Four-component Pd-catalysed cascade/ring closing metathesis. Synthesis of heterocyclic enones

Article abstract of DOI:10.1016/j.tet.2005.09.015

A palladium-catalysed four-component process is described involving carbon monoxide, allene and aryl/heteroaryl iodides generating (π-allyl) palladium species, which are intercepted by alkene tethered nitrogen nucleophiles to afford 1,6- and 1,7-dienones.

Full text of DOI:10.1016/j.tet.2005.09.015

Tetrahedron 61 (2005) 11380–11392
Four-component Pd-catalysed cascade/ring closing metathesis.
Synthesis of heterocyclic enones*
b
a
a
Ronald Grigg,a, William Martin, James Morris and Visuvanathar Sridharan
*
aMolecular innovation, Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry, Leeds University, Leeds LS2 9JT, UK
bProcess Research and Development, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK
Received 14 July 2005; revised 9 August 2005; accepted 2 September 2005
Available online 26 September 2005
Abstract—A palladium-catalysed four-component process is described involving carbon monoxide, allene and aryl/heteroaryl iodides
generating (p-allyl) palladium species, which are intercepted by alkene tethered nitrogen nucleophiles to afford 1,6- and 1,7-dienones.
Subsequent ring closing metathesis affords five- and six-membered N-heterocyclic enones. The N-heterocyclic enones are active
dipolarophiles in 1,3-dipolar cycloaddition reactions as exemplified by azomethine ylide and nitrone cycloadditions.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Previously, we reported the devlopment of a Pd-catalysed
three-component cascade/ring closing metathesis (RCM)
route for five- and six-membered N-heterocycles.2 In this
system the muti-component cascade created the diversity,
which is relayed into the final heterocycle by a RCM.
Amongst the extended substrate scope second generation Ru
Success of this methodology prompted us into investigate a
catalyst 2 tolerates electron deficient alkenes particularly
more challenging four-component cascade (4CC)/RCM
well. Access via RCM to various cyclic a,b-unsaturated
process accessing versatile heterocylic enones 1 (Scheme 1).
Scheme 1.
The development of new improved metathesis catalysts
continues to increase the popularity of this reaction.3 Whilst
RCM reports of acrylates catalysed by 2 can be found in the
literature they are not general and often require Lewis acids
to achieve synthetically useful yields.4,5
* See Ref. 1.
Keywords: Ring closing metathesis; Catalytic cascades; Heterocyclic
enones; 1,3-Dipolar cycloadditions.
*
Corresponding author. Tel.: C44 113 343 6501; fax: C44 113 233 6530;
e-mail: r.grigg@chem.leeds.ac.uk
Scheme 2.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.015

R. Grigg et al. / Tetrahedron 61 (2005) 11380–11392
11381
esters, amides and ketones employing 3 is being exploited
by a growing number of groups.6
2. Results and discussion
2.1. Four-component cascades employing pronucleo-
philes 4 and 5
In the studies reported herein, we have explored interfacing
a 4CC with RCM and RCM with cycloadditions. For the
4CC to be successful carbonylation must occur before allene
insertion and allene insertion must in turn be faster than
nucleophilic substitution (Scheme 2). An incorrect reac-
tivity order would lead inter alia to shunt pathways (v) and
(vi) (Scheme 2). The desired ‘molecular queuing’ in these
4CC has been reported by the Grigg group for certain
nucleophiles7 and examples employing solid phase combi-
natorial chemistry reported.8
Nitrogen protected alkenyl tethered amine pronucleophiles
4–7 were prepared by literature procedures.2,8,9 Initial
studies employed 4 along with iodothiophene, palladium
acetate, triphenylphosphine and potassium carbonate as
Table 1. Sequential four-component cascade-RCM employing nucleophiles 4 and 5
Entry
1
Aryl/heteroaryl iodide
Pd-cascade producta
Yield (%)b
RCM productc
Yield (%)b
75
94
8
9
17
18
2
3
4
5
6
75
70
70
55
70
88
90
93
92
87
10
11
12
13
19
20
21
22
7
8
68
65
25d
14
15
23
24
56
9
65
93
26
25
16
a Pd(OAc)2 10 mol%, PPh3 20 mol%, K2CO3 2 mol equiv, toluene, 70 8C, 22–44 h.
b Isolated yields.
c Compound 3 (5 mol%), toluene 80 8C, 1–14 h.
d Compound 3 (12 mol%) employed.

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R. Grigg et al. / Tetrahedron 61 (2005) 11380–11392
base. The reaction was conducted in toluene at 70 8C under
1 atm of allene and 1 atm of carbon monoxide in a Schlenk
tube. To our delight, complete chemoselective conversion to
the dienone, 8 was achieved within 38 h (Table 1, entry 1).
resulted in a 1:1 mixture of 26 and 27 (Table 2, entry 2)
whilst sodium tertiary butoxide gave poor conversion
(Table 2, entry 3). Polar solvents gave greater conversion
to product (Table 2, entries 4 and 7) when employing
potassium carbonate as the base. However, addition of
tetraethylammonium chloride suppressed the reaction
(Table 2, entry 5). Preformed Pd(0) catalyst tetrakis
triphenylphosphinepalladium did not improve the con-
version (Table 2, entry 6). However, rubidium carbonate
as base resulted in complete chemoselective conversion to
26 (Table 1, entry 8).
Subjecting dienone 8 to 3 (5 mol%) in toluene at 80 8C
produced complete conversion to heterocyclic enone 17
(Table 1, entry 1). The scope of the reaction was then
explored through variation of the aryl/heteroaryl iodide
(Table 1). Electron deficient, electron rich and heteroaryl
iodides worked equally well in the tetramolecular cascade,
furnishing the dienones 8–15 inside 44 h and with complete
conversion in all cases. In each case the 1H NMR spectrum
of the crude reaction mixture was devoid of by-products
confirming the cascade is chemo- and regioselective.
Nucleophile 4 could also be interfaced with the cyclisation-
anion capture methodology developed by Grigg et al.,10
affording dienone 16 from the ‘zipper’ starting species 26.
Three new carbon–carbon and one carbon–nitrogen bonds
are thus formed in this cascade (Table 1, entry 9).
Possible explanations for the unique effect of Rb2CO3
include an increased concentration of deprotonated pro-
nucleophile, that is, a low concentration of deprotonated
pronucleophile results in poor product conversion (Table 1,
entry 1). However, an excess of pronucleophile 6 leads to
trapping of the acyl-palladium intermediate (Scheme 2) and
the formation of amide 27 (Table 2, entry 2). On moving
down group 1 of the periodic table, metal carbonate bonding
becomes less covalent in character resulting in a higher
concentration of the basic carbonate anion. The concen-
tration of anion follows the trend K2CO3!Rb2CO3!
Cs2CO3. Perhaps rubidium carbonate serendipitously
forms the optimum concentration of deprotonated pro-
nucleophile required for total chemoselectivity and con-
version to 26 (Table 1, entry 8). Alternatively or
additionally it may produce a more active Pd(0) species as
a polycarbonate12 [Pd(0)(CO3)n]2nK analogous to the effect
of ClK ions from R4NCClK.13 To our knowledge there is
only one other report14 describing the superiority of Rb2CO3
over the more usual K2CO3 and Cs2CO3.
2.2. RCM affording 3-pyrrolines
Catalyst 3 effected complete RCM of 8–16 to the
heterocyclic enones, 17–25 within 1–8 h in all cases with
the exception of 23. In this latter case a maximum 40%
conversion was achieved with a total catalyst loading of
12 mol%, added in three separate portions of 5, 5 and
2 mol% after 2 and 13 h with a total reaction time of 14 h
(Table 1, entry 7). Catalyst poisoning by the nucleophilic
sulphur of 14 may be a reason for this. Another possibility
could be the formation of an unfavourable and stable
chelate. Chelation has been shown in many cases to be
detrimental to the ring closing reaction.11
A comparison of the predicted pKa’s for the protected
allylamine, 4 (10.0) and homoallylamine 6 (11.6),15 shows a
difference of over 1.5 units. This suggests, to achieve
complete product conversion the necessary concentration of
anion is formed from 4 with potassium carbonate (Table 1,
entry 1). However, due to its less acidic proton, 6 is only
partially deprotonated and poor conversion results (Table 2,
entry 1).
Table 2. Effect of solvent/base on Scheme 3
Entry
Solvent
Base
Yield (%)a
1
2
3
4
Toluene
Toluene
Toluene
CH3CN
CH3CN
CH3CN
DMF
K2CO3
Cs2CO3
NaOtBu
K2CO3
K2CO3
K2CO3
K2CO3
Rb2CO3
33 (20)
100 (71)b
13
60 (41)
20
57
5c
6d
7
2.4. RCM affording 3-piperideines
50
100 (74)
With the reaction conditions optimised for 6 the scope of the
reaction with respect to the aryl iodide was evaluated
(Table 3). The process worked well for a series of iodides
yielding acylic dienones 26–31 in 68–75% yield. Subjecting
dienones 26–31 to 3 (5 mol%) afforded the six-membered
heterocylic enones 32–36 in 73–92% yield (Table 3).
Interestingly RCM of thioether analogue 30 afforded 92%
conversion and 73% isolated yield of heterocylic enone 35
with 7 mol% of 3 added in two separate portions (Table 3,
entry 4). Comparisons with the synthesis of 23 in the
analogous five-membered series indicates the formation of a
six-membered ring by RCM is more favourable.
8
Toluene
a Conversion calculated from 1H NMR. Isolated yield in parenthesis.
b 1:1 mixture of 26 and 27.
c NEt4Cl (1 mol equiv) added.
d Pd(PPh3)4 used as catalyst.
2.3. Four-component cascades employing nucleophile 6
Initial attempts to employ 6 in the 4CC with iodothiophene
resulted in poor conversion to the desired product (Scheme
3, Table 2, entry 1). Optimisation of the reaction conditions
was thus investigated. Using cesium carbonate as base
2.5. Four-component cascades employing pronucleo-
phile 7
Results achieved from using alkenyl tethered amine 7 in
the four-component Pd-cascade parallel those obtained
employing 6. Potassium carbonate was found to give poor
Scheme 3.

