N-Acyliminium ion chemistry and palladium catalysis: A useful combination to obtain bicyclic heterocycles

Article abstract of DOI:10.1016/S0040-4020(01)00364-7

By using N-acyliminium ion chemistry, several ω-propadienyllactams and a propadienyloxazolidine were prepared from N-acyliminium ion precursors and propargylsilanes. Treatment of these allene containing lactams and oxazolidinone with allyl halides or an a

Full text of DOI:10.1016/S0040-4020(01)00364-7

TETRAHEDRON
Pergamon
Tetrahedron 57 22001) 5123±5130
N-Acyliminium ion chemistry and palladium catalysis: a useful
combination to obtain bicyclic heterocycles
²
³
Willem F. J. Karstens, Dirk Klomp, Floris P. J. T. Rutjes and Henk Hiemstrap
Institute of Molecular Chemistry, University of Amsterdam, Nieuwe Achtergracht 129, 1018 WS Amsterdam, Netherlands
Dedicated to Professor BarryM. Trost on the occasion of his 60th birthday
Received 3 February2001; revised 28 February2001; accepted 1 March 2001
AbstractÐByusing N-acyliminium ion chemistry, several v-propadienyllactams and a propadienyloxazolidine were prepared from
N-acyliminium ion precursors and propargylsilanes. Treatment of these allene containing lactams and oxazolidinone with allyl halides or
an allyl carbonate using Pd2II)-salts as the catalyst gave rise to a coupling±cyclization reaction, yielding bicyclic systems in which the allyl
moietyis incorporated. With this methodologyseveral substituted pyrrolizinones, an oxazolone and indolizinone were prepared. q 2001
Elsevier Science Ltd. All rights reserved.
1. Introduction
In one of the earlier examples, Prasad and Liebeskind
described a remarkable reaction in which b-lactam 1 was
reacted with an excess of allyl bromide and catalytic palla-
dium acetate to give carbapenem skeleton 2.8 We were
particularlyintrigued bythis reaction, because some time
ago we reported an ef®cient synthesis of the allene substi-
tuted lactam 3.9 This allene was prepared utilizing N-acyl-
iminium ion chemistry, which we have also used in our
laboratoryto prepare a varietyof interesting compounds,
natural products and natural product analogs.10 It seemed
promising to combine our ef®cient N-acyliminium ion tech-
nologywith palladium catalysis to obtain an easyentryinto
the class of pyrrolizine alkaloid analogues, e.g. pyrrolizi-
dinones 4. Furthermore, this investigation is an extension
of other recent work from our group on palladium catalyzed
cyclization reactions of acetylene11 and allene12 containing
lactams and amino acids.13
The construction of nitrogen heterocycles is an important
goal in organic synthesis because of their abundance in
natural and pharmaceutical products.1 Among the well
established methods for the preparation of such compounds
are heteroannulation processes involving unsaturated
2,3
functionalityand Pd-catalysis.
Despite their interesting
chemical properties due to the cumulated double bonds,4
allenes have received relativelylittle attention in this area.
However, interest in the preparation of heterocyclic
molecules via cyclization of heteroatoms onto tethered
allenes has increased considerablyover the last few
years.5±7
2. Results
Some years ago, we developed syntheses of allenyllactams
bymeans of N-acyliminium ion chemistry. The reaction can
be carried out with an acyliminium ion precursor 2viz. 5) in
the presence of a Lewis acid and a propargylsilane, both in
intra-14 and intermolecular9 fashion. In order to obtain the
®rst starting material, ethoxylactam 5 was reacted with
commerciallyavailable proparglytrimethlysilane
the presence of a Lewis acid to give allenyllactam 3.9
6a15 in
Keywords: palladium catalysis; pyrrolizines; allenes; propargylsilanes;
indolizines.
p
Corresponding author. Tel.: 131-20-5255941; fax: 131-20-5255670;
e-mail: henkh@org.chem.uva.nl
Current address: Department of Medicinal Chemistry, N.V. Organon,
Oss, Netherlands.
²
ꢀ1†
³
Current address: Department of Organic Chemistry, University of Nijme-
gen, Netherlands.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020201)00364-7

5124
W. F. J. Karstens et al. / Tetrahedron 57 *2001) 5123±5130
Table 1.
Then, we set out to prepare substituted 5-propadienyl-2-
pyrrolidinones. In order to introduce substituents on the
allenic moietyof the pyrrolidinones, two other p-nucleo-
philes for the N-acyliminium ion reactions were prepared.
2-Butynyltrimethylsilane 26b) was convenientlyprepared
following a literature procedure,16 while the corresponding
Ph-substituted propargylsilane 6c was synthesized via a new
route using a modi®cation of the Sonogashira reaction17 in
52% yield 2Eq. 2):
pure allenyllactam 14 2entry5). A small amount 2ca. 2%) of
the cis-isomer of 14 was also formed in this reaction, but this
diastereoisomer could be separated from 14 bymeans of
column chromatography.
In addition to these lactams, an oxazolidinone analogue was
prepared in two steps, starting from oxazolidin-2-one 15.
Methoxylation of 15 bymeans of electrochemical oxidation
afforded N,O-acetal 16 240%),20 which after reaction with
6b 22 equiv.) gave 17 in a yield of 37% 2Eq. 3):
ꢀ2†
The required N-acyliminium ion precursors were readily
available bypartial reduction of ccylic imides using
NaBH4 in ethanol, followed byethanolysis at pH 2 of the
intermediate N,O-hemiacetals.18 For example, reduction of
succinimide afforded ethoxylactam 5 in 81% yield. Lewis
acid mediated coupling 2BF3´OEt2, 2±3.5 equiv.) of this
N-acyliminium ion precursor with propargyltrimethylsilane
6a 22 equiv.) afforded allenyllactam 3 in 55% yield 2entry 1,
Table 1). Similarly, the methyl-substituted allenyllactam 8
was obtained in 64% yield when 2-butynyltrimethylsilane
6b was reacted with 5 2entry 2). Unfortunately, the phenyl-
substituted allene was obtained in a much lower yield
218%).
