Sequential oxopyridinium betaine cycloaddition-palladium catalysed cyclisation-anion capture processes

Article abstract of DOI:10.1016/S0040-4020(01)00740-2

Katritzky's oxopyridinium betaine cycloaddition is employed to generate bridged bicyclic substrates suitable for our palladium(0) catalysed cyclisation-anion capture methodology. A variety of polycyclic heterocycles have been synthesised via monocyclisation-organotin(IV) capture with or without incorporation of carbon monoxide. Sequential cycloaddition-cyclisation can be performed as a one pot process to deliver substantial gain in molecular complexity.

Full text of DOI:10.1016/S0040-4020(01)00740-2

TETRAHEDRON
Pergamon
Tetrahedron 57 02001) 7737±7748
Sequential oxopyridinium betaine cycloaddition±palladium
catalysed cyclisation±anion capture processes
Mark R. Fielding,a Ronald Grigg,a,p Visuvanathar Sridharan,a Mark Thornton-Petta
and Christopher J. Urchb
aMolecular Innovation, Diversity and Automated Synthesis ꢀMIDAS) Centre, School of Chemistry, Leeds University, Leeds LS2 9JT, UK
bSyngenta, Jealott's Hill Research Station, Bracknell, Berkshire RG42 6EY, UK
Dedicated to Professor K. Undheim on the occasion of his 70th birthday
Received 11 December 2000; revised 14 June 2001; accepted 12 July 2001
AbstractÐKatritzky's oxopyridinium betaine cycloaddition is employed to generate bridged bicyclic substrates suitable for our
palladium00) catalysed cyclisation±anion capture methodology. A variety of polycyclic heterocycles have been synthesised via mono-
cyclisation±organotin0IV) capture with or without incorporation of carbon monoxide. Sequential cycloaddition±cyclisation can be
performed as a one pot process to deliver substantial gain in molecular complexity. q 2001 Elsevier Science Ltd. All rights reserved.
The 1,3-dipolar cycloaddition of oxopyridinium betaines,
pioneered by Katritzky et al.,1±3 is a versatile synthetic
procedure for the construction of [3.2.1]-azabridged
bicyclic enones. In this reaction a 3-hydroxypyridinium
salt is treated with base in the presence of a suitable
dipolarophile to afford a mixture of endo- and exo-cyclo-
adducts via a cyclic azomethine ylide. A variety of activated
alkenes1 serve as dipolarophiles for this cycloaddition.
Applications of this chemistry have been reported by a
number of authors4±7 and manipulation of the enone
moiety has been used to modify of the azabicyclic scaffold.
The quaternary salts of the cycloadducts can also be
converted into tropones1 under Hofmann elimination
conditions.
complex heterocycles in which one or more rings are
created in a single step. In these reactions a capture reagent17
is required in order to make the ®nal bond 0C±C, C±N,
C±H, etc.) and thus allow regeneration of the Pd00) catalyst.
We have employed a range of such reagents in mono-, bis-
and tris-cyclisations.14±17 Organotin0IV) reagents are par-
ticularly attractive due to their ease of preparation and
tolerance of air and moisture. The sequential Tactical
Combination of the oxopyridinium betaine cycloaddition
with our cyclisation±anion capture methodology provides
the opportunity for linking two disparate ring forming reac-
tions to engineer highly ef®cient and selective protocols
allowing one-pot access to target molecules possessing a
high degree of complexity which would otherwise require
tedious and/or technically demanding multistep syntheses.
We have previously reported examples of such Tactical
Combinations which combined azomethine ylide±cyclo-
addition cascades with palladium00) catalysed cyclisation
reactions.18,19 A similar approach was employed by our
group in the synthesis of bicyclic b-lactams.20 Herein, we
demonstrate the ®rst examples of palladium-catalysed
cyclisation±stannane capture applied to oxopyridinium
betaine cycloadducts which utilise the cycloadduct enone
moiety as terminating species. The products from these
reactions are similar to the `front bridged' cocaine
analogues reported by Kozikowski et al.12,13 and serve as
an interesting series for biological evaluation.
Hart8 has applied Katritzky's cycloaddition to the synthesis
of a range of substrates suitable for radical mediated
cyclisations with tri-n-butyltin hydride. The intramolecular
version of the cycloaddition was reported9 in 1976 and
has since been used in the synthesis of polycyclic
enones.10,11 A similar approach was adopted by Kozikowski
et al.12,13 in their preparation of `back bridged' cocaine-like
analogues.
Our group has reported extensively on palladium00)
catalysed cyclisation±anion capture.14±16 This has been
developed into a powerful method for the construction of
1. Cycloadditions of 3-hydroxypyridinium salts
ꢀKatritzky's cycloaddition)
Keywords: palladium catalysis; cyclisation; 1,3-dipolar cycloaddition;
molecular queuing.
Corresponding author. Tel./fax: 144-113-233-6501;
e-mail: r.grigg@chem.leeds.ac.uk
p
Heating 3-hydroxypyridine in the presence of 2-iodo-
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020001)00740-2

7738
M. R. Fielding et al. / Tetrahedron 57 ꢀ2001) 7737±7748
Scheme 1.
Table 1. Cycloaddition between 3-hydroxy-N-02-iodobenzyl)pyridinium
bromide and 2a±d
2. Palladium catalysed cyclisation±anion capture
2.1. Non-carbonylative processes
Maleimide
Time 0h)
Products 0%)a
2a
2b
2c
16
17
28
39
3a 062)
3b 084)
3c 067)
3d 030)
4a 010)
±
±
4d 033)
2.1.1. Cyclisation±hydride capture. Cycloadduct 3a
0Scheme 1) was selected to evaluate palladium00) catalysed
cyclisation±hydride capture employing sodium formate22 as
the source of hydride ion 0Scheme 2; Table 2). Scheme 2
highlights the advantage of using Katritzky's cycloadducts
as cyclisation substrates because b-hydride elimination of 5
is not possible, allowing capture of an external `anion'. In
all cases we isolated a mixture of 6 0via 5) and 7 resulting
from competitive 6-exo- and 7-endo-trig processes, respec-
tively. The structure of 7 was con®rmed by single crystal
X-ray analysis 0Fig. 1).23
2db
All reactions were carried out with 2.5 equiv. NEt3 at 1108C in toluene.
Isolated yields.
Reaction went to 82% completion.
a
b
benzyl bromide afforded 1 in 90% yield. The desired
exo-cycloadducts 3a±d were prepared from the reaction of
1 with maleimides 2a±d and triethylamine in toluene at
1108C 0Scheme 1; Table 1). The use of maleimides 2a
and 2d resulted in the formation of endo-cycloadducts 4a
and 4d in addition to 3a and 3d 0Table 1).
²
In the absence of additives, cyclisation±hydride capture of
3a was found to be very slow and a very poor yield of 6 was
obtained. The addition of 1 equiv. of tetraethyl-ammonium
chloride,22±26 allowed the reaction to go to completion
affording 6 and 7 in 90% combined yield. The ratio of 6/7
was improved by the addition of zinc chloride to the reac-
tion mixture, presumably due to polarisation of the enone
upon Lewis acid coordination to the enone carbonyl group.
The cycloaddition of maleimide 2a occurred in good overall
yield affording a 6:1 ratio of exo-/endo-cycloadducts 3a and
4a. Maleimides 2b and 2c, on the other hand, exclusively
reacted in the exo sense to yield 3b and 3c, respectively.
Reaction of 2d with the oxopyridinium betaine afforded ca.
1:1 mixture of exo-/endo-cycloadducts. In this particular
case, the reaction only went to 82% completion after 39 h
in boiling toluene. Such a slow conversion can be attributed
to the bulky ortho isopropyl groups on the maleimide.
Maleimide 2d was synthesised using established methods21
from 2,6-diisopropylaniline.
2.1.2. OrganotinꢀIV) capture agents. Organostannanes
have proved versatile anion capture agents for our catalytic
cascade cyclisation±anion capture methodology.14±17,27 The
organostannanes can be pre-formed or, in many instances,
generated in situ by hydrostannylation of appropriate
alkynes16,17,27 or allenes.28 Tributylstannanes serve as
excellent nucleophilic components in the Stille29,30 cross-
coupling reaction. Treatment of 3a with commercially
available tributylvinylstannane was evaluated in boiling
toluene 0Scheme 3; Table 3).
²
Cycloadducts 3a±d are deemed to be exo due to the relationship of the
maleimide with the enone bridge 0trans). These adducts can also be
considered to be endo by virtue of the endo approach of the maleimide
to the 1,3-dipole.

M. R. Fielding et al. / Tetrahedron 57 ꢀ2001) 7737±7748
7739
Scheme 2.
