Pd-Cu bimetallic catalyzed domino cyclization of α-allenols followed by a coupling reaction: New sequence leading to functionalized spirolactams

Article abstract of DOI:10.1002/chem.200500228

A novel regioselective metal-catalyzed spirocyclization of α-allenolscross coupling (Heck, Sonogashira, and Suzuki) reaction sequence, leading to potentially bioactive spirocyclic lactam derivatives has been developed. Precursors for the tandem spirocycli

Full text of DOI:10.1002/chem.200500228

DOI: 10.1002/chem.200500228
Pd–Cu Bimetallic Catalyzed Domino Cyclization of a-Allenols Followed by a
Coupling Reaction: New Sequence Leading to Functionalized Spirolactams
Benito Alcaide,*[a] Pedro Almendros,*[b] and Raquel Rodríguez-Acebes[a]
Dedicated to Professor Joaquín Plumet on the occasion of his 60th birthday
Abstract: Anovel regioselective metal-catalyzed spirocyclization of a-allenols–
cross coupling (Heck, Sonogashira, and Suzuki) reaction sequence, leading to po-
tentially bioactive spirocyclic lactam derivatives has been developed. Precursors
for the tandem spirocyclization–coupling reaction, a-allenols 2a–d were obtained
starting from a-oxolactams 1a–c via indium-mediated Barbier-type carbonyl-alle-
nylation reaction in aqueous media by using our previously described methodolo-
gies.
Keywords:
reactions · lactams · palladium ·
spiro compounds
allenes
·
domino
Introduction
terns. Metal-catalyzed domino heterocyclization–functionali-
zation reaction of allenes are relatively unknown; only Trost
and Lu have independently reported the tandem cycliza-
tion–Michael addition reaction of unsubstituted at the
allene carbon atom, where the cyclization occurs, d- and g-
allenols,[4] d- and g-allenamines,[5] a-allene carbamates,[6] or
a-allenoic acids.[7] We are currently involved in a project
aimed at the synthesis of nitrogen heterocycles.[8] We report
here a novel one-pot catalyzed heterocyclization of substi-
tuted at the allene carbon a-allenols-coupling (Heck, Sono-
gashira, and Suzuki) reactions, leading to potentially bioac-
tive spirolactams.[9]
The evolution of organic synthesis relies on the design and
discovery of new reactions that generate structural complex-
ity and value with step economy.[1] Towards this end, transi-
tion-metal-catalyzed processes have become a powerful tool
for the construction of sensitive functionalized molecules
under very mild conditions.[2] Allenes are versatile building
blocks in metal-catalyzed processes but are still under utiliz-
ed in organic synthesis. In the context of heterocyclic syn-
thesis, allenes offer expeditious routes to a wide range of
oxygen and nitrogen heterocycles.[3] Afurther feature of in-
corporation of allenes into heterocyclic synthesis is their
ability to provide unusual substituents and substitution pat-
Results and Discussion
[a] Prof. Dr. B. Alcaide, Dipl.-Chem. R. Rodríguez-Acebes
Departamento de Química Orgµnica I
Facultad de Química, Universidad Complutense de Madrid
28040 Madrid (Spain)
Precursors for the tandem spirocyclization–coupling reac-
tion, a-allenols 2a–d were obtained starting from a-oxolac-
tams 1a–c via indium-mediated Barbier-type carbonyl-alle-
nylation reaction in aqueous media by using our previously
described methodologies (Scheme 1).[10]
Fax : (+34)91-394-4103
E-mail: alcaideb@quim.ucm.es
[b] Dr. P. Almendros
The final goal of this study was to intercept the halovinyl
moiety of a proposed dihydrofuran intermediate with a con-
venient coupling partner using a multitasking catalytic
system.[11] After considerable experimentation, it was found
that reaction of a-allenol 2a with methyl acrylate at room
temperature in acetonitrile in the presence of 9 mol% Pd-
(OAc)2, 0.2 equiv PPh3, 5 equiv LiBr, 2 equiv Cu(OAc)2 and
7 equiv K2CO3 under an atmospheric pressure of oxygen af-
Instituto de Química Orgµnica General
Consejo Superior de Investigaciones Científicas
Juan de la Cierva 3, 28006 Madrid (Spain)
Fax : (+34)91-564-4853
E-mail: iqoa392@iqog.csic.es
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the authors. Supporting In-
formation: It contains compound characterization data and experi-
mental procedures for compounds 2a–d, 7a, and 10.