R. Grigg et al. / Tetrahedron 61 (2005) 11380–11392
Table 3. Sequential four-component cascade-RCM employing nucleophile 6
11383
Entry
Aryl/heteroaryl iodide
Pd-cascade producta
Yield (%)b
RCM productc
Yield (%)b
1
74
92
90
91
73d
86
26
28
29
32
33
34
35
2
3
4
5
72
68
75
70
30
31
36
a Pd(OAc)2 10 mol%, PPh3 20 mol%, Rb2CO3 2 mol equiv, toluene, 70 8C, 18–25 h.
b Isolated yields.
c Compound 3 (5 mol%), toluene 80 8C, 2–7 h.
d Compound 3 (5 mol%) added time zero followed by 2 mol% of 3 after 4 h.
conversions, cesium carbonate gave product mixtures,
whilst rubidium carbonate gave near complete conversion
to dienone 37, in 56% isolated yield when using
2-iodothiophene (Table 4, entry 1). This was expected,
considering the essential equivalence of the pKa’s of 6
(11.6) and 7 (11.74).14 Dienone 38 was also formed with
complete conversion from iodobenzene in 68% isolated
yield employing the same conditions (Table 4, entry 2).
Unfortunately subjecting 37 and 38 to RCM using 3 failed to
afford any of the seven-membered ring analogues. The
acyclic dienone was recovered unchanged after 24 h in both
cases.
a number of metal catalysed reactions.16 This encouraged us
to evaluate the technique for RCM processes of our acyclic
enones. Initially, we studied the microwave-accelerated
RCM of 8 using the Smith Creator microwave. DCM was
the solvent of choice owing to its microwave transparency17
allowing the maximum uptake of microwave energy by the
substrate and catalyst. A target temperature of 100 8C was
set and the catalyst loading and concentration of 8 varied
to find the optimum reaction conditions. The results are
summarised in Table 5. The best set of conditions (Table 5,
entry 3) furnished 17 in 86% yield. Increasing the
concentration was found to impede the reaction (Table 5,
entries 3 and 4). The temperature profile of the reaction
mixture shows rapid heating, which could be ascribed to
energy absorption by the ruthenium catalyst 3 or the diene
substrate. However, a recent report by Lavastre et al. rules
out the former.18 The pressure of the sealed reaction vessel
was monitored and found to stay below 5 bar. Next, we
studied the formation of a range of 3-substituted five- and
six-membered heterocyclic enones via microwave induced
RCM by varying the aryl/heteroaryl group (Table 6).
Table 4. Sequential four-component cascade-RCM employing
nucleophile 7
Entry
Aryl/heteroaryl iodide
Pd-cascade producta
Yield
(%)b
1
56
68
37
38
Table 5. Optimisation of microwave RCM reaction conditionsa
Entry
Time (min)
Concn
(mM)
Catalyst
loading
(mol%)
Conversion
(%)
2
1
2
3
4
5
6
5
1
1
1
2
1
1.5
1.5
1.5
3.0
3.0
3.0
5
5
2.5
2.5
1
100
100
100
90
88
88
a Pd(OAc)2 10 mol%, PPh3 20 mol%, Rb2CO3 2 mol equiv, toluene, 70 8C,
25 h.
b Isolated yields.
2.6. Microwave-accelerated RCM1
1
a All reactions performed in CH2Cl2. The temperature was set to reach a
maximum of 100 8C in all cases.
Microwave irradiation is reported to dramatically accelerate

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R. Grigg et al. / Tetrahedron 61 (2005) 11380–11392
Table 6. Microwave acclerated RCMa
Entry
Starting material
Catalyst loading
(mol%)
Product
Conversion (%)b
Yield (%)c
1
2
3
4
5
6
13
11
16
8
29
30
2.5
2.5
1
2.5
5
22
20
25
17
34
35
93
80
87
90
86
77
78
100
100
100
92
2.5
92
a As for Table 6 with a 1 min reaction time and a substrate concentration of 1.5–3.0 mM.
b Conversion calculated by 1H NMR.
c Isolated yield.
Microwave heating results in shorter reaction times and
lower catalyst loadings. Wilson et al. have reported a closely
related process.19
Table 7. Cycloadditions of enones 17–19 and nitrone 42a
Entry
Enone
Product
Yield (%)b
2.7. 1,3-Dipolar cycloaddition reactions
1
17
80c
The heterocyclic enones described above were shown to be
active dipolarophiles in cycloadditions with azomethine
ylides and nitrones. Thus, stiring imine 39 with silver
acetate, triethylamine and enone 17 in toluene at room
temperature for 20 h afforded a single cycloadduct 41 in
80% isolated yield arising via an endo-transition state of the
syn-metallodipole 40 (Scheme 4). The regio- and stereo-
chemistry of the cycloadduct 41 were established by NOE
studies and conform to that expected for Grigg’s metal
catalysed proline synthesis.20
43
2
18
70
44
3
19
58
45
a Toluene 120 8C, sealed tube, 54–60 h.
b Isolated yield.
c Trace amounts of isomer 45 formed.
Scheme 4.
Heating the five-membered heterocylic enones 17–19 with
diphenyl nitrone 42 in toluene at 120 8C (Schlenk tube)
afforded the bicyclic isoxazolidines 43–45 in 58–80% yield
as single regio- and diastereoisomers (Scheme 5, Table 7).
The nitrone cycloadditions proved to be extremely sensitive
towards variation in reaction temperature. Employing enone
17 and decreasing the reaction temperature to 80 8C causes a
change in the regioselectivity of the reaction affording a
3.5:1 mixture of diastereoisomers 46 and 47, respectively,
in 70% yield (Scheme 6). Only trace amounts of the
thermodynamic regioisomer 43 are formed at this tempera-
ture as shown by 1H NMR. Subjecting 46 to reflux in
toluene affords the thermodynamic isomer 43 via a retro-
cycloaddition/1,3-dipolar cycloaddition along with trace
Scheme 6.
amounts of enone 17 and diphenyl nitrone 42. Regioisomer
43 is thought to be favoured under thermodynamic control
due to the minimization of steric interactions between the
3-phenyl group of the nitrone and the aryl ketone of the enone.
2.8. Cascade RCM-1,3-dipolar cycloaddition
Finally, a cascade RCM-nitrone cycloaddition was shown to
be possible. The ability to create a dipolarophile (dieno-
phile) in situ and interface it with a cycloaddition in a
cascade provides valuable synthetic flexibility. Addition-
ally, in this case it results in the formation of three-new
bonds and four stereocentres. Heating a mixture of dienone
8, diphenyl nitrone 42 and catalyst 3 in toluene at 70 8C for
Scheme 5.

R. Grigg et al. / Tetrahedron 61 (2005) 11380–11392
11385
1 h followed by further heating at 90 8C for 17 h afforded a
3:1 mixture of 46 and 47 in 59% isolated yield. Heating to
higher temperatures afforded complex mixtures. We have
previously reported numerous examples of palladium
catalysed multi-component cascades directly interfaced
with cycloadditions.21
1.1 Hz, ArH), 7.58–7.55 (1H, m, SO2PhH), 7.51–7.48 (2H,
m, SO2PhH), 7.12 (1H, dd, JZ5.0, 3.8 Hz, ArH), 6.10 (1H,
t, JZ1.5 Hz, ]CHCHD), 6.05 (1H, t, JZ1.0 Hz,
]CHCHD), 5.60 (1H, ddt, JZ16.7, 10.0, 6.6 Hz, CHX]
CHAHB), 5.14 (1H, ddd, JZ16.7, 2.7, 1.3 Hz, CHX]CHA-
HB), 5.11 (1H, ddd, JZ10.0, 2.3, 1.7 Hz, CHX]CHAHB),
4.14 (2H, s, NCH2), 3.86 (2H, d, JZ6.6 Hz, NCH2); dC
(125 MHz, CDCl3) 187.9 (C]O), 143.4, 142.9, 139.8,
134.3, 134.2, 132.7, 132.1, 129.1, 128.0, 127.2, 125.8,
119.9, 51.5 (NCH2), 47.7 (NCH2); m/z (CI) 365 (60%, MC
NHC4 ), 215 (100%).
In summary, a novel and diverse route accessing 3-aryl/
heteroaryl-acyl substituted heterocyles has been developed
via the sequential application of a chemoselective four-
component Pd-cascade/RCM sequences. The heterocyclic
enones produced via this method can be further elaborated
via cycloaddition chemistry. Investigation into the com-
patibility of other alkene-tethered nucleophiles and sub-
stituted allenes in this process is currently underway.
3.2. General tetramolecular cascade procedure
3.2.1. N-Allyl-N-(2-benzoylprop-2-enyl)benzenesulfona-
mide (9). Palladium acetate (112 mg, 0.5 mmol), triphenyl
phosphine (262 mg, 1 mmol), potassium carbonate
(1.381 g, 10 mmol) and toluene (10 ml) were added to a
Schlenk tube, containing a magnetic stirrer bar. A solution
of the sulfonamide 4 (985 mg, 5 mmol), and iodobenzene
(1.224 g, 6 mmol) in toluene (4 ml) was then added. The
tube was sealed and the mixture frozen in liquid nitrogen,
and degassed by vacuum pump. The mixture was then
allowed to reach room temperature, followed by refreezing
and degassing for a second time. Allene (1 bar) was then
added to the Schlenk tube and the mixture frozen in a liquid
nitrogen bath. Following this CO (1 bar) was added, the tube
sealed and the mixture allowed to reach room temperature,
before heating in an oil bath at 65–70 8C for 44 h. On
completion of the reaction the mixture was allowed to cool
to room temperature, the excess gas released and the
mixture filtered. Concentration of the filtrate in vacuo gave
an orange oil, which was purified by flash chromatography,
eluting with 1:4 v/v ether/petrol to afford the product
(1.275 mg, 75%) as a viscous, colourless oil; Rf 0.2; (Found:
C, 66.55; H, 5.85; N, 4.15. C19H19NO3S requires C, 66.85;
H, 5.60; N, 4.10%); ymax/cmK1 (film) 1653 (C]O), 1447,
1344 (S]Oas), 1160 (S]Os), 1092, 983, 932; dH
(250 MHz, CDCl3) 7.88–7.84 (2H, m, ArH), 7.72–7.60
(2H, m, ArH), 7.60–7.53 (6H, m, ArH), 6.27 (1H, t, JZ
1.3 Hz, ]CHCHD), 5.89 (1H, s, ]CHCHD), 5.62 (1H, ddt,
JZ16.6, 10.0, 6.6 Hz, CHX]CHAHB), 5.19–5.10 (2H, m,
CHX]CHAHB), 4.15 (2H, t, JZ1.3 Hz, NCH2), 3.89 (2H,
d, JZ6.6 Hz, NCH2); dC (63 MHz, CDCl3) 197.3 (C]O),
143.4, 140.0, 137.6, 133.1, 132.9, 132.7, 129.9, 129.6,
129.2, 128.7, 127.6, 120.3, 52.2 (NCH2), 47.9 (NCH2); m/z
(ES) 364 (MCCNa).
3. Experimental
Melting points were determined on a Reichert hot-stage
apparatus and are uncorrected. Mass spectral data were
obtained from a VG Autospec instrument operating at 70 eV
(EI and FAB) or ZD 2000 electrospray instrument (ES).
Accurate molecular masses were obtained from the EPSRC
Swansea Mass Spectroscopy service using perfluorotri-
butylamine or polyethylenimine as an internal standard.
Microanalyses were obtained using a Carbo Erba
MOD11016 instrument. IR spectra were determined on a
Nicolet Magna FT-IR 560 spectrometer. The IR samples
were prepared as thin films by evaporation of a solution of
the compound in DCM onto a germanium plate. Nuclear
magnetic resonance spectra were recorded on Bruker
DPX250, DPX300 and DPX500 instruments operating at
250, 300 and 500 MHz, respectively. The following
abbreviations are used: s, singlet; d, doublet; t, triplet; q,
quartet; qi, quintet; m, multiplet; dd, doublet of doublets;
ddd, double doublet of doublets; ddt, double doublet of
triplets; b, broad. Solvents were dried according to
established methods, unless purchased dry from Aldrich in
sure-seal bottles. Palladium acetate was supplied by
Johnson Matthey and ruthenium alkylidene catalysts were
were purchased from Strem and Aldrich and used as
received. The term ether refers to diethyl ether and the term
petrol refers to the 40–60 8C boiling point fraction of
petroleum ether. All the compounds are named according to
the IUPAC system and names were obtained using the
ACD/i-Lab software version 4.5.
3.2.2. N-Allyl-N-[2-(1-naphthoyl)prop-2-enyl]benzene-
sulfonamide (10). Prepared by the general cascade
procedure on a 5 mmol scale, using 5.5 mmol of aryl iodide
and a reaction time of 42 h. Purification by flash
chromatography eluting with DCM afforded the product
(1.350 g, 70%) as a viscous colourless oil; Rf 0.32; (Found:
C, 70.30; H, 5.35; N, 3.60. C23H21NO3S requires C, 70.55;
H, 5.40; N, 3.60%); ymax/cmK1 (film) 1652 (C]O), 1446,
1342 (S]Oas), 1160 (S]Os), 1090; dH (250 MHz, CDCl3)
8.05–7.87 (5H, m, ArH), 7.62–7.43 (7H, m, ArH), 6.63 (1H,
t, JZ1.5 Hz, ]CHCHD), 5.91 (1H, s, ]CHCHD), 5.66 (1H,
ddt, JZ16.9, 9.9, 6.8 Hz, CHX]CHAHB), 5.21 (1H, ddd,
JZ16.9, 2.6, 1.3 Hz, CHX]CHAHB), 5.18 (1H, dd, JZ9.9,
1.1 Hz, CHX]CHAHB), 4.27 (2H, s, NCH2), 3.93 (2H, d,
JZ6.8 Hz, NCH2); dC (63 MHz, CDCl3), 199.1 (C]O),
1
3.1. H NMR proton labels:
3.1.1. N-Allyl-N-[2-(thien-2-ylcarbonyl)prop-2-enyl]ben-
zenesulfonamide (8). Prepared by the general cascade
procedure (below) on a 5 mmol scale, using 5.5 mmol of
aryl iodide and a reaction time of 38 h. Purification by flash
chromatography eluting with 1:20 v/v ether/petrol afforded
the product (1.29 g, 75%) as a viscous pale yellow oil; Rf
0.05; (Found: C, 58.80; H, 4.90; N, 4.10. C17H17NO3S2
requires C, 58.75; H, 4.95; N, 4.05%) ymax/cmK1 (film)
1637 (C]O), 1621, 1413, 1342 (S]Oas), 1159 (S]Os),
1091; dH (500 MHz, CDCl3) 7.84–7.82 (2H, m, SO2PhH),
7.68 (1H, dd, JZ5.0, 1.1 Hz, ArH), 7.63 (1H, dd, JZ3.8,

