Assessment of Double-Barrelled Heck Cyclizations as a Means for Construction of the 14-Phenyl-8,9-dihydro-6H-[1]benzopyrano[4',3':4,5]pyrrolo[2,1-a]isoquinolin-6-one Core Associated with Certain Members of the Lamellarin Class of Marine Natural Product

Article abstract of DOI:10.1071/CH99021

The 1,2,4-trisubstituted pyrrole (4), which is readily prepared from pyrrole itself, undergoes double-barrelled Heck cyclizations to give, inter alia, compounds (3) and (17) for which crystal structures have been determined. Product (3) constitutes the co

Full text of DOI:10.1071/CH99021

C S I R O P U B L I S H I N G
Australian Journal
of Chemistry
Volume 52, 1999
© CSIRO Australia 1999
A journal for the publication of original research
in all branches of chemistry and chemical technology
w w w. p u b l i s h . c s i ro . a u / j o u rn a l s / a j c
All enquiries and manuscripts should be directed to
The Managing Editor
Australian Journal of Chemistry
CSIRO PUBLISHING
PO Box 1139 (150 Oxford St)
Collingwood
Vic. 3066
Australia
Telephone: 61 3 9662 7630
Facsimile: 61 3 9662 7611
Email: john.zdysiewicz@publish.csiro.au
Published by CSIRO PUBLISHING
for CSIRO Australia and
the Australian Academy of Science

Aust. J. Chem., 1998, 52, 755–765
.
Assessment of Double-Barrelled Heck Cyclizations as a
Means for Construction of the 14-Phenyl-8,9-dihydro-
6H -[1]benzopyrano[40,30:4,5]pyrrolo[2,1-a]isoquinolin-
6-one Core Associated with Certain Members of the
Lamellarin Class of Marine Natural Product†
Martin G. Banwell,A,B Bernard L. Flynn,A,C David C. R. Hockless,A
Robert W. Longmore A and A. David Rae A
A
Research School of Chemistry, Institute of Advanced Studies,
The Australian National University, Canberra, A.C.T. 0200.
B
To whom correspondence should be addressed.
Current address: Department of Chemistry, The Faculties,
C
The Australian National University, Canberra, A.C.T. 0200.
The 1,2,4-trisubstituted pyrrole (4), which is readily prepared from pyrrole itself, undergoes double-
barrelled Heck cyclizations to give, inter alia, compounds (3) and (17) for which crystal structures
have been determined. Product (3) constitutes the core associated with several key members, e.g. (1)
and (2), of the lamellarin class of marine alkaloid.
Introduction
non-cytotoxic concentrations.5 In this regard, lamel-
larin K is even more e ective than verapamil and,
thus, has considerable potential for resensitizing cancer
cells to various chemotherapeutic agents.5
Lamellarins K (1)1 and N (2)1 are representative
members of a small group of alkaloids that possess the
hexacyclic framework (3)‡ (Scheme 1).§ A number of
these natural products, which have been isolated from
a diverse range of marine organisms, show some rather
interesting biological activities. For example, lamellarin
N (2) has been identi ed4 as a type IV spindle toxin
while the tri-O-acetyl derivative of congener (1) shows
remarkable selectivity against the A549 human lung
Comprehensive investigations of the therapeutic
potential of compounds such as (1) and (2) require
access to gram quantities of material and the natural
sources are unlikely to be useful in this regard. Conse-
8
quently, several groups6 have focused on developing
total syntheses of various of the lamellarins as well as
certain related compounds. We have recently disclosed9
the rst total synthesis of lamellarin K which involved,
as the pivotal step, addition of an azomethine ylide to
cancer cell line (IC 0 005 mg/ml).5 Furthermore, like
a number of other lamellarins, compound (1) reverses
multidrug resistance in certain cell lines by inhibiting
P-glycoprotein mediated drug e ux and does so at
50
† The work described herein is the subject of a patent application (AIPO Patent O ce Provisional Application No. PP 4333/98,
lodged 24 November 1998).
‡ 14-Phenyl-8,9-dihydro-6H -[1]benzopyrano[40,30:4,5]pyrrolo[2,1-a]isoquinolin-6-one.
§ For other members of the lamellarin class which possess this or the corresponding fully unsaturated framework, see refs 1,2. A
number of lamellarins possessing simpler frameworks have been isolated (Urban et al.3), and some of these have been synthesized
(Banwell et al.3).
Manuscript received 18 February 1999
᭧ CSIRO 1999
0004-9425/98/080755$ 05.00
10.1071/CH99021

756
M. G. Banwell et al.
a tolan triple bond that are tethered to one another via
an ester linkage. This reaction resulted in construction
of the pyrrole core at a very late stage in the overall
synthesis. Herein, we report on the almost exact
opposite of this approach wherein the pyrrole core is in
place at the start of the synthesis and the remainder of
the lamellarin framework, as embodied in compound
(3), is built around this core by using Negishi and
double-barrelled Heck-type reactions to establish key
carbon–carbon bonds.
at 18 C and in this manner the desired substrate (4)
was obtained in 95% yield. There were no complications
associated with coupling between organometallic (15)
and the brominated carbon centres within compound
(14), and this result is testimony to the impressive
chemoselectivity usually encountered with the Negishi
cross-coupling reaction. The proposed structures of
compound (4) and all of its precursors were supported
by the acquisition of the usual range of spectral data
and substantiated through the X-ray crystallographic
studies (see below) of the products derived from the
foreshadowed Heck cyclization reactions.
Results and Discussion
(a) Retrosynthetic Analysis
The intramolecular Heck-type reactions of aryl bro-
mides tethered to other aromatic nuclei have provided
a useful means for the construction of various biaryl
linkages including those observed in a number of natural
products.10 The seminal contributions of Bringmann
and coworkers in this area11 serve to highlight the
utility of this strategy and prompted us to consider
such an approach for construction of the title frame-
work. In particular, we envisaged (Scheme 1) that the
C 13a/C 13b and C 14a/C 14b bonds within compound
(3) could be installed concurrently via double-barrelled
intramolecular Heck reactions involving a substrate
such as (4). During the course of the present study
Steglich and coworkers reported6 a novel variant on the
intramolecular Heck reaction which they used to estab-
lish the C 13a/C 13b bond of lamellarin G trimethyl
ether. However, to the best of our knowledge the
double-barrelled Heck reaction sequence outlined above
has not been employed for the construction of the title
framework.
(b) Construction of Cyclization Substrate (4)
The synthetic sequence leading to the cyclization
substrate (4) is shown in Scheme 2 and its imple-
mentation proved to be a relatively straightforward
matter. Thus, following the procedure de ned by Bai-
ley et al.12 pyrrole (5) was reacted with trichloroacetyl
chloride. The resulting 2-substituted pyrrole (6) (80%)
was treated with molecular iodine in the presence
of silver tri uoroacetate and the 4-iodinated product
(7)13 (82%) thereby obtained was hydrolysed with
potassium carbonate in aqueous dimethyl sulfoxide to
give the previously unreported acid (8) (92%). The
corresponding acid chloride (9) was readily prepared
by standard methods and reacted with o-bromophenol
(10) to give the expected ester (11) in 92% yield [from
(8)]. Treatment of this last compound with tosylate
(13), derived by standard methods from the commer-
cially available alcohol (12), resulted in alkylation at
nitrogen and formation of the trisubstituted pyrrole
(14) (89%) which contains the two tethered aryl bro-
mide units required for the projected double-barrelled
Heck cyclization studies. However, prior to conducting
such studies compound (14) was subjected to a Negishi
cross-coupling reaction14 with phenylzinc chloride (15)
(c) Cyclization Studies
Heck cyclization reactions of the type being con-
templated here (Scheme 1) are usually carried out at
elevated temperatures, often with dimethylformamide
as solvent and with sodium acetate as the base.10,11
The active Pd0 species is generated in situ from palla-
dium(II) acetate and triphenylphosphine. When such
conditions were applied to substrate (4) and reaction
temperatures of 135 C were employed (Scheme 3) then,
after 6 h, the only isolable species was the desired

Double-Barrelled Heck Cyclizations
757
double-barrelled cyclization product (3) although this
was obtained in rather low (16%) yield. In the 70
eV electron impact mass spectrum of compound (3)
the expected molecular ion was observed at m/z 363
but convincing spectroscopic characterization of this
material could not be obtained because the 1H and 13
C
n.m.r. spectra were rather non-descript. Consequently,
a single-crystal X-ray analysis of compound (3) was
undertaken (Fig. 1 and Tables 1–3) in order to provide
rigorous proof of structure. The poor yields obtained
when the conversion (4) → (3) was run under the
conditions de ned above prompted an examination of
the e ects of lower reaction temperatures. However,
when substrate (4) was reacted at 110 C for 19 h
the target compound was not observed, rather the
monocyclized materials (16) and (17) were obtained in
yields of 17% and 8 5%, respectively. The structure
of product (17) follows from an X-ray crystallographic
study (Fig. 2 and Tables 4–6) while the structure of
compound (16) derives from 1H n.m.r. spectroscopic
analysis. In particular, the up eld shift of the reso-
nances due to the methylene protons at C 9† ( 3 05)
relative to those of their counterparts in precursor (4)
substrate (4) in 4 : 1 diethyl ether/tetrahydrofuran
containing the much touted and readily prepared
Herrmann–Beller catalyst16 {trans-di( -acetato)bis[o-
(di-o-tolylphosphino)benzyl]dipalladium(II)} was main-
tained at 15 kbar (1 bar = 105 Pa) and 25 C for
20 h. Disappointingly, no reaction was observed
under these conditions. A related experiment using
1 : 3 tetrahydrofuran/acetonitrile as solvent and 10
kbar pressure was similarly unsuccessful. Use of
the same catalyst under more conventional conditions
(namely, dimethylformamide, sodium acetate, 130 C,
16 h) also failed to give any reaction. Similarly,
the palladium carbene complexes Pd(dmiy)2MeCl and
Pd(tmiy)2(NC)2C=C(CN)2, which have recently been
shown17 to be especially e ective catalysts for inter-
molecular Heck reactions, did not provide any useful con-
version of compound (4) into (3) when used at elevated
temperatures (110 C, N ,N -dimethylacetamide, sodium
acetate, 16 h) or pressures (15 kbar, 1 : 3 tetrahydro-
furan/acetonitrile, triethylamine, 16 h). The Je rey18
phase-transfer conditions for e ecting Heck-type reac-
tions were also investigated but no consumption of the
substrate (4) was observed under these types of condi-
tions. It has been reported19 that when triphenylarsine,
rather than triphenyphosphine, is used as a ligand for
palladium in various coupling processes, including the
Heck reaction,20 then large rate accelerations can be
observed. However, various e orts to apply such obser-
vations to the present case failed to provide a useful
outcome. In fact the only other interesting reaction of
compound (4) was observed when this material was
(
3 32) is taken as a re ection of the loss of the
bromine substituent in an ortho-relationship to the
carbon bearing these protons. This, in turn, implies
that the Heck reaction leading to compound (16) has
involved formation of the C 13a/13b rather than the
C 14a/14b bond. Con rmation of these arguments
follows from analysis of electron impact mass spectrum
of compound (16) which reveals the presence of a frag-
ment ion (base peak at m/z 272) corresponding to loss
of an o-bromophenoxy radical from the molecular ion.
This type of fragmentation process, which also features
signi cantly in the mass spectra of the precursors to
this compound, can be accommodated by structure
(16) but not the alternate mono-Heck-type product
derived from Pd0-mediated C 14a/C 14b bond closure
within substrate (4). These results clearly suggest
that Heck-type cyclization to form the C 13a/C 13b
bond is more facile than the analogous process in
which the C 14a/C 14b bond is produced. The rate
of formation of the latter bond may be slowed by
unfavourable rotamer populations about the ‘doubly
vinylogous’ carbamate-type linkage within compounds
such as (17) and/or poor orbital overlap associated
with the 6-endo-trig-type ring closure that could be
involved in converting this material into target (3)‡.
In an e ort to improve the yield of compound (3)
derived from precursor (4) several modi cations to
the standard conditions employed in Heck reactions
were explored. For example, since various workers
have shown15 that the Heck reaction is promoted
by the application of high pressures, a solution of
† In order to facilitate structural comparisons, throughout the Results and Discussion section of this paper the lamellarin
numbering scheme [see structure (3)] is used for compounds (1), (3), (4) and (16)–(19).
‡ Thus far, the question of whether the cyclization processes described herein follow the classic Heck pathway or one involving
PdIV-pallacyclic intermediates remains unanswered.