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FULL PAPER
Scheme 1. Regioselective preparation of a-allenic alcohols 2 in aqueous
media. PMP = 4-MeOC6H4.
forded the allene cyclization Heck trapping product 3a in a
reasonable 53% isolated yield. The use of lithium iodide in-
stead of lithium bromide in the domino sequence gave es-
sentially the same yield of 3a. Compound 3a can be consid-
ered as a hybrid scaffold as combination at the spiro junc-
tion of the oxindole and the dihydrofuran moieties.[12] When
phenylacetylene, (trimethylsilyl)acetylene, or thiophene-2-
boronic acid were used as the cross-coupling reagent under
our optimized conditions, the corresponding domino Sono-
gashira or Suzuki–Miyaura adducts 3b–d were obtained
(Scheme 2). Thus, the same catalytic system is able to pro-
mote two different, but sequential catalytic cycles, allowing
different transformations in a single reaction flask.
Scheme 2. One-pot synthesis of spirocyclic oxindoles 3 through metal-cat-
alyzed domino cyclization of a-allenols-cross coupling (Heck, Sonoga-
shira, and Suzuki) reactions. TMS = trimethylsilyl.
Having demonstrated that oxindole-tethered allenols
were viable substrates for the domino spirocyclization–cou-
pling process, we investigated the achievement of this
single-pot catalytic sequence for the synthesis of spiranic b-
lactams. Treatment of enantiopure a-allenols 2b–d with the
appropriate coupling partner under similar above conditions
for allene 2a, led to formation of the desired products 4 as
single isomers (Scheme 3).
The domino cyclization reaction is highly regioselective,[13]
giving five-membered heterocycles. Besides, the stereochem-
ical integrity of the stereogenic centers at the lactam sub-
stituents, when applicable, remained unaltered.
The formation of spirolactams 3 and 4 could be rational-
ized in terms of a novel sequence domino cyclization of a-
allenols-cross coupling reactions. Apalladium( ii)-catalyzed
mechanism for the domino sequence leading to spiranic ad-
ducts 3 and 4 is proposed in Scheme 4.[14] It can be assumed
that the initially formed allenepalladium complex 5 under-
Scheme 3. One-pot synthesis of enantiopure spirocyclic 2-azetidinones 4
through metal-catalyzed domino cyclization of a-allenols-cross coupling
(Heck, Sonogashira, and Suzuki) reactions.
goes an intramolecular attack by the hydroxyl group (oxy-
palladation), giving rise to the spirocyclic vinylic palladium
species 6. Next, palladadihydrofuran intermediate 6 is trap-
ped by the cross-coupling reagents leading to compounds 3
and 4. For example, the palladium species 6 can then form
the intermediate 7 in a subsequent Heck reaction with acry-
late, which leads to the final spirocycles 3a, 4a, and 4b and
Pd0 in a b-hydride elimination. It is necessary for the catalyt-
Abstract in Spanish: Se ha descubierto un nuevo proceso de
espirociclación de a-alenoles-reacción de acoplamiento cru-
zado (Heck, Sonogashira, y Suzuki), catalizado por un siste-
ma bimetµlico Pd–Cu, que proporciona de forma totalmente
regioselectiva lactamas espirocíclicas potencialmente bioacti-
vas.
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B. Alcaide, P. Almendros and R. Rodríguez-Acebes
conditions resulted in a considerable lower yield (Table 1,
entry 2). Replacing Pd(OAc)2 with PdCl2 in the domino se-
quence gave rise to a complex mixture; bromodihydrofuran
8 was obtained as the major component (Table 1, entry 3).
The absence of Cu(OAc)2 and oxygen (Table 1, entry 4), or
the absence of LiBr, Cu(OAc)2 and oxygen (Table 1,
entry 5) on the standard reaction conditions afforded mix-
tures of the domino adduct 3a and the dihydrofuran 9 albeit
in modest yields.
Scheme 4. Rationalization for the metal-catalyzed domino allene cycliza-
tion–coupling sequence.
Scheme 6. Reaction of a-allenol 2a under modified domino cyclization
conditions.
ic cycle that Pd0 is reoxidized to PdII; this is achieved by the
addition of Cu(OAc)2, which does not interfere with the
course of the reaction.