Table 2. Effect of additives on cyclisation-hydride capture of 3a with sodium formate
Time 0h)
Additive 0equiv.)
Equiv. HCO2Na
Products 0%)a
15
21.5
16
±
Et4NCl 01)
Et4NCl 01) ZnCl2 01)
1.1
3
1.1
6 06)
6 046)
6 051)
7 00)
7 044)
7 028)
Reaction carried out at 808C in acetonitrile. Catalyst system: 10 mol% Pd0OAc)2 and 20 mol% PPh3.
Isolated yields.
a
In all cases a mixture of 8, 9 and 10 was isolated in the
reaction of 3a with tributylvinylstannane 0Scheme 3).
Compound 9 is formed by direct capture22 of the vinyl
group from tin by the arylpalladium iodide species whilst
6 arises from hydride capture by 5 0Scheme 2). We have not
been able to suppress formation of 6 completely. There are
many instances of unwanted hydride capture in the
literature.29 In the absence of additives 0Table 3) at 858C
in toluene, product 8 was formed in 71% yield. The addition
of 1 equivalent of tetraethylammonium chloride and a
reaction temperature 1108C had a detrimental effect on the
ef®ciency of the reaction. Silver0I) acetate as additive was
essentially neutral in effect. The best conditions 0Table 3)
employed a 4:1 ratio of phosphine/palladium and no addi-
tives when 8 was formed in 85% yield. At this point it was
decided to assess the reactivity of 4a 0endo-cycloadduct,
Scheme 1) towards palladium00) catalysed cyclisation±
anion capture with tributylvinylstannane 0Scheme 4).
Treatment of 4a with 10 mol% Pd0OAc)2, 20 mol% PPh3
and 3.5 equiv. of the stannane in boiling toluene afforded
direct capture byproduct 10 in 68% yield. This result
shows that in substrate 4a, cyclisation is slower than direct
capture of the vinyl group. Such a remarkable difference in
reactivity is attributed to the buttressing effect of the
maleimide group in the exo-cycloadduct substrates 0Fig. 2).
The exo-cycloadduct 3a has restricted inversion about the
nitrogen atom due to the buttressing of the aryl moiety by
the maleimide group. This effect, which is absent in the
Figure 1. ORTEP24 representation of the molecular structure of 7. Note that the structural asymmetric unit contains two almost identical molecules. In the
interests of brevity only one molecule is shown.

7740
M. R. Fielding et al. / Tetrahedron 57 ꢀ2001) 7737±7748
Scheme 3.
Table 3. Cyclisation±vinyl capture of 3a with tributylvinylstannane 03.5 equiv.)
Time 0h)
Temperature 08C)
Ratio Pd/PPh3
Additive 0equiv.)
Products 0%)a
24
47
14
14
85
110
110
110
1:2
1:2
1:2
1:4
±
8 071)
8 042)
8 074)
8 085)
9 014)
9 010)
9 016)
9 06)
6 014)
6 024)
6 08)
NEt4Cl01)
AgOAc01)
-
6 07)
Reactions carried out in toluene. Catalyst system: 10 mol% Pd0OAc)2 and 20±40 mol% PPh3.
Isolated yields.
a
Scheme 4.
endo-cycloadduct 4a, facilitates the desired cyclisation in
3a.
2.2. Carbonylative processes
Certain reactants, of which carbon monoxide and allenes are
prime examples, allow extension of the relay phase of
cyclisation±anion capture processes and offer the oppor-
tunity to switch the cascade between inter- and intra-
molecular processes. These reactants we have termed
relay switch components.31 Use of carbon monoxide 0CO)
as a relay switch offers access to aldehydes,14 ketones,31
esters, amides, etc.
Figure 2.

M. R. Fielding et al. / Tetrahedron 57 ꢀ2001) 7737±7748
7741
Scheme 5.
We have studied the combination of CO, organostannanes
and oxopyridinium betaines as a route to ketones. Cyclo-
adduct 3a was employed as the substrate for palladium00)
catalysed cyclisation±carbonylation±anion capture employ-
ing a range of tributylstannanes as capture reagents 0Scheme
5; Table 4).
In all cases 0Table 4) a mixture of 12 0via 11, Scheme 5) and
6 was isolated from the reactions. Initially, we employed a
triphenylphosphine±palladium acetate catalyst system. This
promoted cyclisation±carbonylation±capture of 2-thienyl-
012a)- and 2-furyl-012b)-tributylstannane in 66 and 70%
yield, respectively. Vinyl group transfer was successful
but 12c was isolated in a lower yield 051%). Aryl/heteroaryl
stannanes were also found to be effective capture reagents
with phenyl- and 2-pyridyl-tributylstannane reacting with
3a to afford 12d and 12e, respectively 0Table 4). These
last two reactions, however, required a longer time to
achieve complete conversion. Changing the catalyst to
Table 4. Cyclisation±carbonylation±organostannane capture of 3a catalyst
system
Time 0h)
PR3
Bu3SnY 0Yˆ)
Products 0%)a
4
P0Ph)3
12a 066), 6 013)
5
TFPb
12a 080), 6 09)
12b 070), 6 014)
12c 051), 6 016)
12d 055), 6 013)
tris02-furyl)phosphine32-palladium acetate effected
a
5
P0Ph)3
P0Ph)3
P0Ph)3
marked improvement in the yield of 12a 080%) and 12d
086%) but only a slight improvement in the yield of 12e
062%) 0Table 4). The cyclisation±carbonylation±capture
of tributyl03-pyridyl)stannane under the new conditions
afforded 12f in 57% yield. The aldehyde corresponding to
hydride capture of 11 0Scheme 5) was not detected.
3
15
Analogous reactions were carried out with 3c and 3d using
the Pd0OAc)2±TFP catalyst system 0Scheme 6; Table 5).
14
14
15
15
TFP
12d 086), 6 010)
12e 051), 6 019)
12e 062), 6 022)
12f 057), 6 018)
Substrate 3c was subjected to palladium00) catalysed cycli-
sation±carbonylation±anion capture using 3-quinolyl-013)
and 2-thiazolyl-tributylstannane, which were synthesised
by known methods.33 The transfer of bicyclic aromatics
was successful as exempli®ed by the formation of 14a in
good yield 0Table 5). Aromatic groups containing two
heteroatoms also serve as effective capture reagents. Thus,
14b was isolated in 54% yield when 2-thiazolyl tributyl-
stannane was employed. Under identical conditions,
substrate 3d was subjected to cyclisation±carbonylation±
anion capture. Reaction of 3d with tributyl02-thienyl)tin
afforded 14c in 84% yield whereas the 2-furyl stannane
gave 14d in a signi®cantly lower yield 051%) 0Table 5).
P0Ph)3
TFP
TFP
Reactions carried out in toluene at 858C with CO 01 atm) and Bu3SnY
02 equiv.). Catalyst system: 10 mol% Pd0OAc)2 and 20 mol% PR3.
Isolated yields.
a
b
TFPˆtris02-furyl)phosphine.

7742
M. R. Fielding et al. / Tetrahedron 57 ꢀ2001) 7737±7748
Scheme 6.
Table 5. Cyclisation±carbonylation±organostannane capture reactions of
3c and 3d
We have demonstrated that a wide range of tributylstannane
capture reagents readily partake in the cyclisation±
carbonylation±anion capture of substrates 3a, 3c and d.
Also, that direct capture byproducts were not detected in
the reactions carried out in the presence of CO suggesting
that 6-exo-trig processes in these substrates is rapid.
Time 0h)
Substrate
Bu3SnY 0Yˆ)
Products 0%)a
13
3c
14a 075)
4
6
7
3c
3d
3d
14b 054)
14c 084)
14d 051)
2.2.1. Sequential one-pot cycloaddition±palladium cata-
lysed cyclisation±carbonylation±anion capture. Our
cyclisation methodology was combined with Katritzky's
oxopyridinium betaine cycloaddition in a two step, one
pot process 0Scheme 7; Table 6).
N-Phenylmaleimide was the dipolarophile selected for
these one pot reactions due to the excellent yield and
exo-selectivity observed in its cycloadditions with oxo-
pyridinium betaines 0Scheme 1; Table 1). Employing
Reactions carried out in toluene at 858C with CO 01 atm) and Bu3SnY
02 equiv.). Catalyst system: 10 mol% Pd0OAc)2 and 20 mol% TFP.
Isolated yields.
a
Scheme 7.
