The intramolecular Heck reaction and the synthesis of indolizidinone, quinolizidinone and benzoazepinone derivatives

Article abstract of DOI:10.1055/s-2002-19293

The intramolecular Heck cyclization of N-allyl-, -aryl- or -benzyl-5-allyl-2-pyrrolidinones and N-allyl-, -aryl- or -benzyl-6-allyl-2-piperidinones (1a-f), prepared through allyltrimethylsilane addition to the corresponding cyclic N-acyliminium ions, affo

Full text of DOI:10.1055/s-2002-19293

PAPER
87
The Intramolecular Heck Reaction and the Synthesis of Indolizidinone,
Quinolizidinone and Benzoazepinone Derivatives
T
he Intramolecu
e
lar
H
eckR
o
eactioninA
n
lkaloids ardo Silva Santos, Ronaldo Aloise Pilli*
Instituto de Química, UNICAMP, P.O. Box 6154, 13083-970 Campinas, SP, Brazil
Fax +55(19)37883023; E-mail: pilli@iqm.unicamp.br
Received 26 January 2001; revised 15 June 2001
at least one six membered ring arises when an intramolec-
ular Heck reaction or palladium-catalyzed enyne cycloi-
somerization, which gives a vicinal exo-bismethylene
cycloalkane is immediately followed by a Diels Alder re-
Abstract: The intramolecular Heck cyclization of N-allyl-, -aryl- or
-benzyl-5-allyl-2-pyrrolidinones and N-allyl-, -aryl- or -benzyl-6-
allyl-2-piperidinones (1a f), prepared through allyltrimethylsilane
addition to the corresponding cyclic N-acyliminium ions, afforded
indolizidinones (3a, 5a, 5b), quinolizidinones (3b, 4b) and ben- action.4
zoazepinones (7a, 8a, 7b, 8b) in moderate to good yields (56
The intramolecular Heck coupling of bromodialkenyl
90%). Exclusive exo-trig over endo-trig mode of cyclization was
observed in all examples investigated, and it was accompanied by
double bond migration, which precluded our attempts of a one-pot
tandem Diels–Alder cycloaddition with dienophiles such as maleic
anhydride, methyl vinyl ketone and diethyl azodicarboxylate. Cata-
lytic hydrogenation of a 2:1 mixture of regioisomeric indolizidino-
nes 5a–5b afforded the stereoisomerically enriched cis
indolizidinone 6a (20:1 mixture) in quantitative yield. A similar be-
havior was observed in the catalytic hydrogenation of regioisomeric
benzoazepinones 7b–8b.
amines, lactams and ethers has been reported5 and recent-
ly de Meijere6 and coworkers described the formation of
substituted tetrahydroisoindolines, tetrahydroisoindolin-
1-ones and hexahydrobenzo[c]furans through the in-
tramolecular 5-exo cyclization of 2-bromo-4-aza- and 2-
bromo-4-oxa-1,6-dienes, followed by in situ [4+2] cy-
cloaddition.
As part of our current interest in the synthesis of pyrroliz-
idine and indolizidine alkaloids,7 we were attracted to
study the regiochemistry of the intramolecular Heck reac-
tion when applied to 2-allyl lactams derived from 2-pyr-
rolidinone and 2-piperidinone. These compounds feature
a 2-bromo-4-aza-1,7-diene moiety amenable to undergo
either a 6-exo-trig or a 7-endo-trig cyclization. Addition-
ally, the intramolecular 7-exo-trig vs. 8-endo-trig Heck re-
action of N-(o-halobenzyl)-2-allyllactams was envisioned
as a short approach to benzoazepine derivatives. Lactams
1a f were prepared in good yields from the correspond-
ing imides according to literature procedure8 after
LiBEt3H reduction to the corresponding ethoxylactams,
followed by BF3 OEt2 promoted addition of allyltrimeth-
ylsilane. Our first choice of reaction conditions for the in-
tramolecular Heck reaction with 1a included the use of 5
mol% palladium acetate as catalyst, (which is assumed to
be reduced in situ to palladium(0) species by the solvent,
amine or the added ligand)9 degassed DMF as solvent,
Key words: Heck reaction, intramolecular cylization, hydrogena-
tion
Over the last decade palladium-catalyzed reactions have
emerged as extremely versatile methods for the synthesis
of highly complex carbo- and heterocyclic systems.1 The
coupling of vinyl or aryl halides, triflates or similar inter-
mediates with alkenes under palladium(0) catalysis is
known as the Heck reaction and both its inter- and in-
tramolecular versions are powerful tools in organic syn-
thesis due to their chemo- and regioselectivity, mild
reaction conditions and efficiency.2 In particular, the
Heck reaction has proved its synthetic value when incor-
porated in a tandem process, which allows the regio- and
stereocontrolled formation of several bonds and/or ring
systems in a single synthetic operation.3 An interesting se-
quence for the construction of bicyclic systems containing
Scheme 1
Synthesis 2002, No. 1, 28 12 2001. Article Identifier:
1437-210X,E;2002,0,01,0087,0093,ftx,en;M00701SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

88
L. S. Santos, R. A. Pilli
PAPER
Table Intramolecular Heck Reaction of 1a and 1b (Scheme 1)
triphenylphosphine (10 mol%) and potassium carbonate
(10 equiv) or triethylamine (1.2 equiv) as base. Under
these conditions, a smooth reaction ensued upon heating
at 115 ºC under an inert atmosphere and indolizidinone 3a
was isolated in 56% yield after column chromatography.
The same results were observed when tri-o-
tolylphosphine10 or DIPHOS were employed whereas at-
tempts to carry out the cyclization in acetonitrile were un-
successful (Table).
Entry
Substrate
Methoda
Ratio
(3:4)
Yield
(%)c
1
2
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
A, B, E
1:0
–
55
–
Cb, Ib, Lb
3
D
1:0
1:0
1:0
1:0
–
56
52
50
53
–
4
F, J
The reaction product was characterized by the absence of
the stretching of the Csp2 Br at 920 cm 1 in the IR spec-
trum and by significant changes in the 3.50 5.70 region
of its 1H NMR spectrum as compared to the same region
for 1a: H 8a appeared at 4.26 as a broad triplet (3J = 6.0
Hz), the olefinic protons of the exocyclic methylene as
doublets (2J = 1.5 Hz) at 4.99 and 5.09 and the endocy-
clic hydrogen H 8 as a singlet at 5.63. The presence of
a methyl group at 1.86 as a singlet and of the two meth-
ylenic hydrogens at C 5 as doublets (2J = 15.4 Hz) at
5
G, K
6
H
7
I
8
A
5.2:1
6:1
–
74
70
–
9
B
10
Cb, Ib, Lb
3.57 and 4.70 were diagnostic for the assignment of struc- 11
D
5:1
6.4:1
6.4:1
5.8:1
5:1
60
52
67
68
48
ture 3a to the isolated indolizidinone (HRMS m/z: [M+]
calcd for C10H13NO, 163.0997; found, 163.0994). The
downfield shift observed for one of the hydrogens at C-5
12
E
13
14
15
F
(
1.13 ) was assigned to the anisotropic shift of the car-
G
bonyl group as inspection of molecular models and geom-
etry optimization by ab initio method (HF/6-31g(d))
revealed the coplanar orientation of one of the hydrogens
at C-5 and the carbonyl group.11
H, J, K
a Reaction temperature: 115 ºC; reaction time: 12 h.