To gain an insight into the mechanism, additional experi-
ments were carried out (Schemes 5, 6, Table 1). When the
sequence was conducted step by step, it was possible to iso-
late the bromodihydrofuran 8, which after addition of
methyl acrylate and PPh3 to the catalytic medium did not af-
forded spirolactam 3a (Scheme 5).[15] In the absence of lithi-
Although the exact mechanism of this tandem allene het-
erocyclization reaction has yet to be elucidated, it is obvious
that the presence of the bromide ion is not essential. How-
ever, it plays an important role on increasing the yield of
the final domino adduct.[16] The bromodihydrofuran deriva-
tive 8 was not an intermediate in the formation of the
domino adduct 3a, since it was
not converted into 3a under the
reaction conditions. This result
rules out the possibility that
oxybromination occurs first, fol-
lowed by the cross-coupling re-
action. At the present time,
based on the experimental evi-
Scheme 5. Metal-catalyzed oxybromination of the a-allenol 2a followed by the addition of the cross-coupling
reagent.
dences of Schemes 5, 6, and
Table 1, we propose the mecha-
nism outlined in Scheme 4.[14]
um bromide, the spirocyclization tandem reaction occurred
as well, but led to a significantly decreased yield of 3a
(24%) (Table 1, entry 1). The use of lithium fluoride instead
of lithium bromide in the domino sequence under the same
Conclusion
In summary, using a single catalytic system we have success-
fully accomplished an unprecedented domino cyclization of
a-allenols-cross coupling reaction strategy for the synthesis
of potentially bioactive spirolactams.
Table 1. Reaction of a-allenol 2a under modified domino cyclization
conditions.[a]
Reagents[a]
Product [yield (%)][b]
1
2
3
4
5
Pd(OAc)2, PPh3, Cu(OAc)2, K2CO3, O2
Pd(OAc)2, LiF, PPh3, Cu(OAc)2, K2CO3, O2
PdCl2, LiBr, PPh3, Cu(OAc)2, K2CO3, O2
Pd(OAc)2, LiBr, PPh3, K2CO3
3a [24]
3a [18]
8 [8]
Experimental Section
General methods: Melting points were obtained with a Gallenkamp ap-
paratus and are uncorrected. IR spectra were recorded on a Perkin–
Elmer 781 spectrophotometer. 1H NMR and 13C NMR spectra were re-
corded on a Bruker Avance-300, Varian VRX-300S or Bruker AC-200.
NMR spectra were recorded in CDCl3 solutions, except otherwise stated.
Chemical shifts are given in ppm relative to TMS (1H, 0.0 ppm), or
CDCl3 (13C, 76.9 ppm). Low and high resolution mass spectra were taken
3a [16], 9 [8]
3a [10], 9 [11]
Pd(OAc)2, PPh3, K2CO3
[a] All reactions were conducted in dry acetonitrile at room temperature.
[b] Yield of pure, isolated product with correct analytical and spectral
data. Disappearance of starting 2a was observed in all cases. Unidentified
decomposition products were also detected.
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Domino Cyclization
FULL PAPER
on a HP5989Aspectrometer using the electronic impact (EI) or electro-
spray modes (ES) unless otherwise stated. Optical rotations were mea-
sured with a Perkin–Elmer 241 polarimeter. Specific rotation [a]D is
given in degcm2 gÀ1 at 258C, and the concentration (c) is expressed in g
per 100 mL. All commercially available compounds were used without
further purification. THF was distilled from Na/benzophenone. Benzene,
dichloromethane and triethylamine were distilled from CaH2. Flame-
dried glassware and standard Schlenk techniques were used for moisture
sensitive reactions. Flash chromatography was performed using Merck
silica gel 60 (230–400 mesh).
compound (À)-4a (23 mg, 58%) as a colorless oil. [a]D =À79.7 (c=0.8 in
1
CHCl3); H NMR (300 MHz, CDCl3, 258C): d=7.40 (d, J=16.1 Hz, 1H),
7.35 (m, 5H), 5.65 (d, J=16.1 Hz, 1H), 4.91 (d, J=14.4 Hz, 1H), 4.40 (m,
1H), 4.21 (d, J=14.4 Hz, 1H), 4.11 (dd, J=10.4, 6.9 Hz, 1H), 3.77 (s,
3H), 3.75 (m, 1H), 3.44 (t, J=8.9 Hz, 1H), 3.39 (dd, J=8.7, 5.5 Hz, 1H),
1.70 (t, 3H, J=1.8 Hz), 1.40, 1.35 (s, 3H each); 13C NMR (75 MHz,
CDCl3, 258C): d=167.5, 167.2, 135.9, 133.4, 132.6, 129.5, 129.1, 128.4,
120.9, 110.3, 102.3, 77.6, 76.1, 66.8, 64.2, 52.3, 45.8, 27.1, 25.3, 9.8; IR
(CHCl3): n˜ = 1748, 1718 cmÀ1; MS (ES): m/z (%): 414 (100) [M+H]+,
413 (25) [M]+; elemental analysis calcd (%) for C23H27NO6 (413.5): C
66.81, H 6.58, N 3.39; found C 66.93, H 6.55, N 3.37.
