The Pd-catalyzed Alder-ene reactions of N-protected and propargylated 1-amino-2-aryl-2-cyclohexenes as a new route to C3a-arylhexahydroindoles: Towards the total synthesis of tazettine

Article abstract of DOI:10.1071/CH10359

A series of N-protected and propargylated 1-amino-2-aryl-2-cyclohexenes (4) has been prepared. Several of these have been shown to undergo an intramolecular Alder-ene reaction in the presence of palladium acetate and the ligand BBEDA to afford C3a-arylhex

Full text of DOI:10.1071/CH10359

RESEARCH FRONT
Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2010, 63, 1665–1678
The Pd-Catalyzed Alder Ene Reactions of N-Protected
]
and Propargylated 1-Amino-2-aryl-2-cyclohexenes
as a New Route to C3a-Arylhexahydroindoles:
Towards the Total Synthesis of Tazettine
A
A
A B
,
Anna L. Lehmann, Anthony C. Willis, and Martin G. Banwell
A
Research School of Chemistry, Institute of Advanced Studies, The Australian
National University, Canberra, ACT 0200, Australia.
B
Corresponding author. Email: mgb@rsc.anu.edu.au
A series of N-protected and propargylated 1-amino-2-aryl-2-cyclohexenes (4) has been prepared. Several of these have
been shown to undergo an intramolecular Alder–ene reaction in the presence of palladium acetate and the ligand BBEDA
to afford C3a-arylhexahydroindoles of the general form 1. Certain of these products may serve as precursors to the alkaloid
tazettine (2).
Manuscript received: 30 September 2010.
Manuscript accepted: 25 October 2010.
Introduction
concise new routes to C3a-arylhexahydroindoles and now report
on the successful identification of one.
The C3a-arylhexahydroindole unit (1, Fig. 1) is the key sub-
structure encountered in a number of Amaryllidaceae alkaloids
including Sceletium-type systems such as mesembrine,[1] the
crinines,[2] and tazettine (2).[3] As a consequence various
methods have been established for the synthesis of this impor-
tant structural motif although, partly because of the presence of a
quaternary carbon centre (C3a), most of these involve relatively
complex reaction sequences.[2c,4] In connection with our con-
tinuing interest in the synthesis of Amaryllidaceae alka-
loids,[2f,5] we have been seeking to develop abbreviated total
syntheses of tazettine (2) and related systems such as macro-
nine[6] and pretazettine.[7] To that end, we sought to establish
Results and Discussion
The key feature of the present approach to the target structure 1
is shown in Fig. 2 and involves the conversion, by an intra-
molecular Alder–ene (IMAE) reaction, of an N-protected and
propargylated 1-amino-2-aryl-2-cyclohexene of the general
form 3 into a C3a-arylhexahydroindole 4 (corresponding to a
protected form of 1) incorporating the required D4-double bond
as well as an exocyclic one at C3. Provided the latter alkene
could be oxidatively cleaved in a selective manner, this moiety
should serve as a precursor to a carbonyl or hydroxy group that is
often encountered at C3 in the abovementioned natural pro-
ducts. Given the geometrical requirements of the IMAE reaction
(Fig. 2) the nature of the protecting group, P, at the nitrogen in
C3a
6
Rꢀ
3
Ar
Δ or M0
1
H
N
R
Ar
H
P
H
N
N
1
P
4
3
O
O
O
O
O
OMe
OMe
H
H
HO
Δ or M0
Ar
P
Ar
P
O
H
H
N
H
N
H
H
H
N
N
HO
Me
Me
2a
2b
Fig. 2. Proposed synthesis of C3a-arylhexahydroindoles via an IMAE
Fig. 1. Structure of tazettine (2a) and its ring-opened isomer (2b).
reaction.
Ó CSIRO 2010
10.1071/CH10359
0004-9425/10/121665

RESEARCH FRONT
1666
A. L. Lehmann, A. C. Willis, and M. G. Banwell
substrate 3 will be crucial to success. In particular, this group
must allow the nitrogen and its substituents to assume a tetra-
hedral geometry and, thereby, the alkyne to interact in the
necessary fashion with the cyclohexene double bond and the
associated allylic methylene unit. In principle, the IMAE reac-
tion could be promoted thermally or by using a transition metal
such as palladium (in a low valent state).[8] In this context it
should be noted that Nishimata and Mori[2a] have exploited a
thermally induced intramolecular carbonyl–ene reaction of a
cyclohexenylamine incorporating an acetaldehyde residue on
nitrogen to prepare (þ)-crinamine and (þ)-pretazettine. How-
ever, temperatures in the range of 230–2408C were required to
effect the required ene reaction while treatment of the same
substrate (at ,08C) with SnCl2 led to an undesired tricyclic
species.
Of course, the utility of the process shown in Fig. 2 will
be dependent upon how readily, or otherwise, substrates of
the general form 3 can be obtained. The approach we have
used to prepare such systems is shown in Scheme 1 and
utilizes the electrocyclic ring-opening of the ring-fused gem-
dibromocyclopropane 5 as the key step in forming the required
cyclohexenylamine unit.[9] Thus, as we have reported earlier,[10]
treatment of the readily available compound 5 with silver
cyanate effected the desired ring-opening process and the
p-allyl cation 6 so-formed was intercepted by the nitrogen
terminus of the cyanate anion to afford the allylic isocyanate
7. This last species was itself trapped with added t-butanol to
afford the Boc-protected primary amine 8 which was obtained in
79% yield. Since Boc-protection of nitrogen results in a planar
geometry of substituents attached to this heteroatom[11] this was
considered to be an unsuitable protecting group for the substrate
3 to be engaged in the IMAE reaction. Accordingly, the Boc-
group within compound 8 was cleaved using trimethylsilyl
trifluoromethanesulfonate (TMSOTf) in the presence of 2,6-
lutidene[12] or trifluoroacetic acid (TFA) and the free amine
9 obtained after aqueous work-up was treated with either
p-toluenesulfonyl chloride (TsCl) or o-nitrobenzenesulfonyl
(nosyl) chloride (NsCl) in the presence of triethylamine and
thereby afforded the corresponding sulfonamide 10 (86% from
8) or 11 (87% from 8). The sulfonamide-based protecting group
was chosen because of the likelihood of the associated nitrogen
assuming a geometry[13] that would allow for the desired
cyclization reaction. The nosyl protecting group was also
considered a particularly attractive one because of the ease with
which it can be removed using the phenylthiolate anion.[14]
Suzuki–Miyaura cross-coupling[15] of the cycloalkenyl
bromides 10 and 11 with either commercially available 3,4-
methylenedioxyphenylboronic acid or the readily prepared
methyl 6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzo[d][1,3]
dioxole-5-carboxylate[5a] resulted in the expected cyclohex-
enes 12 (78%), 13 (77%), or 14 (69%) incorporating the 3,4-
methylenedioxyphenyl moiety commonly encountered in the
target alkaloids. In addition, the last of these coupling products
contains a suitably positioned carbomethoxy group that could
ultimately be converted into the hydroxymethyl unit required
for the formation of the lactol residue embodied within
tazettine (see conversion 2a - 2b). Installation of the pivotal
propargyl group at nitrogen within compounds 12–14 was
readily achieved by their successive treatment with sodium
hydride and then propargyl bromide. In this way three of the
substrates, 15 (89%), 16 (91%), and 17 (80%), required for the
IMAE reaction were obtained. The spectroscopic data derived
from these compounds were in complete accord with the
assigned structures.
AgOCN
Br
Br
Br
Br
NCO
5
6
7
t-BuOH
TFA or
TMSOTf,
ArB(OR)2,
Pd0,
X
2,6-lutidene
base
N
Br
Br
H
P
O
O
NHP
N
Since our preliminary studies on the IMAE reaction of
terminal alkynes 15–17 revealed that they also undergo a
competitive dimerization reaction (see below), the ‘methyl-
capped’ analogues 18 and 19, which would be incapable of
engaging in this undesired side reaction, were prepared. This
was readily achieved by successive treatment of the nosyl-
protected precursors 13 and 14 with sodium hydride followed
by 1-bromobut-2-yne. By such means the substrates 18 and 19
required for the IMAE reaction were obtained in 86% and 83%
yields, respectively.
H
Boc
12–P ꢁ Ts, X ꢁ H
13–P ꢁ Ns, X ꢁ H
14–P ꢁ Ns, X ꢁ CO2Me
9–P ꢁ H
10–P ꢁ Tsor
11–P ꢁ Ns
8
TsCl or
NsCl,
Et3N
(i) NaH, DMF
(i) NaH, DMF
(ii) 1-Bromoprop-2-yne
(ii) 1-Bromobut-2-yne
Given that many of the target alkaloids incorporate oxygen
at C6 within the C3a-arylhexahydroindole subunit, we sought to
prepare substrates for the IMAE reaction that acknowledged the
presence of such functionality. The reaction sequence used for
this purpose is shown in Scheme 2 and started with the conver-
sion, under standard conditions, of readily accessible diallyl
ketone 20[16] into the corresponding ketal 21 (91%). This
particular ketal derivative was employed because it was sig-
nificantly less volatile (and therefore much more easily handled)
than, for example, the corresponding ethylene ketal. Treatment
of a dichloromethane solution of compound 21 with 2 mol-%
of Grubbs’ II (second generation) catalyst[17] resulted in an
efficient ring-closing metathesis reaction and thus provided the
X
X
N
P
N
Ns
O
O
O
O
15–P ꢁ Ts, X ꢁ H
16–P ꢁ Ns, X ꢁ H
17–P ꢁ Ns, X ꢁ CO2Me
18–X ꢁ H
19–X ꢁ CO2Me
Scheme 1.

RESEARCH FRONT
The Pd-Catalyzed Alder–Ene Reactions of N-Protected and Propargylated 1-Amino-2-aryl-2-cyclohexenes
1667
O
O
O
2,2-Dimethylpropane-1,3-diol
Grubbs’ II
O
·
BF3 Et2O
O
20
21
22
CHBr3,
NaOH,
TEBAC
O
O
O
O
(i) TMSOTf, 2,6-lutidene
(ii) NsCl, Et3N
(i) AgOCN
O
O
Br
Br
(ii) t-BuOH
Br
Br
N
N
H
Ns
H
Boc
25
24
23
ArB(OH)2, Pd0,
base
O
O
O
O
O
X
X
X
(i) NaH, DMF
O
or
(ii) 1-Bromoprop-2-yne,
1-bromobut-2-yne
N
N
N
Ns
H
Ns
Ns
O
O
O
O
O
O
26 X ꢁ H
28 X ꢁ H
30 X ꢁ H
27 X ꢁ CO2Me
29 X ꢁ CO2Me
31 X ꢁ CO2Me
Scheme 2.
O10
C8
cyclopentene 22 in 95% yield. Subjection of alkene 22 to
reaction with dibromocarbene, generated under Makosza con-
ditions[18] from bromoform and sodium hydroxide in the pre-
sence of the phase-transfer catalyst triethylbenzyl ammonium
chloride (TEBAC), gave the anticipated cyclopropane 23 in
67% yield. Following the protocols used earlier,[10] compound
23 was treated successively with silver cyanate and t-butanol
to give the Boc-protected cyclohexenylamine 24 in 73% yield.
Cleavage of the Boc-group within the latter compound and
reaction of the resulting free amine with nosyl chloride in the
presence of triethylamine then gave the sulfonamide 25 in 72%
yield (from 24). Cross-coupling of compound 25 with the same
pair of aryl boronic acids used earlier gave the anticipated
products 26 and 27 in yields of 81% and 68%, respectively.
Finally, successive treatment of these cross-coupling pro-
ducts with sodium hydride followed by either propargyl bro-
mide or 1-bromobut-2-yne gave either alkynes 28 (89%) and
29 (74%) or their ‘methyl-capped’ equivalents 30 (85%) and
31 (96%), respectively. Once again, the spectroscopic data
obtained on compounds 28–31 were in complete accord with
the assigned structures. Further support for these assignments
derives from a single-crystal X-ray analysis of sulfonamide 28.
The ORTEP diagram so-obtained is presented in Fig. 3 while
further details are included in the Experimental section. Sig-
nificantly, this analysis reveals that, in the solid state at least,
compound 28 possesses a pyramidalized geometry at nitrogen
and, as a partial consequence, the alkynyl and cyclohexenyl
residues appear reasonably well aligned for participation in the
anticipated IMAE reaction.
C11
C9
C6
C3
C7
C12
C26
O4
C5
C13
C25
C2
C1
C22
C14
C24
C21
C20
N23
S27
O28
C15
C16
O19
O29
C30
O37
N36
C31
O17
C18
C35
C33
C32
O38
C34
Fig. 3. ORTEP diagram derived from the single-crystal X-ray analysis
of compound 28 (CCDC 790929) with labelling of non-hydrogen atoms.
Anisotropic displacement ellipsoids display 30% probability levels. Hydro-
gen atoms are drawn as circles with small radii.
With compounds 15–19 and 28–31 to hand, their capacities
to engage in the pivotal IMAE reaction could be investigated.
To such ends we subjected these substrates to conditions used
by Trost and Pedregal (Scheme 3).[19] Specifically, each was
treated with Pd(OAc)2 and the strong s-donating ligand
N,N0-bis(benzylidene)ethylenediamine (BBEDA) (,5 mol-% of

