonated with potassium tert-
butoxide to afford the alleneamine. Subsequent protonation
with tert-butyl alcohol gave N-allylideneamine 1b by imine–
enamine tautomerism (Scheme 7).
MnO2
r.t., 14 h
[a] Benzophenone was obtained in 66% yield.
Although various oxidants such as MnO2, DDQ, and
SeO2 were used, oxidized imine 1 was not obtained (Table 1,
Entries 1–5). When the allylamine protected with the di-
phenylmethyl group was oxidized with MnO2 at reflux in
CH2Cl2, only benzophenone (5) was obtained (Table 1, En-
try 4; Scheme 5). The formation of benzophenone may in-
volve the oxidation of the diphenylmethyl moiety. These re-
sults suggest that a relatively stable derivative of the desired
N-allylideneamine might have a bulky substituent at the ni-
trogen atom without a hydrogen α to the nitrogen. However,
the oxidation product was not formed when an allylamine
Scheme 7. Mechanism of the isomerisation reaction.
To find more direct alternatives, the dehydration of acro-
with a bulky trityl group was used, but recovery of the start- lein with bulky amines was again examined in the presence
ing material was observed (Table 1, Entry 6). of Ti(OEt)4, a relatively weak Lewis acid. Indeed, the reac-
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N-Allylideneamines Derived from Acrolein
tion proceeded smoothly to afford N-allylideneamines 1b,c allylideneamine with a diphenylethyl group also led to the
bearing
a
diphenylethyl or trityl group, respectively decomposition of the imine in the presence of AlCl3 and
(Scheme 8).
TiCl4 (Table 3).
Table 3. Double nucleophilic addition reactions using Lewis acids.
Scheme 8. Preparation of N-allylideneamines bearing a diphenyle-
thyl or trityl group.
To study the characteristics of these N-allylideneamines,
the LUMO coefficients of the carbonyl (or imino) and β
carbon atoms were calculated, which should provide an in-
dication of the regioselectivities of the nucleophilic addition
reactions.[5] Based on molecular orbital calculations, the
electronic and steric effects of the substituent at the imino
nitrogen atom should be rationalized (Figure 1).[6]
[a] tBuC6H4SCPh3 was obtained in 43% yield. [b] tBuC6H4SCPh3
was obtained in 50% yield.
However, when Ti(OiPr)4 was used as a Lewis acid, the
formation of the 1,2 adduct of TMSCN as a byproduct was
1
confirmed by H NMR spectroscopy (Scheme 9). These re-
sults indicate that proton sources might be essential.[4j] The
reaction was then carried out in the presence of 4 Å molecu-
lar sieves containing one equivalent of H2O to give the de-
sired 1,4- and 1,2-addition product 7aa in 63% yield. Be-
cause the presence of a limited amount of H2O affected the
double addition, the reaction conditions were examined in
detail and the results are summarized in Table 4.
Figure 1. LUMO coefficients of acrolein and N-allylideneamine.
Structures were fully optimized at the HF/6-31G* level
of theory by geometry optimization. The calculations were
shown to be comparable to the ab initio (HF/STO-3G)
method.[7] The values of the LUMO coefficients at each re-
action site (the 2- and 4-positions) and the absolute differ-
ences between these coefficients for the optimized geome-
tries are given for comparison (Figure 1). Comparison of
the LUMO coefficients of acrolein and N-allylideneamine
1b provides an indication of the regioselectivity of the 1,4-
and 1,2-addition reactions. Both acrolein and N-allylidene-
amine 1b have larger coefficients at the 4-position, and the
major reaction course based on the HOMO–LUMO inter-
Scheme 9. Double nucleophilic addition reactions of N-allylidene-
amine.
The best result was obtained when the addition was car-
action would be 1,4-addition. Steric factors suggest that it ried out with three equivalents of each nucleophile in the
would be easier for the N-allylideneamines to be attacked presence of 4 Å MS containing three equivalents of H2O
at the 4-position than acrolein.
without the use of Ti(OiPr)4 as a Lewis acid (Table 4, En-
1,4- and 1,2-Double nucleophilic additions to N-allylid- try 10). Because the presence of Ti(OiPr)4 was not essential
eneamine were next examined by using ketene silyl acetals the effect of additives as reaction promoters was next exam-
(KSAs) and trimethylsilyl cyanide (TMSCN). When the re- ined and the results are shown in Table 5. N-Allylidene-
action was carried out with N-allylideneamine bearing a trit- amine 1b was treated with a mixture of ketene silyl acetal
yl group, it decomposed in the presence of Lewis acids and TMSCN in the presence of various additives to give
such as AlCl3, TiCl4, and Ti(OiPr)4. Similarly, the use of N- doubly alkylated product 7aa.
Eur. J. Org. Chem. 2009, 4073–4084
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Table 4. Examination of reaction conditions in the synthesis of 7aa.
Table 6. Examination of the effect of different forms of silica gel
on the reaction.
Entry
Ti(iPrO)4
[equiv.]
4 Å MS (H2O)
KSA
[equiv.]
TMSCN
[equiv.]
Yield
[%]
[equiv.]
Entry
SiO2 gel
Yield [%]
1
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
0.5
0.5
0.5
0.5
–
1
3
6
3
1
3
6
3
1
3
6
3
3.0
3.0
3.0
1.5
3.0
3.0
3.0
1.5
3.0
3.0
3.0
1.5
3.0
3.0
3.0
1.5
3.0
3.0
3.0
1.5
3.0
3.0
3.0
1.5
6
63
35
54
61
67
62
55
23
69
63
65
1
2
3
4
Spherical, dry, 2.5 g/mmol
Irregular, dry, 2.5 g/mmol
Spherical, H2O (3 equiv.)
Spherical, H2O (6 equiv.)
76
65–82
42
47
The double nucleophilic addition reactions were next
carried out with various ketene silyl acetals under the opti-
mized conditions and the results are summarized in Table 7.
9
10
11
12
–
–
–
Table 7. Examination of 1,4-nucleophiles for the double nucleo-
philic addition and deprotection reactions with N-allylideneamine
bearing the diphenylethyl group.
Table 5. Examination of the effect of additives on the synthesis of
7aa.
Entry
Additive
(equiv.)
KSA
[equiv.]
TMSCN
[equiv.]
Yield
[%]
1
2
3
4
5
6
7
8
MeOH (3.0)
PhOH (3.0)
AcOH (3.0)
3.0
3.0
3.0
1.5
3.0
3.0
3.0
3.0
3.0
3.0
3.0
1.5
3.0
3.0
3.0
3.0
20
33
27
30
13
21
80
83
Na2SO4·10H2O (0.3)
Amberlyst 15DRY (3.0)
SiO2 gel (dry, 0.3 g/mmol)
SiO2 gel (dry, 1.5 g/mmol)
SiO2 gel (dry, 2.5 g/mmol)
Dried silica gel was the most effective additive in this
reaction.[8] In the presence of 0.3 g/mmol of silica gel, the
1,4- and 1,2-addition product was isolated in 21% yield,
whereas the use of 2.5 g/mmol of silica gel gave the 1,4- and
1,2-addition product in 83% yield (Table 5, Entries 6 and
8). The use of other promoters such as MeOH, PhOH,
AcOH, Na2SO4·10H2O, and Amberlyst 15DRY gave 1,4-
and 1,2-addition product 7aa in low yields (Table 5, En-
tries 1–5).
The use of ketene silyl acetals derived from ethyl and
It was also discovered that the shape and form of the methyl isobutyrate gave desired 1,4 and 1,2 adducts 7aa and
silica gel influenced the product yields (Table 6). Dried 7ab in high yields (Table 7, Entries 1 and 2). The use of
spherical silica gel was found to be effective for the reaction. ketene silyl thioacetal (KSTA)[4h] also gave the desired 1,4-
Similarly, the dried irregular analogue gave the product in and 1,2-addition adduct 7ag in 56% yield (Table 7, En-
good yield, although the reproducibility of the reaction was try 7). Because of the instability of some of the 1,4- and
somewhat lost (Table 6, Entry 2). The addition of H2O led 1,2-addition products,[9] the transformation into the amino
to a decrease in the yield (Table 6, Entries 3 and 4).
nitriles was next carried out. The use of 1.5 equivalents of
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N-Allylideneamines Derived from Acrolein
ketene silyl acetals and 1.2 equivalents of TMSCN gave the Table 8. Examination of 1,4-nucleophiles for the double nucleo-
philic addition and deprotection reactions with N-allylideneamine
bearing the trityl group.
best results. Amino nitrile 8a was obtained in 78% yield on
quenching the reaction with TFA after the double nucleo-
philic addition reaction (Table 7, Entry 1). Under the best
reaction conditions, the double nucleophilic addition of
various ketene silyl acetals and TMSCN to N-allylidene-
amine 1b proceeded smoothly to give the 1,4–1,2 products
8b–f in moderate-to-high yields (Table 7, Entries 2–6).
