Palladium catalysed tandem cyclisation-anion capture. Part 8: Cascade hydrostannylation-cyclisation-anion capture and cascade hydroboration-cyclisation-anion capture on solid phase

Article abstract of DOI:10.1016/S0040-4020(01)01061-4

Up to four bonds and five stereocentres are created, in five component processes (five point diversity), utilising resin bound aryl iodides by hydroboration or hydrostannylation of alkynes, followed by cyclisation-anion capture involving Suzuki or Stille reactions. Three small libraries were prepared to validate the chemistry.

Full text of DOI:10.1016/S0040-4020(01)01061-4

TETRAHEDRON
Pergamon
Tetrahedron 57 +2001) 10335±10345
Palladium catalysed tandem cyclisation±anion capture. Part 8:
Cascade hydrostannylationÐcyclisation±anion capture and
cascade hydroborationÐcyclisation±anion capture on solid phase
Ronald Grigg,a,p William S. MacLachlan,b David T. MacPherson,b Visuvanathar Sridharana
and Selvaratnam Suganthana
aMolecular Innovation, Diversity and Automated Synthesis ꢀMIDAS) Centre, School of Chemistry, University of Leeds, Leeds LS2 9JT, UK
bGlaxoSmithKline, New Frontiers Science Park, Harlow, Essex CM19 5AW, UK
Received 14 August 2001; revised 21 September 2001; accepted 18 October 2001
AbstractÐUp to four bonds and ®ve stereocentres are created, in ®ve component processes +®ve point diversity), utilising resin bound aryl
iodides by hydroboration or hydrostannylation of alkynes, followed by cyclisation±anion capture involving Suzuki or Stille reactions. Three
small libraries were prepared to validate the chemistry. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
alkynes can be achieved by the incorporation of a b- or
g-heteroatom.4
Solid phase synthesis is now established as a powerful tool
for the preparation of combinatorial libraries of small
molecules for drug lead discovery.1 The molecular diversity
of these libraries is the key element in their usefulness and
this is enhanced by incorporating a variety of chemistries
and diverse building blocks.
Initially we prepared a series of terminal alkynes 1a±p.
We have been developing palladium catalysed cyclisation±
anion capture cascades as powerful protocols for the
assembly of complex heterocycles.2 We now report appli-
cations of this chemistry to solid phase synthesis. In this
paper we focus on organostannanes and organoboranes as
anion capture agents.
2. Results and discussion
2.1. Cascade hydrostannylationÐcyclisation±anion
capture
Palladium catalysed hydrostannylation of terminal alkynes
followed by insertion of palladium+0) into an aryl iodide and
cyclisation onto a proximate alkene terminating in an inter-
molecular Stille reaction potentially provides a wide range
of diverse compounds.3 It has been established that excel-
lent regioselectivity in the hydrostannylation of terminal
Keywords: cascade reactions; palladium catalysis; hydrostannylation;
hydroboration; Stille coupling; Suzuki coupling; cyclisation.
p
Corresponding author. Tel./fax: 144-113-233-6501;
e-mail: r.grigg@chem.leeds.ac.uk
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020+01)01061-4

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R. Grigg et al. / Tetrahedron 57 ꢀ2001) 10335±10345
In the case of alkynes, 1n±p, fragmentation to allene via
allenylpalladium complex 4 renders them unsuitable
substrates +Scheme 2).
The resin bound starter species 7 was prepared from methyl
3-iodo-4-aminobenzoate 5 as shown in Scheme 3 using
Wang resin.
Heating the resin bound aryl iodide +1 mol equiv.) with
vinylstannanes derived from 1a±m +2 mol equiv.) in
toluene +1108C, 8 h) induced cyclisation±anion capture
furnishing 8. Transesteri®cation of the resin bound 8 using
NaCN, Et3N and 1:3 v/v MeOH±THF +508C, 2 days) gave 9
and in some cases mixtures of 9 and 10 +Table 1).
The alkynes 1a±m were allowed to react with Bu3SnH
+2 equiv.) in the presence of 5 mol% Pd2+dba)3 and
20 mol% +2-furyl)3P over 2 h at 08C to rt at which time
hydrostannylation was judged complete by 1H NMR
monitoring. The hydrostannylation was highly regio-
selective +Table 1) affording 2 as the sole isomer in the
majority of cases.
Cleavage of resin bound 8a using 20% TFAin CH 2Cl2 gave
11 in 85% yield. Thus allowing two variants +CO2Me and
CO2H) of the `stub'.
The propynamides are believed to undergo regiospeci®c
hydrostannylation due to the stronger coordination of the
carbonyl oxygen with tin compared to the coordination of
nitrogen in propynamines +Scheme 1).
Interestingly for entries 2, 5 and 11 +Table 1) the ratio of 9/
10 is higher than the precursor a- and b-vinylstannane ratio
indicating that b-vinylstannanes are more reactive than
the a-vinylstannanes. However another possibility for the
variation in the ratio of 9/10 is rearrangement analogous to
that observed by Busacca.5
Scheme 1.
Scheme 2.

R. Grigg et al. / Tetrahedron 57 ꢀ2001) 10335±10345
10337
Table 1. Regioselectivity of formation of stannanes 2a±m and 3a±m and the products of their cyclisation-anion capture 9a±k/10a±k
Entry
Alkynes
Ratio of 2/3
R
Ratio of 9/10
Yielda +%)
1
1a
100:0
100:0
65
2
3
4
5
1b
1c
1d
1e
85:15
100:0
100:0
85:15
75:25
100:0
100:0
75:25
86
72
59
65
6
7
1f
100:0
100:0
100:0
100:0
62b
74
1g
8
1h
100:0
100:0
79
9
1i
1j
100:0
100:0
100:0
100:0
70
58
10
11
12
1k
1l
80:20
91:10
29:71
±
84
±
13
1m
100:0
±
±
a
Isolated yield.
1:1 mixture of diastereoisomers.
b
When vinylstannanes 2l and 2m derived in situ from 1l and
1m were heated with resin bound aryl iodide 7 followed by
transesteri®cation they gave complex mixtures +Table 1,
entries 12 and 13). The literature reports5 that reaction
between iodobenzene and vinylstannane 2m gave methyl
cinnamate as the major product while the expected Stille
product was only present in trace amounts. Busacca
proposed that methyl cinnamate was formed via a palladium
carbene intermediate.
Further structural variation is required in this cascade to
make a diverse library. An illustrative example of how
this can be achieved is shown in Scheme 4. Resin bound
allyl chloride 12 was reacted with excess of benzylamine
+4 equiv.) followed by acetylation to give 13 +Scheme 4).
This sequence of reactions allows three site variations for
library synthesis. Palladium catalysed cyclisation±Stille
coupling using vinylstannane 2h and ®nally transesteri®-
cation gave 14 in 70% yield +Scheme 4).

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R. Grigg et al. / Tetrahedron 57 ꢀ2001) 10335±10345
Scheme 3. +a) +i) ClCO2Me +1.2 equiv.), pyridine +2 equiv.) rt, 15 h, 95%, +ii) NaH +1.1 equiv.), DMF methallyl chloride +1.5 equiv.), rt, 87%; +b) +i) 2N
NaOH, THF, 458C, 15 h, 94%, +ii) Wang resin +loading 1.2 mmol/g), DIPCDI +2 equiv.), DMAP +5 mol%), DCM, rt, 24 h.
Scheme 4.
