Total synthesis of (-)-strychnine via the Wieland - Gumlich aldehyde

Article abstract of DOI:10.1002/(SICI)1521-3773(19990201)38:3<395::AID-ANIE395>3.0.CO;2-5

Fifteen steps suffice for an enantioselective total synthesis of (-)- strychnine (1) from 1,3-cyclohexanedione. The key steps are the easy generation of the enantiopure intermediate 2, the closure of the piperidine ring by a reductive Heck reaction, and the elaboration of the indoline nucleus in an advanced synthetic stage. TBDMS = tert-butyldimethylsilyl.

Full text of DOI:10.1002/(SICI)1521-3773(19990201)38:3<395::AID-ANIE395>3.0.CO;2-5

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structure was solved by direct methods with SHELXS-86 and refined
by the full-matrix least-squares procedure against F 2 with SHELXL-
93. a) Crystal structure data for 1-CA: C24H40O5 ´ C5H10N2O, crystal
size 0.6  0.3  0.07 mm, Tˆ 100 K, monoclinic, P21, a ˆ 13.268(4),
b ˆ 7.909(2), c ˆ 13.818(4) Š, b ˆ 106.03(2)8, Vˆ 1393.6(7) Š3, Z ˆ 2,
1calcd ˆ 1.246 gcm 3, m ˆ 0.086 mm 1, MoKa radiation (l ˆ 0.71073 Š).
Data were collected up to 2q ˆ 488 (q-2q scans). The structure was
refined on 2058 reflections with positive F 2 values; 334 refined
parameters; R1 ˆ 0.044, wR2 ˆ 0.102, GOF ˆ 1.102 for 1691 reflections
with F > 4s(F) (R1 ˆ 0.106, wR2 ˆ 0.141, GOF ˆ 1.281 for all 2376
independent reflections). b) Crystal structure data for 2-CA:
C24H40O5 ´ C6H12N2O, crystal size 0.6  0.2  0.07 mm, Tˆ 100 K, P21,
a ˆ 12.353(2), b ˆ 7.675(1), c ˆ 16.359(4) Š, b ˆ 111.09(2)8, Vˆ
1447.1(5) Š3, Z ˆ 2, 1calcd ˆ 1.232 gcm 3, m ˆ 0.085 mm 1, MoKa radia-
tion (l ˆ 0.71073 Š). Data were collected up to 2q ˆ 528 (q-2q scans).
The structure was refined on 2823 reflections with positive F 2 values;
343 refined parameters; R1 ˆ 0.043, wR2 ˆ 0.110, GOF ˆ 1.051 for
2425 reflections with F > 4s(F) (R1 ˆ 0.076, wR2 ˆ 0.125, GOF ˆ 1.084
for all 3066 independent reflections). c) Crystal structure data for 3-
CA: C24H40O5 ´ C7H14N2O, crystal size 0.6  0.2  0.1, Tˆ 293 K,
monoclinic, space group P21, a ˆ 12.754(3), b ˆ 7.881(2), c ˆ
4172; c) R. R. Fraser, T. B. Grindley, S. Passannanti, Can. J. Chem.
1975, 53, 2473 ± 2480.
[13] A mixture of the complex (5 mg) and KBr (300 mg) was ground and
formed into a disk with a radius of 10 mm. The disk was rotated
around the optical axis, and the CD recordings were made for several
positions in order to check the reproducibility of the spectra. For
details of the experimental procedure, see also a) R. Kuroda, Y. Saito,
Bull. Chem. Soc. Jpn. 1976, 49, 433 ± 436; b) K. Rasmussen, N. Ch. P.
Hald, Acta Chem. Scand. Ser. A 1982, 36, 549 ± 554.
[14] L. Lunazzi, D. Macciantelli, J. Chem. Soc. Perkin Trans. 2 1981, 604 ±
609.
[15] a) G. V. Shustov, A. V. Kachanov, G. K. Kadorkina, R. G. Kostyanov-
sky, A. Rauk, J. Am. Chem. Soc. 1992, 114, 8257 ± 8262; b) G. V.
Shustov, A. Rauk, J. Am. Chem. Soc. 1995, 117, 928 ± 934.
[16] G. Snatzke, Angew. Chem. 1979, 91, 380; Angew. Chem. Int. Ed. Engl.
1979, 18, 363 ± 377.