RESEARCH FRONT
1668
A. L. Lehmann, A. C. Willis, and M. G. Banwell
15–19, 28–31
Pd(OAc)2,
each) or Ph3P in either 1,2-dichloroethane (DCE), benzene, or
toluene. The outcomes of the relevant experiments are shown in
Table 1. Thus, for example, heating a solution of substrate 15,
Pd(OAc)2, and BBEDA in DCE for 2 h at 568C (Entry 1, Table 1)
afforded the hoped for C3a-arylhexahydroindole 37 (26%) but
the major product of reaction (60%) was a species tentatively
assigned as the dimeric compound 32. These two products could
be separated by flash chromatographic methods and the former
(37) was subjected to comprehensive spectroscopic character-
ization and its structure finally confirmed by a single-crystal X-
ray analysis (see Fig. 4 and the Experimental section for details).
The structure of compound 32 follows from the similarity of its
1H NMR spectrum with that derived from a related but more
tractable compound for which comprehensive spectroscopic
characterization could be undertaken (see below).
ligand, Δ
O
Rꢀ
Rꢂ
O
X
X
N
P
N
P
O
O
Rꢂ Rꢀ
32 X ꢁ Rꢀ ꢁ Rꢂ ꢁ H, P ꢁ Ts
33 X ꢁ Rꢀ ꢁ Rꢂ ꢁ H, P ꢁ Ns
34 X ꢁ CO2Me, Rꢀ ꢁ Rꢂ ꢁ H, P ꢁ Ns
Subjection of the N-nosyl analogue, 16, of compound 15
to analogous cyclization conditions (Entry 2, Table 1) resulted
in essentially the same outcome, namely the co-production of a
,2:1 mixture of the chromatographically separable dimer 33
(66%) and the desired C3a-arylhexahydroindole 38 (26%).
The mass spectrometric data obtained on compound 33 clearly
established it was a dimeric form of substrate 16 while the
35 X ꢁ H, Rꢀ ꢁ Rꢂ ꢁ OCH2C(Me2)CH2O, P ꢁ Ns
36 X ꢁ CO2Me, Rꢀ ꢁ Rꢂ ꢁ OCH2C(Me2)CH2O, P ꢁ Ns
and/or
X
Rꢀ
Rꢂ
O
O
H
R
N
P
37 X ꢁ R ꢁ Rꢀ ꢁ Rꢂ ꢁ H, P ꢁ Ts
38 X ꢁ R ꢁ Rꢀ ꢁ Rꢂ ꢁ H, P ꢁ Ns
39 X ꢁ Rꢀ ꢁ Rꢂ ꢁ H, R ꢁ Me, P ꢁ Ns
40 X ꢁ H, Rꢀ ꢁ Rꢂ ꢁ OCH2C(Me2)CH2O, R ꢁ Me, P ꢁ Ns
41 X ꢁ CO2Me, Rꢀ ꢁ Rꢂ ꢁ H, R ꢁ Me, P ꢁ Ns
and/or
C6
C5
C13
C12
C11
C19
O15
O17
C14
C18
C7
C16
C4
C8
C10
X
O
C9
C3
C2
O
O
O
C24
C25
N1
H
N
Ns
C26
O21
C29
S20
C23
42 X ꢁ CO2Me
C27
C28
O22
Scheme 3.
Fig. 4. ORTEP diagram derived from the single-crystal X-ray analysis
of compound 37 (CCDC 790930) with labelling of non-hydrogen atoms
(illustrated enantiomer opposite to that shown in Scheme 3). Anisotropic
displacement ellipsoids display 30% probability levels. Hydrogen atoms are
drawn as circles with small radii.
Table 1. Outcomes of subjecting compounds 15 19 and 28 31 to reaction with Pd(OAc) in the presence of
]
]
2
N,N0-bis(benzylidene)ethylenediamine (BBEDA) or Ph3P
Entry
1
Substrate
Reaction conditions
Product(s) (% yield)
15
16
DCE, 568C, 2 h, ligand BBEDA
32 (60)
37 (26)
33 (66)
38 (26)
34 (47)
39 (94)
41 (55)
35 (53)
36 (72)
40 (100)
42 (92)
2
DCE, 568C, 4 h, ligand BBEDA
3
4
5
6
7
8
9
17
18
19
28
29
30
31
C6H6, 808C, 1 h, ligand Ph3P
C6H6, 808C, 7 h, ligand BBEDA
Toluene, 1108C, 6 h, ligand BBEDA
C6H6, 808C, 2 h, ligand Ph3P
C6H6, 808C, 2 h, ligand Ph3P
C6H6, 808C, 5 h, ligand BBEDA
Toluene, 1108C, 5 h, ligand BBEDA

RESEARCH FRONT
The Pd-Catalyzed Alder–Ene Reactions of N-Protected and Propargylated 1-Amino-2-aryl-2-cyclohexenes
1669
‘doubling up’ of signals in the 13C NMR spectrum suggested it
comprised a ,1:1 mixture of diastereoisomers, as might be
expected for a product arising from the coupling of the racemic
form of two monomeric units incorporating a single centre of
chirality. While the two acetylenic units of monomer 16 could
be joined in two distinct ways, so as to produce either the
C11
C12
C10
C9
illustrated terminal alkene or the isomeric internal one, work by
Yang and Nolan[20] suggests that the process leading to the
former type of dimer often predominates. An inspection of the
1H NMR spectrum of compound 33 revealed two one-proton
resonances at dH 5.45 and 5.27 suggestive of the presence of
hydrogens attached to a terminal carbon–carbon double bond.
Such spectroscopic features and the literature precedent men-
tioned above form the basis for the illustrated structural assign-
ments of the dimeric compounds shown in Scheme 3.
In slight contrast to the outcome of the reaction represented
in Entry 2 of Table 1, treatment of the carbomethoxy-substituted
system 17 with Pd(OAc)2 and Ph3P in refluxing benzene for 1 h
(Entry 3, Table 1) resulted in the exclusive formation of the
corresponding dimer 34, although this was only isolated in 47%
yield.
O22
C13
O14
O8
C6
C23
C21
C7
C20
C5
C15
O24
C25
C19
C16
C26
C4
O33
N1
C3
C27
C18
C2
S32
C17
C28
C36
C37
O34
C35
O29
The dimerization process described above could be pre-
vented by using the ‘methyl-capped’ system 18 (Entry 4,
Table 1) and then the IMAE reaction proceeded very effectively
and the desired C3a-arylhexahydroindole 39 was generated in
94% yield. This cyclization product was obtained as a single
geometric isomer and, consistent with the likely mechanism of
the reaction (see Fig. 2), the illustrated Z-configuration about the
exocyclic double bond was established by single-crystal X-ray
analysis (see Experimental section for details).
When the carbomethoxy-substituted analogue, 19, of com-
pound 18 was subjected to the same cyclization conditions as
described immediately above no reaction was observed. Such
an outcome may be attributed to the more sterically congested
nature of compound 19. Accordingly, a solution of the same
substrate, Pd(OAc)2, and BBEDA in toluene was heated at
reflux and after 6 h complete consumption of the starting
material was observed. Upon work-up product 41 was obtained
in 55% yield. The structure of compound 41 follows from the
derived spectroscopic data.
In keeping with earlier observations, when the terminal
alkynes 28 and 29 were treated with Pd(OAc)2 and Ph3P at
elevated temperatures (Entries 6 and 7, Table 1), the correspond-
ing dimers, 35 (53%) and 36 (72%), respectively, were obtained,
again as mixtures of diastereoisomers but this time as the only
isolable products of the reaction. In pleasing contrast, when the
methyl-capped analogue, 30, of compound 28 was reacted in
the same way (Entry 8, Table 1), the C3a-arylhexahydroinole 40
was obtained in quantitative yield. A less satisfying observation
was that analogous treatment of the carbomethoxy-substituted
congener, 31, of substrate 30 gave (Entry 9, Table 1) the
cyclopropane-annulated product 42 (92%), the structure of
which was established by single-crystal X-ray analysis (Fig. 5).
Presumably, this cyclopropane-annulated hexahydroindole
arises through participation of the initially formed (and desired)
C3a-arylhexahydroindole in a secondary IMAE reaction invol-
ving the ethylidene and endo-cyclic alkene units. Attempts to
suppress this secondary process by using milder reaction con-
ditions have not been effective thus far.
O30
C40
C31
C38
C39
N41
O43
O42
Fig. 5. ORTEP diagram derived from the single-crystal X-ray analysis
of compound 42 (CCDC 790932) with labelling of non-hydrogen atoms
(illustrated enantiomer opposite to that shown in Scheme 3). Anisotropic
displacement ellipsoids display 30% probability levels. Hydrogen atoms are
drawn as circles with small radii.
form 3 are readily obtained through reaction sequences invol-
ving initial silver cyanate-promoted electrocyclic ring-opening
of 6,6-dibromobicyclo[4.1.0]hexane derivatives. Furthermore,
certain of these cyclohexenes participate, under relatively mild
conditions, in Pd0-catalyzed IMAE reactions and thereby
affording C3a-arylated hexahydroindoles 4, some of which
may serve as precursors to various Amaryllidaceae alkaloids
including tazettine 2. Two (undesirable) processes that can
compete with the IMAE reaction have been identified. One of
these involves the dimerization of those substrates, 3, that
incorporate a terminal alkyne residue but this is readily pre-
vented by employing ‘methyl-capped’ propargyl groups. The
other process appears to involve a second ene reaction that
converts the initially formed C3a-arylhexahydroindole into a
cyclopropane-containing isomer. This secondary reaction takes
place at the higher temperatures required to promote the initial
IMAE reaction of sterically congested substrates.
Experimental
General Experimental Procedures
Proton (1H) and carbon (13C) NMR spectra were recorded on
a Varian Gemini 300 machine (operating at 300 and 75 MHz
for 1H and 13C spectra, respectively), a Varian MR400
instrument (operating at 400 and 100 MHz for 1H and 13C
spectra, respectively), or a Varian VXR500 machine with an
Conclusions
The work presented here demonstrates that N-protected and
propargylated 1-amino-2-aryl-2-cyclohexenes of the general