Table 6. Sequential one-pot cycloaddition±palladium00) catalysed cyclisa-
tion±carbonylation±anion capture of 1 via 3b
phenyl- or 2-thienyl-tributylstannane as capture reagents
gave products 15a 052%) and 15b 061%) 0Table 6). Whilst
there is no improvement in the overall yield for the sequen-
tial one pot processes, puri®cation of the cycloadduct inter-
mediate has been avoided and a substantial increase in
molecular complexity has been achieved involving forma-
tion of 2 rings, 5 bonds and 6 stereocentres regio- and
stereo-selectively in a one pot protocol.
Time 0h)a
Bu3SnY 0Yˆ)
Products 0%)b
22
15a 052)
8
15b 061)
In summary, we have shown that Katritzky's oxopyridinium
betaine cycloadducts serve as excellent substrates for our
palladium00) catalysed cyclisation±anion capture method-
ology. In the absence of CO, hydride and vinyl capture from
organotin0IV) occurred in excellent yield using exo-
cycloadduct 3a. Cyclisation of the corresponding endo-
cycloadduct 4a was found to be very slow. Reactions
Reactions carried out in two steps: 0i) 1 was reacted with NEt3 02.5 equiv.)
and N-phenylmaleimide 01 equiv.) at 1108C in toluene; 0ii) after cooling to
rt catalyst, CO 01 atm) and Bu3SnY 02 equiv.) were added and the reaction
heated to 858C. Catalyst system 0for second step): 10 mol% Pd0OAc)2 and
20 mol% P02-furyl)3.
a
Overall time for the two step procedure.
Isolated yields.
b

M. R. Fielding et al. / Tetrahedron 57 ꢀ2001) 7737±7748
7743
performed in the presence of CO were generally ef®cient
and were successful for a broad range of organotin0IV)
reagents. Performing such reactions as a sequential, one
pot process affords the desired 1,3-diketones whilst bypass-
ing the need for time consuming intermediate puri®cation.
product 05.53 g, 51%) as colourless prisms, mp 111±1148C.
0Found: C, 74.45; H, 7.6; N, 5.15. C16H19NO2 requires: C,
74.7; H, 7.6; N, 5.15%.) nmax 1712, 1457, 1390, 1375, 1155,
833 and 802 cm21. d 7.43 0t, 1H, Jˆ7.3 Hz, ArH), 7.26 0d,
2H, Jˆ7.8 Hz, ArH), 6.88 0s, 2H, COCHvCHCO), 2.62
0quin., 2H, Jˆ6.9 Hz, ArCH0CH3)2) and 1.16 0d, 12H,
Jˆ6.9 Hz, ArCH0CH3)2). m/z 0%) 258 00M1H)1, 100),
214 051) and 174 082).
3. Experimental
3.1. General
3.2. General procedure for 1,3-dipolar cycloaddition
between 1 and 2a±d
Melting points were determined on a Reichert apparatus and
are uncorrected. Mass spectral data were obtained from a
VG Autospec mass spectrometer operating at 70 eV.
Nuclear magnetic resonance spectra spectra were recorded
on Bruker DPX250, QE300, AM 400 and DRX 500
machines operating at 250, 300, 400 and 500 MHz, respec-
tively. Unless otherwise speci®ed, deuterochloroform was
used as solvent with tetramethylsilane as internal standard.
Microanalyses were obtained using a Carlo Erba MOD
11016 instrument and all IR spectra were obtained as
®lms on a Nicolet Magna FT-IR 560 spectrometer. Thin
layer chromatography was carried out on Whatman PESIL
G/UV polyester plates coated with a 0.2 mm layer of silica
gel 60 0Merck 9385). Column chromatography was
performed with silica gel 60 0Merck 9385). Petroleum
ether refers to the fraction with bp 40±608C. Anhydrous
toluene was commercially available 0Aldrich), MeCN was
distilled from calcium hydride, THF was distilled from
sodium and petroleum ether was distilled prior to use.
Non-commercially available organo0IV) compounds and
N-02,6-diisopropylphenyl)maleimide were synthesised
according to known methods.21,33 All compounds are
named according to the IUPAC system and were
determined using the ACD/ILAB webservice 0http://
www.acdlabs.com).
A mixture of 1 015.2 mmol), the N-substituted maleimide
015.2 mmol) and triethylamine 05.3 mL, 38 mmol) in
toluene 0110 mL) were heated under re¯ux for 16±39 h.
After cooling to room temperature, the solvent was removed
under vacuum and the residue puri®ed by column chromato-
graphy to yield a mixture of exo- and endo-cycloadducts as
pale yellow solids.
3.2.1. ꢀ1/2)-exoꢀand endo)-4-Methyl-11-ꢀ2-iodobenzyl)-
4,11-diaza-tricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione
ꢀ3a and 4a). Obtained from 1 05.88 g, 15 mmol) and
maleimide 2a 01.67 g, 15 mmol) after column chromato-
graphy eluting with 1:20, 1:15 and 1:10 v/v EtOAc/
petroleum ether. The exo isomer 3a 03.91 g, 62%) was
obtained as pale yellow rods from EtOAc, mp 150±1518C
and the endo isomer 4a 00.71 g, 10%) as pale yellow prisms
from EtOAc, mp 148±1498C. 3a: 0Found: C, 48.55; H, 3.85;
N, 6.45. C17H13IN2O3 requires: C, 48.35; H, 3.55; N,
6.65%). nmax 1697, 1436 and 1289 cm21. d 7.80 0d, 1H,
Jˆ7.9 Hz, ArH), 7.30±7.24 0m, 1H, ArH), 7.13 0dd, 1H,
Jˆ9.9, 4.8 Hz, COCHvCH), 7.04±6.99 0m, 1H, ArH),
6.95 0dd, 1H, Jˆ7.6, 1.6 Hz, ArH), 6.22 0dd, 1H, Jˆ9.9,
1.4 Hz, COCHvCH), 4.06 0d, 1H, Jˆ4.8 Hz, NCHCHv),
3.84 0s, 1H, NCH), 3.81, 3.74 02£d, 2H, Jˆ13.2 Hz,
NCH2Ar), 3.30, 3.11 02£d, 2H, Jˆ7.2 Hz, 2£NCOCH)
and 3.05 0s, 3H, NCH3). m/z 0%) 422 0M1, 34), 393 045),
295 038), 217062), 205 0100) and 90 048). 4a: 0Found: C,
48.15; H, 3.5; N, 6.5. C17H13IN2O3 requires: C, 48.35; H,
3.55; N, 6.65%). nmax 1733, 1702, 1457, 1435, 1380 and
1284 cm21. d 7.84 0dd, 1H, Jˆ7.9, 1.1 Hz, ArH), 7.34 0dd,
1H, Jˆ7.6, 1.1 Hz, ArH), 7.27 0td, 1H, Jˆ7.4, 1.1 Hz, ArH),
7.04 0dd, 1H, Jˆ9.8, 5.1 Hz, COCHvCH), 7.00±6.96 0m,
1H, ArH), 6.17 0dd, 1H, Jˆ9.8, 0.7 Hz, COCHvCH), 4.20±
4.15 0m, 1H, NCH), 4.03±3.89 0m, 3H, NCH, 2£NCOCH),
3.82, 3.75 02£d, 2H, Jˆ13.7 Hz, NCH2Ar) and 2.88 0s, 3H,
NCH3). m/z 0%) 422 0M1,17), 393 028), 295030), 217075),
2050100) and 90046).
3.1.1. 3-Hydroxy-N-ꢀ2-iodobenzyl)pyridinium bromide
ꢀ1). 3-Hydroxypyridine 03.8 g, 0.04 mol) and 2-iodobenzyl
bromide 012 g, 0.04 mol) were added to dry THF 0200 mL)
and heated under re¯ux for 18 h. The solution was then
reduced in volume to ca. 100 mL and ®ltered to afford 1
014.07 g, 90%) as a colourless, non-crystalline solid, mp
172±1748C. 0Found: C, 36.8; H, 2.8; N, 3.65. BrC12H11INO
requires: C, 36.75; H, 2.8; N, 3.55%.) nmax 3385, 1653, 1576,
1540, 1507, 1497, 1457 and 1437 cm21. d 0d6-DMSO)
8.57±8.54 0m, 2H, ArH), 8.04±8.00 0m, 3H, ArH), 7.51
0dt, 1H, Jˆ7.5, 1.1 Hz, ArH), 7.23 0t, 2H, Jˆ7.9 Hz, ArH)
and 5.86 0s, 2H, ArCH2). m/z 0%) 312 00M2Br)1, 100) and
217 019).