ꢀ3†
With the different allenes in hand, the stage was set to study
the palladium catalyzed cyclization reactions. Unsubstituted
allenyllactam 3 was treated under Liebeskind's conditions
with allyl bromide 25 equiv.) and PdCl2 20.1 equiv.) in
CH2Cl2. Unfortunately, a complex mixture of reaction
products was obtained in which the desired product 18
1
could not be detected by H NMR 2Eq. 4):
The methylallene-substituted piperidinone 11 was prepared
via reduction18 of glutarimide to 10, followed byreaction
with propargylsilane 6b 2entry4). Moreover, an enantiopure
allenyllactam was prepared using similar methodology.
Thus, reduction of the 2S)-malic acid derived imide 1219c
gave a cis/trans mixture of ethoxylactams 13,19 which
after BF3´OEt2 mediated reaction with 6b gave the enantio-
ꢀ4†
The successful example presented byLiebeskind involved

W. F. J. Karstens et al. / Tetrahedron 57 *2001) 5123±5130
5125
Table 2. Reagents and conditions: 2a) 8 20.5 mmol), allyl bromide 25 equiv.), PdX2 20.1 equiv.), base 20±2 equiv.), indicated solvent 20.1 M)
EntrySolvent
st Cataly
CH2Cl2
Base
T 2
8C)
Time 2h)
Yield 2%)
1
2
3
4
5
6
7
8
9
Pd2OAc)2
±
±
±
±
Rt
Rt
Rt
Rt
Rt
Rt
Rt
0
18
18
18
18
18
18
18
18
1
,5
42
41
,5
,5
50
,5
45
CH2Cl2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Pd22MeCN)2
Pd22MeCN)2
Pd2OAc)2
PdCl22MeCN)2
PdCl22MeCN)2
PdCl22PPh3)2
PdCl22MeCN)2
PdCl22MeCN)2
Et3N
K2CO3
K2CO3
K2CO3
K2CO3
75
56
allenic b-lactam 1 which contained a methyl substituent on
the internal allenic carbon. When we applied the afore-
mentioned cyclization conditions to methyl-substituted
allene 8, a successful reaction occurred, giving pyrrolizi-
dinone 19 in 31% yield 2Eq. 4).
2Table 2). First, Pd2OAc)2 was used, which was reported
byLiebeskind to be an equallyeffective catalyst for this
type of conversion. In our case, however, this catalyst was
not active at all and the starting material could be recovered
after stirring for 18 h at room temperature 2entry1, Table 2).
When the more soluble bisacetonitrile complex of PdCl2
was used in the reaction, the yield increased substantially
to 42% 2entry2). Use of the same catalyst in acetonitrile
Encouraged bythe formation of the desired biccylic
product, we tried to increase the yield of the reaction
Table 3.
a
Allenyllactam 21 equiv), allylating agent 25 equiv), PdCl22MeCN)2 20.1 equiv), K2CO3 22 equiv), MeCN 20.1 M).
b The reaction was run without K2CO3.

5126
W. F. J. Karstens et al. / Tetrahedron 57 *2001) 5123±5130
Scheme 1.
gave a similar yield of the product 2entry 3), whereas
Pd2OAc)2 was equallyineffective in this solvent as in
CH2Cl2 2entry4).
behaved in a similar fashion as the allenic lactams, giving
49% of the desired cyclization product 23 2entry7).
One equivalent of hydrogen bromide is formed in the reac-
tion. This strong acid might in¯uence the reaction, or
prevent the use of acid-sensitive groups in the starting
material. Therefore, a base was added to the reaction
mixture. In the case of triethylamine the bicyclic product
could not be isolated, whereas the use of K2CO3 increased
the yield to 50% 2entries 5 and 6). No conversion of starting
material was observed when the bistriphenylphosphine
analogue of the catalyst was used 2entry 7). Lowering the
temperature of the reaction mixture slightlydecreased
the yield, but when the reaction was performed at 758C,
the yield increased to 56% and the reaction time was
lowered considerably2entries 8 and 9). It was decided to
use the latter set of reaction conditions to convert the other
allenyllactams to the corresponding bicyclic products with
different allylating agents 2Table 3).
ꢀ5†
The enantiopure precursor 14 was ®rst transprotected in
order to prevent deprotection of the acetate under the cycli-
zation conditions. First it was deprotected with K2CO3 in
MeOH and then reprotected with the more stable tert-butyl-
dimethylsilyl group to give allene 24 260%). Subjection to
the optimal cyclization conditions afforded the enantiopure
pyrrolizidinone 25 in 43% yield 2Eq. 5).
Unfortunately, allenyllactam 3 still did not afford the
desired bicyclic product using the improved reaction con-
ditions 2entry1). When methyl-substituted allene 8 was
subjected to an allylic carbonate rather than an allylic
halide, the yield dropped to 21%. The use of base, however,
is not necessaryin this case, because no acid is produced in
the reaction. When the reaction was run without base, 19
was produced in 48% yield 2entries 2 and 3). Methallyl
chloride could also be used, leading to the expected product
20 in a moderate yield of 23% 2entry 4). Although the syn-
thesis of phenylallene 9 was not veryef®cient, the cycli-
zation reaction with allyl bromide afforded 21 in a good
yield of 72% 2entry 5).
3. Mechanism
Both Liebeskind and Kimura have suggested a mechanism
for this type of reaction. Liebeskind's proposal involves
attack of the lactam nucleophile onto the p-complex of
the palladium2II) salt and the allene, giving rise to the
s-vinylpalladium complex 26. An insertion of allyl bromide
gives s-palladium complex 27, which after b-elimination
affords the product 19 regenerating a palladium2II) salt that
can enter the next catalytic cycle 2Scheme 1).8
The glutarimide derived methylallene 11 could also be
effectively cyclized to the corresponding allylated indolizi-
dinone 22 266%, entry6). Finally, allenic oxazolidinone 17
Although this might be the mechanism in operation, another
possibilitywas suggested byKimura for related reactions of
Scheme 2.