b Quantitative substrate recovery.
c Isolated yield after column chromatography; Conditions: (A): 0.02
equiv Pd(OAc)2, 0.04 equiv PPh3, 10 equiv K2CO3, DMF (B): 0.02
equiv Pd(OAc)2, 0.04 equiv. PPh3, 1.2 equiv Et3N, DMF (C): 0.02
equiv Pd(OAc)2, 0.04 equiv PPh3, 2.0 equiv Ag2CO3, DMF (D): 0.02
equiv Pd(OAc)2, 0.04 equiv P(o-tol)3, 10 equiv K2CO3, DMF (E):
0.02 equiv Pd(OAc)2 , 0.04 equiv P(o-tol)3, 1.2 equiv Et3N, DMF (F):
0.02 equiv Pd(OAc)2, 0.04 equiv PPh3, 10 equiv K2CO3, 1.2 equiv
Bu4NCl, DMF (G): 0.02 equiv Pd(OAc)2, 0.04 equiv PPh3, 1.2 equiv
Et3N, 1.2 equiv Bu4NCl, DMF (H): 0.02 equiv Pd(OAc)2, 0.04 equiv
DIPHOS, 10 equiv K2CO3, DMF (I): 0.02 equiv Pd(OAc)2, 0.04 equiv
DIPHOS, 2.0 equiv Ag2CO3, DMF (J): 0.02 equiv Pd(Ph3)4, 0.04
The isolation of 3a as the sole product was rationalized as
involving the initial formation of the exo-bismethylene 2a
followed by prototropic shift promoted either thermally or
through a sequence of -hydride elimination, re-addition
of a hydridopalladium species and elimination as ob-
served in the arylation of allylic alcohols.12
In our case, changing the base from triethylamine to po-
tassium carbonate13 did not avoid prototropic shift. At-
tempts to carry out the reaction at lower temperatures
using the conditions described by Jeffery14 (tetrabutyl am- equiv PPh3, 10 equiv K2CO3, DMF (K): 0.02 equiv Pd(Ph3)4, 0.04
equiv PPh3, 1.2 equiv Et3N, DMF (L): 0.02 equiv Pd(Ph3)4, 0.04 equiv
PPh3, 2.0 equiv Ag2CO3, DMF.
monium chloride as phase-transfer catalyst and potassium
carbonate as base) were unsuccessful and the intramolec-
ular coupling with this catalytic system was only observed
above 100 ºC with exclusive formation of 3a in 52%
yield.
mixture is readily separable by silica gel column chroma-
tography. The H NMR spectrum of the major regioiso-
1
A final attempt to preclude double bond migration during
cyclization of 1a involved the use of silver carbonate as a
halide scavenger6,15 but no reaction was observed in the
presence of either triphenylphosphine or DIPHOS even
after 7 d at 115 ºC. The lack of reactivity with these cata-
lytic systems contrasts with the results by de Meijere and
coworkers6 for the 5-exo-trig cyclization of 2-bromo-4-
aza-1,6-dienes and was rationalized through the interven-
tion of a stable cationic palladium intermediate (Figure)
mer 3b closely resembled that of 3a with the major
differences being the downfield shift of H-6 ( 5.22 and
3.28) and an upfield shift of H-9a ( 4.04) that appeared
as a broad doublet (3J = 5.0 Hz). The structural assign-
1
ment of 4b emerged from its H NMR spectrum, which
An analogous reactivity pattern emerged for 2-allyllactam
1b. No cyclization was observed when silver carbonate
was employed but a 5:1 6.4:1 diastereomeric mixture of
quinolizidinones 3b–4b was formed when potassium car-
bonate or triethylamine was used as the base (Table). This
Figure
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PAPER
The Intramolecular Heck Reaction in Alkaloid Synthesis
89
featured the strongly deshielded H 6 as a singlet at 7.21 cyclization. In fact, only products arising from 7-exo-trig
and H-9a as a multiplet at 3.54. The formation of regio- cyclization were isolated from 1e (6.5:1 mixture of ben-
isomers 3b and 4b was not thermally promoted as no in- zoazepines 7a and 8a, in 80% combined yield) and from
terconversion was observed even under extended heating 1f (2:1 mixture of 7b and 8b, in 90% combined yield)
(Condition A, Table: 5 d at 115 ºC).
when condition A was employed (Table, Scheme 3).
Despite the elusive nature of the exo bismethylene inter- The structure of the major isomer formed from 1e was un-
mediates 2a and 2b, we attempted their in situ [4+2] cy- ambiguously established by NMR spectroscopy: the pres-
cloaddition with several dienophiles, such as maleic ence of two olefinic hydrogens as doublets (2J = 1.5 Hz)
anhydride, methyl vinyl ketone and diethyl azodicarboxy- at 5.25 and 5.20 together with the absence of a methyl
late under conditions A and B, described in Table. In each signal in the 1H NMR spectrum and an olefinic methylene
case, only indolizidinone 3a (from 2a) and quinolizidino- at 117.1 in the corresponding 13C NMR spectrum fully
nes 3b and 4b (from 2b) were formed.
agree with 7a as the major benzoazepine.
When double bond isomerization to the C7-C8 position As before, the mixtures of regioisomers obtained from 1e
was blocked, intramolecular cyclization of 1c (condition and 1f were inseparable by flash chromatography on silica
A, Table) afforded exo bismethylenic indolizidinone 2c in gel and benzoazepines 7a–8a and 7b–8b were hydroge-
65% yield characterized by the presence of four terminal nated under the conditions described previously for 5a–
1
olefinic hydrogens ( 5.06, 4.90 and 4.84) in H NMR 5b. In both cases, the cis isomer was obtained preferen-
spectrum and two CH2 in the olefinic region ( 112.3 and tially with some erosion of diastereoselectivity observed
108.5) in 13C NMR spectrum. Interestingly, double bond for 7a–8a (4.5:1 molar ratio of 9a–10a, in 94% yield)
migration to the C5-C6 position was not observed but at- while a significant increment in the cis–trans ratio was
tempts to trap 2c in situ with maleic anhydride failed.
observed in the hydrogenation of an equimolar mixture of
7b–8b (6.5:1 mixture of 9b–10b, in 98% yield).