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R. Grigg et al. / Tetrahedron 61 (2005) 11380–11392
145.3, 140.0, 136.1, 134.1, 133.2, 132.9, 132.1, 131.8,
131.1, 129.7, 128.9, 128.1, 127.7, 127.6, 126.9, 125.7,
124.7, 120.03, 52.5 (NCH2), 47.3 (NCH2); m/z (%) (FAB)
364 (37, MCCH), 250 (31, MKSO2Ph), 210 (100), 195
(32), 141 (28, SO2Ph).
(1H, s, ]CHCHD), 5.64 (1H, ddt, JZ16.7, 10.0, 6.6 Hz,
CHX]CHAHB), 5.18 (1H, dd, JZ16.7, 1.3 Hz, CHX]
CHAHB), 5.13 (1H, dd, JZ10.0, 1.3 Hz, CHX]CHAHB)
4.20 (2H, s, NCH2), 3.91 (2H, d, JZ6.6 Hz, NCH2), 3.84
(3H, s, CH3); dC (63 MHz, CDCl3), 197.0 (C]O), 143.4,
139.9, 132.6, 132.3, 130.4, 129.1, 128.7, 127.6, 127.3,
126.3, 124.8, 123.2, 119.8, 109.1, 103.0, 51.5 (NCH2), 48.0
(NCH2); 33.0 (CH3); m/z (%) (EI) 394 (4, MC), 253 (100,
MC), 198, (28), 144, (75), 77 (57).
3.2.3. N-[2-(4-Acetobenzoyl)prop-2-enyl]-N-allylben-
zenesulfonamide (11). Prepared by the general cascade
procedure on a 3 mmol scale, using 3.1 mmol of aryl iodide
and a reaction time of 40 h. Purification by flash
chromatography eluting with 3:2 v/v ether/petrol afforded
the product (800 mg, 70%) as a pale yellow oil; Rf 0.2;
(Found: C, 66.05; H, 5.65; N, 3.40. C21H21NO4S requires C,
65.80; H, 5.50; N, 3.60%); ymax/cmK1 (film) 1686 (C]O),
1652 (C]O), 1446, 1343 (S]Oas), 1264, 1160 (S]Os),
1091; dH (250 MHz, CDCl3) 8.01 (2H, d, JZ8.3 Hz, ArH),
7.87–7.84 (2H, m, SO2PhH), 7.77 (2H, d, JZ8.3 Hz, ArH),
7.60–7.51 (3H, m, SO2PhH), 6.35 (H, s, ]CHCHD), 5.90
(1H, s, ]CHCHD), 5.61 (1H, ddt, JZ16.9, 9.7, 6.5 Hz,
CHX]CHAHB), 5.15 (1H, d, JZ16.9 Hz, CHX]CHAHB),
5.14 (1H, d, JZ9.7 Hz, CHX]CHAHB), 4.14 (2H, s,
NCH2), 3.89 (2H, d, JZ6.5 Hz, NCH2), 2.66 (3H, s,
CH3); dC (63 MHz, CDCl3) 197.9 (C]O), 198.6 (C]O),
143.5, 141.3, 140.0, 139.8, 133.2, 132.7, 130.2, 130.0
(]CH2), 129.7, 128.6, 127.7, 120.4 (]CH2), 52.4 (NCH2),
47.7 (NCH2), 27.3 (CH3); m/z (%) (FAB) 384 (33, MCCH),
242 (40, MKSO2Ph), 210 (77), 147 (100), 141 (28, SO2Ph),
115 (47).
3.2.6. N-Allyl-N-{2-[2-(methylthio)benzoyl]prop-2-en-1-
yl}benzenesulfonamide(14). Prepared by the general
cascade procedure on a 5 mmol scale, using 6 mmol of
aryl iodide and a reaction time of 22 h. Purification by flash
chromatography eluting with DCM afforded the product
(1.320 g, 68%) as a viscous pale yellow oil, which solidified
on standing, mp 44–46 8C; Rf 0.15; (Found: C, 61.70; H,
5.50; N, 3.75. C20H21NO3S2 requires C, 62.00; H, 5.45; N,
3.60%); ymax/cmK1 (film) 1655 (C]O), 1446, 1434, 1344
(S]Oas), 1161 (S]Os), 1092; dH (250 MHz, CDCl3) 7.88–
7.85 (2H, m, SO2PhH), 7.60–7.53 (3H, m, SO2PhH), 7.44–
7.19 (4H, m, ArH), 6.27 (1H, s, ]CHCHD) 5.80 (1H, s,
]CHCHD), 5.59 (1H, ddt, JZ16.7, 10.0, 6.6 Hz, CHX]
CHAHB), 5.15 (1H, d, JZ16.7 Hz, CHX]CHAHB), 5.13
(1H, d, JZ10 Hz, CHX]CHAHB), 4.18 (2H, s, NCH2), 3.89
(2H, d, JZ6.6 Hz, NCH2), 2.42 (3H, s, CH3); dC (63 MHz,
CDCl3), 197.9 (C]O), 144.3, 140.2, 138.8, 138.1, 133.1,
132.5, 131.5, 130.7, 129.7, 129.6, 127.9, 127.6, 125.0,
120.4, 52.1 (NCH2), 47.0 (NCH2), 17.4 (CH3); m/z (ES) 388
(MCCH).
3.2.4. N-Allyl-N-[2-(4-methoxybenzoyl)prop-2-enyl]ben-
zenesulfonamide (12). Prepared by the general cascade
procedure on a 1 mmol scale, using 1.2 mmol of aryl iodide
and a reaction time of 44 h. Purification by flash
chromatography eluting with 3:7 v/v ethyl acetate/petrol
afforded the product (204 mg, 55%) as a colourless oil; Rf
0.25; (Found: C, 64.40; H, 5.75; N, 3.95. C20H21NO4S
requires C, 64.65; H, 5.70; N, 3.75%); ymax/cmK1 (film)
1647 (C]O), 1599, 1333 (S]Oas), 1308, 1258 (OCH3),
1160 (S]Os), 1091; dH (250 MHz, CDCl3), 7.87–7.83 (2H,
m, SO2PhH), 7.26 (2H, d, JZ8.9 Hz, ArH), 7.59–7.47 (3H,
m, SO2PhH), 6.92 (2H, d, JZ8.9 Hz, ArH), 6.14 (1H, s,
]CHCHD), 5.79 (1H, s, ]CHCHD), 5.61 (1H, ddt, JZ16.6,
10.0, 6.6 Hz, CHX]CHAHB), 5.20–5.06 (2H, m, CHX]
CHAHB), 4.14 (2H, s, NCH2), 3.88 (2H, d, JZ6.5 Hz,
NCH2), 3.87 (3H, s, CH3); dC (63 MHz, CDCl3), 195.9
(C]O), 163.8, 143.5, 140.1, 133.1, 132.7, 132.4, 130.0,
129.6, 127.6, 126.9, 120.2, 114.0, 55.9 (OMe), 52.0
(NCH2), 48.3 (NCH2); m/z (ES) 394 (MCCNa).
3.2.7. N-Allyl-4-nitro-N-[2-(2-thienylcarbonyl)prop-2-
en-1-yl]benzenesulfonamide (15). Prepared by the general
cascade procedure on a 5 mmol scale, using 5.5 mmol of
aryl iodide and a reaction time of 38 h. Purification by flash
chromatography eluting with DCM afforded the product
(1.260 g, 65%) as colourless viscous oil; Rf 0.18; (Found: C,
52.25; H, 4.15; N, 7.15. C17H16N2O5S2 requires C, 52.05; H,
4.10; N, 7.15%); ymax/cmK1 (film) 1633 (C]O), 1615,
1527 (NO2), 1345 (S]Oas), 1153 (S]Os), 1093; dH
(250 MHz, CDCl3) 8.29 (2H, d, JZ9.0 Hz, ArH), 7.98
(2H, d, JZ9.0 Hz, ArH), 7.69 (1H, dd, JZ4.8, 1.1 Hz,
ArH), 7.57 (1H, dd, JZ3.8, 1.1 Hz, ArH), 7.11 (1H, dd, JZ
5.0, 3.8 Hz, ArH), 6.06 (1H, s, ]CHCHD), 6.05 (1H, s,
]CHCHD), 5.64 (1H, ddt, JZ16.4, 9.9, 6.5 Hz, CHX]
HAHB), 5.21 (1H, dd, JZ16.4, 1.1 Hz, CHX]HAHB), 5.20
(1H, dd, JZ9.9, 1.3 Hz, CHX]CHAHB), 4.21 (2H, s,
NCH2), 3.95 (2H, d, JZ6.5 Hz, NCH2); dC (75 MHz,
CDCl3) 187.9 (C]O), 150.3, 146.3, 143.0, 142.9, 135.2,
134.6, 131.9, 128.8, 128.5, 126.8, 124.7, 120.9, 51.6
(NCH2), 48.2 (NCH2); m/z (%) (EI) 206 (100, MK
SO2PhNO2), 111 (69).
3.2.5. N-Allyl-N-{2-[(1-methyl-1H-indol-5-yl)carbonyl]
prop-2-en-1-yl}benzenesulfonamide (13). Prepared by
the general cascade procedure on a 5 mmol scale, using
5.5 mmol of aryl iodide and a reaction time of 44 h.
Purification by flash chromatography eluting with DCM
afforded the product (1.320 g, 70%) as a viscous pale yellow
oil; Rf 0.15; (Found: C, 67.05; H, 5.65; N, 7.10.
3.2.8. N-Allyl-N-{[2-[1,3-dimethyl-2-oxo-2,3-dihydro-1H-
indol-3-yl]acetyl]prop-2-enyl}benzenesulfonamide (16).
Prepared by the general cascade procedure on a 1 mmol
scale, using 1 mmol of aryl iodide and a reaction time of
28 h. Purification by flash column chromatography eluting
with 4:1 v/v ether/petrol afforded the product (282 mg,
65%) as a viscous colourless oil; Rf 0.17; (Found: C, 65.50;
H, 6.15; N, 6.50. C24H26N2O4S requires C, 65.75; H, 6.00;
N, 6.80%); ymax/cmK1 (film) 1711 (C]O), 1679
(N–C]O), 1614, 1348 (S]Oas), 1159 (S]Os), 1092; dH
C22H22N2O3S requires C, 67.00; H, 5.60; N, 7.10%); ymax
/
cmK1 (film) 1652 (C]O), 1605, 1340 (S]Oas), 1159
(S]Os), 1091; dH (250 MHz, CDCl3) 8.06 (1H, d, JZ
1.6 Hz, ArH), 7.89–7.84 (2H, m, SO2PhH), 7.71 (1H, dd,
JZ8.7, 1.6 Hz, ArH), 7.61–7.47 (3H, m, SO2PhH), 7.34 (d,
1H, JZ8.7 Hz, ArH) 7.13 (d, 1H, JZ3.2 Hz, ArH), 6.60
(dd, 1H, JZ3.2, 0.5 Hz, ArH), 6.15 (1H, s, ]CHCHD), 5.83