16.355(3) Š, b ˆ 111.97(3)8, Vˆ 1524.5(6) Š3, Z ˆ 2, 1calcd
ˆ
1.200 gcm 3, m ˆ 0.655 mm 1, CuKa radiation (l ˆ 1.54178 Š). Data
were collected up to 2q ˆ 1408 (q-2q scans). The structure was refined
on 2534 reflections with positive F 2 values; 343 refined parameters;
R1 ˆ 0.041, wR2 ˆ 0.111, GOF ˆ 1.077 for 2340 reflections with F >
4s(F) (R1 ˆ 0.052, wR2 ˆ 0.122, GOF ˆ 1.084 for all 2639 independent
reflections). The guest N-nitroso group is disordered over two
positions. Restraints were imposed on 1 ± 2 and 1 ± 3 distances and
planarity of the N-nitrosamino group during refinement. d) Crystal
data for 1-DCA: 2C24H40O4 ´ C5H10N2O, crystal size 0.6 Â 0.45 Â
Total Synthesis of ( )-Strychnine via the
Wieland ± Gumlich Aldehyde**
Â
Daniel Sole, Josep Bonjoch,* Silvina García-Rubio,
Â
Emma Peidro, and Joan Bosch*
Strychnine, the most famous of the Strychnos alkaloids,[1] is
a natural product that has been known for a long time. Its
complex heptacyclic structure, which is assembled from only
24 skeletal atoms and contains six contiguous asymmetric
carbon atoms (five of which are in the core cyclohexane ring),
represents a permanent challenge for synthetic organic
chemists.[2] The classical, pioneering total synthesis by Wood-
ward et al.[3] remained the only synthesis of strychnine for
nearly 40 years, and five research groups have recently
reported new total syntheses of this alkaloid, either via
isostrychnine[4] or via the Wieland ± Gumlich aldehyde.[5]
However, only in one case has the enantioselective total
synthesis of the natural enantiomer, ( )-strychnine, been
achieved.[5c] The elegant enantioselective synthesis of ( )-
strychnine by Overman et al. takes advantage of the tandem
cationic aza-Cope rearrangement/Mannich cyclization strat-
egy for the construction of the basic skeleton of the alkaloid
andÐwith almost the same number of reaction steps as the
synthesis by Woodward et al.Ðupped the overall yield by a
factor of 105.
0.2 mm, Tˆ 130 K, orthorhombic, P212121, a ˆ 26.730(4), b ˆ
3
13.228(2), c ˆ 13.971(4) Š, Vˆ 4346(2) Š3, Z ˆ 4, 1calcd ˆ 1.209 gcm
,
m ˆ 0.081 mm 1, MoKa radiation (l ˆ 0.71073 Š). Data were collected
up to 2q ˆ 488 (w-q scans). The structure was refined on 4345
reflections with the positive F 2 values; 530 refined parameters; R1 ˆ
0.056, wR2 ˆ 0.132, GOF ˆ 1.070 for 3459 reflections with F > 4s(F)
(R1 ˆ 0.080, wR2 ˆ 0.148, GOF ˆ 1.073 for all 4347 independent
reflections). The guest molecule is disordered over three positions.
It was refined isotropically as a rigid body with molecular geometry
fitted to that of 1 in 1-CA. Sum of the occupancy factors was refined to
1.00 (0.55(1) for the pR isomer and 0.30(1) and 0.15(1) for the pS
isomer). e) Crystal structure data for 3-DCA: 2C24H40O4 ´ C7H14N2O,
crystal size 0.4  0.2  0.2 mm, Tˆ 130 K, orthorhombic, P212121, a ˆ
26.845(5), b ˆ 13.583(3), c ˆ 14.001(3) Š, Vˆ 5105(2) Š3, Z ˆ 4,
1calcd ˆ 1.206 gcm 3, m ˆ 0.080 mm 1, MoKa radiation (l ˆ 0.71073 Š).
Data were collected up to 2q ˆ 488 (w-q scans). The structure was
refined on 3661 reflections with the positive F 2 values; 539 refined
parameters; R1 ˆ 0.059, wR2 ˆ 0.147, GOF ˆ 1.013 for 2496 reflections
with F > 4s(F) (R1 ˆ 0.176, wR2 ˆ 0.200, GOF ˆ 1.094 for all 4485
independent reflections). The guest molecule was refined anisotropi-
cally, but disorder was suspected because of poor molecular geometry,
the shape of the elipsoids, and large residual peaks close to the N-
nitroso atom. Therefore, the geometry of the guest was fitted to that
found for 3 in the 3-CA complex. Subsequently, the guest molecule
was refined isotropically as a rigid body. Sum of the two occupancy
factors of the guest molecules was kept fixed at 1.0. The occupancy of
As the culmination of our studies on the synthesis of
Strychnos alkaloids,[6] we present here a new synthesis of ( )-
strychnine which proceeds via the Wieland ± Gumlich alde-
hyde and starts with 1,3-cyclohexanedione (the core ring E of
strychnine),[7] from which the pyrrolidine, piperidine, and
indoline rings are successively built in three well-differenti-
the higher populated
E stereoisomer was refined at 0.67(1).