758
M. G. Banwell et al.
treated, in the presence of sodium acetate, with the
Herrmann–Beller catalyst in N ,N -dimethylacetamide
at 115–140 C. Under these conditions (Scheme 3) a
1 : 3 mixture of compounds (18) and (19) (52% com-
between the latter protons supports the illustrated
structure for compound (18) but not the isomeric one
in which the phenyl substituent is attached at C 14a.
Further con rmation of the gross structures assigned
to compounds (18) and (19) followed from g.l.c./m.s.
studies which revealed that the chromatographically
more mobile compound [(18)] has a molecular ion at
m/z 245 while the other [(19)] has a pair of equal
intensity molecular ions at m/z 327 and 325. However,
additional characterization of these compounds was
not undertaken because of their instabilities and our
inability to readily separate them on a preparative
scale.
1
bined yield) was observed. In the 300 MHz H n.m.r.
spectrum of this mixture the resonances due to the
three pyrrolic protons associated with compound (19)
were readily discerned as were those due the vici-
nally related and mutually coupled protons attached
to the ve-membered ring within compound (18).
The magnitude (J 2 7 Hz) of the spin–spin coupling
Table 1. Final fractional atomic coordinates and equivalent
isotropic displacement factors (A2) for (3), C25H17NO2
In Tables 1–6, estimated standard deviations are given in
parentheses
8
3
Beq
=
2[U 11(aa*)2+U 22(bb*)2+
U
33(cc*)2+2U 12(aa*bb*)cos
2U 13(aa*cc*)cos +2U 23(bb*cc*)cos
+
]
Atom
x
y
z
Beq
O(5A)
O(6A)
N(7A)
0 0947(2)
0 0266(3)
0 2294(3)
0 0432(4)
0 3437(4)
0 0640(5)
0 3411(4)
0 1754(4)
0 4109(4)
0 0767(4)
0 1839(4)
0 4862(4)
0 4905(4)
0 1202(4)
0 0017(4)
0 4191(4)
0 2501(4)
0 3589(4)
0 4687(4)
0 5857(4)
0 6866(4)
0 6702(4)
0 5530(4)
0 4500(4)
0 3240(4)
0 2734(4)
0 1444(4)
0 0394(4)
0 2769(4)
0 0265(3)
0 3541(4)
0 0114(4)
0 4769(4)
0 1102(4)
0 4484(4)
0 5260(4)
0 1731(4)
0 5076(2)
0 1360(4)
0 3216(4)
0 5129(3)
0 4491(4)
0 0359(4)
0 2422(3)
0 2696(4)
0 1885(4)
0 0557(4)
0 0384(5)
0 1595(4)
0 1889(4)
0 0972(4)
0 0252(4)
0 1265(4)
0 1314(4)
0 2553(3)
0 3239(4)
0 0979(3)
0 0388(3)
0 0860(3)
0 2297(4)
0 2081(4)
0 2531(5)
0 1512(4)
0 2227(5)
0 1908(4)
0 1487(4)
0 1705(4)
0 2884(4)
0 3458(4)
0 1005(4)
0 0758(4)
0 3070(4)
0 0304(4)
0 0899(4)
0 0892(4)
0 0715(4)
0 0759(4)
0 0955(4)
0 1099(4)
0 1082(4)
0 1213(4)
0 1604(4)
0 1465(4)
0 1751(4)
0 2287(4)
0 2851(4)
0 1860(4)
0 3434(4)
0 2180(4)
0 3023(4)
0 3252(4)
0 2881(4)
0 2041(4)
0 3874(3)
0 1441(4)
0 3895(4)
0 4589(3)
0 4142(4)
0 1844(4)
0 4087(3)
0 4604(4)
0 4010(4)
0 4037(4)
0 4189(4)
0 4209(4)
0 4094(4)
0 3960(4)
0 3910(4)
0 3739(4)
0 3306(4)
0 3398(4)
0 3001(4)
0 0482(1)
0 1218(1)
0 1065(1)
0 0469(2)
0 0041(1)
0 0790(2)
0 0389(1)
0 0689(2)
0 0710(1)
0 0056(1)
0 0267(2)
0 0600(2)
0 0175(2)
0 0756(1)
0 0859(2)
0 0143(1)
0 1537(1)
0 1841(1)
0 1605(1)
0 1860(2)
0 1642(2)
0 1158(2)
0 0894(2)
0 1111(1)
0 0848(1)
0 0390(1)
0 0337(1)
0 0035(1)
0 2894(1)
0 2448(1)
0 3180(1)
0 2879(1)
0 3102(2)
0 3206(1)
0 2419(1)
0 2717(2)
0 3110(2)
0 2017(1)
0 2682(2)
0 1735(1)
0 1295(1)
0 1643(1)
0 2354(1)
0 1427(1)
0 0948(1)
0 0655(2)
0 0894(2)
0 0640(2)
0 0867(2)
0 1355(2)
0 1613(2)
0 1389(2)
0 1642(1)
0 2094(1)
0 2145(1)
0 2501(1)
3 21(7)
3 67(8)
2 60(8)
3 4(1)
2 8(1)
4 3(1)
3 2(1)
4 3(1)
3 4(1)
3 1(1)
3 9(1)
3 3(1)
3 3(1)
2 6(1)
3 0(1)
3 1(1)
3 2(1)
3 2(1)
2 8(1)
3 2(1)
3 5(1)
3 4(1)
3 2(1)
2 7(1)
2 6(1)
2 6(1)
2 5(1)
2 9(1)
3 0(1)
2 7(1)
3 5(1)
3 1(1)
3 7(1)
3 3(1)
2 8(1)
3 3(1)
3 3(1)
3 29(8)
3 5(1)
2 5(1)
3 67(8)
2 8(1)
3 0(1)
2 63(8)
3 1(1)
3 7(1)
3 2(1)
4 0(1)
4 4(1)
4 3(1)
3 6(1)
2 9(1)
2 6(1)
2 7(1)
2 46(9)
2 6(1)
C(1A)
C(10A)
C(2A)
C(20A)
C(3A)
C(30A)
C(4aA)
C(4A)
C(40A)
C(50A)
C(6aA)
C(6A)
C(60A)
C(8A)
C(9A)
Fig. 1. ORTEP derived from X-ray crystallographic structure
analysis of compound (3).
C(9aA)
C(10A)
C(11A)
C(12A)
C(13A)
C(13aA)
C(13bA)
C(14A)
C(14aA)
C(14bA)
C(1B)
Table 2. Bond lengths (A) for (3), C25H17NO2
Atoms
Distance
Atoms
Distance
O(5A)–C(4aA)
O(6A)–C(6A)
N(7A)–C(8A)
1 398(5)
1 208(5)
1 472(5)
1 382(6)
1 388(5)
1 480(5)
1 383(6)
1 384(6)
1 390(5)
1 384(6)
1 381(5)
1 497(6)
1 410(5)
1 384(6)
1 398(5)
1 398(5)
1 459(5)
1 403(6)
1 385(5)
1 383(6)
1 384(6)
1 386(5)
1 383(5)
1 388(5)
1 413(5)
1 383(5)
1 471(5)
1 499(6)
1 390(6)
1 374(6)
1 373(6)
1 457(5)
1 409(5)
O(5A)–C(6A)
1 390(5)
1 366(5)
1 375(5)
1 398(6)
1 393(6)
1 364(7)
1 367(6)
1 382(6)
1 376(6)
1 424(5)
1 504(6)
1 376(5)
1 381(6)
1 381(6)
1 463(5)
1 416(5)
1 379(6)
1 395(5)
1 482(5)
1 379(6)
1 366(6)
1 402(5)
1 395(6)
1 388(6)
1 376(5)
1 218(5)
1 370(5)
1 499(6)
1 405(6)
1 383(6)
1 386(6)
1 398(5)
1 455(5)
N(7A)–C(6aA)
N(7A)–C(13bA)
C(1A)–C(14bA)
C(10A)–C(60A)
C(2A)–C(3A)
C(1A)–C(2A)
C(10A)–C(20A)
C(10A)–C(14A)
C(20A)–C(30A)
C(30A)–C(40A)
C(4aA)–C(14bA)
C(50A)–C(60A)
C(6aA)–C(14aA)
C(9A)–C(9aA)
C(9aA)–C(13aA)
C(11A)–C(12A)
C(13A)–C(13aA)
C(13bA)–C(14A)
C(14aA)–C(14bA)
C(1B)–C(14bB)
C(10B)–C(60B)
C(2B)–C(3B)
C(10B)
C(2B)
C(3A)–C(4A)
C(4aA)–C(4A)
C(40A)–C(50A)
C(6aA)–C(6A)
C(8A)–C(9A)
C(9aA)–C(10A)
C(10A)–C(11A)
C(12A)–C(13A)
C(13aA)–C(13bA)
C(14A)–C(14aA)
C(1B)–C(2B)
C(20B)
C(3B)
C(30B)
C(4aB)
C(4B)
C(40B)
O(5B)
C(50B)
C(6aB)
O(6B)
C(10B)–C(20B)
C(10B)–C(14B)
C(20B)–C(30B)
C(30B)–C(40B)
C(4aB)–O(5B)
C(40B)–C(50B)
C(50B)–C(60B)
C(6aB)–N(7B)
O(6B)–C(6B)
N(7B)–C(13bB)
C(9B)–C(9aB)
C(9aB)–C(13aB)
C(11B)–C(12B)
C(13B)–C(13aB)
C(13bB)–C(14B)
C(14aB)–C(14bB)
C(6B)
C(60B)
N(7B)
C(8B)
C(3B)–C(4B)
C(4aB)–C(4B)
C(4aB)–C(14bB)
O(5B)–C(6B)
C(6aB)–C(6B)
C(6aB)–C(14aB)
N(7B)–C(8B)
C(9B)
C(9aB)
C(10B)
C(11B)
C(12B)
C(13B)
C(13aB)
C(13bB)
C(14B)
C(14aB)
C(14bB)
C(8B)–C(9B)
C(9aB)–C(10B)
C(10B)–C(11B)
C(12B)–C(13B)
C(13aB)–C(13bB)
C(14B)–C(14aB)