Having achieved these cascade reactions on solid support
we extended the technology to the preparation of two small
Table 2. Split and mix libraries derived from 12 via amination/acylation/
cyclisationÐStille coupling
libraries using split and mix methodology. For this purpose
resin bound allyl chloride 12 was split into ®ve equal parts
+5.7 g£5) and displacement of allyl chloride with an excess
of ®ve different primary amines was carried out separately
+Table 2). These ®ve resin bound compounds were mixed
and split into ®ve equal parts +5.5 g£5) and each of these
was acylated using an excess of ®ve different acylating
reagents +Table 2). The resin beads +25 compounds) were
then mixed and the resin pool was split into two equal parts
+9.2 g£2) and palladium catalysed cyclisation±Stille
coupling with two different vinylstannanes generated in
situ from the corresponding alkynes +Table 2) was carried
out. The products were cleaved from the resin by transester-
i®cation and ®ltered through a short plug of silica to give L1
+5.0 g), L2 +5.0 g). Each library was shown to comprise a
mixture of 25 compounds as expected by HPLC/MS. The
libraries were analysed by LC/MS: a Waters Symmetryw
C18 +2.1£150 mm) column eluting +0.2 ml/min) with
mixtures of water +0.1% TFA) and acetonitrile +0.1%
TFA); gradient decreasing linearly from 100% water
Aminesa
Acylating agents
Alkynes
TsCl, Et3N, DCM, rt,
24 h
1d and 1h
Ac2O, pyridine,
MeCN, 508C, 24 h
Et3N, rt, 24 h
BuNH2
EtNCO, DCM, rt, 24 h
PhNCO, DCM, rt, 24 h
a
MeCN, K2CO3 +2 equiv.), 808C, 24 h.

R. Grigg et al. / Tetrahedron 57 ꢀ2001) 10335±10345
10339
+0.1% TFA) to 20% water +0.1% TFA) over 20 min with
maintenance of the mobile phase at 20% water +0.1% TFA)
for 10 min; UV detection 214 mm; MS Finnigan LCQ or
Micromass ZMD 2000 using electrospray positive ioni-
sation.
demonstrated9 palladium catalysed cyclisation±anion
capture methodology employing boronic acids as anion
transfer reagents, which employed Na2CO3 as base. There-
fore after hydroboration water was added to the reaction
mixture and the resulting mixture was stirred for 1 h at
808C to effect hydrolysis of 16a±e and 16k to the corre-
sponding boronic acids. Subsequent addition of resin bound
zipper 7, 10 mol% Pd+OAc)2, 20 mol% PPh3, Na2CO3
+3 mol equiv.), Et4NCl +1 mol equiv.) and toluene and heat-
ing +1108C, 15 h) gave 17a±c and 17k. Transesteri®cation
gave 18a±c and 18k in good yields +Table 3). Hydride
ion capture product 19 +,10%) was also formed in most
reactions +Table 3).
2.2. Cascade hydroborationÐcyclisation±anion capture
Hydroboration of terminal alkynes followed by insertion of
palladium+0) into an aryl iodide and cyclisation onto a
proximate alkene terminating in an intermolecular Suzuki
reaction potentially provides a wide range of diverse com-
pounds. Here we report examples of this cascade on solid
phase.
Hydroboration, using catecholborane only works well for
simple alkyl and aryl alkynes. Heteroatom functionalised
alkynes fail to hydroborate, because of the coordination of
the heteroatom to boron.
To illustrate viable approaches to diverse libraries, resin
bound allyl chloride 12 was reacted with excess benzyl-
amine followed by reaction with ethyl isocyanate. The
resulting resin bound product was then subjected to
palladium catalysed cyclisation±Suzuki coupling with 16c
and ®nally cleaved from the resin by transesteri®cation to
give 20 in 52% yield.
Afurther variant is illustrated by the reaction between resin
bound allyl chloride 12 and excess butylamine followed by
reaction with phenyl isocyanate. Palladium catalysed cycli-
sation±Suzuki coupling of this resin bound product with
16d and ®nally Diels±Alder reaction with N-methyl-
maleimide +endo transition state) and subsequent cleavage
from the resin by methanolysis gave 21 in 30% yield over
The terminal alkynes 15a±e, 1k and 1d were allowed to
react with catecholborane +1 mol equiv.) at 708C for 1.5 h
in the absence of solvent6 and the crude products were
1
®ve steps. H NMR spectroscopy showed 21 to comprise a
2:1 mixture of diastereoisomers. The overall sequence
generates four C±C bonds, ®ve stereocentres and employs
®ve reactants. This illustrates the potential for achieving
considerable diversity in the libraries.
1
examined by H NMR. In the case of 15a±e and 1k the
E-2-alkenyl-1,3,2-benzodioxaborates 16a±e and 16k were
obtained stereo- and regio-speci®cally. In the case of 1d
starting material was recovered.
Using split and mix methodology another small library was
assembled. For this purpose resin bound allyl chloride 12
was split into four equal parts +1.7 g£4) and displacement of
the chloride with excess of four different primary amines
was carried out separately +Table 4). For the purpose of
making the library these four resin bound compounds
were mixed. The resin `pool' was split into two equal
parts +3.3 g£2) and each of these was acylated using excess
of two different acylating reagents +Table 4). The resin
beads +eight compounds) were then mixed. The resin pool
was split into two equal parts +3.5 g£2) and palladium
catalysed cyclisation±Suzuki coupling with two different
Attempted Suzuki coupling of zipper 7 using alkenylborates
16a and 16k derived from 15a and 1k in the presence of
10 mol% Pd+OAc)2, 20 mol% PPh3 and Na2CO3 +2 equiv.)/
K3PO4 +2 equiv.) failed to give the desired product. Only
starting material was recovered.
Table 3. Split and mix libraries derived from 7 via cyclisationÐSuzuki
coupling with in situ generated boronates.
Entry
Alkyne
R
18 +%)a
19 +%)b
The literature reports7 that relatively strong bases such as
NaOR or NaOH were required for the coupling of alkenyl
borates with aryl halides. These bases are strong enough to
cleave 7 from the resin. However, there are some literature
reports8 that Na2CO3, or K2CO3 suspended in alcoholic
solvents are effective bases for these reactions, but alcoholic
solvents are not suitable for resin chemistry. We have
1
2
3
4
15a
15b
15c
1k
n-Bu
84
71
93
81
5
5
±
8
c-C5H9
c-C6H11CH2
Ph
a
Isolated yield.
Determined from the 1H NMR spectrum of the reaction mixture.
b

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R. Grigg et al. / Tetrahedron 57 ꢀ2001) 10335±10345
in situ generated boronates +Table 4) was carried out. The
resin beads +16 compounds) were then mixed and the resin
pool +5.6 g) subjected to the Diels±Alder reaction with
dimethyl maleate. The products were cleaved from the
resin by transesteri®cation and ®ltered through a short
plug of silica to give the library +2.4 g) which was shown
to comprise a mixture of the expected 16 compounds by
HPLC/MS as previously discussed.
In summary, three libraries have been prepared to demon-
strate the ef®ciency and power of the new cascade tech-
nology. The new technology offers unique series of
compounds. It effects major increases in molecular
complexity and occurs in excellent yield. It is capable
of substantial further development in many directions
including parallel synthesis of single compounds.
3. Experimental
3.1. General
analyses were obtained using a Carlo Erba MOD 11016
instrument. Thin layer chromatography was carried out on
Whatman PESIL G/UV polyester plates coated with a
0.2 mm layer of silica-gel 60 +Merck 9385). Anhydrous
DMF was commercially available +Aldrich), THF and
toluene were sodium dried under a nitrogen atmosphere
and n-hexane was distilled prior to use. Petroleum ether
refers to the fraction with boiling point 40±608C. Non-
commercially available alkynes were synthesised according
to literature methods.10
Melting points were determined on a Ko¯er hot-stage appa-
ratus and are uncorrected. Mass spectral data were obtained
from a VG Autospec operating at 70 eV. Nuclear magnetic
resonance spectra were recorded on Bruker QE 300 and AM
400 machines operating at 300 and 400 MHz, respectively.
