Stereoselective synthesis of 5-(1-hydroxyalkyl)-2-pyrrolidinones utilizing oxidation of 5-alkylidene-2-pyrrolidinones to acyliminium ion precursors

Article abstract of DOI:10.1016/S0040-4020(00)00841-3

A general method was devised for the LiN(TMS)₂/AgOTf (=2:1)-catalyzed intramolecular (5-exo-dig) cyclization of β-alkynylamides 1 possessing alkyl, aryl or no functional groups at the terminal alkynes, to 5-alkylidene-2-pyrrolidinones 2. These 5-alkylidene-2-pyrrolidinones were oxidized to the diol-type alkoxylactams 3 by dimethyldioxirane (DMD) or mCPBA in MeOH. These alkoxylactams are useful as tertiary N-acyliminium ion precursors for the synthesis of threo-5-(1-hydroxyalkyl)-2-pyrrolidinone derivatives 5. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00841-3

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 8855±8865
Stereoselective Synthesis of 5-(1-Hydroxyalkyl)-2-pyrrolidinones
Utilizing Oxidation of 5-Alkylidene-2-pyrrolidinones
to Acyliminium Ion Precursors
*
Yuji Koseki, Shuichi Kusano, Daisuke Ichi, Keiji Yoshida and Tatsuo Nagasaka
Tokyo University of Pharmacy and Life Science, School of Pharmacy, 1432-1 Horinouchi, Hachiouji, Tokyo 192-0392, Japan
Received 8 August 2000; accepted 18 September 2000
AbstractÐA general method was devised for the LiN(TMS)2/AgOTf (ˆ2:1)-catalyzed intramolecular (5-exo-dig) cyclization of b-alkynyl-
amides 1 possessing alkyl, aryl or no functional groups at the terminal alkynes, to 5-alkylidene-2-pyrrolidinones 2. These 5-alkylidene-2-
pyrrolidinones were oxidized to the diol-type alkoxylactams 3 by dimethyldioxirane (DMD) or mCPBA in MeOH. These alkoxylactams are
useful as tertiary N-acyliminium ion precursors for the synthesis of threo-5-(1-hydroxyalkyl)-2-pyrrolidinone derivatives 5. q 2000 Elsevier
Science Ltd. All rights reserved.
Introduction
synthesis of isoindolobenzazepine alkaloids, such as
lennoxamine or chilenine.7 We applied this strategy to
the synthesis of 2-pyrrolidinone derivatives, especially
N-Acyliminium ions have high potential reactivity to
various nucleophilic reagents, a fact which is re¯ected in
the large number of synthetic applications of nitrogen
heterocycles. Various methods have been described for
the preparation of alkoxycarbamates and alkoxylactams as
precursors of the N-acyliminium ion.1 The most frequently
used methods to achieve this are partial reduction of the
corresponding carbonyl groups of imides, anodic methoxyl-
ation of amides, Grignard addition to the cyclic imides, and
condensation of ketones or aldehydes with amides or
amines.1,2 On the other hand, one study also described
oxidation of endocyclic enamides, a process which provides
alkoxycarbamates, alkoxylactams or enamide epoxides as
precursors of the N-acyliminium ion,3 whereas only a few
studies have investigated exocyclic enamides (such as alkyl-
idenelactams 2).4 In such a reaction, oxidation of exocyclic
enamides is expected to afford alkoxylactams, which are
useful as tertiary N-acyliminium ion precursors5,6 for the
synthesis of 5- or 6-membered nitrogen heterocycles.
However, as only one example of this type reaction, oxida-
tion of ethylidenetetrahydro-1,3-oxazine-2-one by mCPBA
(m-chloroperbenzoic acid) in MeOH has been reported by
Back et al.4a and such a method has not been applied to
synthesis of pyrrolidine or piperidine derivatives.
5-(1-hydroxyalkyl)-2-pyrrolidinones 5, via
a tertiary
N-acyliminium ion 4 derived from diol-type alkoxylactams
3. These were obtained by oxidation of 5-alkylidene-2-
pyrrolidinones 2 (Scheme 1).
We previously reported that alkylidenelactams 2 were
readily obtained by base-catalyzed (5-exo-dig) cyclization
of b-alkynylamides 1 in the presence or absence of AgOTf.8
Herein, we describe the full experimental details of cycliza-
tion of 1 to 2 and a convenient method of the stereoselective
synthesis of 5-(1-hydroxyalkyl)-2-pyrrolidinones deriva-
tives 5 utilizing the conversion of alkylidenelactams 2 to
the diol-type alkoxylactams 3 as a tertiary N-acyliminium
ion precursor.
In our laboratory, a tertiary N-acyliminium ion precursor
obtained by oxidation of methylideneisoindolone (exocyclic
enamide) has been shown to be a useful intermediate for
Keywords: acyliminium ion; cyclization; oxidation; pyrrolidinone.
* Corresponding author. Tel./fax: 181-426-76-4479;
e-mail: nagasaka@ps.toyaku.ac.jp
Scheme 1.
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00841-3

8856
Y. Koseki et al. / Tetrahedron 56 (2000) 8855±8865
Table 1. Intramolecular cyclization of b-alkynylamides to 5-alkylidene-2-pyrrolidinones
Run
Alkynylamide
R1
Base (equiv.)
Additive (equiv.)
Solvent
Temp (C8)
Time (h)
Product
Isomerratiob
7(Z):8(E)
6
Yield (%)a
1
2
3
4
5
6
7
6a
6a
6a
6a
6b
6c
6c
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
H
LHMDS (1.0)
n-BuLi (1.0)
±
±
±
THF
THF
DMF
THF
toluene
THF
DMF
66
0±66
60±65
rt
60
66
18
10
3
4
3
a 42
a 8
a 64
a 71
b 89c
c 0
(85:15)
(±)
(55:45)
(64:36)
(±)
LHMDS (1.0)
KHMDS (0.5)
NaHMDS (0.3)
KHMDS (0.3)
LHMDS (1.0)
18-crown-6 (0.4)
18-crown-6 (0.3)
18-crown-6 (0.3)
±
Me
Me
18
5
(±)
(±)
60±65
c 0
a Isolated yield after puri®cation by basic (NH±) silica gel column.
b Determined based on 1H NMR spectra of the crude products.
c Endo-form 7b0 was accompained by the desired product 7b (exo-7b/endo-7b0ˆ14:1)
.
Discussion and Results
establish a general method for the base-catalyzed cycli-
zation of b-alkynylamides 1. In the initial experiments,
we investigated the cyclization of b-alkynylamides 6
possessing aryl, hydrogen or alkyl groups at the terminal
alkynes under base conditions. The results are shown in
Table 1.
Synthesis of alkilidene-2-pyrrolidinones8
Very little research has been directed to the synthesis of
lactams by the intramolecular cyclization of alkynylamides,
such as Bu4NF- or LiAl(NHBn)4-catalyzed cyclization of
alkynylamides,9 cyclization of v-phenylseleno-substituted
alkynylamides by t-BuOK/18-crown-6,10 and the synthesis
of 1,3-oxazolidine-2-ones by base-catalyzed cyclization of
alkynylcarbamates in the presence of Ag-, Cu-salt or Pd.11
Firstly, following a method similar to the one outlined above
(LiN(TMS)2 in THF), cyclization of aryl-substituted alkynyl-
amide 6a was conducted to provide a moderate yield of 7a
and 8a (Run 1). When DMF was used, the yield increased
but product isolation from DMF was sluggish (Run 3).
KN(TMS)2/18-crown-6 in THF at room temperature gave
the best result (Run 4). In the case of possessing hydrogen,
cyclization of 6b under a catalytic amount of base and mild
conditions proceeded more readily than that of 6a to afford
the mixture of exo-7b and endo-7b0 (14:1) (Run 5). The use
of a slightly more basic medium (e.g. KN(TMS)2 in THF)
Recently, a similar (5-exo-dig) cyclization of 4-pentyn-
Â
12
amides was reported by Domõnguez et al. However, no
such cyclization has been reported for b-alkynylamides 1
(R1ˆalkyl) possessing alkyl groups at the terminal acetyl-
enes. The cyclization of o-ethynylbenzamides derivatives
under base conditions (LiN(TMS)2 in THF) has been
reported by our laboratory.13 Hence, the authors sought to
Table 2. Intramolecular cyclization of b-alkynylamides to 5-alkylidene-2-pyrrolidinones utilizing the catalytic AgOTf/LHMDS-system
Run
Alkynylamide
Time (h)
Product
Isomer ratio 7(Z):8(E)a
6a±i
R1
R2
Yield (%)b
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
6f
6g
6h
6j
4-MeOC6H4
H
Me
Me
Me
3-MeOC6H4CH2
3-MeOC6H4CH2
3-MeOC6H4CH2
CH3(Ph)CH (S)
3
3
3
3
4
3
4
3
3
96:4
±
85
86
89
89
88
85
84
89
88
100:0
100:0
100:0
100:0
100:0
100:0
97:3
MeOCH2(Ph)CH (R)
Me
Cl(CH2)3
n-C12H25
4-ClC6H4
3-MeOC6H4CH2
3-MeOC6H4CH2
3-MeOC6H4CH2
10
6j
BnOCH2CH2
3
86:14
89
a Determined based on 1H NMR spectra of the crude products.
b Isolated yield after puri®cation by basic (NH±) silicagel column.