Double-Barrelled Heck Cyclizations
759
The formation of compound (18) can be rational-
ized by invoking initial conversion of precursor (4)
into compound (17) which experiences extrusion of
benzyne and concomitant migration of palladium from
carbon to oxygen with the resulting formation of a
palladium(II) carboxylate. Like other metal salts of
pyrrole-2-carboxylic acids,21 this latter species might
be expected to undergo thermally promoted decar-
boxylation so as to give, after protonation, product
(18). It is also conceivable that the above-mentioned
palladium(II) carboxylate could be generated by simple
hydrolysis of the ester linkage within a compound such
as (16). Clearly, the production of compound (19)
would likely involve the same sorts of reactions (except
for the initial Heck process) as suggested above to
account for the formation of co-product (18).
Conclusion
The work described herein suggests that the title
reactions could provide a useful and rapid means for
assembling the hexacyclic framework associated with
certain members of the lamellarin class of marine nat-
ural product. Indeed, the synthetic sequence leading
to the cyclization precursor (4) is an especially e cient
one and should be capable of ready adaptation to the
construction of highly oxygenated analogues as would
be required for synthesis of the lamellarins themselves.
However, the modest yields associated with the pivotal
Table 3. Bond angles (degrees) for (3), C25H17NO2
Angle Atoms
122 6(3) C(6aA)–N(7A)–C(8A)
Atoms
Angle
C(4aA)–O(5A)–C(6A)
C(6aA)–N(7A)–C(13bA)
C(2A)–C(1A)–C(14bA)
C(20A)–C(10A)–C(14A)
C(1A)–C(2A)–C(3A)
127 9(3)
122 8(3)
118 0(4)
121 5(4)
121 4(4)
119 7(4)
122 8(4)
118 5(4)
120 4(4)
108 5(4)
116 2(4)
129 9(4)
108 0(3)
121 6(4)
120 1(4)
119 8(4)
120 9(4)
118 6(4)
118 0(4)
133 7(4)
128 1(4)
107 9(3)
134 5(4)
126 6(4)
120 2(4)
120 6(4)
120 8(4)
120 3(4)
114 3(4)
122 6(4)
119 8(4)
120 0(4)
126 2(4)
114 0(4)
129 7(4)
128 3(3)
123 0(3)
111 9(4)
119 2(4)
121 0(5)
120 1(4)
119 4(4)
123 4(4)
108 7(3)
126 5(4)
106 3(3)
117 4(4)
117 5(4)
116 9(4)
109 0(3)
120 8(4)
120 5(4)
120 4(5)
121 0(4)
114 4(4)
122 8(4)
119 7(4)
125 2(4)
126 3(4)
113 8(4)
120 7(4)
111 4(4)
118 4(4)
120 9(4)
120 0(4)
118 2(4)
123 1(4)
108 3(3)
125 6(4)
106 3(3)
117 5(4)
116 6(4)
116 8(4)
118 9(4)
120 5(4)
120 7(4)
120 4(4)
123 1(4)
118 0(4)
122 2(3)
125 7(4)
108 1(3)
116 3(4)
120 2(4)
108 7(3)
107 8(4)
122 0(4)
118 9(4)
119 9(4)
120 7(5)
117 2(4)
118 6(4)
132 6(4)
127 2(4)
108 1(4)
134 2(4)
125 4(4)
C(8A)–N(7A)–C(13bA)
C(20A)–C(10A)–C(60A)
C(60A)–C(10A)–C(14A)
C(10A)–C(20A)–C(30A)
C(20A)–C(30A)–C(40A)
O(5A)–C(4aA)–C(14bA)
C(3A)–C(4A)–C(4aA)
C(40A)–C(50A)–C(60A)
N(7A)–C(6aA)–C(14aA)
O(5A)–C(6A)–O(6A)
C(2A)–C(3A)–C(4A)
O(5A)–C(4aA)–C(4A)
C(4A)–C(4aA)–C(14bA)
C(30A)–C(40A)–C(50A)
N(7A)–C(6aA)–C(6A)
C(6A)–C(6aA)–C(14aA)
O(5A)–C(6A)–C(6aA)
C(10A)–C(60A)–C(50A)
C(8A)–C(9A)–C(9aA)
C(9A)–C(9aA)–C(13aA)
C(9aA)–C(10A)–C(11A)
C(11A)–C(12A)–C(13A)
C(9aA)–C(13aA)–C(13A)
C(13A)–C(13aA)–C(13bA)
N(7A)–C(13bA)–C(14A)
C(10A)–C(14A)–C(13bA)
C(13bA)–C(14A)–C(14aA)
C(6aA)–C(14aA)–C(14bA)
C(1A)–C(14bA)–C(4aA)
C(4aA)–C(14bA)–C(14aA)
C(20B)–C(10B)–C(60B)
C(60B)–C(10B)–C(14B)
C(10B)–C(20B)–C(30B)
C(20B)–C(30B)–C(40B)
C(4B)–C(4aB)–C(14bB)
C(3B)–C(4B)–C(4aB)
C(4aB)–O(5B)–C(6B)
C(6B)–C(6aB)–N(7B)
N(7B)–C(6aB)–C(14aB)
O(5B)–C(6B)–O(6B)
O(6A)–C(6A)–C(6aA)
N(7A)–C(8A)–C(9A)
C(9A)–C(9aA)–C(10A)
C(10A)–C(9aA)–C(13aA)
C(10A)–C(11A)–C(12A)
C(12A)–C(13A)–C(13aA)
C(9aA)–C(13aA)–C(13bA)
N(7A)–C(13bA)–C(13aA)
C(13aA)–C(13bA)–C(14A)
C(10A)–C(14A)–C(14aA)
C(6aA)–C(14aA)–C(14A)
C(14A)–C(14aA)–C(14bA)
C(1A)–C(14bA)–C(14aA)
C(2B)–C(1B)–C(14bB)
C(20B)–C(10B)–C(14B)
C(1B)–C(2B)–C(3B)
C(2B)–C(3B)–C(4B)
C(4B)–C(4aB)–O(5B)
O(5B)–C(4aB)–C(14bB)
C(30B)–C(40B)–C(50B)
C(40B)–C(50B)–C(60B)
C(6B)–C(6aB)–C(14aB)
O(5B)–C(6B)–C(6aB)
C(6aB)–C(6B)–O(6B)
C(6aB)–N(7B)–C(8B)
C(8B)–N(7B)–C(13bB)
C(8B)–C(9B)–C(9aB)
C(9B)–C(9aB)–C(13aB)
C(9aB)–C(10B)–C(11B)
C(11B)–C(12B)–C(13B)
C(9aB)–C(13aB)–C(13B)
C(13B)–C(13aB)–C(13bB)
N(7B)–C(13bB)–C(14B)
C(10B)–C(14B)–C(13bB)
C(13bB)–C(14B)–C(14aB)
C(6aB)–C(14aB)–C(14bB)
C(1B)–C(14bB)–C(4aB)
C(4aB)–C(14bB)–C(14aB)
C(10B)–C(60B)–C(50B)
C(6aB)–N(7B)–C(13bB)
N(7B)–C(8B)–C(9B)
C(9B)–C(9aB)–C(10B)
C(10B)–C(9aB)–C(13aB)
C(10B)–C(11B)–C(12B)
C(12B)–C(13B)–C(13aB)
C(9aB)–C(13aB)–C(13bB)
N(7B)–C(13bB)–C(13aB)
C(13aB)–C(13bB)–C(14B)
C(10B)–C(14B)–C(14aB)
C(6aB)–C(14aB)–C(14B)
C(14B)–C(14aB)–C(14bB)
C(1B)–C(14bB)–C(14aB)