R. Grigg et al. / Tetrahedron 61 (2005) 11380–11392
11387
(250 MHz, CDCl3) 7.74–7.71 (2H, m, SO2PhH), 7.56–7.46
(3H, m, SO2PhH), 7.24 (1H, td, JZ7.7, 1.3 Hz, ArH), 7.09
(1H, dd, JZ7.5, 1.0 Hz, ArH), 7.02 (1H, td, JZ7.5, 0.9 Hz,
ArH), 6.88 (1H, d, JZ7.5 Hz, ArH), 6.25 (1H, s,
]CHCHD), 6.14 (1H, s, ]CHCHD), 5.39 (1H, ddt, JZ
16.8, 10.1, 6.6 Hz, CHX]CHAHB), 4.97 (1H, d, JZ
10.1 Hz, CHX]CHAHB), 4.93 (1H, d, JZ16.8 Hz,
CHX]CHAHB), 3.73 (2H, d, JZ1.3 Hz, NCH2), 3.66
(2H, d, JZ6.6 Hz, ]CHCH2), 3.49 (1H, d, JZ17.8 Hz,
O]CCHH), 3.37 (1H, d, JZ17.8 Hz, COCHH), 3.27 (3H,
s, NCH3), 1.36 (3H, s, CCH3); dC (63 MHz, CDCl3) 197.3
(C]O), 180.4 (C]O), 143.7, 142.9, 139.5, 133.4, 132.6,
131.8, 129.1, 127.9, 127.1, 126.5 (]CH2), 122.2, 121.8,
119.7 (]CH2), 108.1, 51.5 (CH2), 46.4 (CH2), 45.3
(CH2), 45.1 (CCH3), 26.4 (CH3), 24.9 (CH3); m/z (ES)
461 (MCCNa).
3.3.3. 1-Naphthyl[1-(phenylsulfonyl)-2,5-dihydro-1H-
pyrrol-3-yl]methanone (19). Prepared by the general
RCM procedure on a 0.2 mmol scale and a reaction time
of 5 h. Purification by flash chromatography eluting with
DCM afforded the product (63 mg, 90%) as an off white
amorphous solid, mp 61–63 8C; Rf 0.05; (Found: C, 68.85;
H, 4.85; N, 4.00. C21H17NO3S requires C, 69.40; H, 4.70; N,
3.85%); ymax/cmK1 (film) 1644 (C]O), 1446, 1347
(S]Oas), 1290, 1166 (S]Os), 1102; dH (CDCl3,
250 MHz) 8.00–7.90 (5H, m, ArH), 7.62–7.45 (7H, m,
ArH), 6.26 (1H, q, JZ2.1 Hz, ]CH), 4.56 (2H, 2!dd, JZ
4.2, 2.1 Hz, NCH2), 4.39 (2H, 2!dd, JZ4.4, 2.1 Hz,
NCH2); dC (CDCl3, 63 MHz), 199.5 (C]O), 145.3, 139.9,
136.1, 134.1, 133.2, 132.9, 132.1, 131.8, 131.1, 129.7,
128.1, 127.7, 127.6, 126.9, 125.7, 124.7, 120.3, 52.4
(NCH2), 47.3 (NCH2); m/z (%) (EI) 363 (11, MC), 155
(55), 127 (72), 77 (100); HRMS found 364.1000.
C21H18NO3S requires 364.1007.
3.3. General RCM procedure
3.3.4. 1-{(4-[(1-Phenylsulfonyl)-2,5-dihydro-1H-pyrrol-
3-yl]carbonyl)phenyl}ethanone (20). Prepared by the
general RCM procedure on a 0.15 mmol scale and a
reaction time of 2 h. Purification by flash chromatography
eluting with ether afforded the product (50 mg, 93%) as
colourless needles, mp 167–169 8C; Rf 0.27; (Found: C,
64.30; H, 4.75; N, 3.90. C17H19NO4S requires C, 64.20; H,
4.80; N, 3.95%); ymax/cmK1 (film) 1685 (C]O), 1652
(C]O), 1350 (S]Oas), 1167 (S]Os), 1092; dH (250 MHz,
CDCl3) 8.01 (2H, d, JZ8.6 Hz, ArH), 7.91–7.88 (2H, m,
SO2PhH), 7.73 (2H, d, JZ8.6 Hz, ArH), 7.65–7.53 (3H, m,
SO2PhH), 6.40–6.39 (1H, br m, ]CH), 4.49–4.34 (4H, m,
2!NCH2), 2.64 (3H, s, CH3); dC (75 MHz, CDCl3) 197.3
(C]O), 189.9 (C]O), 141.1, 140.3, 139.3, 138.8, 136.6,
133.6, 129.8, 129.3, 128.8, 127.9, 56.6 (NCH2), 54.6
(NCH2), 27.3 (CH3); m/z (%) (EI) 355 (6, MC), 214 (67,
MKSO2Ph), 147 (100), 77 (78).
Grubb’s second generation catalyst 3 (5.5 mg, 6.5 mmol)
was added to a magnetically stirred solution of acyclic
enone (0.13 mmol), in anhydrous toluene (50 ml) and the
mixture stirred under argon atmosphere at 80 8C for 1–14 h.
Concentration in vacuo yielded the crude product, which
was purified by flash chromatography.
3.3.1. [1-(Phenysulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]
(thien-2-yl)methanone (17). Prepared by the general
RCM procedure on a 0.33 mmol scale and a reaction time
of 3 h. Purification by flash chromatography eluting with
DCM afforded the product (99 mg, 94%), which crystallised
from petrol/DCM as colourless needles, mp 152–154 8C; Rf
0.1; (Found: C, 56.15; H, 4.20; N, 4.50; C15H13NO3S2
requires C, 56.40; H, 4.10; N, 4.30%); ymax/cmK1 (film); dH
(500 MHz, CDCl3) 7.90–7.86 (2H, m, SO2PhH), 7.67 (1H,
dd, JZ4.9, 1.1 Hz, ArH), 7.65 (1H, dd, JZ3.8, 1.1 Hz,
ArH) 7.63–7.60 (1H, m, SO2PhH), 7.57–7.54 (2H, m,
SO2PhH), 7.12 (1H, dd, JZ4.9, 3.8 Hz, ArH), 6.58 (1H, qi,
JZ2.1 Hz, ]CH), 4.48 (2H, 2!ddd, JZ4.9, 2.1, 1.0 Hz,
NCH2), 4.44 (2H, 2!ddd, JZ4.9, 2.1, 1.0 Hz, NCH2); dC
(125 MHz, CDCl3) 181.2 (C]O), 142.3, 138.9, 136.8,
134.8, 134.2, 133.1, 133.0, 129.4, 128.1, 127.5, 57.0
(NCH2), 54.5 (NCH2); m/z (%) (FAB) 320 (100, MCC
H), 178 (23, MKSO2Ph), 111 (60).
3.3.5. (4-Methoxyphenyl)[1-(phenylsulfonyl)-2, 5-di-
hydro-1H-pyrrol-3-yl]methanone (21). Prepared by the
general RCM procedure on a 0.3 mmol scale and a reaction
time of 4 h. Purification by flash chromatography eluting
with 3:2 v/v ether/petrol afforded the product (89 mg, 92%)
as colourless needles, mp 162–164 8C; Rf 0.17; (Found: C,
62.70; H, 5.00; N, 4.05. C18H17NO4S requires C, 62.95; H,
5.00; N, 4.10%); ymax/cmK1 (film) 1633 (C]O), 1568,
1334 (S]Oas), 1153 (S]Os), 1099, 1023; dH (250 MHz,
CDCl3) 7.91–7.87 (2H, m, SO2PhH), 7.71 (2H, d, JZ
9.0 Hz, ArH), 7.63–7.57 (3H, m, SO2PhH), 6.92 (2H, d, JZ
9.0 Hz, ArH), 6.30 (1H, q, JZ2.0 Hz, ]CH), 3.87 (3H, s,
CH3) 4.50–4.39 (4H, m, 2!NCH2); dC (63 MHz, CDCl3)
189.5 (C]O), 163.9, 139.3, 137.1, 135.9, 133.4, 131.6,
130.1, 129.8, 127.9, 114.2, 56.4, 55.9, 55.0; m/z (ES) 344
(MCHC).
3.3.2. Phenyl[1-(phenylsulfonyl)-2,5-dihydro-1H-pyrrol-
3-yl]methanone (18). Prepared by the general RCM
procedure on a 0.12 mmol scale and a reaction time of
3 h. Purification by flash chromatography eluting with 7:3
v/v petrol/ethyl acetate afforded the product (34 mg, 88%),
which crystallised from petrol/ether as colourless needles,
mp 102–104 8C; Rf 0.19; (Found: C, 65.05; H, 4.90; N, 4.60.
C17H15NO3S requires C, 65.15; H, 4.80; N, 4.45%); ymax
/
cmK1 (film) 1644 (C]O), 1446, 1346 (S]Oas), 1291, 1165
(S]Os), 1103; dH (500 MHz, CDCl3) 7.90–7.88 (2H, m,
ArH), 7.68–7.61 (3H, m, ArH), 7.59–7.54 (3H, m, ArH),
7.46–7.42 (m, 2H, ArH), 6.36 (1H, q, JZ2.1 Hz, ]CH),
4.48 (2H, 2!ddd, JZ4.7, 2.1, 1.0 Hz, NCH2), 4.43 (2H,
2!ddd, JZ4.7, 2.1, 1.0 Hz, NCH2); dC (125 MHz, CDCl3)
190.6 (C]O), 138.9, 137.2, 137.1, 136.9, 133.0, 132.8,
129.4, 128.8, 128.6, 127.5, 56.1 (NCH2), 54.4 (NCH2); m/z
(%) (CI), 331 (100, MCNHC4 ), 172 (100, MKSO2Ph).
3.3.6. (1-Methyl-1H-indol-5-yl)[1-(phenylsulfonyl)-2,5-
dihydro-1H-pyrrol-3-yl]methanone (22). Prepared by
the general RCM procedure on a 0.4 mmol scale and a
reaction time of 2 h. Purification by flash chromatography
eluting with 3:2 v/v ether/petrol afforded the product
(129 mg, 87%) as colourless needles, mp 139–141 8C; Rf
0.2; (Found: C, 65.45; H, 5.15; N, 7.60. C20H18N2O3S
requires C, 65.55; H, 4.95; N, 7.65%); ymax/cmK1 (film)
1652 (C]O), 1344 (S]Oas), 1166 (S]Os); dH (250 MHz,