Y. Koseki et al. / Tetrahedron 56 (2000) 8855±8865
8857
alkyl-substituted alkynylamides (R1ˆH, chloropropyl,
dodecyl, 6b, 6g, 6h, respectively) or alkynylamides having
bulky N-substituted alkynyl groups (6d, 6e, 6f) led to satis-
factory yields and stereoselectivity (Runs 2, 4±8). Further-
more, when those having aryl-substituted alkynylamides
(6a, 6i, 6j) were applied to this system, the cyclization
proceeded smoothly to afford benzylidenelactams (7a, 7i,
7j, respectively) along with a trace amount of E-form 8a, 8i,
8j (respectively) in good yields (85±89%, Runs 1, 9±10).
This may have been due to the isomerization of 7 to the
thermodynamically stable 8 that occurred during this
reaction process.
Figure 1. NOE Correlation of 7d (Z-form) and 8d (E-form).
However, (6-exo-dig) cyclization of 5-hexynamide to
d-valerolactam under the same conditions failed to occur.
Compound 7 was found to have the Z-form structure by
NOE (in pyridine-d5),14 a fact which was supported by
examination of the isomerization of 7d to the thermo-
dynamically stable product 8d (E-form) in CDCl3 for
5±6 h (30% of Z-form converted to E-form)14 or after stand-
ing at room temperature for 2 days (46% of Z-form
converted to E-form) (Fig. 1).
The reaction mechanism for the present cyclization remains
to be clari®ed. The LiN(TMS)2/AgOTf (ˆ1:1) system in
toluene did not yield any product, thus suggesting the
mechanism in Scheme 2. Reaction of 6 with silver- and
lithium-amides (AgN(TMS)2´LiN(TMS)2), prepared from
a mixture of 1 equiv. of AgOTf and 2 equiv. of LiN(TMS)2,
produced the alkyne-Ag species complex and the lithium
imidate I, which underwent trans-aminometallation11f to
vinylmetal-species II, followed by protonolysis11f to afford
7.
Scheme 2.
led to an increased ratio for the formation of endo-7b0. In
contrast, alkynylamides 6c having an alkyl group on the
terminal alkyne produced no cyclized product in the
presence of any bases or phase-transfer-conditions (Runs
6 and 7).
Hence, the authors sought to establish a general method for
the base-catalyzed cyclization of b-alkynylamides 6 with-
out in¯uencing substituent (RˆH, Ar, alkyl) on the terminal
acetylene. The results are summarized in Table 2.
Oxidation of alkylidenelactams to alkoxylactams
followed by reductive deoxygenation. Synthesis of
5-(1-hydroxyalkyl)-2-pyrrolidinones
With the catalytic LiN(TMS)2/AgOTf (ˆ2:1) system in
toluene, the cyclization of 6c proceeded more ef®ciently
to yield only a Z-form product 7c (Run 3). The use of
THF or dimethoxyethane as a solvent did not promote this
cyclization. This catalytic system when used with various
The obtained 5-alkylidene-2-pyrrolidinones 7 were then
applied to the oxidation reaction in order to produce the
5-alkoxy-2-pyrrolidinones 9, 10 (diol-type alkoxylactams)
as tertiary N-acyliminium ion precursors. The results are
summarized in Table 3.
Table 3. Oxidation of 5-alkylidene- or 5-benzylidene-2-pyrrolidinones
Run
Substrate
Condition
Temp.
Producta and yieldb (%)
9
10
11
1
2
3
4
5
6
7a
7a
7a
7c
7c
7c
R1ˆ4-MeO±C6H4±
R1ˆ4-MeO±C6H4±
R1ˆ4-MeO±C6H4±
R1ˆMe
m-CPBAc/CH2Cl2
m-CPBAc/MeOH-CH2Cl2
DMD/acetone
2608C
0 to rt
278 to 2308C
0 to rt
278 to 2308C
278 to 2308C
a
a
a
c
c
c
0
83
±
93
±
0
0
95
0
96
17
50
trace
0
trace
0
0
m-CPBAc/MeOH
DMD/acetone
DMD/MeOH
R1ˆMe
R1ˆMe
76
a All products (9, 10) were various ratios of diastereomer mixtures.
b Isolated yields.
c The amount of m-CPBA used was 1.3 equiv.

8858
Y. Koseki et al. / Tetrahedron 56 (2000) 8855±8865
Table 4. Reductive deoxygenation of quarternary methoxy- or hydroxy-lactams by Et3SiH
Run
Substrate
R1
Lewis acid
Temp.
Product
Yield (%)a
X
12
threo:erythrob
1
2
3
4
5
9a
9c
9c
9c
4-MeO±C6H4±
Me
Me
Me
Me
H
TiCl4 (1.1 equiv.)
TiCl4 (1.2 equiv.)
BF3´OEt2 (1.2 equiv.)
BF3´OEt2 (2.2 equiv.)
BF3´OEt2 (2.2 equiv.)
2608C
12a
12c
12c
12c
12c
0c
86
0
97
89
±
2:1
±
30:1
30:1
Me
Me
Me
Me
278 to 2208C
2788C to rt
2788C to rt
2788C to rt
10c
a Isolated yield after puri®cation by silica gel column.
b Determined based on 1H NMR spectra of the crude product.
c Ketone 13a was given in 80% yield.
The oxidation of 7a by mCPBA was examined. When done
in CH2Cl2, an unexpected N-(3-methoxybenzyl)succinimide
11a was obtained (Run 1).15 According to Back's report,4a
by carrying out the reaction in the presence of methanol, the
desired methoxylactam 9a could be obtained (Run 2). In
contrast, the oxidation7 of 7a by DMD (dimethyldioxirane)
even in the absence of MeOH proceeded more rapidly than
that of mCPBA to afford only diol 10a in 95% yield without
inducing formation of 11a (Run 3). Furthermore, the oxi-
dation of 7c (R1ˆMe) under similar conditions also afforded
9c and 10c (by mCPBA/MeOH or DMD), both in a high
yield (Runs 4±6).
the case of 9c possessing the hydroxyalkyl group (R1ˆMe),
the desired deoxygenation reaction via an acyliminium ion
intermediate proceeded smoothly to give 5-(1-hydroxy-
methyl)pyrrolidinone 12c in good yield (86%), although
low threo-selectivity was observed (threo/erythroˆ2:1,
Run 2). However, the use of 2.2 equiv. of BF3´OEt2 instead
of TiCl4 provided high threo selectivity (threo/erythroˆ
30:1, Run 4).16 Furthermore, the same threo-selectivity
was observed during reductive deoxygenation of hydroxy-
lactam 10c (Run 5).
To determine the structure of the products, the two isomers,
threo-12c and erythro-12c, were converted to bicyclo-rings
14 and 15, respectively. Their relative stereochemistries
were con®rmed by the NOESY spectral data measured in
CDCl3 (Scheme 3).
Next, reductive deoxygenation of quarternary methoxy- or
hydroxy-group by Et3SiH16 in these diol-type alkoxylactams
(9, 10) obtained from alkylidenelactams was investigated.
The results are shown in Table 4.
Given that the use of 1.2 equiv. of BF3´OEt2 failed to yield
any product (Table 4, Run 3), the stereochemical product of
these reductive deoxygenations via an acyliminium ion can
be rationalized based on a conformation whereby the
hydroxy group coordinated with BF3 and occupied the
`outside position' to the iminium double bond in order to
minimize the electronic repulsion between the positively
charged hydroxy group and the iminium ion.17 This arrange-
ment allows the attack of Et3SiH from the less hindered
Surprisingly, when 9a possessing the hydroxybenzyl group
(R1ˆAr) at the 5-position of the 2-pyrrolidinone ring was
treated with Et3SiH/TiCl4 in CH2Cl2, only an unexpected
ketone 13a was found (Run 1). The elimination of benzylic
proton via an acyliminium ion intermediate in the presence
of Lewis acid would likely proceed rapidly to afford 13a. In
Scheme 3. Reagent and conditions: a. LiAlH4, THF rt, 10 h; b. cat.
20%Pd(OH)2/H2 (1.5 atm), MeOH, 2 days; c. Cbz-Cl, Et3N, CH2Cl2, rt,
10 h; d. K2CO3, 18-crown-6, THF, re¯ux, 10 h.
Figure 2. Plausible transition-state structure.