Unless otherwise speci®ed, deuterochloroform was used as
solvent with tetramethylsilane as internal standard. Micro-
Table 4. Split and mix libraries derived from 12 via amination/acylation/cylisationÐSuzuki coupling +in situ generated boronates)./Diels±Alder reactions
Aminea
Acylating agent
Alkyne
Dienophileb
Ac2O, Pyridine, MeCN, 508C,
24 h and PhNCO, DCM, rt, 24 h
15d and 15e
BuNH2
a
MeCN, K2CO3 +2 equiv.), 808C, 24 h.
Toluene, 1108C, 36 h.
b

R. Grigg et al. / Tetrahedron 57 ꢀ2001) 10335±10345
10341
3.1.1. Methyl 3-iodo-4[1methoxycarbonyl)12-methyl-2-
propenyl)amino]benzoate 6. Methyl chloroformate +4 g,
0.043 mol) was added dropwise with stirring to a solution
of the methyl 3-iodo-4-aminobenzoate 5 +10 g, 0.036 mol)
and pyridine +5.6 g, 0.072 mol) in dry DCM +200 ml) at 08C.
The resulting mixture was stirred at room temperature for
15 h. Water +100 ml) was then added and the mixture
extracted with DCM +2£150 ml). The combined organic
layers were dried +MgSO4) and evaporated and the residual
crude product +11.5 g, 95%) was used directly for the next
stage without further puri®cation. d +CDCl3, 300 MHz):
8.43 +d, 1H, Jˆ1.8 Hz, ArH), 8.19 +dd, 1H, Jˆ1.8 and
8.1 Hz, ArH), 7.95 +d, 1H, Jˆ8.1 Hz, ArH), 7.22 +br, 1H,
NH), 3.92 and 3.81 +2£s, 2£3H, 2£OMe); m/z +%): 335
+M1, 4), 304 +100), 276 +56) and 91 +12). Asolution
of methyl 3-iodo-4+N-methoxycarbonyl)aminobenzoate
+9.6 g, 0.045 mol) in DMF +75 ml) was added dropwise at
08C to a stirred suspension of sodium hydride +50% dis-
persion in mineral oil, 4.44 g, 0.09 mol) in dry DMF
+75 ml) and the resulting solution was stirred at room
temperature for 1 h. Methallyl chloride +4.17 g, 0.045 mol)
was added dropwise at 08C to this stirred solution and the
stirring continued at room temperature for 15 h. The solvent
was then evaporated, water +75 ml) was added and the
mixture extracted with DCM +2£100 ml). The combined
organic layers were dried +MgSO4), the solvent evaporated
and the residual oil puri®ed by ¯ash chromatography eluting
with 5:1 v/v hexane±ethyl acetate to give the ester 6 +9.6 g,
87%) as a pale yellow gum. +Found: C, 42.8; H, 4.1; N, 3.55;
C14H16INO4 requires: C, 43.2; H, 4.15; N, 3.6%.) d +CDCl3,
300 MHz): 8.55 +d, 1H, Jˆ1.7 Hz, ArH), 8.0 +dd, 1H, Jˆ1.7
and 8.2 Hz, ArH), 7.22 +d, 1H, Jˆ8.2 Hz, ArH), 4.86 and
4.75 +2£s, 2£1H, vCH2), 4.63 and 3.61 +2£d, 2£1H, Jˆ
13.2 Hz, NCH2), 3.94 and 3.65 +2£s, 2£3H, 2£OMe), and
1.81 +s, 3H, Me); m/z +%): 389 +M1, 8), 358 +100), 330 +70)
and 299 +12).
ideneacetone) dipalladium+0) +0.0423 mmol) and tris-
+2-furyl)phosphine +0.169 mmol) in dry toluene +20 ml)
was stirred and cooled at 08C and tributyltin hydride
+1.69 mmol) added. After 5 min the cooling bath was
removed and stirring continued for 2 h at room temperature.
1
The vinylstannane was readily detected in the H NMR
spectrum +presence of ol®nic protons) of the crude product.
After addition of resin bound aryl iodide 7 +1 g, 0.84 mmol)
the mixture was heated at 1108C for 8±12 h. The resin was
then ®ltered off, washed thoroughly with MeOH, DCM and
ether and dried under vaccum. Transesteri®cation was
carried out using NaCN +0.4 g, 0.84 mmol) and Et3N
+0.57 g, 5.9 mmol) in 1:3 v/v MeOH±THF +10 ml) and the
mixture was heated at 508C for 2 days. Following removal
of the resin by ®ltration, evaporation of the ®ltrate afforded
the product.
3.2.1. 3-Methyl-3-12-phenylcarbamoyl-allyl)2,3-dihydro-
indole-1,5-dicarboxylic acid dimethyl ester 9a. Prepared
from alkyne 1a by the general procedure. Hydrostannylation
gave only a-vinylstannane. After cyclisation and trans-
esteri®cation the crude product was puri®ed by ¯ash
chromatography eluting with 2:1 v/v ether±hexane to
afford the product 9a +65%) as colourless prisms, mp
154±1578C. +Found: C, 67.5; H, 5.85; N, 6.55;
C23H24N2O5 requires: C, 67.65; H, 5.9; N, 6.85%.) d
+CDCl3, 300 MHz): 7.92±7.12 +m, 8H, ArH), 5.47 and
4.95 +2£s, 2£1H, vCH2), 4.58 and 4.18 +2£d, 2£1H,
Jˆ11.8 Hz, NCH2), 3.82 and 3.5 +2£s, 2£3H, 2£OMe),
2.88 and 2.51 +2£d, 2£1H, Jˆ 13.2 Hz, CH2±Cv) and
1.42 +s, 3H, Me); m/z +%): 408 +M1, 1), 377 +7), 248 +84),
216 +51) and 161 +100).
3.2.2. 3-Methyl-3-12-phenylaminomethyl-allyl)-2,3-di-
hydro-indole-1,5-dicarboxylic acid dimethylester 9b
and 3-methyl-3-11E)-4-phenylamino-but-2-enyl)-2,3-di-
hydro-indole-1,5-dicarboxylic acid dimethyl ester 10b.
Prepared from alkyne 1b by the general procedure.
Hydrostannylation gave 85:15 ratio of a- and b-vinyl-
stannanes. After cyclisation and transesteri®cation the
crude product comprised a 3:1 mixture of 9b and 10b.
Flash chromatography eluting with 1:2 v/v ether±hexane
gave 9b as colourless prisms, mp 109±1128C, and the
minor isomer 10b contaminated with 9b. The total yield
was 86%.
3.1.2. Hydrolysis of methyl ester 6 and attachment to the
resin 7. Ester 6 +6.25 g, 0.016 mol) was treated with 2 M
NaOH +35 ml) in THF +35 ml) and stirred for 15 h at 458C.
The THF was removed under reduced pressure, the aqueous
mixture neutralised with 2N HCl +35 ml) and extracted with
ether +3£75 ml). The combined organic layers were dried
+MgSO4) and evaporated to give acid +5.66 g, 94%) as
colourless solid which was used for the next step without
further puri®cation. d +CDCl3, 300 MHz): 8.59 +s, 1H,
ArH), 8.05 and 7.2 +2£d, 2£1H, Jˆ8.1 Hz, ArH), 4.83
and 4.77 +2£s, 2£1H, vCH2), 4.61 and 3.6 +2£d, 2£1H,
Jˆ14.2 Hz, NCH2), 3.67 +s, 3H, OMe), and 1.8 +s, 3H, Me).