W. F. J. Karstens et al. / Tetrahedron 57 *2001) 5123±5130
5127
allenic tosylcarbamates.7n,o This mechanism starts with in
situ reduction of Pd2II) to Pd20), which thus reacts with allyl
bromide to give p-allylpalladium bromide. This organo-
palladium2II) species can coordinate to the allene resulting
in the formation of p-complex 28. This p-complex has two
possible modes of reaction. PathwayA consists of a nucleo-
philic attack of the lactam nitrogen onto the allene which is
activated bythe coordination of the electrophilic organo-
palladium2II) species. A reductive elimination of Pd20)
would convert vinyl2allyl)palladium2II) intermediate 29
into 19 2Scheme 2). On the other hand, an insertion reaction
of the allene into the palladium±allyl bond converts 28 into
p-allylpalladium complex 30.21 Intramolecular nucleophilic
attack of the lactam nitrogen would also afford the observed
product 2pathwayB, Scheme 2).
Chemical shifts 2d) are given in ppm down®eld from tetra-
methylsilane. Mass spectra and accurate mass measure-
ments were carried out using a JEOL JMS-SX/SX 102 A
Tandem Mass Spectrometer, a Varian NIAT 711 or a VG
Micromass ZAB-HFQQ instrument. Elemental analyses
were performed byDornis u. Kolbe Mikroanaltyisches
Laboratorium, MuÈlheim an der Ruhr, Germany. Optical
rotations were measured with a Perkin±Elmer 241 polari-
meter in a 1 dm cell in the indicated solvent. Rf values were
obtained byusing thin laeyr chromatography2TLC) on
silica gel-coated plastic sheets 2Merck silica gel 60 F254
with the indicated solvent 2mixture). DryTHF and Et O
)
2
were distilled from sodium benzophenone ketyl prior to
use. DryDMF, CH Cl2, and MeCN were distilled from
2
Ê
CaH2 and stored over 4 A MS under a drynitrogen atmos-
phere. BF3´OEt2 was distilled and stored under a drynitro-
gen atmosphere. Triethylamine and pyridine were dried and
distilled from KOH pellets. All commerciallyavailable
reagents were used as received, unless indicated otherwise.
Apart from the fact that we cannot exclude that other
mechanisms are also possible, an experiment was performed
to test the possible involvement of the two mechanistic
proposals shown in Scheme 2. Thus, a reaction was
performed employing a stoichiometric amount of p-allyl-
palladium chloride dimer as the allylating agent 2Eq. 6). As
it turned out, this reaction was successful affording 19 in
48% yield. In this case, the reaction cannot occur via the
mechanism illustrated in Scheme 1, but has to involve
p-complex 31, similar to 28. Unfortunately, we are not
able to discern between path A or B. PathwayB involves
a geometricallyunfavorable 5- endo-trig cyclization,22
whereas in palladium complex 28 the allene double bond
might not be suf®cientlyactivated to allow ccylization
toward 29.
4.1.1. 5-Propa-1,2-dienylpyrrolidin-2-one +3). Ethoxy-
lactam 5 2500 mg, 3.87 mmol)18 was dissolved in CH2Cl2
27.5 mL) and to this solution propargyltrimethylsilane 6a
21.30 g, 11.6 mmol)15 was added. The solution was cooled
to 2208C and BF3´OEt2 21.47 mL, 11.6 mmol) was added
dropwise. The solution was allowed to warm to rt and was
stirred for an additional 30 min and poured into brine
210 mL). Extraction with CH2Cl2 23£15 mL), followed by
drying of the combined organic layers 2NaSO4), gave after
concentration and ¯ash chromatography2EtOAc/acetone
3:1) 39 2260 mg, 2.11 mmol, 55%) as a light yellow oil; Rf
1
0.4 2EtOAc/acetone 1:1); IR 2neat) 3249, 1958, 1684; H
NMR 2400 MHz, CDCl3) d 6.12 2br s, 1H), 5.15 2q, Jˆ
6.6 Hz, 1H), 4.87 2dd, Jˆ6.6, 2.1 Hz, 2H), 4.20±4.17 2m,
1H), 2.43±2.26 2m, 3H), 1.98±1.87 2m, 1H); 13C NMR
2100 MHz, CDCl3) d 206.8, 178.0, 92.5, 77.4, 53.1, 29.7,
27.6; HRMS 2EI) calcd for C7H9NO 123.0684, found
123.0693.
ꢀ6†
4.1.2. +3-Phenyl-2-propynyl)trimethylsilane +6c). Pyrrol-
idine 22.5 mL) was degassed with nitrogen. Iodobenzene
21.0 mL, 8.91 mmol) was added and the temperature was
lowered to 08C. Pd2PPh3)4 252 mg, 0.05 mmol) and propar-
gyltrimethylsilane 6a 20.50 g, 4.45 mmol) were added and
the reaction mixture was stirred overnight at rt. The solution
was poured into water 215 mL) and extracted with hexanes
24£15 mL). The organic layers were washed with brine
215 mL), dried 2NaSO4) and concentrated. Puri®cation by
4. Experimental
means of ¯ash chromatography2pentane) gave
6c23
4.1. General information
1
2431 mg, 2.24 mmol, 52%) as a reddish liquid; H NMR
2400 MHz, CDCl3) d 7.38±7.35 2m, 2H), 7.29±7.22 2m,
3H), 1.70 2s, 2H), 0.17 2s, 9H).
All reactions were carried out under an inert atmosphere of
drynitrogen, unless stated otherwise. Standard sryinge
techniques were applied for transfer of Lewis acids and
drysolvents. Infrared 2IR) spectra were obtained from
CHCl3 solutions or neat, using a Perkin±Elmer 298
spectrophotometer or a Bruker IFS 28 FT-spectrophoto-
meter and wavelengths 2n) are reported in cm21. Proton
nuclear magnetic resonance 21H NMR) spectra were deter-
mined in CDCl3 2unless stated otherwise) using a Bruker AC
200 2200 MHz), a Bruker ARX 400 2400 MHz) or a Varian
Inova 2500 MHz) spectrometer. The latter machines were
also used for 13C NMR 2APT) spectra 2100 MHz and
125 MHz, respectively) in CDCl3 2unless stated otherwise).
4.1.3. 5-+1-Methylpropa-1,2-dienyl)pyrrolidin-2-one +8).