Y. Koseki et al. / Tetrahedron 56 (2000) 8855±8865
Table 5. Conversion of alkylidenelactams to 5-(1-hydroxy)alkyl-2-pyrrolidinones
8859
Run
Substrate
Ratio of isomer, threo:erythro
Product and yield (%)
1
2
7g
7h
R1ˆCl(CH2)3
R1ˆC12H25
99:1
99q1
12g
12h
71
77
bottom face and leads to the preferential formation of threo
product (Fig. 2).
be useful as N-acyliminium ion precursors for the synthesis
of a-substituted pyrrolidine derivatives.
However, the use of TiCl4 resulted in low threo-selectivity,
the reason for which is not understood at present.
Experimental
Next, an attempt was made to apply this method to the
synthesis of other threo-5-(1-hydroxyalkyl)pyrrolidinones
12, especially aza-muricatacin 16, which is an aza-
analogue of (1)-muricatacin that shows in vitro cytotoxic
activity.18a,b The conversion of alkylidenelactams 7 to threo-
5-(1-hydroxyalkyl)pyrrolidinones 12 by the successive
procedure (oxidation followed by reductive deoxygenation)
is shown in Table 5.
General
AgOTf was purchased from Aldrich Chemical company
without further puri®cation. DMD (dimethyldioxirane)±
acetone solution (ca. 0.078 M) was prepared according to
Adam's method.20 Tetrahydrofuran (THF) and toluene were
distilled from Na/benzophenone ketyl. Dichloromethane
was distilled from P2O5. Flash chromatography was
performed using Fuji Silysia silica gel BW 127 ZH and
BW 300, and Chromatorexw as the basic silica gel (NH-
silica gel). Melting points were uncorrected. IR spectra of
solids were recorded as KBr pellets, and IR spectra of oil
were recorded as thin ®lms on NaCl plates. 1H and 13C NMR
spectra were recorded at 300 and 75 MHz or 400 and
100 MHz, respectively in CDCl3 with TMS as an internal
standard. The NMR assignments for compounds 7d, 8d, 14
and 15 were based on 2D NMR experiments (NOE).
Chloropropylidenelactam 7g was oxidized by DMD in
MeOH to afford the mixture consisting of alkoxylactams 9
and 10, not followed by puri®cation, which was treated with
Et3SiH in the presence of BF3´OEt2 to give 12g in 71% yield
with a high threo-selectivity (99:1, Run 1). In the same
manner, dodecylidenelactam 7h afforded N-benzyl-threo-
aza-muricatacin 12h as the sole product (Run 2).
Finally, debenzylation of 12h by Birch reduction19 gave
threo-dl-aza muricatacin 16 in 45% yield (Scheme 4).
The spectral data of synthetic 16 showed complete agree-
ment with those of threo-form aza-muricatacin reported in
the literature.18a,c
Preparation of 4-pentynamides 6a, b, i, j
5-Arylsubstituted 4-pentynamides 6a, i, j and 4-pentyn-
amide 6b were prepared as reported previously.21
N-(3-Methoxybenzyl)-5-(4-methoxyphenyl)-4-pentynamide
(6a). Mp 97±988C (from AcOEt±iPr2O, colorless crystal);
1H NMR (300 MHz, CDCl3) d: 2.51 (t, Jˆ7.0 Hz, 2H), 2.77
(t, Jˆ7.0 Hz, 2H), 3.76 (s, 3H), 3.80 (s, 3H), 4.46 (d,
Jˆ5.8 Hz, 2H, ArCH2), 6.03 (br, 1H), 6.77±6.89 (m, 5H),
7.17±7.24 (m, 3H); 13C NMR (75 MHz, CDCl3) d: 15.9,
35.8, 43.6, 55.1, 55.2, 81.5, 86.7, 112.9, 113.3, 113.8,
115.4, 120.0, 129.7, 132.9, 139.6, 159.2, 159.8, 171.1; IR
(KBr) cm21: 3295, 1620, 1600, 1240; MS m/z: 323 (M1);
Anal. Calcd for C20H21NO3: C, 74.28; H, 6.55; N, 4.33.
Found: C, 74.16; H, 6.55; N, 4.47.
Conclusion
In conclusion, the authors have established a new method
for the ef®cient intramolecular cyclization of b-alkynyl-
amides to 5-alkylidene-2-pyrrolidinones. The alkylidene-
lactames obtained in the present study have been shown to
N-(3-Methoxybenzyl)-4-pentynamide (6b). Mp 64±658C
(from AcOEt±iPr2O, colorless crystal); 1H NMR (300 MHz,
CDCl3) d: 2.00 (t, Jˆ2.6 Hz, 1H, CuCH), 2.44 (m, 2H),
2.51 (m, 2H), 3.80 (s, 3H), 4.44 (d, Jˆ5.8 Hz, 2H, ArCH2),
5.93 (br, 1H), 6.80±6.89 (m, 3H), 7.25 (dt, Jˆ1.0, 7.5 Hz);
13C NMR (100 MHz, CDCl3) d: 15.3, 35.8, 44.0, 55.6, 69.8,
83.4, 113.3, 113.8, 120.4, 130.1, 140.1, 160.3, 171.2; IR
(KBr) cm21: 3380, 1630, 1260, 1050; MS m/z: 217 (M1);
Scheme 4. threo -aza-muricatacin 16.

8860
Y. Koseki et al. / Tetrahedron 56 (2000) 8855±8865
Anal. Calcd for C13H15NO2: C, 71.89; H, 6.96; N, 6.45.
Found: C, 71.78; H, 7.01; N, 6.45.
under reduced pressure (200±100 mmHg) to give a crude
product, which was used in the next step without further
puri®cation. To a solution of this crude product and
2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) (305 mg,
1.95 mmol) in MeCN (176 ml) and phosphate buffer
(132 ml, pHˆ6.86) was added 5% NaClO (0.79 ml) in
H2O (14.9 ml) and NaClO2 (5.05 g, 55.8 mmol) in H2O
(36 ml) simultaneously over 2 h at 378C.22 After the mixture
was stirred at 378C for 3 h, cooled at 08C, diluted with water
(100 ml), quenched by adding 10% Na2S2O3 and then acid-
i®ed to pH 2±3 by adding 5% HCl. After further addition of
10% Na2S2O3, the mixture was extracted with t-BuOMe
according to a conventional work-up to give a white solid.
The crude solid was recrystallized from hexane to give
4-hexynoic acid (2.4 g, 76%) as a colorless crystal. Mp
95±968C.23 Condensation of 4-hexynoic acid (1.18 g,
10.5 mmol) with 3-methoxybenzylamine (1.44 g, 10.5
mmol) was carried out according to Shioiri's method24 to
give 6c (2.33 g, 96%). Mp 100±1018C (from iPr2O±hexane,
N-(3-Methoxybenzyl)-5-(4-chlorophenyl)-4-pentynamide
(6i). Mp 108.5±109.08C (from iPr2O±hexane, colorless
crystal); 1H NMR (300 MHz, CDCl3) d: 2.51 (t, Jˆ
7.1 Hz, 2H), 2.79 (t, Jˆ7.1 Hz, 2H), 3.76 (s, 3H), 4.46 (d,
Jˆ5.7 Hz, 2H, ArCH2), 5.94 (b, 1H), 6.80±6.89 (m, 3H),
7.18±7.27 (m, 5H); 13C NMR (75 MHz, CDCl3) d: 15.9,
35.5, 43.6, 55.1, 80.5, 89.4, 112.8, 113.4, 119.9, 121.8,
128.4, 129.7, 132.7, 133.7, 139.6, 159.8, 170.9; IR (KBr)
cm21: 3300, 1640, 1500, 1265; MS m/z: 327 (M1, Cl35), 329
(M1, Cl37); Anal. Calcd for C19H18NO2Cl: C, 69.62; H,
5.53; N, 4.27. Found: C, 69.62; H, 5.56; N, 4.17.
N-[2-(Benzyloxy)ethyl]-5-(3,4-methylenedioxyphenyl)-4-
pentynamide (6j). Mp 99±1008C (from AcOEt±hexane,
colorless crystal); 1H NMR (300 MHz, CDCl3) d: 2.46
(uneven t, Jù7.2 Hz, 2H), 2.72 (uneven t, Jù7.2 Hz, 2H),
3.49±3.60 (m, 4H), 4.49 (s, 2H), 5.95 (s, 2H), 6.06 (b, 1H),
6.70 (d, Jˆ8.0 Hz, 1H), 6.84 (d, Jˆ1.5 Hz, 1H), 6.90 (dd,
Jˆ1.5, 8.0 Hz, 1H), 7.27±7.38 (m, 5H); 13C NMR
(100 MHz, CDCl3) d: 15.8, 35.7, 39.4, 68.9, 73.1, 81.3,
86.6, 101.1, 108.3, 111.6, 116.7, 126.0, 127.7, 127.8,
128.5, 137.8, 147.3, 147.4, 171.2; IR (KBr) cm21: 3310,
1640, 1220, 1100; MS m/z: 351 (M1); Anal. Calcd for
C21H21NO4: C, 71.78; H, 6.02; N, 3.99. Found: C, 71.81;
H, 6.17; N, 4.07.