DCM +30 ml) was added to Wang resin +loading 1.2 mmol/
g) +6.25 g, 7.5 mmol) and the resin allowed to swell for
5 min. Acid +5.62 g, 0.015 mol) in DCM +40 ml) and diiso-
propylcarbodiimide +DIPCDI) +1.92 g, 0.015 mol) were
then added followed by DMAP +0.045 g, 0.37 mmol) after
10 min. The mixture was stirred slowly for 24 h, then
®ltered and washed successively with MeOH, DCM and
ether and dried under vacuum to give the resin bound aryl
iodide 7 +8.85 g).
9b: +found: C, 69.75; H, 6.75; N, 7.0; C24H26N2O4 requires:
C, 70.05; H, 6.65; N, 7.1%). d +CDCl3, 300 MHz): 7.96 +d,
2H, Jˆ7.3 Hz, ArH), 7.84 +s, 1H, ArH), 7.1 +t, 2H, Jˆ
7.6 Hz, ArH), 6.65 +t, 1H, 7.5 Hz, ArH), 6.41 +d, 2H, Jˆ
6.5 Hz, ArH), 5.12 and 4.8 +2£s, 2£1H, vCH2), 4.13 and
3.71 +2£d, 2£1H, Jˆ11.1 Hz, NCH2), 3.87 and 3.83 +2£s,
2£3H, 2£OMe), 3.65 +br, 1H, NH), 3.25 +br, 2H, NCH2),
2.55 and 2.4 +2£d, 2£1H, Jˆ13.9 Hz, CH2±Cv) and 1.12
+s, 3H, Me); m/z +%): 394 +M1, 56), 363 +12), 248 +55), 216
+31) and 146 +100).
10b: d +CDCl3, 300 MHz): 7.95 +d, 2H, Jˆ7.3 Hz, ArH),
7.75 +s, 1H, ArH), 7.15 +t, 2H, Jˆ7.6 Hz, ArH), 6.65 +t, 1H,
7.5 Hz, ArH), 6.55 +d, 2H, Jˆ6.5 Hz, ArH), 5.55 +m, 2H,
2£vCH), 3.84 and 3.8 +2£s, 2£3H, 2£OMe), 3.6 +m, 4H,
2£NH2), 3.25 +br, 2H, NCH2), 2.32 +m, 2H, CH2±Cv) and
1.31 +s, 3H, Me).
3.2. General procedure for palladium catalysed cascade
hydrostannylationÐcyclisation±anion capture
Asolution of terminal alkyne +1.69 mmol), tris+dibenzyl-

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R. Grigg et al. / Tetrahedron 57 ꢀ2001) 10335±10345
3.2.3. 3-12-Benzylcarbamoyl-allyl)-3-methyl-2,3-dihydro-
indole-1,5-dicarboxylic acid dimethyl ester 9c. Prepared
from alkyne 1c by the general procedure. Hydrostannylation
gave only a-vinylstannane. After cyclisation and transester-
i®cation the crude product was puri®ed by ¯ash chroma-
tography eluting with ether to afford the product 9c +72%)
as colourless prisms, mp 52±558C. +Found: C, 67.95; H,
6.25; N, 6.45; C24H26N2O5 requires: C, 68.25; H, 6.2; N,
6.65%.) d +CDCl3, 300 MHz): 7.9 +d, 1H, Jˆ7.8 Hz,
ArH), 7.76 +s, 1H, ArH), 7.29 +m, 6H, ArH), 6.14 +br, 1H,
NH), 5.44 and 4.98 +2£s, 2£1H, vCH2), 4.27 +t, 2H,
Jˆ5.8 Hz, CH2Ph), 4.1 and 3.61 +2£d, 2£1H, Jˆ11.2 Hz,
NCH2), 3.84 and 3.77 +2£s, 2£3H, 2£OMe), 2.78 and 2.59
+2£d, 2£1H, Jˆ13.3 Hz, CH2±Cv) and 1.35 +s, 3H, Me);
m/z +%): 422 +M1, 1), 391 +7), 248 +55), 216 +41), 175 +100)
and 91 +37).
3.2.6. 3-[2-11-Methoxycarbonyl-2-phenyl-ethylcarbamoyl)-
allyl]-3-methyl-2,3-dihydro-indole-1,5-dicarboxylic acid
dimethyl ester 9f. Prepared from alkyne 1f by the general
procedure. Hydrostannylation gave only a-vinylstannane.
After cyclisation and transesteri®cation the crude product
was puri®ed by ¯ash chromatography eluting with ether to
afford the product 9f +62%) as colourless prisms, mp 65±
688C +1:1 mixture of diastereoisomers). +Found: C, 65.3; H,
6.0; N, 5.5; C27H30N2O7 requires: C, 65.55; H, 6.10; N,
5.65%.) d +CDCl3, 300 MHz): 7.89 +m, 3H, ArH), 7.3±
7.05 +m, 5H, ArH), 6.2 and 6.15 +2£d, 1H, Jˆ7.6 Hz, NH,
isomers), 5.43, 5.42, 5.07 and 5.02 +4£s, 2H, vCH2,
isomers), 4.8 and 4.79 +2£q, 1H, Jˆ7.9 Hz, NCH, isomers),
4.05 +dd, 1H, Jˆ11.3 and 5 Hz, CHPh), 3.88 and 3.87 +2£s,
3H, 2£OMe, isomers), 3.81 +s, 3H, OMe), 3.73 and 3.72
+2£s, 3H, 2£OMe, isomers), 3.59 +t, 1H, Jˆ11.5 Hz,
CHPh), 3.15 +m, 2H, NCH2), 2.81 2.69, 2.67 and 2.5
+4£d, 2H, Jˆ13.4 Hz, CH2±Cv, isomers), 1.31 and 1.3
+2£s, 3H, Me, isomers); m/z +%): 494 +M1, 5), 463 +10),
248 +100), 216 +35), 144 +30) and 91 +40).
3.2.4. 3-{2-[1Acetyl-benzyl-amino)-methyl]-allyl}-3-methyl-
2,3-dihydro-indole-1,5-dicarboxylic acid dimethyl ester
9d. Prepared from alkyne 1d by the general procedure.
Hydrostannylation gave only a-vinylstannane. After cycli-
sation and transesteri®cation the crude product was puri®ed
by ¯ash chromatography eluting with ether to afford the
product 9d +59%) as a pale yellow gum. +Found: C, 68.8;
H, 6.55; N, 5.85; C26H30N2O5 requires: C, 69.3; H, 6.7; N,
6.2%.) d +CDCl3, 300 MHz). An asterisk indicates the
presence of a pair of signals of almost equal intensity which
represent the same proton+s) of the amide rotamers: 7.84±7.0
+m, 8H, ArH), 5.91 and 4.78 +2£s, 2£1H, vCH2, 4.86p and
4.72p), 4.15±4.34 +m, 2H, CH2Ph), 3.8 and 3.82 +2£s, 2£3H,
2£OMe), 3.51±3.72 +m, 2H, NCH2), 3.15 and 3.38 +2£d,
2£1H, Jˆ13.2 Hz, NCH2), 2.37 +m, 2H, CH2±Cv), 2.14 +s,
3H, COCH3, 1.84p) and 1.4 +s, 3H, Me); m/z +%): 451 +M111,
2), 419 +20), 248 +91), 203 +90) and 91 +100).