Because the 1,4- and 1,2-addition products obtained
from N-allylideneamine bearing the diphenylethyl group
were not stable, the reactions of the N-allylideneamine bear-
ing the trityl group were next investigated (Table 8). These
reactions also proceeded smoothly to give the 1,4–1,2 ad-
ducts 7ba–7bi, which were all reasonably stable, in moder-
ate-to-high yields (Table 8, Entries 1–9). With a disubsti-
tuted ketene silyl thioacetal, the N-allylideneamine was con-
verted into product 7bg but in a low yield (Table 8, En-
try 7). However, when a trisubstituted ketene silyl acetal
was used, 1,4-addition did not proceed (Table 8, Entry 10).
Silyl enol ether was also not an effective nucleophile in this
reaction (Table 8, Entry 11).
Similarly, transformation to the unprotected amino ni-
trile after the double nucleophilic addition was next exam-
ined (Table 8). It was found that various ketene silyl acetals
were good nucleophiles for N-trityl-N-allylideneamine (1c).
In fact, by using the ketene silyl acetal derived from isopro-
pyl isobutyrate, amino nitrile 8d was obtained in good yield,
which is in contrast to the result obtained with 1b (Table 7,
Entry 4).
When the trisubstituted ketene silyl thioacetal derived
from S-cyclohexyl propanethioate was used in the double
nucleophilic addition, followed by conversion into an
amino nitrile by quenching with TFA, valerolactam 10a was
obtained in high yield by cyclization of the amino nitrile
due to the high leaving ability of the alkylthio group
(Table 9, Entry 1). Valerolactams are often observed in nat-
ural products, and many of them are currently of great
interest because of their unique biological activities.[10]
1
Thus, valerolactams were synthesized by using various ke-
tene silyl thioacetals. The 1,4- and 1,2-double nucleophilic
addition reactions proceeded smoothly and 1,4–1,2 adducts
9a–f were obtained in moderate-to-good yields (Table 9,
Entries 1–6) when trisubstituted ketene silyl thioacetals
were used. A tetrasubstituted analogue also gave product
9g in moderate yield (Table 9, Entry 7). Valerolactams 10
were obtained in moderate-to-high yields under conditions
B (Table 9, Entries 1–7).
[a] Although the formation of valerolactam was confirmed by H
NMR spectroscopy, isolation was not successful. [b] dr = 53:47.
Conclusions
N-Allylideneamines have successfully been prepared in
high yields. Although previous double nucleophilic addition
From these results we have proposed a plausible mecha- reactions used strong Lewis acids such as TiCl4 or AlCl3, it
nism for the reaction, as shown in Scheme 10. First, the N- has been discovered that even the use of silica gel, a weak
allylideneamine was activated with silica gel followed by the acid, promoted the double nucleophilic addition.[11,12] Tet-
1,4-addition of ketene silyl (thio)acetal to give an intermedi- rasubstituted ketene silyl acetals and trisubstituted ketene
ary enamine species 11. Isomerization to the iminium ion silyl thioacetals were found to be useful reagents for this
was then promoted by silica gel followed by 1,2-addition of reaction. Amino nitriles and valerolactams were synthesized
TMSCN to give the 1,4- and 1,2-addition product.
in good yields using ketene silyl acetals and silyl thioacetals
The hydrolysis of the nitrile moiety of amino nitrile 8a under the influence of TFA, which removed the diphenyl-
was also readily achieved with aqueous HCl in AcOH at ethyl and trityl protecting groups. Moreover, hydrolysis of
reflux to give amino acid 12 in high yield (Scheme 11).
the amino nitrile moiety was readily achieved to yield the
amino acid in high yield.
Eur. J. Org. Chem. 2009, 4073–4084
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I. Mizota, Y. Matsuda, I. Hachiya, M. Shimizu
FULL PAPER
Table 9. Examination of 1,4-nucleophiles for double nucleophilic addition and transformation to valerolactam using N-allylideneamine
bearing a trityl group.
[a] Ketene silyl thioacetal (Z/E = 91:9) was used. [b] Ketene silyl thioacetal (Z/E = 92:8) was used. [c] Treatment with TFA at room
temperature for 10 min. [d] The reaction time was 24 h.
Scheme 10. Proposed mechanism for the formation of the amino nitriles.
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N-Allylideneamines Derived from Acrolein
Scheme 11. Hydrolysis of amino nitrile 8a.
3055, 1637, 1600, 1488, 1445, 1034, 1002, 699 cm–1. HRMS (EI):
calcd. for C22H19N [M]+ 297.1518; found 297.1516.
N-(1,1-Diphenylethyl)prop-2-ynamine (6a): Under argon, a suspen-
sion of Na2CO3 (2.54 g, 23.9 mmol) in C2H4Cl2 (50 mL) was stirred
at room temperature for 10 min. A solution of 1,1-diphenylethana-
mine in C2H4Cl2 (15 mL) was added to the mixture. After stirring
for 10 min, 3-bromoprop-1-yne was added to the mixture. The mix-
ture was heated at reflux for 13 h. H2O (10 mL) was then added to
quench the reaction, and the mixture was extracted with CH2Cl2
(3ϫ5.0 mL). The combined extracts were dried with Na2SO4 and
concentrated in vacuo to give the crude product. It was purified by
column chromatography on silica gel (n-hexane/ethyl acetate, 4:1)
to give title compound 6a (3.06 g, 54%). Yellow oil. 1H NMR
(500 MHz, CDCl3): δ = 1.81 (s, 3 H, Ph2CCH3), 1.87 (br. s, 1 H,
NH), 2.17 (t, J = 2.4 Hz, 1 H, NCH2CCH), 3.15 (d, J = 2.4 Hz, 2
H, NCH2CCH), 7.20–7.36 (m, 10 H, ArH) ppm. 13C NMR
(126 MHz, CDCl3): δ = 27.6, 32.8, 62.8, 70.8, 82.9, 126.6, 127.0,
Experimental Section
General: Infrared spectra were recorded with a JASCO FT/ IR-460
1
plus spectrometer. H and 13C NMR spectra were recorded with a
JEOL EX-270, ECX-400P, or A-500 spectrometer using tetrameth-
ylsilane as an internal standard. Mass spectra were recorded with a
JEOL MS-700D spectrometer. Dichloromethane was distilled from
calcium hydride and stored over 4 Å molecular sieves. THF was
distilled from benzophenone ketyl immediately before use. MeOH
was distilled from magnesium and stored over 3 Å molecular sieves.
Products were purified by column chromatography on silica gel
(Kanto Chemical Co., Silica 60N) and/or preparative TLC on silica
gel (Merck Kiesel Gel PF254).
128.1, 147.0 ppm. IR (neat): ν = 3291, 3058, 3024, 2978, 2834,
˜
1491, 1444, 1373, 1027, 762, 700 cm–1. HRMS (EI): calcd. for
C17H17N [M]+ 235.1361; found 235.1363.
General Procedure for the 1,4- and 1,2-Double Nucleophilic Addition
Reactions of Ketene Silyl (Thio)acetals and Trimethylsilyl Cyanide
(Table 7, Entry 1; product 7aa): Under argon, a suspension of N-
allylideneamine 1b (47.1 mg, 0.20 mmol) in CH2Cl2 (1.0 mL) was
stirred at room temperature for 10 min. Dried silica gel (500 mg)
and CH2Cl2 (0.30 mL) were added to the mixture, which was co-
oled to –78 °C. A solution of (1-ethoxy-2-methylprop-1-enyloxy)
trimethylsilane (113.0 mg, 0.60 mmol) in CH2Cl2 (0.90 mL) was
added to the mixture. After stirring for 10 min, a solution of tri-
methylsilyl cyanide (59.5 mg, 0.60 mmol) in CH2Cl2 (0.80 mL) was
added to the resulting mixture. The mixture was gradually warmed
to room temperature over 17 h. Saturated aqueous NaHCO3
(10 mL) was added to quench the reaction. The mixture was filtered
with suction through a Celite pad and washed with ethyl acetate.