11388
R. Grigg et al. / Tetrahedron 61 (2005) 11380–11392
CDCl3) 8.03 (s, 1H, ArH), 7.92–7.90 (2H, m, SO2PhH),
7.70–7.54 (4H, m, SO2PhH and ArH), 7.34 (1H, d, JZ
8.8 Hz, ArH), 7.13 (1H, d, JZ3.1 Hz, ArH), 6.58 (1H, d,
JZ3.1 Hz, ArH), 6.32 (1H, br s, ]CH), 4.53–4.51 (2H, br
m, NCH2), 4.45–4.44 (2H, br m, NCH2); dC (63 MHz,
CDCl3) 190.8 (C]O), 139.3, 139.1, 136.9, 135.0, 133.0,
130.6, 129.3, 128.8, 127.7, 127.5, 123.8, 122.5, 109.4,
103.0, 56.0 (NCH2), 54.8 (NCH2), 33.1 (CH3); m/z (ES) 344
(MCCNa).
3.3.10. N-But-3-en-1-yl-4-methyl-N-[2-(2-thienylcarbo-
nyl)prop-2-en-1-yl]benzenesulfonamide (26). Prepared
by the general cascade procedure employing rubidium
carbonate base on a 2 mmol scale, using 2.4 mmol of aryl
iodide and a reaction time of 18 h. Purification by flash
chromatography eluting with petrol/ether 7:3 v/v afforded
the product (540 mg, 72%) as a pale yellow oil; Rf 0.2;
(Found: C, 60.55; H, 5.65; N, 3.65. C19H21NO3S2 requires
C, 60.75; H, 5.65; N, 3.75%); ymax/cmK1 (film) 1641
(C]O), 1432, 1342 (S]Oas), 1298, 1166 (S]Os), 1093;
dH (250 MHz, CDCl3) 7.71 (2H, d, JZ8.2 Hz, ArH), 7.79
(1H, dd, JZ4.9, 1.1 Hz, ArH), 7.64 (1H, dd, JZ3.8, 1.1 Hz,
ArH), 7.29 (2H, d, JZ8.2 Hz, ArH), 7.13 (1H, dd, JZ4.9,
3.8 Hz, ArH), 6.15 (1H, t, JZ1.5 Hz, ]CHCHD), 6.07 (1H,
s, ]CHCHD), 5.66 (1H, ddt, JZ17.0, 10.5, 6.7 Hz,
CHX]CHAHB), 5.06–4.97 (2H, m, CHX]CHAHB), 4.14
(2H, s, NCH2), 3.25 (2H, t, JZ7.5 Hz, NCH2), 2.43 (3H, s,
CH3), 2.26 (2H, m, CH2); dC (75 MHz, CDCl3) 188.4
(C]O), 143.8, 143.2, 136.9, 134.9, 134.8, 134.8, 130.2,
128.4, 127.6, 126.5, 117.7, 49.4 (NCH2), 49.3 (NCH2), 33.1
(]CHCH2), 21.9 (CH3); m/z (ES) 348 (MCHC).
3.3.7. [2-(Methylthio)phenyl][1-(phenylsulfonyl)-2,5-
dihydro-1H-pyrrol-3-yl]methanone (23). Prepared by
the general RCM procedure on a 0.18 mmol scale and a
reaction time of 14 h. Purification by flash chromatography
eluting with DCM afforded the product (16 mg, 25%),
which crystallised from DCM/hexane as colourless needles,
mp 135–137 8C; Rf 0.1; (Found: C, 59.95; H, 4.50; N, 3.70.
C18H17NO3S2 requires C, 60.15; H, 4.75; N, 3.90%); ymax
/
cmK1 1625 (C]O), 1460, 1332 (S]Oas), 1159 (S]Os),
1073; dH (300 MHz, CDCl3) 7.88 (2H, m, SO2PhH), 7.66–
7.54 (3H, m, SO2PhH), 7.43 (1H, t, JZ7.5 Hz, ArH), 7.33
(2H, d, JZ7.5 Hz, ArH), 7.16 (1H, t, JZ7.5 Hz, ArH), 6.20
(1H, br s, ]CH), 4.48–4.47 (2H, br m, NCH2), 4.38–4.37
(2H, br m, NCH2), 2.40 (3H, s, CH3); dC (75 MHz, CDCl3)
191.5 (C]O), 140.4, 139.5, 138.6, 137.1, 137.0, 133.4,
131.9, 129.7, 129.4, 127.9, 127.5, 124.8, 56.4 (NCH2),
54.18 (NCH2), 17.0 (CH3); m/z (ES) 360 (MCHC).
3.3.11. N-(2-Benzoylprop-2-en-1-yl)-N-but-3-en-1-yl-4-
methylbenzenesulfonamide (28). Prepared by the general
cascade procedure employing rubidium carbonate base on a
1 mmol scale, using 1.2 mmol of aryl iodide and a reaction
time of 19 h. Purification by flash chromatography eluting
with petrol/ether 4:1 v/v afforded the product (265 mg,
72%) as a viscous colourless oil; Rf 0.12; ymax/cmK1 (film)
1652 (C]O), 1340 (S]Oas), 1157 (S]Os), 1091; dH
(250 MHz, CDCl3) 7.74–7.70 (3H, m, ArH), 7.73 (2H, d,
JZ8.0 Hz, ArH) 7.61–7.53 (1H, m, ArH), 7.48–7.41 (2H,
m, ArH), 7.32 (2H, d, JZ8.0 Hz, ArH), 6.31 (1H, t, JZ
1.5 Hz, ]CHCHD), 5.91 (1H, s, ]CHCHD), 5.68 (1H, ddt,
JZ17, 10.4, 6.7 Hz, CHX]CHAHB), 5.07–4.99 (2H, m,
CHX]CHAHB), 4.16 (2H, s, NCH2), 3.29–3.23 (2H, m,
NCH2), 2.44 (3H, s, CH3), 2.31–2.22 (2H, m, CH2); dC
(63 MHz, CDCl3) 197.3 (C]O), 143.9, 143.6, 137.6, 136.9,
134.8, 133.0, 130.2, 130.0, 129.3, 128.7, 127.7, 117.7, 49.5
(NCH2), 49.2 (NCH2), 33.1 (]CHCH2), 21.9 (CH3); m/z
(EI) 370 (MCHC); HRMS found 370.1472, C21H24NO3S
requires 370.1471.
3.3.8. {1-[(4-Nitrophenyl)sulfonyl]-2, 5-dihydro-1H-pyr-
rol-3-yl}(2-thienyl)methanone (24). Prepared by the
general RCM procedure on a 1.45 mmol scale and a
reaction time of 6 h. The product precipitated as an off
white solid (295 mg, 56%), mp 216–218 8C; Rf 0.1; (Found:
C, 49.50; H, 3.50; N, 7.90. C15H12N2O5S2 requires C, 49.45;
H, 3.30; N, 7.7%); ymax/cmK1 1633 (C]O), 1596, 1527
(NO2), 1345 (S]Oas), 1157 (S]Os), 1108, 1062; dH
(250 MHz, CDCl3) 8.41 (2H, d, JZ8.9 Hz, ArH), 8.07 (2H,
d, JZ8.9 Hz, ArH), 7.71–7.68 (2H, m, ArH and ArH), 7.14
(1H, dd, JZ4.8, 3.9 Hz, ArH), 6.60 (1H, qi, JZ1.9 Hz,
]CH), 4.52–4.46 (br m, 1H, 2!NCH2); m/z (%) (EI) 178
(49, MKSO2PhNO2), 111 (100).
3.3.9. 1,3-Dimethyl-3-{2-oxo-2-[(1-phenylsulfonyl)-2,5-
dihydro-1H-pyrrol-3-yl]ethyl}-1,3-dihydro-2H-indol-2-
one (25). Prepared by the general RCM procedure on a
0.08 mmol scale and a reaction time of 1 h. Purification by
flash chromatography eluting with ether yielded the product
(33 mg, 93%) as a colourless solid, mp 69–71 8C; Rf 0.1;
(Found: C, 64.30; H, 5.45; N, 6.55. C22H22N2O4S requires
C, 64.35; H, 5.40; N, 6.80%); ymax/cmK1 (film) 1709
(C]O), 1677 (N–C]O), 1614, 1348 (S]Oas), 1167
(S]Os), 1104; dH (250 MHz, CDCl3) 7.79 (2H, m,
SO2PhH), 7.61–7.48 (3H, m, SO2PhH), 7.25 (1H, td, JZ
7.5, 1.4 Hz, ArH), 7.06 (1H, dd, JZ7.5, 1.4 Hz, ArH), 6.98
(1H, td, JZ7.5, 0.9 Hz, ArH), 6.86 (1H, d, JZ7.5 Hz, ArH),
6.50 (1H, qi, JZ2.0 Hz, ]CH), 4.43–4.29 (2H, m, NCH2),
4.09–4.05 (2H, m, NCH2), 3.26 (2H, s, CCH2), 3.24 (3H, s,
CH3), 1.33 (3H, s, CH3); dC (63 MHz, CDCl3) 192.5
(C]O), 180.5 (C]O), 143.9, 139.8, 136.9, 135.1, 133.5,
133.4, 129.8, 128.5, 127.8, 122.7, 122.2, 108.7, 56.2, 53.6,
46.3, 45.4, 26.8, 25.0; m/z (FAB) 411 (28%, MCCH), 215
(48%, MKSO2Ph), 174 (49%), 160 (100%), 108 (90%).
3.3.12. N-But-3-en-1-yl-4-methyl-N-{2-[(1-methyl-1H-
indol-5-yl)carbonyl]prop-2-en-1-yl}benzenesulfonamide
(29). Prepared by the general cascade procedure employing
rubidium carbonate on a 1 mmol scale, using 1.2 mmol of
aryl iodide and a reaction time of 25 h. Purification by flash
chromatography eluting with DCM afforded the product
(282 mg, 68%), which crystallised from DCM/petrol as
colourless prisms, mp 103–105 8C; Rf 0.26; (Found: C,
67.90; H, 6.10; N, 6.60. C24H26N2O3S requires C, 68.20; H,
6.20; N, 6.65%); ymax/cmK1 (film) 1645 (C]O), 1339
(S]Oas), 1157 (S]Os), 1091; dH (250 MHz, CDCl3) 8.09
(1H, d, JZ1.5 Hz, ArH), 7.73 (2H, d, JZ8.2 Hz, ArH), 7.72
(1H, dd, JZ8.7, 1.5 Hz, ArH), 7.33 (1H, d, JZ8.7 Hz,
ArH), 7.28 (2H, d, JZ8.2 Hz, ArH), 7.12 (1H, d, JZ3.2 Hz,
ArH), 6.58 (1H, d, JZ3.2 Hz, ArH), 6.17 (1H, s,
]CHCHD), 5.83 (1H, s, ]CHHD), 5.69 (1H, ddt, JZ
17.0, 10.2, 6.7 Hz, CHX]CHAHB), 5.07–4.99 (2H, m,
CHX]CHAHB), 4.22 (2H, s, NCH2), 3.81 (3H, s, CH3),
3.32–3.26 (2H, m, NCH2), 2.40 (3H, s, CH3), 2.40–2.26
(2H, m, CH2); dC (63 MHz, CDCl3) 198.5 (C]O), 144.1,