An additional example for the preference of 6-exo-trig vs.
7-endo-trig with double bond migration emerged from the The cis configuration of 9a was assigned after NOE ex-
intramolecular cyclization of lactam 1d, readily prepared periments with an analytically pure sample obtained after
from succinic anhydride after 3 steps. Under condition A, flash chromatography on silica gel: a 3.2% increment in
depicted in the Table, a 2:1 molar ratio of indolizidinones the H-11a signal was observed upon irradiation of H-10
5a and 5b (74% combined yield) were isolated, however while a 2.6% enhancement in the H-10 signal was ob-
they were inseparable by flash chromatography served upon irradiation of H-11a. Only 0.8% increment
(Scheme 2).
was observed in the methyl doublet signal when H-11a
was irradiated. Even stronger increments were observed
when 9b was submitted to NOE studies: irradiation of H-
11 led to a 8.4% enhancement of H 12a signal while
4.7% increment of H-11 signal was observed upon irradi-
ation of H-12a.
Fortunately, hydrogenation of a 2:1 mixture of regioiso-
mers 5a and 5b in methanol and palladium over carbon as
catalyst afforded a 20:1 mixture of stereoisomeric indoliz-
idinones 6a and 6b in quantitative yield (Scheme 2). The
cis relationship of the hydrogens at C-5 and C-6a in the
major isomer 6a was corroborated by NOE increments Allyltrimethylsilane addition to N-acyliminium ions de-
observed at H-6a (2.3%) upon irradiation at H-5 and at H- rived from succinimide and glutarimide provided an expe-
5 (3.4%) upon irradiation at H-6a. No increment in the in- ditious access to 5-allyl lactams 1a f in moderate to good
tensity of the methyl absorption was observed upon irra- yields. The intramolecular Heck cyclization of lactam 1a
diation of H-6a. The reason for the high diastereoisomeric was extensively investigated and indolizidinone 3a was
ratio, which accompanied hydrogenation of the mixture of formed exclusively in moderate yields (50 56%) through
regioisomers 5a–5b has not being fully explored but it a 6-exo-trig pathway. Lactam 1a was recovered when
may be associated with double bond migration from exo- Ag2CO3 was employed as base.
cyclic to the endocyclic position before reduction.
An analogous reactivity pattern was observed in the cy-
The study on regioselectivity of the intramolecular Heck clization of 1b and mixtures (5:1, 6.4:1) of indolizidino-
reactions was next extended to lactams 1e and 1f, which nes 3b and 4b were isolated in moderate to good yields
could conceivably undergo a 7-exo-trig or a 8-endo-trig (48 74%). An additional example of the preference for a
Scheme 2 a) 0.02 equiv Pd (OAc)2, 0.04 equiv PPh3, 10 equiv K2CO3, DMF, 115 °C (5a:5b, 2:1, 74%); b) H2, Pd/C, MeOH, r.t. (100%).
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90
L. S. Santos, R. A. Pilli
PAPER
N-2-Bromopropenyl-5-allylpyrrolidin-2-one (1a)
To a solution of N-2-bromopropenyl-5-ethoxy-2-pyrrolidin-2-one16
(0.412 g, 1.14 mmol) in CH2Cl2 (5.70 mL) at 0 °C was added allyl-
trimethylsilane (0.262 g, 2.29 mmol). To the resulting solution was
added BF3 OEt2 (0.486 g, 0.421 mL, 3.42 mmol). The mixture was
stirred at 0 °C for 12 h and quenched by the addition of 1% NaHCO3
solution (5.7 mL). The layers were separated and the aqueous layer
was extracted with CH2Cl2 (3 5.7 mL). The combined organic lay-
ers was dried (MgSO4), filtered and concentrated under reduced
pressure, the residue was purified by column chromatography (hex-
ane EtOAc, 1:1) to afford 1a in 59% yield as a colorless oil.
IR (KBr): 3073, 2979, 2915, 1700, 1646, 1631, 1443, 1428 and 922
1
cm .
1H NMR (CDCl3): 1.76 1.85 (m, 1 H, CH2CH2), 2.10 2.33 (m, 2
H, CH2CH2 and CH2CH=), 2.35 2.46 (m, 3 H, CH2CO and
CH2CH=), 3.74 (d, J =15.7, 1 H, CH2N), 3.70 3.76 (m, 1 H, CHN),
4.65 (d, J = 15.7, 1 H, CH2N), 5.16 (d, 1 H, J =16.1, CH2=CH), 5.17
(d, 1 H, J =17.6, CH2=CH), 5.62 5.80 (m, 3 H, CH2=CBr and
CH=CH2).
Scheme 3 a) 0.02 equiv Pd (OAc)2, 0.04 equiv PPh3, 10 equiv K2CO3,
DMF, 115 °C (7a:8a, 6.5:1, 80%; 7b:9b, 2:1, 90%); b) H2, Pd/C,
MeOH, r.t. (9a:10a, 4.5:1, 94%; 9b:10b, 6.5:1, 98%).
13C NMR (CDCl3):
(CH2CH= ), 48.5 (CH2N), 56.7 (CHN), 119.5 (CH2=CH), 119.7
(CH2=CBr), 128.9 (CBr), 133.2 (CH=CH2) and 176.0 (CO).
23.6 (CH2CH2), 30.0 (CH2CO), 37.6
HRMS (EI): m/z calcd for C10H14NOBr, 245.0239. Found:
245.0242.
6-exo-trig vs. 7-endo-trig process came from the intramo-
lecular cyclization of lactam 1d, which provided a 2:1
mixture of indolizidinones 5a and 5b (74% yield). Sur-
prisingly, catalytic hydrogenation stereoselectively con-
verted the above mixture to cis-6a (20:1 ratio) in
quantitative yield.
N-2-Bromopropenyl-6-allylpiperidin-2-one (1b)
The same procedure as described above for 1a was employed start-
ing from N-2-bromopropenyl-5-ethoxypiperidin-2-one.16 After
evaporation under reduced pressure, the residue was purified by
column chromatography (hexane EtOAc, 1:1) to afford 1b in 55%
yield as a grey oil.
Despite the propensity for double bond migration of the
putative exo bismethylene intermediates 2a and 2b, at-
tempts to carry out a one pot tandem [4+2] cycloadditon
with maleic anhydride, methylvinylketone and diethyl
azodicarboxylate were unsuccessful. When double bond
migration was precluded in lactam 1c, the corresponding
exo bismethylene intermediate was isolated in 65%
yield. Finally, exclusive 7-exo-trig cyclization was ob-
served for lactams 1e and 1f and benzoazepines 7a–8a
(4.5:1 ratio) and 7b–8b (6.5:1 ratio) were formed in good
yields. The results described here provide an attractive
route to indolizidinones, quinolizidinones and benzodiaz-
epinones and the utilization of this approach in the total
synthesis of alkaloids will be investigated.