The reaction was performed as described for allene 3, with
ethoxylactam 5 21.50 g, 11.6 mmol), 2-butynyltrimethyl-
silane 6b 22.91 g, 23.2 mmol)16 and BF3´OEt2 22.9 mL,
23.2 mmol) in CH2Cl2 230 mL). Stirring for 2 h at rt,
followed bywork-up and chromatographyand an additional
bulb-to-bulb distillation 20.05 mbar), gave 8 21.02 g,
5.4 mmol, 64%) as a colorless oil; IR 2neat) 3245, 1959,
1684; 1H NMR 2400 MHz, CDCl3) d 6.78 2br s, 1H),
4.75±4.72 2m, 2H), 4.09±4.05 2m, 1H), 2.37±2.22 2m,

5128
W. F. J. Karstens et al. / Tetrahedron 57 *2001) 5123±5130
3H), 2.00±1.91 2m, 1H), 1.66 2t, Jˆ3.1 Hz, 3H); 13C NMR
2100 MHz, CDCl3) d 204.8, 178.3, 99.8, 77.1, 56.0, 29.9,
26.2, 14.5; HRMS 2EI) calcd for C8H11NO 137.0841, found
137.0842.
chromatography, gave 14 231 mg, 0.16 mmol, 37%) as a
light yellow oil. A small amount 2ca. 2 mg, 0.01 mmol,
2%) of the cis-isomer was also isolated. Trans-14: Rf 0.30
2EtOAc); [a]D124.3 2c 0.3, CHCl3); IR 2neat) 3229, 2918,
1960, 1741, 1711; 1H NMR 2400 MHz, CDCl3) d 6.65 2br s,
1H), 5.19 2d, Jˆ6.5 Hz, 1H), 4.87±4.79 2m, 2H), 3.94 2s,
1H), 2.71 2dd, Jˆ6.6, 17.8 Hz, 1H), 2.28 2dd, Jˆ1.4,
17.8 Hz, 1H), 2.07 2s, 3H), 1.77 2t, Jˆ3.1, 3H); 13C NMR
2100 MHz, CDCl3) d 175.3, 170.2, 98.0, 78.4, 72.8, 62.1,
4.1.4. 5-+1-Phenylpropa-1,2-dienyl)pyrrolidin-2-one +9).
The reaction was performed as described for allene 3,
with ethoxylactam 5 21.90 g, 14.7 mmol), 23-phenyl-prop-
2-ynyl)trimethylsilane 8c 25.53 g, 29.4 mmol)17,22 and BF3´
OEt2 25.58 mL, 44.05 mmol) in CH2Cl2 250 mL). Stirring
for 18 h at rt, followed bywork-up and chromatography,
gave 9 22.26 g, 2.20 mmol, 18%) as a light orange solid;
mp 33±358C; Rf 0.3 2EtOAc); IR 2neat) 3214, 1940. 1695;
1H NMR 2400 MHz, CDCl3) d 7.36±7.32 2m, 3H), 7.27±
7.22 2m, 2H), 5.65 2br s, 1H), 5.30±5.22 2m, 2H), 4.72±4.67
2m, 1H), 2.52±2.42 2m, 1H), 2.40±2.29 2m, 2H), 2.13±2.06
2m, 1H); 13C NMR 2100 MHz, CDCl3) d 205.3, 178.2,
133.7, 128.6, 127.2, 126.2, 108.0, 81.7, 52.6, 29.4, 27.4;
HRMS 2EI) calcd for C13H13NO 199.0997, found 199.1004.
1
35.9, 20.9, 15.2 2C-10). cis-14: Rf 0.25 2EtOAc); H NMR
2400 MHz, CDCl3) d 5.74 2br s, 1H), 5.54 2m, Jˆ3.7, 5.6,
6.2 Hz, 1H), 4.85±4.82 2m, 2H), 4.29 2m, 1H), 2.72 2dd, Jˆ
6.8, 17.4 Hz, 1H), 2.44 2dd, Jˆ3.7, 17.4 Hz, 1H), 2.07 2s,
3H), 1.69 2t, Jˆ3.1 Hz, 3H).
4.1.8. 4-+1-Methylpropa-1,2-dienyl)oxazolidin-2-one +17).
The reaction was performed as described for allene 3,
with methoxy-oxazolidinone 26 2710 mg, 6.07 mmol),20
2-butynyltrimethylsilane 6b 21.53 g, 12.1 mmol) and BF3´
OEt2 215.4 mL, 12.1 mmol) in CH2Cl2 215 mL). Stirring
for 2 h at rt, followed bywork-up and chromatography,
gave 17 2312 mg, 2.21 mmol, 37%) as a colorless oil; Rf
0.4 2EtOAc); IR 2neat) 3264, 1960, 1749; 1H NMR
2400 MHz, CDCl3) d 5.89 2br s, 1H), 4.87±4.80 2m, 2H),
4.51 2t, Jˆ8.4 Hz, 1H), 4.35±4.31 2m, 1H), 4.27±4.24 2m,
1H), 1.72 2t, Jˆ3.2 Hz, 3H); 13C NMR 2100 MHz, CDCl3) d
205.3, 160.0, 97.6, 77.5, 68.8, 54.4, 13.7; HRMS 2EI) calcd
for C7H9NO2 139.0633, found 139.0628.
4.1.5. 6-+1-Methylpropa-1,2-dienyl)piperidin-2-one +11).
The reaction was performed as described for allene 3, with
6-ethoxypiperidin-2-one 10 21.00 g, 6.98 mmol),18 2-butynyl-
trimethylsilane 6b 21.76 g, 14.0 mmol) and BF3´OEt2
21.77 mL, 13.97 mmol) in CH2Cl2 215 mL). Stirring for
4 h at rt, followed bywork-up and chromatography, gave
11 20.71 g, 4.72 mmol, 68%) as a colorless oil; Rf 0.2
2EtOAc); IR 2neat) 3215, 2949, 1959, 1656; 1H NMR
2400 MHz, CDCl3) d 5.85 2br s, 1H), 4.85±4.77 2m, 2H),
3.84±3.82 2m, 1H), 2.42±2.25 2m, 2H), 2.01±1.87 2m, 2H),
1.73±1.64 2m, 1H), 1.69 2t, Jˆ3.1 Hz, 3H), 1.61±1.52 2m,
1H); 13C NMR 2100 MHz, CDCl3) d 205.2, 172.1, 100.4,
77.9, 54.8, 31.2, 26.8, 19.2, 14.9; HRMS 2EI) calcd for
C9H13NO 151.0997, found 151.0990.