R. Grigg et al. / Tetrahedron 61 (2005) 11380–11392
11389
143.8, 139.5, 137.1, 135.0, 131.0, 130.1, 129.0, 128.0,
127.7, 126.9 (]CH2), 125.2, 123.6, 117.6 (]CH2), 109.6,
103.4, 49.7 (NCH2), 49.3 (NCH2), 33.5 (]CHCH2), 33.1
(NCH3), 21.9 (CH3); m/z (%) (EI) 422 (1, MC), 267 (43,
MKTs), 144 (51), 91 (49).
d, JZ8.1 Hz, ArH), 7.11 (1H, dd, JZ4.9, 3.7 Hz, ArH),
6.83 (1H, br s, ]CH), 3.95 (2H, s, NCH2), 3.26 (2H, t, JZ
5.6 Hz, NCH2), 2.51–2.50 (2H, br m, CH2), 2.43 (3H, s,
CH3); dC (100 MHz, CDCl3) 186.2 (C]O), 143.8, 142.2,
137.3, 135.3, 133.6, 133.4, 133.2, 129.8, 127.8, 44.5
(NCH2), 42.0 (NCH2), 25.9 (]CHCH2), 21.5 (CH3); m/z
(%) (EI) 347 (3, MC), 192 (80, MKTs), 124.1 (49), 111
(92), 91 (100).
3.3.13. N-But-3-en-1-yl-4-methyl-N-{2-[2(methylthio)
benzoyl]prop-2-en-1-yl}benzenesulfonamide (30). Pre-
pared by the general cascade procedure employing rubidium
carbonate on a 1 mmol scale, using 1.2 mmol of aryl iodide
and a reaction time of 22 h. Purification by flash
chromatography eluting with petrol/ether 4:1 v/v afforded
the product (310 mg, 75%), which crystallised from DCM/
petrol as pale yellow needles, mp 97–99 8C; Rf 0.1; (Found:
C, 63.30; H, 5.95; N, 3.60. C22H25NO3S2 requires C, 63.60;
H, 6.05; N, 3.35%); ymax/cmK1 (film) 1653 (C]O), 1340
(S]Oas), 1157 (S]Os), 1091; dH (250 MHz, CDCl3) 7.74
(2H, d, JZ8.0 Hz, ArH), 7.47–7.16 (4H, m, ArH), 7.33 (2H,
d, JZ8.0 Hz, ArH), 6.32 (1H, s, ]CHCHD), 5.81 (1H, s,
]CHCHD), 5.67 (1H, ddt, JZ17.0, 10.4, 6.8 Hz, CHX]
CHAHB), 5.07–4.99 (2H, m, CHX]CHAHB), 4.18 (2H, s,
NCH2), 3.27 (2H, m, NCH2), 2.44 (3H, s, CH3), 2.43 (3H, s,
CH3), 2.33–2.22 (2H, m, CH2); dC (63 MHz, CDCl3) 198.5
(C]O), 144.6, 143.9, 138.7, 138.2, 136.9, 134.9, 131.5,
130.9, 130.2, 129.6, 128.0, 127.6, 125.1, 117.7, 49.5
(NCH2), 48.3 (NCH2), 33.1 (]CCH2), 21.9 (CH3), 17.5
(CH3); m/z (%) (EI) 260 (22, MKTs), 191 (75), 137 (63), 91
(100).
3.3.16. {1-[(4-Methylphenyl)sulfonyl]-1,2,5,6-tetra-
hydropyridin-3-yl}(phenyl)methanone (33). Prepared by
the general RCM procedure on a 0.2 mmol scale and a
reaction time of 2 h. Purification by flash chromatography
eluting with 7:3 v/v petrol/ether afforded the product
(60 mg, 90%) as colourless needles, mp 134–135 8C; Rf
0.05; (Found: C, 67.05; H, 5.65; N, 4.10. C19H19NO3S
requires C, 66.85; H, 5.60; N, 4.15%); ymax/cmK1 (film)
1642 (C]O), 1343 (S]Oas), 1166 (S]Os), 1092; dH
(250 MHz, CDCl3) 7.74 (2H, d, JZ8.2 Hz, ArH), 7.59–7.50
(3H, m, ArH), 7.44–7.27 (2H, m, ArH), 7.34 (2H, d, JZ
8.2 Hz, ArH), 6.2 (1H, q, JZ2.1 Hz, ]CH), 3.96 (2H, br d,
JZ2.1 Hz, NCH2), 3.23 (2H, t, JZ5.7 Hz, NCH2), 2.53–
2.46 (2H, m, CH2), 2.44 (3H, s, CH3); dC (63 MHz, CDCl3)
198.0 (C]O), 144.3, 141.4, 137.7, 135.4, 133.4, 132.4,
130.2, 129.5, 128.7, 128.2, 44.7 (NCH2), 42.4 (NCH2), 26.5
(]CHCH2), 22.0 (CH3); m/z (ES) 342 (MCCH).
3.3.17. (1-Methyl-2,3-dihydro-1H-indol-5-yl){1-[(4-
methylphenyl)sulfonyl]-1,2,5,6-tetrahydropyridin-3-
yl}methanone (34). Prepared by the general RCM
procedure on a 0.15 mmol scale and a reaction time of
5 h. Purification by flash chromatography eluting with 2:3
v/v petrol/ether afforded the product (54 mg, 91%) as
colourless needles, mp 116–118 8C; Rf 0.16; ymax/cmK1
(film) 1635 (C]O), 1340 (S]Oas), 1164 (S]Os), 1098; dH
(250 MHz, CDCl3) 7.95 (1H, d, JZ1.5 Hz, ArH), 7.74 (2H,
d, JZ8.2 Hz, ArH), 7.59 (1H, dd, JZ8.6, 1.5 Hz, ArH),
7.34 (2H, d, JZ8.2 Hz, ArH) 7.33 (1H, d, JZ8.6 Hz, ArH),
7.13 (1H, d, JZ3.5 Hz, ArH), 6.57 (1H, d, JZ3.5 Hz, ArH),
6.57–6.54 (H, m, ]CH), 4.01 (2H, br d, JZ2.1 Hz, NCH2),
3.82 (3H, s, CH3), 3.26 (2H, t, JZ5.7 Hz, NCH2), 2.52–2.47
(2H, m, CH2), 2.44 (3H, s, CH3); dC (63 MHz, CDCl3) 198.0
(C]O), 144.1, 139.2, 138.6, 135.7, 133.6, 130.9, 130.2,
129.1, 128.2, 128.0, 124.5, 123.4, 109.6, 103.1, 45.2
(NCH2), 42.6 (NCH2), 33.5, 26.2, 22.0; m/z (%) (CI) 395
(100, MCCH), 241 (90) 189 (31); HRMS found 395.1426,
C22H23N2O3S requires 384.1424.
3.3.14. Methyl 4-[2-({but-3-en-1-yl[(4-methylphenyl)sul-
fonyl]amino}methyl)acryloyl]benzenesulfonamide (31).
Prepared by the general cascade procedure employing
rubidium carbonate on a 1 mmol scale, using 1.2 mmol of
aryl iodide and a reaction time of 21 h. Purification by flash
chromatography eluting with petrol/ether 1:1 v/v afforded
the product (300 mg, 70%), which crystallised from ether/
hexane as colourless needles, mp 79–80 8C; Rf 0.2; (Found:
C, 64.60; H, 6.00; N, 3.25. C23H25NO5S requires C, 64.60;
H, 5.90; N, 3.30%); ymax/cmK1 (film) 1723 (MeOC]O),
1653 (C]O), 1340 (S]Oas), 1158 (S]Os), 1109, 1092; dH
(250 MHz, CDCl3) 8.11 (2H, d, JZ8.2 Hz, ArH), 7.75 (2H,
d, JZ8.2 Hz, ArH), 7.72 (2H, d, JZ8.2 Hz, ArH), 7.32 (2H,
d, JZ8.2 Hz, ArH), 6.38 (1H, s, ]CHCHD), 5.91 (1H, s,
]CHCHD), 5.68 (1H, ddt, JZ17.3, 10.7, 6.7 Hz, CHX]
CHAHB), 5.07–5.00 (2H, m, CHX]CHAHB), 4.15 (2H, s,
NCH2), 3.96 (3H, s, CH3), 3.30–3.29 (2H, m, NCH2), 2.44
(3H, s, CH3), 2.31–2.22 (2H, m, CH2); dC (63 MHz, CDCl3)
196.7 (C]O), 166.6 (C]O), 144.0, 143.6, 141.3, 136.8,
134.8, 133.7, 130.4, 130.2, 129.9, 129.7, 127.7, 117.7, 52.9
(OCH3), 49.7 (NCH2), 49.1 (NCH2), 33.2 (]CHCH2), 21.9
(CH3); m/z (ES) 428 (MCHC).
3.3.18. {1-[(4-Methylphenyl)sulfonyl]-1,2,5,6-tetra-
hydropyridin-3-yl}[2-(methylthio)phenyl]methanone
(35). Prepared by the general RCM procedure employing
5 mol% of 3, followed by an extra 2 mol% of 3 after 4 h on a
0.32 mmol scale and a reaction time of 7 h. Purification by
flash chromatography eluting with 3:2 v/v petrol/ether
afforded the product (90 mg, 73%), which crystallised from
DCM/petrol as colourless needles, mp 139–141 8C; Rf 0.11;
(Found: C, 62.00; H, 5.50; N, 3.60. C20H21NO3S2 requires
C, 62.00; H, 5.45; N, 3.60%); ymax/cmK1 (film) 1644
(C]O), 1340 (S]Oas), 1162 (S]Os), 1091; dH (250 MHz,
CDCl3) 7.74 (2H, d, JZ8.1 Hz, ArH), 7.43–7.32 (2H, m,
ArH), 7.36 (2H, d, JZ8.1 Hz, ArH), 7.19–7.17 (2H, m,
ArH), 6.49 (1H, br s, ]CH), 3.97 (2H, br d, JZ1.8 Hz,
NCH2), 3.21 (2H, t, JZ5.7 Hz, NCH2), 2.44 (5H, s, CH3
3.3.15. {1-[(4-Methylphenyl)sulfonyl]-1,2,5,6-tetra-
hydropyridin-3-yl}(2-thienyl)methanone (32). Prepared
by the general RCM procedure on a 0.26 mmol scale and a
reaction time of 3 h. Purification by flash chromatography
eluting with 3:2 v/v petrol/ether afforded the product
(83 mg, 92%) as colourless needles, mp 119–120 8C; Rf
0.06; (Found: C, 58.65; H, 5.20; N, 4.30. C17H17NO3S2
requires C, 58.75; H, 4.95; N, 4.05%); ymax/cmK1 (film)
1642 (C]O), 1343 (S]Oas), 1273, 1166 (S]Os), 1093; dH
(400 MHz, CDCl3) 7.72 (2H, d, JZ8.1 Hz, ArH), 7.65 (1H,
d, JZ4.9 Hz, ArH), 7.56 (1H, d, JZ3.7 Hz, ArH), 7.34 (2H,