1
IR (KBr): 3082, 2959, 1650, 1445, 1426 and 922 cm .
1H NMR (CDCl3): 1.76 1.80 (m, 1 H, CH2CH2CO), 1.80 1.96
(m, 3 H, CH2CH2CO and CH2CH2CH2), 2.21 2.39 (m, 1 H,
CH2CH=), 2.40 2.49 (m, 3 H, CH2CH= and CH2CO), 3.46 3.55
(m, 1 H, CHN), 3.67 (d, J = 15.0, 1 H, CH2N), 5.00 (d, J = 15.0, 1
H, CH2N), 5.10 5.20 (m, 2 H, CH2=CHCH2), 5.60 5.78 (m, 3 H,
CH2=CBr and CH=CH2).
13C NMR (CDCl3): 17.3 (CH2CH2CH2), 26.5 (CH2CH2CO), 32.1
(CH2CO), 37.3 (CH2N), 51.9 (CH2CH=), 55.8 (CHN), 118.7
(CH2=CBr), 119.0 (CH2=CHCH2), 129.4 (CBr), 134.4 (CH=CH2),
171.2 (CO).
GC-MS (70 eV): m/z (%) = 218 (98), 216 (100), 178 (39), 98 (14).
HRMS (CI: iso-butane): m/z calcd for C11H16NOBr: 257.0415.
Found: 259.0395, 257.0420 and 259.0400.
1H and 13C NMR spectra were recorded at 300.1 MHz and 75.4
MHz, respectively, on a Varian Gemini 2000 instrument using
CDCl3 as solvent and tetramethylsilane as the internal standard, un-
less otherwise noted. Chemical shifts ( ) are reported in ppm and
coupling constants (J) in Hz. Signal multiplicities are abbreviated as
follows: singlet (s), doublet (d), triplet (t), double dublet (dd), dou-
ble triplet (dt), q (quartet), dq (double quartet), m (multiplet), quint
(quintet). Infrared spectra were recorded as film on KBr cells on a
Nicolet Impact 410 FT-IR instrument and the wavenumbers are ex-
N-2-Bromopropenyl-5-(1,1-dimethylallylpyrrolidin-2-one (1c)
The same procedure as described above for 1a was employed ex-
cept (3,3 dimethylallyl)tributylstannane (2.0 equiv) was used in-
stead of allyltrimethylsilane. After evaporation of the solvent under
reduced pressure, the residue was purified by column chromatogra-
phy (hexane EtOAc, 1:1) to afford 1c in 40% yield as a grey oil.
1
IR (KBr): 3084, 2964, 2929, 2875, 1697, 1633, 1415 and 914 cm .
1H NMR (500 MHz, CDCl3): 1.01 (s, 3 H, CH3), 1.02 (s, 3 H,
CH3), 1.94 (m, 1 H, CH2CH2CO), 2.03 2.10 (m, 1 H, CH2CH2CO),
2.33 2.43 (m, 2 H, CH2CO), 3.50 (dd, J = 9.0 and 2.7, 1 H, CHN),
3.90 (d, J = 15.9, 1 H, CH2N), 4.78 (d, J = 15.9, 1 H, CH2N), 5.06
(dd, J = 17.6 and 1.0, 1 H, CH2=CH), 5.07 (dd, J = 10.5, 1.0, 1 H,
CH2=CH), 5.63 (dd, J = 3.5, 2.0, 1 H, CH2=CBr), 5.73 (dd, J = 3.5,
2.0, 1 H, CH2=CBr), 5.83 (dd, J = 17.6, 10.5, 1 H, CH=CH2).
1
pressed in cm . Melting points were measured with an Eletrother-
mal AZ9003 MK3 apparatus and are uncorrected. GC analyses
were recorded on Hewlett-Packard 5890 instrument, and GC-MS
analyses were recorded on Hewlett-Packard 5890 coupled to HP-
5988. HRMS analyses were recorded on Micromass VGAutoSpec
instrument.Column chromatography was preformed with silica gel
(70 230 Mesh).
13C NMR (125 MHz, CDCl3): 21.8 (CH3), 22.0 (CH2CH2CO),
25.9 (CH3), 30.9 (CH2CO), 42.7 (CCH3), 51.2 (CH2N), 65.5 (CHN),
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The Intramolecular Heck Reaction in Alkaloid Synthesis
91
113.5 (CH2=CH), 120.1 (CH2=CBr), 129.6 (CBr), 146.5
(CH=CH2), 177.6 (CO).
13C NMR (CDCl3): 17.0 (CH2CH2CH2), 26.0 (CH2CH2CO), 31.9
(CH2CO), 37.0 (CH2CH=), 52.5 (CH2N), 55.5 (CHN), 98.7 (CI),
118.2 (CH2=CH), 128.0 (CHAr), 128.4 (CHAr), 128.8 (CHAr), 133.9
(CH=CH2), 139.2 (CHAr), 139.4 (CAr), 170.5 (CO).
HRMS (CI- iso-butane): m/z calcd for C12H18NOBr: 271.0572 and
273. 0552. Found: 271.0570 and 273.0550.
HRMS (EI): m/z calcd for C15H18NOI: 355.0429. Found: 355.0454.
N-2-Iodophenyl-5-allylpyrrolidin-2-one (1d)
The same procedure as described above for 1a was employed start-
ing from N-(2-iodophenyl)-5-ethoxypyrrolidin-2-one.17 After evap-
oration of the solvent under reduced pressure, the residue was
purified by column chromatography (hexane EtOAc, 1:1) to afford
1d in 65% yield as a colorless oil.
7-Methyl-6-methylene-1,2,3,5,6,8a-hexahydroindolizin-3-one
(3a)
In a Pyrex flask was added a solution of 1a (0.412 g, 1,14 mmol) in
DMF (16.0 mL), followed by Pd(OAc)2 (0.0040 g, 0.018 mmol),
PPh3 (0.011 g, 0.040 mmol) and K2CO3 (0.538 g, 3.90 mmol) under
an Ar atmosphere. The mixture was kept at 110 °C for 12 h. Upon
completion of the reaction, DMF was carefully evaporated under re-
duced pressure (0.2 mmHg, 40 50 °C), the residue was dissolved
in EtOAc and filtered through a column of celite. Purification by
column chromatography (hexane EtOAc, 1:1) afforded 3a (36.0
mg, 0.220 mmol) in 56% yield as a pale yellow oil.
1
IR (KBr): 3069, 2974, 2925, 1698, 1577, 1016, 920 and 758 cm .