760
M. G. Banwell et al.
Table 4. Final fractional atomic coordinates and equivalent isotropic displacement factors (A2) for (17),
61H48BrNO2P2Pd.C4H10
C
O
Atom
x
y
z
Uiso
Atom
x
y
z
Uiso
Pd(1A)
Br(1A)
C1(4bA)
C(1A)
C(2A)
C(3A)
C(4A)
C(4aA)
O(5A)
C(6A)
0 7099(1)
0 7760(2)
0 6579(9)
0 6033(9)
0 5655(9)
0 5851(10)
0 6399(10)
0 6747(10)
0 7288(6)
0 7512(10)
0 7241(6)
0 8078(9)
0 8410(7)
0 8243(9)
0 8656(9)
0 9202(9)
0 9584(10)
1 0120(9)
1 0278(8)
0 9901(7)
0 9361(8)
0 8941(8)
0 8967(9)
0 8410(9)
0 9586(9)
1 0039(10)
1 0322(11)
1 0155(9)
0 9711(8)
0 9436(9)
0 6913(3)
0 7437(4)
0 7944(4)
0 8345(5)
0 8250(7)
0 7748(8)
0 7345(6)
0 6293(4)
0 6268(6)
0 5793(7)
0 5333(6)
0 5354(4)
0 5828(4)
0 6820(3)
0 6889(7)
0 6818(8)
0 6676(6)
0 6606(8)
0 6677(7)
0 7213(3)
0 7865(4)
0 8325(4)
0 8825(4)
0 8876(6)
0 8420(6)
0 7920(5)
0 6811(4)
0 6906(7)
0 6598(8)
0 6188(7)
0 6091(7)
0 6398(5)
0 7051(4)
0 7381(6)
0 7256(8)
0 6801(8)
0 6471(7)
0 6594(6)
0 2175(1)
0 2884(2)
0 1649(9)
0 1102(9)
0 0720(9)
0 0912(10)
0 1461(10)
0 1813(10)
0 2358(6)
0 2256(2)
0 2648(3)
0 1970(6)
0 1907(11)
0 1701(14)
0 1560(11)
0 1621(11)
0 1822(9)
0 1892(11)
0 2533(13)
0 3094(10)
0 2458(12)
0 3025(11)
0 3816(15)
0 3640(18)
0 3577(11)
0 3923(14)
0 3839(15)
0 3408(16)
0 3059(14)
0 3143(10)
0 2760(13)
0 1992(13)
0 1834(13)
0 0452(19)
0 0005(23)
0 0472(21)
0 1442(25)
0 2002(20)
0 1465(14)
0 4111(6)
0 4747(7)
0 4276(13)
0 4765(17)
0 5733(16)
0 6208(14)
0 5722(11)
0 4354(6)
0 4267(13)
0 4453(15)
0 4730(13)
0 4818(16)
0 4633(14)
0 4890(7)
0 6018(8)
0 6614(11)
0 6098(14)
0 4978(15)
0 4379(11)
0 0370(6)
0 0213(7)
0 0426(12)
0 0023(16)
0 1117(15)
0 1759(13)
0 1314(9)
0 0559(7)
0 0700(13)
0 1413(15)
0 2000(12)
0 1865(13)
0 1154(11)
0 0096(6)
0 0563(12)
0 0771(15)
0 0327(14)
0 0329(16)
0 0540(13)
0 1460(2)
0 2354(3)
0 0692(12)
0 0847(14)
0 0294(16)
0 0424(15)
0 0590(14)
0 0036(13)
0 0133(11)
0 2219(1)
0 1796(1)
0 2556(6)
0 2419(6)
0 2661(7)
0 3048(7)
0 3190(6)
0 2945(6)
0 3061(4)
0 3345(5)
0 3509(4)
0 3421(4)
0 3697(4)
0 3967(6)
0 4345(5)
0 4336(4)
0 4627(5)
0 4601(6)
0 4284(6)
0 3991(5)
0 4017(5)
0 3694(5)
0 3408(4)
0 3245(5)
0 3423(6)
0 3299(7)
0 3073(6)
0 2959(7)
0 3056(6)
0 3292(4)
0 2274(2)
0 2605(3)
0 2690(5)
0 2944(5)
0 3119(4)
0 3035(5)
0 2782(4)
0 2442(2)
0 2822(3)
0 2950(4)
0 2702(5)
0 2323(5)
0 2194(4)
0 1844(3)
0 1851(4)
0 1521(4)
0 1178(4)
0 1168(3)
0 1497(3)
0 2160(2)
0 2325(2)
0 2360(5)
0 2486(5)
0 2581(4)
0 2546(5)
0 2420(5)
0 2381(3)
0 2769(3)
0 2938(5)
0 2724(6)
0 2338(6)
0 2167(4)
0 1662(3)
0 1486(3)
0 1105(4)
0 0892(3)
0 1064(3)
0 1445(3)
0 5002(1)
0 4708(1)
0 5252(5)
0 5140(5)
0 5320(6)
0 5618(6)
0 5734(6)
0 5552(5)
0 5645(3)
0 035(0)
0 080(1)
0 030(6)
0 039(6)
0 046(7)
0 042(6)
0 040(6)
0 035(6)
0 038(4)
0 040(3)
0 042(3)
0 041(3)
0 044(3)
0 050(3)
0 053(3)
0 054(4)
0 060(5)
0 061(5)
0 056(5)
0 051(4)
0 049(3)
0 045(3)
0 043(3)
0 040(3)
0 093(6)
0 137(15)
0 150(22)
0 140(19)
0 096(8)
0 056(4)
0 033(3)
0 040(3)
0 055(6)
0 075(10)
0 077(10)
0 067(9)
0 050(5)
0 037(3)
0 040(4)
0 048(7)
0 059(10)
0 060(8)
0 047(4)
0 037(3)
0 047(5)
0 058(9)
0 059(7)
0 055(5)
0 044(3)
0 040(3)
0 043(3)
0 052(5)
0 060(7)
0 060(6)
0 057(6)
0 049(5)
0 045(3)
0 054(4)
0 069(6)
0 074(9)
0 065(9)
0 051(5)
0 044(3)
0 051(5)
0 063(10)
0 068(11)
0 063(9)
0 051(5)
0 034(1)
0 072(1)
0 036(8)
0 039(8)
0 044(8)
0 046(7)
0 045(7)
0 040(7)
0 042(4)
C(6B)
O(6B)
C(6aB)
N(7B)
C(8B)
0 2609(10)
0 2364(6)
0 3171(9)
0 3527(7)
0 3395(9)
0 3899(7)
0 4387(8)
0 4779(10)
0 5255(9)
0 5343(8)
0 4956(7)
0 4475(8)
0 4045(8)
0 4037(9)
0 3474(9)
0 4836(8)
0 5232(9)
0 5272(10)
0 4903(10)
0 4481(9)
0 4465(9)
0 2012(3)
0 2543(4)
0 3022(4)
0 3429(5)
0 3367(6)
0 2892(7)
0 2484(6)
0 1409(4)
0 0936(4)
0 0475(4)
0 0474(6)
0 0942(7)
0 1404(6)
0 1854(3)
0 1653(8)
0 1532(9)
0 1609(7)
0 1808(8)
0 1930(7)
0 2210(3)
0 2826(4)
0 3316(4)
0 3788(4)
0 3782(6)
0 3297(7)
0 2824(5)
0 1712(4)
0 1775(7)
0 1393(8)
0 0940(7)
0 0874(6)
0 1255(5)
0 2079(4)
0 2426(6)
0 2325(8)
0 1875(8)
0 1528(8)
0 1627(6)
0 3809(9)
0 4350(10)
0 4749(13)
0 5279(12)
0 5412(9)
0 5018(7)
0 4484(8)
0 4409(34)
0 4733(29)
0 4584(23)
0 4521(28)
0 4973(37)
1 0154(31)
0 9678(29)
0 9459(21)
0 8974(30)
0 8883(34)
0 1096(18)
0 1920(12)
0 1009(16)
0 1867(14)
0 3037(18)
0 3614(9)
0 3398(7)
0 4169(16)
0 3904(20)
0 2865(21)
0 2084(18)
0 2351(15)
0 1494(15)
0 0352(16)
0 0094(17)
0 0644(18)
0 1430(20)
0 1983(21)
0 1762(18)
0 1002(17)
0 0457(15)
0 0219(5)
0 0771(7)
0 0644(12)
0 1403(15)
0 2305(13)
0 2439(11)
0 1682(9)
0 0572(7)
0 0289(12)
0 0896(15)
0 1796(13)
0 2083(11)
0 1479(9)
0 0891(8)
0 1951(10)
0 2465(14)
0 1932(16)
0 0878(17)
0 0362(12)
0 2855(5)
0 3154(6)
0 2787(13)
0 3017(16)
0 3617(14)
0 3985(15)
0 3757(13)
0 2736(6)
0 1990(12)
0 1900(15)
0 2553(15)
0 3298(16)
0 3390(13)
0 4030(8)
0 4920(9)
0 5820(10)
0 5853(11)
0 4973(13)
0 4071(11)
0 3692(9)
0 3417(8)
0 4168(19)
0 3844(24)
0 2764(26)
0 2003(21)
0 2329(16)
0 1033(63)
0 1897(62)
0 2843(44)
0 3863(59)
0 4263(59)
0 0537(78)
0 0387(60)
0 1360(54)
0 1391(64)
0 2258(75)
0 5656(3)
0 5573(3)
0 5774(3)
0 5810(3)
0 5736(4)
0 5647(5)
0 5877(5)
0 5963(6)
0 6194(6)
0 6339(6)
0 6256(5)
0 6024(3)
0 5931(3)
0 5976(3)
0 5873(3)
0 5871(7)
0 6003(8)
0 6315(6)
0 6515(8)
0 6423(7)
0 6093(4)
0 4507(2)
0 4528(2)
0 4780(4)
0 4795(5)
0 4561(5)
0 4311(5)
0 4294(4)
0 4498(2)
0 4259(4)
0 4252(5)
0 4483(5)
0 4722(5)
0 4729(4)
0 4058(3)
0 4030(4)
0 3685(5)
0 3361(4)
0 3385(3)
0 3730(3)
0 5446(2)
0 5761(3)
0 5684(4)
0 5926(5)
0 6250(5)
0 6329(4)
0 6087(3)
0 5745(3)
0 6040(4)
0 6269(4)
0 6208(5)
0 5916(6)
0 5686(5)
0 5144(3)
0 5186(4)
0 4954(5)
0 4675(4)
0 4631(4)
0 4862(4)
0 6026(5)
0 6078(6)
0 6171(11)
0 6219(14)
0 6175(13)
0 6082(9)
0 6033(5)
0 4800(21)
0 4804(22)
0 4937(14)
0 5026(23)
0 5055(25)
0 1817(31)
0 1684(31)
0 1578(20)
0 1374(29)
0 1385(32)
0 044(4)
0 048(4)
0 046(4)
0 050(4)
0 060(4)
0 071(5)
0 068(5)
0 078(6)
0 074(7)
0 064(6)
0 057(5)
0 057(4)
0 052(4)
0 051(4)
0 048(4)
0 089(11)
0 107(14)
0 112(14)
0 097(11)
0 078(8)
0 073(8)
0 035(3)
0 039(3)
0 044(4)
0 054(7)
0 059(10)
0 056(8)
0 045(4)
0 038(3)
0 043(4)
0 051(9)
0 054(12)
0 049(9)
0 042(4)
0 041(3)
0 058(7)
0 077(11)
0 075(13)
0 062(13)
0 048(7)
0 040(3)
0 044(3)
0 049(3)
0 060(5)
0 068(8)
0 061(7)
0 050(4)
0 045(3)
0 056(3)
0 072(5)
0 075(8)
0 067(9)
0 053(5)
0 043(3)
0 046(4)
0 053(8)
0 060(10)
0 060(8)
0 051(4)
0 065(6)
0 064(5)
0 074(7)
0 073(7)
0 067(6)
0 061(5)
0 057(4)
0 447(32)
0 447(32)
0 447(32)
0 447(32)
0 447(32)
0 511(48)
0 511(48)
0 511(48)
0 511(48)
0 511(48)
C(9B)
C(9aB)
C(10B)
C(11B)
C(12B)
C(13B)
C(13aB)
C(13bB)
C(14B)
C(14aB)
C(10B)
C(20B)
C(30B)
C(40B)
C(50B)
C(60B)
P(1B)
C(15B)
C(16B)
C(17B)
C(18B)
C(19B)
C(20B)
C(21B)
C(22B)
C(23B)
C(24B)
C(25B)
C(26B)
C(27B)
C(28B)
C(29B)
C(30B)
C(31B)
C(32B)
P(2B)
C(33B)
C(34B)
C(35B)
C(36B)
C(37B)
C(38B)
C(39B)
C(40B)
C(41B)
C(42B)
C(43B)
C(44B)
C(45B)
C(46B)
C(47B)
C(48B)
C(49B)
C(50B)
C(9B0)
C(9aB0)
C(10B0)
C(11B0)
C(12B0)
C(13B0)
C(13aB0)
C(2)
O(6A)
C(6aA)
N(7A)
C(8A)
C(9A)
C(9aA)
C(10A)
C(11A)
C(12A)
C(13A)
C(13aA)
C(13bA)
C(14A)
C(14aA)
C(10A)
C(20A)
C(30A)
C(40A)
C(50A)
C(60A)
P(1A)
C(15A)
C(16A)
C(17A)
C(18A)
C(19A)
C(20A)
C(21A)
C(22A)
C(23A)
C(24A)
C(25A)
C(26A)
C(27A)
C(28A)
C(29A)
C(30A)
C(31A)
C(32A)
P(2A)
C(33A)
C(34A)
C(35A)
C(36A)
C(37A)
C(38A)
C(39A)
C(40A)
C(41A)
C(42A)
C(43A)
C(44A)
C(45A)
C(46A)
C(47A)
C(48A)
C(49A)
C(50A)
Pd(1B)
Br(1B)
C(14bB)
C(1B)
C(1)
O(1)
C(10)
C(20)
C(4)
C(2B)
C(3B)
C(4B)
C(4aB)
O(5B)
C(3)
O(2)
C(30)
C(40)