11390
R. Grigg et al. / Tetrahedron 61 (2005) 11380–11392
and CH2), 2.40 (3H, s, CH3); dC (63 MHz, CDCl3) 195.9
(C]O), 144.2, 142.9, 138.3, 138.0, 136.4, 133.4, 131.1,
130.2, 128.8, 128.2, 128.0, 125.1, 44.2 (NCH2), 42.3
(NCH2), 26.7, 22.0, 17.4; m/z (ES) 388 (MCCH).
3.18 (2H, t, JZ7.7 Hz, NCH2), 2.44 (3H, s, CH3), 2.06–1.97
(2H, m, ]CHCH2), 1.60 (2H, qi, JZ7.7 Hz, CH2); dC
(63 MHz, CDCl3) 197.1 (C]O), 143.8, 143.7, 137.7, 137.6,
136.9, 133.0, 130.2, 130.0, 129.2, 128.7, 127.7, 115.8, 49.8
(NCH2), 49.2 (NCH2), 31.2 (]CHCH2), 27.8 (CH2), 21.9
(CH3); m/z (%) (CI) 384 (10, MCCH), 164 (90), 86 (100);
HRMS found 384.1632, C22H26NO3S requires 384.1628.
3.3.19. Methyl 4-({1-[(4-methylphenyl)sulfonyl]-1,2,5,6-
tetrahydropyridin-3-yl}carbonyl)benzoate (36). Prepared
by the general ring closing metathesis procedure on a
0.12 mmol scale and a reaction time of 3 h. Purification by
flash chromatography eluting with 7:3 v/v petrol/ether
afforded the product (41 mg, 86%) as colourless needles, mp
157–159 8C; Rf 0.15; (Found: C, 62.70; H, 5.50; N, 3.20.
3.4. General procedure for microwave RCM
Substrate and CH2Cl2 (4 ml) were combined in a
microwave pressure vial, containing a small magnetic
stirrer bar, to afford solutions of either 1.5 or 3.0 mM.
Catalyst 3 (1–5 mol%) was then added to this solution
and the pressure vial immediately sealed and subjected
to microwave irradiation (Smith Creator model). The
solvent was then removed and the product conversion
measured by 500 MHz NMR analysis. Passing the crude
product through a small pad of silica, eluting with ether/
petrol, afforded the product.
C21H21NO5S requires C, 63.15; H, 5.30; N, 3.50%); ymax
/
cmK1 (film) 1723 (MeOC]O) 1645 (C]O), 1344
(S]Oas), 1280, 1166 (S]Os), 1093; dH (250 MHz,
CDCl3) 8.09 (2H, d, JZ8.3 Hz, ArH), 7.74 (2H, d, JZ
8.2 Hz, ArH), 7.61 (2H, d, JZ8.3 Hz, ArH), 7.36 (2H, d,
JZ8.2 Hz, ArH), 6.62 (1H, q, JZ2.0 Hz, ]CH), 3.96–3.94
(2H, m, NCH2), 3.94 (3H, s, OCH3), 3.25 (2H, t, JZ5.7 Hz,
NCH2), 2.52–2.50 (2H, m, CH2), 2.45 (3H, s, CH3); dC
(63 MHz, CDCl3) 197.7 (C]O), 166.6 (C]O), 144.3,
142.5, 141.6, 135.5, 133.4, 133.3, 130.2, 129.9, 129.2,
128.2, 52.9 (OCH3), 44.5 (NCH2), 42.3 (NCH2), 26.6
(]CHCH2), 22.0 (CH3); m/z (ES) 400 (MCCH); HRMS
found 417.1476, C21H25N2O5S requires 417.1479.
3.4.1. Methyl 1-methyl-2,3-diphenyl-5-(phenylsulfonyl)-
3a-(thien-2-yl carbonyl)octahydropyrrolo[3,4-c]pyrrole-
1-carboxylate (41). Triethylamine (57 ml, 0.4 mmol), and
silver acetate (66 mg, 0.4 mmol) were added to a stirred
solution of enone 17 (84 mg, 0.26 mmol) in toluene (10 ml).
A solution of imine (60 mg, 0.29 mmol) in toluene (1 ml)
was then added and reaction mixture stirred at room
temperature for 20 h. Filtration and concentration in vacuo
afforded the crude product as a single isomer. Purification
by flash column chromatography eluting with 1:2 v/v ethyl
acetate/petrol afforded the product as a colourless
amorphous solid, mp 75–77 8C; Rf 0.15; ymax /cmK1 (film)
3334 (NH), 1733 (C]O), 1637 (MeOC]O), 1412, 1350
(S]Oas), 1246, 1169 (S]Os), dH (500 MHz, CDCl3)
7.83–7.81 (2H, m, SO2PhH), 7.62–7.60 (1H, m, SO2PhH),
7.55–7.52 (2H, m, SO2PhH), 7.37 (1H, dd, JZ5.0, 1.0 Hz,
ArH), 7.14–7.12 (2H, m, ArH), 7.09–7.07 (3H, m, ArH),
6.84 (1H, dd, JZ4.0, 1.0 Hz, ArH), 6.75 (1H, dd, JZ5.0,
4.0 Hz, ArH), 4.48 (1H, s, NCHAPh), 4.03 (1H, d, JZ
10.0 Hz, NCHH), 3.82 (3H, s, OCH3), 3.77–3.71 (2H, m,
NCH2), 3.27 (1H, d, JZ10.0 Hz, NCHH), 3.14 (1H, br s,
NH), 2.93 (1H, dd, JZ10.2, 8.1 Hz, CH), 1.61 (3H, s, CH3);
m/z (ES) 533 (MCCNa); HRMS found 533.6284,
C26H26N2O5S2CNa requires 533.6280.
3.3.20. N-Pent-4-en-1-yl-N-[2-(2-(thienyl)prop-2-en-1-yl
(37). Prepared by the general cascade procedure on a
2 mmol scale, using 2.5 mmol of aryl iodide and a reaction
time of 25 h. Purification by flash chromatography eluting
with 4:1 v/v petrol/ether afforded the product (440 mg,
56%) as a viscous pale yellow oil; Rf 0.12; ymax/cmK1 (film)
1636 (C]O), 1622, 1413, 1340 (S]Oas), 1158 (S]Os),
1091; dH (250 MHz, CDCl3) 7.70 (2H, d, JZ8.2 Hz, ArH),
7.69 (1H, d, JZ5.1 Hz, ArH), 7.64 (1H, d, JZ3.6 Hz, ArH)
7.33 (2H, d, JZ8.2 Hz, ArH), 7.12 (1H, dd, JZ5.1, 3.6 Hz,
ArH), 6.16 (1H, s, ]CHCHD), 6.06 (1H, s, ]CHCHD), 5.71
(1H, ddt, JZ16.9, 10.3, 6.6 Hz, CHX]CHAHB), 4.99 (1H,
d, JZ10.3 Hz, CHX]CHAHB), 4.97 (1H, d, JZ16.9 Hz,
CHX]CHAHB), 4.11 (2H, s, NCH2), 3.17 (2H, t, JZ7.7 Hz,
NCH2), 2.43 (3H, s, CH3), 2.04–1.96 (2H, m, ]CHCH2),
1.59 (2H, qi, JZ7.7 Hz, CH2); dC (63 MHz, CDCl3) 188.5
(C]O), 144.1, 143.8, 143.3, 137.7, 136.9, 134.9, 134.8,
130.1, 128.4, 127.6, 126.4 (]CH2), 115.8 (]CH2), 49.6
(NCH2), 49.4 (NCH2), 31.2 (]CHCH2), 27.7 (CH2), 21.9
(CH3); m/z (%) (CI) 390 (5, MCCH), 170 (48), 99 (100), 86
(100); HRMS found 390.1192, C20H24NO3S2 requires
390.1192.
3.3.21. N-Pent-4-en-1-yl-N-(2-phenyl)prop-2-en-1-yl]
benzenesulfonamide (38). Prepared by the general cascade
procedure on a 2 mmol scale, using 2.5 mmol of aryl iodide
and a reaction time of 25 h. Purification by flash
chromatography eluting with DCM afforded the product
NOE data:
Signal irradiated
Enhancement (%)
HA
(520 mg, 68%) as a viscous pale yellow oil; Rf 0.27; ymax
/
CH3
2.1
cmK1 (film) 1654 (C]O), 1448, 1339 (S]Oas), 1159
(S]Os), 1091; dH (250 MHz, CDCl3) 7.72 (2H, d, JZ
8.2 Hz, ArH), 7.71 (2H, d, JZ7.5 Hz, ArH), 7.57 (1H, t, JZ
7.5 Hz, ArH), 7.44 (2H, t, JZ7.5 Hz, ArH), 7.31 (2H, d, JZ
8.2 Hz, ArH), 6.31 (1H, s, ]CHCHD), 5.90 (1H, s,
]CHCHD), 5.73 (1H, ddt, JZ16.9, 10.2, 6.6 Hz, CHX]
CHAHB), 5.00 (1H, d, JZ10.2 Hz, CHX]CHAHB), 4.97
(1H, d, JZ16.9 Hz, CHX]CHAHB), 4.13 (2H, s, NCH2),
3.5. General thermodynamic controlled nitrone cyclo-
addition procedure (A)
Diphenyl nitrone (183 mg, 0.93 mmol) was added to a
solution of 17 (145 mg, 0.46 mmol) in toluene (20 ml) in