1H NMR (CDCl3): 1.92 2.02 (m, 1 H, CH2CH2CO), 2.13 2.51
(m, 3 H, CH2CH2CO and CH2CO), 2.54 2.61 (m, 2 H, CH2CH2),
4.16 (s, br, 1 H, CHN), 5.10 (d, br, J = 15.7, 2 H, CH2=CH), 5.64
5.73 (m, 1 H, CH=CH2), 7.09 (dt, J = 6.0, 1.5, 1 H, CHAr), 7.19 (dd,
J = 6.0, 1.5, 1 H, CHAr), 7.40 (dt, J = 7.0, 1.5, 1 H, CHAr), 7.92 (dd,
J = 7.0, 1.5, 1 H, CHAr).
13C NMR (CDCl3): 24.3 (br, CH2CH2CO), 29.7 (CH2CO), 38.3
(CH2N), 59.1 (br, CHN), 98.0 (br, CI), 118.8 (CH2=CH), 129.4
(CHAr), 130.0 (CHAr), 131.8 (br,CAr), 133.1 (2 CHAr), 140.3
(CH=CH2), 175.1 (CO).
1
IR (KBr): 2925, 2857, 1694, 1606, 1445 and 1423 cm .
1H NMR (CDCl3): 1.61 1.72 (m, 1 H, CH2CH2CO), 1.86 (s, 3 H,
CH3), 2.26 2.28 (m, 1 H, CH2CH2CO), 2.39 2.49 (m, 2 H,
CH2CO), 3.57 (d, J = 15.4, 1 H, CH2N), 4.26 (t, br, J = 6.0, 1 H,
CHN), 4.70 (d, J = 15.4, 1 H, CH2N), 4.99 (d, J = 1.5, 1 H, CH2=C),
5.09 (d, J = 1.5, 1 H, CH2=C), 5.63 (s, 1 H, CH=H).
HRMS (EI): m/z calcd for C13H14NOI: 327.0123. Found: 327.0120.
13C NMR (CDCl3):
19.3 (CH3), 26.3 (CH2CH2CO), 31.4
(CH2CO), 43.1 (CH2N), 55.6 (CHN), 111.5 (CH2=C), 128.0
(CH=C), 132.1 (CCH3), 139.2 (C=CH2), 173.6 (CO). HRMS (EI):
m/z calcd for C10H13NO: 163.0994. Found: 163.0997.
N-2-Bromobenzyl-5-allylpyrrolidin-2-one (1e)
The same procedure as described above for 1a was employed start-
ing from N-(2-bromobenzyl)-5-ethoxypyrrolidin-2-one.16 After
evaporation under reduced pressure, the residue was purified by
column chromatography (hexane EtOAc, 1:1) to afford 1e in 95%
yield as a colorless oil.
8-Methyl-7-methylene-1,3,4,6,7,9a-hexahydro-2H-quinolizin-4-
one (3b) and 7-Methyl-8-methylene-1,3,4,8,9,9a-hexahydro-2H-
quinolizin-4-one (4b)
The same procedure as described above for 3a was employed start-
ing from 1b. Quinolizidinone 3b was obtained in 62% yield as a
brown oil and 4b was obtained in 12% yield as a red oil after column
chromatography (hexane EtOAc, 1:1).
1
IR (KBr): 3068, 2972, 2925, 1691, 1570, 1441, 754 and 661 cm .
1H NMR (CDCl3): 1.78 1.88 (m, 1 H, CH2CH2CO), 2.05 2.25
(m, 2 H, CH2CH2CO and CH2CO), 2.37 2.57 (m, 3 H, CH2CO,
CH2CH=), 3.52 3.60 (m, 1 H, CHN), 4.32 (d, J = 16.1, 1 H, CH2N),
4.94 (d, J = 16.1, 1 H, CH2N), 5.11 (d, J = 11.3, 1 H, CH2=CH),
5.12 (d, J = 14.3, 1 H, CH2=CH), 5.60 5.74 (m, 1 H, CH=CH2),
7.12 7.17 (m, 1 H, CHAr), 7.24 7.32 (m, 2 H, CHAr), 7.55 (d, J =
7.7, 1 H, CHAr).
1
3b: IR (KBr): 2945, 2864, 1641, 1442 and 1412 cm .
1H NMR (CDCl3): 1.44 1.50 (m, 1 H, CH2CH2CO), 1.53 1.74
(m, 2 H, CH2CH2CH2), 1.83 (s, 3 H, CH3), 1.97 2.08 (m, 1 H,
CH2CH2CO), 2.22 2.37 (m, 1 H, CH2CO), 2.39 2.48 (m, 1 H,
CH2CO), 3.28 (d, J = 15.0, 1 H, CH2N), 4.04 (d, br, J = 5.0, 1 H,
CHN), 4.99 (s, br, 2 H, CH2=C), 5.22 (d, J = 15.0, 1 H, CH2N), 5.42
(s, br, 1 H, CH=CCH3).
13C NMR (CDCl3):
23.0 (CH2CH2CO), 29.6 (CH2CO), 37.2
(CH2CH=), 44.0 (CH2N), 57.0 (CHN), 119.0 (CH2=CH), 123.5
(CBr), 127.9 (CHAr), 129.2 (CHAr), 129.7 (CHAr), 132.8 (CHAr),
133.1 (CH=CH2r), 136.0 (CAr), 175.8 (C, CO).
13C NMR (CDCl3,):
18.1 (CH3), 19.4 (CH2CH2CH2), 29.9
HRMS (EI): m/z calcd for C14H16NOBr: 293.0415 and 295.0396.
(CH2CH2CO), 32.1 (CH2CO), 44.5 (CH2N), 55.5 (CHN), 110.1
(CH2=C), 128.2 (CH=CCH3), 132.2 (=CCH3), 139.8 (C=CH2),
169.2 (CO).
Found: 251.9360 and 253.9343 (M+ - C3H5).
N-2-Iodobenzyl-6-allylpiperidin-2-one (1f)
GC-MS: m/z (%) = 177 (40), 162 (100), 107 (24).
The same procedure as described above for 1a was employed start-
ing from N-(-2-iodobenzyl)-5-ethoxy-2-piperidinone.16 After evap-
oration of the solvent under reduced pressure, the residue was
purified by column chromatography on silica gel (hexane EtOAc,
1:1) to afford 1f in 95% yield as a yellow oil: mp 27 28 °C.
HRMS (EI): m/z calcd for C11H15NO: 177.1153. Found: 177.1154.
1
4b: IR (KBr): 3082, 2935, 2876, 1641, 1450 and 1406 cm .