3.2.7.
3-Methyl-3-12-pyrazol-1-ylmethyl-allyl)-2,3-di-
hydro-indole-1,5-dicarboxylic acid dimethyl ester 9g.
Prepared from alkyne 1g by the general procedure. Hydro-
stannylation gave only the a-vinylstannane. After cycli-
sation and transesteri®cation the crude product was
puri®ed by ¯ash chromatography eluting with 3:1 v/v
ether±hexane to afford the product 9g +74%) as a pale
yellow gum. +Found: C, 64.7; H, 6.15; N, 10.9;
C20H23N3O4 requires: C, 65.0; H, 6.25; N, 11.35%.) d
+CDCl3, 300 MHz): 7.9 +d, 2H, Jˆ7.8 Hz, ArH), 7.8, 7.45,
7.18 and 6.21 +4£s, 4£1H, ArH), 4.92 and 4.8 +2£s, 2£1H,
vCH2), 4.27 +s, 2H, NCH2), 4.1 and 3.71 +2£d, 2£1H,
Jˆ11.2 Hz, NCH2), 3.9 and 3.82 +2£s, 2£3H, 2£OMe),
2.78 +s, 2H, CH2±Cv) and 1.41 +s, 3H, Me); m/z +%):
370 +M111, 12), 338 +7), 248 +35), 216 +26), 122 +100)
and 59 +22).
3.2.5. 3-12-Imidazol-1-ylmethyl-allyl)-3-methyl-2,3-di-
hydro-indole-1,5-dicarboxylic acid dimethyl ester 9e
and 3-11E)-4-imidazol-1-yl-but-2-enyl)-3-methyl-2,3-di-
hydro-indole-1,5-dicarboxylic acid dimethyl ester 10e.
Prepared from alkyne 1e by the general procedure. Hydro-
stannylation gave 87:13 ratio of a- and b-vinylstannane +1H
NMR). After cyclisation and transesteri®cation the crude
product comprised a 3:1 mixture of 9e and 10e. Flash
chromatography eluting with 95:5 v/v ethyl acetate±metha-
nol gave the products 9e and 10e in 65% combined yield as
pale yellow gums.
3.2.8. 3-12-Benzotriazol-1-ylmethyl-allyl)3-methyl-2,3-
dihydro-indole-1,5-dicarboxylic acid dimethyl ester 9h.
Prepared from alkyne 1h by the general procedure. Hydro-
stannylation gave only the a-vinylstannane. After cycli-
sation and transesteri®cation the crude product was
puri®ed by ¯ash chromatography eluting with 2:1 v/v
ether±hexane to afford the product 9h +79%) as colourless
prisms, mp 120±1238C. +Found: C, 65.7; H, 5.9; N, 13.35;
C23H24N4O4 requires: C, 65.7; H, 5.75; N, 13.3%.) d
+CDCl3, 300 MHz): 8.0 +m, 3H, ArH), 7.8 +s, 1H, ArH),
7.21±7.47 +m, 3H, ArH), 4.96±4.7 +m, 4H, NCH2 and
vCH2), 4.18 and 3.77 +2£d, 2£1H, Jˆ11.2 Hz, NCH2),
3.9 +s, 6H, 2£OMe), 2.4 +s, 2H, CH2±Cv) and 1.41 +s,
3H, Me); m/z +%): 420 +M1, 12), 389 +6), 248 +60), 216
+36), 173 +100) and 59 +16).
9e: +found: C, 64.7; H, 5.95; N, 10.95; C20H23N3O4 requires:
C, 65.0; H, 6.25; N, 11.35%). d +CDCl3, 300 MHz): 8.05 +d,
2H, Jˆ7.9 Hz, ArH), 7.81, 7.25, 7.05 and 6.68 +4£s, 4£1H,
ArH), 4.98 and 4.77 +2£s, 2£1H, vCH2), 4.1 and 3.75 +2£d,
2£1H, Jˆ13.1 Hz, NCH2), 3.92 +s, 3H, OMe), 3.82 +m, 5H,
OMe and NCH2), 2.3 +s, 2H, CH2±Cv) and 1.41 +s, 3H,
Me); m/z +%): 369 +M1, 7), 338 +11), 248 +81), 216 +53) and
122 +100).
3.2.9. 3-[2-12-Methoxycarbonyl-phenyl)allyl]-3-methyl-
2,3-dihydro-indole-1,5-dicarboxylic acid dimethyl ester
9i. Prepared from alkyne 1i by the general procedure.
Hydrostannylation gave only the a-vinylstannane. After
cyclisation and transesteri®cation the crude product was
puri®ed by ¯ash chromatography eluting with 2:1 v/v
ether±hexane to afford the product 9i +70%) as colourless
prisms, mp 135±1388C. +Found: C, 67.8; H, 6.1; N, 3.2;
C24H25NO6 requires: C, 68.05; H, 5.95; N, 3.3%.) d
10e: d +CDCl3, 300 MHz): 7.97 +d, 2H, Jˆ8.0 Hz, ArH),
7.75, 7.41, 7.02 and 6.78 +4£s, 4£1H, ArH), 5.6 and 5.4
+2£m, 2£1H, 2£vCH), 4.41 +d, 1H, 7.5 Hz, NCH2), 3.91
and 3.84 +2£s, 2£3H, 2£OMe), 3.86 and 3.65 +2£d, 2H,
Jˆ13.5 Hz, NCH2), 2.38 +m, 2H, CH2±Cv) and 1.39 +s,
3H, Me); m/z +%): 369 +M1, 6), 338 +11), 262 +12), 248
+81), 122 +100) and 59 +32).

R. Grigg et al. / Tetrahedron 57 ꢀ2001) 10335±10345
10343
+CDCl3, 300 MHz): 7.8 +m, 3H, ArH), 7.6 +s, 1H, ArH), 7.25
+m, 2H, ArH), 6.95 +d, 1H, Jˆ6.8 Hz, ArH), 5.03 and 5.0
+2£s, 2H, vCH2), 3.9 +m, 7H, NCH and 2£OMe), 3.8 +s,
3H, OMe), 3.57 +d, 1H, Jˆ13.2 Hz, NCH), 2.85 and 2.78
+2£d, Jˆ13.5 Hz, 2H, CH2±Cv) and 1.3 +s, 3H, Me); m/z
+%): 423 +M1, 2), 248 +100), 216 +40), 145 +26) and 130
+11).
ArH), 7.63 +d, 2H, Jˆ7.6 Hz, ArH), 7.28 +t, 2H, Jˆ7.8 Hz,
ArH), 7.02 +t, 1H, Jˆ7.8 Hz, ArH), 5.77 and 5.21 +2£s,
2£1H, vCH2), 4.2 and 3.62 +2£d, 2£1H, Jˆ11.2 Hz,
NCH2), 3.6 +s, 3H, OMe), 2.94 and 2.68 +2£d, 2£1H, Jˆ
12.8 Hz, CH2±Cv) and 1.41 +s, 3H, Me); m/z +%): 394
+M1, 2), 302 +3), 234 +65), 161 +100), 131 +40) and 77 +15).