The mixture was extracted with ethyl acetate (3ϫ5.0 mL). The
combined extracts were dried with Na2SO4 and concentrated in
vacuo to give the crude product. Purification on buffered silica gel
TLC (n-hexane/ethyl acetate, 5:1) gave the compound 7aa (63.0 mg,
N-Allylidene-1,1-diphenylethylamine (1b): 1,1-Diphenylethylamine
(493 mg, 2.50 mmol), DCM (5.0 mL), acrolein (0.18 mL,
2.75 mmol), and Ti(OEt)4 (2.6 mL, 12.5 mmol) were placed in a 30-
mL two-necked round-bottomed flask equipped with a magnetic
stirring bar, a rubber septum, and an argon balloon. The solution
was stirred for 15 h at room temperature, quenched with ice/H2O
(5.0 mL), and filtered. The white precipitate was washed with DCM
(3ϫ10 mL), and the aqueous phase was separated and extracted
with DCM (3ϫ5.0 mL). The combined organic phases were
washed with brine (15 mL), dried (Na2SO4), and concentrated. The
residue was distilled under reduced pressure (137 °C/0.30 Torr) to
give title compound 1b (359 mg, 61%). White crystals; m.p. 36–
37 °C; b.p. 137 °C/0.30 Torr. 1H NMR (500 MHz, CDCl3): δ = 1.89
(s,
3
H, Ph2CCH3), 5.54 [dd,
J
=
0.9, 17.4 Hz,
1
1
H,
H,
NCHCHCHH(trans)], 5.74 [dd,
J
= 0.9, 10.2 Hz,
NCHCHCHH(cis)], 6.66 (ddd, J = 8.9, 10.2, 17.4 Hz, 1 H,
NCHCHCH2), 7.20–7.32 (m, 10 H, ArH), 7.50 (d, J = 8.9 Hz, 1
H, NCHCHCH2) ppm. 13C NMR (126 MHz, CDCl3): δ = 29.5,
69.4, 126.5, 126.9, 127.8, 128.0, 137.9, 147.2, 161.4 ppm. IR (neat):
1
83%). Yellow oil. H NMR (500 MHz, CDCl3): δ = 1.15 (s, 3 H,
COCCH3CH3), 1.16 (s, 3 H, COCCH3CH3), 1.23 (t, J = 7.0 Hz, 3
H, COOCH2CH3), 1.58–1.71 (m, 4 H, NHCHCNCH2CH2), 1.95
(s, 3 H, Ph2CCH3), 1.97 (br. s, 1 H, NH), 3.27 (br. s, 1 H,
NHCHCN), 4.10 (q, J = 7.0 Hz, 2 H, COOCH2CH3), 7.21–7.37
(m, 10 H, ArH) ppm. 13C NMR (67.8 MHz, CDCl3): δ = 14.2,
24.9, 25.2, 27.8, 31.3, 35.9, 41.7, 44.8, 60.5, 63.1, 121.8, 126.5,
126.9, 127.1, 127.3, 128.2, 128.3, 145.7, 147.6, 177.2 ppm. IR
ν = 3057, 3024, 2979, 2871, 1641, 1604, 1490, 1444, 1026, 997,
˜
700 cm–1. HRMS (EI): calcd. for C17H17N [M]+ 235.1361; found
235.1350.
N-Allylidenetriphenylmethylamine (1c): Triphenylmethylamine
(5.44 g, 21.0 mmol), DCM (42 mL), acrolein (1.5 mL, 23.1 mmol),
and Ti(OEt)4 (22 mL, 105 mmol) were placed in a 100-mL two-
necked round-bottomed flask equipped with a magnetic stirring
bar, a rubber septum, and an argon balloon. The solution was
stirred for 31 h at room temperature, quenched with ice/H2O
(15 mL), and filtered. The white precipitate was washed with DCM
(3ϫ10 mL), and the aqueous phase was separated and extracted
with DCM (3ϫ5.0 mL). The combined organic phases were
washed with brine (15 mL), dried (Na2SO4), and concentrated. The
residue was recrystallized from toluene to give title compound 1c
(3.43 g, 55%). White crystals; m.p. 173–174 °C. 1H NMR
(500 MHz, CDCl3): δ = 5.56 [dd, J = 0.9, 17.4 Hz, 1 H,
(neat): ν = 3334, 3059, 3025, 2978, 2935, 2873, 2289, 1724, 1599,
˜
1474, 1389, 1186, 1142, 762, 702 cm–1. HRMS (EI): calcd. for
C24H30N2O2 [M]+ 378.2307; found 378.2296.
7ab: Yield: 63.5 mg, 87%. Yellow oil. 1H NMR (500 MHz, CDCl3):
δ = 1.16 (s, 3 H, COCCH3CH3), 1.17 (s, 3 H, COCCH3CH3), 1.59–
1.68 (m, 4 H, NHCHCNCH2CH2), 1.94 (s, 3 H, Ph2CCH3), 1.98
(br. s, 1 H, NH), 3.27 (br. s, 1 H, NHCHCN), 3.64 (s, 3 H, CO-
OCH3), 7.21–7.37 (m, 10 H, ArH) ppm. 13C NMR (126 MHz,
CDCl3): δ = 24.9, 25.2, 27.7, 31.2, 35.9, 41.8, 44.8, 51.8, 63.1, 121.7,
126.4, 126.8, 127.1, 127.3, 128.2, 128.3, 145.7, 147.6, 177.6 ppm.
IR (neat): ν = 3546, 3338, 3020, 2979, 2230, 1724, 1642, 1447, 1216,
˜
1144, 757, 703 cm–1. HRMS (EI): calcd. for C23H28N2O2 [M]+
364.2151; found 364.2146.
NCHCHCHH(trans)], 5.79 [dd,
J = 0.9, 10.1 Hz, 1 H,
NCHCHCHH(cis)], 6.77 (ddd, J = 8.9, 10.1, 17.4 Hz, 1 H,
NCHCHCH2), 7.17–7.30 (m, 15 H, ArH), 7.51 (d, J = 8.9 Hz, 1
7ae: Yield: 70.5 mg, 87%. Yellow oil. 1H NMR (500 MHz, CDCl3):
H, NCHCHCH2) ppm. 13C NMR (126 MHz, CDCl3): δ = 78.5, δ = 1.16–1.37 [m, 6 H, COC(CH2)5], 1.54–1.64 [m, 8 H, COC(CH2)
126.8, 127.4, 127.7, 129.8, 137.9, 145.5, 162.2 ppm. IR (neat): ν =
and NHCHCNCH2CH2], 1.94 (s, 3 H, Ph2CCH3), 2.02–2.04 (m,
˜
5
Eur. J. Org. Chem. 2009, 4073–4084
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4079

I. Mizota, Y. Matsuda, I. Hachiya, M. Shimizu
FULL PAPER
1 H, NH), 3.23 (br. s, 1 H, NHCHCN), 3.66 (s, 3 H, COOCH3), 2936, 2879, 2231, 1718, 1473, 1393, 1216, 1181, 760 cm–1. HRMS
7.21–7.36 (m, 10 H, ArH) ppm. 13C NMR (126 MHz, CDCl3): δ = (EI): calcd. for C11H20N2O2 [M]+ 212.1525; found 212.1524.
23.0, 23.0, 25.7, 27.7, 30.4, 33.8, 34.0, 44.8, 46.5, 51.6, 63.1, 121.8,
8d: Yield: 11.5 mg, 27%. Colorless oil. 1H NMR (400 MHz,
CDCl3): δ = 1.16 (s, 6 H, COCCH3CH3), 1.21 (d, J = 6.4 Hz, 6
H, COOCHCH3CH3), 1.62 (br. s, 2 H, NH2), 1.66–1.71 (m, 4 H,
NH2CHCNCH2CH2), 3.60–3.66 (m, 1 H, NH2CHCN), 4.97 (sept,
J = 6.4 Hz, 1 H, COOCHCH3CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 21.8, 25.1, 25.3, 31.2, 36.0, 41.7, 43.8, 67.8, 122.0,
126.4, 126.9, 127.1, 127.3, 128.2, 128.3, 145.7, 147.6, 176.6 ppm.
IR (neat): ν = 3332, 3085, 3059, 3022, 2936, 2857, 2229, 1725, 1599,
˜
1449, 1210, 1135, 758, 702 cm–1. HRMS (EI): calcd. for
C26H32N2O2 [M]+ 404.2464; found 404.2445.
7ag: Yield: 44.5 mg, 56%. Yellow oil. 1H NMR (500 MHz, CDCl3):
δ
=
1.45 (s,
9
H, SCCH3CH3CH3), 1.70–1.80 (m,
4
H, 176.7 ppm. IR (neat): ν = 3585, 3382, 3314, 2979, 2936, 2874, 2229,
˜
NHCHCNCH2CH2), 1.96 (s including a br. s, 4 H, Ph2CCH3 and
NH), 2.40 (dt, J = 2.4, 7.0 Hz, 2 H, COCH2), 3.28–3.31 (m, 1 H,
NHCHCN), 7.21–7.38 (m, 10 H, ArH) ppm. 13C NMR (126 MHz,
CDCl3): δ = 21.4, 27.7, 29.8, 34.6, 43.3, 44.1, 48.1, 63.1, 121.8,
126.4, 126.9, 127.2, 127.3, 128.2, 128.4, 145.6, 147.6, 199.4 ppm.
1718, 1614, 1473, 1375, 1183, 1108 931, 885 cm–1. HRMS (EI):
calcd. for C11H20N2O2 [M]+ 212.1525; found 212.1529.
8e: Yield: 34.4 mg, 76%. Colorless oil. 1H NMR (500 MHz,
CDCl3): δ = 1.21–1.39 [m, 4 H, COC(CH2)5], 1.55–1.71 [m, 10 H,
COC(CH2)5 and NH2CHCNCH2CH2], 2.07 (d, J = 11.3 Hz, 2 H,
IR (neat): ν = 3332, 3059, 3024, 2962, 2925, 2228, 1681, 1600, 1449,
˜
NH2), 3.60–3.63 (m,
1 H, NH2CHCN), 3.70 (s, 3 H,
759, 702 cm–1. HRMS (EI): calcd. for C24H30N2OS [M]+ 394.2079;
found 394.2072.