3.2.2. ꢀ1/2)-exo-4-Phenyl-11-ꢀ2-iodobenzyl)-4,11-diaza-
tricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione ꢀ3b). Obtained
from 1 0392 mg, 1 mmol) and maleimide 2b 0173 mg,
1 mmol) after column chromatography eluting with 1:15
and 1:10 v/v EtOAc/petroleum ether. The product 3b
0407 mg, 84%) was obtained as pale yellow prisms from
EtOAc, mp 208±2108C dec. 0Found: C, 54.25; H, 3.45; N,
5.5. C22H17IN2O3 requires: C, 54.55; H, 3.5; N, 5.8%.) nmax
1713, 1701, 1684, 1389, 1203 and 1192 cm21. d 7.81 0d,
1H, Jˆ7.5 Hz, ArH), 7.49±7.37 0m, 3H, ArH), 7.35±7.27
0m, 3H, ArH), 7.20 0dd, 1H, Jˆ9.7, 4.8 Hz, COCHvCH),
7.12 0d, 1H, Jˆ7.6 Hz, ArH), 6.99 0t, 1H, Jˆ7.5 Hz, ArH),
6.28 0dd, 1H, Jˆ9.8, 1.3 Hz, COCHvCH), 4.23 0d, 1H,
3.1.2. N-ꢀ2,6-Diisopropylphenyl)maleimide ꢀ2d). A solu-
tion of 2,6-diisopropylaniline 09.04 g, 5 mmol) in diethyl
ether 010 mL) was added dropwise to a strirred solution of
maleic anhydride 05 g, 5 mmol) in diethyl ether 065 mL) and
stirring continued for 1 h at rt. The solution was cooled to
108C 0ice) and the resulting solid ®ltered off and added to a
mixture of acetic anhydride 017.1 mL) and sodium acetate
01.66 g, 25.2 mmol). The mixture was heated to 1008C for
40 min, allowed to cool to rt, poured into ice-water 060 mL)
and the precipitate ®ltered off, washed with water
02£50 mL) and petroleum ether 0100 mL) and dried under
vacuum at 608C. Crystallisation from hexane afforded the

7744
M. R. Fielding et al. / Tetrahedron 57 ꢀ2001) 7737±7748
Jˆ4.8 Hz, NCHCHv), 4.00 0s, 1H, NCH), 3.90, 3.82 02£d,
2H, Jˆ13.3 Hz, NCH2Ar) and 3.48, 3.2902£d, 2H,
Jˆ7.4 Hz, 2£NCOCH). m/z 0%) 48500M1H)1, 15), 357
09), 339 028), 312 026) and 283 033).
3.3.1. ꢀ1/2)-exo-16-Methyl-2,16-diazapentacyclo[8.8.0.
2,13.04,9.014,18]octadeca-4,6,8-triene-12,15,17-trione ꢀ6)
and ꢀ1/2)-exo-15-methyl-2,15-diazapentacyclo-[8.7.1.
2,12.04,9.013,17]octadeca-4,6,8-triene-11,14,16-trione ꢀ7).
0
0
Obtained from 3a 0101 mg, 0.25 mmol) after column
chromatography eluting with 1:9, 1:5 and 1:1 v/v EtOAc/
petroleum ether. The 6-membered ring product 6 034 mg,
46%) was obtained as ®ne needles from diethyl ether-
hexane, mp 200±2018C dec. and the 7-membered ring
product 7 033 mg, 44%) was obtained as colourless prisms
from diethyl ether, mp 230±2328C. 6: 0Found: C, 68.7; H,
5.65; N, 9.45. C17H16N2O3 requires: C, 68.9; H, 5.4; N,
9.45%). nmax 1734, 1696, 1436, 1386, 1289, 1128 and
1004 cm21. d 0C6D6) 6.96±6.89 0m, 2H, ArH), 6.57 0d,
1H, Jˆ7.1 Hz, ArH), 6.41 0d, 1H, Jˆ6.6 Hz, ArH), 3.88
0d, 1H, Jˆ1.6 Hz, NCH), 3.82, 3.61 02£d, 2H, Jˆ18.7 Hz,
NCH2Ar), 3.50 0d, 1H, Jˆ1.9 Hz, NCH), 2.65 0s, 3H,
NCH3), 2.53±2.51 0m, 1H, ArCHCH2), 2.48, 2.30 02£d,
2H, Jˆ7.7 Hz, 2£NCOCH) and 2.07±1.96 0m, 2H,
ArCHCH2). m/z 0%) 296 0M1, 39), 284 037), 268 0100),
149 030), 117 0100), 91 083), 57 030) and 39 033). 7:
0Found: C, 68.65; H, 5.45; N, 9.55. C17H16N2O3 requires:
C, 68.9; H, 5.4; N, 9.45%). nmax 1733, 1695, 1437, 1296,
1239 1133 and 1115 cm21. d 0C6D6) 6.88±6.86 0m, 2H,
ArH), 6.79±6.77 0m, 1H, ArH), 6.47±6.45 0m, 1H, ArH),
3.85 0s, 1H, NCH), 3.84, 3.74 02£d, 2H, Jˆ18.2 Hz,
NCH2Ar), 3.51 0d, 1H, Jˆ8.9 Hz, NCHCH), 3.18 0d, 1H,
Jˆ7.5 Hz, ArCHCO), 2.71 0dd, 1H, Jˆ7.2, 1.9 Hz,
NCOCH), 2.61 0s, 3H, NCH3), 2.08 0m, 1H, NCOCH),
1.95 0dd, 1H, Jˆ10.2, 9.1 Hz, COCHCH2) and 1.39±1.33
0m, 1H, COCHCH2). m/z 0%) 297 00M1H)1, 20), 268 090),
117 0100) and 91 045).
3.2.3. ꢀ1/2)-exo-4-ꢀ4-Ethylphenyl)-11-ꢀ2-iodobenzyl)-
4,11-diaza-tricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione
ꢀ3c). Obtained from 1 05.59 g, 14.3 mmol) and maleimide
2c 02.87 g, 14.3 mmol) after column chromatography
eluting with 1:10 v/v EtOAc/petroleum ether. The product
04.9 g, 67%) was obtained as pale yellow rods from EtOAc,
mp 187±1888C. 0Found: C, 55.95; H, 4.2; N, 5.2.
C24H21IN2O3 requires: C, 56.25; H, 4.1; N, 5.45%.) nmax
1711, 1685, 1514, 1388, 1206 and 1190 cm21. d 7.36±
6.93 0m, 8H, ArH), 4.25 0d, 1H, Jˆ4.7 Hz, NCH), 4.01 0s,
1H, NCH), 3.92, 3.82 02£d, 2H, Jˆ14.1 Hz, NCH2Ar), 3.48,
3.28 02£d, 2H, Jˆ7.6 Hz, 2£NCOCH), 2.71 0q, 2H,
Jˆ7.7 Hz, ArCH2CH3) and 1.27 0t, 3H, Jˆ7.6 Hz,
ArCH2CH3). m/z 0%) 512 0M1, 15), 484 040), 311 024),
295 034), 217 0100), 201 051) and 186 081).
3.2.4. ꢀ1/2)-exoꢀand endo)-4-ꢀ2,6-Diisopropylphenyl)-
11-ꢀ2-iodobenzyl)-4,11-diaza-tricyclo[5.3.1.02,6]undec-9-
ene-3,5,8-trione ꢀ3d and 4d). Obtained from 1 05.06 g,
12.9 mmol) and maleimide 2d 03.32 g, 12.9 mmol) after
column chromatography eluting with 1:10, 1:5 and 1:1 v/v
EtOAc/petroleum ether. The exo isomer 3d 02.20 g, 30%)
was obtained as colourless rods from EtOAc, mp 130±
1358C and the endo isomer 4d 02.46 g, 33%) as colourless
rods from EtOAc, mp 182±1848C. 3d: 0Found: C, 59.05; H,
5.35; N, 4.6. C28H29IN2O3 requires: C, 59.15; H, 5.1; N,
4.9%). nmax 2966, 1712, 1685, 1465, 1457, 1375 and
1187 cm21. d 7.83 0dd, 1H, Jˆ7.9, 1.0 Hz, ArH), 7.43 0t,
1H, Jˆ7.8 Hz, ArH), 7.34±7.23 0m, 4H, ArH), 7.15 0dd, 1H,
Jˆ9.9, 4.8 Hz, COCHvCH), 6.97 0td, 1H, Jˆ7.8, 1.9 Hz,
ArH), 6.25 0dd, 1H, Jˆ9.9, 1.5 Hz, COCHvCH), 4.37 0d,
1H, Jˆ4.8 Hz, NCHCHv), 4.16 0d, 1H, Jˆ1.1 Hz, NCH),
4.04, 3.93 02£d, 2H, Jˆ14.5 Hz, NCH2Ar), 3.60, 3.40 02£d,
2£1H, Jˆ7.7 Hz, 2£NCOCH), 2.77 0spt, 1H, Jˆ6.7 Hz,
ArCH0Me)2), 2.55 0spt, 1H, Jˆ6.8 Hz, ArCH0Me)2) and
1.17±1.03 0m, 12H, Jˆ6.8 Hz, ArCH0CH3)2). m/z 0%) 569
00M1H)1, 33), 441 015), 351 054), 334 029), 312 0100), 217
096) and 73 052). 4d: 0Found: C, 59.05; H, 5.3; N, 4.7.