R. Grigg et al. / Tetrahedron 61 (2005) 11380–11392
11391
a Schlenk tube. The reaction mixture was immersed in a
NOE data:
pre-heated oil bath at 120 8C and stirred under a nitrogen
atmosphere for 54 h. Concentration in vacuo afforded the
crude product comprising of a 9:1 mixture of 43 and 46.
Flash chromatograph eluting with DCM afforded the pure
isomers in a 80% combined yield.
Signal irradiated
Enhancement (%)
HB
HA
HC
4.8
HA
HC
0
11.2
3.5.1. 2,3-Diphenyl-5-(phenylsulfonyl)hexahydro-6aH-
pyrrolo[3,4-a]isoxazol-6a-yl(thien-2-yl)methanone (43).
Crystallisation from DCM/petrol afforded colourless
needles; mp 157–159 8C; Rf 0.3; (Found: C, 65.25; H,
4.80; N, 5.60. C28H24N2O4S2 requires C, 65.10; H, 4.70; N,
5.40%); ymax/cmK1 (film) 1657 (C]O), 1490, 1446, 1353
(S]Oas), 1170 (S]Os), 1091; dH (500 MHz, CDCl3) 8.22
(1H, dd, JZ3.2, 1.2 Hz, ArH), 7.80–7.88 (2H, m, SO2PhH),
7.71 (1H, dd, JZ3.2, 1.2 Hz, ArH), 7.61 (1H, tt, JZ6.7,
1.2 Hz, SO2PhH), 7.54–7.50 (2H, m, SO2PhH), 7.36–7.28
(4H, m, ArH), 7.18–7.15 (3H, m, ArH) 7.06 (1H, tt, JZ6.7,
1.2 Hz, ArH), 7.00–6.96 (3H, m, ArH), 4.11 (1H, d, JZ
11 Hz, NCH), 4.10 (1H, d, JZ8.0 Hz, NCHA), 3.78 (1H, td,
JZ8.0, 1.3 Hz, CHB), 3.73 (1H, br d, JZ10.4 Hz, NCHD),
3.03 (1H, dd, JZ10.4, 8 Hz, NCHC), 3.02 (1H, d, JZ11 Hz,
NCH); dC (125 MHz, CDCl3) 191.7 (C]O), 147.8, 139.4,
137.5, 136.0, 135.8, 135.0, 133.3, 129.3, 129.0, 128.6,
128.5, 128.3, 128.0, 127.9, 125.1, 119.9, 94.1, 77.9, 61.1,
57.0, 51.7; m/z (ES) 517 (MCCH).
3.5.3. 2,3-Diphenyl-5-(phenylsulfonyl)hexahydro-6aH-
pyrrolo [3,4-a]isoxazol-6a-yl(1-napththyl)methanone
(45). Following proceedure A (0.43 mmol scale, 58 h)
using enone 19 a single isomer was obtained. Purification by
flash column chromatograph eluting with DCM afforded the
product (140 mg, 58%), which crystallised from DCM/
petrol as colourless needles, mp 165–167 8C; Rf 0.35;
(Found: C, 72.60; H, 5.05; N, 5.15. C34H28N2O4S requires
C, 72.85; H, 5.05; N, 5.00%); ymax/cmK1 (film) 1641
(C]O), 1490, 1446, 1350 (S]Oas), 1170 (S]Os), 1091;
dH (500 MHz, CDCl3) 8.21 (1H, d, JZ8.2 Hz, ArH), 8.07
(1H, d, JZ7.3 Hz, ArH), 8.02 (1H, d, JZ8.3 Hz, ArH), 7.90
(1H, d, JZ7.3 Hz, ArH), 7.84 (2H, d, JZ7.3 Hz, ArH),
7.60–7.50 (6H, m, ArH), 7.29–7.23 (5H, m, ArH), 7.02 (2H,
t, JZ7.5 Hz, ArH), 6.92 (1H, t, JZ7.5 Hz, ArH), 6.60 (2H,
d, JZ7.5 Hz, ArH), 4.20 (1H, d, JZ11.0 Hz, NCH), 4.09
(1H, d, JZ7.3 Hz, NCHA), 3.80 (1H, d, JZ10.3 Hz,
NCHD), 3.81–3.76 (1H, m, CHB), 3.32 (1H, d, JZ
11.0 Hz, NCH), 3.20 (1H, dd, JZ10.3, 7.3 Hz, NCHC); dC
(125 MHz, CDCl3) 205.05 (C]O), 147.1, 138.1, 135.3,
133.9, 133.3, 133.0, 132.6, 130.7, 129.3, 129.2, 128.7, 28.4,
128.3, 128.1, 127.9, 127.8, 127.2, 126.4, 125.2, 124.5,
124.1, 119.5, 94.7, 75.6, 63.5, 56.9, 51.7; m/z (%) (EI) 560
(16, MC), 155 (100), 127 (68), 77 (78).
3.5.2. 2,3-Diphenyl-5-(phenylsulfonyl)hexahydro-6aH-
pyrrolo[3,4-a]isoxazol-6a-yl(phenyl)methanone (44).
Following procedure A (0.47 mmol scale, 60 h) using
enone 18 a single isomer was obtained. Purification by
flash column chromatography eluting with DCM afforded
the product (140 mg, 70%), which crystallised from DCM/
petrol as colourless needles, mp 161–163 8C; Rf 0.4;
(Found: C, 70.40; H, 5.05; N, 5.50. C30H26N2O4S requires
C, 70.55; H, 5.15; N, 5.50%); ymax/cmK1 (film) 1681
(C]O), 1490, 1446, 1351 (S]Oas), 1170 (S]Os), 1091;
dH (500 MHz, CDCl3) 8.18 (2H, d, JZ7.9 Hz, ArH), 7.79
(2H, d, JZ7.9 Hz, ArH), 7.63–7.57 (2H, m, ArH), 7.51–
7.48 (4H, m, ArH), 7.31–7.30 (5H, m, ArH), 7.12 (2H, t, JZ
7.9 Hz, ArH), 6.99 (1H, t, JZ7.2 Hz, ArH), 6.84 (2H, d, JZ
7.9 Hz, ArH), 4.19 (1H, d, JZ11.2 Hz, NCH), 4.10 (1H, d,
JZ7.3 Hz, NCHAPh), 3.96 (1H, dd, JZ7.3, 7.2 Hz, CHB),
3.72 (1H, d, JZ10.3 Hz, NCHD), 3.04 (1H, dd, JZ10.3,
7.2 Hz, NCHC), 3.02 (1H, d, JZ11.2 Hz, NCH); dC
(125 MHz, CDCl3) 198.2 (C]O), 147.6, 137.9, 135.0,
134.2, 133.8, 133.3, 130.0, 129.9, 129.1, 128.6, 128.5 128.4,
127.9, 127.7, 124.7, 119.6, 94.2, 76.7, 60.8, 56.6, 51.3; m/z
(ES) 511 (MCCH).
NOE data:
Signal irradiated
Enhancement (%)
HB
HA
5.1
HC
HA
HC
0
11.1
3.6. General kinetic controlled nitrone cycloaddition
procedure (B)
Diphenyl nitrone (125 mg, 0.63 mmol) was added to a
solution of 17 (180 mg, 0.57 mmol) in toluene (20 ml). The
reaction mixture was immersed in a pre-heated oil bath at
80 8C and stirred under a nitrogen atmosphere for 32 h.
Concentration in vacuo afforded the crude product com-
prising of a 3.5:1 mixture of 45 and 46, respectively. Flash
chromatography eluting with DCM afforded the pure isomers
in a 70% combined yield. The data for 45 is collected above.
3.6.1. exo-[2,3-Diphenyl-(5-(phenylsulfonyl)hexahydro-
3aH-pyrrolo[3,4-a]isoxazol-3a-yl]thien-2-yl)methanone
(46). Crystallisation from DCM/petrol afforded colourless
needles, mp 149–151 8C; Rf 0.2; (Found: C, 65.30; H, 4.95;
N, 5.55. C28H24N2O4S2 requires C, 65.10; H, 4.70; N,
5.40%); ymax/cmK1 (film) 1652 (C]O), 1352 (S]Oas),

11392
R. Grigg et al. / Tetrahedron 61 (2005) 11380–11392
B.; Cetinkaya, B.; Grigg. R.; Kilner, C.; Morris, J.; Sridharan,
V. Tetrahedron. 61, see doi: 10.1016/j.tet.2005.08.078.
3. (a) Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012–3043.
(b) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
18–29. (c) Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int.
Ed. 2003, 42, 4592–4633.
1167 (S]Os), dH (500 MHz, CDCl3) 7.81–7.79 (2H, m,
SO2PhH), 7.66 (1H, dd, JZ3.7, 0.8 Hz, ArHC), 7.61–7.57
(1H, m, SO2PhH), 7.53 (1H, dd, JZ4.9, 0.8 Hz, ArH), 7.50–
7.48 (2H, m, SO2PhH), 7.18–6.88 (11H, m, 10!ArH), 5.57
(1H, dd, JZ5.1, 1.2 Hz, OCHA), 4.74 (1H, s, PhCHB), 3.94
(1H, d, JZ10.5 Hz, NCH), 3.82 (1H, d, JZ10.5 Hz, NCH),
3.76 (1H, dd, JZ11.3, 1.2 Hz, NCHC), 3.38 (1H, dd, JZ
11.3, 5.1 Hz, NCHD); dC (125 MHz, CDCl3) 188.0 (C]O),
147.5, 143.6, 135.0, 134.6, 134.5, 133.3, 133.2, 129.3,
128.7, 128.6, 128.5, 128.3, 127.9, 127.8, 123.9, 118.3, 81.8,
77.6, 74.9, 56.1, 53.4; m/z (ES) 539 (MCCNa).
4. (a) Nicolaou, K. C.; Rodriguez, R. M.; Mitchell, H. J.; van
Delft, F. L. Angew. Chem., Int. Ed. 1998, 37, 1874–1876 and
references cited therein. (b) Wipf, P.; Weiner, W. S. J. Org.
Chem. 1999, 64, 5321–5324 and references cited therein.
5. For a classic paper evaluating, categorising and exemplifying
the application of 2 and 3 to alkene cross-metathesis see:
Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H.
J. Am. Chem. Soc. 2003, 125, 11360–11370.
6. Furstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.;
Nolan, S. P. J. Org. Chem. 2000, 65, 2204–2207. Davis, F. A.;
Deng, J. Org. Lett. 2005, 6, 3719–3722. Davis, F. A.; Wu, Y.
Org. Lett. 2004, 6, 1269–1272.
NOE data:
Signal irradiated
Enhancement (%)
HC
7. Grigg, R.; Brown, S.; Sridharan, V.; Uttley, M. D. Tetrahedron
Lett. 1997, 38, 5031–5034.
8. Grigg, R.; Machachlan, W.; Rasparini, M. Chem. Commun.
2000, 2241–2242.
HA
HB
5.9
4.0
9. Henry, J. R.; Marcin, L. R.; McIntosh, M. C.; Scola, P. M.;
Harris, G. D., Jr.; Weinreb, S. M. Tetrahedron Lett. 1989, 30,
5709–5712.
3.6.2. [endo-2,3-Diphenyl-(5-(phenylsulfonyl)hexahydro-
3aH-pyrrolo[3,4-a]isoxazol-3a-yl]thien-2-yl)methanone
(47). The product is isolated as a pale yellow froth. Rf 0.15;
(Found: C, 64.95; H, 4.70; N, 5.40. C28H24N2O4S2 requires
C, 65.10; H, 4.70; N, 5.40%); ymax/cmK1 (film) 1644
(C]O), 1490, 1353 (S]Oas), 1169 (S]Os), dH (250 MHz,
CDCl3) 7.84 (1H, dd, JZ3.92, 0.9 Hz, ArH), 7.76–7.53
(5H, m, ArH), 7.67 (1H, dd, JZ4.9, 0.9 Hz, ArH) 7.08 1H,
dd, JZ4.9, 3.9 Hz, ArH) 7.34–6.99 (10H, m, ArH), 5.35
(1H, dd, JZ6.8, 3.0 Hz, OCHA), 5.07 (1H, s, NCHB), 3.79
(1H, dd, JZ10.0, 3.0 Hz, NCHC), 3.47 (1H, dd, JZ10.6,
6.8 Hz, NCHD), 3.25 (1H, d, JZ11.2 Hz, NCH), 3.19 (1H,
d, JZ11.2 Hz, NCH); m/z (ES) 539 (MCCNa).
10. Brown, S.; Clarkson, S.; Grigg, R.; Thomas, W. A.; Sridharan,
V.; Wilson, D. M. Tetrahedron 2001, 57, 1347–1359. Anwar,
U.; Casaschi, A.; Grigg, R.; Sansano, J. M. Tetrahedron 2001,
57, 1361–1367. Grigg, R.; Sridharan, V. J. Organomet. Chem.
1999, 576, 65–87.
11. (a) Furstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119,
9130–9136. (b) Furstner, A. Synlett 1999, 1523–1533.
12. Gai, X.; Grigg, R.; Collard, S.; Muir, J. E. Chem. Commun.
2000, 1765–1766.
13. (a) Jeffrey, T. Tetrahedron Lett. 1985, 26, 2667–2670.
(b) Jeffrey, T. Synthesis 1987, 70–71. Amatore, C.; Jutand, A.
Acc. Chem. Res. 2000, 33, 314–321.
14. Furstner, A.; Dierkes, T.; Thiel, O. R.; Blanda, G. Chem. Eur.
J. 2001, 7, 5286–5298.
15. pKa’s calculated using the ACD/I-Lab service, version 4.5.
16. Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002,
35, 717–727.
17. Nayo, K. G.; Hearhoof, E. H.; Leiddle, J. Org. Lett. 2002, 4,
1567–1570.
Acknowledgements
18. Gabacia, S.; Desai, B.; Lavastre, O.; Kappe, C. O. J. Org.
Chem. 2003, 68, 9136–9139.
We thank GlaxoSmithKline, the EPSRC and Leeds
University for their support.
19. Yang, C.; Murray, W.; Wilson, L. J. Tetrahedron Lett. 2003,
44, 1783–1786.
20. Barr, D. A.; Grigg, R.; Gunaratne, H. Q. N.; Kemp, J.;
McMeekin, P.; Sridharan, V. Tetrahedron 1988, 44, 557–570.
21. Grigg, R.; Liu, A.; Shaw, D.; Suganthan, S.; Washington,
M. L.; Woodall, D. E.; Yoganathan, G. Tetrahedron Lett.
2000, 41, 7129–7133.Aftab, T.; Grigg, R.; Ladlow, M.;
Sridharan, V.; Thornton-Pett, M. Chem. Commun.,
1754–1755. Grigg, R.; Millington, E. L.; Thornton-Pett, M.
Tetrahedron Lett. 2002, 43, 2685–2688. Fielding, M. R.;
Grigg, R.; Sridharan, V.; Thornton-Pett, M.; Urch, C. J.
Tetrahedron 2003, 57, 7737–7748.
References and notes
1. Preliminary communications: Grigg, R.; Hodgson, A.; Morris,
J.; Sridharan, V. Tetrahedron Lett. 2003, 44, 1023–1026.
Grigg, R.; Martin, W.; Morris, J.; Sridharan, V. Tetrahedron
Lett. 2003, 44, 4899–4901.
2. Preliminary communication: Dondas, H. A.; Blame, G.;
Clique, B.; Grigg, R.; Hodgson, A.; Morris, J.; Sridharan, V.
Tetrahedron Lett. 2001, 42, 8673–8675. Dondas, H. A; Clique,