COOCH3) ppm. 13C NMR (126 MHz, CDCl3): δ = 23.0, 23.0, 25.7,
30.2, 33.8, 34.0, 35.6, 43.6, 46.4, 51.6, 121.8, 176.6 ppm. IR (neat):
General Procedure for the Transformation into Amino Nitriles for
the Deprotection of the 1,4- and 1,2-Double Nucleophilic Adducts
(Table 7, Entry 1; product 8a): Under argon, a suspension of N-
allylideneamine 1b (47.1 mg, 0.20 mmol) in CH2Cl2 (1.0 mL) was
stirred at room temperature for 10 min. Dried silica gel (500 mg)
and CH2Cl2 (0.30 mL) were added to the reaction mixture, which
was cooled to –78 °C. A solution of (1-ethoxy-2-methylprop-1-en-
yloxy)trimethylsilane (56.5 mg, 0.30 mmol) in CH2Cl2 (0.90 mL)
was added to the mixture. After stirring for 10 min, a solution of
trimethylsilyl cyanide (23.8 mg, 0.24 mmol) in CH2Cl2 (0.80 mL)
was added to the resulting mixture. The mixture was gradually
warmed to room temperature over 17 h. The reaction mixture was
then cooled to 0 °C, distilled TFA (1.0 mL) was added, and the
mixture stirred for 15 min. A 10% aqueous Na2CO3 solution
(10 mL) was added to quench the reaction. The mixture was filtered
with suction through a Celite pad and washed with ethyl acetate
and the mixture was extracted with ethyl acetate (3ϫ5.0 mL). The
combined extracts were dried with Na2SO4 and concentrated in
vacuo to give the crude product, which was purified by column
chromatography on silica gel (n-hexane/ethyl acetate, 1:1) to give
title compound 8a (31.0 mg, 78%). Colorless oil. 1H NMR
(500 MHz, CDCl3): δ = 1.20 (s, 6 H, COCCH3CH3), 1.26 (t, J =
7.0 Hz, 3 H, COOCH2CH3), 1.65 (br. s, 2 H, NH2), 1.67–1.75 (m,
4 H, NH2CHCNCH2CH2), 3.64–3.67 (m, 1 H, NH2CHCN), 4.13
(q, J = 7.0 Hz, 2 H, COOCH2CH3) ppm. 13C NMR (126 MHz,
CDCl3): δ = 14.2, 25.0, 25.2, 31.0, 36.0, 41.7, 43.6, 60.5, 121.8,
ν = 3288, 3207, 3020, 2938, 2862, 2240, 1721, 1658, 1452, 1209,
˜
756 cm–1. HRMS (EI): calcd. for C12H20N2O2 [M]+ 224.1525;
found 224.1530.
8f: Yield: 20.7 mg, 40%. Colorless oil. 1H NMR (500 MHz,
CDCl3): δ = 1.24 [t, J = 7.0 Hz, 3 H, COC(CH2CH3)2], 1.24 [t, J
= 7.0 Hz, 3 H, COC(CH2CH3)2], 1.33 (t, J = 7.0 Hz, 3 H,
COOCH2CH3), 1.62 (br. s, 2 H, NH2), 1.69–1.74 (m, 2 H,
NH2CHCNCH2CH2), 2.04–2.14 (m, 2 H, NH2CHCNCH2CH2),
3.45–3.52 [m,
2 H, COC(CH2CH3)2], 3.53–3.60 [m, 2 H,
COC(CH2CH3)2], 3.72 (t, J = 7.3 Hz, 1 H, NH2CHCN), 4.27 (q,
J = 7.0 Hz, 2 H, COOCH2CH3) ppm. 13C NMR (126 MHz,
CDCl3): δ = 14.2, 15.1, 29.6, 30.4, 43.0, 57.9, 58.0, 61.6, 101.2,
121.7, 168.9 ppm. IR (neat): ν = 3676, 3389, 3321, 3018, 2981,
˜
2936, 2898, 2231, 1744, 1618, 1449, 1392, 1216, 1170, 757 cm–1.
HRMS (EI): calcd. for C12H22N2O4 [M]+ 258.1580; found
258.1572.
General Procedure for the 1,4- and 1,2-Double Nucleophilic Addition
Reactions of Ketene Silyl (Thio)Acetals and Trimethylsilyl Cyanide
(Table 8, Entry 1; conditions A): Under argon, a suspension of N-
allylideneamine 1c (59.5 mg, 0.20 mmol) in CH2Cl2 (1.0 mL) was
stirred at room temperature for 10 min. Dried silica gel (500 mg)
and CH2Cl2 (0.30 mL) were added and the reaction mixture was
cooled to –78 °C. A solution of (1-ethoxy-2-methylprop-1-enyloxy)
trimethylsilane (56.5 mg, 0.30 mmol) in CH2Cl2 (0.90 mL) was
added to the mixture. After stirring for 10 min, a solution of tri-
methylsilyl cyanide (23.8 mg, 0.24 mmol) in CH2Cl2 (0.80 mL) was
added to the resulting mixture, which was gradually warmed to
room temperature over 17 h. Saturated aqueous NaHCO3 (5.0 mL)
was added to quench the reaction and the mixture was filtered with
suction through a Celite pad and washed with ethyl acetate. The
mixture was extracted with ethyl acetate (3ϫ5.0 mL) and the com-
bined extracts were dried with Na2SO4 and concentrated in vacuo
to give the crude product. Purification on buffered silica gel TLC
(n-hexane/ethyl acetate, 4:1) gave title compound 7ba (70.8 mg,
177.1 ppm. IR (neat): ν = 3592, 3384, 3319, 2978, 2936, 2873, 2228,
˜
1722, 1608, 1475, 1454, 1181, 1152, 1027, 863 cm–1. HRMS (EI):
calcd. for C10H18N2O2 [M]+ 198.1368; found 198.1366.
8b: Yield: 24.7 mg, 67%. Colorless oil. 1H NMR (500 MHz,
CDCl3): δ = 1.21 (s, 6 H, COCCH3CH3), 1.66–1.76, (m, 4 H, NH2
and NH2CHCNCH2CH2), 3.64–3.66 (m, 1 H, NH2CHCN), 3.68
(s, 3 H, COOCH3) ppm. 13C NMR (126 MHz, CDCl3): δ = 25.0,
25.2, 31.1, 36.1, 41.8, 43.6, 51.9, 121.8, 177.7 ppm. IR (neat): ν =
˜
3630, 3379, 3314, 2954, 2932, 2875, 2227, 1725, 1623, 1475, 1454,
1196, 1147, 1034, 864 cm–1. HRMS (EI): calcd. for C9H16N2O2
[M]+ 184.1212; found 184.1207.
1
80%). Yellow oil. H NMR (500 MHz, CDCl3): δ = 1.11 (s, 3 H,
COCCH3CH3), 1.14 (s, 3 H, COCCH3CH3), 1.24 (t, J = 7.0 Hz, 3
H, COOCH2CH3), 1.45–1.62 (m, 3 H, NHCHCNCH2CH2), 1.69–
8c: Yield: 20.3 mg, 47%. Colorless oil. 1H NMR (500 MHz, 1.75 (m, 1 H, NHCHCNCH2CH2), 2.12 (d, J = 9.8 Hz, 1 H, NH),
CDCl3): δ = 0.95 (t, J = 7.6 Hz, 3 H, COOCH2CH2CH3), 1.21
3.36–3.41 (m, 1 H, NHCHCN), 4.11 (q, J = 7.0 Hz, 2 H, CO-
(s, 6 H, COCCH3CH3), 1.62–1.72 (m, 8 H, NH2CHCNCH2CH2, OCH2CH3), 7.21–7.24 (m, 3 H, ArH), 7.29–7.32 (m, 6 H, ArH),
COOCH2CH2CH3, and NH2), 3.64–3.66 (m, 1 H, NH2CHCN), 7.50–7.51 (m, 6 H, ArH) ppm. 13C NMR (126 MHz, CDCl3): δ =
4.04 (t, J = 6.7 Hz, 2 H, COOCH2CH2CH3) ppm. 13C NMR
(126 MHz, CDCl3): δ = 10.4, 21.9, 25.0, 25.2, 31.1, 36.0, 41.8, 43.6,
14.2, 25.0, 25.0, 31.1, 35.8, 41.6, 46.0, 60.5, 71.5, 120.1, 127.0,
128.3, 128.4, 144.9, 177.1 ppm. IR (neat): ν = 3535, 3328, 3084,
˜
66.2, 121.8, 177.2 ppm. IR (neat): ν = 3680, 3390, 3328, 3021, 2972, 3059, 3020, 2977, 2933, 2871, 2232, 1723, 1597, 1489, 1474, 1450,
˜
4080
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4073–4084

N-Allylideneamines Derived from Acrolein
1390, 1183, 1140, 1029, 752, 708 cm–1. HRMS (EI): calcd. for
C29H32N2O2 [M]+ 440.2464; found 440.2448.
7bb: Yield: 55.3 mg, 64%. Yellow oil. 1H NMR (400 MHz, CDCl3):
δ = 1.12 (s, 3 H, COCCH3CH3), 1.15 (s, 3 H, COCCH3CH3), 1.43–
101.3, 119.9, 127.2, 127.3, 128.0, 128.4, 128.5, 144.9, 168.9 ppm.