C28H29IN2O3 requires: C, 59.15; H, 5.1; N, 4.9%). nmax
1712, 1685, 1365 and 1181 cm21. d 7.86 0dd, 1H, Jˆ7.9,
1.0 Hz, ArH), 7.68±7.19 0m, 6H, ArH, COCHvCH), 7.01
0td, 1H, Jˆ7.8, 2.1 Hz, ArH), 6.27 0dd, 1H, Jˆ9.8, 1.4 Hz,
COCHvCH), 4.29±4.16 0m, 3H, 2£NCH, NCOCH), 4.12±
4.09 0m, 1H, NCOCH), 3.87, 3.81 02£d, 2H, Jˆ13.7 Hz,
NCH2Ar), 2.49 0spt, 2H, Jˆ6.9 Hz, ArCH0CH3)2) and
1.17±1.09 0m, 12H, ArCH0CH3)2). m/z 0%) 569 00M1H)1,
36), 351 056), 312 0100) and 217 075).
3.4. General procedure for cyclisation±vinyl capture
with tributylꢀvinyl)stannane
3a or 4a 0106 mg, 0.25 mmol), palladium0II) acetate
05.6 mg, 10 mol%), the phenylphosphine 020±40 mol%)
and tributyl0vinyl)stannane 01±3.5 equiv.) in toluene 02.5±
5 mL) were rapidly heated to re¯ux for 14±47 h. The
reaction mixture was allowed to cool to rt, evaporated to
dryness, dissolved in MeCN 010 mL), washed with hexane
03£20 mL) and the MeCN layer separated and evaporated to
dryness. The residue was chromatographed to afford
mixtures of 8, 9 and 6.
3.4.1. ꢀ1/2)-exo-16-Methyl-11-vinyl-2,16-diazapenta-
cyclo[8.8.0.02,13.04,9.014,18]octadeca-4,6,8-triene-12,15,17-
trione ꢀ8) and ꢀ1/2)-exo-4-methyl-11-ꢀ2-vinylbenzyl)-
4,11-diaza-tricyclo[5.3.1.02,6]-undec-9-ene-3,5,8-trione
ꢀ9). Obtained from 3a 0422 mg, 1 mmol) after column
chromatography eluting with 1:5, 1:3 and 3:2 v/v EtOAc/
petroleum ether. The product 8 0274 mg, 85%) was obtained
as colourless prisms from EtOAc/petroleum ether, mp 180±
1838C and the direct capture byproduct 9 019.3 mg, 6%)
was obtained as colourless prisms from EtOAc/petroleum
ether, mp 157±1608C. 8: 0Found: C, 70.7; H, 5.6; N, 8.5.
C19H18N2O3 requires: C, 70.8; H, 5.6; N, 8.7%). d 7.30±
7.11 0m, 2H, ArH), 7.02 0t, 2H, Jˆ7.3 Hz, ArH), 5.45±5.35
0m, 1H, H2CvCH), 5.10 0d, 1H, Jˆ16.0 Hz, H2CvCH),
4.98 0d, 1H, Jˆ10.0 Hz, H2CvCH), 4.50, 4.40 02£d, 2H,
Jˆ18.1 Hz, NCH2Ar), 4.01 0s, 1H, NCHCH), 3.73 0s, 1H,
NCHCO), 3.55 0d, 1H, Jˆ7.0 Hz, ArCH), 3.25, 3.05 02£d,
3.3. General procedure for cyclisation±hydride capture
with sodium formate
3a 0106 mg, 0.25 mmol), palladium0II) acetate 05.6 mg,
10 mol%), triphenyl phosphine 013.2 mg, 20 mol%), addi-
tive 0NEt4Cl or ZnCl2, 0.25 mmol) and sodium formate
018.7 mg, 0.275 mmol) were added to MeCN 010 mL) and
heated under re¯ux for 15±21.5 h. The mixture was evapo-
rated to dryness and chromatographed to afford a mixture of
6 and 7as colourless solids.

M. R. Fielding et al. / Tetrahedron 57 ꢀ2001) 7737±7748
7745
2H, Jˆ8.0 Hz, 2£NCOCH), 3.02 0s, 3H, NCH3) and 2.84 0t,
1H, Jˆ7.0 Hz, COCH0CHvCH2)). m/z 0%) 32300M1H)1,
33), 81 037), 69 062) and 55 0100). 9: 0Found: C, 70.55; H,
5.55; N, 8.4. C19H18N2O3 requires: C, 70.8; H, 5.6; N, 8.7%).
d 7.49 0d, 1H, Jˆ7.4 Hz, ArH), 7.28±7.13 0m, 2H, ArH),
7.05±6.96 0m, 2H, ArH, CHvCHCO), 6.77 0dd, 1H,
Jˆ15.6, 11.0 Hz, ArCHvCH2), 6.18 0d, 1H, Jˆ9.4 Hz,
COCHvCH), 5.55 0d, 1H, Jˆ15.6 Hz, ArCHvCH2), 5.12
0d, 1H, Jˆ11.0 Hz, ArCHvCH2), 3.92 0d, 1H, Jˆ4.7 Hz,
NCHCHv), 3.80±3.73 0m, 3H, NCH2Ar, NCH), 3.24, 3.08
02£d, 2H, Jˆ7.7 Hz, 2£NCOCH) and 2.97 0s, 3H, NCH3).
m/z 0%) 322 0M1, 13), 294 032), 268 081), 115 0100) and
91060).
NCOCH). m/z 0%) 407 00M1H)1, 100), 378 065), 267
077) and 111 034).
3.5.2.
ꢀ1/2)-exo-11-ꢀ2-Furoyl)-16-methyl-2,16-diaza-
pentacyclo[8.8.0.02,13.04,9.014,18]-octadeca-4,6,8-triene-
12,15,17-trione ꢀ12b). Obtained from 3a 0422 mg, 1 mmol)
after column chromatography eluting with 1:4 and 1:1 v/v
EtOAc/petroleum ether. The product 12b 0273 mg, 70%)
was obtained as colourless prisms from DCM/petroleum
ether, mp 249±2518C dec. 0Found: C, 62.3; H, 4.45; N,
6.45. C22H18N2O5´0.5CH2Cl2 requires: C, 62.4; H, 4.4; N,
6.45%.) nmax 1698, 1675, 1466, 1437, 1290, 1117, 1028 and
880 cm21. d 7.59 0d, 1H, Jˆ1.0 Hz, ArH), 7.15 0t, 1H,
Jˆ8.7 Hz, ArH), 7.12±6.99 0m, 2H, ArH), 6.94 0t, 1H,
Jˆ8.1 Hz, ArH), 6.59 0d, 1H, Jˆ7.1 Hz, ArH), 6.54 0dd,
Jˆ3.7, 1.8 Hz, 1H, ArH), 4.69, 4.33 02£d, 2H, Jˆ19.1 Hz,
NCH2Ar), 4.65 0s, 1H, NCH), 4.20, 3.95 02£d, 2H,
Jˆ7.1 Hz, COCHCH), 4.11 0s, 1H, NCH), 3.31, 3.05
02£d, 2H, Jˆ7.4 Hz, 2£NCOCH) and 3.06 0s, 3H, NCH3).
m/z 0%) 391 00M1H)1, 100), 362 063), 267 068) and 73 031).
3.4.2. ꢀ1/2)-endo-4-Methyl-11-ꢀ2-vinylbenzyl)-4,11-diaza-
tricyclo[5.3.1.02,6]undec-9-ene-3,5,8-trione ꢀ10). Obtained
from 4a 0422 mg, 1 mmol) after column chromatography
eluting with 1:5, 1:3 and 1:1 v/v EtOAc/petroleum ether.