1
colorless crystal); H NMR (300 MHz, CDCl3) d: 1.71 (t,
Jˆ2.5 Hz, 3H, uCCH3), 2.38 (m, 2H), 2.49 (m, 2H), 3.79
(s, 3H), 4.43 (d, Jˆ5.6 Hz, 2H, ArCH2), 6.00 (br, 1H), 6.78±
6.89 (m, 3H), 7.24 (t, Jˆ7.7 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d: 3.35, 15.3, 35.9, 43.6, 55.2, 77.6, 112.8, 113.4,
119.9, 129.7, 139.8, 159.9, 171.3; IR (KBr) cm21: 3270,
1630, 1590, 1260, 1050; MS m/z: 231 (M1); Anal. Calcd
for C14H17NO2: C, 72.70; H, 7.41; N, 6.06. Found: C, 72.53;
H, 7.39; N, 6.01.
N-[(1S)-1-phenylethyl]-4-hexynamide (6d). Mp 96±988C
(from iPr2O±hexane, colorless crystal); 1H NMR
(300 MHz, CDCl3) d: 1.50 (d, Jˆ6.8 Hz, 3H), 1.72 (t,
Jˆ2.5 Hz, 3H, uCCH3), 2.34 (m, 2H), 2.47 (m, 2H), 5.15
(m, 1H, PhCH), 6.05 (br, 1H), 7.33 (m, 5H); 13C NMR
(100 MHz, CDCl3) d: 3.35, 15.3, 21.8, 35.9, 48.7, 77.1,
Preparation of 4-pentynamides 6c±h
5-Alkylsubstituted 4-pentynamides 6c±h were prepared
according to the procedures outline below.
77.7, 126.1, 127.2, 128.6, 143.1, 171.0; IR (KBr) cm21
:
3260, 1640, 1540; MS m/z: 215 (M1); [a]D23ˆ287.16 (c
1.01, toluene); Anal. Calcd for C14H17NO: C, 78.10; H,
7.96; N, 6.51. Found: C, 78.19; H, 7.92; N, 6.50.
N-[(1R)-2-Methoxy-1-phenylethyl]-4-hexynamide (6e).
Mp 81±828C (from iPr2O±hexane, colorless crystal); H
1
NMR (300 MHz, CDCl3) d: 1.76 (t, Jˆ2.5 Hz, 3H), 2.40±
2.50 (m, 4H), 3.36 (s, 3H), 3.68 (d, Jˆ4.7 Hz, 2H), 5.19 (m,
1H, PhCH), 6.49 (br, 1H), 7.25±7.35 (m, 5H); 13C NMR
(100 MHz, CDCl3) d: 3.36, 15.2, 35.9, 52.5, 59.0, 75.0,
77.7, 126.7, 127.3, 128.4, 139.9, 171.0; IR (KBr) cm21
:
N-(3-Methoxybenzyl)-4-hexynamide (6c). To a solution of
O-silylated 4-pentyn-1-ol (6.19 g, 31.23 mmol) in THF
(30 ml) under Ar was added dropwise n-BuLi in hexane
(1.52 M, 22.6 ml, 34.35 mmol) at 258C. After the solution
was stirred for 1.5 h, MeI (5.76 g, 40.60 mmol) in HMPA
(15 ml) was added dropwise at the same temperature. The
reaction mixture was stirred at rt for 10 h, quenched with
ice-water and the mixture was extracted with Et2O accord-
ing to a conventional work-up. The residue was chromato-
graphed (silica gel, hexane±iPr2Oˆ15:1) to give O-silylated
4-hexyn-1-ol (5.92 g, 90%) as a colorless oil, which was
used in the next step. To a solution of O-silylated
4-hexyn-1-ol (5.92 g, 27.9 mmol) in MeCN (100 g) was
added 45% HF (8 g) at 08C. The reaction mixture was stirred
at rt for 0.5 h, quenched by adding sat. NaHCO3 and the
mixture was extracted with Et2O, washed with sat. NaCl,
dried over MgSO4, ®ltered and then evaporated at 408C
3280, 1640, 1540, 1120; MS m/z: 245 (M1); [a]D26ˆ225.4
(c 1.02, toluene); Anal. Calcd for C15H19NO2: C, 73.44; H,
7.81; N, 5.71. Found: C, 73.37; H, 7.74; N, 5.74.
N-[(1R)-2-(1,1-dimethylpropyl)oxy-1-phenylethyl]-4-
hexynamide (6f). Colorless oil. 1H NMR (300 MHz,
CDCl3) d: 0.79 (t, Jˆ7.5 Hz, 3H), 1.07 (s, 3H), 1.08 (s,
3H), 1.46 (q, Jˆ7.4 Hz, 2H), 1.77 (t, Jˆ2.5 Hz, 3H,
uCCH3), 2.40±2.52 (m, 4H), 3.56 (dd, Jˆ4.1, 9.1 Hz,
1H), 3.62 (dd, Jˆ4.1, 9.1 Hz, 1H), 5.10 (m, 1H, PhCH),
6.53 (br, 1H), 7.20±7.40 (m, 5H); IR (neat) cm21: 3270,
2950, 2900, 1640, 1540; MS m/z: 302 (M121); [a]D21ˆ
29.83 (c 0.99, toluene).
N-(3-Methoxybenzyl)-8-chloro-4-octynamide (6g). Mp
43±448C (from iPr2O±hexane, colorless crystal); H NMR
1

Y. Koseki et al. / Tetrahedron 56 (2000) 8855±8865
8861
(300 MHz, CDCl3) d: 1.85 (m, 2H), 2.28 (m, 2H), 2.38 (m,
2H), 2.50 (m, 2H), 3.58 (t, Jˆ6.3 Hz, 2H, ClCH2), 3.79 (s,
3H), 4.42 (d, Jˆ6.3 Hz, 2H, ArCH2), 6.10 (br, 1H), 6.82 (m,
3H, Ar-H), 7.24 (t, Jˆ7.7 Hz, 1H, Ar±H); 13C NMR
(100 MHz, CDCl3) d: 15.2, 16.0, 31.4, 35.8, 43.5, 43.7,
55.2, 79.5, 79.6, 112.7, 113.5, 119.9, 129.7, 139.7, 159.8,
171.2; IR (KBr) cm21: 3360, 2900, 1640, 1610, 1590, 1540,
1480, 1430, 1290, 1250, 1210, 1150; MS m/z: 293 (M1).
2.62 ml, 2.62 mmol) was added slowly at rt. After 0.5 h,
the mixture, which consisted of a clear solution and a
black-brown paste, was stirred at 65±708C for 3 h, where-
upon the system became a black suspension. The reaction
mixture was quenched with ice-water, diluted with AcOEt
and ®ltered through celite by suction. The ®ltrate was
extracted with AcOEt. The organic phase was washed
with sat. NaCl, dried over MgSO4, ®ltered and then evapo-
rated. The residue was chromatographed (basic silica gel,
hexane±AcOEtˆ15:1) to give 7c (1.75 g, 89%) as a color-
N-(3-Methoxybenzyl)-4-heptadecynamide (6h). Mp 83±
848C (from AcOEt±hexane, colorless crystal); H NMR
1
1
less oil. H NMR (300 MHz, CDCl3) d: 1.57 (dt, Jˆ7.5,
(300 MHz, CDCl3) d: 0.89 (t, Jˆ6.7 Hz, 3H), 1.20±1.45
(m, 20H), 2.08 (m, 2H), 2.41 (m, 2H), 2.52 (m, 2H), 3.81
(s, 3H), 4.44 (d, Jˆ5.8 Hz, 2H, ArCH2), 6.04 (br, 1H), 6.80±
6.90 (m, 3H), 7.25 (t, Jˆ7.5 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d: 14.1, 15.4, 18.6, 22.7, 28.9, 29.1, 29.3, 29.5, 29.6,
31.9, 36.1, 43.6, 55.2, 78.4, 82.0, 112.8, 113.4, 119.9, 129.7,
139.8, 159.9, 171.4; IR (KBr) cm21: 3270, 2900, 1630,
1540, 1460; MS m/z: 385 (M1); Anal. Calcd for
C25H39NO2: C, 77.87; H, 10.19; N, 3.63. Found: C, 77.59;
H, 10.25; N, 3.68.
1.6 Hz, 3H, CH3), 2.56 (m, 2H), 2.64 (m, 2H), 3.79 (s,
3H), 4.48 (tq, Jˆ1.6, 7.5 Hz, 1H, CHv), 4.92 (s, 2H,
ArCH2), 6.69 (s, 1H, Harom), 6.73±6.80 (m, 2H), 7.24 (t,
Jˆ7.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) d: 11.2, 26.2,
29.3, 45.0, 55.1, 96.4, 111.8, 111.9, 118.1, 129.6, 137.6,
139.2, 159.8, 177.2; IR (neat) cm21: 2950, 1720, 1670,
1600; MS m/z: 231 (M1); Anal. Calcd for C14H17NO: C,
72.70; H, 7.41; N, 6.06. Found: C, 72.48; H, 7.32; N, 5.96.