RESEARCH FRONT
1670
A. L. Lehmann, A. C. Willis, and M. G. Banwell
Innova console (operating at 500 and 125 MHz for 1H and 13
C
1702, 1676, 1541, 1364, 1266, 1249, 1170, 1056, 982 cmꢀ1. m/z
(ESI, þve) 300 and 298 [(M þ Na)þ, both 100%].
spectra, respectively). Unless otherwise specified, spectra
were acquired at 208C in deuterochloroform (CDCl3) that
had been stored over anhydrous sodium carbonate. Chemical
shifts are recorded as d values in parts per million [ppm].
Infrared spectra (nmax) were normally recorded on a Perkin–
Elmer 1800 Series FTIR Spectrometer and samples were
analyzed as thin films on KBr plates (for liquids) or as a KBr
disk (for solids). Low-resolution electrospray ionization (ESI)
mass spectra were recorded in positive-ion mode on a
Micromass–Waters LC-ZMD single quadrupole liquid
chromatograph–mass spectrometer while low- and high-
resolution electron impact (EI) mass spectra were recorded on
a VG Fisions AUTOSPEC three-sector, double-focussing
instrument. Melting points were measured on a Stanford
Research Systems Optimelt-Automated Melting Point System
and are uncorrected. Analytical TLC was performed on
aluminium-backed 0.2 mm thick silica gel 60 F254 plates as
supplied by Merck. Eluted plates were visualized using a
254 nm UV lamp and/or by treatment with a suitable dip
followed by heating. These dips included a mixture of
vanillin/sulfuric acid/ethanol (1 g/1 g/18 mL) or phosphomo-
lybdic acid/ceric sulphate/conc. sulfuric acid/water (37.5 g/
7.5 g/37.5 g/720 mL). The retardation factor (RF) values cited
here have been rounded to the first decimal point. Flash
chromatographic separations were carried out following pro-
tocols defined by Still et al.[21] with silica gel 60 (40–63 mm)
as the stationary phase and using the AR- or HPLC-grade
solvents indicated. Starting materials and reagents were
generally available from the Sigma–Aldrich, Merck, TCI,
Strem, or Lancaster Chemical Companies and were either
used as supplied or, in the case of liquids, distilled when
required. Drying agents and other inorganic salts were
purchased from the AJAX, BDH, or Unilab Chemical Com-
panies. Tetrahydrofuran (THF), dichloromethane, acetonitrile,
and benzene were dried using a Glass Contour solvent pur-
ification system that is based upon a technology originally
described by Grubbs et al.[22] Where necessary, reactions
were performed under a nitrogen or argon atmosphere.
Compound 10
Step i: A solution of carbamate 8 (1.61 g, 5.86 mmol) in dry
CH2Cl2 (29 mL) was treated, dropwise over 10 min, with TFA
(2.9 mL). The resulting mixture was stirred at 188C under an
atmosphere of nitrogen for 2.5 h and then NaOH (15 mL of a 2 M
aqueous solution) was added. The separated aqueous phase was
extracted with CH2Cl2 (3 ꢁ 20 mL), and the combined organic
fractions were then dried (MgSO4), filtered, and concentrated
under reduced pressure to afford amine 9 (1.12 g, 88%) as a
clear, yellow oil. This material was used directly in Step ii of the
reaction sequence.
Step ii: A solution of amine 9 (1.12 g, 6.36 mmol) in dry
CH2Cl2 (19 mL) was treated with p-toluenesulfonyl chloride
(1.33 g, 7.00 mmol), 4-(N,N-dimethylamino)pyridine (DMAP,
single crystal) and dropwise over 10 min, triethylamine
(1.06 mL, 7.93 mmol). The resulting mixture was stirred at
188C for 1 h under an atmosphere of nitrogen. HCl (20 mL of a
2 M aqueous solution) was then added and the separated aqueous
phase was extracted with CH2Cl2 (3 ꢁ 20 mL) followed by ethyl
acetate (2 ꢁ 20 mL). The combined organic fractions were dried
(MgSO4), filtered, and concentrated under reduced pressure to
afford a cream solid, recrystallization (CH2Cl2/hexane) of which
afforded the title compound 10 (2.05 g, 98%) as white needles,
mp 100–1018C, RF 0.3 (in 3/7 v/v ethyl acetate/hexane) [Found:
(M þ Na)þ, 351.9987. C13H1679BrNO2S requires (M þ Na)þ,
351.9983]. dH (300 MHz) 7.80 (dm, J 8.4, 2H), 7.30 (dm, J 8.4,
2H), 6.19 (m, 1H), 4.80 (d, J 6.6, 1H), 3.81 (m, 1H), 2.42 (s, 3H),
2.15–1.93 (complex m, 3H), 1.81 (m, 1H), 1.66–1.57 (complex
m, 2H). dC (75 MHz) 143.5 (C), 136.9 (C), 135.2 (CH), 129.5
(CH), 127.5 (CH), 120.1 (C), 55.1 (CH), 31.6 (CH2), 27.4
(CH2), 21.6 (CH3), 16.5 (CH2). nmax 3276, 3063, 3041, 2942,
1642, 1598, 1446, 1427, 1330, 1156, 1087, 914, 813, 738,
665 cmꢀ1. m/z (ESI, þve) 354 and 352 [(M þ Na)þ, 92 and
88%], 102 (100).
Compound 11
A solution of amine 9 (1.62 g, 9.20 mmol) in dry CH2Cl2
(28 mL) was treated with triethylamine (1.54 mL, 11.04 mmol),
DMAP (one crystal), and 2-nitrobenzenesulfonyl chloride
(2.24 g, 10.12 mmol). The resulting mixture was stirred at
188C under an atmosphere of nitrogen for 1.5 h and then treated
with NH4Cl (20 mL of a saturated aqueous solution). The
separated aqueous phase was extracted with CH2Cl2
(3 ꢁ 20 mL) and the combined organic fractions were then dried
(MgSO4), filtered, and concentrated under reduced pressure.
The ensuing residue was subjected to flash chromatography
(silica gel, 3/7 v/v ethyl acetate/hexane elution) to afford, after
concentration of the relevant fractions (RF 0.6 in 1/1 v/v ethyl
acetate/hexane), the title sulfonamide 11 (3.31 mg, 99%) as a
fine, white solid, mp 149–1508C [Found: (M ꢀ H)ꢀ, 358.9697.
C12H1379BrN2O4S requires (M ꢀ H)ꢀ, 358.9701]. dH
(300 MHz) 8.17 (m, 1H), 7.93 (m, 1H), 7.80–7.58 (complex
m, 2H), 6.24 (m, 1H), 5.67 (d, J 7.1, 1H), 4.03 (m, 1H), 2.20–
2.00 (complex m, 3H), 1.95–1.84 (m, 1H), 1.73–1.62 (complex
m, 2H). dC (75 MHz) 147.5 (C), 135.7 (CH), 134.1 (C), 133.5
(CH), 132.9 (CH), 130.6 (CH), 125.4 (C), 119.3 (CH), 56.3
(CH), 32.2 (CH2), 27.3 (CH2), 16.3 (CH2). nmax 3351, 2939,
1539, 1410, 1358, 1172 cmꢀ1. m/z (ESI, –ve) 361 and 359
[(M ꢀ H)ꢀ, 100 and 92%).
Specific Synthetic Procedures and Product
Characterization
Compound 8
A magnetically stirred mixture of compound 5[10a] (4.50 g,
18.8 mmol) and silver cyanate (3.23 g, 21.6 mmol) in anhydrous
1,4-dioxane (38 mL) was heated at 1058C under an atmosphere
of nitrogen for 4 h and then t-butanol (4.7 mL) was added and the
ensuing mixture heated at the same temperature for a further
18 h. The resulting slurry was cooled and then filtered through a
pad of Celite that was washed with CH2Cl2 (200 mL). The
combined filtrates were concentrated under reduced pressure
and the ensuing residue subjected to flash chromatography
(silica gel, 1/19 v/v ethyl acetate/hexane elution) to afford, after
concentration of the relevant fractions (RF 0.4 in 1/4 v/v ethyl
acetate/hexane), the title compound 8 (4.11 g, 79%) as a white,
crystalline solid, mp 112–1148C [Found: (M þ Na)þ, 298.0416.
C11H1879BrNO2 requires (M þ Na)þ, 298.0419]. dH (300 MHz)
6.21 (td, J 4.0, 1.0, 1H), 4.70 (br d, J 7.0, 1H), 4.32 (br s, 1H),
2.14–2.02 (complex m, 2H), 1.96–1.79 (complex m, 2H), 1.74–
1.54 (complex m, 2H), 1.46 (s, 9H). dC (75 MHz) 155.1 (C),
133.3 (CH), 122.9 (C), 79.5 (C), 51.7 (CH), 31.2 (CH2), 28.3
(CH3), 27.5 (CH2), 17.9 (CH2). nmax 3255, 2978, 2947, 2912,

RESEARCH FRONT
The Pd-Catalyzed Alder–Ene Reactions of N-Protected and Propargylated 1-Amino-2-aryl-2-cyclohexenes
1671
Compound 12
subjected to microwave irradiation at 908C for 1.5 h. The cooled
reaction mixture was diluted with ethyl acetate (20 mL) and
washed with water (2 ꢁ 20 mL) followed by brine (1 ꢁ 10 mL)
before being dried (MgSO4), filtered, and concentrated under
reduced pressure. The ensuing residue was subjected to flash
chromatography (silica gel, 1/3 v/v ethyl acetate/hexane elution)
to afford, after concentration of the appropriate fractions (RF 0.5
in 1/1 v/v ethyl acetate/hexane), the title compound 14 (176 mg,
69%) as a white, foamy solid lacking a distinct melting
point [Found: (M þ Na)þ, 483.0825. C21H20N2O8S requires
(M þ Na)þ, 483.0838]. dH (400 MHz) 7.86 (m, 1H), 7.61 (m,
1H), 7.58–7.55 (complex m, 2H), 6.98 (s, 1H), 6.49 (br s, 1H),
6.23 (s, 1H), 5.88 (d, J 1.2, 1H), 5.87 (d, J 1.2, 1H), 5.56 (m, 1H),
4.20 (m, 1H), 3.84 (s, 3H), 2.20–1.94 (complex m, 4H), 1.83–
1.66 (complex m, 2H). dC (100 MHz) 167.3 (C), 149.4 (C), 146.8
(C), 146.3 (C), 138.4 (C), 136.6 (C), 134.4 (C), 132.4 (CH),
132.3 (CH), 130.4 (CH), 130.3 (CH), 124.7 (CH), 123.6 (C),
109.6 (CH), 109.4 (CH), 101.7 (CH2), 53.9 (CH), 52.3 (CH3),
31.9 (CH2), 25.2 (CH2), 17.9 (CH2). nmax 3315, 3095, 2950,
1710, 1614, 1540, 1486, 1375, 1250, 1172, 1216, 1037,
740 cmꢀ1. m/z (ESI, þve) 483 [(M þ Na)þ, 20%], 260 (25),
259 (100), 227 (36).
A solution of bromide 10 (580 mg, 1.76 mmol) in benzene
(19 mL) and ethanol (1 mL) was treated with 3,4-methylene-
dioxyphenylboronic acid (320 mg, 1.93 mmol), tetrakis(triphe-
nylphosphine)palladium(0) (101 mg, 0.09 mmol), and Na2CO3
(4.5 mL of a 2 M aqueous solution). The resulting mixture was
stirred at 808C under an atmosphere of nitrogen for 5 h and then
NaHCO3 (20 mL of a saturated aqueous solution) and ethyl
acetate (20 mL) were added to the cooled reaction mixture.
The separated aqueous phase was extracted with ethyl acetate
(3 ꢁ 20 mL) and the combined organic fractions dried (MgSO4),
filtered, and concentrated under reduced pressure. The ensuing
residue was subjectedto flash chromatography (silicagel, 1/4 v/v
ethyl acetate/hexane elution) to afford, after concentration of the
relevant fractions (RF 0.4 in 3/7 v/v ethyl acetate/hexane), the
title compound 12 (478 mg, 78%) as a white solid, mp 161.5–
162.58C [Found: (M þ Na)þ, 394.1089. C20H21NO4S requires
(M þ Na)þ, 394.1089]. dH (300 MHz) 7.53 (dm, J 8.1, 2H), 7.18
(dm, J 8.1, 2H), 6.49 (dd, J 7.8, 0.3, 1H), 6.39 (dd, J 7.8 and 1.8,
1H), 6.33 (d, J 1.8, 1H), 5.94 (m, 1H), 5.90 (q, J 1.5, 2H), 4.41 (d,
J 5.7, 1H), 4.09 (d, J 3.9, 1H), 2.42 (s, 3H), 2.23–2.02 (complex
m, 3H), 1.74–1.61 (complex, 3H). dC (75 MHz) 147.2 (C), 146.5
(C), 142.9 (C), 137.0 (C), 135.8 (C), 133.7 (C), 130.3 (CH), 129.2
(CH), 126.9 (CH), 119.8 (CH), 107.8 (CH), 106.6 (CH), 100.8
(CH2), 49.5 (CH), 29.9 (CH2), 25.4 (CH2), 21.4 (CH3), 16.3
(CH2). nmax 3257, 2921, 1503, 1488, 1244, 1165, 1157, 1034,
929, 813, 798, 674cmꢀ1. m/z (ESI, þve) 394 [(M þ Na)þ,
100%], 201 (73).
Compound 15
A solution of sulfonamide 12 (206 mg, 0.56 mmol) in dry
DMF (3 mL), maintained at 08C under an atmosphere of nitro-
gen, was treated with sodium hydride (60% dispersion in
mineral oil, 27 mg, 0.67 mmol). After 1 h the reaction mixture
was treated with propargyl bromide (310 mL of an 80% solution
in toluene, 2.8 mmol) and then allowed to warm to 188C, stirred
at this temperature for 3.5 h, treated with NH4Cl (20 mL of a
saturated aqueous solution), stirred for 5 min, and then extracted
with ethyl acetate (4 ꢁ 20 mL). The combined organic fractions
were dried (MgSO4), filtered, and concentrated under reduced
pressure and the ensuing residue subjected to flash chromato-
graphy (silica gel, 1/9 v/v ethyl acetate/hexane elution). Con-
centration of the appropriate fractions (RF 0.5 in 3/7 v/v ethyl
acetate/hexane) gave the title compound 15 (202 mg, 89%)
as a pale-yellow solid, mp 144–1468C [Found: (M þ Na)þ,
432.1250. C23H23NO4S requires (M þ Na)þ, 432.1245]. dH
(300 MHz) 7.73 (dt, J 8.4 and 1.8, 2H), 7.23 (dm, J 8.4, 2H),
6.71 (dd, J 7.5 and 1.8, 1H), 6.69 (s, 1H), 6.64 (dd, J 7.5 and 1.5,
1H), 6.11 (m, 1H), 5.92 (s, 2H), 5.03 (m, 1H), 3.93 (dd, J 18.6
and 2.4, 1H), 3.60 (dd, J 18.6 and 2.4, 1H), 2.42 (s, 3H), 2.21–
2.10 (complex m, 2H), 2.07 (t, J 2.4, 1H), 2.04 (m, 1H), 1.92–
1.75 (complex m, 2H), 1.61 (m, 1H). dC (75 MHz) 147.3 (C),
146.6 (C), 143.1 (C), 137.9 (C), 136.5 (C), 134.1 (CH), 133.2
(C), 129.2 (CH), 127.7 (CH), 120.1 (CH), 107.9 (CH), 107.3
(CH), 100.9 (CH2), 80.2 (C), 72.3 (CH), 55.3 (CH), 33.3 (CH2),
28.8 (CH2), 25.5 (CH2), 21.5 (CH3), 20.2 (CH2). nmax 3290,
2937, 1597, 1503, 1489, 1438, 1334, 1244, 1155, 1038, 935,
807, 668 cmꢀ1. m/z (ESI, þve) 432 [(M þ Na)þ, 24%], 201
(100).
Compound 13
A solution of bromide 11 (188 mg, 0.52 mmol) and 3,4-
methylenedioxyphenylboronic acid (146 mg, 0.88 mmol),
triethylamine (1 mL), PdCl2(dppf)ꢂCH2Cl2 (26 mg, 0.03 mmol),
and water (0.2 mL) in THF (1.4 mL) was sparged with nitrogen
for 5 min and then subjected to microwave irradiation at 908C
for 1.5 h. The cooled reaction mixture was diluted with ethyl
acetate (20 mL) and washed with water (2 ꢁ 20 mL) followed by
brine (1 ꢁ 10 mL) before being dried (MgSO4), filtered, and
concentrated under reduced pressure. The ensuing residue was
subjected to flash chromatography (silica gel, 1/3 v/v ethyl
acetate/hexane elution) to afford, after concentration of
the relevant fractions (RF 0.5 in 2/3 v/v ethyl acetate/hexane),
the title compound 13 (160 mg, 77%) as a pale-yellow, crystal-
line solid, mp 158–1658C (Found: Mþꢃ
,
402.0896.
C19H18N2O6S requires Mþꢃ, 402.0886). dH (300 MHz) 8.07
(dd, J 7.6 and 2.0, 1H), 7.74–7.62 (complex m, 3H), 6.44 (dd,
J 7.6 and 2.4, 1H), 6.37 (s, 1H), 6.36 (d, J 6.8, 1H), 5.94 (m, 1H),
5.83 (s, 2H), 5.43 (d, J 6.8, 1H), 4.33 (m, 1H), 2.28–2.05
(complex m, 3H), 1.84–1.66 (complex m, 3H). dC (75 MHz)
147.0 (C), 146.8 (C), 146.5 (C), 136.0 (C), 134.4 (C), 134.0 (C),
132.9 (CH), 132.8 (CH), 131.0 (CH), 130.7 (CH), 125.5 (CH),
120.2 (CH), 107.7 (CH), 106.9 (CH), 100.8 (CH2), 51.4 (CH),
30.9 (CH2), 25.4 (CH2), 16.3 (CH2). nmax 3354, 2934, 1537,
1488, 1440, 1402, 1358, 1341, 1244, 1171, 1039 cmꢀ1. m/z (EI)
402 (Mþꢃ, 62%), 200 (100).
Compound 16
A magnetically stirred solution of sulfonamide 13 (119 mg,
0.30 mmol) in dry DMF (1.5 mL), maintained at 08C under
an atmosphere of argon, was treated with sodium hydride
(60% dispersion in mineral oil, 14 mg, 0.36 mmol). After 1 h
the reaction mixture was treated with propargyl bromide (33 mL
of an 80% solution in toluene, 1.48 mmol) and then allowed to
warm to 188C and stirred at this temperature for 3 h. The reaction
Compound 14
A mixture of bromide 11 (200 mg, 0.55 mmol), methyl
6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzo[d][1,3]dioxole-
5-carboxylate[5a] (275 mg, 0.94 mmol), triethylamine (1.1 mL),
PdCl2(dppf)ꢂCH2Cl2 (27 mg, 0.03 mmol), and water (0.3 mL)
in THF (2.5 mL) was sparged with nitrogen for 5 min and then