IR (neat): ν = 3330, 3059, 3016, 2979, 2932, 2231, 1745, 1597, 1490,
˜
1449, 1370, 1185, 1120, 753, 707 cm–1. HRMS (EI): calcd. for
C31H36N2O4 [M]+ 500.2675; found 500.2652.
7bg: Yield: 20.1 mg, 22%. Yellow oil. 1H NMR (500 MHz, CDCl3):
δ = 1.46 (s, 9 H, COSCCH3CH3CH3), 1.58–1.64 (m, 1 H,
NHCHCNCH2CH2), 1.65–1.75 (m, 2 H, NHCHCNCH2CH2),
1.82–1.90 (m, 1 H, NHCHCNCH2CH2), 2.13 (d, J = 10.1 Hz, 1 H,
NH), 2.36–2.46 (m, 2 H, COCH2), 3.38–3.43 (m, 1 H, NHCHCN),
7.12–7.27 (m, 3 H, ArH), 7.29–7.33 (m, 6 H, ArH), 7.50–7.55 (m,
6 H, ArH) ppm. 13C NMR (126 MHz, CDCl3): δ = 21.3, 29.8, 34.7,
43.5, 45.5, 48.1, 71.4, 120.0, 127.1, 127.7, 127.9, 128.3, 128.4, 144.9,
1.61 (m,
3 H, NHCHCNCH2CH2), 1.68–1.75 (m, 1 H,
NHCHCNCH2CH2), 2.12 (d, J = 9.2 Hz, 1 H, NH), 3.36–3.39 (m,
1 H, NHCHCN), 3.66 (s, 3 H, COOCH3), 7.22–7.26 (m, 3 H, ArH),
7.28–7.33 (m, 6 H, ArH), 7.50–7.54 (m, 6 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 25.1, 25.2, 31.2, 36.0, 41.9, 46.2, 52.0, 71.6,
120.3, 127.2, 128.4, 128.5, 145.0, 177.7 ppm. IR (neat): ν = 3327,
˜
3085, 3058, 3020, 2974, 2950, 2870, 2235, 1728, 1596, 1489, 1448,
1390, 1199, 1138, 1032, 753, 708 cm–1. HRMS (EI): calcd. for
C28H30N2O2 [M]+ 426.2307; found 426.2290.
199.3 ppm. IR (neat): ν = 3685, 3619, 3020, 2974, 2927, 2232, 1710,
˜
1676, 1599, 1448, 1422, 1365, 1216, 929, 770, 669, 626 cm–1. HRMS
(EI): calcd. for C29H32N2OS [M]+ 456.2235; found 456.2242.
7bc: Yield: 53.1 mg, 58%. Yellow oil. 1H NMR (500 MHz, CDCl3):
δ = 0.94 (t, J = 7.3 Hz, 3 H, COOCH2CH2CH3), 1.12 (s, 3 H,
COCCH3CH3), 1.15 (s, 3 H, COCCH3CH3), 1.46–1.53 (m, 2 H,
NHCHCNCH2CH2), 1.55–1.61 (m, 1 H, NHCHCNCH2CH2),
1.62–1.68 (m, 2 H, COOCH2CH2CH3), 1.70–1.76 (m, 1 H,
NHCHCNCH2CH2), 2.11 (d, J = 10.1 Hz, 1 H, NH), 3.36–3.41
(m, 1 H, NHCHCN), 4.02 (t, J = 6.7 Hz, 2 H, COOCH2CH2CH3),
7.21–7.27 (m, 3 H, ArH), 7.29–7.36 (m, 6 H, ArH), 7.46–7.55 (m,
6 H, ArH) ppm. 13C NMR (126 MHz, CDCl3): δ = 10.4, 22.0, 25.0,
25.1, 31.1, 35.9, 41.8, 46.0, 66.1, 71.4, 120.1, 127.0, 128.3, 128.4,
7bh: Yield: 55.7 mg, 59%. Yellow oil. 1H NMR (400 MHz, CDCl3):
δ = 1.08 (s, 3 H, COCCH3CH3), 1.11 (s, 3 H, COCCH3CH3),
1.45 (s,
9 H, COOCCH3CH3CH3), 1.47–1.74 (m, 4 H,
NHCHCNCH2CH2), 2.13 (d, J = 10.1 Hz, 1 H, NH), 3.37–3.42
(m, 1 H, NHCHCN), 7.22–7.25 (m, 3 H, ArH), 7.28–7.33 (m, 6 H,
ArH), 7.50–7.52 (m, 6 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 25.2, 28.1, 31.4, 36.1, 42.3, 46.1, 71.6, 80.3, 120.2,
127.2, 128.0, 128.4, 128.5, 145.0, 176.5 ppm. IR (neat): ν = 3326,
˜
144.9, 177.1 ppm. IR (neat): ν = 3327, 3059, 3020, 2970, 2933,
˜
3060, 3018, 2976, 2931, 2871, 2232, 1718, 1597, 1489, 1452, 1391,
1368, 1214, 1140, 755, 708 cm–1. HRMS (EI): calcd. for
C31H36N2O2 [M]+ 468.2777; found 468.2763.
2877, 2232, 1724, 1597, 1490, 1452, 1391, 1183, 1139, 1034, 753,
708 cm–1. HRMS (EI): calcd. for C30H34N2O2 [M]+ 454.2620;
found 454.2611.
1
7bi: Yield: 22.8 mg, 24%. Yellow oil. H NMR (500 MHz, CDCl3,
7bd: Yield: 62.6 mg, 68%. Yellow oil. 1H NMR (500 MHz, CDCl3):
δ = 1.10 (s, 3 H, COCCH3CH3), 1.13 (s, 3 H, COCCH3CH3), 1.22
(d, J = 6.1 Hz, 3 H, COOCHCH3CH3), 1.23 (d, J = 6.1 Hz, 3 H,
COOCHCH3CH3), 1.49–1.64 (m, 3 H, NHCHCNCH2CH2), 1.70–
1.75 (m, 1 H, NHCHCNCH2CH2), 2.12 (d, J = 10.1 Hz, 1 H, NH),
3.37–3.41 (m, 1 H, NHCHCN), 4.98 (sept, J = 6.1 Hz, 1 H,
COOCHCH3CH3), 7.22–7.25 (m, 3 H, ArH), 7.29–7.32 (m, 6 H,
ArH), 7.50–7.51 (m, 6 H, ArH) ppm. 13C NMR (126 MHz,
CDCl3): δ = 21.7, 25.0, 25.0, 31.2, 35.8, 41.6, 46.0, 67.6, 71.4, 120.0,
dr = 53:47 mixture): δ = 1.25–1.30 (m, 3 H, COOCH2CH3), 1.37
(s, 1.59 H, COCCH3), 1.38 (s, 1.41 H, COCCH3), 1.60–1.63 (m,
1.06 H, NHCHCNCH2CH2), 1.71–1.77 (m, 2 H, NHCHCNCH2-
CH2), 1.86–1.95 (m, 0.94 H, NHCHCNCH2CH2), 2.04 (s, 1.59 H,
COCSCH3), 2.07 (s, 1.41 H, COCSCH3), 2.13–2.17 (m, 1 H, NH),
3.44 (br. s, 1 H, NHCHCN), 4.11–4.21 (m, 2 H, COOCH2CH3),
7.23–7.30 (m, 3 H, ArH), 7.32–7.33 (m, 6 H, ArH), 7.50–7.52 (m,
6 H, ArH) ppm. 13C NMR (126 MHz, CDCl3): δ = 12.4, 12.5, 14.2,
21.1, 21.7, 30.9, 31.0, 32.3, 32.3, 45.8, 45.9, 49.5, 49.5, 60.4, 61.3,
61.4, 71.5, 71.6, 120.0, 120.0, 127.1, 128.4, 128.4, 144.8, 172.7,
127.0, 128.3, 128.4, 144.9, 176.6 ppm. IR (neat): ν = 3326, 3059,
˜
3020, 2979, 2933, 2872, 2234, 1717, 1596, 1489, 1450, 1372, 1184,
930, 755, 708 cm–1. HRMS (EI): calcd. for C30H34N2O2 [M]+
454.2620; found 454.2623.
172.7 ppm. IR (neat): ν = 3326, 3084, 3059, 2980, 2929, 2249, 1716,
˜
1598, 1490, 1447, 1244, 733, 708 cm–1. HRMS (EI): calcd. for
C29H32N2O2S [M]+ 472.2185; found 472.2181.