Metal-catalyzed domino cyclization of a-allenols–cross coupling reac-
tions—General procedure for the synthesis of spirolactams 3a–d and
4a–d: Palladium(ii) acetate (0.009 mmol), triphenylphosphine (0.02 mmol),
lithium bromide (0.49 mmol), potassium carbonate (0.70 mmol), copper-
(ii) acetate (0.21 mmol), and the appropriate coupling reagent
(0.12 mmol) were sequentially added to a stirred solution of the corre-
sponding a-allenic alcohol 2 (0.10 mmol) in acetonitrile (5 mL). The re-
sulting suspension was stirred at room temperature under an oxygen at-
mosphere until disappearance (TLC) of the starting material. The organic
phase was diluted with brine (2 mL), extracted with ethyl acetate (5”
5 mL), washed with brine (2 mL), dried (MgSO4) and concentrated under
reduced pressure. Chromatography of the residue eluting with hexanes/
ethyl acetate mixtures gave analytically pure spirolactams 3 and 4. Spec-
troscopic and analytical data for some representative pure forms
follow.[17]
Spirolactam (À)-4b: From a-allenol (À)-2c (50 mg, 0.128 mmol), com-
pound (À)-4b was obtained as a colorless oil (56%, 34 mg). [a]D =À4.6
(c=0.9 in CHCl3); 1H NMR (300 MHz, CDCl3, 258C): d=7.25 (m, 9H),
6.82 (dd, J=7.7, 1.4 Hz, 1H), 5.75 (d, J=16.1 Hz, 1H), 5.10 and 4.88 (d,
J=12.0 Hz, 1H), 4.79 (d, J=14.4 Hz, 1H), 4.41 (ddd, J=8.9, 6.7, 5.9 Hz,
1H), 4.13 (m, 1H), 4.12 (d, J=14.6 Hz, 1H), 3.72 (s, 3H), 3.43 (dd, J=
8.4, 5.5 Hz, 1H), 3.28 (d, J=8.8 Hz, 1H), 1.30 and 1.19 (s, each 3H);
13C NMR (75 MHz, CDCl3, 258C): d=167.1, 166.5, 142.1, 135.0, 134.6,
133.9, 130.0, 129.2, 129.1, 129.0, 128.4, 128.3, 127.3, 122.1, 109.9, 102.2,
76.8, 75.7, 66.5, 64.1, 51.8, 45.1, 26.4, 24.8.; IR (CHCl3): n˜
= 1750,
1716 cmÀ1; MS (ES): m/z (%): 476 (100) [M+H]+, 475 (30) [M]+; ele-
mental analysis calcd (%) for C28H29NO6 (475.5): C 70.72, H 6.15, N 2.95;
found C 70.58, H 6.20, N 2.98.
Spirolactam (+)-4c: From a-allenol (+)-2d (34 mg, 0.10 mmol), com-
pound (+)-4c was obtained as a colorless oil (19 mg, 43%). [a]D =+5.8
(c=0.6 in CHCl3); 1H NMR (300 MHz, CDCl3, 258C): d=7.73, 6.89 (d,
J=9.0 Hz, 2H each), 5.36, 5.20 (dqd, J=12.5, 2.0, 1.0 Hz, 1H), 4.48 (m,
1H), 4.29 (dd, J=8.5, 7.1 Hz, 1H), 4.10 (d, J=8.5 Hz, 1H), 3.81 (s, 3H),
3.58 (dd, J=8.7, 6.2 Hz, 1H), 1.75 (t, 3H, J=2.1 Hz), 1.63, 1.35 (s, 3H
each), 0.08 (s, 9H); 13C NMR (75 MHz, CDCl3, 258C): d=167.6, 156.7,
133.2, 130.9, 129.3, 119.8, 114.1, 109.9, 103.3, 77.4, 77.2, 75.6, 74.5, 68.9,
66.7, 55.5, 26.7, 24.7, 9.8, 1.0; IR (CHCl3): n˜ = 1746 cmÀ1; MS (ES): m/z
(%): 442 (100) [M+H]+, 441 (15) [M]+; elemental analysis calcd (%) for
C24H31NO5Si (441.6): C 65.28, H 7.08, N 3.17; found C 65.39, H 7.05, N
3.15.