Double-Barrelled Heck Cyclizations
761
Table 5. Bond lengths (A) for (17),
61H48BrNO2P2Pd.C4H10
conversion (4) → (3) detract somewhat from the overall
scheme. It will be necessary, therefore, to address this
matter before a truly useful synthesis of the lamellarins
can be realized by this sort of approach. The present
work further highlights the need to design catalysts
which can promote, in an e cient manner, the cur-
rently problematic 6-endo-trig-type Heck cyclization
reaction22 as exempli ed by the desired conversion
(16) → (3).
C
O
Atoms
Distance Atoms
Molecule A Molecule B
Pd(1)–Br(1) Pd(1)–Br(1)
Distance
2 503(4)
1 978(20)
2 340(7)
2 348(7)
2 498(4)
1 978(20)
2 334(7)
2 338(7)
Pd(1)–C(14b)
Pd(1)–P(1)
Pd(1)–P(2)
Pd(1)–C(14b)
Pd(1)–P(1)
Pd(1)–P(2)
Selected distances constrained to be
equal for both molecules
Experimental
C(14b)–C(1)
C(1)–C(2)
C(2)–C(3)
C(4)–C(4a)
O(5)–C(6)
1 389(26)
1 431(26)
1 412(28)
1 379(26)
1 339(22)
1 419(27)
1 373(25)
1 389(21)
1 394(24)
1 394(14)
1 383(18)
1 394(14)
1 412(23)
1 478(29)
1 361(20)
1 307(23)
1 361(20)
1 807(9)
C(14b)–C(4a)
C(2)–C(3)
C(3)–C(4)
C(4a)–O(5)
C(6)–O(6)
C(6a)–N(7)
N(7)–C(8)
C(8)–C(9)
C(9a)–C(10)
C(10)–C(11)
C(12)–C(13)
C(13a)–C(13b)
C(14)–C(14a)
C(10)–C(20)
C(20)–C(30)
C(40)–C(50)
P(1)–C(15)
P(1)–C(27)
C(15)–C(20)
C(17)–C(18)
C(19)–C(20)
1 411(26)
1 412(28)
1 398(27)
1 369(23)
1 199(21)
1 378(24)
1 489(24)
1 588(27)
1 368(18)
1 383(18)
1 368(18)
1 511(28)
1 447(25)
1 415(23)
1 307(23)
1 415(23)
1 807(9)
Melting points were recorded with a Ko er hot-stage appara-
tus and are uncorrected. Proton (1H) and carbon (13C) n.m.r.
spectra were recorded with a Varian Gemini 300 spectrometer
operating at 300 MHz for proton and 75 MHz for carbon. Unless
otherwise stated, all such spectra were recorded in (D)chloroform
(CDCl3) solution at 22 C. The protonicities of the carbon atoms
observed in 13C n.m.r. spectra were determined by attached
proton test (a.p.t.) experiments. Infrared spectra ( max) were
recorded with either a Perkin–Elmer 683G infrared spectropho-
tometer or a Perkin–Elmer 1800 Fourier-transform infrared
C(6)–C(6a)
C(6a)–C(14a)
N(7)–C(3b)
C(9)–C(9a)
C(9a)–C(13a)
C(11)–C(12)
C(13)–C(13a)
C(13b)–C(14)
C(14)–C(60)
C(10)–C(60)
C(30)–C(40)
C(50)–C(60)
P(1)–C(21)
C(15)–C(16)
C(16)–C(17)
C(18)–C(19)
Table 6. Selected bond angles (degrees) for (17),
C61H48BrNO2P2Pd.C4H10O
Atoms
Molecule A
Molecule B
Br(1)–Pd(1)–P(1)
Br(1)–Pd(1)–P(2)
C(14b)–Pd(1)–P(1)
C(14b)–Pd(1)–P(2)
Br(1)–Pd(1)–C(14b)
P(1)–Pd(1)–P(2)
91 8(2)
91 6(2)
87 4(2)
89 2(2)
179 1(3)
175 4(3)
90 3(2)
91 6(2)
89 8(3)
89 0(2)
176 4(7)
170 3(3)
1 807(9)
1 395(7)
1 386(8)
1 384(8)
1 395(7)
1 384(8)
1 386(8)
Fig. 2. ORTEP derived from X-ray crystallographic structure analysis of compound (17).