7be: Yield: 27.6 mg, 59%. Yellow oil. 1H NMR (500 MHz, CDCl3):
δ = 1.11–1.36 [m, 6 H, COC(CH2)5], 1.39–1.48 [m, 2 H, COC-
(CH2)5], 1.50–1.56 (m, 3 H, NHCHCNCH2CH2), 1.64–1.70 (m, 1
H, NHCHCNCH2CH2), 1.95–2.03 [m, 2 H, COC(CH2)5], 2.08 (d,
J = 9.8 Hz, 1 H, NH), 3.32–3.37 (m, 1 H, NHCHCN), 3.67 (s, 3
H, COOCH3), 7.22–7.25 (m, 3 H, ArH), 7.29–7.31 (m, 6 H, ArH),
7.48–7.50 (m, 6 H, ArH) ppm. 13C NMR (126 MHz, CDCl3): δ =
23.0, 25.7, 30.4, 33.9, 33.9, 46.1, 46.5, 51.6, 71.5, 120.2, 127.1,
General Procedure for the Transformation Into Amino Nitriles for
Deprotection of the 1,4- and 1,2-Double Nucleophilic Adducts
(Table 8, Entry 8; product 8h): The 1,4- and 1,2-double nucleophilic
addition reaction was performed according to the procedure de-
scribed above under Conditions A. After 17 h the reaction mixture
was cooled to 0 °C, distilled TFA (1.0 mL) was added, and the
mixture was stirred for 15 min. A 10% aqueous Na2CO3 (10 mL)
solution was added to quench the reaction and the mixture was
filtered with suction through a Celite pad and washed with ethyl
acetate. The mixture was extracted with ethyl acetate (3ϫ5.0 mL)
and the combined extracts were dried with Na2SO4 and concen-
trated in vacuo to give the crude product, which was purified by
column chromatography on silica gel (n-hexane/ethyl acetate, 1:1)
to give title compound 8h (28.0 mg, 61%). Yellow oil. 1H NMR
128.3, 128.4, 144.9, 176.5 ppm. IR (neat): ν = 3329, 3059, 3020,
˜
2936, 2857, 2232, 1724, 1597, 1490, 1452, 1208, 755, 708 cm–1.
HRMS (EI): calcd. for C31H34N2O2 [M]+ 466.2620; found
466.2627.
7bf: Yield: 51.8 mg, 51%. Yellow oil. 1H NMR (400 MHz, CDCl3):
δ = 1.19 [t, J = 7.3 Hz, 3 H, COC(OCH2CH3)2], 1.22 [t, J = 7.3 Hz,
3 H, COC(OCH2CH3)2], 1.32 (t, J = 7.3 Hz, 3 H, COOCH2CH3), (400 MHz, CDCl3): δ = 1.15 (s, 6 H, COCCH3CH3), 1.44 (s, 9 H,
1.60–1.72 (m, 2 H, NHCHCNCH2CH2), 1.90–1.98 (m, 1 H, COOCCH3CH3CH3), 1.60 (br. s, 1 H, NH2CHCNCH2CH2), 1.68–
NHCHCNCH2CH2), 2.08–2.15 (m, 2 H, NHCHCNCH2CH2 and 1.70 (m,
NH), 3.45 [q, J = 7.3 Hz, 2 H, COC(OCH2CH3)2], 3.47 [q, J =
NH2CHCN) ppm. 13C NMR (100 MHz, CDCl3): δ = 25.2, 25.3,
7.3 Hz, 2 H, COC(OCH2CH3)2], 3.52–3.59 (m, 1 H, NHCHCN), 28.1, 31.3, 36.1, 42.3, 43.8, 80.4, 122.0, 176.5 ppm. IR (neat): ν =
3 H, NHCHCNCH2CH2), 3.63–3.66 (m, 1 H,
˜
4.27 (q, J = 7.3 Hz, 2 H, COOCH2CH3), 7.21–7.27 (m, 3 H, ArH),
7.28–7.32 (m, 6 H, ArH), 7.47–7.49 (m, 6 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 14.4, 15.2, 29.9, 30.4, 45.5, 58.0, 61.7, 71.5,
3385, 3314, 2977, 2933, 2872, 2230, 1717, 1611, 1456, 1392, 1370,
1148, 756 cm–1. HRMS (EI): calcd. for C12H22N2O2 [M]+ 226.1681;
found 226.1682.
Eur. J. Org. Chem. 2009, 4073–4084
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4081

I. Mizota, Y. Matsuda, I. Hachiya, M. Shimizu
FULL PAPER
General Procedure for the 1,4- and 1,2-Double Nucleophilic Addition
1.15 (d, J = 6.9 Hz, 1.74 H, COCHCH3), 1.30–1.33 (m, 6 H,
Reactions of Ketene Silyl Thioacetals and Trimethylsilyl Cyanide COSCHCH3CH3), 1.44–1.84 (m, 3.55 H, NHCHCNCH2CH2),
(Table 9, Entry 1; Conditions B): Under argon, a suspension of N-
allylideneamine 1c (59.5 mg, 0.20 mmol) in CH2Cl2 (1.0 mL) was
stirred at room temperature for 10 min. Dried silica gel (500 mg)
1.88–1.97 (m, 0.45 H, NHCHCNCH2CH2), 2.14 (d, J = 10.1 Hz,
1 H, NH), 2.53 (tq, J = 6.9, 6.9 Hz, 1 H, COCHCH3), 3.40–3.46
(m, 1 H, NHCHCN), 3.58–3.70 (m, 1 H, COSCHCH3CH3), 7.22–
and CH2Cl2 (0.30 mL) were added and the reaction mixture was 7.26 (m, 3 H, ArH), 7.29–7.34 (m, 6 H, ArH), 7.50–7.52 (m, 6 H,
cooled to –78 °C. A solution of (Z)-[1-(cyclohexylthio)prop-1-en-
yloxy]trimethylsilane (Z/E = 92:8, 73.3 mg, 0.30 mmol) in CH2Cl2
(0.90 mL) was added to the mixture. After stirring for 10 min, a
solution of trimethylsilyl cyanide (23.8 mg, 0.24 mmol) in CH2Cl2
(0.80 mL) was added and the mixture was gradually warmed to
room temperature over 17 h. Saturated aqueous NaHCO3 (5.0 mL)
was added to quench the reaction and the mixture was filtered with
suction through a Celite pad and washed with ethyl acetate. The
mixture was extracted with ethyl acetate (3ϫ5.0 mL) and the com-
bined extracts were dried with Na2SO4 and concentrated in vacuo
to give the crude product. Purification on buffered silica gel TLC
(toluene/ethyl acetate, 20:1) gave title compound 9a (74.5 mg, 75%,
dr = 50:50, as determined by 1H NMR analysis). Clear oil. 1H
NMR (400 MHz, CDCl3, dr = 50:50 mixture): δ = 1.14 (d, J =
ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 17.7, 18.0, 23.1,
23.1, 29.6, 29.8, 33.0, 33.2, 34.6, 34.6, 45.7, 45.9, 48.0, 48.0, 71.5,
71.6, 120.0, 120.2, 127.1, 127.2, 128.4, 128.4, 128.6, 145.0, 145.0,
203.1 ppm. IR (neat): ν = 3678, 3343, 3060, 3020, 2971, 2931, 2869,
˜
2232, 1677, 1597, 1490, 1451, 1372, 1216, 752, 709, 669 cm–1.
HRMS (EI): calcd. for C29H32N2OS [M]+ 456.2235; found
456.2234.
1
9e: Yield: 54.0 mg, 55%. Yellow oil. H NMR (400 MHz, CDCl3,
dr = 55:45 mixture): δ = 1.24 (d, J = 6.9 Hz, 1.35 H, COCHCH3),
1.26 (d, J = 6.9 Hz, 1.65 H, COCHCH3), 1.54–1.85 (m, 3.55 H,
NHCHCNCH2CH2), 1.95–2.06 (m, 0.45 H, NHCHCNCH2CH2),
2.16 (d, J = 9.6 Hz, 1 H, NH), 2.72 (tq, J = 6.7, 6.9 Hz, 1 H,
COCHCH3), 3.38–3.50 (m, 1 H, NHCHCN), 7.19–7.58 (m, 20 H,
ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 17.7, 18.0, 29.6,
29.8, 33.0, 33.2, 45.8, 45.9, 47.8, 47.8, 71.6, 71.6, 120.0, 120.2,
127.2, 127.6, 128.0, 128.5, 128.6, 129.3, 129.5, 134.6, 145.0, 145.0,
6.4 Hz, 1.5 H, COCHCH3), 1.15 (d,
J = 6.4 Hz, 1.5 H,
COCHCH3), 1.23–1.37 (m, 1 H, NHCHCNCH2CH2), 1.43–1.54
[m, 4.5 H, COSCH(CH2)5], 1.56–1.74 [m, 6 H, NHCHCNCH2CH2
and COSCH(CH2)5], 1.93–1.94 [m, 2.5 H, NHCHCNCH2CH2 and
COSCH(CH2)5], 2.14 (d, J = 10.1 Hz, 1 H, NHCHCN), 2.54 (tq,
J = 6.4, 6.8 Hz, 1 H, COCHCH3), 3.37–3.53 [m, 2 H, NHCHCN
and COSCH(CH2)5], 7.23–7.26 (m, 3 H, ArH), 7.30–7.34 (m, 6 H,
ArH), 7.51–7.53 (m, 6 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 17.8, 18.0, 25.7, 26.1, 29.7, 29.8, 30.0, 33.1, 33.2, 42.4,
45.7, 45.9, 48.0, 48.1, 71.5, 120.0, 120.2, 127.2, 128.4, 128.6, 145.0,
200.7 ppm. IR (neat): ν = 3682, 3620, 3345, 3062, 3019, 2976, 2934,
˜
2231, 1706, 1597, 1491, 1449, 1216, 749, 709, 621 cm–1. HRMS
(EI): calcd. for C32H30N2OS [M]+ 490.2079; found 490.2100.