f) Crystallographic data (excluding structure factors) for the structures
reported in this paper have been deposited with the Cambridge
Crystallographic Data Center as supplementary publication no.
CCDC-101943 ± CCDC-101947. Copies of the data can be obtained
free of charge on application to CCDC, 12 Union Road, Cambridge
CB21EZ, UK (fax: (‡44)1223-336-033; e-mail: deposit@ccdc.cam.
ac.uk).
Â
[*] Prof. Dr. J. Bonjoch, Prof. Dr. J. Bosch, Dr. D. Sole,
Â
Dr. S. García-Rubio, E. Peidro
Laboratory of Organic Chemistry, Faculty of Pharmacy
University of Barcelona
[10] E. L. Eliel, S. H. Wilen, Stereochemistry of Organic Compounds,
Wiley, New York, 1994, p. 1137 ± 1138.
[11] a) F. Johnson, S. K. Malhotra, J. Am. Chem. Soc. 1965, 87, 5492 ± 5493;
b) F. Johnson, Chem. Rev. 1968, 68, 375 ± 413; c) M. Gdaniec, M. J.
Av. Joan XXIII s/n, E-08028-Barcelona (Spain)
Fax : (‡ 34)93-4021896
E-mail: bonjoch@farmacia.far.ub.es
Â
Milewska, T. Poøonski, J. Org. Chem. 1995, 60, 7411 ± 7418.
[**] This work was supported by DGICYT, Spain (Projects PB94-0214 and
PB97-0877). Financial support for DGEU, Catalonia (1997SGR-0018
and 1997SGR-00166) is also acknowledged.
[12] a) Y. L. Chow, C. J. Colon, J. N. S. Tam, Can. J. Chem. 1968, 46, 2821 ±
2825; b) R. R. Fraser, T. B. Grindley, Tetrahedron Lett. 1974, 4169 ±
Angew. Chem. Int. Ed. 1999, 38, No. 3
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ated phases. This strategy has proved to be useful for the
synthesis of pentacyclic Strychnos alkaloids of the curan
type.[6d] The most remarkable aspects of the synthesis are
1) easy generation (in only four steps from 1,3-cyclohexane-
dione) of the first enantiopure intermediate, the 4-(2-nitro-
phenyl)octahydroindol-4-one 2, which contains the crucial
quaternary C7 center (Scheme 1); 2) closure of the piperidine
enone moiety, deprotection of the pyrrolidine nitrogen atom,
and finally alkylation of the resulting bicyclic secondary
amine with (Z)-1-bromo-4-[(tert-butyldimethylsilyl)oxy]-2-
iodobut-2-ene[9] led to the key intermediate 4.
It was our original hope that the closure of the piperidine
ring containing the ethylidene group and the introduction of
the functionalized one-carbon substituent at C16 could be
achieved in a palladium-catalyzed tandem process.[10] Disap-
pointingly, however, numerous attempts to promote the
tandem cyclization/carbonylation process (Pd catalyst, CO,
MeOH)[11] failed. Instead, the ester resulting from methoxy-
carbonylation of the initially formed vinyl palladium deriva-
tive was isolated.[12] In light of these results, we turned our
attention to a less direct strategy, in which cyclization and
introduction of the functionalized C17 carbon atom would be
achieved in two separate steps. After considerable exper-
imentation with racemic compounds, the best results for the
cyclization were obtained with Pd(OAc)2 (0.3 equiv) and PPh3
(0.6 equiv) as the catalyst in Et3N at 908C for a short time
(30 min). Under these conditions the tricyclic ketone 5 was
isolated in 53% yield. This key Heck-type cyclization takes
place in a reductive form, and is a variant of the Heck reaction
which has received comparatively little attention from a
synthetic standpoint.[13] Methoxycarbonylation of 5 with
LiHMDS (HMDS ˆ hexamethyldisilazane) and methyl cya-
noformate provided b-keto ester 6 (55% yield), a compound
containing all but the two acetate-derived carbon atoms of the
heptacyclic target molecule.