762
M. G. Banwell et al.
spectrophotometer. Samples were analysed as potassium bro-
mide disks. Low-resolution electron impact mass spectra (m/z)
were recorded at 70 eV on a VG Micromass 7070F mass
spectrometer. High-resolution mass spectra were recorded on
the same instrument. High-pressure reactions were conducted
by using a PSIKA 20 kbar high-pressure reactor. Diethyl ether
and tetrahydrofuran were distilled under nitrogen from sodium
benzophenone ketyl. Dichloromethane and hexane were each
distilled from calcium hydride. N ,N -Dimethylformamide was
distilled from calcium hydride under reduced pressure (c. 25
Torr) G.l.c./m.s. studies were conducted by using an HP 5890
gas chromatograph interfaced with an HP 5970 mass-selective
detector. The gas chromatograph was tted with a 12 5 m by
0 2 mm (i.d.) by 0 33 m HP-1 (cross-linked methyl silicone
gum) capillary column. A carrier gas (helium) ow rate of c.
35 cm/s was used in conjunction with the following gradient
temperature program: initial temperature of 200 C held for
2 min, then heating at 20 C/min to a nal temperature of
300 C which was maintained for 10 min.
2-Bromophenyl 4-Iodopyrrole-2-carboxylate (11)
Oxalyl chloride (203 l, 2 32 mmol) was added to a mag-
netically stirred suspension of 4-iodopyrrole-2-carboxylic acid
(8) (500 mg, 2 11 mmol) in dry CH2Cl2 (15 0 ml) containing
dimethylformamide (1 drop). After the resulting solution had
been stirred at 18 C for 2 h it was added to a magnetically stirred
solution of o-bromophenol (363 mg, 2 11 mmol), triethylamine
(660 l, 4 73 mmol) and 4-(dimethylamino)pyridine (several
crystals) in CH2Cl2 (10 ml). After 1 h the reaction mixture
was concentrated onto silica gel (5 g) and the residue subjected
to ash chromatography (silica gel, 3 : 1 hexane/ether elution).
Concentration of the appropriate fractions (RF 0 2) then gave
the title compound (11) (761 mg, 92%) as a white crystalline
solid, m.p. 126–127 C (Found: C, 33 9; H, 1 7; Br, 20 4; I,
32 4; N, 4 0.
20 4; I, 32 4; N, 3 6%).
1541, 1472, 1444, 1377, 1312, 1218, 1169, 1133, 1043 cm
C11H7BrINO2 requires C, 33 7; H, 1 8; Br,
(KBr) 3383, 2969, 1709, 1580,
max
1
.
1H n.m.r. 9 57, broad s, 1H; 7 65, dd, J 8 1 and 1 5 Hz,
1H; 7 37, td, J 8 1 and 1 5 Hz, 1H; 7 27, m, 2H; 7 18,
td, J 8 1 and 1 5 Hz, 1H; 7 08, m, 1H. 13C n.m.r. 158 0
(C), 148 3 (C), 134 0 (CH), 129 8 (CH), 129 1 (CH), 128 1
(CH), 124 4 (CH), 124 3 (CH), 123 6 (C), 116 9 (C), 62 9
(C). Mass spectrum m/z 393 (24%) 391 (22) (M+ ); 220 (100)
[(M C6H4BrO)+ ].
2-(Trichloroacetyl)pyrrole (6)
Compound (6) was prepared from pyrrole (12 5 g, 186 mmol)
and trichloroacetyl chloride (36 5 g, 200 mmol) according to
the method of Bailey et al.12 In this manner the title compound
(6)12 (31 3 g, 80%) was obtained as a cream solid, m.p. 73–74 C
(lit.12 m.p. 73–75 C). 1H n.m.r. 9 30, broad s, 1H; 7 39, m,
1H; 7 17, m, 1H; 6 40, dt, J 3 9 and 2 4 Hz, 1H.
2-(2 0-Bromophenyl)ethyl 4-Methylbenzenesulfonate (13)
A magnetically stirred solution of o-bromophenethyl alcohol
(12) (5 00 g, 24 9 mmol, ex Aldrich) and 4-methylbenzene-
sulfonyl chloride (11 20 g, 59 7 mmol) in diethyl ether (50 ml)
was cooled to 0 C (ice bath) then treated with powdered KOH
(3 2 g, 2 4 mole equiv.). The reaction mixture thus obtained
was allowed to warm to 18 C, stirred at this temperature
for 2 0 h then diluted with water (100 ml). The separated
organic phase was washed with water (1 100 ml) then dried
(MgSO4), ltered and concentrated under reduced pressure
to give a white solid. Since this material contained residual
4-methylbenzenesulfonyl chloride it was dissolved in pyridine
(75 ml) and the resulting solution stirred at 18 C for 0 16 h
then diluted with water (500 ml) and extracted with diethyl
ether (1 500 ml). The separated organic phase was washed
with HCl (1 250 ml of a 5 M aqueous solution) then sodium
hydrogen carbonate (1 250 ml of a 0 5 M aqueous solution)
before being dried (MgSO4), ltered and concentrated under
reduced pressure to give the title compound (13)23 (8 66 g,
98%) as white crystalline masses, m.p. 39–39 5 C (Found: C,
50 9; H, 4 2; Br, 22 6; S, 8 8. Calc. for C15H15BrO3S: C,
4-Iodo-2-(trichloroacetyl)pyrrole (7)
The title compound was prepared from 2-(trichloroacetyl)-
pyrrole (6) according to the method of Belanger.13 Thus,
iodine (12 0 g, 47 2 mmol) was added portionwise (approxi-
mately 1 g per portion) over 0 17 h to a magnetically stirred
mixture of silver tri uoroacetate (11 0 g, 49 8 mmol) and 2-
(trichloroacetyl)pyrrole (10 0 g, 47 1 mmol) in dry chloroform
(70 ml) maintained at 0 C (ice bath). After addition was
complete the reaction mixture was allowed to warm to 18 C
and stirred at this temperature for a further 2 h. The resultant
suspension was ltered through a sintered glass funnel (No. 3
porosity) and the ltrate washed with Na2S2O5 (1 80 ml of
5% w/v aqueous solution) and water (2 80 ml), then dried
(MgSO4), ltered and concentrated under reduced pressure.
The solid residue thus obtained was treated with hexane/ether
(50 ml of a 4 : 1 v/v mixture) and the resulting suspension
stirred at 18 C for 5 h; then the solid was ltered o to give
the title compound (7)13 (13 1 g, 82%) as a cream solid, m.p.
129–130 C (lit.13 m.p. 128–130 C). 1H n.m.r. 9 45, broad s,
1H; 7 44, dd, J 2 6 and 1 3 Hz, 1H; 7 19, dd, J 2 6 and 1 3
Hz, 1H.
50 7; H, 4 3; Br, 22 5; S, 9 0%).
1021, 980, 962, 895, 812, 769, 752, 665, 557 cm
(KBr) 1356, 1177,
1
max
.
1H n.m.r.
7 68, d, J 8 3 Hz, 2H; 7 45, d, J 7 7 Hz, 1H; 7 27, d, J
8 3 Hz, 2H; 7 17, m, 2H; 7 07, m, 1H; 4 25, t, J 7 0 Hz, 2H;
3 09, t, J 7 0 Hz, 2H; 2 43, s, 3H. 13C n.m.r. 144 5 (C),
135 3 (C), 132 7 (CH), 132 8 (C), 131 3 (CH), 129 7 (CH),
128 5 (CH), 127 6 (CH), 127 4 (CH), 124 2 (C), 68 6 (CH2),
35 5 (CH2), 21 5 (CH3). Mass spectrum m/z 356 (0 7%) 354
(0 7) (M+ ); 184 (98) 182 (100) [(M H3CC6H4SO3H)+ ];
171 (49) 169 (51); 155 (45); 103 (32); 91 (80) (C7H7+).
4-Iodopyrrole-2-carboxylic Acid (8)
K2CO3 (100 ml of a 2 M aqueous solution) was added to a
solution of 4-iodo-2-(trichloroacetyl)pyrrole (8 5 g, 2 5 mmol)
in dimethyl sulfoxide (30 ml) and the resulting mixture stirred
at 18 C for 3 h then diluted with H2O (200 ml). The solu-
tion thus obtained was washed with ethyl acetate (2 100 ml)
then acidi ed, by dropwise addition of HCl (2 M aqueous
solution), to pH 3. The resulting slurry was extracted with
ethyl acetate (3 100 ml) and the combined organic fractions
were dried (MgSO4), ltered and concentrated under reduced
pressure to give the title compound (8) (5 51 g, 92%) as a
white solid, m.p. 200 C (Found: M+ , 236 9285. C5H4INO2
2-Bromophenyl 1-[2 0-(2 00-Bromophenyl)ethyl]-4-iodopyrrole-2-
carboxylate (14)
Compound (13) (700 mg, 1 97 mmol), tetraethylammonium
chloride (30 mg, 0 18 mmol) and K2CO3 (278 mg, 2 0 mmol)
were added to a solution of compound (11) (700 mg, 1 79 mmol)
in dry dimethylformamide (30 ml) and the resultant slurry was
stirred at 80 C for 2 h. The cooled reaction mixture was diluted
with ethyl acetate (150 ml) and washed with water (3 150 ml).
The separated organic phase was then dried (MgSO4), ltered
and concentrated under reduced pressure. The solid residue
thus obtained was subjected to ash chromatography (silica gel,
4 : 1 hexane/ether elution) and concentration of the appropriate
requires M+ , 236 9287).
1544, 1430, 1300, 1212, 1122 cm
(KBr) 3287, 3129, 3035, 1703,
1
max
.
1H n.m.r. [300 MHz, 3 : 1
(CD3)2SO/CDCl3] 11 98, broad s, 1H; 6 98, t, J 1 5 Hz, 1H;
6 76, broadened s, 1H (resonance due to N–H not observed).
13C n.m.r. [75 5 MHz, 3 : 1 (CD3)2SO/CDCl3] 159 0 (C),
126 0 (CH), 123 3 (C), 118 8 (CH), 59 0 (C). Mass spectrum
m/z 237 (100%) (M+ ); 219 (87) [(M H2O)+ ].