(Z)-N-[(1S)-(1-phenylethyl)]-5-ethylidene-2-pyrrolidi-
none (7d). Cyclization of 6d (72 mg, 0.33 mmol) under the
same conditions described in the general procedure and
subsequent chromatography (basic silica gel, hexane±
(Z)-N-(3-Methoxybenzyl)-5-(4-methoxybenzylidene)-2-
pyrrolidinone (7a) and (E)-N-(3-methoxybenzyl)-5-(4-
methoxybenzylidene)-2-pyrrolidinone (8a). A mixture of
6a (100 mg, 0.31 mmol), 18-crown-6 (20 mg, 0.12 mmol),
KHMDS (31 mg, 0.15 mmol) and THF (1.5 ml) was stirred
under Ar at rt for 3 h. The reaction was quenched by adding
10% citric acid solution, and the mixture was extracted with
AcOEt. The organic phase was washed with sat. NaCl, dried
over MgSO4, ®ltered and then evaporated. The residue was
chromatographed (basic silica gel, hexane±AcOEtˆ8:1) to
give 7a and 8a (71 mg, 71%; 7a/8aˆ64:36).
1
AcOEtˆ15:1) gave 7d (64 mg, 89%) as a colorless oil. H
NMR (300 MHz, CDCl3) d: 1.36 (dt, Jˆ7.5, 1.6 Hz, 3H,
CH3Cv), 1.79 (d, Jˆ7.1 Hz, 3H), 2.40±2.70 (m, 4H), 4.51
(tq, Jˆ1.6, 7.5 Hz, 1H, CHv), 5.62 (q, Jˆ7.1 Hz, 1H,
1
PhCH), 7.20±7.36 (m, 5H); H NMR (300 MHz, pyridine-
d5) d: 1.23 (d, Jˆ7.4 Hz, 3H, CH3Cv), 1.66 (d, Jˆ7.1 Hz,
3H), 2.20±2.40 (m, 4H), 4.25 (q, Jˆ7.4 Hz, 1H, CHv),
5.60 (q, Jˆ7.1 Hz, 1H, PhCH), 7.10±7.29 (m, 5H); 13C
NMR (100 MHz, CDCl3) d: 13.3, 18.2, 28.4, 30.5, 51.7,
97.4, 126.3, 126.8, 128.8, 138.3, 141.8, 177.9; IR (neat)
cm21: 1730, 1670, 1310; MS m/z: 215 (M1); [a]2D3ˆ
25.97 (c 1.01, toluene); Anal. Calcd for C14H17NO: C,
78.10; H, 7.96; N, 6.51. Found: C, 78.00; H, 7.90; N, 6.49.
7a(Z): Mp 79±808C (from AcOEt±hexane, colorless
crystal); H NMR (300 MHz, CDCl3) d: 2.62 (m, 2H),
1
2.79 (m, 2H), 3.67 (s, 3H), 3.79 (s, 3H), 4.57 (s, 2H,
ArCH2), 5.61 (s, 1H, vCH), 6.10 (s, 1H, Harom), 6.27 (d,
Jˆ7.5 Hz, 1H, Harom), 6.65±6.73 (m, 3H), 6.84 (d, Jˆ
7.8 Hz, 2H, Harom), 7.00 (t, Jˆ7.9 Hz, 1H, Harom); IR
(KBr) cm21: 1700, 1660, 1350, 1240; MS m/z: 323 (M1);
Anal. Calcd for C20H21NO3: C, 74.28; H, 6.55; N, 4.33.
Found: C, 74.18; H, 6.56; N, 4.35.
(Z)-N-[(1R)-(2-Methoxy-1-phenylethyl)]-5-ethylidene-2-
pyrrolidinone (7e). Cyclization of 6e (400 mg, 1.63 mmol)
under the same conditions described in the general pro-
cedure and subsequent chromatography (basic silica gel,
hexane±AcOEtˆ20:1) gave 7e (353 mg, 88%). Mp 73±
748C (from iPr2O±hexane, colorless crystal). 1H NMR
(300 MHz, CDCl3) d; 1.53 (d, Jˆ7.4 Hz, 3H), 2.48 (m,
2H), 2.55±2.80 (m, 2H), 3.42 (s, 3H), 4.00 (dd, Jˆ5.9,
9.7 Hz, 1H), 4.35 (dd, Jˆ8.2, 9.7 Hz, 1H), 4.52 (q,
Jˆ7.4 Hz, 1H, CHv), 5.38 (dd, Jˆ5.9, 8.2 Hz, PhCH),
7.32 (m, 5H); 13C NMR (75 MHz, CDCl3) 12.3, 27.9,
30.3, 58.5, 58.7, 72.8, 96.8, 126.6, 127.2, 128.4, 138.4,
139.6, 178.0; IR (KBr) cm21: 2900, 1670, 1320; MS m/z
245 (M1); [a]2D4ˆ170.18 (c 1.02, toluene); Anal. Calcd for
C15H19NO2: C, 73.44; H, 7.81; N, 5.71. Found: C, 73.42; H,
7.81; N, 5.68.
8a(E): Mp 80±818C (from AcOEt±hexane, colorless crys-
tal); 1H NMR (300 MHz, CDCl3) d: 2.65 (m, 2H), 2.97 (m,
2H), 3.77 (s, 6H), 4.77 (s, 2H, ArCH2), 5.70 (s, 1H, vCH),
6.77±6.87 (m, 5H), 7.09 (d, Jˆ8.8 Hz, 2H), 7.23 (t,
Jˆ7.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) d: 23.6, 28.9,
43.7, 55.0, 55.1, 103.4, 112.3, 112.8, 113.7, 119.2, 128.6,
129.0, 129.5, 137.5, 139.7, 157.3, 159.7, 175.3; IR (KBr)
cm21: 2950, 1710, 1650, 1520, 1250; MS m/z: 323 (M1);
Anal. Calcd for C20H21NO3: C, 74.28; H, 6.55; N, 4.33.
Found: C, 74.17; H, 6.48; N, 4.37.
(Z)-N-[(1R)-2-[(1,1-Dimethylpropyl)oxy]-1-phenylethyl]-
5-ethylidene-2-pyrrolidinone (7f). Cyclization of 6f
(300 mg, 0.99 mmol) under the same conditions described
in the general procedure and subsequent chromatography
(basic silica gel, hexane±AcOEtˆ20:1) gave 7f (225 mg,
General procedure for the preparation of 5-alkylidene-
2-pyrrolidinone (7a, c±j) utilizing LHMDS/AgOTf
system
(Z)-N-(3-Methoxybenzyl)-5-ethylidene-2-pyrrolidinone
(7c). To a solution of alkynylamide 6c (2.01 g, 8.72 mmol)
and AgOTf (336 mg, 1.31 mmol) in toluene (45 ml) stirred
under Ar a solution of LiN(TMS)2 in hexane (1.0 M,
1
85%) as a colorless oil. H NMR (300 MHz, CDCl3) d:
0.86 (t, Jˆ7.4 Hz, CH2CH3), 1.12 (s, 3H), 1.13 (s, 3H),
1.49 (q, Jˆ7.4 Hz, 2H, CH2CH3), 1.55 (dt, Jˆ7.5, 1.5 Hz,

8862
Y. Koseki et al. / Tetrahedron 56 (2000) 8855±8865
1H, CH3Cv), 2.46 (m, 2H), 2.63 (m, 2H), 3.93 (dd, Jˆ5.5,
9.1 Hz, 1H), 4.25 (dd, Jˆ8.2, 9.1 Hz, 1H), 4.51 (tq, J ˆ1.5,
7.5 Hz, 1H, CHv), 5.26 (dd, Jˆ5.5, 8.2 Hz, 1H, PhCH),
7.20±7.40 (m, 5H); IR (neat) cm21: 2960, 1720, 1670, 1310;
MS m/z: 301 (M1); [a]D22ˆ130.47 (c 1.17, toluene); Anal.
Calcd for C19H27NO2: C, 75.71; H, 9.03; N, 4.65. Found: C,
75.68; H, 9.08; N, 4.72.