4.1.9. 6-Allyl-7-methyl-1,2,5,7a-tetrahydropyrrolizin-3-
one +19). Allyl bromide 20.22 mL, 2.50 mmol), K2CO3
2138 mg, 1.00 mmol) and PdCl22MeCN)2 220 mg, 0.08
mmol) were added to a solution of allene 8 269 mg,
0.50 mmol) in MeCN 25 mL). After stirring for 2 h at
758C, the mixture was poured into brine 210 mL) and
extracted with CH2Cl2 23£15 mL). The combined organic
layers were washed with brine 210 mL), dried 2Na2SO4) and
concentrated in vacuo. Flash chromatographygave 19
250 mg, 0.28 mmol, 56%) as a colorless oil; Rf 0.3
4.1.6. +4S,5R)-4-Acetoxy-5-ethoxy-pyrrolidin-2-one +13).
To a solution of imide 1219c 23.97 g, 25.3 mmol) in ethanol
2215 mL) NaBH4 2870 mg, 23.0 mmol) was added at
2158C. After 20 min, the temperature was lowered to
2308C and the mixture was acidi®ed with a 2 M H2SO4
solution in ethanol to pHˆ2. The solution was warmed to
rt and stirred for 2.5 h. The mixture was neutralized using a
5% NaOH solution in EtOH. The solvent was evaporated
and the residue was dissolved in CHCl3, ®ltered over
Celitew and the ®ltrate was washed with brine. After drying
2Na2SO4) and evaporation, the product was puri®ed using
chromatography2EtOAc/hexanes 3:2) to give 13 22.3 g,
12.4 mmol, 49%) as a yellow oil 24:1 mixture of trans:cis
isomers). Data of the trans isomer: Rf 0.25 2EtOAc/hexanes
1
2EtOAc/PE 4:1); IR 2neat) 2975, 2859, 1707; H NMR
2400 MHz, CDCl3) d 5.72±5.62 2m, Jˆ2£6.7, 10.0,
16.9 Hz, 1H), 5.02±5.97 2m, 2H), 4.48 2br m, 1H), 4.22
2d, Jˆ14.9 Hz, 1H), 3.57 2d, Jˆ14.9 Hz, 1H), 2.84±2.74
2m, 2H), 2.64 2ddd, Jˆ8.3, 12.7, 16.1 Hz, 1H), 2.33±2.23
2m, 2H), 1.77±1.66 2m, 1H), 1.60 2s, 3H); 13C NMR
2100 MHz, CDCl3) d 178.6, 134.3, 131.9, 130.9, 116.2,
70.5, 51.6, 33.5, 30.9, 28.7, 9.5; HRMS 2EI) calcd for
C11H15NO 177.1154, found 177.1148.
1
3:2); IR 2neat): 3440, 3000, 2970, 2930, 1710, 1240. H
The reaction was also performed using allyl methyl carbo-
nate: allene 8 269 mg, 0.50 mmol) was dissolved in aceto-
nitrile 25 mL). To this solution allyl methyl carbonate
20.29 ml, 2.50 mmol) and PdCl22MeCN)2 220 mg, 0.08
mmol) were added. The reaction mixture was stirred over-
night at ambient temperature and was worked up in the same
wayas in the procedure mentioned above, giving 19 233 mg,
0.24 mmol, 48%) as a colorless oil.
NMR 2400 MHz, CDCl3) d 8.25 2br s, 1H), 5.07 2d, Jˆ
6.2 Hz, 1H), 4.77 2s, 1H), 3.60±3.47 2m, 2H), 2.82 2dd,
Jˆ6.3, 18.0 Hz, 1H), 2.19 2d, Jˆ18.0 Hz, 1H), 2.03 2s,
3H), 1.16 2t, Jˆ7.0 Hz, 3H). 13C NMR 2100 MHz, CDCl3)
d 177.1, 170.1, 89.2, 73.4, 63.4, 35.4, 20.8, 14.9. HRMS 2EI)
calcd for C8H13NO4 187.0845, found 187.0875.
4.1.7. +4S,5R)-4-Acetoxy-5-+1-methylpropa-1,2-dienyl)-
pyrrolidin-2-one +14). The reaction was performed as
described for allene 3, with ethoxylactam 13 276 mg,
0.41 mmol), 2-butynyltrimethylsilane 6b 2103 mg, 0.81
mmol) and BF3´OEt2 20.36 mL, 2.80 mmol) in CH2Cl2
25 mL). Stirring for 5 days at rt, followed by work-up and
The reaction was also performed using a stoichiometric
amount of allylpalladium chloride dimer: allene 8 213 mg,
0.09 mmol) was dissolved in acetonitrile 22.5 mL). To this
solution K2CO3 228 mg, 0.20 mmol) and allylpalladium
chloride dimer 217.7 mg, 0.05 mmol) were added. This

W. F. J. Karstens et al. / Tetrahedron 57 *2001) 5123±5130
5129
mixture was heated up to 758C and stirred for 1.5 h. The
work-up was performed as mentioned above, giving 19
25.9 mg, 0.04 mmol, 48%) as a colorless oil.
2.00 mmol) and PdCl22MeCN)2 226 mg, 0.10 mmol) in
MeCN 210 mL) at 758C for 2 h. Work-up and ¯ash chroma-
tographygave 23 289 mg, 0.49 mmol, 49%) as a colorless
oil; IR 2neat) 2974, 2911, 2854, 1753; 1H NMR 2400 MHz,
CDCl3) d 5.74±5.64 2m, 1H), 5.05±5.01 2m, 2H), 4.56 2br
m, 1H), 4.50 2t, Jˆ8.5 Hz, 1H), 4.22 2d, Jˆ14.8 Hz, 1H),
4.21 2dd, Jˆ4.7, 8.3 Hz, 1H), 3.75 2d, Jˆ14.8, 1H), 2.89±
2.78 2m, 2H), 1.65 2s, 3H); 13C NMR 2100 MHz, CDCl3) d
163.1, 133.8, 133.5, 133.0, 116.4, 67.7, 67.4, 56.7, 30.5, 9.4;
HRMS 2EI) calcd for C10H13NO2 179.0946, found
179.0951.