1H NMR (CDCl3): 1.50 1.59 (m, 1 H, CH2CH2CO), 1.64 1.97
(m, 2 H, CH2CH2CH2), 1.84 (s, 3 H, CH3), 2.03 2.10 (m, 1 H,
CH2CH2CO), 2.29 2.61 (m, 4 H, CH2CO, CH2C=), 3.54 (m, 1 H,
CHN), 4.82 (d, J = 1.1, 1 H, CH2=C), 4.90 (d, J = 1.1, 1 H,
CH2=C), 7.21 (s, 1 H, =CHN).
IR (KBr): 3064, 2947, 2873, 1643, 1564, 1463, 1344, 1279, 1012,
1
918, 748 cm .
1H NMR (CDCl3):
1.74 1.82 (m, 3 H, CH2CH2CH2 and
CH2CH2CO), 1.83 1.96 (m, 1 H, CH2CH2CH2), 2.23 2.29 (m, 1 H,
CH2CH=), 2.49 2.52 (m, 3 H, CH2CO and CH2CH=), 3.30 3.34
(m, 1 H, CHN), 4.21 (d, J = 16.0, 1 H, CH2N), 5.07 5.13 (m, 2 H,
CH2=CH), 5.21 (d, J = 16.0, 1 H, CH2N), 5.62 5.70 (m, 1 H,
CH=CH2 ), 6.95 (dt, J = 8.1, 1.5, 1 H, CHAr), 7.26 (dd, J = 8.1, 1.5,
1 H, CHAr), 7.72 (dt, J = 3.0, 1.5, 1 H, CHAr), 7.82 (dd, J = 8.1, 1.5,
1 H, CHAr).
13C NMR (CDCl3):
(CH2CH2CO), 32.2 (CH2CO), 38.6 (CH2C=), 55.9 (CHN), 108.0
(CH2=C), 117.5 (=CCH3), 122.9 (=CHN), 139.8 (C=CH2), 167.6
(CO).
16.1 (CH3), 19.5 (CH2CH2CH2), 29.6
GC-MS: m/z (%) = 177 (100), 148 (18), 134 (20), 120 (36), 108 (85)
and 93 (20).
HRMS (EI): m/z calcd for C11H15NO: 177.1157. Found: 177.1154.
Synthesis 2002, No. 1, 87–93 ISSN 0039-7881 © Thieme Stuttgart · New York

92
L. S. Santos, R. A. Pilli
PAPER
8,8-Dimethyl-6,7-dimethyleneperhydro-indolizin-3-one (2c)
The same procedure as described above for 3a was employed start-
ing from 1c. Indolizidinone 2c was obtained in 67% yield as a yel-
low oil.
GC-MS: m/z (%) = 213 (78), 198 (5), 184 (5), 170 (8), 156 (4), 130
(100), 115 (54), 102 (4), 91 (7), 84 (28) and 77 (8).
HRMS (EI): m/z calcd for C14H15NO: 213.1154. Found: 213.1153.
8a (data from an enriched fraction of the mixture 7a–8a):
1H NMR (CDCl3) = 1.77 1.84 (m, 1 H, CH2CH2CO), 2.18 (s, 3
H, CH3), 2.20 2.34 (m, 1 H, CH2CH2CO), 2.35 2.43 (m, 2 H,
CH2CO), 3.81 3.87 (m, 1 H, CHN), 3.90 (d, J = 13.5, 1 H, CH2N),
4.69 (d, J = 13.5, 1 H, CH2N), 5.74 (d, J = 1.1, 1 H, CH=CCH3),
7.20 7.26(m, 1 H, CH-Ar), 7.32 7.37 (m, 3 H, CHAr).
IR (KBr): 2968, 2875, 1689, 1458, 1421, 1284, 1255 and 1182
1
cm .
1H NMR (CDCl3): 0.84 (s, 3 H, CH3), 1.11 (s, 3 H, CH3), 1.81
1.86 (m, 1 H, CH2CH2CO), 2.01 2.08 (m, 1 H, CH2CH2CO), 2.38
(t, J = 7.7, 2 H, CH2CO), 3.36 (dd, J = 8.4, 5.5, 1 H, CHN), 3.46 (d,
br, J = 14.6, 1 H, CH2N ), 4.60 (d, J = 14.6, 1 H, CH2N), 4.84 (s, br,
1 H, CH2=CCH2), 4.90 (s, br, 1 H, CH2=CCH2), 5.06 (s, br, 2 H,
CH2=CCCH3).
GC-MS: m/z (%) = 213 (23), 198 (100), 184 (4), 170 (6), 156 (9),
142 (6), 128 (12), 115 (14), 91 (6), 84 (3) and 77 (6).
13C NMR(CDCl3): 18.7 (CH2CH2CO), 20.0 (CH3), 22.1 (CH3),
30.3 (CH2CO), 40.1 (C(CH3)2), 45.7 (CH2N), 64.4 (CHN), 108.5
(CH2=C), 112.3 (CH2=C), 141.8 (C=CH2), 155.0 (C=CH2), 174.0
(CO).
10-Methyl-2,3,5,10,11,11a-hexahydro-1H-azolo[1,2-a]benzo-
[e]azepin-3-one (9a)
A 6.5:1 mixture of 7a–8a was dissolved in MeOH (5 mL) and
stirred for 10 h under H2 atmosphere (4 bar) at r.t. After evaporation
under reduced pressure and column chromatography (hexane
EtOAc, 1:1), a 4.5:1 mixture of 9a–10a was obtained in 94% yield.
HRMS (EI): m/z calcd for C12H17NO: 191.1310. Found: 191.1392.
5-Methyl-5,6,6a,7,8,9-hexahydroazolo[1,2-a]quinolin-9-one
(6a)
Data for the major isomer: white solid, mp 89–90 °C.
1
IR (KBr): 2962, 2922, 2875, 2852, 1682, 1489 and 760 cm .
The same procedure as described above for 3a was employed start-
ing from 1d. An inseparable 2:1 mixture of 5a–5b was obtained in
74% yield (HRMS [EI]: m/z calcd for C13H13NO: 199.0997; found:
199.0994) and dissolved in MeOH (2.0 mL). After addition of 10%
Pd/C (0.002 g),the resulting mixture was purged with H2 and stirred
for 8 h under H2 atmosphere (2 bar) at r.t.. Upon completion of the
reaction, the residue was filtered through a column of celite. Evap-
oration of the solvent under reduced pressure afforded 6a (0.024 g,
0.12 mmol, 20:1 mixture with 6b) in quantitative yield as a hygro-
scopic white solid.