The synthesis of the Wieland ± Gumlich aldehyde from 6
only required closure of the indoline ring and reduction of the
ester functionality to an aldehyde. Treatment of 6 with zinc
dust in 10% sulfuric acid (in methanol) brought about both
the removal of the TBDMS protecting group and the
reductive cyclization of the a-(2-nitrophenyl) ketone moiety.
Under the reaction conditions the initially formed anilino-
acrylate intermediate undergoes further reduction to an
epimeric mixture of esters 7 and 8 (ratio approximately 9:1).
The mixture was equilibrated to pure 8, which has the natural
stereochemistry at C16, by treatment with NaH in refluxing
MeOH. The pentacyclic ester 8, which is also an intermediate
in the synthesis by Overman et al.,[5c] was isolated in 26%
overall yield from 6. Finally, further adjustment of the
oxidation level by partial reduction of ester 8 with DIBAH
(DIBAH ˆ diisobutylaluminum hydride) in toluene at 408C
afforded the Wieland ± Gumlich aldehyde.[14, 15]
Scheme 1. Synthesis of ( )-strychnine: a) 2-IC6H4NO2, K2CO3, DMSO,
ˆ
85 ± 908C, 72%; b) BrCH2CH CH2, K2CO3, acetone, reflux, 85%; c) tol-
uene, sealed tube, 180 ± 1908C, 80%; d) O3, CH2Cl2, 788C, then (S)-
PhCH(CH3)NH2 ´ HCl, NaBH3CN, iPrOH, 37%; e) ClCO2CHClMe,
1358C, 72%; f) HN(SiMe3)2, Me3SiI, CH2Cl2/pentane 1/1,
208C;
g) PhSeCl, (PhSe)2, THF, 70%; h) O3, CH2Cl2, 788C, then iPr2NH,
ˆ
72%; i) MeOH, reflux, then (Z)-BrCH2CI CHCH2OTBDMS, K2CO3, LiI,
CH3CN, 508C, 74%; j) Pd(OAc)2, PPh3, Et3N, 908C, 53%; k) LiN(SiMe3)2,
HMPA, THF, 788C, then NCCO2Me, 67%; l) Zn dust, H2SO4, MeOH,
reflux; m) NaH, MeOH, reflux, 26%; n) DIBAL, toluene, 408C, 65%;
o) CH2(CO2H)2, Ac2O, NaOAc, AcOH, 1108C, 49%. DMSO ˆ dimethyl
sulfoxide, HMPA ˆ hexamethyl phosphoramide, TBDMS ˆ tert-butyldi-
methylsilyl.
Although the conversion of the Wieland ± Gumlich alde-
hyde into strychnine was reported many years ago,[16] and
there would therefore seem to be little need to perform such a
conversion, for the sake of completion we followed the
described protocol, thus fulfilling the total synthesis of the
natural product. The resulting ( )-strychnine was identical to
a natural specimen, as determined by thin-layer chromatog-
ring by a Pd-catalyzed reaction (formation of the C15 C20
bond), which ensures the stereoselective incorporation of the
C20 E-configured double bond; and 3) closure of the indoline
ring in an advanced synthetic stage by reductive cyclization of
the a-(2-nitrophenyl) ketone moiety.
The chiral nonracemic cis-octahydroindolone 2 was pre-
pared as previously reported[6d] from the prochiral dione 1 by
a one-pot procedure consisting of an ozonolysis followed by a
double reductive amination with (S)-1-phenylethylamine as
the aminocyclization agent.[8] Removal of the a-phenylethyl
substituent via a carbamate followed by generation of the
1
raphy (TLC) as well as IR, H NMR, and 13C NMR spectro-
scopy. The [a]2D5 value was 119.4 (c ˆ 0.35, CHCl3; refer-
ence [16]: [a]2D5
ˆ
139 (c ˆ 2.0, CHCl3)), which represents
86% ee,[17] a value very similar to that obtained in our enan-
tioselective synthesis of ( )-tubifolidine from azabicycle 2.[6d]
We have accomplished a short enantioselective synthesis of
( )-strychnine (15 steps from commercially available 1,3-
396
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Angew. Chem. Int. Ed. 1999, 38, No. 3

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compound (<10%); b) R. Grigg, V. Santhakumar, V. Sridharan,
Tetrahedron Lett. 1993, 34, 3163 ± 3164.
cyclohexanedione), involving a transfer of chirality from (S)-
1-phenylethylamine to generate an enantiopure 3a-(2-nitro-
phenyl)hexahydroindol-4-one, from which the additional
rings of the target molecule are assembled with high stereo-
control. Taking into account our previous work,[6d] the strategy
developed here provides a general synthetic route for the
enantioselective synthesis of Strychnos alkaloids.