1
9f: Yield: 41.5 mg, 45%. Yellow oil. H NMR (400 MHz, CDCl3,
dr
= 51:49 mixture): δ = 0.98 (t, J = 7.3 Hz, 1.47 H,
COSCH2CH2CH3), 0.98 (t, J = 7.3 Hz, 1.53 H, COSCH2CH2CH3),
1.14 (d, J = 6.9 Hz, 1.47 H, COCHCH3), 1.15 (d, J = 6.9 Hz, 1.53
H, COCHCH3), 1.45–1.84 (m, 5.49 H, NHCHCNCH2CH2 and
COSCH2CH2CH3), 1.88–1.97 (m, 0.51 H, NHCHCNCH2CH2 and
COSCH2CH2CH3), 2.11 (d, J = 10.1 Hz, 0.49 H, NH), 2.11 (d, J
= 10.1 Hz, 0.51 H, NH), 2.57 (tq, J = 6.9, 6.9 Hz, 1 H,
COCHCH3), 2.80–2.92 (m, 2 H, COSCH2CH2CH3), 3.35–3.45 (m,
1 H, NHCHCN), 7.18–7.33 (m, 9 H, ArH), 7.49–7.51 (m, 6 H,
ArH) ppm. 13C NMR (126 MHz, CDCl3): δ = 13.3, 17.6, 17.9,
22.9, 29.5, 29.6, 30.5, 32.9, 33.0, 45.6, 45.7, 47.9, 47.9, 71.4, 71.4,
119.9, 120.0, 127.0, 127.0, 127.9, 128.3, 128.4, 144.8, 202.9 ppm.
202.8 ppm. IR (neat): ν = 3678, 3345, 3060, 3019, 2934, 2856, 2231,
˜
1710, 1677, 1597, 1449, 1216, 760, 708 cm–1. HRMS (EI): calcd.
for C32H36N2OS [M]+ 496.2548; found 496.2540.
9b: Yield: 61.1 mg, 69%. Clear oil. 1H NMR (400 MHz, CDCl3,
dr = 71:29 mixture): δ = 1.14 (d, J = 6.9 Hz, 0.87 H, COCHCH3),
1.15 (d, J = 6.9 Hz, 2.13 H, COCHCH3), 1.25 (t, J = 7.3 Hz, 0.87
H, COSCH2CH3), 1.26 (t, J = 7.3 Hz, 2.13 H, COSCH2CH3), 1.44–
1.80 (m, 3.71 H, NHCHCNCH2CH2), 1.88–1.93 (m, 0.29 H,
NHCHCNCH2CH2), 2.11 (d, J = 9.6 Hz, 1 H, NH), 2.55 (tq, J =
6.9, 6.9 Hz, 1 H, COCHCH3), 2.81–2.94 (m, 2 H, COSCH2CH3),
3.39–3.45 (m, 1 H, NHCHCN), 7.18–7.27 (m, 3 H, ArH), 7.29–
7.36 (m, 6 H, ArH), 7.49–7.51 (m, 6 H, ArH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 14.9, 17.7, 18.0, 23.3, 29.6, 29.8, 33.0, 33.2,
45.8, 45.9, 47.9, 48.0, 71.6, 120.0, 120.2, 126.5, 127.2, 128.0, 128.2,
IR (neat): ν = 3683, 3618, 3346, 3019, 2972, 2933, 2875, 2233, 1679,
˜
1598, 1521, 1452, 1217, 770, 670 cm–1. HRMS (EI): calcd. for
C29H32N2OS [M]+ 456.2235; found 456.2234.
1
9g: Yield: 35.8 mg, 39%. Yellow oil. H NMR (400 MHz, CDCl3):
δ = 1.15 (s, 3 H, COCH3CH3), 1.19 (s, 3 H, COCH3CH3), 1.25 (t,
128.4, 128.6, 128.7, 145.0, 203.0 ppm. IR (neat): ν = 3682, 3617,
˜
J
=
7.3 Hz,
3
H, COSCH2CH3), 1.46–1.63 (m,
3
H,
3345, 3019, 2975, 2933, 2874, 2232, 1679, 1598, 1452, 1216, 767,
669 cm–1. HRMS (EI): calcd. for C28H30N2OS [M]+ 442.2079;
found 442.2061.
NHCHCNCH2CH2), 1.73–1.81 (m, 1 H, NHCHCNCH2CH2),
2.12 (d, J = 10.1 Hz, 1 H, NH), 2.86 (q, J = 7.3 Hz, 2 H,
COSCH2CH3), 3.36–3.41 (m, 1 H, NHCHCN), 7.22–7.33 (m, 9 H,
ArH), 7.50–7.54 (m, 6 H, ArH) ppm. 13C NMR (126 MHz,
CDCl3): δ = 14.7, 23.0, 25.2, 25.3, 30.8, 36.4, 46.0, 49.0, 71.5, 120.0,
9c: Yield: 61.2 mg, 65%. Clear oil. 1H NMR (400 MHz, CDCl3, dr
= 55:45 mixture): δ = 1.11 (t, J = 6.4 Hz, 3 H, COCHCH3), 1.47 (s,
4.05 H, COSCCH3CH3CH3), 1.48 (s, 4.95 H, COSCCH3CH3CH3),
1.56–1.74 (m, 3.55 H, NHCHCNCH2CH2), 1.86–1.99 (m, 0.45 H,
NHCHCNCH2CH2), 2.12 (d, J = 10.3 Hz, 0.45 H, NH), 2.13 (d,
J = 10.3 Hz, 0.55 H, NH), 2.43–2.49 (m, 1 H, COCHCH3), 3.35–
3.48 (m, 1 H, NHCHCN), 7.19–7.27 (m, 3 H, ArH), 7.29–7.33 (m,
6 H, ArH), 7.49–7.51 (m, 6 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 17.6, 17.8, 29.5, 29.7, 29.8, 29.8, 32.9, 33.1, 45.6, 45.7,
47.9, 48.2, 71.4, 119.9, 120.0, 127.1, 128.1, 128.3, 128.4, 144.9,
127.0, 127.9, 128.3, 128.4, 144.9, 205.7 ppm. IR (neat): ν = 3683,
˜
3618, 3346, 3019, 2974, 2933, 2234, 1669, 1599, 1521, 1424, 1218,
771, 670 cm–1. HRMS (EI): calcd. for C29H32N2OS [M]+ 456.2235;
found 456.2234.
General Procedure for the Transformation Into Valerolactams for the
Deprotection of 1,4- and 1,2-Double Nucleophilic Adducts (Table 9,
Entry 1; product 10a): The 1,4- and 1,2- double nucleophilic ad-
dition reaction was performed according to the procedure de-
scribed above under conditions B. After 17 h TFA (1.0 mL) was
added and the mixture was stirred for 10 min at room temperature.
A 10% aqueous Na2CO3 solution (10 mL) was added to quench
the reaction and the mixture was filtered with suction through a
203.7 ppm. IR (neat): ν = 3682, 3618, 3346, 3019, 2968, 2929, 2869,
˜
2232, 1674, 1453, 1367, 1216, 961, 771, 669, 621 cm–1. HRMS (EI):
calcd. for C30H34N2OS [M]+ 470.2392; found 470.2382.
1
9d: Yield: 62.1 mg, 68%. Yellow oil. H NMR (400 MHz, CDCl3,
dr = 58:42 mixture): δ = 1.13 (d, J = 6.9 Hz, 1.26 H, COCHCH3), Celite pad and washed with ethyl acetate. The mixture was ex-
4082 Eur. J. Org. Chem. 2009, 4073–4084
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

N-Allylideneamines Derived from Acrolein
1991, 32, 4371–4374; d) E. W. Colvin, D. McGarry, M. J. Nug-
ent, Tetrahedron 1988, 44, 4157–4172; e) H. Bock, R. Dammel,
Chem. Ber. 1987, 120, 1971–1985; f) D. R. Boyd, P. B. Coulter,
R. Hamilton, N. T. Thompson, N. D. Sharma, M. E. Stubbs,
J. Chem. Soc. Perkin Trans. 1 1985, 2123–2127; g) A. Hakiki,
J.-L. Ripoll, A. Thuillier, Tetrahedron Lett. 1984, 25, 3459–
3460; h) J.-C. Guillemin, J.-M. Denis, Angew. Chem. Int. Ed.
1982, 21, 690; i) R. A. Earl, K. P. C. Vollhardt, Heterocycles
1982, 19, 265–271; j) A. Arques, P. Molina, A. Soler, Synthesis
1980, 702–704; k) D. R. Boyd, R. Hamilton, N. T. Thompson,
M. E. Stubbs, Tetrahedron Lett. 1979, 20, 3201–3204; l) Y. Ta-
mura, H. Mtsushima, J. Minamikawa, M. Ikeda, K. Sumoto,
Tetrahedron 1975, 31, 3035–3040; m) D. A. Ben-Efraim, Tetra-
hedron 1973, 29, 4111–4125; n) R. Levine, W. C. Fernelius,
Chem. Rev. 1954, 54, 449–573.