1H NMR (CDCl3): 1.44 (d, J = 7.1, 3 H, CH3), 1.43 1.58(m, 1 H,
CH2CHCH3), 1.74 (m, 1 H, CH2CHCH3), 1.88 (dd, J = 14.5, 3.3, 1
H, CH2CH2CO), 2.19 2.37 (m, 3 H, CH2CH2CO and CH2CO),
3.20 3.29 (m, 1 H, CHN), 3.87 3.93 (m, 1 H, CHCH3), 4.09 (d, J
= 14.3, 1 H, CH2N), 4.97 (d, J = 14.3, 1 H, CH2N), 7.16 7.32 (m,
3 H, CHAr), 7.36 (m, 1 H, CHAr).
13C NMR (75 MHz, CDCl3): 20.6 (CH3), 24.9 (CH2CH2CO), 29.7
(CH2CO), 34.3 (CHCH3), 44.4 (CH2CHCH3), 46.0 (CH2N), 62.1
(CHN), 124.7 (CHAr), 126.5 (CHAr), 128.1 (CHAr), 129.9 (CHAr),
136.6 (CAr), 145.4 (CAr), 174.1(CO).
1
IR (KBr): 2962, 1687, 1485, 1092, 1024, 800 cm .
1H NMR (500 MHz, CDCl3): 1.37 (d, J = 6.8, 3 H, CH3), 1.50 (q,
J = 12.0, 1 H, CH2CHCH3), 1.70 1.75 (m, 1 H, CH2CH2CO), 2.20
(ddd, J = 12.0, 5.6, 2.4, 1 H, CH2CHCH3), 2.27 2.30 (m, 1 H,
CH2CH2CO), 2.47 2.57 (m, 1 H, CH2CO), 2.59 2.65 (m, 1 H,
CH2CO), 3.04 3.06 (m, 1 H, CHCH3), 3.95 3.97 (m, 1 H, CHN),
7.07 (dt, J = 7.8, 3.2, 1 H, CHAr), 7.21 (dt, J = 7.8, 1.0, 1 H, CHAr),
7.29 7.31 (m, 1 H, CHAr), 8.67 (dd, J = 8.5, 1.2, 1 H, CHAr).
13C NMR (125 MHz, CDCl3): 20.8 (CH3), 25.2 (CH2CH2CO),
31.4 (CHCH3), 32.0 (CH2CO), 39.3 (CH2CHCH3), 57.5 (CHN),
119.0 (CAr), 123.7 (CHAr), 126.8 (CHAr), 127.0 (CHAr), 130.7
(CHAr), 136.2 (CAr), 173.4 (CO).
HRMS (EI): m/z calcd for C14H17NO: 215.1310. Found: 215.1310.
11-Methyl-1,2,3,4,6,11,12,12a-octahydrobenzo[e]pyrido[1,2-
a]azepin-4-one (9b, 10b)
The same procedure as described above for 3a was employed start-
ing from 1f. After evaporation under reduced pressure, the residue
was purified by column chromatography (hexane EtOAc,
5:3 1:1) to afford an inseparable 2:1 mixture of 7b–8b in 90%
yield as a colorless oil.
GC-MS: 7b m/z (%) = 227 (76), 212 (5), 198 (3), 184 (5), 170 (10),
156 (6), 144 (7), 130 (100), 115 (5), 98 (5). 8b m/z (%) = 227 (31),
212 (100), 198 (23), 184 (13), 170 (13), 157 (21), 143 (8), 130 (21),
115 (22), 98 (21).
HRMS (EI): m/z calcd for C13H15NO: 201.1154. Found: 201.1153.
10-Methylene-2,3,5,10,11,11a-hexahydro-1H-azolo[1,2-a]ben-
zo[e]azepin-3-one (7a) and 10-Methyl-2,3,5,11a-tetrahydro-1H-
azolo[1,2-a]benzo[e]azepin-3-one (8a)
The same procedure as described above for 3a was employed start-
ing from 1e. After evaporation under reduced pressure, the residue
was purified by column chromatography (hexane-EtOAc, 1:1) to af-
ford a 6.5:1 mixture of 7a–8a in 80% yield as a colorless oil.
The above mixture was dissolved in MeOH (5.0 mL) and stirred for
10 h under H2 atmosphere (4 bar). After evaporation under reduced
pressure, a 6.5:1 mixture of 9b–10b was obtained in 98% yield.
Column chromatography (hexane EtOAc, 1:1) afforded the major
isomer 9b as a white solid: mp 114 115 °C.
IR (KBr): 3060, 3030, 2939, 2873, 1635, 1464, 1417, 1365, 1259,
1
1184 and 760 cm .
7a (data from an analytically pure sample):
1H NMR (500 MHz, CDCl3): 1.25 (d, J = 5.0, 3 H, CH3), 1.56
1.76 (m, 5 H, CH2CH2CH2, CH2CHCH3 and CH2CH2CO), 1.91
2.12 (m, 1 H, CH2CH2CO), 2.19 2.25(m, 1 H, CH2CO), 2.29 2.39
(m, 1 H, CH2CO), 3.26 3.33 (m, 1 H, CHN), 3.83 3.89 (m, 1 H,
CHCH3), 3.87 (d, J = 13.9, 1 H, CH2N), 5.30 (d, J = 13.9, 1 H,
CH2N), 7.16 7.26 (m, 3 H, CHAr), 7.45 (dd, J = 7.4, 1.5, 1 H,
CHAr).
13C NMR (125 MHz, CDCl3): 18.3 (CH3), 20.9 (CH2CH2CH2),
30.5 (CH2CH2CO), 32.8 (CH2CO), 35.4 (CHCH3), 44.6
(CH2CHCH3), 49.9 (CH2N), 61.4 (CHN), 124.7 (CHAr), 126.4
(CHAr), 127.7 (CHAr), 130.4 (CHAr), 137.7 (CAr), 145.0 (CAr), 169.3
(C).
1
IR (KBr): 3068, 2929, 1682 and 784 cm .
1H NMR(CDCl3): 1.77 1.81 (m, 1 H, CH2CH2CO), 2.20 2.36
(m, 1 H, CH2CH2CO), 2.38 2.46 (m, 3 H, CH2C= and CH2CO),
2.80 (dd, J = 13.2, 3.7, 1 H, CH2C= ), 3.91 (m, 1 H, CHN), 4.10 (d,
J = 15.0, 1 H, CH2N), 4.95 (d, J = 15.0, 1 H, CH2N), 5.20 (d, J =
1.5, 1 H, CH2=C), 5.25 (d, J = 1.5, 1 H, CH2=C), 7.22 7.32 (m, 4
H, CHAr).
13C NMR (CDCl3):
23.7 (CH2CH2CO), 29.8 (CH2CO), 43.0
(CH2=C), 45.9 (CH2N), 60.7 (CHN), 117.1 (CH2=C), 127.8
(CHAr, 2), 128.6 (CHAr), 128.7 (CHAr), 134.6 (CAr), 142.4 (CAr),
146.4 (C=CH2), 174.2 (CO).
Synthesis 2002, No. 1, 87–93 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
The Intramolecular Heck Reaction in Alkaloid Synthesis
93
HRMS (EI): m/z calcd for C15H19NO: 229.1466.Found: 229.1467.