4.1.10. 7-Methyl-6-+2-methylallyl)-1,2,5,7a-tetrahydro-
pyrrolizin-3-one +20). The reaction was performed as
described for pyrrolizinone 19 with allene 8 269 mg,
0.5 mmol), 3-chloro-2-methylpropene 20.25 mL, 2.50
mmol), K2CO3 2138 mg, 1.00 mmol) and PdCl22MeCN)2
220 mg, 0.08 mmol) in MeCN 25 mL) at 758C. Stirring for
2 h, followed bywork-up and chromatography, gave 20
222 mg, 0.12 mmol, 23%) as a colorless oil. Continued
elution with EtOAc afforded starting material 8 216 mg,
0.12 mmol, 23%). 19: Rf 0.3 2EtOAc/PE 4:1); IR 2neat)
4.1.14. +4S,5R)-5-+1-Methylpropa-1,2-dienyl)-4-+tert-butyl-
dimethylsilyloxy)-pyrrolidin-2-one +24). To a solution of
allene 14 230 mg, 0.15 mmol) in methanol 21.5 mL) K2CO3
23 mg) was added and the reaction was stirred at rt for 1 h.
Et2O 215 mL) was added and the mixture was ®ltered over
Celite. The ®lter was washed with Et2O 245 mL) and
CH2Cl2 245 mL), followed byconcentration of the ®ltrates
in vacuo. The residue was dissolved in DMF 21mL), and
imidazole 221.0 mg, 0.31 mmol), TBDMSCl 225.5 mg,
0.17 mmol) and DMAP 24 mg) were added. After stirring
for 4 h, extra imidazole 210.5 mg, 0.15 mmol) and
TBDMSCl 212.8 mg, 0.08 mmol) were added and the solu-
tion was stirred for an additional 18 h. DMF was evaporated
in vacuo and the product was puri®ed using ¯ash chroma-
tographygiving 24 224.5 mg, 0.09 mmol, 60%) as white
crystals; mp 76±798C; Rf 0.3 2EtOAc/PE 1:1); [a]D141.1
2c 1.2, CHCl3); IR 2neat) 3214, 2930, 1960, 1710; 1H NMR
2400 MHz, CDCl3) d 6.55 2br s, 1H), 4.76 2t, Jˆ2.7 Hz, 2H),
4.31±4.28 2m, 1H), 3.90±3.81 2m, 1H), 2.59 2dd, Jˆ6.7,
16.9 Hz, 1H), 2.22 2dd, Jˆ3.9, 16.9 Hz, 1H), 1.70 2t, Jˆ
3.1 Hz, 3H), 0.87 2s, 9H), 0.06 2s, 6H); 13C NMR 2100
MHz, CDCl3) d 205.1, 175.5, 97.8, 77.2, 72.2, 65.3, 40.0,
25.5, 17.8, 15.0, 24.8, 25.0; HRMS 2FAB) calcd. for
C14H26NO2Si 2MH1) 268.1733, found 268.1725.
1
2969, 2913, 2854, 1710; H NMR 2400 MHz, CDCl3) d
4.73 2s, 1H), 4.66 2s, 1H), 4.53±4.50 2br m, 1H), 4.21 2d,
Jˆ14.9 Hz, 1H), 3.56 2d, Jˆ14.9 Hz, 1H), 2.75 2br s, 2H),
2.66 2ddd, Jˆ8.3, 12.7, 16.1 Hz, 1H), 2.36±2.26 2m, 2H),
1.78±1.68 2m, 1H), 1.63 2s, 6H); 13C NMR 2100 MHz,
CDCl3) d 177.5, 142.0, 132.6, 130.9, 111.8, 70.6, 51.7,
35.0, 33.5, 28.9, 22.0, 9.6; HRMS 2EI) calcd for
C12H17NO 191.1310, found 191.1308.
4.1.11. 6-Allyl-7-phenyl-1,2,5,7a-tetrahydropyrrolizin-3-
one +21). The reaction was performed as described for
pyrrolizinone 19 with allene 9 2200 mg, 1.00 mmol), allyl
bromide 20.43 mL, 5.00 mmol), K2CO3 2278 mg, 2.01
mmol) and PdCl22MeCN)2 239 mg, 0.15 mmol) in MeCN
210 mL) at 758C for 1 h. Work-up and ¯ash chromatography
gave 21 2173 mg, 0.72 mmol, 72%) as an oil; Rf 0.5
2EtOAc); IR 2neat) 2975, 2853, 1703, 1386; 1H NMR
2400 MHz, CDCl3) d 7.39±7.33 2m, 2H), 7.29±7.25 2m,
1H), 7.23±7.19 2m, 2H), 5.84±5.74 2m, 1H), 5.12±5.06
2m, 3H), 4.49 2dd, Jˆ3.6, 15.6 Hz, 1H), 3.72 2dd, Jˆ3.7,
15.6 Hz, 1H), 3.04 2dd, Jˆ6.1, 15.5 Hz, 1H), 2.89 2dd, Jˆ
6.1, 15.5 Hz, 1H), 2.67 2ddd, Jˆ8.5, 12.6, 16.2 Hz, 1H),
2.35±2.26 2m, 2H), 1.81±1.70 2m, 1H); 13C NMR 2100
MHz, CDCl3) d 177.4, 136.7, 134.2, 133.3, 134.0, 128.4,
127.4, 127.3, 116.7, 69.3, 52.2, 33.2, 31.8, 29.0; HRMS 2EI)
calcd for C16H17NO 239.1310, found 239.1305.