3.2.13. Resin bound allyl chloride 12. Asolution of methyl
3-iodo-4+N-methoxycarbonyl)aminobenzoate +1.69 g, 0.005
mol) in DMF +25 ml) was added dropwise at 08C to a stirred
suspension of sodium hydride +50% dispersion in mineral
oil, 0.242 g, 0.01 mol) in dry DMF +25 ml) and the resulting
solution was stirred at room temperature for 1 h. 3-Chloro-
2-chloromethyl-1-propene +1.26 g, 0.01 mol) was added
dropwise at 08C to this stirred solution and the stirring
continued at room temperature for 15 h. The solvent was
then evaporated, water +25 ml) added and the mixture
extracted with DCM +2£50 ml). The combined organic
layers were dried +MgSO4), the solvent evaporated and the
residual oil puri®ed by ¯ash chromatography eluting with
2:1 v/v hexane±ether to give the ester +1.8 g, 85%) as a pale
yellow gum. +Found: C, 39.5; H, 3.5; N, 3.2; I, 30.0;
C14H15ClINO4 requires: C, 39.7; H, 3.55; N, 3.3; I,
29.95%.) d +CDCl3, 300 MHz): 8.55 +d, 1H, Jˆ1.7 Hz,
ArH), 8.0 +dd, 1H, Jˆ1.7 and 8.2 Hz, ArH), 7.25 +d, 1H,
Jˆ8.2 Hz, ArH), 5.3 and 5.03 +2£s, 2£1H, vCH2), 4.62 and
3.95 +2£d, 2£1H, Jˆ13.1 Hz, NCH2), 4.2 and 4.13 +2£d,
2H, Jˆ12.9 Hz, CH2Cl), 3.9 and 3.65 +2£s, 2£3H, 2£OMe);
m/z +%): 423 +M1, 8), 388 +34), 392 +100), and 364 +12).
3.2.10. 3-[2-12-Acetylamino-phenyl)-allyl]-3-methyl-2,3-
dihydro-indole-1,5-dicarboxylic acid dimethyl ester 9j.
Prepared from alkyne 1j by the general procedure. Hydro-
stannylation gave only the a-vinylstannane. After cycli-
sation and transesteri®cation the crude product was
puri®ed by ¯ash chromatography eluting with 2:1 v/v
ether±hexane to afford the product 9j +58%) as a colourless
gum. +Found: C, 68.0; H, 6.1; N, 6.6; C24H26N2O5 requires:
C, 68.25; H, 6.2; N, 6.65%.) d +CDCl3, 300 MHz): 8.1 +d,
1H, Jˆ7.2 Hz, ArH), 7.85 +m, 2H, ArH and NH), 7.62 +s,
1H, ArH), 7.2±7.0 +m, 4H, ArH), 5.2 and 5.02 +2£s, 2H,
vCH2), 3.9 +s, 3H, OMe), 3.75 +m, 4H, NCH and OMe), 3.5
+d, 1H, Jˆ13.0 Hz, NCH), 2.87 and 2.8 +2£d, Jˆ13.0 Hz,
2H, CH2±Cv), 2.0 +s, 3H, COMe) and 1.4 +s, 3H, Me); m/z
+%): 422 +M1, 2), 391 +5), 248 +100), 216 +40), 132 +76) and
84 +60).
3.2.11. 3-Methyl-3-11E)-3-phenyl-allyl)-2,3-dihydro-in-
dole-1,5-dicarboxylic acid dimethyl ester 10k and
3-methyl-3-12-phenyl-allyl)-2,3-dihydro-indole-1,5-dicar-
boxylic acid dimethyl ester 9k. Prepared from alkyne 1k
by the general procedure. Hydrostannylation gave an 80:20
ratio of a a- and b-vinylstannanes +1H NMR). After cycli-
sation and transesteri®cation the crude product comprised a
71:29 mixture of 10k and 9k. Flash chromatography eluting
with 1:1 v/v ethyl acetate±hexane gave the products 10k
and 9k in 84% combined yield as pale yellow gums.
Hydrolysis of methyl ester and attachment to the resin were
carried out as described for resin bound aryl iodide 7.
3.2.14. 3-[1Acetyl-benzyl-amino)-methyl]-3,2-12-benzo-
triazol-1-ylmethyl-allyl)-2,3-dihydro-indole-1,5-dicarb-
oxylic acid dimethyl ester 14. Benzylamine +0.45 g,
4.2 mmol) and K2CO3 +0.58 g, 4.2 mmol) were added to a
stirred suspension of the resin bound allyl chloride 5 +12 g,
1.05 mmol) +loading 0.87 mmol/g) in MeCN +15 ml) under a
nitrogen atmosphere. The resulting mixture was heated
at 808C for 12 h. The resin was then ®ltered off, washed
thoroughly with water, MeOH, DCM and ether and dried
under vaccum. Ac2O +0.43 g, 4.2 mmol) and pyridine
+0.33 g, 4.2 mmol) were added to a stirred suspension of
the solid support in MeCN +15 ml) under nitrogen atmos-
phere. The resulting mixture was heated at 508C for 12 h.
The resin was then ®ltered off, washed throughly with
MeOH, DCM and ether and dried under vacuum. Compound
14 was then prepared from this resin by the general proce-
dure. Hydrostannylation gave only the a-vinylstannane.
After cyclisation and transesteri®cation the crude product
was puri®ed by ¯ash chromatography eluting with 2:1 v/v
ether±hexane to afford the product 14 +70%) as a pale yellow
gum. +Found: C, 67.55; H, 5.7; N, 12.4; C32H33N5O5 requires:
C, 67.7; H, 5.8; N, 12.35%.) d +CDCl3, 300 MHz): 8.1 +m,
3H, ArH), 7.8 +s, 1H, ArH), 7.5±7.25 +m, 6H, ArH), 6.91 +m,
2H, ArH), 5.05 and 4.8 +2£s, 2H, vCH2), 4.85 and 4.75 +2£d,
2£1H, Jˆ13.8 Hz, NCH2), 4.34 and 4.1 +2£d, 2£1H,
Jˆ13.5 Hz, NCH2), 4.3 +d, 1H, Jˆ13.2 Hz, NCH), 3.95±
3.72 +m, 8H, 2£NCH and 2£OMe), 3.22 +d, 1H,
Jˆ13.7 Hz, NCH), 2.55 and 2.42 +2£d, Jˆ13.5 Hz, 2H,
CH2±Cv) and 2.1 +s, 3H, COMe); m/z +%): 567 +M1, 2),
536 +4), 405 +37), 373 +100), 120 +86) and 91 +85).
10k: colourless prisms from ether, mp 99±1028C. +Found:
C, 72.1; H, 6.4; N, 3.5; C22H23NO4 requires: C, 72.3; H, 6.3;
N, 3.85%.) d +CDCl3, 300 MHz): 7.95±7.8 +m, 3H, ArH),
7.31±7.12 +m, 5H, ArH), 6.05 +d, 1H, Jˆ16.5 Hz, PhCHv),
6.0 +m, 1H, CHv), 4.03 and 3.7 +2£d, 2H, 13.5 Hz, NCH2),
3.91 and 3.8 +2£s, 2£3H, 2£OMe), 2.48 +m, 2H, CH2±Cv)
and 1.41 +s, 3H, Me); m/z +%): 365 +M1, 6), 298 +6), 248
+100), 216 +35) and 59 +32).
9k: d +CDCl3, 300 MHz): 7.95±7.8 +m, 3H, ArH), 7.31±
7.12 +m, 5H, ArH), 5.15 and 4.81 +2£s, 2£1H, vCH2), 3.75
and 3.42 +2£d, 2£1H, Jˆ13.1 Hz, NCH2), 3.91 and 3.8
+2£s, 2£3H, 2£OMe), 2.82 and 2.76 +2£d, 2H, Jˆ
12.5 Hz, CH2±Cv) and 1.41 +s, 3H, Me); m/z +%): 365
+M1, 1), 276 +7), 248 +100), 189 +24) and 59 +20).
3.2.12.