N-(3-Methoxybenzyl)-5-methylidene-2-pyrrolidinone
(7b). To a solution of 6b (100 mg, 0.46 mmol) in toluene
(1 ml) was added toluene solution (0.6 ml) of LHMDS/
AgOTf complex generated from LHMDS (0.14 ml,
0.14 mmol, 1 M hexane-solution) and AgOTf (17.6 mg,
0.07 mmol) at rt, followed by the same manner described
in the general procedure subsequent chromatography (basic
silica gel, hexane±AcOEtˆ15:1) gave 7b (86 mg, 86%) as a
colorless oil. 1H NMR (300 MHz, CDCl3) d: 2.60 (m, 2H),
2.72 (m, 2H), 3.79 (s, 3H), 4.13 (d, Jˆ1.8 Hz, 1H, CH2v),
4.20 (d, Jˆ2.0 Hz, 1H, CH2v), 4.65 (s, 2H, ArCH2), 6.78±
6.84 (m, 3H), 7.23 (t, Jˆ7.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d: 23.7, 28.9, 43.5, 55.1, 85.4, 112.5, 113.0, 119.5,
129.5, 137.6, 146.2, 159.8, 175.9; IR (neat) cm21: 1620,
1660, 1600, 1400; MS m/z: 217 (M1); Anal. Calcd for
C13H15NO2: C, 71.86; H, 6.96; N, 6.45. Found: C, 71.60;
H, 6.96; N, 6.38.
(Z)-N-(3-Methoxybenzyl)-5-(4-chlorobutylidene)-2-pyrro-
lidinone (7g). Cyclization of 6g (199 mg, 0.68 mmol) under
the same conditions described in the general procedure and
subsequent chromatography (basic silica gel, hexane±
AcOEtˆ15:1) gave 7g (167 mg, 84%) as a colorless oil.
1H NMR (300 MHz, CDCl3) d: 1.58 (m, 2H), 2.11 (m,
2H), 2.57 (m, 2H), 2.70 (m, 2H), 3.31 (t, Jˆ6.6 Hz, 2H,
ClCH2), 3.79 (s, 3H), 4.32 (m, 1H, CHv), 4.91 (s, 2H),
6.73 (m, 3H), 7.24 (t, Jˆ7.9 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d: 23.1, 26.1, 29.1, 33.5, 44.2, 45.1,
55.2, 101.1, 111.8, 112.0, 118.0, 129.7, 137.5, 138.6,
159.9, 177.2; IR (neat) cm21: 2950, 1720, 1670, 1600,
1440, 1400, 1360, 1280; MS m/z: 293 (M1).
N-(3-Methoxybenzyl)-5-[hydroxy(4-methoxyphenyl)-
methyl]-5-methoxy-2-pyrrolidinone (9a). To a solution of
7a (527 mg, 1.63 mmol) in abs. MeOH (30 ml) and CH2Cl2
(15 ml) was added dropwise a solution of mCPBA (475 mg,
2.20 mmol) in CH2Cl2 (15 ml) at 2508C under Ar. The
reaction mixture was allowed to stand at rt and then stirred
for 1 h. The reaction was quenched by adding 10% Na2S2O3
and sat. NaHCO3 and the mixture was extracted with
CH2Cl2. The organic phase was washed with sat. NaCl,
dried over MgSO4, ®ltered and then evaporated. The residue
was chromatographed (silica gel, hexane±acetoneˆ5:1) to
give 9a (498 mg, 83%) as a mixture of diastereomers (less
(Z)-N-(3-Methoxybenzyl)-5-tridecylidene-2-pyrrolidi-
none (7h). Cyclization of 6h (280 mg, 0.73 mmol) under the
same conditions described in the general procedure and
subsequent chromatography (basic silica gel, hexane±
AcOEtˆ30:1) gave 7h (250 mg, 89%) as a colorless oil.
1H NMR (400 MHz, CDCl3) d: 0.88 (t, Jˆ7.0 Hz, 3H),
1.05±1.30 (m, 20H), 1.95 (m, 2H), 2.55 (m, 2H), 2.67 (m,
2H), 3.77 (s, 3H), 4.36 (t, Jˆ7.0 Hz, 1H, CHv), 4.87 (s, 2H,
ArCH2), 6.65 (s, 1H, Harom), 6.70±6.77 (m, 2H), 7.22 (t,
Jˆ7.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) d: 14.1,
22.7, 25.7, 26.2, 29.0, 29.2, 29.3, 29.55, 25.59, 29.61,
29.64, 30.9, 31.9, 45.2, 55.1, 103.6, 111.8, 111.9, 118.1,
129.6, 136.2, 138.9, 159.9, 177.2. IR (neat) cm21: 2900,
1720, 1670, 1360; MS m/z: 385 (M1); Anal. Calcd for
C25H39NO2: C, 77.87; H, 10.20; N, 3.63. Found: C, 77.78;
H, 10.17; N, 3.64.
1
polar/more polarˆ4.3:1). 9a (less polar): colorless oil. H
NMR (300 MHz, CDCl3) d:1.51 (m, 1H), 2.30±2.50 (m,
4H1OH), 3.01 (s, 3H), 3.780 (s, 3H), 3.789 (s, 3H), 4.02
(d, Jˆ15.0 Hz, 1H), 4.63 (d, Jˆ3.5 Hz, 1H, CH(OH)), 4.97
(d, Jˆ15.0 Hz, 1H), 6.79±7.32 (m, 8H). 9a (more polar):
mp 133±1348C (from toluene±hexane, colorless crystal). 1H
NMR (300 MHz, CDCl3) d: 1.48 (m, 1H), 1.82 (m, 1H),
2.05±2.23 (m, 2H), 2.90 (d, Jˆ3.1 Hz, 1H, OH, D2O
exchangeable), 2.91 (s, 3H), 3.79 (s, 3H), 3.81 (s, 3H),
4.46 (d, Jˆ14.5 Hz, 1H), 4.69 (d, Jˆ14.5 Hz, 1H), 4.84
(d, Jˆ3.1 Hz, 1H, CH(OH), after D2O exchange, d
converted to s), 6.78±6.85 (m, 3H), 7.08±7.27 (m, 5H);
13C NMR (75 MHz, CDCl3) d: 21.5, 29.3, 43.8, 49.7,
55.15, 55.21, 75.2, 97.9, 113.2, 113.5, 114.7, 121.6, 128.1,
129.4, 139.5, 159.3, 159.6, 175.4; IR (KBr) cm21 3340,
1680, 1250. MS m/z: 371 (M1), 339 (M2MeOH); Anal.
Calcd for C21H25NO5: C, 67.90; H, 6.78; N, 3.77. Found:
C, 67.95; H, 6.67; N, 3.54.
(Z)-N-(3-Methoxybenzyl)-5-(4-chlorobenzylidene)-2-
pyrrolidinone (7i). Cyclization of 6i (100 mg, 0.31 mmol)
under the same conditions described in the general pro-
cedure and subsequent chromatography (basic silica gel,
hexane±AcOEtˆ10:1) gave 7i and 8i (88 mg, 88%).
Major product, 7i(Z): mp 96±978C (from tBuOMe±hexane,
1
colorless crystal). H NMR (400 MHz, CDCl3) d: 2.64 (m,
2H), 2.81 (m, 2H), 3.68 (s, 3H), 4.55 (s, 2H, ArCH2), 5.57 (s,
1H, vCH), 6.06 (s, 1H, Harom), 6.21 (d, Jˆ8.0 Hz, 1H), 6.67
(dd, Jˆ2.3, 8.0 Hz, 1H), 6.81 (d, Jˆ8.1 Hz, 2H), 7.03 (t,
Jˆ8.0 Hz, 1H), 7.11 (d, Jˆ8.1 Hz, 2H); 13C NMR
(100 MHz, CDCl3) d: 26.8, 29.1, 44.8, 55.0, 102.2, 111.6,
112.6, 118.4, 127.6, 129.0, 130.9, 132.1, 134.2, 137.5,
139.1, 159.4, 177.5; IR (KBr) cm21: 1720, 1660, 1600,
1260; MS m/z: 327 (M1, Cl35), 329 (M1, Cl37); Anal.
Calcd for C19H18NO2Cl: C, 69.61; H, 5.54; N, 4.27.
Found: C, 69.57; H, 5.73; N, 4.34.
N-(3-Methoxybenzyl)-5-[hydroxy(4-methoxyphenyl)-
methyl]-5-hydroxy-2-pyrrolidinone (10a). To a DMD±
acetone solution was added dropwise a solution of 7a
(169 mg, 0.523 mmol) in acetone (2 ml) at 2788C. The
reaction mixture was allowed to warm to 2308C over
20 min, and an additional 15 min at the same temperature.
The reaction mixture was cooled to ca. 2608C, and then
quenched with 10% Na2S2O3. After removal of organic
solvents by a rotary evaporator, the residue was extracted
with AcOEt, washed with sat. NaCl, dried over MgSO4,
®ltered and then evaporated. The residue was chromato-
graphed (silica gel, hexane±acetoneˆ3:1±2:1) to give 10a
(178 mg, 95%) as a mixture of diastereomers (less polar/
(Z)-N-[2-(Benzyloxy)ethyl]-5-(3,4-methylendioxybenzyl-
idene)-2-pyrrolidinone (7j). Cyclization of 6j (92 mg,
0.26 mmol) under the same conditions described in the
general procedure and subsequent chromatography (basic
silica gel, hexane±AcOEtˆ15:1) gave 7j and 8j (82 mg,
81%).