[13] a) In the Heck reaction with electron-deficient olefins, two competing
reaction pathways can operate, namely, substitution (which involves b-
H elimination) and 1,4-conjugate addition (which involves reduction
of the s-alkylpalladium intermediate); see, for example, G. K.
Friestad, B. P. Branchaud, Tetrahedron Lett. 1997, 38, 5933 ± 5936; H.
Hagiwara, Y. Eda, K. Morohashi, T. Suzuki, M. Ando, N. Ito,
Tetrahedron Lett. 1998, 39, 4055 ± 4058, and references therein; b) the
closure of the piperidine ring in the synthesis of strychnine by Rawal
and Iwasa[4b] involves a nonreductive intramolecular Heck reaction
from a tetracyclic ABCE intermediate.
Received: July 14, 1998 [Z12141IE]
German version: Angew. Chem. 1999, 111, 408 ± 410
[14] The chemical shifts of our synthetic sample were coincident with those
reported for a natural sample of the Wieland ± Gumlich aldehyde: G.
Keywords: alkaloids
heterocycles ´ palladium ´ total synthesis
´ asymmetric synthesis ´ nitrogen
Â
Â
Massiot, B. Massoussa, M.-J. Jacquier, P. Thepenier, L. Le Men-
Olivier, C. Delaude, R. Verpoorte, Phytochemistry 1988, 27, 3293 ±
3304.
[15] Starting from rac-4, which is prepared from the N-methyl analogue of
2,[6d] we have also completed the synthesis of the racemic Wieland ±
Gumlich aldehyde.
[16] F. A. L. Anet, R. Robinson, Chem. Ind. (London) 1953, 245.
[17] This ee value is in agreement with the optical purity of 2, which was
prepared from an (S)-1-phenylethylamine with about 96 %ee and
[1] a) U. Beifuss, Angew. Chem. 1994, 106, 1204 ± 1209; Angew. Chem. Int.
Ed. Engl. 1994, 33, 1144 ± 1149; b) ªMonoterpenoid Indole Alka-
loidsº: J. Sapi, G. Massiot in The Chemistry of Heterocyclic Com-
pounds, Suppl. to Vol. 25, Part 4 (Eds.: J. E. Saxton, E. C. Taylor),
Wiley, New York, 1994, pp. 279 ± 355; c) J. Bosch, J. Bonjoch, M. Amat
in The Alkaloids, Vol. 48 (Ed.: G. A. Cordell), Academic Press, New
York, 1996, pp. 75 ± 189; d) K. C. Nicolaou, E. J. Sorensen, Classics in
Total Synthesis, VHC, Weinheim, 1996, pp. 21 ± 40, 641 ± 653.
[2] Moreover, it remains to be of interest from a pharmacological point of
view; see, for example, P. Gharagozloo, M. Miyauchi, B. Birdsall,
N. J. M. Birdsall, J. Org. Chem. 1998, 63, 1974 ± 1980, and references
therein.
used as
a 97:3 mixture (according to HPLC analysis) of cis
diastereomers.
[3] R. B. Woodward, M. P. Cava, W. D. Ollis, A. Hunger, H. U. Daeniker,
K. Schenker, J. Am. Chem. Soc. 1954, 76, 4749 ± 4751; R. B. Wood-
ward, M. P. Cava, W. D. Ollis, A. Hunger, H. U. Daeniker, K.
Schenker, Tetrahedron 1963, 19, 247 ± 288.
[4] a) M. E. Kuehne, F. Xu, J. Org. Chem. 1993, 58, 7490 ± 7497; b) V. H.
Rawal, S. Iwasa, J. Org. Chem. 1994, 59, 2685 ± 2686; see also
reference [3].
[5] a) P. Magnus, M. Giles, R. Bonnert, C. S. Kim, L. McQuire, A. Merritt,
N. Vicker, J. Am. Chem. Soc. 1992, 114, 4403 ± 4405; P. Magnus, M.
Giles, R. Bonnert, G. Johnson, L. McQuire, M. Deluca, A. Merritt,
C. S. Kim, N. Vicker, J. Am. Chem. Soc. 1993, 115, 8116 ± 8129; b) G.
Stork, reported at the Ischia Advanced School of Organic Chemistry,
Ischia Porto, Italy, 1992; c) S. D. Knight, L. E. Overman, G.