Double-Barrelled Heck Cyclizations
763
fractions (RF 0 5, 3 : 1 hexane/ether elution) gave the title
compound (14) (920 mg, 89%) as a white crystalline solid, m.p.
122–123 C (Found: C, 39 5; H, 2 1; Br, 27 6; I, 22 1; N, 2 3.
m, 3H; 4 88, t, J 6 9 Hz, 2H; 3 21, t, J 6 9 Hz, 2H. 13C
n.m.r. 155 3 (C), 151 2 (C), 135 6 (C), 135 3 (C), 133 8
(C), 130 7 (CH), 129 4 (CH), 128 3 (CH), 128 1 (CH), 127 5
(C), 127 4 (CH), 126 9 (CH), 125 7 (CH), 123 7 (CH), 123 3
(CH), 118 2 (C), 117 5 (C), 117 1 (CH), 42 3 (CH2), 29 3
(CH2) (three peaks obscured or overlapping). Mass spectrum
m/z 363 (100%) (M+ ).
C
19H14Br2INO2 requires C, 39 7; H, 2 5; Br, 27 8; I, 22 1; N,
2 4%). (KBr) 2949, 1716, 1517, 1468, 1438, 1411, 1374,
1326, 1232, 1216, 1191, 1055, 1028 cm
max
1
.
1H n.m.r. 7 65,
dd, J 7 8 and 1 8 Hz, 1H; 7 55, dd, J 7 8 and 1 8 Hz, 1H;
7 37, m, 2H; 7 28–7 04, m, 5H; 6 70, d, J 2 1 Hz, 1H; 4 55,
t, J 7 5 Hz, 2H; 3 20, t, J 7 5 Hz, 2H. 13C n.m.r. 157 0 (C),
147 8 (C), 136 9 (C), 134 5 (CH), 133 3 (CH), 132 7 (CH),
131 2 (CH), 128 6 (CH), 128 4 (CH), 127 6 (CH), 127 3 (CH),
126 7 (CH), 124 4 (C), 124 0 (CH), 122 0 (C), 116 6 (C),
59 6 (C), 49 0 (CH2), 38 0 (CH2). Mass spectrum m/z 577
(1%) 575 (2) 573 (1) (M+ ); 496 (10) 494 (11) [(M Br )+];
404 (98) 402 (100) [(M C6H4BrO )+].
2 0-Bromophenyl 1-Phenyl-5,6-dihydropyrrolo[2,1-a]-
isoquinoline-3-carboxylate (16) and Bromo{2 0-(1 00-phenyl-
5 00,6 00-dihydropyrrolo[2,1-a]isoquinolin-3 00-ylcarbonyloxy)-
phenyl}bis(triphenylphosphine)palladium (17)
Pd(OAc)2 (197 mg, 0 88 mmol) was added to
a solu-
tion of compound (4) (230 mg, 0 438 mmol), NaOAc (80 mg,
0 975 mmol) and PPh3 (460 mg, 1 75 mmol) in dimethylfor-
mamide (20 ml). The solution was evacuated (1 0 mmHg)
and back- lled with N2 (gas) three times to remove dissolved
oxygen and then heated under nitrogen at 110 C for 19 h. The
cooled reaction mixture was diluted with ethyl acetate (25 ml)
then washed with brine (2 20 ml) and water (1 20 ml). The
separated organic phase was then dried (MgSO4), ltered and
concentrated under reduced pressure onto silica (2 g). Subjec-
tion of the resulting material to ash chromatography (silica,
1 : 2 then 1 : 1 CH2Cl2/hexane followed by 4 : 1 CH2Cl2/ethyl
acetate elution) gave two fractions, A and B.
2-Bromophenyl 1-[2 0-(2 00-Bromophenyl)ethyl]-4-phenylpyrrole-
2-carboxylate (4)
Phenylzinc chloride [prepared by the addition of anhydrous
zinc chloride (540 mg, 3 96 mmol) to a solution of phenyllithium
(2 0 ml of a 1 8 M solution in cyclohexane/ether, 3 6 mmol)
in tetrahydrofuran (4 0 ml)] was added dropwise, over 2 min,
to a magnetically stirred solution of compound (14) (1 75
g, 3 04 mmol) and Pd(PPh3)2Cl2 (106 mg, 0 152 mmol) in
dimethylformamide (15 ml). Stirring was continued at 18 C for
1 h then the reaction mixture was transferred to a separatory
funnel, diluted with ethyl acetate (100 ml) and washed with
NH4Cl (100 ml of a saturated aqueous solution) then H2O
(2 100 ml). The separated organic phase was dried (MgSO4),
ltered and concentrated under reduced pressure to give a
light-yellow oil which was subjected to ash chromatography
(silica, 2 : 1 hexane/CH2Cl2 elution). Concentration of the
appropriate fractions (RF 0 5) gave the title compound (4)
(1 52 g, 95%) as a microcrystalline solid, m.p. 90–92 C (Found:
C, 57 1; H, 3 4; Br, 30 7; N, 2 5. C25H19Br2NO2 requires C,
Concentration of fraction A (RF 0 6, 2 : 1 CH2Cl2/hexane
elution) a orded compound (16) (34 mg, 17%) as o -white
crystalline masses, m.p. 130–131 C (Found: M+ , 443 0529.
C
25H1879BrNO2 requires M+ , 443 0521).
(KBr) 2950,
max
1
1710, 1471, 1439, 1418, 1240, 1212, 1176, 1046 cm
.
1H n.m.r.
7 57, dd, J 8 1 and 1 5 Hz, 1H; 7 45–7 05, m, 12H; 6 95,
br t, J 8 1 Hz, 1H; 4 57, t, J 6 3 Hz, 2H; 3 05, t, J 6 3 Hz,
2H. 13C n.m.r. 158 5 (C), 148 1 (C), 136 1 (C), 133 4 (C),
133 3 (CH), 132 9 (C), 129 1 (CH), 128 6 (C), 128 4 (CH),
128 1 (C), 127 9 (CH), 127 7 (CH), 127 1 (CH), 126 9 (CH),
126 7 (CH), 125 5 (CH), 124 2 (CH), 123 5 (C), 121 3 (CH),
119 4 (C), 116 7 (C), 42 4 (CH2), 29 5 (CH2). Mass spectrum
m/z 445 (10%) 443 (9) (M+ ); 272 (100) [(M C6H4BrO )+].
57 2; H, 3 7; Br, 30 4; N, 2 7%). max (KBr) 2958, 2930, 1718,
1
1603, 1580, 1562, 1472, 1397, 1215, 1196, 1066, 1024 cm
.
1H n.m.r. 7 70, dd, J 8 0 and 1 5 Hz, 1H; 7 60–7 00, m,
14H; 4 63, t, J 6 9 Hz, 2H; 3 32, t, J 6 9 Hz, 2H. 13C n.m.r.
(75 5 MHz, CDCl3) 158 4 (C), 148 3 (C), 137 5 (C), 134 2
(C), 133 5 (CH), 132 9 (C), 131 5 (CH), 128 9 (CH), 128 6(3)
(CH), 128 6(1) (CH), 127 8 (CH), 127 4 (CH), 127 3 (CH),
126 5 (CH), 125 4 (CH), 124 8 (C), 124 6 (C), 124 4 (CH),
120 9 (C), 117 5 (CH), 116 9 (C), 49 3 (CH2), 38 2 (CH2).
Mass spectrum m/z 527 (3%) 525 (6) 523 (3) (M+ ); 446 (12)
444 (11) [(M Br )+]; 354 (100) 352 (96) [(M C6H4BrO )+].
Concentration of fraction
a orded compound (17) (40 mg, 8 5%) as o -white crystalline
masses, m.p. 159–162 C. (KBr) 3052, 2923, 1705, 1481,
1435, 1416, 1238, 1172, 1095, 1058, 1024 cm
B (RF 0 1, CH2Cl2 elution)
max
1
.
1H n.m.r.
7 65–7 40, m, 18H; 7 30–7 05, m, 22H; 6 58, m, 1H; 6 52, t,
J 6 6 Hz, 1H; 6 39, m, 1H; 6 07, q, J 6 6 Hz, 1H; 4 73, m,
2H; 3 05, m, 2H. 13C n.m.r. 159 2 (C), 151 8 (C), 138 3
(CH), 136 5 (C), 134 8 (CH), 133 2 (C), 131 8 (C), 131 5
(C), 131 0 (C), 129 9 (CH), 129 8 (CH), 129 5 (CH), 129 0
(CH), 128 7 (C), 127 8 (CH), 127 5 (CH), 127 2 (CH), 127 0
(CH), 125 7 (CH), 125 0 (CH), 123 2 (C), 123 0 (CH), 121 9
(CH), 121 1 (C), 120 5 (CH), 42 2 (CH2), 29 7 (CH2). Mass
spectrum m/z 365 (6%) [(M Pd(PPh3)2Br+H)+ ]; 277 (26);
272 (32) {[M C6H4OPd(PPh3)2Br]+}; 262 (100) (Ph3P+ ).
14-Phenyl-8,9-dihydro-6 H-[1]benzopyrano[4 0,3 0:4,5]pyrrolo-
[2,1-a]isoquinolin-6-one (3)
Pd(OAc)2 (32 mg, 0 143 mmol) was added to a magnetically
stirred solution of compound (4) (148 mg, 0 282 mmol), NaOAc
(92 7 mg, 1 13 mmol) and PPh3 (74 0 mg, 0 282 mmol) in
dimethylformamide (2 ml) contained in a Schlenk tube. The
resulting mixture was evacuated (1 0 mmHg) and back- lled
with N2 (gas) three times (to remove dissolved oxygen) then
heated under nitrogen at 135 C for 6 h. The cooled reaction
mixture was diluted with ether (25 ml) and washed with brine
(2 20 ml) then water (20 ml) before being dried (MgSO4),
ltered and concentrated onto silica (2 g). The residue was
subjected to ash chromatography (silica, 1 : 2, 1 : 1 then 2 : 1
CH2Cl2/hexane elution) and the appropriate fractions (RF 0 3,
2 : 1 CH2Cl2/hexane elution) were concentrated under reduced
pressure to give the title compound (3) (16 mg, 16%) as
1-Phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline (18) and 1-
[2 0-(2 00-Bromophenyl)ethyl]-3-phenylpyrrole (19)
A
solution of the dibromide (4) (13 mg, 25 mol),
trans-di( -acetato)bis[o -(di-o -tolylphosphino)benzyl]dipalla-
dium(II)16 (2 5 mg, 2 5 mol) and anhydrous sodium acetate
(6 2 mg, 75 mol) in degassed N,N -dimethylacetamide (0 25
ml) was heated, under nitrogen, at 140 C for 72 h. The cooled
reaction mixture was then diluted with diethyl ether (5 ml)
and the resulting solution washed with brine/water (3 5 ml
of a 1 : 1 v/v mixture). The organic phase was then dried
(MgSO4), ltered and concentrated under reduced pressure to
give a light-yellow oil. Subjection of this material to ash
chromatography (silica, 3 : 7 then 7 : 3 CH2Cl2/hexane elution)
gave, after concentration of the appropriate fractions (RF 0 7,
3 : 7 CH2Cl2/hexane elution), a 1 : 3 mixture of compounds
(18) and (19) (4 mg, 52% combined yield) as a light-yellow
cream-coloured microcrystals, m.p. 259–260 C (Found: M+
363 1257. C25H17NO2 requires M+ , 363 1259).
(KBr)
2925, 2853, 1708, 1449, 1420, 1396, 1339, 1281, 1241, 1198,
,
max
1
1151, 1133, 1106, 1085, 1047 cm
.
1H n.m.r.
7 58–7 55,
m, 2H; 7 51–7 50, m, 2H; 7 40, dd, J 7 5 and 0 9 Hz, 1H;
7 32–7 18, m, 4H; 7 10, dd, J 7 8 and 1 2 Hz, 1H; 7 01–6 97,

764
M. G. Banwell et al.
and unstable oil.
1441, 1359, 1202, 1071, 1027, 751, 694, 655 cm
(KBr) 1705, 41 2, 1555, 1500, 1471,
1
restrained to have opposite signs and approach equivalence
with the torsional angle N(7A)–C(8A)–C(9A)–C(9aA), nal
value 46 7(16) . The Pd, Br and P atoms were re ned as
implicitly independent anisotropic atoms but the remaining
atoms in the A and B molecules were re ned with constraints
max
.
1H n.m.r.
[compound (19)] 7 60–6 95, complex m, 9H; 6 92, t, J 2 0
Hz, 1H, H 2; 6 63, t, J 1 6 Hz, 1H, H 5; 6 43, broadened t,
J 2 3 Hz, 1H, H 4; 4 14, t, J 7 7 Hz, 2H; 3 22, t, J 7 7 Hz,
2H; [compound (18)] 7 60–6 95, complex m, 9H; 6 73, d, J
2 7 Hz, 1H, H 3; 6 23, d, J 2 7 Hz, 1H, H 2; 4 08, t, J 7 7
Hz, 2H; 3 10, t, J 7 7 Hz, 2H. G.l.c./m.s. [compound (18)]
(RT 4 52 min) 245 (100%) (M+ ), 167 (21), 149 (28), 120 (6);
g.l.c./m.s. [compound (19)] (RT 5 85 min) 327 (12%) 325 (12)
(M+ ), 246 (100) [(M Br )+].
imposed by using re nable local coordinates de ned relative
29
to re nable local orthonormal axial systems.27
Tabulated
errors have implicit assumptions about the appropriateness of
the constraints used. An ordered molecule was considered
to contain 10 strictly planar fragments (local Z coordinates
are 0 0), based on nine six-membered rings and one ve-
membered ring. These fragments were constrained to be
identical (i.e. reference the same re nable local coordinates)
for both molecules. However, the molecules had independent
thermal parameterizations. The origins of three phenyl rings
attached to each phosphorus atom were constrained to coincide
with the phosphorus atom and the local coordinates constrained
to have the same re nable mm2 symmetry for all six phenyl
rings per molecule, implying all P–C bonds are identical. The
thermal motion of each of these phenyl rings was described by
a TL model,27 the Translational component being identical to
the anisotropic thermal motion of the associated phosphorus
atom, while the Librational component was centred on the
phosphorus and was di erent for each ring. Thus, the four
phosphorus and 72 carbon atoms were meaningfully described
by just 54 positional and 96 thermal parameters. The origin of
the six-membered ring attached to a palladium was constrained
to coincide with the Pd position, implying the Pd is coplanar
with the ring. The thermal parameters for these seven atoms
were re ned using a TL model centred on the palladium. The
ve-membered ring and the attached O(5), C(6), O(6) and
C(8) atoms were considered a coplanar fragment, as were the
seven-atom fragment C(9) to C(13a) (see earlier) and the phenyl
ring C(10) to C(60). A multiple axial system28 in which these
latter two rings are de ned relative to the ve-membered ring
allowed the constraint that C(13b) and C(14) could be used as
origins for the attached rings, implying C(13b) is coplanar with
the rst attached ring and C(14) is coplanar with the second.
All these atoms were included in a single TL model centred
on O(5) to describe their thermal motion. Further libration
centred on C(14) was allowed for the phenyl ring C(10) to
C(60). Further restraints were used to relate the connections
between fragments for the two molecules. O(5) was restrained
to approach a position consistent with being included in the
six-atom fragment attached to the palladium (i.e. zero angle
out of plane and equal bond lengths and angles). Likewise,
C(60) relative to the ve-membered ring to which it is attached.
Restraints on the C(13a) relative to the ve-membered ring
were not imposed because they were counterproductive and
because of the implicit non-planarity of the six-membered ring
N(7)–C(8)–C(9)–C(9a)–C(13a)–C(13b).
Crystallography
Crystal Data
Compound (3).
monoclinic, space group P 21/c, a 11 063(4), b 11 316(3), c
28 688(3) A,
100 91(2) , V 3526(2) A3, Dc(Z = 8) 1 369
g cm 3, F(000) 1520, (Cu K ) 6 50 cm 1, semiempirical
absorption correction; 5577 unique data (2 120 4 ), 3294
C25H17NO2, M 363 41, T 183(1) K,
max
with I > 3 (I ); R 0 049, wR 0 051, goodness of t 2 37.
Compound (17). C61H48BrNO2P2Pd.C4H10O, M 1149 43,
T 183(1) K, monoclinic, space group P 21/c, a 25 377(5),
b 12 272(5), c 36 200(11) A,
100 01(2) , V 11102(6) A3,
Dc(Z = 8) 1 375 g cm 3, F(000) 4720, (Cu K ) 44 46 cm
Other data are discussed below.
.
1
Structure Determination
Compound (3). Data were measured on a Rigaku AFC6R
rotating-anode di ractometer (graphite crystal monochroma-
tor, 1 54180 A). The structure of compound (3) was solved
by direct methods,24 and re nement was by full-matrix least
squares analysis on F with anisotropic thermal parameters on
all non-hydrogen atoms. Hydrogen atoms were located from dif-
ference maps and included at idealized locations. The structure
contains two molecules in the asymmetric unit, labelled A and
B. All calculations were performed with the teXsan structure
analysis software of Molecular Structure Corporation.25
Compound (17). Data were measured on a Rigaku AFC6R
rotating-anode di ractometer (graphite crystal monochroma-
tor,
1 54180 A). The crystal was coated to prevent decay
and data were corrected for absorption, A, by using the slowly
moving empirical expression:
ln A = [h, g1h] + [h, g2h]/h.h
where h is the scattering vector and the [h,gih] are quadratic
forms each involving six variables. The trace of g2 correlates
with the scale constant and is not re ned, and the trace of g1
correlates with the overall temperature factor and is given a
value estimated from the absorption correction of a sphere that
approximates the crystal. For a monoclinic crystal only the 12
and 23 terms of g1 do not correlate with an overall anisotropic
thermal factor with the Laue symmetry of the crystal. This left
seven parameters that could be meaningfully re ned as part
of the structure re nement. Data were subsequently corrected
for absorption and merged before use in the nal re nement.
The solid-state structure of compound (17) contained two
formula units per asymmetric unit and one diethyl ether of crys-
tallization per molecule. Only 3213 of the 11633 independent
re ections collected were considered to be reliably observed (I
Hydrogen atoms were included in geometrically sensible
positions which were updated in each re nement cycle. Their
thermal parameters were determined by the rigid group thermal
motion parameters pertaining to the atoms to which they were
attached. The atoms of the two solvent molecules were poorly
de ned and simply ll up an available space. The re nement
used 363 independent variables to describe 153 non-hydrogen
atom positions and gave a nal value of R1 0 073 for the 3213
re ections used in the re nement.
An uncorrelated 4% error in F was included along with
26
> 3 (I )) and so the constrained re nement program RAELS
counting statistic error in the evaluation of weights w
=
1/( (F)2+(0 04F)2). A nal value for the goodness of t was
1 42 for the 3213 re ections used and 0 96 (R1 = 0 69) for
the remaining 8420 re ections with I < 3 (I ).
was used for structure re nement. Atoms in molecule A have
labels that nish with A and atoms in molecule B have labels
that nish in B or B0. Molecule A is ordered but part of
molecule B [the planar fragment C(9), C(9a), C(10), C(11),
C(12), C(13), C(13a)] is 0 75(2) : 0 25 disordered with the minor
component denoted by B0. In the re nement the torsional
angles N(7B)–C(8B)–C(9B)–C(9aB), nal value 45 5(11) , and
N(7B)–C(8B)–C(9B0)–C(9aB0), nal value 46 6(14) , were
The two molecules in the asymmetric unit are approximately
mirror-related; corresponding torsional angles are of opposite
signs and approximately equal magnitude, e.g. 129 0(8) for
C(14bA)–C(4aA)–O(5A)–C(6A) and 125 0(8) for C(14bB)–
C(4aB)–O(5B)–C(6B).