RESEARCH FRONT
1672
A. L. Lehmann, A. C. Willis, and M. G. Banwell
mixture was then treated with NH4Cl (20 mL of a saturated
aqueous solution), stirred at 188C for 5 min, and then extracted
with ethyl acetate (4 ꢁ 20 mL). The combined organic fractions
were dried (MgSO4), filtered, and concentrated under reduced
pressure and the ensuing residue subjected to flash chromato-
graphy (silica gel, 1/3 v/v ethyl acetate/hexane elution).
Concentration of the relevant fractions (RF 0.5 in 2/3 v/v ethyl
acetate/hexane) gave the title compound 16 (118 mg, 91%)
as a pale-yellow solid, mp 140–1418C [Found: (M þ Na)þ,
463.0937. C22H20N2O6S requires (M þ Na)þ, 463.0940]. dH
(400 MHz) 8.05 (dd, J 8.0 and 1.2, 1H), 7.67 (td, J 7.6 and
1.2, 1H), 7.61 (dd, J 8.0 and 1.6, 1H), 7.57 (td, J 7.6 and 1.6, 1H),
6.57 (dd, J 8.0 and 1.6, 1H), 6.54–6.51 (complex m, 2H), 6.09
(m, 1H), 5.88 (d, J 1.2, 1H), 5.87 (d, J 1.2, 1H), 4.99 (m, 1H),
4.11 (dd, J 18.4 and 2.4, 1H), 3.72 (dd, J 18.4 and 2.4, 1H), 2.28–
2.08 (complex m, 4H), 2.17 (t, J 2.4, 1H), 1.86 (m, 1H), 1.70 (m,
1H). dC (100 MHz) 148.0 (C), 147.1 (C), 146.5 (C), 136.3 (C),
134.1 (CH), 133.5 (CH), 131.3 (CH), 131.2 (CH), 123.8 (CH),
120.2 (CH), 107.8 (CH), 107.3 (CH), 100.8 (CH2), 80.2 (C), 72.7
(C), 56.2 (CH), 33.9 (CH2), 29.3 (CH2), 25.4 (CH2), 20.2 (CH2)
(two signals obscured or overlapping). nmax 3292, 3096, 2940,
2257, 1543, 1503, 1489, 1438, 1372, 1244, 1166, 1126, 1039,
935, 905, 736 cmꢀ1. m/z (ESI, þve) 463 [(M þ Na)þ, 100%],
201 (67).
2.42 mmol) and then allowed to warm to 188C and stirred at this
temperature for 2 h. After this time the reaction mixture was
treated with NH4Cl (20 mL of a saturated aqueous solution),
stirred for 5 min, and then extracted with ethyl acetate
(4 ꢁ 20 mL). The combined organic fractions were dried
(MgSO4), filtered, and concentrated under reduced pressure
and the ensuing residue subjected to flash chromatography
(silica gel, 3/7 v/v ethyl acetate/hexane elution) to afford, after
concentration of the relevant fractions (RF 0.5 in 1/1 v/v ethyl
acetate/hexane), the title compound 18 (189 mg, 86%) as a pale-
yellow, crystalline solid, mp 159–1638C [Found: (M þ Na)þ,
477.1095. C23H22N2O6S requires (M þ Na)þ, 477.1096]. dH
(400 MHz) 8.04 (dd, J 8.0 and 1.6, 1H), 7.65 (td, J 7.6 and
1.6, 1H), 7.58 (dd, J 7.6 and 1.2, 1H), 7.54 (dd, J 7.6 and 1.6, 1H),
6.62 (dd, J 8.0 and 1.6, 1H), 6.59 (d, J 1.2, 1H), 6.56 (d, J 8.0,
1H), 6.08 (m, 1H), 5.88 (d, J 1.2, 1H), 5.87 (d, J 1.2, 1H), 5.01
(m, 1H), 4.03 (dq, J 18.4 and 2.4, 1H), 3.68 (dq, J 18.4 and 2.4,
1H), 2.26–2.05 (complex m, 4H), 1.92–1.83 (m, 1H), 1.75–1.66
(m, 1H), 1.66 (t, J 2.4, 3H). dC (100 MHz) 148.0 (C), 147.0 (C),
146.4 (C), 136.5 (C), 134.2 (C), 133.7 (C), 133.6 (CH), 133.2
(CH), 131.2 (CH), 130.8 (CH), 123.5 (CH), 120.2 (CH), 107.7
(CH), 107.4 (CH), 100.7 (CH2), 80.5 (C), 75.3 (C), 56.0 (CH),
34.4 (CH2), 29.2 (CH2), 25.3 (CH2), 20.1 (CH2), 3.4 (CH3). nmax
3026, 2937, 1587, 1542, 1503, 1490, 1438, 1370, 1344, 1293,
1244, 1223, 1160, 1037, 933, 878, 808, 736cmꢀ1. m/z (ESI, þve)
477 [(M þ Na)þ, 100%], 201 (50).
Compound 17
A magnetically stirred solution of sulfonamide 14 (149 mg,
0.32 mmol) in dry DMF (1.6 mL), maintained at 08C under
an atmosphere of nitrogen, was treated with sodium hydride
(60% dispersion in mineral oil, 16 mg, 0.39 mmol). After 1 h the
reaction mixture was treated with propargyl bromide (180 mL of
an 80% solution in toluene, 1.62 mmol) and then allowed to
warm to 188C, stirred at this temperature for 2 h, and then treated
with NH4Cl (20 mL of a saturated aqueous solution) and stirred
for 5 min before being extracted with ethyl acetate (4 ꢁ 20 mL).
The combined organic fractions were dried (MgSO4), filtered,
and concentrated under reduced pressure. The ensuing residue
was subjected to flash chromatography (silica gel, 2/3 v/v ethyl
acetate/hexane elution) to afford, after concentration of the
relevant fractions (RF 0.3 in 1/1 v/v ethyl acetate/hexane), the
title compound 17 (128 mg, 80%) as a pale-yellow and foamy
solid lacking a distinct melting point [Found: (M þ Na)þ,
521.0998. C24H22N2O8S requires (M þ Na)þ, 521.0995]. dH
(400 MHz) 7.90 (dd, J 8.2 and 1.4, 1H), 7.58 (td, J 7.6 and
1.2, 1H), 7.50–7.45 (complex m, 2H), 7.05 (s, 1H), 6.48 (s, 1H),
5.93 (d, J 1.2, 1H), 5.92 (d, J 1.2, 1H), 5.83 (td, J 3.8 and 1.6,
1H), 4.98 (m, 1H), 4.27 (dd, J 18.8 and 2.6, 1H), 4.01 (dd, J 18.8
and 2.0, 1H), 3.78 (s, 3H), 2.27–2.08 (complex m, 4H), 2.21 (t,
J 2.4, 1H), 1.98–1.88 (complex m, 1H), 1.84–1.75 (complex m,
1H). dC (100 MHz) 166.1, 150.0, 147.3, 146.3, 138.4, 137.0,
133.3, 133.2, 133.1, 131.3, 131.2, 123.8, 122.0, 110.7, 110.0,
101.8, 80.5, 72.3, 56.7, 51.8, 34.2, 28.7, 25.1, 19.7. nmax 3291,
2949, 1716, 1613, 1543, 1505, 1486, 1437, 1369, 1248, 1161,
1127, 1037, 874, 785, 738 cmꢀ1. m/z (ESI, þve) 521
[(M þ Na)þ, 19%), 259 (100).
Compound 19
A magnetically stirred solution of sulfonamide 14 (78 mg,
0.19 mmol) in dry DMF (1 mL) maintained at 08C under an
atmosphere of nitrogen was treated with sodium hydride (10 mg
of a 60% dispersion in mineral oil, 0.23 mmol). After 1 h the
mixture was treated with 1-bromobut-2-yne (88 mL, 0.97 mmol)
and then allowed to warm to 188C and stirred at this temperature
for 2 h. After this time the reaction mixture was treated with
NH4Cl (20 mL of a saturated aqueous solution), stirred for
5 min, and then extracted with ethyl acetate (4 ꢁ 20 mL). The
combined organic fractions were dried (MgSO4), filtered,
and concentrated under reduced pressure. The ensuing residue
was subjected to flash chromatography (silica gel, 3/7 v/v ethyl
acetate/hexane elution) to afford, after concentration of the
relevant fractions (RF 0.4 in 1/1 ethyl acetate/hexane), the title
compound 19 (82 mg, 83%) as a pale-yellow, foamy solid
lacking a distinct melting point [Found: (M þ Na)þ, 535.1151.
C25H24N2O8S requires (M þ Na)þ, 535.1151]. dH (400 MHz)
7.94 (d, J 8.0, 1H), 7.58 (m, 1H), 7.51–7.46 (complex m, 2H),
7.13 (s, 1H), 6.53 (s, 1H), 5.96 (d, J 1.2, 1H), 5.95 (d, J 1.2, 1H),
5.85 (m, 1H), 5.02 (m, 1H), 4.20 (dm, J 18.4, 1H), 3.94 (dm,
J 18.4, 1H), 3.81 (s, 3H), 2.24–2.09 (complex m, 4H), 1.93 (m,
1H), 1.81 (m, 1H), 1.69 (t, J 2.4, 3H). dC (100 MHz) 166.2 (C),
150.0 (C), 147.6 (C), 146.3 (C), 138.6 (C), 137.5 (C), 133.7 (C),
132.9 (CH), 132.8 (CH), 131.3 (CH), 130.8 (CH), 123.6 (CH),
122.2 (C), 110.8 (CH), 110.0 (CH), 101.7 (CH2), 80.2 (C), 75.5
(C), 56.7 (CH), 51.8 (CH3), 34.7 (CH2), 28.7 (CH2), 25.1 (CH2),
19.8 (CH2), 3.4 (CH3). nmax 3094, 2949, 1718, 1613, 1543, 1505,
1485, 1437, 1369, 1248, 1161, 1127, 1036, 877, 785, 737 cmꢀ1
m/z (ESI, þve) 535 [(M þ Na)þ, 71%], 259 (100).
.
Compound 18
A magnetically stirred solution of sulfonamide 13 (195 mg,
0.49 mmol) in dry DMF (2.4 mL), maintained at 08C under
an atmosphere of nitrogen, was treated with sodium hydride
(60% dispersion in mineral oil, 23 mg, 0.58 mmol). After
1 h the mixture was treated with 1-bromobut-2-yne (322 mL,
Compound 21
A magnetically stirred solution of ketone 20[16] (4.90 g,
44.6 mmol) and 2,2-dimethylpropane-1,3-diol (13.93 g,
133.7 mmol) in dry THF (45 mL) was maintained at 08C under