The direct capture byproduct 10 0219 mg, 68%) was
obtained as a pale yellow, non-crystalline solid, mp 87±
898C. 0Found: C, 70.65; H, 5.85; N, 8.4. C19H18N2O3
requires: C, 70.8; H, 5.6; N, 8.7%.) d 7.54 0d, 1H,
Jˆ7.6 Hz, ArH), 7.30 0t, 1H, Jˆ7.5 Hz, ArH), 7.23 0t, 1H,
Jˆ7.6 Hz, ArH), 7.12 0d, 1H, Jˆ7.6 Hz, ArH), 7.04±6.92
0m, 2H, ArCHvCH2, COCHvCH), 6.15 0d, 1H, Jˆ9.3 Hz,
COCHvCH), 5.64 0d, 1H, Jˆ16.9 Hz, ArCHvCH2), 5.29
0d, 1H, Jˆ10.2 Hz, ArCHvCH2), 4.05 0t, 1H, Jˆ5.6 Hz,
NCHCHv), 4.01±3.92 0m, 3H, NCH, NCH2Ar), 3.87 0d,
1H, Jˆ7.1 Hz, NCOCH), 3.82±3.79 0m, 1H, NCOCH) and
2.86 0s, 3H, NCH3). m/z 0%) 323 00M1H)1, 25), 212 047),
205 038), 149 047) and 117 0100).
3.5.3. ꢀ1/2)-exo-11-Acryloyl-16-methyl-2,16-diazapenta-
cyclo[8.8.0.02,13.04,9.014,18]octadeca-4,6,8-triene-12,15, 17-
trione ꢀ12c). Obtained from 3a 0422 mg, 1 mmol) after
column chromatography eluting with 1:4 and 1:1 v/v
EtOAc/petroleum ether. The product 12c 0179 mg, 51%)
was obtained as colourless prisms from EtOAc-petroleum
ether, mp 127±1298C. 0Found: C, 68.15; H, 5.15; N, 8.0.
C20H18N2O4 requires: C, 68.55; H, 5.15; N, 8.0%.) nmax
1698, 1436, 1290, 1136, 1117 and 996 cm21. d 7.19 0t,
1H, Jˆ7.4 Hz, ArH), 7.08 0t, 1H, Jˆ7.4 Hz, ArH), 7.00
0d, 1H, Jˆ7.6 Hz, ArH), 6.92 0d, 1H, Jˆ7.4 Hz, ArH),
6.27 0dd, 1H, Jˆ17.4, 10.3 Hz, COCHvCH2), 6.09 0d,
1H, Jˆ16.9 Hz, COCHvCH2), 5.79 0d, 1H, Jˆ10.8 Hz,
COCHvCH2), 4.62, 4.31 02£d, 2H, Jˆ16.9 Hz,
NCH2Ar), 4.58 0s, 1H, NCH), 4.08 0s, 1H, NCH), 3.92,
3.54 02£d, 2H, Jˆ7.0 Hz, COCHCH), 3.28, 2.98 02£d,
2H, Jˆ7.4 Hz, 2£NCOCH) and 3.05 0s, 3H, NCH3).
m/z 0%) 351 00M1H)1, 100), 322 063), 267 097) and 182
015).
3.5. General procedure for cyclisation±CO insertion±
anion capture with tributyl-stannanes
3a, 3c or 3d 00.25 mmol), palladium0II) acetate 05.6 mg,
10 mol%), the trisubstituted phosphine 020 mol%) and the
trialkylstannane 02 equiv.) in toluenep 02.5 mL) were rapidly
heated to 858C for 3±15 h under 1 atm of carbon
monoxide 0balloon). On cooling to rt the reaction mixture
was evaporated to dryness, dissolved in MeCN 010 mL),
washed with hexane 03£20 mL), the MeCN layer separated
and evaporated to dryness. The residue was chromato-
graphed to afford mixtures of 12a±f and 6. [p CO gas was
bubbled through the solvent at rt for 5 min prior to reagent
addition.]
3.5.4. ꢀ1/2)-exo-11-Benzoyl-16-methyl-2,16-diazapenta-
cyclo[8.8.0.02,13.04,9.014,18]octadeca-4,6,8-triene-12,15,17-
trione ꢀ12d). Obtained from 3a 0212 mg, 0.5 mmol) after
column chromatography eluting with 1:4 and 1:1 v/v
EtOAc/petroleum ether. The product 12d 0172 mg, 86%)
was obtained as colourless rods from DCM/petroleum
ether, mp 167±1698C. 0Found: C, 70.45; H, 5.0; N, 6.9.
C24H20N2O4´0.25H2O requires: C, 70.4; H, 5.15; N,
6.85%.) nmax 1733, 1699, 1653, 1436, 1386, 1289, 1247
and 1117 cm21. d 8.06±7.54 0m, 3H, ArH), 7.42 0t, 2H,
Jˆ7.4 Hz, ArH), 7.14 0dt, 1H, Jˆ7.5, 1.2 Hz, ArH), 7.01
0d, 1H, Jˆ6.9 Hz, ArH), 6.84 0dt, 1H, Jˆ7.6, 1.2 Hz, ArH),
6.29 0dd, 1H, Jˆ7.6, 0.8 Hz, ArH), 4.73 0s, 1H, NCH), 4.71,
4.34 02£d, 2£H, Jˆ18.4 Hz, NCH2Ar), 4.13, 3.91 02£d, 2H,
Jˆ7.1 Hz, COCHCH), 4.10 0s, 1H, NCH), 3.34 0d, 1H,
Jˆ7.3 Hz, NCOCH) and 3.11±3.07 0m, 4H, NCH3,
NCOCH). m/z 0%) 401 00M1H)1, 75), 372 037), 267
0100) and 105 055).
3.5.1. ꢀ1/2)-exo-11-ꢀ2-Thienoyl)-16-methyl-2,16-diaza-
pentacyclo[8.8.0.02,13.04,9.014,18]-octadeca-4,6,8-triene-
12,15,17-trione ꢀ12a). Obtained from 3a 0106 mg,
0.25 mmol) after column chromatography eluting with 1:4
and 1:1 v/v EtOAc/petroleum ether. The product 12a
082 mg, 80%) was obtained as colourless plates from
EtOAc/petroleum ether, mp 251±2528C dec. 0Found: C,
63.5; H, 4.4; N, 6.65. C22H18N2O4S´0.5H2O requires: C,
63.6; H, 4.6; N, 6.75%.) nmax 1733, 1716, 1698, 1668,
1662, 1558, 1436 and 1290 cm21. d 7.66±7.64 0m, 2H,
ArH), 7.20±7.14 0m, 2H, ArH), 7.02 0d, 1H, Jˆ7.6 Hz,
ArH), 6.93 0t, 1H, Jˆ7.5 Hz, ArH), 6.53 0d, 1H,
Jˆ7.7 Hz, ArH), 4.73, 4.35 02£d, 2H, Jˆ18.5 Hz,
NCH2Ar), 4.62 0s, 1H, NCH), 4.11 0s, 1H, NCH), 4.02,
3.98 02£d, 2H, Jˆ7.2 Hz, COCHCH), 3.33 0d, 1H,
Jˆ7.4 Hz, NCOCH) and 3.09±3.06 0m, 4H, NCH3,
3.5.5. ꢀ1/2)-exo-11-ꢀ2-Pyridoyl)-16-methyl-2,16-diaza-
pentacyclo[8.8.0.02,13.04,9.014,18]-octadeca-4,6,8-triene-
12,15,17-trione ꢀ12e). Obtained from 3a 0422 mg, 1 mmol)

7746
M. R. Fielding et al. / Tetrahedron 57 ꢀ2001) 7737±7748
after column chromatography eluting with 0:0:1, 0.5:1:98
and 0.5:3:96 v/v NEt3/MeOH/DCM. The product 12e
0249 mg, 62%) was obtained as colourless prisms from
EtOAc/petroleum ether, mp 242±2468C. 0Found: C, 68.5;
H, 4.8; N, 10.75. C23H19N3O4 requires: C, 68.8; H, 4.7; N,
10.5%.) nmax 1774, 1697, 1437, 1289, 1244, 1117 and
997 cm21. d 8.70 0m, 1H, ArH), 7.74 0t, 1H, Jˆ7.7 Hz,
ArH), 7.59 0d, 1H, Jˆ7.8 Hz, ArH), 7.50 0m, 1H, ArH),
7.11 0t, 1H, Jˆ7.6 Hz, ArH), 7.00 0d, 1H, Jˆ7.1 Hz,
ArH), 6.82 0t, 1H, Jˆ7.2 Hz, ArH), 6.34 0d, 1H,
Jˆ7.0 Hz, ArH), 4.69, 4.35 02£d, 2H, Jˆ18.4 Hz,
NCH2Ar), 4.67 0s, 1H, NCH), 4.59, 4.39 02£d, 1H,
Jˆ7.0 Hz, 2£COCHCH), 4.10 0s, 1H, NCH), 3.34, 3.11
02£d, 2H Jˆ7.4 Hz, 2£NCOCH) and 3.07 0s, 3H, NCH3).
m/z 0%) 402 00M1H)1, 100), 373 045), 308 09) and 267
038).