Double-Barrelled Heck Cyclizations
765
Atomic coordinates, bond lengths and angles, and thermal
parameters have been deposited along with structure factor
listings for compounds (3) and (17). Copies are available (until
31 December 2004) from the Australian Journal of Chemistry,
P.O. Box 1139, Collingwood, Vic. 3066.
pp. 99–166 (Wiley–VCH: Weinheim 1998); Crisp, G. T.,
Chem. Soc. Rev., 1998, 27, 427.
11
12
For example: Bringmann, G., Walter, R., and Weirich, R.,
Angew. Chem., Int. Ed. Engl., 1990, 29, 977.
Bailey, D. M., Johnson, R. E., and Albertson, N. F., Org.
Synth., 1971, 51, 100; also Harbuck, J. W., and Rappoport,
H., J. Org. Chem., 1972, 37, 3618; Wallace, D. M., Leung,
S. H., Senge, M. O., and Smith, K. M., J. Org. Chem.,
1993, 58, 7245.
Belanger, P., Tetrahedron Lett., 1979, 2505; Volz, H., and
Holzbecher, M., Angew. Chem., Int. Ed. Engl., 1997, 36,
1442.
Negishi, E., Takahashi, T., and King, A. O., Org. Synth.,
1987, 66, 67; Knochel, P., and Singer, R. D., Chem. Rev.,
1993, 93, 2117.
Voigt, K., Schick, U., Meyer, F. E., and de Meijere, A.,
Synlett, 1994, 189; Sugihara, T., Takebayashi, M., and
Kaneko, C., Tetrahedron Lett., 1995, 36, 5547; Hillers, S.,
Sartori, S., and Reiser, O., J. Am. Chem. Soc., 1996, 118,
2087.
Acknowledgments
We thank the Institute of Advanced Studies at
the Australian National University for generous nan-
cial support including the provision of a Postdoctoral
Fellowship to B.L.F. Mr David Wong is thanked for
acquiring 1H n.m.r. spectral data on compound (6) and
we gratefully acknowledge Associate Professor Kings-
ley Cavell and Mr David McGuinness (Department
of Chemistry, University of Tasmania) for providing
the palladium carbene complexes Pd(dmiy)2MeCl and
Pd(tmiy)2(TCNE).
13
14
15
16
17
18
Herrmann, W. A., Brossmer, C., Reisinger, C.-P., Riermeier,
T. H., Ofele, K., and Beller, M., Chem. Eur. J., 1997, 3,
1357.
McGuinness, D. S., Green, M. J., Cavell, K. J., Skelton, B.
W., and White, A. H., J. Organomet. Chem., 1998, 565,
165; Cavell, K. J., unpublished data.
Je rey, T., Tetrahedron Lett., 1994, 35, 3051; Tetrahedron,
1996, 52, 10113; Moreno-Man˜as, M., Pleixats, R., and
Roglans, A., Synlett, 1997, 1157.
Farina, V., and Krishnan, B., J. Am. Chem. Soc., 1991,
113, 9585.
Ripa, L., and Hallberg, A., J. Org. Chem., 1997, 62, 595;
Cho, Y., and Shibasaki, M., Tetrahedron Lett., 1998, 39,
1773; Namyslo, J. C., and Kaufmann, D. D., Synlett, 1999,
114.
For example: Leroy, J., and Wakselman, C., Tetrahedron
Lett., 1994, 35, 8605, and references cited therein.
For a useful discussion of palladium-mediated 6-endo-trig
cyclization reactions see: Dankwardt, J. W., and Flippin,
L. A., J. Org. Chem., 1995, 60, 2312.
Desarbre, E., and Merour, J.-Y., Heterocycles, 1995, 41,
1987.
SIR92: Altomare, A., Burla, M. C., Camalli, M., Cascarano,
M., Giacovazzo, C., Guagliardi, A., and Polidori, G., J.
Appl. Crystallogr., 1994, 27, 435.
teXsan: Single Crystal Structure Analysis Software, Version
1.7-1, Molecular Structure Corporation, The Woodlands,
Texas 77381, U.S.A., 1995.
RAELS96: Rae, A. D., Australian National University, Can-
berra, Australia, 1996.
Rae, A. D., Acta Crystallogr., Sect. A, 1975, 31, 560, 570.
Haller, K. J., Rae, A. D., Heerdegen, A. P., Hockless, D. C.
R., and Welberry, T. R., Acta Crystallogr., Sect. B, 1995,
51, 187.
Rae, A. D., Acta Crystallogr., Sect. A., Suppl., 1984, 40,
C-428.
References
1
Carroll, A. R., Bowden, B. F., and Coll, J. C., Aust. J.
Chem., 1993, 46, 489.
Andersen, R. J., Faulkner, D. J., Cun-Heng, H., Van Duyne,
2
G. D., and Clardy, J., J. Am. Chem. Soc., 1985, 107, 5492;
Lindquist, N., Fenical, W., Van Duyne, G. D., and Clardy,
J., J. Org. Chem., 1988, 53, 4570; Venkata Rami Reddy,
M., Faulkner, D. J., Venkateswarlu, Y., and Rama Rao,
M., Tetrahedron, 1997, 53, 3457; Urban, S., and Capon, R.
J., Aust. J. Chem., 1996, 49, 711.
19
20
3
Urban, S., Butler, M. S., and Capon, R. J., Aust. J. Chem.,
1994, 47, 1919; Urban, S., Hobbs, L., Hooper, J. N. A.,
and Capon, R. J., Aust. J. Chem., 1995, 48, 1491; Banwell,
M. G., Flynn, B. L., Hamel, E., and Hockless, D. C. R.,
Chem. Commun., 1997, 207.
21
22
4
Avila, J., J. Cancer, 1997, 10, 6 (http://www.infobiogen.fr/
agora/journals/cancer/articles/20-6/avil.htm).
Quesada, A. R., Garc a Gravalos, M. D., and Fernandez
5
Puentes, J. L., Br. J. Cancer, 1996, 74, 677; PCT Int.
Appl., WO 9701336 A1 970116 (Chem. Abstr., 1996, 126,
166474).
Heim, A., Terpin, A., and Steglich, W., Angew. Chem.,
Int. Ed. Engl., 1997, 36, 155.
Ishibashi, F., Miyazaki, Y., and Iwao, M., Tetrahedron,
1997, 53, 5951.
Boger, D. L., Boyce, C. W., Labroli, M. A., Schon, C. A.,
23
24
6
7
25
26
8
and Jin, Q., J. Am. Chem. Soc., 1999, 121, 54.
Banwell, M. G., Flynn, B., and Hockless, D., Chem.
Commun., 1997, 2259.
9
10
27
28
For useful recent reviews of the Heck reaction see: de Meijere,
A., and Meyer, F. E., Angew. Chem., Int. Ed. Engl., 1994,
33, 2379; Cabri, W., and Candiani, I., Acc. Chem. Res.,
1995, 28, 2; Je ery, T., Adv. Met.-Org. Chem., 1996, 5, 153;
Brase, S., and de Meijere, A., in ‘Metal-Catalysed Cross
Coupling Reactions’ (Eds P. J. Stang and F. Diederich)
29