RESEARCH FRONT
The Pd-Catalyzed Alder–Ene Reactions of N-Protected and Propargylated 1-Amino-2-aryl-2-cyclohexenes
1673
an atmosphere of nitrogen and treated, in three equal portions
over 2 h, with boron trifluoride diethyl etherate (3.3 mL,
26.7 mmol). The resulting mixture was stirred at 08C for a
further 2.5 h and then poured into ice-cold NaHCO3 (100 mL
of a saturated aqueous solution). The separated aqueous layer
was extracted with CH2Cl2 (6 ꢁ 50 mL) and then the combined
organic phases were dried (MgSO4), filtered, and concentrated
under reduced pressure. The ensuing residue was subjected to
flash chromatography (silica gel, 1/49 v/v diethyl ether/pentane
elution) to afford, after concentration of the relevant fractions
(RF in 0.6 in 1/4 v/v ethyl acetate/hexane), the title compound 21
(7.93 g, 91%) as a clear, colourless oil. dH (400 MHz) 5.83 (m,
2H), 5.12 (m, 2H), 5.09 (m, 2H), 3.53 (s, 4H), 2.51 (dt, J 7.6 and
0.8, 4H), 0.97 (s, 6H). dC (100 MHz) 132.9 (CH), 117.8 (CH2),
99.2 (C), 70.2 (CH2), 38.2 (CH2), 29.8 (C), 22.6 (CH3). nmax
3077, 2955, 2865, 1642, 1473, 1434, 1395, 1330, 1173, 1150,
1097, 988, 912, 835 cmꢀ1. The volatility of this material pre-
cluded the acquisition of mass spectrometric data.
anhydrous 1,4-dioxane (19 mL) was heated at 808C for 18 h
while being maintained under an atmosphere of argon. After this
time the reaction mixture was treated with t-butanol (1.9 mL)
and then heated at 1058C for a further 24 h. The resulting slurry
was cooled and then filtered through a pad of Celite that was
washed with CH2Cl2 (200 mL) and the combined filtrates were
then concentrated under reduced pressure. The ensuing residue
was subjected to flash chromatography (silica gel, 1/9 v/v ethyl
acetate/hexane elution) to afford, after concentration of the
relevant fractions (RF 0.4 in 1/1 v/v ethyl acetate/hexane), the
title compound 24 (1.04 g, 73%) as a white, crystalline solid,
mp 86–908C (Found: Mþꢃ, 375.1046. C16H2679BrNO4 requires
M
þꢃ, 375.1045). dH (400 MHz) 6.00 (t, J 3.8, 1H), 5.09 (d,
J 10.0, 1H), 4.49 (m, 1H), 3.56 (dd, J 11.2 and 8.0, 2H), 3.45
(t, J 10.0, 2H), 2.62 (dd, J 18.0 and 4.4, 1H), 2.35 (m, 1H), 2.24
(d, J 18.0, 1H), 2.16 (dd, J 14.4 and 5.6, 1H), 1.47 (s, 9H), 1.00 (s,
3H), 0.94 (s, 3H). dC (100 MHz) 155.4 (C), 127.9 (CH), 122.8
(C), 95.7 (C), 79.5 (C), 70.4 (CH2), 70.3 (CH2), 51.7 (CH), 36.4
(CH2), 35.2 (CH2), 30.0 (C), 28.4 (CH3), 22.6 (CH3), 22.5 (CH3).
nmax 3444, 3348, 2957, 2869, 1713, 1493, 1366, 1244, 1166,
1114, 1051, 1018, 934, 733 cmꢀ1. m/z (EI, 70 eV) 377 and 375
(Mþꢃ, both 8%), 240 (83), 128 (100), 69 (67), 57 (82), 41 (55).
Compound 22
A magnetically stirred solution of diene 21 (2.00 g,
10.2 mmol) and the Grubbs’ II catalyst (173 mg, 0.20 mmol) in
dry CH2Cl2 (500 mL) was heated at 408C for 3 h while being
maintained under an atmosphere of nitrogen. The cooled reac-
tion mixture was then concentrated under reduced pressure at
ꢀ158C and the ensuing residue subjected to flash chromato-
graphy (silica gel, 1/49 v/v diethyl ether/pentane elution). After
concentration of the relevant fractions (RF 0.5 in 1/4 v/v ethyl
acetate/hexane) at ꢀ158C, the title compound 22 (1.63 g, 95%)
was obtained as a clear, colourless oil. dH (300 MHz) 5.67 (s,
2H), 3.52 (s, 4H), 2.66 (s, 4H), 0.99 (s, 6H). dC (75 MHz) 127.7
(CH), 109.2 (C), 71.9 (CH2), 42.3 (CH2), 30.0 (C), 22.4 (CH3).
m/z (EI, 70 eV) 168 (Mþꢃ, 27%), 32 (100). This rather volatile
material was used immediately in the next step of the reaction
sequence.
Compound 25
Step i: A magnetically stirred solution of carbamate 24
(284 mg, 0.76 mmol) and 2,6-lutidine (700 mL, 6.04 mmol) in
dry CH2Cl2 (4 mL) was treated with TMSOTf (550 mL,
3.02 mmol) in a dropwise fashion over 10 min. The resulting
mixture was stirred at 08C under an atmosphere of nitrogen for
3 h and then quenched with NaOH (25 mL of a 2 M aqueous
solution). The separated aqueous phase was extracted with ethyl
acetate (3 ꢁ 30 mL) and the combined organic fractions were
then dried (MgSO4), filtered, and concentrated under reduced
pressure to afford the expected amine as a clear, colourless oil.
dH (300 MHz) 5.90 (t, J 4.5, 1H), 3.68 (d, J 11.7, 1H), 3.59 (d,
J 11.7, 1H), 3.49–3.37 (complex m, 3H), 2.54–2.44 (complex m,
1H), 2.40–2.30 (complex m, 2H), 2.17 (ddd, J 13.5, 6.0, and 1.2,
1H), 1.71 (br s, 2H), 1.02 (s, 3H), 0.91 (s, 3H). This material was
used, as obtained, in Step ii of the reaction sequence.
Compound 23
A mixture of cyclopentene 22 (1.53 g, 9.10 mmol), CHBr3
(7.9 mL, 90.9 mmol), NaOH (7.3 g in 7.3 mL of water,
182 mmol), and TEBAC (42 mg, 0.18 mmol) in CH2Cl2
(8 mL), maintained at 188C under an atmosphere of nitrogen,
was stirred vigorously for 4 h and then diluted with CH2Cl2
(100 mL). The resulting slurry was filtered through a pad of
Celite that was washed with CH2Cl2 (1 ꢁ 400 mL). The com-
bined filtrates were concentrated under reduced pressure and the
ensuing residue subjected to flash chromatography (silica gel, 1/
19 v/v diethyl ether/pentane elution) to afford, after concentra-
tion of the appropriate fractions (RF 0.6 in 1/1 v/v ethyl acetate/
hexane), the title compound 23 (2.07 g, 67%) as a white, crystal-
line solid, mp 51–538C [Found: (M ꢀ Brꢃ)þ, 259.0336.
C11H1679Br2O2 requires (M – Brꢃ)þ, 259.0334]. dH (500 MHz)
3.48 (s, 2H), 3.37 (s, 2H), 2.57 (m, 2H), 2.22 (m, 2H), 1.69 (d, J 15,
2H), 0.94 (s, 6H). dC (125MHz) 115.2 (C), 73.2 (CH2), 71.2
(CH2), 44.9 (C), 38.2 (CH2), 35.6 (CH), 29.9 (C), 22.3 (CH3). nmax
3055, 2963, 2935, 2859, 1468, 1423, 1242, 1114, 1036, 1014, 994,
850, 766, 730 cmꢀ1. m/z (EI) 261 and 259 [(M ꢀ Brꢃ)þ, 94 and
95%], 147 and 145 (71 and 69), 128 (100), 69 (95), 65 (80), 56
(54), 41 (70).
Step ii: A magnetically stirred solution of the amine obtained
as described in Step i and triethylamine (315 mL, 2.26 mmol)
in dry CH2Cl2 (4 mL) was treated with 2-nitrobenzenesulfonyl
chloride (176 mg, 0.79 mmol) and the resulting mixture stirred
at 188C under an atmosphere of nitrogen for 2 h. NaOH (20 mL
of a 2 M aqueous solution) was then added to the reaction
mixture and the separated aqueous phase was extracted with
CH2Cl2 (3 ꢁ 20 mL) and the combined organic fractions were
then dried (MgSO4), filtered, and concentrated under reduced
pressure. The ensuing residue was subjected to flash chromato-
graphy (silica gel, 1/4 v/v ethyl acetate/hexane elution) to afford,
after concentration of the appropriate fractions (RF 0.4 in 1/1 v/v
ethyl acetate/hexane), the title compound 25 (252 mg, 72% from
24) as a white, crystalline solid, mp 98–1008C (Found: Mþꢃ
,
460.0309. C17H2179BrN2O6S requires Mþꢃ, 460.0304). dH
(500 MHz) 8.19 (dd, J 8.0 and 1.8, 1H), 7.92 (dd, J 7.5 and
2.0, 1H), 7.76–7.68 (complex m, 2H), 6.46 (d, J 9.5, 1H), 6.03
(dd, J 5.0 and 3.0, 1H), 4.37 (m, 1H), 3.61 (dd, J 11.5 and 1.0,
1H), 3.52 (d, J 11.5, 1H), 3.48 (d, J 11.5, 1H), 3.44 (dd, J
11.5 and 1.0, 1H), 2.82 (ddd, J 18.0, 5.5, and 1.5, 1H), 2.25 (dt,
J 14.0 and 2.5, 1H), 2.12 (ddd, J 18.0, 2.8, and 1.8, 1H), 2.05
(dd, J 14.0 and 5.5, 1H), 0.91 (s, 3H), 0.89 (s, 3H). dC (125 MHz)
147.5 (C), 135.5 (C), 133.3 (CH), 133.0 (CH), 130.4 (CH),
Compound 24
A magnetically stirred mixture of gem-dibromide 23
(1.28 g, 3.77 mmol) and silver cyanate (2.83 g, 18.87 mmol) in