3-Methyl-3-12-phenylcarbamoyl-allyl)-2,3-di-
hydro-indole-1,5-dicarboxylic acid 1-methyl ester 11.
Prepared by the general procedure. Hydrostannylation
gave only the a-vinylstannane. After cyclisation the product
was cleaved from the resin using 20% TFAin CH Cl2 at
2
room temperature over 3 h. After the normal work up the
crude product was puri®ed by ¯ash chromatography eluting
with 4:1 v/v ether±hexane to afford the product +85%) as
colourless prisms, mp 89±918C. +Found: C, 67.0; H, 5.6; N,
7.1; C22H22N2O5 requires: C, 66.85; H, 5.7; N, 7.05%.) d
+CD3COCD3, 300 MHz): 9.05 +br, 1H, OH), 7.82 +m, 3H,

10344
R. Grigg et al. / Tetrahedron 57 ꢀ2001) 10335±10345
3.3. General procedure for cascade hydroborationÐ
palladium catalysed cyclisation±anion capture
1,5-dicarboxylic acid dimethyl ester 18k. Prepared from
alkyne 1k by the general procedure. The crude product was
puri®ed by ¯ash chromatography eluting with 1:4 v/v ether±
petroleum ether to afford the product 18k +81%) as colour-
less prisms from ether, mp 100±1038C. +Found: C, 71.8; H,
6.55; N, 3.4; C22H23NO4 requires: C, 72.3; H, 6.35; N,
3.85%.) d +CDCl3, 300 MHz): 7.95±7.81 +m, 3H, ArH),
7.3±7.1 +m, 5H, ArH), 6.05 +d, Jˆ15.1 Hz, 1H, vCH),
6.0 +m, 1H, vCH), 4.0 and 3.61 +2£d, 2£1H, Jˆ13.5 Hz,
NCH2), 3.85 and 3.77 +2£s, 2£3H, 2£OMe), 2.48 +m, 2H,
CH2±Cv) and 1.4 +s, 3H, Me); m/z +%): 366 +M111, 9),
334 +4), 248 +100), 216 +28), 145 +25) and 77 +10).
Amixture of terminal alkyne +5 equiv., 4.23 mmol) and
catecholborane +5 equiv., 4.23 mmol) was stirred under
nitrogen in the absence of solvent at 708C for 1.5 h. Water
+3 ml) was then added and the mixture was stirred for a
further 1 h at 808C. After addition of resin bound aryl iodide
7 +1 equiv., 0.84 mmol), Pd+OAc)2 +10 mol%, 0.084 mmol),
PPh3 +20 mol%, 0.16 mmol), Na2CO3 +3 equiv., 2.5 mmol)
Et4NCl +1 equiv., 0.84 mmol) and toluene +15 ml) the
mixture was heated at 1108C for 12 h. The resin was then
®ltered off, washed throughly with H2O, MeOH, DCM and
ether and dried under vaccum. After transesteri®cation as
described earlier and following removal of the resin by
®ltration, evaporation of the ®ltrate afforded the product.
3.3.5. 3-11-Benzyl-3-ethyl-ureidomethyl)-3-11E)-4-cyclo-
hexyl-but-2-enyl)-2,3-dihydro-indole-1,5-dicarboxylic
acid dimethyl ester 20. Benzylamine +0.45 g, 4.2 mmol)
and K2CO3 +0.58 g, 4.2 mmol) were added to a stirred
suspension of the resin bound allyl chloride 12 +12 g,
1.05 mmol) +loading 0.87 mmol/g) in MeCN +15 ml)
under a nitrogen atmosphere. The resulting mixture was
heated at 808C for 12 h. The resin was then ®ltered off,
washed throughly with water, MeOH, DCM and ether and
dried under vaccum. Ethyl isocyanate +0.29 g, 4.2 mmol)
was added to a stirred suspension of the solid support in
DCM +15 ml) under a nitrogen atmosphere. The resulting
mixture was stirred at room temperature for 24 h. The resin
was then ®ltered off, washed throughly with MeOH, DCM
and ether and dried under vacuum. Compound 20 was then
prepared from this resin by the general procedure using
alkyne 15c. After cyclisation and transesteri®cation the
crude product was puri®ed by ¯ash chromatography eluting
with 1:1 v/v ethyl acetate±hexane to afford the product 20
+52%) as colourless prisms from ether, mp 55±588C.
+Found: C, 70.3; H, 7.70; N, 7.3; C33H43N3O5 requires: C,
70.55; H, 7.70; N, 7.5%.) d +CDCl3, 300 MHz): 7.92 +m,
2H, ArH), 7.81 +s, 1H, ArH), 7.25 +m, 3H, ArH), 6.95 +d,
2H, Jˆ6.9 Hz, ArH), 5.44 and 5.1 +2£m, 2£1H, 2£vCH2),
4.4 and 4.04 +m, 5H, 2£NCH2 and NCH), 3.91 and 3.85
+2£S, 2£3H, 2£OMe), 3.43 +d, 1H, Jˆ14.5 Hz, NCH),
3.22 +q, 2H, Jˆ6.9 Hz, NCH2CH3), 2.4 +m, 2H, CH2±
Cv), 1.81 +t, 2H, Jˆ6.8 Hz, CH2±Cv), 1.42±1.7 +m, 5H,
2£CH2 and CH), 1.1±1.25 +m, 4H, 2£CH2), 0.95 +t, 3H,
Jˆ6.9 Hz, CH3) and 0.8 +m, 2H, CH2); m/z +%): 561 +M1,
6), 530 +5), 457 +15), 234 +15), 120 +100) and 91 +85).
3.3.1. 3-1E)-Hept-2-enyl-3-methyl-2,3-dihydro-indole-
1,5-dicarboxylic acid dimethyl ester 18a. Prepared from
alkyne 15a by the general procedure. The crude product was
puri®ed by ¯ash chromatography eluting with 1:5 v/v ether±
petroleum ether to afford the product 18a +84%) as a colour-
less gum. +Found: C, 69.4; H, 8.0; N, 4.05; C20H27NO4
requires: C, 69.55; H, 7.85; N, 4.05%.) d +CDCl3,
300 MHz): 7.9±7.76 +m, 3H, ArH), 5.42 and 5.2 +2£m,
2£1H, 2£vCH), 3.95 and 3.61 +2£d, 2£1H, Jˆ11.1 Hz,
NCH2), 3.9 and 3.81 +2£s, 2£3H, 2£OMe), 2.28 +m, 2H,
CH2±Cv), 1.9 +m, 2H, CH2±Cv), 1.38 +s, 3H, Me), 1.25
+m, 4H, 2£CH2) and 0.82 +t, 3H, Jˆ6.7 Hz, Me); m/z +%):
346 +M111, 5), 314 +4), 248 +100), 216 +50), 130 +25) and
77 +6).
3.3.2. 3-11E)-3-Cyclopentyl-allyl)-3-methyl-2,3-dihydro-
indole-1,5-dicarboxylic acid dimethyl ester 18b. Prepared
from alkyne 15b by the general procedure. The crude
product was puri®ed by ¯ash chromatography eluting with
1:5 v/v ether±petroleum ether to afford the product 18b
+71%) as a colourless gum. +Found: C, 70.6; H, 7.2; N,
3.65; C21H27NO4 requires: C, 70.5; H, 7.6; N, 3.9%.) d
+CDCl3, 300 MHz): 7.9±7.75 +m, 3H, ArH), 5.4 +dd, 1H,
Jˆ16.2 and 7.4 Hz, vCH), 5.15 +m, 1H, vCH), 3.95 and
3.6 +2£d, 2£1H, Jˆ11.0 Hz, NCH2), 3.9 and 3.82 +2£s,
2£3H, 2£OMe), 2.3 +m, 3H, CH2±Cv and CH±Cv),
1.8±1.5 +m, 6H, 3£CH2), 1.39 +s, 3H, Me) and 1.2 +m,
2H, CH2); m/z +%): 357 +M1 5), 326 +10), 248 +100), 216
+35), 189 +24) and 145 +30).