(6) Bhat, L.; Steinig, A.; Appelbe, R.; de Meijere, A. Eur. J.
Org. Chem. 2001, 9, 1673.
(7) (a) Alves, C. F.; Böckelmann, M. A.; Mascarenhas, Y. P.;
Nery, J. G.; Vencato, I.; Pilli, R. A. Tetrahedron Lett. 1999,
40, 2891. (b) Maldaner, A. O.; Pilli, R. A. Tetrahedron
1999, 55, 13321. (c) Maldaner, A. O.; Pilli, R. A.
Tetrahedron Lett. 2000, 41, 7843. (d) D`Oca, M. G. M.;
Vencato, I.; Pilli, R. A. Tetrahedron Lett. 2000, 41, 9709.
(e) Santos, L. S.; Pilli, R. A. Tetrahedron Lett. 2001, 42,
6999. (f) Pilli, R. A.; Zanotto, P. R.; Böckelmann, M. A.
Tetrahedron Lett. 2001, 42, 7003.
Acknowledgements
Fellowships from CAPES (LSS) and CNPq (RAP) are gratefully
acknowledged as well as financial support from Fapesp (Brazil) and
Volkswagen Stiftung (Germany). The authors wish to thank Profes-
sor Timothy J. Brocksom (UFSCar, Brazil), Helena M. C. Ferraz
(USP, Brazil) and Armin de Meijere (Georg-August Universität.
Göttingen, Germany) for generous gift of reagents.
(8) For recent reviews on the addition of carbon nucleophiles to
N-acyliminium ions: (a) Russowsky, D.; Pilli, R. A. Trends
Org. Chem. 1997, 6, 101. (b) Moolenaar, M. J.; Speckamp,
W. N. Tetrahedron 2000, 56, 3817.
(9) For the in situ reduction of palladium(II) to palladium(0)
species, see: (a) Trost, B. M.; Murphy, D. J.
References
(1) (a) Negishi, E. I.; Liu, F. In Metal-catalyzed Cross-coupling
Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-VCH:
Weinheim, 1998, Chap.1, 1. (b) Negishi, E. I.; Coperet, C.;
Ma, S. M.; Liou, S. Y.; Liu, F. Chem. Rev. 1996, 96, 365.
(c) Daves, G. D.; Hallberg, A. Chem. Rev. 1989, 89, 1433.
(2) (a) Bräse, S.; de Meijere, A. In Metal-catalyzed Cross-
coupling Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-
VCH: Weinheim, 1998, 99. (b) Cabri, W.; Cadiani, I. Acc.
Chem. Res. 1995, 28, 2. (c) de Meijere, A.; Meyer, F. E.
Angew. Chem. Int. Ed. Engl. 1994, 106, 2473. (d) Heck, R.
F. In Comprehensive Organic Synthesis, Vol. 4; Trost, B.
M.; Fleming, I., Eds.; Pergamon Press: Oxford, 1991, 833.
(e) Heck, R. F. In Palladium Reagents in Organic Synthesis;
Academic Press: London, 1985.
Organometallics 1985, 4, 1143. (b) McCrindle, R.;
Ferguson, G.; Arsenault, G. J.; McAlees, A. J. J. Chem. Soc.,
Chem. Commun. 1983, 571; and references cited therein.
(c) Amatore, C.; Jutand, A.; M’Barki, M. A.
Organometallics 1992, 11, 3009. (d) Hayashi, T.; Kubo, A.;
Ozawa, F. Pure Appl. Chem. 1992, 64, 421.
(10) Herrmann, W. A.; Brömer, C.; Öfele, K.; Reisinger, C.-P.;
Priermeier, T.; Beller, M.; Fischer, H. Angew. Chem. Int. Ed.
Engl. 1995, 34, 1844.
(11) Gaussian 98, Revision A.6, Gaussian, Inc., Pittsburgh PA,
1998.
(3) (a) Tietze, L. F. Chem. Rev. 1996, 96, 115. (b) Waldmann,
H. In Domino Reactions in Organic Synthesis Highlights II;
Waldmann, H., Ed.; VCH: Weinheim, 1995, 193.
(12) (a) Melpolder, J. B.; Heck, R. F. J. Org. Chem. 1976, 41,
265. (b) Chalk, A. J.; Magennis, S. A. J. Org. Chem. 1976,
41, 273. (c) Chalk, A. J.; Magennis, S. A. J. Org. Chem.
1976, 41, 1206.
(13) Kang, S.-K.; Jung, K.-Y.; Park, C.-H.; Namkoong, E.-Y.;
Kim, T.-H. Tetrahedron Lett. 1995, 36, 6287.
(14) (a) Jeffery, T. Tetrahedron Lett. 1985, 26, 2667. (b)Jeffery,
T. J. Chem. Soc., Chem. Commun. 1984, 1287. (c) Jeffery,
T. Tetrahedron 1996, 52, 10113.
(15) Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem.
1987, 52, 4130.
(16) Schuch, C. M.; Pilli, R. A. Tetrahedron: Asymmetry 2000,
11, 753.
(c) Tietze, L. F.; Beifuss, U. Angew. Chem. Int. Ed. Engl.
1993, 32, 131. (d) Curran, D. P. In Comprehensive Organic
Synthesis, Vol. 4; Trost, B. M.; Fleming, I., Eds.; Pergamon
Press: Oxford, 1991, 779.
(4) (a) Moreno-Manãs, M.; Pleixats, R.; Roglans, A. Liebigs
Ann. Chem. 1995, 1807. (b) Ang, K. H.; Bräse, S.; Steinig,
A. G.; Meyer, F. E.; Llebaria, A.; Voigt, K.; de Meijere, A.
Tetrahedron 1996, 52, 11503. (c) Meyer, F. E.; Ang, K. H.;
Steinig, G. A.; de Meijere, A. Synlett 1994, 191.
(5) (a) Ikeda, M.; El Bialy, S. A. A.; Yakura, T. Heterocycles
1999, 51, 1957. (b) Lemaire-Audoire, S.; Savignac, M.;
Dupuis, C.; Genêt, J.-P. Tetrahedron Lett. 1996, 2003.
(c) Grigg, R.; Stevenson, P. J.; Worakun, T. Tetrahedron
1988, 44, 2033. (d) Shi, L.; Narula, C. K.; Mak, K. T.; Kao,
L.; Xu, Y.; Heck, R. F. J. Org. Chem. 1983, 48, 3894.
(17) N-2-iodophenyl succinimide was prepared from succinic
anhydride, 2-iodoaniline and acetyl chloride according to
ref.16.
Synthesis 2002, No. 1, 87–93 ISSN 0039-7881 © Thieme Stuttgart · New York