1
more polarˆ6:1). 10a (less polar): colorless oil; H NMR

Y. Koseki et al. / Tetrahedron 56 (2000) 8855±8865
8863
(300 MHz, CDCl3) d: 1.53 (m, 2H), 2.16 (m, 2H), 2.9 (b,
1H, OH, D2O exchangeable), 3.77 (s, 6H), 4.02 (b, 1H, OH,
D2O exchangeable), 4.50 (d, Jˆ15.1 Hz, 1H), 4.66 (d,
Jˆ15.1 Hz, 1H), 4.67 (bs, 1H, CH(OH), after D2O
exchange, bs converted to s), 6.76±7.25 (m, 8H, Ar-H);
10a (more polar): mp 121±1228C (from dist. CHCl3±hex-
ane, colorless crystal); 1H NMR (300 MHz, CDCl3) d: 1.58
(m, 1H), 2.10±2.21 (m, 1H1OH), 2.30±2.50 (m, 2H), 3.21
(b, 1H), 3.78 (s, 3H), 3.79 (s, 3H), 4.45 (d, Jˆ15.3 Hz, 1H),
4.69 (d, Jˆ3.2 Hz, 1H, CH(OH)), 4.81 (d, Jˆ15.3 Hz, 1H),
6.79±7.33 (m, 8H, Ar-H); 13C NMR (75 MHz, CDCl3) d:
28.6, 29.1, 42.9, 55.2, 75.2, 94.1, 112.9, 113.5, 113.7, 120.0,
128.5, 129.9, 130.1, 140.2, 159.4, 159.9, 176.1; MS m/z: 358
(M111), 339 (M2H2O); HRMS (EI) calcd for C20H21NO4
(M12H2O) 339.1471, found 339.1468.
Jˆ15.4 Hz, 1Hp), 4.73 (d, Jˆ15.4 Hz, 1H), 6.78±7.29 (m,
4H14Hp, Ar±H); IR (KBr) cm21: 3250, 3210, 1650, 1440,
1250; MS m/z: 265 (M1), 247 (M2H2O); Anal. Calcd for
C14H19NO4: C, 63.38; H, 7.22; N, 5.28. Found: C, 63.45; H,
7.20; N, 5.10.
N-(3-Methoxybenzyl)-5-(4-methoxybenzoyl)-2-pyrroli-
dinone (13a). A CH2Cl2 (1 ml) solution of 9a (98 mg,
0.26 mmol) and Et3SiH (104 mg, 0.39 mmol) under Ar
was cooled at 2788C, and TiCl4 in CH2Cl2 (2.3 M,
0.13 ml, 0.29 mmol) was then added dropwise to the solu-
tion. The reaction mixture was allowed to warm to 2208C
over 30 min, and then stirred at 2208C for 1 h. The reaction
mixture was quenched with sat. NaHCO3, extracted with
CH2Cl2, washed with sat. NaCl, dried over MgSO4, ®ltered
and then evaporated. The residue was chromatographed
(silica gel, hexane±AcOEtˆ4:1) to give 13a (86 mg,
N-(3-Methoxybenzyl)-5-(1-hydroxyethyl)-5-methoxy-2-
pyrrolidinone (9c). Oxidation of 7c (681 mg, 2.94 mmol)
in the same manner as described for 9a and subsequent
chromatography (silica gel, hexane±AcOEtˆ3:1) gave 9c
(766 mg, 93%) as a mixture of diastereomers (less polar/
1
80%) as a dark yellow oil. H NMR (300 MHz, CDCl3) d:
1.96 (m, 1H), 2.46 (m, 3H), 3.72 (s, 3H), 3.75 (d, Jˆ
14.8 Hz, 1H), 3.87 (s, 3H), 4.87 (dd, Jˆ3.3, 9.1 Hz, 1H,
CHN), 5.23 (d, Jˆ14.8 Hz, 1H), 6.70 (d, Jˆ1.9 Hz, 1H,
Harom), 6.73 (d, Jˆ7.5 Hz, 1H), (dd, Jˆ2.5, 8.1 Hz, 1H),
6.92 (m, 2H), 7.18 (t, Jˆ7.5 Hz, 1H), 7.81 (m, 2H); IR
(neat) cm21: 3050, 1730, 1650, 1480, 1300; MS m/z: 339
(M1).
1
more polarˆ1:2.7). 9c (less polar): colorless oil. H NMR
(400 MHz, CDCl3) d: 1.08 (d, Jˆ6.4 Hz, 3H), 1.22 (b, OH,
D2O exchangeable), 1.88 (m, 1H), 2.45 (m, 1H), 2.50 (m,
2H), 3.07 (s, 3H), 3.71 (dq, Jˆ2.6, 6.4 Hz, 1H, CH(OH),
after D2O exchange, dq converted to q, Jˆ6.4 Hz), 3.78 (s,
3H), 3.83 (d, Jˆ14.9 Hz, 1H), 4.92 (d, Jˆ14.9 Hz, 1H), 6.82
(d, Jˆ8.1 Hz, 1H, Ar±H), 6.99 (m, 2H, Ar±H), 7.27 (t,
Jˆ8.1 Hz, 1H, Ar±H); 13C NMR (100 MHz, CDCl3) d:
16.3, 21.0, 29.9, 42.3, 49.5, 55.6, 68.4, 99.5, 113.8, 114.0,
120.4, 129.9, 140.3, 160.4, 177.3; IR (CHCl3) cm21: 3400,
2900, 1720, 1640, 1450; MS m/z: 279 (M1). 9c (more
polar): mp 91±928C (from AcOEt±hexane, colorless
crystal); 1H NMR (400 MHz, CDCl3) d: 0.78 (d, Jˆ
6.4 Hz, 3H), 1.94 (m, 1H), 2.23 (m, 1H), 2.30 (s, 1H, OH,
D2O exchangeable), 2.47 (m, 2H), 3.00 (s, 3H), 3.78 (s, 3H),
3.94 (dq, Jˆ2.6, 6.4 Hz, 1H, CH(OH), after D2O exchange,
dq converted to q, Jˆ6.4 Hz), 4.07 (d, Jˆ14.6 Hz, 1H), 4.61
(d, Jˆ14.6 Hz, 1H), 6.79 (d, Jˆ7.6 Hz, 1H), 6.96 (m, 2H),
7.20 (t, Jˆ7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d:
16.2, 20.9, 29.7, 43.4, 49.5, 55.6, 71.2, 98.9, 113.5, 114.9,
121.6, 129.8, 139.8, 160.0, 176.4; IR (KBr) cm21: 3330,
2900, 1660, 1600, 1400, 1260; MS m/z: 279 (M1); Anal.
Calcd for C15H21NO4: C, 64.50; H, 7.58; N, 5.01. Found: C,
64.23; H, 7.51; N, 4.97.
threo and erythro-N-(3-Methoxybenzyl)-5-(1-hydroxy-
ethyl)-2-pyrrolidinone (12c). Reductive deoxygenation of
9c by Et3SiH/TiCl4 (Run 2 in Table 4). A CH2Cl2 (0.5 ml)
solution of 9c (50 mg, 0.18 mmol) and Et3SiH (104 mg,
0.90 mmol) under Ar was cooled at 2788C, and TiCl4 in
CH2Cl2 (1.03 M, 0.21 ml, 0.21 mmol) was then added
dropwise to the solution. The reaction mixture was allowed
to warm to 2208C. over 30 min, and then stirred at 2208C
for 2 h. The reaction mixture was quenched with sat.
NaHCO3, extracted with CH2Cl2, washed with sat. NaCl,
dried over MgSO4, ®ltered and then evaporated. The residue
was chromatographed (silica gel, hexane±acetoneˆ2:1) to
give 12c (38 mg, 86%) as an inseparable mixture of dia-
stereomers (threo/erythroˆ2:1).
1
erythro-12c: H NMR (300 MHz, CDCl3) d: 1.08 (d, Jˆ
6.6 Hz, 3H, CH3), 1.89 (m, 1H, CH2), 2.06 (m, 1H, CH2),
2.39 (m, 1H), 2.51 (m, 1H, CHN), 3.35 (m, 1H), 3.77 (s,
3H), 3.80 (b, 1H, OH, D2O exchangeable), 4.06 (d, Jˆ
15.1 Hz, 1H), 4.14 (m, 1H, CH(OH)), 4.94 (d, Jˆ15.1 Hz,
1H), 6.79 (m, 3H, Harom), 7.23 (t, Jˆ7.7 Hz, 1H);
N-(3-Methoxybenzyl)-5-hydroxy-5-(1-hydroxyethyl)-2-
pyrrolidinone (10c). Oxidation of 7c (178 mg, 2.94 mmol)
in the same manner as described for 10a and subsequent
chromatography (silica gel, hexane±acetoneˆ2:1) gave
10c (195 mg, 96%) as a mixture of diastereomers (2:1).