4.1.15. +1S,7aR)-6-Allyl-1-+tert-Butyldimethylsilyloxy)-7-
methyl-1,2,5,7a-tetrahydropyrrolizin-3-one +25). The
reaction was performed as described for pyrrolizinone 19
with allene 24 224.5 mg, 0.09 mmol), allyl bromide
20.04 mL, 0.46 mmol), K2CO3 225 mg, 0.18 mmol) and
PdCl22MeCN)2 23 mg, 0.01 mmol) in MeCN 21 mL) at
758C for 3 h. Work-up and ¯ash chromatographygave 24
212 mg, 0.04 mmol, 43%) as a white solid; mp 33±358C;
[a]Dˆ161.8 2c 0.60, CHCl3); IR 2neat) 2955, 2929, 2857,
4.1.12. 2-Allyl-1-methyl-6,7,8,8a-tetrahydroindolizin-5-
one +22). The reaction was performed as described for
pyrrolizinone 19 with allene 11 276 mg, 0.50 mmol), allyl
bromide 20.22 mL, 2.50 mmol), K2CO3 2138 mg, 1.00
mmol) and Pd2MeCN)2Cl2 220 mg, 0.08 mmol) in MeCN
25 mL) at 758C for 1 h. Work-up and ¯ash chromatography
gave 22 263 mg, 0.33 mmol, 66%) as a colorless oil; Rf 0.3
1
1714; H NMR 2400 MHz, CDCl3) d 5.74±5.64 2m, 1H),
5.05±5.01 2m, 2H), 4.28±4.16 2m, 3H), 3.58 2d, Jˆ14.6 Hz,
1H), 2.88±2.77 2m, 2H), 2.58 2dd, Jˆ9.8, 15.3 Hz, 1H), 2.53
2dd, Jˆ7.5, 15.3 Hz, 1H), 1.71 2s, 3H), 0.90 2s, 9H), 0.08 2s,
3H), 0.06 2s, 3H); 13C NMR 2100 MHz, CDCl3) d 174,
134.2, 131.6, 130.7, 116.4, 77.8, 75.1, 51.6, 43.4, 30.9,
25.6, 17.7, 10.1, 24.2, 25.1; HRMS 2EI) calcd for
C17H29NO2Si 307.1968, found 307.1970.
1
2EtOAc); IR 2neat) 2945, 2856, 1640; H NMR 2400 MHz,
CDCl3) d 5.76±5.66 2m, 1H, H-11), 5.07±5.00 2m, 2H), 4.40
2d, Jˆ15.4 Hz, 1H), 4.14 2br d, Jˆ10.5 Hz, 1H), 3.92 2d,
Jˆ15.4 Hz, 1H), 2.90±2.80 2m, 2H), 2.4 2ddd, Jˆ2.6, 7.8,
17.8 Hz, 1H), 2.33 2ddd, Jˆ8.0, 9.7, 17.8 Hz, 1H), 2.16±
2.04 2m, 1H), 2.00±1.92 2m, 1H), 1.83±1.70 2m, 1H), 1.63
2s, 3H), 1.26±1.16 2dq, Jˆ4.4, 12.3 Hz, 1H); 13C NMR
2100 MHz, CDCl3) d 168.8, 134.3, 130.6, 128.8, 116.2,
67.5, 54.2, 30.6, 30.4, 27.4, 20.4, 10.2; HRMS calcd for
C12H17NO 191.1310, found 191.1306.
5. Conclusion
In conclusion, the preparation of allenyl substituted lactams
was described bymeans of N-acyliminium ion reactions
between imide derived N,O-acetals and several propargyl-
silanes. These allenes could be ef®cientlyccylized to
denselyfunctionalized pyrrolizidinones and indolizidinones,
4.1.13. 6-Allyl-7-methyl-5,7a-dihydropyrrolo[1,2-c]oxazol-
3-one +23). The reaction was performed as described for
pyrrolizinone 19 with allene 17 2117 mg, 1.00 mmol),
allyl bromide 20.43 mL, 5.00 mmol), K2CO3 2276 mg,

5130
W. F. J. Karstens et al. / Tetrahedron 57 *2001) 5123±5130
1998, 39, 5421. 2k) Meguro, M.; Yamamoto, Y. Tetrahedron
Â
Lett. 1998, 39, 5421. 2l) Desarbre, E.; Merour, J. Y.
using PdCl22MeCN)2 and allyl halides or carbonates,
provided that theya contained a substituent on the internal
carbon atom of the allene.
Tetrahedron Lett. 1996, 37, 43. 2m) Davies, I. W.; Scopes,
D. I. C.; Gallagher, T. Synlett 1993, 85. 2n) Tamaru, Y.;
Kimura, M. Synlett 1997, 749. 2o) Kimura, M.; Tanaka, S.;
Tamaru, Y. J. Org. Chem. 1995, 60, 3764.
Acknowledgements
8. Prasad, J. S.; Liebeskind, L. S. Tetrahedron Lett. 1988, 29,
4257.
This research was ®nanciallysupported 2in part) bythe
Council for Chemical Sciences of the Netherlands Organi-
zation for Scienti®c Research 2CW±NWO).
9. Hiemstra, H.; Fortgens, H. P.; Speckamp, W. N. Tetrahedron
Lett. 1984, 25, 3115.
10. For reviews, see: 2a) Speckamp, W. N.; Moolenaar, M. J.
Tetrahedron 2000, 56, 3817. 2b) De Koning, H.; Moolenaar,
M. J.; Hiemstra, H.; Speckamp, W. N. In Studies in Natural
Products Chemistry; Atta-ur-Rahman, W. N., Ed.; Elsevier:
Amsterdam, 1993; Vol. 13, p. 473. 2c) Hiemstra, H.;
Speckamp, W. N. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 2, p. 1047.
References
1. For example, see: Gribble, G. W., Gilchrist, T. L., Eds.;
Progress in Heterocyclic Chemistry; Pergamon: Oxford,
2000; Vol. 12.
2. For recent reviews on palladium in organic synthesis, see:
2a) Tsuji, J. Palladium Reagents and Catalysts; John Wiley
11. For acetylenic lactams, see: Karstens, W. F. J.; Stol, M.;
Rutjes, F. P. J. T.; Kooijman, H.; Spek, A. L.; Hiemstra, H.
J. Organomet. Chem. 2001, 624, 245.
È
& Sons: New York, 1995. 2b) Backvall, J. E. In Metal-
catalyzed Cross Coupling Reactions; Stang, P., Diederich,
F., Eds.; VCH: Weinheim, 1998; pp. 339±382.