3.3.6. 3-11-Butyl-3-phenyl-ureidomethyl)-3-12-methyl-
1,3-dioxo-2,3,3a,4,6,7,8,9,9a,9b-decahydro-1H-benzo1E)
isoindol-4-ylmethyl)-2,3-dihydro-indole-1,5-dicarboxylic
acid dimethyl ester 21. n-Butylamine +0.30 g, 4.2 mmol)
and K2CO3 +0.58 g, 4.2 mmol) were added to a stirred
suspension of the resin bound allyl chloride 12 +12 g,
1.05 mmol) +loading 0.87 mmol/g) in MeCN +15 ml)
under a nitrogen atmosphere. The resulting mixture was
heated at 808C for 12 h. The resin was then ®ltered off,
washed throughly with water, MeOH, DCM and ether and
dried under vaccum. Phenyl isocyanate +0.5 g, 4.2 mmol)
was added to a stirred suspension of the solid support in
DCM +15 ml) under nitrogen atmosphere. The resulting
mixture was stirred at room temperature for 24 h. The
resin was then ®ltered off, washed throughly with MeOH,
DCM and ether and dried under vaccum. Hydroboration of
15d and Suzuki coupling were carried out according to the
general procedure. N-Methylmaleimide +0.46 g, 4.2 mmol)
3.3.3. 3-11E)-4-Cyclohexyl-but-2-enyl)-3-methyl-2,3-di-
hydro-indole-1,5-dicarboxylic acid dimethyl ester 18c.
Prepared from alkyne 15c by the general procedure. The
crude product was puri®ed by ¯ash chromatography eluting
with 1:5 v/v ether±petroleum ether to afford the product 18c
+93%) as a pale yellow thick oil. +Found: C, 71.15; H, 7.9;
N, 3.35; C23H31NO4 requires: C, 71.65; H, 8.1; N, 3.65%.) d
+CDCl3, 300 MHz): 7.9±7.7 +m, 3H, ArH), 5.4 and 5.1
+2£m, 2£1H, 2£vCH), 3.95 and 3.61 +2£d, 2£1H, Jˆ
11.3 Hz, NCH2), 3.9 and 3.8 +2£s, 2£3H, 2£OMe), 2.28
+m, 2H, CH2±Cv), 1.8 +t, 2H, Jˆ6.8 Hz, CH2±Cv),
1.7±1.5 +m, 5H, 2£CH2 and CH), 1.38 +s, 3H, Me), 1.18
+m, 4H, 2£CH2) and 0.8 +m, 2H, CH2); m/z +%): 385 +M1
10), 354 +71), 248 +100), 216 +30), 189 +15) and 145 +20).
3.3.4. 3-Methyl-3-11E)-3-phenyl-allyl)-2,3-dihydro-indole-

R. Grigg et al. / Tetrahedron 57 ꢀ2001) 10335±10345
10345
2. Grigg, R.; Sridharan, V. J. Organomet. Chem. 1999, 576, 65±
87. Brown, S.; Clarkson, S.; Grigg, R. Tetrahedron 2001, 57,
1347±1359. Anwar, U.; Casaschi, A.; Grigg, R. Tetrahedron
2001, 57, 1361±1367.
was added to a stirred suspension of the solid support in
toluene +15 ml). The resulting mixture was heated at
1108C for 24 h. The resin was then ®ltered off, washed
thoroughly with MeOH, DCM and ether and dried under
vacuum. After transesteri®cation the crude product was
puri®ed by ¯ash chromatography eluting with 2:1 v/v
ethyl acetate±hexane to afford the product 21 +2:1 mixture
diastereoisomers) +52%) as pale yellow prisms. mp 80±
838C. +Found: C, 67.7; H, 6.8; N, 8.3; C38H46N4O7 requires:
C, 68.0; H, 6.90; N, 8.35%.) d +CDCl3, 300 MHz). An
asterisk indicates the presence of a pair of signals +2:1)
which represent the same proton+s) of the minor diastereo-
isomer. 8.10±7.90 +m, 3H, ArH), 7.18±7.31 +m, 4H, ArH),
7.10 +m, 1H, ArH), 6.35 +br, 1H, CONH), 5.22 +d, 1H, Jˆ
3.5 Hz, CHv, 5.05p), 4.3 +m, 3H, 3£NCH), 3.95 +m, 1H,
NCH), 3.87 +s, 3H, OMe, 3.85p), 3.75 +brs, 3H, OMe), 3.17
+m, 1H, NCH), 2.85 +s, 3H, NMe, 3.94p), 2.81 +m, 1H,
NCH), 2.71±2.31 +m, 4H), 2.2±1.62 +m, 7H), 1.45±1.05
+m, 7H), 0.98±0.7 +m, 4H); m/z +%): 671 +M111, 5), 447
+4), 246 +6), 133 +20), 95 +38) and 55 +100).
3. Casaschi, A.; Grigg, R.; Sansano, J. M.; Sridharan, V.;
Sukirthalingam, S.; Wilson, D.; Redpath, J. Tetrahedron
2000, 56, 7525±7539. Casaschi, A.; Grigg, R.; Sansano,
J. M. Tetrahedron 2000, 56, 7541±7551. Casaschi, A.;
Grigg, R.; Sansano, J. M. Tetrahedron 2000, 56, 7553±7560.
4. Guibe, F.; Balavoine, G.; Zhang, H. X. J. Org. Chem. 1990,
55, 1857±1867.
5. Busacca, C. A.; Swestock, J.; Johnson, R. E.; Bailey, T. R.;
Muzza, L.; Rodger, C. A. J. Org. Chem. 1994, 59, 7553±7556.
6. Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc. 1975, 97, 5225±
5249.
7. Miyaura, N.; Ishiyama, J.; Suzuki, H.; Ishikawa, M.; sato, M.;
Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314±321.
8. Yanagi, T.; Ohe, T.; Miyaura, N.; Suzuki, A. Bull. Chem. Soc.
Jpn 1989, 62, 3892±3895.
9. Grigg, R.; Sansano, J. M.; Santhakumar, V.; Sridharan, V.;
Ravishankar, T.; Thorton-Pett, M.; Wilson, D. Tetrahedron
1997, 53, 11803±11826.
Acknowledgements
10. +a) Coppola, R. A.; Damon, R. E. Synth. Commun. 1993,
2003±2010. +b) Nilsson, B. M.; Vargas, M. H.; Ringdhl, B.
J. Med. Chem. 1992, 35, 285±294. +c) Papanastassion, Z. B.
J. Med. Chem. 1967, 10, 701±706. +d) Capella, L.;
Montevecchi, P. C.; Nanni, D. J. Org. Chem. 1994, 59,
3368±3374. +e) Barra, E. D.; de la Hoz, A.; Loupy, A.;
Migallon, A. S. Heterocycles 1994, 38, 1367±1374.
+f) Padwa, A.; Krumpe, K. E.; Kassir, J. M. J. Org. Chem.
1992, 57, 4940±4949. +g) Davini, E.; Giongo, M.; Riocci, M.
Org. Prep. Proced. Int. 1995, 27, 586±589.
We thank GlaxoSmithKline, Leeds University and the
EPSRC for support.
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