RESEARCH FRONT
1674
A. L. Lehmann, A. C. Willis, and M. G. Banwell
129.6 (CH), 125.4 (CH), 120.5 (C), 95.2 (C), 70.4 (2 ꢁ CH2),
56.4 (CH), 37.4 (CH2), 34.4 (CH2), 30.0 (C), 22.3(1) (CH3),
22.2(6) (CH3). nmax 3307, 2957, 2869, 1541, 1412, 1352, 1173,
137.9, 135.4, 132.6, 132.1, 129.8, 124.8, 124.3, 110.7, 109.7,
101.7, 96.6, 70.4(3), 70.3(8), 54.1, 52.3, 35.4, 35.3, 30.1, 22.7,
22.3 (one signal obscured or overlapping). nmax 3307, 2955,
2870, 1711, 1613, 1540, 1505, 1486, 1437, 1407, 1370, 1344,
1252, 1168, 1123, 1038, 910, 731 cmꢀ1. m/z (EI, 70 eV) 560
(Mþꢃ, 13%), 432 (74), 374 (77), 214 (100), 129 (50), 128 (46),
69 (51).
1155, 1126, 1087, 911, 733 cmꢀ1. m/z (EI) 462 and 460 (Mþꢃ
,
both 34%), 274 and 272 (both 87), 261 and 259 (both 53), 186
(70), 128 (100), 69 (85), 41 (78).
Compound 26
Compound 28
A mixture of bromide 25 (300 mg, 0.65 mmol) and 3,4-
methylenedioxyphenyl boronic acid (183 mg, 1.11 mmol),
A magnetically stirred solution of sulfonamide 26 (130 mg,
0.26 mmol) in dry DMF (1.3 mL), maintained at 08C under an
atmosphere of nitrogen, was treated with sodium hydride (13 mg
of a 60% dispersion in mineral oil, 0.31 mmol). After 1 h the
reaction mixture was treated with propargyl bromide (145 mL
of an 80% solution in toluene, 1.29 mmol) and then allowed to
warm to 188C and stirred at this temperature for 2 h. The reaction
mixture was then treated with NH4Cl (20 mL of a saturated
aqueous solution), stirred for 5 min at 188C, and then extracted
with ethyl acetate (4 ꢁ 20 mL). The combined organic fractions
were dried (MgSO4), filtered, and concentrated under reduced
pressure and the ensuing residue subjected to flash chromato-
graphy (silica gel, 1/4 v/v ethyl acetate/hexane elution) to afford,
after concentration of the relevant fractions (RF 0.6 in 1/1 v/v
ethyl acetate/hexane), the title compound 28 (124 mg, 89%)
as a white, crystalline solid, mp 159–1618C [Found: (M þ Na)þ,
563.1464. C27H28N2O8S requires (M þ Na)þ, 563.1464]. dH
(400 MHz) 8.05 (d, J 8.0, 1H), 7.73–7.61 (complex m, 3H),
6.50–6.49 (complex m, 2H), 6.36 (m, 1H), 5.86 (d, J 1.4, 1H),
5.85 (m, 1H), 5.84 (d, J 1.4, 1H), 5.06 (m, 1H), 4.08 (dd, J 18.8
and 2.4, 1H), 3.79 (d, J 11.2, 1H), 3.71 (d, J 11.2, 1H), 3.66 (dd, J
18.8 and 2.4, 1H), 3.51 (dd, J 18.8 and 1.6, 1H), 3.48 (dd, J 18.8
and 1.6, 1H), 3.06 (ddd, J 13.6, 6.0, and 2.8, 1H), 2.66 (m, 1H),
2.41 (dt, J 18.0 and 3.6, 1H), 2.35 (dd, J 13.2 and 10.0, 1H), 2.17
(t, J 2.4, 1H), 1.09 (s, 3H), 0.93 (s, 3H). dC (100 MHz) 147.9 (C),
147.0 (C), 146.6 (C), 136.5 (C), 133.7 (CH), 133.3 (C), 133.2
(C), 131.4 (CH), 131.2 (CH), 128.7 (CH), 124.1 (CH), 120.2
(CH), 107.7 (CH), 107.3 (CH), 100.8 (CH2), 97.0 (C), 80.0 (C),
73.0 (C), 70.4(3) (CH2), 70.3(8) (CH2), 57.0 (CH), 36.1 (CH2),
34.0 (CH2), 32.8 (CH2), 30.1 (CH), 22.7 (CH3), 22.3 (CH3). nmax
3292, 2956, 2870, 2122, 1544, 1489, 1371, 1351, 1246, 1167,
1117, 1084, 1038, 935, 892, 737 cmꢀ1. m/z (ESI, þve) 563
[(M þ Na)þ, 19%], 302 (20), 301 (100).
triethylamine
(1.3 mL),
PdCl2(dppf)ꢂCH2Cl2
(32 mg,
0.04 mmol), and water (0.3 mL) in THF (2.7 mL) was sparged
with nitrogen for 5 min and then subjected to microwave
irradiation at 908C for 1.5 h. The cooled reaction mixture was
diluted with ethyl acetate (20 mL) and then washed with water
(2 ꢁ 20 mL) and brine (10 mL) before being dried (MgSO4),
filtered, and concentrated under reduced pressure. The ensuing
residue was subjected to flash chromatography (silica gel, 1/3
v/v ethyl acetate/hexane elution) to afford, after concentration
of the relevant fractions (RF 0.5 in 1/1 v/v ethyl acetate/hexane),
the title compound 26 (284 mg, 81%) as a pale-yellow and
foamy solid lacking a distinct melting point (Found: Mþꢃ
502.1411. C24H26N2O8S requires Mþꢃ
502.1410). dH
,
,
(400 MHz) 7.90 (m, 1H), 7.80 (m, 1H), 7.63–7.57 (complex
m, 2H), 6.68 (dd, J 8.4 and 2.0, 1H), 6.60 (d, J 1.2, 1H), 6.52 (d, J
8.4, 1H), 6.34 (d, J 9.2, 1H, NH), 5.88 (s, 2H), 5.75 (m, 1H), 4.76
(br m, 1H), 3.67 (d, J 12.0, 1H), 3.56 (d, J 12.0, 1H), 3.52 (s, 2H),
2.88 (ddd, J 18.8, 5.2, and 2.0, 1H), 2.48 (dt, J 14.0 and 2.2, 1H),
2.25 (ddd, J 18.8, 2.8, and 2.0, 1H), 1.96 (dd, J 14.0 and 4.8, 1H),
0.97 (s, 3H), 0.88 (s, 3H). dC (100 MHz) 147.2 (C), 146.8 (C),
136.2 (C), 135.8 (C), 133.2 (C), 132.8 (CH), 132.5 (CH), 129.9
(CH), 125.2 (CH), 124.8 (CH), 120.3 (CH), 107.9 (CH), 107.2
(CH), 100.9 (CH2), 96.1 (C), 70.4 (CH2), 70.3 (CH2), 51.8 (CH),
35.7 (CH2), 33.7 (CH2), 30.0 (C), 22.4 (CH3), 22.3 (CH3) (one
signal obscured or overlapping). nmax 3307, 2957, 2870, 1594,
1540, 1490, 1440, 1409, 1344, 1243, 1170, 1123, 1038, 934,
733 cmꢀ1. m/z (EI, 70 eV) 502 (Mþꢃ, 16%), 374 (98), 316 (25),
214 (24), 188 (100), 158 (35), 129 (48), 69 (38).
Compound 27
A solution of bromide 25 (378 mg, 0.82 mmol) in THF
(4.1 mL) was treated with methyl 6-(5,5-dimethyl-1,3,2-dioxa-
borinan-2-yl)benzo[d][1,3]dioxole-5-carboxylate[5a] (263 mg,
0.901 mmol), Cs2CO3 (801 mg, 2.46 mmol), potassium acetate
(81 mg, 0.82 mmol), PdCl2(dppf)ꢂCH2Cl2 (33 mg, 0.04 mmol),
and water (0.41 mL). The ensuing mixture was sparged with
nitrogen and then heated at 658C for 2 h, cooled, diluted with
ethyl acetate (40 mL) and then washed with water (1 ꢁ 40 mL)
and brine (1 ꢁ 40 mL) before being dried (MgSO4), filtered,
and concentrated under reduced pressure. The ensuing residue
was subjected to flash chromatography (silica gel, 1/3 v/v ethyl
acetate/hexane elution) to afford, after concentration of the
relevant fractions (RF 0.4 in 1/1 v/v ethyl acetate/hexane), the
title compound 27 (310 mg, 68%) as a colourless, crystalline
solid, mp 176–1798C (Found: Mþꢃ, 560.1463. C26H28N2O10S
requires Mþꢃ, 560.1465). dH (500 MHz) 7.77 (dd, J 7.0 and 1.0,
1H), 7.70 (dd, J 7.5 and 1.5, 1H), 7.59–7.51 (complex m, 2H),
7.12 (s, 1H), 5.58 (d, J 8.5, 1H), 6.34 (s, 1H), 5.89 (m, 2H), 5.37
(t, J 3.5, 1H), 4.53 (m, 1H), 3.84 (s, 3H), 3.75 (d, J 11.0, 1H),
3.67 (d, J 12.0, 1H), 3.55–3.48 (complex m, 2H), 2.64 (d, J 17.5,
1H), 2.44 (m, 1H), 2.37–2.32 (complex m, 2H), 1.06 (s, 3H),
0.90 (s, 3H). dC (125 MHz) 166.9, 149.7, 146.9, 146.6, 138.0,
Compound 29
A magnetically stirred solution of sulfonamide 27 (95 mg,
0.170 mmol) in dry DMF (1 mL) maintained at 08C under an
atmosphere of nitrogen was treated with sodium hydride (8 mg
of a 60% dispersion in mineral oil, 0.20 mmol). After 1.5 h the
mixture was treated with propargyl bromide (60 mL of an 80%
solution in toluene, 0.84 mmol), allowed to warm to 188C, and
then stirred at this temperature for 2 h. The reaction mixture was
then treated with NH4Cl (20 mL of a saturated aqueous solu-
tion), stirred for 5 min at 188C, and then extracted with ethyl
acetate (4 ꢁ 20 mL). The combined organic fractions were dried
(MgSO4), filtered, and concentrated under reduced pressure.
The residue thus obtained was subjected to flash chromato-
graphy (silica gel, 3/7 v/v ethyl acetate/hexane elution) to afford,
after concentration of the relevant fractions (RF 0.3 in 1/1 v/v
ethyl acetate/hexane), the title compound 29 (75 mg, 74%) as
a pale-yellow and foamy solid lacking a distinct melting
point [Found: (M þ Na)þ, 621.1511. C29H30N2O10S requires
(M þ Na)þ, 621.1519]. dH (400 MHz) 7.99 (d, J 7.6, 1H), 7.65

RESEARCH FRONT
The Pd-Catalyzed Alder–Ene Reactions of N-Protected and Propargylated 1-Amino-2-aryl-2-cyclohexenes
1675
(m, 1H), 7.59–7.55 (complex m, 2H), 7.15 (s, 1H), 6.41 (br s,
1H), 5.94 (m, 2H), 5.62 (m, 1H), 5.20 (br s, 1H), 4.20–4.00
(complex m, 2H), 3.83 (d, J 11.6, 1H), 3.78 (s, 3H), 3.74 (d, J
11.6, 1H), 3.56 (dd, J 11.6 and 1.2, 1H), 3.47 (dd, J 11.6 and 1.2,
1H), 3.08 (ddd, J 13.6, 5.2, and 2.4, 1H), 2.62 (dm, J 18.0, 1H),
2.40 (dt, J 18.0 and 2.8, 1H), 2.23 (dd, J 13.2 and 2.8, 1H), 2.15
(t, J 2.4, 1H), 1.11 (s, 3H), 0.91 (s, 3H). dC (100 MHz) 166.6,
149.9, 147.7, 146.6, 136.7, 133.5, 131.7, 131.4, 128.8, 124.1,
123.1, 110.2, 101.8, 97.2, 80.4, 72.8, 70.5, 70.4, 58.0, 52.0, 36.6,
34.4, 32.3, 30.2, 22.9, 22.4 (signals attributable to three carbons
obscured or overlapping). nmax 3290, 2954, 2870, 2251, 1718,
1544, 1505, 1486, 1436, 1367, 1252, 1167, 1126, 1036, 910,
885, 732 cmꢀ1. m/z (ESI, þve) 621 [(M þ Na)þ, 46%], 359
(100).
The residue thus obtained was subjected to flash chromato-
graphy (silica gel, 1/3 v/v ethyl acetate/hexane) to afford, after
concentration of the relevant fractions (RF 0.4 in 1/1 v/v ethyl
acetate/hexane), the title compound 31 (178 mg, 96%) as a pale-
yellow and foamy solid lacking a distinct melting point [Found:
(M þ Na)þ, 635.1683. C30H32N2O10S requires (M þ Na)þ,
635.1675]. dH (400 MHz) 7.97 (d, J 7.6, 1H), 7.63 (m, 1H),
7.58–7.52 (complex m, 2H), 7.21 (s, 1H), 6.51 (s, 1H), 5.96 (d, J
1.2, 1H), 5.95 (d, J 1.2, 1H), 5.63 (m, 1H), 5.22 (m, 1H), 4.10–
3.92 (complex m, 2H), 3.87 (d, J 11.6, 1H), 3.79 (s, 3H), 3.74 (d,
J 11.2, 1H), 3.57 (dd, J 11.6 and 1.6, 1H), 3.47 (dd, J 11.2 and
1.6, 1H), 3.03 (ddd, J 13.6, 5.6, and 2.4, 1H), 2.63 (m, 1H), 2.39
(m, 1H), 2.17 (dd, J 13.6 and 11.0, 1H), 1.62 (t, J 2.4, 3H), 1.12
(s, 3H), 0.92 (s, 3H). dC (100 MHz) 166.6 (C), 149.9 (C), 147.8
(C), 146.6 (C), 136.8 (C), 133.8 (C), 133.2 (CH), 131.5 (CH),
131.0 (CH), 128.3 (CH), 123.8 (CH), 123.2 (C), 110.5 (CH),
110.1 (CH), 101.7 (CH2), 97.1 (C), 80.6 (C), 75.2 (C), 70.4
(CH2), 70.3 (CH2), 57.9 (CH), 51.9 (CH3), 36.4 (CH2), 34.8 (C),
32.2 (CH2), 30.1 (CH2), 29.6 (C), 22.9 (CH3), 22.3 (CH3),
3.4 (CH3). nmax 2953, 2925, 2869, 1719, 1544, 1486, 1366,
1253, 1166, 1125, 1036, 887, 737 cmꢀ1. m/z (ESI, þve) 635
[(M þ Na)þ, 100%], 359 (48).
Compound 30
A magnetically stirred solution of sulfonamide 26 (100 mg,
0.20 mmol) in dry DMF (1 mL), maintained at 08C under an
atmosphere of nitrogen, was treated with sodium hydride (10 mg
of a 60% dispersion in mineral oil, 0.24 mmol). After 2 h at 08C
the reaction mixture was treated with 1-bromobut-2-yne (90 mL,
1.0 mmol), allowed to warm to 188C, and then maintained at this
temperature for 2 h. After this time the reaction mixture was
treated with NH4Cl (20 mL of a saturated aqueous solution),
stirred for 5 min at 188C, and then extracted with ethyl acetate
(4 ꢁ 20 mL). The combined organic fractions were dried
(MgSO4), filtered, and concentrated under reduced pressure
and the ensuing residue subjected to flash chromatography
(silica gel, 1/3 v/v ethyl acetate/hexane elution) to afford, after
concentration of the relevant fractions (RF 0.6 in 1/1 v/v ethyl
acetate/hexane), the title compound 30 (94 mg, 85%) as a clear,
colourless oil [Found: (M þ Na)þ, 577.1616. C28H30N2O8S
requires (M þ Na)þ, 577.1621]. dH (400 MHz) 8.02 (d, J 7.6,
1H), 7.68 (m, 1H), 7.63–7.57 (complex m, 2H), 6.55 (dd, J 8.0
and 1.6, 1H), 6.49 (d, J 8.0, 1H), 6.45 (d, J 1.6, 1H), 5.86 (d, J 1.4,
1H), 5.84 (d, J 1.4, 1H), 5.83 (m, 1H), 5.08 (m, 1H), 3.98 (dq, J
18.4 and 2.4, 1H), 3.79 (d, J 11.6, 1H), 3.70 (d, J 11.6, 1H), 3.63
(dq, J 18.4, 1H), 3.50 (dd, J 17.3 and 1.6, 1H), 3.47 (dd, J 17.3
and 1.6, 1H), 3.00 (ddd, J 13.5, 5.9, and 2.7, 1H), 2.65 (m, 1H),
2.39 (dm, J 17.9, 1H), 2.29 (dd, J 13.5 and 10.4, 1H), 1.63 (t, J
2.3, 3H), 1.08 (s, 3H), 0.92 (s, 3H). dC (100 MHz) 148.0 (C),
147.0 (C), 146.6 (C), 136.9 (C), 133.7 (C), 133.5 (C), 133.3
(CH), 131.3 (CH), 131.1 (CH), 128.3 (CH), 123.9 (CH), 120.4
(CH), 107.7 (CH), 107.5 (CH), 100.8 (CH2), 97.1 (C), 80.8 (C),
75.0 (C), 70.5 (CH2), 70.4 (CH2), 56.9 (CH), 36.1 (CH2), 34.6
(CH2), 32.7 (CH2), 30.2 (C), 22.8 (CH3), 22.3 (CH3), 3.5 (CH3).
nmax 2956, 2870, 2249, 1544, 1489, 1372, 1349, 1246, 1166,
1114, 1038, 908, 735 cmꢀ1. m/z (ESI, þve) 577 [(M þ Na)þ,
18%], 301 (100).
Compounds 32 and 37
A magnetically stirred mixture of enyne 15 (200 mg,
0.49 mmol), Pd(OAc)2 (5.5 mg, 0.024 mmol), and BBEDA
(6.4 mg, 0.027 mmol) in dry 1,2-dichloroethane (24 mL) was
heated at 568C under an atmosphere of argon for 2 h. The solvent
was then removed under reduced pressure and the residue thus
obtained was subjected to flash chromatography (silica gel, 1/9
v/v ethyl acetate/hexane elution) thereby affording two frac-
tions, A and B.
Concentration of fraction A (RF 0.2 in 1/1 v/v ethyl acetate/
hexane) gave an amorphous white solid (102 mg) that was
tentatively assigned as a ,1:1 mixture of the two diastereoiso-
meric forms of the title compound 32 (60%).
Concentration of fraction B (RF 0.5 in 1/1 v/v ethyl acetate/
hexane) gave the title compound 37 (54 mg, 26%) as colourless
crystals, mp 202–2148C (dec.) [Found: (M þ H)þ, 410.1425.
C23H23NO4S requires (M þ H)þ, 410.1426]. dH (300 MHz) 7.51
(dm, J 8.2, 2H), 7.16 (dm, J 8.2, 2H), 6.52 (dd, J 8.1 and 0.4, 1H),
6.46 (dd, J 8.1 and 1.8, 1H), 6.33 (d, J 1.8, 1H), 5.94–5.86
(complex m, 3H), 5.44 (dt, J 10.0 and 1.9, 1H), 5.15 (t, J 1.9,
1H), 4.82 (t, J 2.2, 1H), 4.19 (dt, J 14.3 and 1.9, 1H), 3.97 (dt, J
14.3 and 1.9, 1H), 3.77 (dd, J 8.2 and 3.5, 1H), 2.41 (s, 3H),
2.36–2.24 (complex m, 1H), 2.20–2.06 (complex m, 1H), 2.02–
1.89 (complex m, 1H), 1.88–1.78 (complex m, 1H). dC
(75 MHz) 149.7, 147.3, 146.2, 143.2, 137.4, 133.9, 129.8,
129.3, 127.6, 127.3, 121.2, 110.4, 108.2, 107.6, 101.0, 67.5,
55.5, 52.6, 26.0, 21.8, 21.5. nmax 2923, 1504, 1484, 1343, 1238,
1161, 1097, 1040, 934, 812, 664 cmꢀ1. m/z (ESI, þve) 432
[(M þ Na)þ, 100%], 410 [(M þ H)þ, 9], 239 (45).
Compound 31
A magnetically stirred solution of sulfonamide 27 (170 mg,
0.303 mmol) in dry DMF (1.5 mL) maintained at 08C under
an atmosphere of nitrogen was treated with sodium hydride
(15 mg of a 60% dispersion in mineral oil, 0.36 mmol). After
1 h the mixture was treated with 1-bromobut-2-yne (137 mL,
1.52 mmol), allowed to warm to 188C, and then stirred at this
temperature for 2 h. After this time the reaction mixture was
treated with NH4Cl (20 mL of a saturated aqueous solution),
stirred for 5 min at 188C, and then extracted with ethyl acetate
(4 ꢁ 20 mL). The combined organic fractions were dried
(MgSO4), filtered, and concentrated under reduced pressure.
Compounds 33 and 38
A magnetically stirred mixture of enyne 16 (100 mg,
0.23 mmol), Pd(OAc)2 (2.6 mg, 0.01 mmol), and BBEDA
(3.0 mg, 0.013 mmol) in dry 1,2-dichloroethane (5 mL) was
heated at 568C under an atmosphere of argon for 4 h. The cooled
reaction mixture was concentrated under reduced pressure and
the residue thus obtained subjected to flash chromatography
(silica gel, 3/7 v/v ethyl acetate/hexane elution) to afford two
fractions, A and B.