3.5.8. ꢀ1/2)-exo-11-ꢀ3-Quinoloyl)-16-ꢀ4-ethylphenyl)-
2,16-diazapentacyclo-[8.8.0.02,13.04,9.014,18]octadeca-4,6,
8-triene-12,15,17-trione ꢀ14a). Obtained from 3c 0256 mg,
0.5 mmol) after column chromatography eluting with 0:0:1,
0.5:1:98 and 0.5:3:96 v/v NEt3/MeOH/DCM. The product
14a 0203 mg, 75%) was obtained as colourless prisms from
EtOAc/petroleum ether, mp 188±1898C. 0Found: C, 73.95;
H, 5.05; N, 7.5. C34H27N3O4´0.5H2O requires: C, 74.2; H,
5.1; N, 7.6%.) nmax 1733, 1708, 1684, 1653, 1559, 1515,
1506, 1387 and 1186 cm21. d 8.95 0d, 1H, Jˆ2.2 Hz, ArH),
8.45 0d, 1H, Jˆ2.0 Hz, ArH), 8.18 0d, 1H, Jˆ8.5 Hz, ArH),
7.95±7.86 0m, 2H, ArH), 7.69 0t, 1H, Jˆ7.0 Hz, ArH),
7.36±7.21 0m, 4H, ArH), 7.16 0d, 1H, Jˆ7.1 Hz, ArH),
7.07 0d, 1H, Jˆ7.3 Hz, ArH), 6.82 0t, 1H, Jˆ6.8 Hz,
ArH), 6.26 0d, 1H, Jˆ7.3 Hz, ArH), 4.92 0s, 1H, NCH),
4.84, 4.46 02£d, 2H, Jˆ18.5 Hz, NCH2Ar), 4.32±4.28
0m, 2H, NCH, COCHCH), 4.00 0d, 1H, Jˆ7.1 Hz,
COCHCH), 3.53, 3.31 02£d, 2H, Jˆ7.6 Hz, 2£NCOCH),
2.70 0q, 2H, Jˆ7.7 Hz, ArCH2CH3) and 1.26 0t, 3H,
Jˆ7.6 Hz, ArCH2CH3). m/z 0%) 542 00M1H)1, 100),
357 096), 285 055), 207 030), 179 065), 147 070) and 133
035).
3.5.6. ꢀ1/2)-exo-11-ꢀ3-Pyridoyl)-16-methyl-2,16-diaza-
pentacyclo[8.8.0.02,13.04,9.014,18]-octadeca-4,6,8-triene-
12,15,17-trione ꢀ12f). Obtained from 3a 0422 mg, 1 mmol)
after column chromatography eluting with 0:0:1, 0.5:1:98
and 0.5:3:96 v/v NEt3/MeOH/DCM. The product 12f
0229 mg, 57%) was obtained as colourless prisms from
EtOAc/petroleum ether, mp 183±1858C. 0Found: C,
68.35; H, 4.85; N, 10.65. C23H19N3O4´0.25H2O requires:
C, 68.06; H, 4.81; N, 10.36%.) nmax 1734, 1717, 1699,
1686 and 1653 cm21. d 8.83±8.79 0m, 2H, ArH), 7.79
0dd, 1H, Jˆ7.9, 2.0 Hz, ArH), 7.38 0dd, 1H, Jˆ8.0,
4.9 Hz, ArH), 7.17 0t, 1H, Jˆ7.6 Hz, ArH), 7.03 0d, 1H,
Jˆ7.7 Hz, ArH), 6.87 0t, 1H, Jˆ7.5 Hz, ArH), 6.31 0d,
1H, Jˆ7.7 Hz, ArH), 4.74 0s, 1H, NCH), 4.69, 4.35 02£d,
2H, Jˆ18.5 Hz, NCH2Ar), 4.12 0s, 1H, NCH), 4.09 0m, 1H,
COCHCH), 3.89 0d, 1H, Jˆ7.1 Hz, COCHCH), 3.35 and
3.11 02£d, 2H, Jˆ7.4 Hz, 2£NCOCH) and 3.08 0s, 3H,
NCH3). m/z 0%) 402 00M1H)1, 100), 373 031), 267 048)
and 220 05).
3.5.9. ꢀ1/2)-exo-11-ꢀ2-Thiazolyl)-16-ꢀ4-ethylphenyl)-2,
16-diazapentacyclo-[8.8.0.02,13.04,9.014,18]octadeca-4,6,8-
triene-12,15,17-trione ꢀ14b). Obtained from 3c 0246 mg,
0.48 mmol) after column chromatography eluting with 1:5
and 1:1 v/v EtOAc/petroleum ether. The product 14b
0131 mg, 54%) was obtained as colourless prisms from
DCM/petroleum ether, mp 162±1658C. 0Found: C, 61.55;
H, 4.35; N, 7.5. C28H23N3O4S´0.75CH2Cl2 requires: C, 61.5;
H, 4.35; N, 7.5%.) nmax 1709, 1685, 1514, 1386, 1183 and
945 cm21. d 8.06 0d, 1H, Jˆ2.9 Hz, ArH), 7.68 0d, 1H,
Jˆ3.0 Hz, ArH), 7.33, 7.24 02£d, 4H, Jˆ8.4 Hz, ArH),
7.15 0t, 1H, Jˆ7.4 Hz, ArH), 7.03 0d, 1H, Jˆ7.5 Hz,
ArH), 6.89 0t, 1H, Jˆ6.8 Hz, ArH), 6.50 0d, 1H,
Jˆ7.5 Hz, ArH), 4.78 0s, 1H, NCH), 4.76 0d, 1H, Jˆ
18.5 Hz, NCH2Ar), 4.51±4.39 0m, 3H, NCH2Ar,
COCHCH), 4.24 0s, 1H, NCH), 3.48, 3.25 02£d, 2H,
Jˆ7.5 Hz, 2£NCOCH), 2.69 0q, 2H, Jˆ7.6 Hz, ArCH2CH3)
and 1.26 0t, 3H, Jˆ7.6 Hz, ArCH2CH3). m/z 0%) 498
00M1H)1, 45), 357 0100), 182 055) and 73 077).
3.5.7. 3-ꢀTributylstannyl)quinoline ꢀ13). Butyl lithium
09.37 mL, 1.6 M in hexanes, 15 mmol) was added dropwise
to a cooled 02788C) stirred solution of 3-bromoquinoline
03.12 g, 15 mmol) in dry diethyl ether 0100 mL) such that
the temperature did not exceed 2708C. The solution was left
at 2788C for a further hour when tributyltin chloride
04.07 mL, 15 mmol) in diethyl ether 020 mL) was added
dropwise and stirring continued for 1 h. The mixture was
allowed to warm to rt and water 080 mL) then carefully
added to the mixture. The organic phase was separated
and the aqueous layer extracted with diethyl ether
03£50 mL). The combined organic extracts were dried
0MgSO4) and the solvent removed under reduced pressure.
The residue was chromatographed eluting with diethyl
ether±pentane mixtures to afford the product 03.89 g,
62%) as a colourless oil. 0Found: C, 60.05; H, 7.8; N,
3.35. C21H33NSn requires: C, 60.30; H, 7.9; N, 3.35%.)
3.5.10. ꢀ1/2)-exo-11-ꢀ2-Thienoyl)-16-ꢀ2,6-diisopropyl-
phenyl)-2,16-diazapentacyclo-[8.8.0.02,13.04,9.014,18]octa-
deca-4,6,8-triene-12,15,17-trione ꢀ14c). Obtained from
3d 0284 mg, 0.5 mmol) after column chromatography
eluting with 1:5 and 1:1 v/v EtOAc/petroleum ether. The
product 14c 0233 mg, 84%) was obtained as a colourless,
non-crystalline solid, mp 220±2258C dec. 0Found: C,
71.7; H, 6.0; N, 4.8. C33H32N2O4S requires: C, 71.75;
H, 5.8; N, 5.05%.) nmax 1709, 1684, 1662, 1653, 1414,
1381 and 1206 cm21. d 7.68±7.66 0m, 2H, ArH), 7.41
0t, 1H, Jˆ7.7 Hz, ArH), 7.28±7.15 0m, 4H, ArH), 7.07
0d, 1H, Jˆ7.2 Hz, ArH), 6.97 0t, 1H, Jˆ7.6 Hz, ArH),
6.58 0d, 1H, Jˆ7.5 Hz, ArH), 4.87, 4.45 02£d, 2H,
Jˆ18.4 Hz, NCH2Ar), 4.74 0s, 1H, NCH), Hz. HHH
4.28 0s, 1H, NCH), 4.09±4.03 0m, 2H, COCHCH),
3.58, 3.32 02£d, 2H, Jˆ7.4 Hz, 2£NCOCH), 2.91 0m,
1H, Jˆ6.7 Hz, ArCH0CH3)2), 2.64 0m, 1H, Jˆ6.8 Hz,
ArCH0CH3)2) and 1.26±1.14 0m, 12H, ArCH0CH3)2).
m/z 0%) 553 00M1H)1, 9), 413 028), 177 045), 91
039) and 69 064).
nmax 2957, 2926, 2871, 2853, 1559, 1488 and 1457 cm21
.
dH 8.92 0d, 1H, Jˆ1.5 Hz, ArH), 8.24 0s, 1H, ArH), 8.07 0d,
1H, Jˆ8.4 Hz, ArH), 7.78 0d, 1H, Jˆ8.1 Hz, ArH), 7.69 0td,
1H, Jˆ8.4, 1.5 Hz, ArH), 7.54 0td, 1H, Jˆ8.0, 1.1 Hz, ArH),
1.62±1.54 0m, 6H, SnBu3), 1.39±1.31 0m, 6H, Jˆ7.1 Hz,
SnBu3), 1.20±1.14 0m, 6H, Jˆ7.8 Hz, Sn0CH2CH2CH2CH3)3)
and 0.89 0t, 9H, Jˆ7.8 Hz, Sn0CH2CH2CH2CH3)3). m/z 0%,
major isotope) 420 00M1H)1, 100), 362 018), 248 045) and
130 027).