Spirolactam 3a: From a-allenol 2a (36 mg, 0.167 mmol), compound 3a
was obtained as
a colorless solid (27 mg, 53%). M.p. 128–1298C;
1H NMR (300 MHz, CDCl3, 258C): d=7.54 (d, J=15.9 Hz, 1H), 7.36 (td,
J=7.6, 1.6 Hz, 1H), 7.17 (ddd, J=7.3, 1.7, 0.5 Hz, 1H), 7.08 (td, J=7.3,
1.0 Hz, 1H), 6.85 (d, J=7.8 Hz, 1H), 5.79 (d, J=15.9 Hz, 1H), 5.19, 5.07
(ddd, J=11.1, 1.7, 0.7 Hz, 1H each), 3.80 (s, 3H), 3.21 (s, 3H), 1.58 (t,
J=1.7 Hz, 3H); 13C NMR (75 MHz, CDCl3, 258C): d=174.8, 167.0,
144.0, 141.2, 133.8, 133.0, 130.5, 127.7, 124.6, 123.4, 120.1, 108.5, 94.3,
75.8, 51.7, 26.4, 9.8; IR (CHCl3): n˜ =1720, 1716 cmÀ1; MS (EI): m/z (%):
299 (100) [M]+, 284 (90) [MÀCH3]+; elemental analysis calcd (%) for
C17H17NO4 (299.3): C 68.21, H 5.72, N 4.68; found C 68.33, H 5.75, N
4.65.
Spirolactam (À)-4d: From a-allenol (À)-2b (33 mg, 0.10 mmol), com-
pound (À)-4d was obtained as a colorless oil (20 mg, 47%). [a]D =À92.5
(c=0.9 in CHCl3); 1H NMR (300 MHz, CDCl3, 258C): d=7.34 (m, 5H),
7.15 (m, 4H), 5.09 (dq, J=12.2, 2.0 Hz, 1H), 4.94 (d, J=14.2 Hz, 1H),
4.83 (dq, J=12.2, 2.0 Hz, 1H), 4.44 (ddd, J=8.9, 6.8, 5.4 Hz, 1H), 4.23
(d, J=14.2 Hz, 1H), 4.15 (dd, J=8.7, 7.0 Hz, 1H), 3.50 (dd, J=8.5,
5.6 Hz, 1H), 3.49 (d, J=9.0 Hz, 1H), 2.35 (s, 3H), 1.66 (t, 3H, J=
2.0 Hz), 1.41, 1.36 (s, 3H each); 13C NMR (75 MHz, CDCl3, 258C): d=
168.2, 138.0, 135.8, 135.1, 129.5, 129.3, 129.1, 128.5, 127.8, 127.4, 125.8,
109.8, 102.9, 78.3, 77.5, 66.5, 64.2, 45.3, 26.7, 24.9, 21.2, 9.9; IR (CHCl3): n˜
= 1751 cmÀ1; MS (ES): m/z (%): 420 (100) [M+H]+, 419 (22) [M]+; ele-
mental analysis calcd (%) for C26H29NO4 (419.5): C 74.44, H 6.97, N 3.34;
found C 74.58, H 6.94, N 3.32.
Spirolactam 3b: From a-allenol 2a (45 mg, 0.209 mmol), compound 3b
was obtained as
a
colorless oil (30 mg, 46%). 1H NMR (300 MHz,
CDCl3, 258C): d=7.60 (m, 1H), 7.31 (m, 6H), 7.12 (dd, J=7.3, 1.0 Hz,
1H), 6.85 (d, J=7.8 Hz, 1H), 5.60 (t, J=1.0 Hz, 2H), 3.23 (s, 3H), 1.49
(t, J=2.0 Hz, 3H); 13C NMR (75 MHz, CDCl3, 258C): d=175.4, 144.0,
140.8, 137.2, 133.6, 130.3, 128.9, 128.4, 127.7, 124.7, 123.3, 122.2, 108.4,
94.0, 77.1, 76.7, 75.8, 26.4, 10.2; IR (CHCl3): n˜ = 1714 cmÀ1; MS (ES):
m/z (%): 316 (100) [M+H]+, 315 (61) [M]+; elemental analysis calcd
(%) for C21H17NO2 (315.4): C 79.98, H 5.43, N 4.44; found C 79.84, H
5.40, N 4.46.