RESEARCH FRONT
1676
A. L. Lehmann, A. C. Willis, and M. G. Banwell
Concentration of fraction A (RF 0.3 in 2/3 v/v ethyl acetate/
hexane) gave dimer 33 (66 mg, 66%) as a white, powdery solid,
mp 42408C [Found: (M þ Na)þ, 903.1980. C44H40N4O12S2
requires (M þ Na)þ, 903.1982]. dH (400 MHz) 8.02 (dt, J 7.6
and 2.0, 1H), 7.91 (dm, J 8.0, 1H), 7.70–7.51 (complex m, 6H),
6.68–6.55 (complex m, 3H), 6.43–6.34 (complex m, 2H), 6.28
(dd, J 6.8 and 1.6, 1H), 6.11 (m, 1H), 6.00 (m, 1H), 5.88 (s, 2H),
5.84 (m, 2H), 5.45 (s, 1H), 5.27 (d, J 2.4, 1H), 5.06 (m, 1H), 4.80
(m, 1H), 4.18 (d, J 18.0, 1H), 3.86 (m, 2H), 3.59 (t, J 18.0, 1H),
2.30–2.06 (complex m, 8H), 1.87 (m, 1H), 1.76–1.59 (complex
m, 3H). dC (100 MHz) 148.1, 147.8, 147.2, 146.9, 146.6, 146.4,
136.6, 136.5, 135.9(9), 135.9(6), 134.9, 134.8(1), 134.7(6),
134.2(2), 134.1(9), 134.0, 133.9, 133.6, 133.5, 133.4(1),
133.3(6), 131.5, 131.3, 131.2, 131.1, 128.5(3), 128.4(9), 124.1
(1), 124.0(7), 123.7(3), 123.6(7), 123.2, 123.1, 120.3, 107.8,
107.7(3), 107.6(9), 107.4(5), 107.4(2), 107.3(5), 100.8(4),
100.7(7), 87.7, 82.9, 60.4, 56.2, 55.8(8), 55.8(3), 49.9, 34.7,
22.6, 30.5(3), 30.4(7), 29.3(4), 29.3(0), 25.5, 25.4, 22.6, 21.0,
20.3(4), 20.2(8), 19.5, 14.2. nmax 2938, 2906, 1543, 1503, 1488,
1438, 1371, 1351, 1244, 1222, 1162, 1125, 1038, 935, 872, 807,
737 cmꢀ1. m/z (ESI, þve) 919 [(M þ K)þ, 100%], 903 [(M þ
Na)þ, 86].
Concentration of fraction B (RF 0.6 in 2/3 v/v ethyl acetate/
hexane) gave the title compound 38 (26 mg, 26%) as a white,
crystalline solid, mp 159–1608C [Found: (M þ Na)þ, 463.0940.
C22H20N2O6S requires (M þ Na)þ, 463.0940]. dH (400 MHz)
7.61 (dd, J 8.0 and 1.6, 1H), 7.56 (td, J 7.6 and 1.2, 1H), 7.47–
7.37 (complex m, 2H), 6.63 (dd, J 7.6 and 1.6, 1H), 6.58 (d, J 1.6,
1H), 6.49 (d, J 7.6, 1H), 5.88 (d, J 1.2, 1H), 5.86 (d, J 1.2, 1H),
5.85 (m, 1H), 5.55 (dt, J 9.6 and 2.0, 1H), 5.33 (t, J 1.8, 1H), 5.03
(t, J 2.2, 1H), 4.41 (dt, J 14.4 and 2.2, 1H), 4.24 (dt, J 14.8 and
1.8, 1H), 4.19 (dd, J 10.4 and 3.8, 1H), 2.25–2.17 (complex m,
2H), 1.99 (m, 1H), 1.81 (m, 1H). dC (100 MHz) 149.0 (C), 148.1
(C), 147.4 (C), 146.3 (C), 137.3 (C), 132.8 (CH), 131.8 (C),
131.0 (CH), 129.9 (CH), 129.8 (CH), 127.1 (CH), 123.5 (CH),
120.8 (CH), 111.3 (CH), 108.1 (CH), 107.7 (CH), 101.0 (CH2),
67.3 (CH2), 55.7 (C), 52.0 (CH2), 26.7 (CH2), 22.9 (CH2). nmax
2916, 1542, 1504, 1485, 1355, 1242, 1169, 1127, 1091, 1038,
934 cmꢀ1. m/z (ESI, þve) 463 [(M þ Na)þ, 100%], 441
[(M þ H)þ, 30], 239 (65).
Compound 35
A mixture of enyne 28 (53 mg, 0.1 mmol), Pd(OAc)2 (1.1 mg,
0.005 mmol), and Ph3P (3.0 mg, 0.01 mmol) in dry benzene
(9.8 mL) was heated at 808C under an atmosphere of argon for
2 h. The reaction mixture was then cooled and concentrated
under reduced pressure and the residue thus obtained subjected
to flash chromatography (silica gel, 1/4 - 7/14 v/v ethyl
acetate/hexane gradient elution) to afford, after concentration
of the relevant fractions (RF 0.3 in 1/1 v/v ethyl acetate/hexane) a
powdery white solid (28 mg) that was tentatively assigned as
a ,1:1 mixture of the two diastereoisomeric forms of the title
compound 35 (53%).
Compound 36
A mixture of enyne 29 (29 mg, 0.05 mmol), Pd(OAc)2
(0.5 mg, 0.002 mmol), and Ph3P (1.27 mg, 0.005 mmol) in dry
benzene (5 mL) was heated at 808C under an atmosphere of
argon for 2 h. The reaction mixture was then cooled and
concentrated under reduced pressure and the residue thus
obtained subjected to flash chromatography (silica gel, 3/7 v/v
ethyl acetate/hexane elution) to afford, after concentration of the
relevant fractions (RF 0.3), a powdery white solid (21 mg) that
was tentatively assigned as a ,1:1 mixture of the two diastereo-
isomeric forms of the title compound 36 (72%).
Compound 39
A magnetically stirred mixture of enyne 18 (50 mg,
0.11 mmol), Pd(OAc)2 (7.4 mg, 0.033 mmol), and BBEDA
(7.8 mg, 0.033 mmol) in dry benzene (5.5 mL) was heated at
808C under an atmosphere of argon for 7 h. The reaction mixture
was then cooled and concentrated under reduced pressure. The
ensuing residue was subjected to flash chromatography (silica
gel, 1/3 v/v ethyl acetate/hexane elution) to afford, after con-
centration of the relevant fractions (RF 0.5 in 1/1 v/v ethyl
acetate/hexane), the title compound 39 (47 mg, 94%) as colour-
less crystals, mp 156–1618C [Found: (M þ Na)þ, 477.1096.
C23H22N2O6S requires (M þ Na)þ, 477.1096]. dH (400 MHz)
7.58 (dd, J 8.4 and 1.2, 1H), 7.53 (dd, J 8.4 and 1.6, 1H), 7.45–
7.35 (complex m, 2H), 6.58 (dd, J 8.0 and 2.0, 1H), 6.54 (d, J 2.0,
1H), 6.46 (d, J 8.0, 1H), 5.87 (d, J 1.2, 1H), 5.85 (d, J 1.2, 1H),
5.82 (m, 1H), 5.54 (dt, J 8.0 and 2.0, 1H), 5.38 (m, 1H), 4.33 (m,
1H), 4.28 (m, 1H), 4.12 (dd, J 10.6 and 3.8, 1H), 2.21–2.17
(complex m, 2H), 1.98 (m, 1H), 1.78 (m, 1H), 1.73 (d, J 6.8, 3H).
dC (100 MHz) 148.0 (C), 147.2 (C), 146.1 (C), 140.5 (C), 138.5
(C), 132.7 (CH), 132.0 (C), 131.0 (CH), 130.3 (CH), 129.9 (CH),
126.4 (CH), 123.4 (CH), 121.4 (CH), 120.9 (CH), 108.1 (CH),
107.6 (CH), 100.9 (CH2), 67.5 (CH), 55.4 (C), 49.1 (CH2), 26.6
(CH2), 23.1 (CH2), 14.6 (CH3). nmax 3025, 2918, 1543, 1504,
1484, 1435, 1372, 1354, 1239, 1166, 1127, 1039, 911, 729,
605 cmꢀ1. m/z (ESI, þve) 477 [(M þ Na)þ, 100%], 455
[(M þ H)þ, 12], 253 (18).
Compound 34
A mixture of enyne 17 (30 mg, 0.06 mmol), Pd(OAc)2
(0.7 mg, 0.003 mmol), and Ph3P (1.6 mg, 0.006 mmol) in dry
benzene (5 mL) was heated at 808C under an atmosphere of
argon for 1 h. The reaction mixture was then cooled and
concentrated under reduced pressure and the residue thus
obtained subjected to flash chromatography (silica gel, 1/3 -
2/3 v/v ethyl acetate/hexane gradient elution) to afford,
after concentration of the relevant fractions (RF 0.5 in 1/3 v/v
ethyl acetate/hexane), dimer 34 (14 mg, 47%) as a white,
powdery solid, mp 42408C [Found: (M þ Na)þ, 1019.2099.
C48H44N4O16S2 requires (M þ Na)þ, 1019.2091]. dH
(400 MHz) 7.94 (dd, J 7.6 and 2.0, 1H), 7.78 (m, 1H), 7.64–
7.48 (complex m, 4H), 7.47–7.41 (complex m, 2H), 7.19 (d, J
2.5, 1H), 6.96 (d, J 2.5, 1H), 6.60 (d, J 3.2, 1H), 6.55 (s, 0.5H),
6.48 (s, 0.5H), 6.00–5.96 (complex m, 3H), 5.03 (m, 1H), 5.89
(m, 1H), 5.81 (m, 1H), 5.59 (m, 1H), 5.32 (d, J 16.0, 1H), 5.12
(m, 1H), 4.93 (m, 1H), 4.35 (dd, J 16.0 and 3.2, 1H), 4.20–4.00
(complex m, 3H), 3.84 (s, 3/2H), 3.83 (s, 3/2H), 3.79 (s, 3/2H),
3.78 (s, 3/2H), 2.35–2.05 (complex m, 8H), 1.90 (m, 1H), 1.85
(m, 1H), 1.68 (m, 2H). m/z (ESI, þve) 1035 [(M þ K)þ, 5%],
1019 [(M þ Na)þ, 100].
Compound 40
A magnetically stirred mixture of enyne 30 (27 mg,
0.05 mmol), Pd(OAc)2 (3.3 mg, 0.015 mmol), and BBEDA
(3.5 mg, 0.015 mmol) in dry benzene (2.4 mL) was heated at
808C under an atmosphere of argon for 5 h. The cooled reaction
mixture was then concentrated under reduced pressure and the
residue thus obtained subjected to flash chromatography (silica
gel, 1/3 v/v ethyl acetate/hexane elution) to afford, after con-
centration of the appropriate fractions (RF 0.6 in 1/1 v/v ethyl
acetate/hexane), the title compound 40 (27 mg, quantitative) as a