M. R. Fielding et al. / Tetrahedron 57 ꢀ2001) 7737±7748
7747
3.5.11. ꢀ1/2)-exo-11-ꢀ2-Furoyl)-16-ꢀ2,6-diisopropylphe-
nyl)-2,16-diazapentacyclo-[8.8.0.02,13.04,9.014,18]octadeca-
4,6,8-triene-12,15,17-trione ꢀ14d). Obtained from 3d
0267 mg, 4.7 mmol) after column chromatography eluting
with 1:5 and 1:1 v/v EtOAc/petroleum ether. The product
14d 0130 mg, 51%) was obtained as colourless rods from
EtOAc/petroleum ether, mp 2458C dec. 0Found: C, 73.85;
H, 6.15; N, 5.05. C33H32N2O5´0.25H2O requires: C, 73.9; H,
5.95; N, 5.2%.) nmax 1712, 1685, 1652, 1458, 1378, 1208
and 1193 cm21. d 7.61 0m, 1H, ArH), 7.50±7.11 0m, 2H,
ArH), 7.10±7.01 0m, 4H, ArH), 6.97 0t, 1H, Jˆ7.2 Hz,
ArH), 6.62 0d, 1H, Jˆ7.3 Hz, ArH), 6.51 0d, 1H,
Jˆ1.0 Hz, ArH), 4.82, 4.43 02£d, 2H, Jˆ18.2 Hz,
NCH2Ar), 4.77 0s, 1H, NCH), 4.25 0s, 1H, NCH), 4.09±
3.99 0m, 2H, COCHCHAr), 3.58, 3.30 02£d, 2H,
Jˆ7.4 Hz, 2£NCOCH), 2.92 0m, 1H, Jˆ6.8 Hz,
ArCH0CH3)2), 2.67 0m, 1H, Jˆ6.8 Hz, ArCH0CH3)2) and
1.30±1.09 0m, 12H, ArCH0CH3)2). m/z 0%) 537 00M1H)1,
100), 185 052), 129 019) and 73 026).
6.0%.) nmax 1733, 1714, 1653, 1558, 1387 and 1184 cm21. d
7.68±7.66 0m, 2H, ArH), 7.51±7.43 0m, 3H, ArH), 7.35 0d,
2H, Jˆ8.5 Hz, ArH), 7.19±7.15 0m, 2H, ArH), 7.05 0d, 1H,
Jˆ6.7 Hz, ArH), 6.95 0t, 1H, Jˆ8.2 Hz, ArH), 6.56 0d, 1H,
Jˆ7.0 Hz, ArH), 4.83, 4.45 02£d, 2H, Jˆ18.2 Hz,
NCH2Ar), 4.76 0s, 1H, NCH), 4.25 0s, 1H, NCH), 4.05±
3.99 0m, 2H, COCHCH) and 3.49, 3.23 02£d, 2H,
Jˆ7.5 Hz, 2£NCOCH). m/z 0%) 469 0M1H1, 9), 440 07),
359 011) and 330 010).
3.7. Single crystal X-ray diffraction analysis of 7
Crystallographic data were measured at 150 K on a Nonius
KappaCCD diffractometer using a mixture of area-detector
v- and f-scans. The structure was solved by direct methods
using SHELXS-8634 and was re®ned by full-matrix least-
squares 0based on F2) using SHELXL-97.35 The weighting
scheme used w ˆ ‰s2ꢀF02† 1 ꢀ0:0661P†2 1 0:2027PŠ
21
where P ˆ ꢀF02 1 2Fc2†=3: All non-hydrogen atoms were
re®ned with anisotropic displacement parameters whilst
hydrogen atoms were constrained to predicted positions
3.6. General procedure for sequential, one pot
cycloaddition±cyclisation±CO insertion±anion capture
with tributyl-stannanes
using a riding model. The residuals wR2 and R1, given
2
P
below,
are
1=2
de®ned
as
wR2 ˆ ꢀ ‰wꢀF0 2 Fc2† Š=
P
P
P
2
‰wꢀFc2† Š† and R1ˆ iF0u2uFci/ uF0u.
A mixture of 1 01 mmol), N-phenylmaleimide 0173 mg,
1 mmol) and triethylamine 00.348 mL, 2.5 mmol) in toluene
010 mL) were heated under re¯ux for 4 h. After cooling to
room temperature, palladium0II) acetate 05.6 mg, 10 mol%),
the trisubstituted phosphine 020 mol%) and the trialkyl-
stannane 02 equiv.) were added and the solution was rapidly
heated to 858C for 3±15 h under 1 atm of carbon monoxide
0balloon). On cooling to rt the reaction mixture was evapo-
rated to dryness, dissolved in MeCN 010 mL), washed with
hexane 03£20 mL), the MeCN layer separated and evapo-
rated to dryness. The residue was chromatographed to afford
15a±b.
Crystal data for 7. C17H16N2O3, 0.66£0.36£0.24 mm3,
Mˆ296.32, monoclinic, space group P21, aˆ12.073402),
Ê
bˆ6.727101), cˆ17.891203) A, bˆ104.3700011), Vˆ
1407.6404) A , Zˆ4, Dcˆ1.4 mg m23, mˆ0.097 mm21
,
Ê 3
F0000)ˆ624, Tˆ150 K.
Data collection. Graphite monochromated Mo-Ka radiation,
Ê
lˆ0.71073 A, 2.0,2u,27.58; Of 34688 data collected,
5502 were unique and 5138 with F0.4.0 s0F0) were
considered `observed'.
Structure re®nement. Number of parametersˆ400, good-
ness of ®t, sˆ1.045; wR2 0all data)ˆ0.1085, R1 0`observed'
data)ˆ0.0398.
3.6.1. ꢀ1/2)-exo-11-Benzoyl-16-phenyl-2,16-diazapenta-
cyclo[8.8.0.02,13.04,9.014,18]octadeca-4,6,8-triene-12,15,17-
trione ꢀ15a). Obtained from 1 0392 mg, 1 mmol) after
column chromatography eluting with 1:5 and 1:1 v/v
EtOAc/petroleum ether. The product 15a 0240 mg, 52%)
was obtained as a colourless, non-crystalline solid from
EtOAc/petroleum ether, mp 2668C dec. 0Found: C, 75.2;
H, 4.7; N, 6.05. C29H22N2O4 requires: C, 75.3; H, 4.8; N,
Acknowledgements
We thank the EPSRC, Leeds University and Zeneca
Agrochemicals 0Syngenta) for support.
6.05%.) nmax 1712, 1684, 1497, 1387, 1206 and 1183 cm21
.
d 7.60 0d, 2H, Jˆ8.0 Hz, ArH), 7.56±7.34 0m, 8H, ArH),
7.16 0t, 1H, Jˆ7.7 Hz, ArH), 7.03 0d, 1H, Jˆ7.5 Hz, ArH),
6.86 0t, 1H, Jˆ7.8 Hz, ArH), 6.32 0d, 1H, Jˆ7.6 Hz, ArH),
4.87 0s, 1H, NCH), 4.80, 4.43 02£d, 2H, Jˆ18.5 Hz,
NCH2Ar), 4.24 0s, 1H, NCH), 4.18, 3.96 02£d, 2H,
Jˆ7.0 Hz, COCHCH) and 3.50, 3.25 02£d, 2H, Jˆ7.5 Hz,
2£NCOCH). m/z 0%) 463 00M1H)1, 26) 434 018) 391 074)
and 329 032).
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