Spirolactam 3c: From a-allenol 2a (36 mg, 0.167 mmol), compound 3c
was obtained as
a
colorless oil (22 mg, 43%). 1H NMR (300 MHz,
CDCl3, 258C): d=7.31 (m, 2H), 7.08 (m, 1H), 6.84 (d, J=7.8 Hz, 1H),
5.54 (d, J=1.5 Hz, 2H), 3.21 (s, 3H), 1.43 (t, J=1.8 Hz, 3H), 0.30 (s,
9H); 13C NMR (75 MHz, CDCl3, 258C): d=171.9, 144.0, 134.3, 132.6,
130.3, 128.3, 124.7, 123.3, 108.4, 93.5, 77.2, 75.8, 74.7, 26.4, 10.1, À1.9; IR
(CHCl3): n˜ =1710 cmÀ1; MS (ES): m/z (%): 312 (100) [M+H]+, 311 (10)
[M]+; elemental analysis calcd (%) for C18H21NO2Si (311.5): C 69.41, H
6.80, N 4.50; found C 69.55, H 6.76, N 4.53.
Acknowledgements
Support for this work by the DGI-MCYT (Project BQU2003–07793-C02-
01) is gratefully acknowledged. R.R.A. thanks the MCYT for a predoc-
toral grant. Dipl.-Chem. Teresa Martínez del Campo is gratefully ac-
knowledged for preliminary experiments.
Spirolactam 3d: From a-allenol 2a (27 mg, 0.126 mmol), compound 3d
was obtained as
a
colorless oil (14 mg, 40%). 1H NMR (300 MHz,
CDCl3, 258C): d=7.30 (m, 3H), 7.09 (m, 2H), 7.03 (td, J=3.7, 1.0 Hz,
1H), 6.86 (d, J=7.6 Hz, 1H), 5.40, 5.28 (dq, J=11.0, 2.0 Hz, 1H each),
3.23 (s, 3H), 1.67 (t, J=1.8 Hz, 3H); 13C NMR (75 MHz, CDCl3, 258C):
d=172.7, 146.8, 144.2, 134.9, 130.3, 129.6, 128.3, 127.0, 125.7, 124.8, 123.3,
108.4, 87.4, 78.1, 26.4, 10.9; IR (CHCl3): n˜ = 1711 cmÀ1; MS (ES): m/z
(%): 298 (100) [M+H]+, 297 (16) [M]+; elemental analysis calcd (%) for
C17H15NO2S (297.4): C 68.66, H 5.08, N 4.71; found C 68.80, H 5.11, N
4.68.
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[13] It has been described (see ref. [6]) that the attempted tandem cycli-
zation–Michael addition reaction of a-allene carbamates substituted
at the allene carbon gave a complex mixture. Our observed regio-
chemistry at the allene moiety is different to the expected one for
the sequence reported above.
[14] The pathway proposed in Scheme 4 is in good accordance with the
literature; see for example: a) Modern Allene Chemistry (Eds.: N.
Krause, A. S. K. Hashmi), Wiley-VCH, Weinheim, 2004, pp. 877–
923; b) S. Ma, Z. Yu, Z. Gu Chem. Eur. J. 2005, 11, 2351; c) S. Ma,
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[15] Similar results were obtained when the oxybromination step was fol-
lowed, in the same pot and using only the initial catalyst, with the
addition of the cross-coupling reagent.
[16] One of the referees had suggested that an influence of bromide
does not necessarily mean that bromide reacts with the organic sub-
strate; bromide could also influence the whole reaction as a ligand
on Pd.
[17] Full spectroscopic and analytical data for compounds not included
in this Experimental Section are described in the Supporting Infor-
mation.
[6] G. Liu, X. Lu, Org. Lett. 2001, 3, 3879.
[7] G. Liu, X. Lu, Tetrahedron Lett. 2003, 44, 127.
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[9] The spirolactam framework is an important structural motif in bio-
logically relevant compounds as natural products and pharmaceuti-
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Hirata, M. M. Weiss, K. Tamaki, T. V. Ovaska, J. L. Wood, Angew.
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Received: March 1, 2005
Published online: July 20, 2005
5712
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