12. For allene containing lactams, see: 2a) Karstens, W. F. J.;
Rutjes, F. P. J. T.; Hiemstra, H. Tetrahedron Lett. 1997, 38,
6275. 2b) Karstens, W. F. J.; Stol, M.; Rutjes, F. P. J. T.;
Hiemstra, H. Synlett 1998, 1126. 2c) Jonasson, C.; Karstens,
3. For general reviews on metal-catalyzed amination, see:
2a) MuÈller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675.
2b) Johanssen, M.; Jorgensen, K. A. Chem. Rev. 1998, 98,
1639.
È
W. F. J.; Hiemstra, H.; Backvall, J. E. Tetrahedron Lett. 2000,
41, 1619.
4. For reviews on allene chemistry, see: 2a) Schuster, H. F.;
Coppola, G. M. Allenes in Organic Synthesis; Wiley-Inter-
science: New York, 1984. 2b) Pasto, D. J. Tetrahedron
1984, 40, 2805. 2c) Smadja, W. Chem. Rev. 1983, 83, 263.
2d) Munson, J. W. In The Chemistry of Ketenes, Allenes and
Related Compounds, Part 1; Patai, S., Ed.; Wiley-Inter-
science: New York, 1980; p. 165.
13. 2a) Rutjes, F. P. J. T.; Tjen, K. C. M. F.; Wolf, L. B.; Karstens,
W. F. J.; Schoemaker, H. E.; Hiemstra, H. Org. Lett. 1999, 1,
717. 2b) Wolf, L. B.; Tjen, K. C. M. F.; Rutjes, F. P. J. T.;
Hiemstra, H.; Schoemaker, H. E. Tetrahedron Lett. 1998, 39,
5081.
14. For example, see: Klaver, W. J.; Moolenaar, M. J.; Hiemstra,
H.; Speckamp, W. N. Tetrahedron 1988, 44, 3805.
15. Brandsma, L.; Verkruijsse, H. D. In Allenes and Cumulenes: a
Laboratory Manual; Elsevier: Amsterdam, 1981; p. 16.
16. Iyer, S.; Liebeskind, L. S. J. Am. Chem. Soc. 1987, 109, 2759.
17. Alami, M.; Ferri, F.; Linstrumelle, G. Tetrahedron Lett. 1993,
34, 6403.
5. For a review on palladium±allene chemistry, see: Zimmer, R.;
Dinesh, C. U.; Nandanan, E.; Khan, F. A. Chem. Rev. 2000,
100, 3067.
6. For oxygen nucleophiles, see for example: 2a) Kang, S. K.;
Yamaguchi, T.; Pyung, S. J.; Lee, Y. T.; Baik, T. G.
Tetrahedron Lett. 1998, 39, 2127. 2b) Ma, S.; Shi, Z. J. Org.
È
Chem. 1998, 63, 6387. 2c) Jonasson, C.; Backvall, J. E.
18. 2a) Hubert, J. C.; Steege, W.; Speckamp, W. N.; Huisman,
H. O. Synth. Commun. 1971, 1, 103. 2b) Hubert, J. C.;
Wijnberg, J. B. P. A.; Speckamp, W. N. Tetrahedron 1975,
31, 1437.
Tetrahedron Lett. 1998, 39, 3601. 2d) Walkup, R. D.; Guan,
L.; Kim, L. S.; Kim, S. W. Tetrahedron Lett. 1995, 36, 3805.
2e) Walkup, R. D.; Guan, L.; Kim, S. W.; Kim, Y. S. Synlett
Â
1993, 88. 2f) Besson, L.; Bazin, J.; Gore, J.; Cazes, B.
Tetrahedron Lett. 1994, 35, 2881.
19. 2a) Koot, W. J. Synthesis and Applications of *R)-1-Acetyl-5-
isopropoxy-3-pyrrolin-2-one. Ph.D. Thesis, Universityof
Amsterdam: The Netherlands, 1993. 2b) Louwrier, S. Studies
towards the Synthesis of Ptilomycalin A. Ph.D. Thesis,
Universityof Amsterdam: The Netherlands, 1996.
2c) Chamberlin, A. R.; Chung, J. Y. L. J. Am. Chem. Soc.
1983, 105, 3653.
7. For nitrogen nucleophiles, see: 2a) Trost, B. M.; Pinkerton,
A. B.; Kremzow, D. J. Am. Chem. Soc. 2000, 122, 12007.
2b) Chang, H. M.; Cheng, C. H. J. Chem. Soc. Perkin Trans.
È
1 2000, 3799. 2c) Jonasson, C.; Horvath, A.; Backvall, J. E.
J. Am. Chem. Soc. 2000, 122, 9600. 2d) Kang, S. K.; Baik,
T. G.; Hur, Y. Tetrahedron 1999, 55, 6863. 2e) Kang, S. K.;
Baik, T. G.; Kulak, A. N. Synlett 1999, 324. 2f) Ohno, H.;
Toda, A.; Miwa, Y.; Taga, T.; Osawa, E.; Yamaoka, Y.;
Fujii, N.; Ibuka, T. J. Org. Chem. 1999, 64, 2992. 2g) Anzai,
M.; Toda, A.; Ohno, H.; Takemoto, Y.; Fujii, N.; Ibuka, T.
Tetrahedron Lett. 1999, 40, 7393. 2h) Zenner, J. M.; Larock,
R. C. J. Org. Chem. 1999, 64, 7312. 2i) Larock, R. C.; He, Y.;
Leong, W. W.; Han, X.; Refvik, M. D.; Zenner, J. M. J. Org.
Chem. 1998, 63, 2154. 2j) Diederen, J. H.; Sinkeldam, R. W.;
FruÈhauf, H. W.; Hiemstra, H.; Vrieze, K. Tetrahedron Lett.
20. Shono, T.; Matsumura, Y.; Uchida, K.; Kobayashi, H. J. Org.
Chem. 1985, 50, 3243.
21. For a stoichiometric example, see: Medema, D.; van Helden,
R. Recl. Trav. Chim. Pays-Bas 1971, 90, 304.
22. Although unfavorable, 5-endo-trig cyclizations are well
known. For examples, see e.g.: Trost, B. M. Angew. Chem.
Int. Ed. 1986, 25, 1.
23. Pornet, J.; Kolani, N.; Mesnard, D.; Miginiac, L.; Jaworski, K.
J. Organomet. Chem. 1982, 236, 177.