Pairaudeau, J. Am. Chem. Soc. 1993, 115, 9293 ± 9294; S. D. Knight,
L. E. Overman, G. Pairaudeau, J. Am. Chem. Soc. 1995, 117, 5776 ±
5788.
Nickel-Catalyzed Homoallylation of Aldehydes
and Ketones with 1,3-Dienes and
Complementary Promotion by Diethylzinc
or Triethylborane**
Masanari Kimura, Hidetaka Fujimatsu, Akihiro Ezoe,
Kazufumi Shibata, Masamichi Shimizu, Satoru
Matsumoto, and Yoshinao Tamaru*
Allylation of carbonyl compounds is a fundamental process
in organic syntheses, and many efficient methodologies have
been developed.[1] Besides the allyl derivatives of alkali and
alkaline earth metals, those of transition metals[2] and metal-
loids (e.g., allylstannanes, -silanes, -boranes, etc.)[1] have been
utilized for the regio- and stereoselective allylation of
carbonyl compounds. Homoallylation could have similar
importance in organic transformations; however, this process
has received little attention, probably owing to the limited
[6] a) M. Amat, A. Linares, J. Bosch, J. Org. Chem. 1990, 55, 6299 ± 6312;
Á
b) J. Gracia, N. Casamitjana, J. Bonjoch, J. Bosch, J. Org. Chem. 1994,
59, 3939 ± 3951; c) M. Amat, M.-D. Coll, J. Bosch, E. Espinosa, E.
Molins, Tetrahedron: Asymmetry 1997, 8, 935 ± 948; d) J. Bonjoch, D.
Â
Sole, S. García-Rubio, J. Bosch, J. Am. Chem. Soc. 1997, 119, 7230 ±
7240.
[7] The numbering system and ring labeling used throughout this paper is
based on the biogenetic interrelationship of indole alkaloids: J.
Le Men, W. I. Taylor, Experientia 1965, 21, 508 ± 510.
[8] In a preliminary study, this amine proved to be the most efficient
chiral auxiliary for the enantioselective preparation of cis-3a-(2-
ˆ
variety of homoallylating agents CH2 CHCH2CH2M, which
are restricted to metals of high electropositivity such as Li and
Mg, since the polarity of homoallylic C M bonds is consid-
erably lower than that of allylic C M bonds.
Â
nitrophenyl)octahydroindol-4-ones: D. Sole, J. Bosch, J. Bonjoch,
Tetrahedron 1996, 52, 4013 ± 4028.
[9] This alkylating agent was prepared following the protocol by Rawal
By analogy with the stoichiometric homoallylation of
carbonyl compounds with [ZrCp2(1,3-diene)] (Cp ˆ cyclo-
and Iwasa.[4b]
[10] It was expected that the transient alkylpalladium intermediate arising
from the cyclization, which has no b-hydrogen atom available for b-
elimination, was stable enough to allow intermolecular trapping with
CO; for related processes, see R. Grigg, P. Kennewell, A. Teasdale,
Tetrahedron Lett. 1992, 33, 7789 ± 7792; E. Negishi, C. Coperet, S. Ma,
T. Mita, T. Sugihara, J. M. Tour, J. Am. Chem. Soc. 1996, 118, 5904 ±
5918.
[11] [Pd(PPh3)4], Pd(OAc)2, and [PdCl2(PPh3)2] were used as catalysts in
several solvents (C6H6, CH3CN, DMF, DMF/H2O) under a variety of
experimental conditions.
[*] Prof. Dr. Y. Tamaru, Dr. M. Kimura, H. Fujimatsu, A. Ezoe,
K. Shibata, M. Shimizu, S. Matsumoto
Department of Applied Chemistry, Faculty of Engineering
Nagasaki University
1-14 Bunkyo-machi, Nagasaki 852 ± 8521 (Japan)
Fax: (‡81)958-47-9008
E-mail: tamaru@net.nagasaki.u-ac.jp
[**] We thank Mr. Y. Ohhama, NMR Facility, for technical assistance.
Financial support by the Ministry of Education, Science, Sports and
Culture, Japanese Government, is gratefully acknowledged.
[12] a) When the reaction was carried out in the presence of the trapping
agent LiCN,[12b] the azatricyclic compound 5 was the only isolable
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