Recrystallization from AcOEt±hexane gave a colorless
crystal as a mixture of diastereomer (1.5:1p). The stereo-
chemistry of each isomer was not assigned. Diastereomer
mixture of 10c: mp 117±1208C, 1H NMR (300 MHz,
CDCl3) d: 0.98 (d, Jˆ6.4 Hz, 1Hp), 1.15 (d, Jˆ6.3 Hz,
1H), 1.53 (d, Jˆ4.1 Hz, 1H, OH, D2O exchangeable),
1.81±1.94 (m, 1H11Hp), 2.19 (d, Jˆ3.6 Hz, 1Hp, OH,
D2O exchangeable), 2.26±2.65 (m, 3H13Hp), 3.24 (s, 1H,
OH, D2O exchangeable), 3.49 (s, 1Hp, OH, D2O exchange-
able), 3.79 (s, 3H13Hp), 3.78±3.90 (m, 1H11Hp, CH(OH),
after D2O exchange, m converted to q, Jˆ6.5 Hz), 4.27 (d,
Jˆ15.4 Hz, 1H), 4.37 (d, Jˆ15.4 Hz, 1Hp), 4.62 (d,
1
threo-12c: colorless oil. H NMR (400 MHz, CDCl3) d:
1.10 (d, Jˆ6.3 Hz, 3H, CH3), 1.84 (m, 1H, CH2), 1.99 (m,
1H, CH2), 2.31 (b, 1H, OH, D2O exchangeable), 2.31±2.54
(m, 2H), 3.49 (m, 1H, CHN), 3.78 (s, 3H), 3.92 (m, 1H,
CH(OH), after D2O exchange, m converted to quint,
Jˆ6.3 Hz), 4.22 (d, Jˆ14.9 Hz, 1H), 4.91 (d, Jˆ14.9 Hz,
1H), 6.80 (m, 3H, Ar±H), 7.22 (t, Jˆ7.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d: 18.9, 20.5, 30.7, 46.2, 55.6, 62.5,
69.5, 113.1, 114.0, 120.6, 130.1, 138.9, 160.2, 176.4; MS
m/z: 249 (M1); HRMS (EI) calcd for C14H19NO3 (M1)
249.1365, found 249.1368.
Reductive deoxygenation of 9c by Et3SiH/BF3´OEt2 (Run 4
in Table 4). A CH2Cl2 (4 ml) solution of 9c (490 mg,
1.75 mmol) and Et3SiH (1.1 g, 8.75 mmol) under Ar was

8864
Y. Koseki et al. / Tetrahedron 56 (2000) 8855±8865
cooled at 2788C, and BF3´OEt2 (0.49 ml, 3.85 mmol) was
then added dropwise to the solution. The reaction mixture
was allowed to warm to rt over 30 min, and then stirred
overnight. The reaction mixture was cooled to 08C,
quenched with sat. NaHCO3, extracted with CH2Cl2,
washed with sat. NaCl, dried over MgSO4, ®ltered and
then evaporated. The residue was chromatographed (silica
gel, hexane±acetoneˆ2:1) to give 12c (427 mg, 97%) as a
mixture of diastereomers (threo/erythroˆ30:1).
(2308C), was added enough lithium to produce a dark blue
color, and the solution was let stand for an additional 40 min
at the same temperature. The reaction was then quenched by
the addition of a small amount of NH4Cl (solid). The result-
ing white solution was allowed to warm to rt over 1 h. After
removal of organic solvents by a rotary evaporator, the resi-
due was diluted with water, extracted with CHCl3, washed
with sat. NaCl, dried over MgSO4, ®ltered and then evapo-
rated. The residue was chromatographed (silica gel,
hexane±acetoneˆ2:1) to give 16 (31 mg, 45%). Mp 78.3±
1
threo-N-(3-Methoxybenzyl)-5-(4-chloro-1-hydroxybutyl)-
2-pyrrolidinone (12g). To a DMD±acetone solution was
added dropwise the solution of 7g (182 mg, 0.62 mmol) in
abs. MeOH (2 ml) at 2788C. The reaction mixture was
allowed to warm to 2308C over 20 min, and an additional
15 min at the same temperature. The reaction mixture was
cooled to ca. 2608C, and then quenched by adding 10%
Na2S2O3. After removal of organic solvents by a rotary
evaporator, the residue was extracted with AcOEt, washed
with sat. NaCl, dried over MgSO4, ®ltered and then evapo-
rated to give a mixture of 9g and 10g. This crude mixture
and Et3SiH were dissolved in CH2Cl2 (2 ml) under Ar, and
the solution was cooled at 2788C. BF3´OEt2 (0.16 ml,
1.36 mmol) was added dropwise, and the reaction mixture
was allowed to warm to rt over 30 min, and stirred over-
night. The reaction mixture was cooled to 08C, quenched
with sat. NaHCO3, extracted with CH2Cl2, washed with sat.
NaCl, dried over MgSO4, ®ltered and then evaporated. The
residue was chromatographed (silica gel, hexane±acetoneˆ
2:1) to give 12g (137 mg, 71%, threo/erythroˆ99:1). threo-
12g: colorless oil. 1H NMR (300 MHz, CDCl3) d: 1.56 (m,
3H, CH2CH2), 1.96 (m, 3H, CH2CH2), 2.42 (m, 3H,
CH2CH2), 3.51 (t, Jˆ6.4 Hz, 2H, ClCH2), 3.54 (m, 1H,
CHN), 3.68 (1H, m, CH(OH)), 3.79 (3H, s, ArOCH3),
4.30 (d, Jˆ15.0 Hz, 1H, ArCH2), 4.82 (d, Jˆ15.0 Hz, 1H,
ArCH2), 6.80 (m, 3H, Ar±H), 7.23 (t, Jˆ7.4 Hz, 1H, Ar±
H); 13C NMR (100 MHz, CDCl3) d: 20.4, 28.7, 29.1, 30.1,
44.8, 46.0, 55.1, 61.9, 72.3, 112.6, 113.6, 120.1, 129.7,
138.4, 159.8, 176.1; IR (CHCl3) cm21: 3330, 2930, 1660,
1600, 1430, 1260, 1150; MS m/z: 311 (M1).
78.58C (from AcOEt±hexane, colorless crystal); H NMR
(400 MHz, CDCl3) d: 0.88 (t, Jˆ6.6 Hz, 3H), 1.20±1.50 (m,
22H), 1.77 (m, 1H), 2.16 (m, 1H), 2.36 (m, 2H), 3.14 (d,
Jˆ6.1 Hz, 1H, OH, D2O exchangeable), 3.36 (m, 1H, CH±
N), 3.53 (t, Jˆ7.0 Hz, 1H, CH(OH)), 6.86 (bs, 1H, NH); 13C
NMR (100 MHz, CDCl3) d: 14.1, 22.7, 23.8, 25.4, 29.3,
29.59, 29.64 (several C), 30.5, 31.9, 33.4, 59.6, 75.3,
178.7; IR (KBr) cm21: 3400, 3200, 2900, 2850, 1690,
1460; MS m/z: 283 (M1); Anal. Calcd for C17H33NO2: C,
72.04; H, 11.73; N, 4.94. Found: C, 71.89; H, 11.69; N, 5.09.
References
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threo-N-(3-Methoxybenzyl)-5-(1-hydroxytridecyl)-2-
pyrrolidinone (12h). Oxidation of 7h (254 mg, 0.659
mmol) was followed by reductive deoxygenation in the
same manner as described for 12g and subsequent chroma-
tography (silica gel, hexane±acetoneˆ3:1) gave threo-12h
(205 mg, 77%) as a colorless oil. 1H NMR (300 MHz,
CDCl3) d: 0.89 (t, Jˆ6.7 Hz, 1H), 1.20±1.45 (m, 1H),
1.53 (d, Jˆ5.4 Hz, 1H, OH), 1.87 (m, 1H), 2.02 (m, 1H),
2.34±2.57 (m, 2H), 3.53 (m, 1H), 3.63 (m, 1H, CHOH), 3.79
(s, 3H), 4.29 (d, Jˆ14.9 Hz, 1H), 4.86 (d, Jˆ14.9 Hz, 1H),
6.79±6.84 (m, 2H), 7.24 (t, Jˆ7.4 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d: 14.1, 20.5, 22.6, 25.8, 29.3, 29.55,
29.60, 30.2, 31.9, 32.0, 46.0, 55.2, 61.7, 73.3, 112.7,
113.5, 120.1, 129.6, 138.7, 159.8, 176.0; IR (neat) cm21
:
3350, 2900, 1660, 1600, 1460, 1260; MS m/z: 403 (M1);
Anal. Calcd for C14H19NO4: C, 74.40; H, 10.24; N, 3.47.
Found: C, 74.28; H, 10.11; N, 3.39.
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and abs. EtOH (0.15 ml) at 2788C. To the resulting cold
5. For some recent examples of tertiary N-acyliminium ion

Y. Koseki et al. / Tetrahedron 56 (2000) 8855±8865
8865
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  Â
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15. The similar result has been reported by Back et al.4a
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