Although we examined the 1,4- and 1,2-double nucleophilic
addition using the imine protected with the TBS group, the
1,4–1,2 product was not obtained.
When the 1,4- and 1,2-double nucleophilic addition with the
α,β-unsaturated imine bearing an electron-withdrawing group
was investigated, the 1,4-addition product was obtained instead
of the 1,4–1,2 adduct.
a) I. Mizota, Y. Matsuda, I. Hachiya, M. Shimizu, Org. Lett.
2008, 10, 3977–3980; b) M. Shimizu, A. Takahashi, S. Kawai,
Org. Lett. 2006, 8, 3585–3587; c) M. Shimizu, M. Kamiya, I.
Hachiya, Chem. Lett. 2005, 34, 1456–1457; d) M. Shimizu, H.
Kurokawa, A. Takahashi, Lett. Org. Chem. 2004, 1, 353–356;
e) M. Shimizu, C. Yamauchi, T. Ogawa, Chem. Lett. 2004, 33,
606–607; f) M. Shimizu, T. Nishi, Synlett 2004, 889–891; g) M.
Shimizu, T. Nishi, A. Yamamoto, Synlett 2003, 1469–1473; h)
M. Shimizu, M. Kamiya, I. Hachiya, Chem. Lett. 2003, 32,
606–607; i) M. Shimizu, T. Nishi, Chem. Lett. 2002, 31, 46–47;
j) M. Shimizu, T. Ogawa, T. Nishi, Tetrahedron Lett. 2001, 42,
5463–5466; k) M. Shimizu, A. Morita, T. Kaga, Tetrahedron
Lett. 1999, 40, 8401–8405.
tracted with ethyl acetate (3ϫ5.0 mL) and the combined extracts
were dried with Na2SO4 and concentrated in vacuo to give the
crude product, which was purified by column chromatography on
silica gel (n-hexane/ethyl acetate, 1:1) to give the title compound
cis-10a (12.4 mg) and trans-10a (11.2 mg, 85%, dr = 53:47). Data
for cis-10a: Yellow solid; m.p. 107–108 °C. 1H NMR (500 MHz,
CDCl3): δ = 1.26 (d, J = 7.3 Hz, 3 H, COCHCH3), 1.60–1.66 (m,
1 H, CH3CHCH2), 2.05–2.11 (m, 1 H, CH3CHCH2), 2.17–2.29 (m,
2 H, CNCHCH2), 2.54 (tq, J = 6.7, 7.3 Hz, 1 H, CH3CHCH2),
4.42–4.44 (m, 1 H, NHCHCN), 6.50 (br. s, 1 H, NH) ppm. 13C
NMR (126 MHz, CDCl3): δ = 17.3, 24.8, 26.6, 35.4, 43.7, 118.2,
174.5 ppm. IR (neat): ν = 3288, 2942, 2876, 2241, 1617, 1475,
˜
777 cm–1. HRMS (EI): calcd. for C7H10N2O [M]+ 138.0793; found
138.0797. Data for trans-10a: Yellow solid; m.p. 157–158 °C. 1H
NMR (500 MHz, CDCl3): δ = 1.29 (d, J = 7.0 Hz, 3 H,
COCHCH3), 1.83–1.91 (m, 1 H, CH3CHCH2), 2.05–2.13 (m, 2 H,
CH3CHCH2), 2.17–2.21 (m, 1 H, CNCHCH2), 2.36–2.44 (m, 1 H,
CH3CHCH2), 4.45–4.47 (m, 1 H, NHCHCN), 6.68 (br. s, 1 H,
NH) ppm. 13C NMR (126 MHz, CDCl3): δ = 16.7, 26.1, 26.7, 36.3,
[2]
[3]
44.0, 118.6, 174.3 ppm. IR (neat): ν = 3443, 3265, 2970, 2943, 2878,
˜
2243, 1629, 1472, 778 cm–1. HRMS (EI): calcd. for C7H10N2O
[M]+ 138.0793; found 138.0795.
[4]
10b: Yield: 16.4 mg, 53%. Yellow solid; m.p. 122–123 °C. 1H NMR
(400 MHz, CDCl3): δ = 1.24 (s, 3 H, COCCH3CH3), 1.28 (s, 3 H,
COCCH3CH3), 1.74–1.79 (m, 1 H, CH3CH3CCH2), 1.99–2.05 (m,
1 H, CH3CH3CCH2), 2.07–2.12 (m, 1 H, CNCHCH2), 2.17–2.24
(m, 1 H, CNCHCH2), 4.43–4.45 (m, 1 H, NHCHCN), 6.75 (br. s,
1 H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 23.5, 26.9, 26.9,
33.2, 38.0, 44.1, 118.5, 177.7 ppm. IR (neat): ν = 3199, 2952, 2875,
˜
2241, 1656, 1481, 1237, 827 cm–1. HRMS (EI): calcd. for
C8H12N2O [M]+ 152.0950; found 152.0944.
Transformation Into Glutamic Acid Derivative 12 (Scheme 11): Un- [5]
der argon, acetic acid (3.0 mL) and hydrochloric acid (12 ,
1.5 mL) were added to ethyl 5-amino-5-cyano-2,2-dimethylpenta-
a) K. Tomioka, Y. Shioya, Y. Nagaoka, K. Yamada, J. Org.
Chem. 2001, 66, 7051–7054; b) K. Tomioka, T. Okamoto, M.
Kanai, H. Yamataka, Tetrahedron Lett. 1994, 35, 1891–1892.
Calculations were carried out by using the SPARTAN pro pro-
gram. 6-31G* calculations were also carried out by using MO-
PAC. PC SPARTAN pro, Wavefunction, Inc., 18401 Von Kar-
man Ave., Suite 370, Irvin, CA 92612, USA, 1999.
Results for the s-cis isomers are nearly the same as those for
the s-trans; the difference in the method of calculation (HF/
STO-3G or PM3) has little influence on a qualitative conclu-
sion.
For examples using silica gel as a reaction promoter, see: M.
Shimizu, M. Tanaka, T. Itho, I. Hachiya, Synlett 2006, 1687–
1690.
[6]
noate (8a; 79.3 mg, 0.40 mmol) and heated at reflux for 12 h. The
reaction mixture was cooled and the solvent evaporated in vacuo
to afford the crude product, which was purified by ion-exchange
chromatography on Amberlyst 15DRY® to give title compound 12
[7]
(86.7 mg, 96%). Yellow powder; m.p. 191–195 °C. 1H NMR
(400 MHz, D2O with 3-trimethylsilyl-1-propanesulfonic acid, so-
dium salt as the internal standard): δ = 1.17 (s, 3 H, COCCH3CH3),
1.18 (s,
3 H, COCCH3CH3), 1.64–1.80 (m, 4 H, NH3-
[8]
[9]
CHCOOHCH2CH2), 4.21 (t, J = 6.2 Hz, 1 H, NH3CHCOOHCH2-
CH2) ppm. 13C NMR (100 MHz, D2O with 3-trimethylsilyl-1-pro-
panesulfonic acid, sodium salt as the internal standard): δ = 24.5,
We confirmed by 1H NMR spectroscopy that 1,4- and 1,2-
addition products 7ac, 7ad, and 7af were converted into 1,4
adducts by a retro-Strecker reaction (Table 7, Entries 3, 4, and
6). Because the adducts were not stable, the addition reactions
with 1b were not examined in detail.
28.6, 28.7, 35.6, 39.8, 57.6, 178.9, 184.4 ppm. IR (neat): ν = 2926,
˜
1737, 1697, 1493, 1415, 1212 cm–1. HRMS (EI): calcd. for
C8H16ClNO4 [M]+ 225.0768; found 225.0767.
Supporting Information (see footnote on the first page of this arti-
[10]
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2673–2676; b) P. J. M. Taylor, S. D. Bull, P. C. Andrews, Synlett
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Acknowledgments
This work was supported by Grants-in-Aid for Scientific Research
(B) and Priority Areas from the Ministry of Education, Culture,
Sports, Science and Technology and the Japan Society for the Pro-
motion of Science.
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Eur. J. Org. Chem. 2009, 4073–4084
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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I. Mizota, Y. Matsuda, I. Hachiya, M. Shimizu
FULL PAPER
[11] The regioselectivity of the addition of nucleophiles to α,β-un-
saturated aldimines has been studied previously, see ref.[4d] For
examples using α,β-unsaturated aldimines for the β-lactam syn-
thesis, see: a) I. Fleming, J. D. Kilburn, J. Chem. Soc. Perkin
Trans. 1 1998, 2663–2671; b) D.-C. Ha, D. J. Hart, T.-K. Yang,
J. Am. Chem. Soc. 1984, 106, 4819–4825.
[12] A control experiment was carried out by using acrolein as the
substrate in place of the imine 1c. Under the conditions A in
Table 8, the reaction gave the 1,4- and 1,2-addition product in
36% yield.
Received: April 28, 2009
Published Online: July 6, 2009
4084
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4073–4084