RESEARCH FRONT
The Pd-Catalyzed Alder–Ene Reactions of N-Protected and Propargylated 1-Amino-2-aryl-2-cyclohexenes
1677
colourless solid lacking a defined melting point [Found:
(M þ Na)þ, 577.1620. C28H30N2O8S requires (M þ Na)þ,
577.1621]. dH (400 MHz) 7.48 (td, J 8.0 and 1.2, 1H), 7.44
(dd, J 8.0 and 1.2, 1H), 7.37 (dd, J 8.0 and 1.2, 1H), 7.27 (m, 1H),
6.56 (dd, J 6.4 and 2.0, 1H), 6.55 (s, 1H), 6.40 (m, 1H), 5.94 (dd,
J 10.0 and 1.6, 1H), 5.85 (d, J 1.4, 1H), 5.84 (d, J 1.4, 1H), 5.72
(d, J 10.0, 1H), 5.50 (m, 1H), 4.47 (dd, J 12.4 and 4.4, 1H), 4.35
(br s, 2H), 3.77 (d, J 11.6, 1H), 3.68 (d, J 11.2, 1H), 3.62 (dd, J
11.6 and 1.2, 1H), 3.55 (dd, J 11.2 and 1.2, 1H), 2.93 (ddd, J
12.8, 4.4, and 1.6, 1H), 1.77 (d, J 6.8, 3H), 1.67 (t, J 12.4, 1H),
1.11 (s, 3H), 0.95 (s, 3H). dC (100 MHz) 147.8 (C), 147.3 (C),
146.3 (C), 134.1 (C), 137.8 (C), 133.2 (CH), 132.5 (CH), 131.8
(C), 130.9 (CH), 129.6 (CH), 126.3 (CH), 123.3 (CH), 122.8
(CH), 120.6 (CH), 108.0 (CH), 107.7 (CH), 100.9 (CH2), 95.8
(C), 71.0 (CH2), 70.5 (CH2), 66.0 (CH), 55.6 (C), 49.1 (CH2),
34.4 (CH2), 30.1 (C), 22.9 (CH3), 22.5 (CH3), 14.7 (CH3). nmax
2956, 2869, 1545, 1484, 1372, 1357, 1238, 1166, 1096, 1039,
911, 729, 604 cmꢀ1. m/z (ESI, þve) 577 [(M þ Na)þ, 100%],
555 [(M þ H)þ, 98], 469 (35), 267 (39).
J 3.2 and 1.1, 1H), 4.67 (d, J 3.6, 1H), 4.27 (d, J 9.4, 1H), 3.71 (d,
J 9.4, 1H), 3.60–3.55 (complex m, 2H), 3.51 (d, J 11.5, 1H), 3.43
(s, 3H), 3.35 (dd, J 11.5 and 1.4, 1H), 2.56–2.48 (complex m,
2H), 2.07 (dd, J 15.6 and 4.4, 1H), 1.77 (dd, J 14.8 and 6.8, 1H),
1.50 (m, 1H), 1.11 (s, 3H), 0.83 (s, 3H). dC (100 MHz) 165.6 (C),
150.6 (C), 148.9 (C), 146.8 (C), 136.2 (CH), 134.3 (C), 133.0
(CH), 131.5 (CH), 130.8 (CH), 124.8 (C), 123.5 (CH), 113.9
(CH2), 113.4 (CH), 110.2 (CH), 101.8 (CH2), 98.5 (C), 70.3
(CH2), 69.9 (CH2), 62.9 (CH), 52.3 (CH2), 51.8 (CH3), 41.4 (C),
38.3 (C), 33.9 (CH2), 30.0 (C), 29.6 (C), 26.9 (CH2), 25.9 (CH),
22.7 (CH3), 22.3 (CH3). nmax 3084, 3064, 2952, 2926, 2856,
1725, 1545, 1505, 1488, 1374, 1353, 1254, 1170, 1131, 1103,
1038, 909, 738 cmꢀ1. m/z (ESI, þve) 635 [(M þ Na)þ, 69%],
613 [(M þ H)þ, 41], 595 (69), 426 (100).
X-ray Crystallographic Studies
Data for Compound 28
C27H28N2O8S, M 540.59, T 200 K, triclinic, space group P1,
˚
Z 2, a 10.0669(2), b 10.9365(3), c 12.8103(3) A, a 74.2505(11)8,
3
1292.00(5) A , Dx
˚
b
72.7388(12)8,
g
81.0724(17)8,
V
Compound 41
1.390 g cmꢀ3, 7544 unique data (2ymax 608), R 0.036 [for 6404
reflections with I 4 2.0s(I)]; Rw 0.095 (all data), S 1.00.
A magnetically stirred mixture of enyne 19 (86 mg,
0.168 mmol), Pd(OAc)2 (11.3 mg, 0.05 mmol), and BBEDA
(11.9 mg, 0.05 mmol) in dry toluene (8.4 mL) was heated at
1108C under an atmosphere of argon for 6 h. The reaction
mixture was then cooled and concentrated under reduced
pressure. The residue thus obtained was subjected to flash
chromatography (silica gel, 1/3 v/v ethyl acetate/hexane elution)
to afford, after concentration of the relevant fractions (RF 0.4 in
1/1 v/v ethyl acetate/hexane), the title compound 41 (47 mg,
55%) as a pale-yellow and foamy solid lacking a distinct melting
point [Found: (M þ Na)þ, 535.1151. C25H24N2O8S requires
(M þ Na)þ, 535.1151]. dH (400 MHz) 7.95 (dd, J 8.0 and 1.4,
1H), 7.63 (td, J 7.6 and 1.6, 1H), 7.56 (td, J 7.6 and 1.2, 1H), 7.52
(dd, J 8.0 and 1.6, 1H), 6.93 (s, 1H), 6.89 (s, 1H), 5.97 (d, J 1.2,
1H), 5.94 (d, J 1.2, 1H), 5.91 (ddd, J 10.0, 4.8, and 2.8, 1H), 5.26
(d, J 9.6, 1H), 4.98 (m, 1H), 4.69 (d, J 2.8, 1H), 4.34 (d, J 14.4,
1H), 4.21 (dt, J 14.4 and 2.0, 1H), 3.51 (s, 3H), 2.22–2.15
(complex m, 2H), 2.01 (m, 1H), 1.61 (m, 1H), 1.53 (d, J 6.8, 3H).
dC (100 MHz) 168.8 (C), 148.8 (C), 148.6 (C), 146.0 (C), 142.6
(C), 137.9 (C), 132.9 (CH), 131.0 (CH), 130.9 (CH), 130.8 (CH),
127.4 (CH), 125.6 (C), 123.4 (CH), 117.1 (CH), 111.5 (CH),
110.1 (CH), 101.8 (CH2), 65.4 (CH), 55.5 (C), 51.8 (CH3), 51.3
(CH2), 22.9 (CH2), 20.1 (CH2), 14.3 (CH3) (one signal obscured
or overlapping). nmax 3022, 2949, 2915, 1723, 1545, 1505, 1487,
1435, 1355, 1253, 1168, 1125, 1037, 734 cmꢀ1. m/z (ESI, þve)
535 [(M þ Na)þ, 100%], 513 [(M þ H)þ, 30], 279 (45).
Data for Compound 37
C23H23NO4S, M 409.51, T 200 K, monoclinic, space
˚
group P21/n, Z 4, a 10.1955(1), b 8.6479(1), c 22.2545(2) A,
3
b 95.5065(8)8, V 1953.12(3) A , Dx 1.393 g cmꢀ3, 4443 unique
˚
data (2ymax 558), R 0.032 [for 3604 reflections with I 4 2.0s(I)];
Rw 0.092 (all data), S 0.95.
Data for Compound 39
C23H22N2O6S, M 454.50, T 200 K, orthorhombic, space
˚
group Pbca, Z 8, a 15.3175(3), b 13.3614(2), c 21.0221(4) A,
3
V 4302.45(13) A , Dx 1.403 g cmꢀ3, 3770 unique data (2ymax
˚
508), R 0.064 [for 3070 reflections with I 4 2.0s(I)]; Rw 0.170
(all data), S 0.99.
Data for Compound 42
C30H32N2O10Sꢂ2CH2Cl2, M 782.52, T 200 K, triclinic, space
˚
group P1, Z 2, a 8.6442(2), b 14.8875(5), c 15.4877(5) A,
a
116.1546(13)8, b 101.4225(17)8, g 91.3334(17)8, V
3
1739.70(9) A , Dx 1.494 g cmꢀ3, 8004 unique data (2ymax 558),
R 0.053 [for 5959 reflections with I 4 2.0s(I)]; Rw 0.132
(all data), S 1.01.
˚
Structure Determination
Compound 42
Images were measured on a Nonius Kappa CCD diffracto-
˚
A magnetically stirred mixture of enyne 31 (91 mg,
0.15 mmol), Pd(OAc)2 (10 mg, 0.045 mmol), and BBEDA
(10.5 mg, 0.045 mmol) in dry toluene (7.4 mL) was heated at
1108C under an atmosphere of argon for 5 h and then cooled and
concentrated under reduced pressure. The residue thus obtained
was subjected to flash chromatography (silica gel, 1/3 v/v ethyl
acetate/hexane elution) to afford, after concentration of the
relevant fractions (RF 0.5 in 1/1 v/v ethyl acetate/hexane), the
title compound 42 (83 mg, 92%) as colourless crystals, mp 210–
2178C [Found: (M þ Na)þ, 635.1660. C30H32N2O10S requires
(M þ Na)þ, 635.1675]. dH (400 MHz) 8.08 (m, 1H), 7.66 (m,
2H), 7.53 (m, 1H), 7.26 (s, 1H), 7.16 (s, 1H), 5.99 (m, 2H), 5.02
(dd, J 17.4 and 10.6, 1H), 4.87 (dd, J 10.0 and 1.1, 1H), 4.83 (dd,
meter (MoKa, graphite monochromator, l 0.71073 A) and data
extracted using the DENZO package.[23] Structure solution was
by direct methods (SIR92).[24] The structure of compounds 28,
37, 39, and 42 were refined using the CRYSTALS program
package.[25] Atomic coordinates, bond lengths and angles,
and displacement parameters have been deposited at the
Cambridge Crystallographic Data Centre (CCDC nos. 790929,
790930, 790931, and 790932 for compounds 28, 37, 39,
and 42, respectively). These data can be obtained free-of-
charge via www.ccdc.cam.ac.uk/data_request/cif, by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: þ44 1223 336033.

RESEARCH FRONT
1678
A. L. Lehmann, A. C. Willis, and M. G. Banwell
Accessory Publication
(b) A. Goeke, M. Sawamura, R. Kuwano, Y. Ito, Angew. Chem. Int. Ed.
Engl. 1996, 35, 662. doi:10.1002/ANIE.199606621
(c) A. Lei, M. He, X. Zhang, J. Am. Chem. Soc. 2002, 124, 8198.
doi:10.1021/JA020052J
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The authors thank the Australian Research Council and the Institute of
Advanced Studies for generous financial support. A.L.L. is the grateful
recipient of an ANU-funded PhD Scholarship.
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