Carbenium ion trapping using sulfonamides: an acid-catalysed synthesis of pyrrolidines by intramolecular hydroamination

Article abstract of DOI:10.1016/j.tet.2010.03.107

Cyclisations of homoallylic sulfonamides proceed smoothly via carbenium ion generation using trifluoromethanesulfonic (triflic) acid, the ease of cyclisation being directly related to the ion stability to give good to excellent yields of the corresponding pyrrolidines. Both toluene- and nitrophenyl-sulfonyl groups are suitable for all substrates tested whereas the corresponding carbamates are only useful in cases of tertiary and highly stabilised carbenium ions. Polyene-derived sulfonamides can also be cyclised to the corresponding polycyclic systems in remarkably high yields, in reactions reminiscent of related cascades encountered in terpene biosynthesis.

Full text of DOI:10.1016/j.tet.2010.03.107

Tetrahedron 66 (2010) 4150–4166
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Carbenium ion trapping using sulfonamides: an acid-catalysed synthesis
of pyrrolidines by intramolecular hydroamination
*
´
Charlotte M. Griffiths-Jones (nee Haskins), David W. Knight
School of Chemistry, Cardiff University, Main College, Park Place, Cardiff CF10 3AT, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Cyclisations of homoallylic sulfonamides proceed smoothly via carbenium ion generation using
trifluoromethanesulfonic (triflic) acid, the ease of cyclisation being directly related to the ion stability to
give good to excellent yields of the corresponding pyrrolidines. Both toluene- and nitrophenyl-sulfonyl
groups are suitable for all substrates tested whereas the corresponding carbamates are only useful in
cases of tertiary and highly stabilised carbenium ions. Polyene-derived sulfonamides can also be cyclised
to the corresponding polycyclic systems in remarkably high yields, in reactions reminiscent of related
cascades encountered in terpene biosynthesis.
Received 11 January 2010
Received in revised form 12 March 2010
Accepted 29 March 2010
Available online 2 April 2010
Keywords:
Cyclisation
Hydroamination
Sulfonamides
Triflic acid
Ó 2010 Elsevier Ltd. All rights reserved.
Pyrrolidines
1. Introduction
cyclisations processes for ring closure, which can operate in a num-
ber of modes, including 5- and 6-exo as well as 5-endo examples.5
The central importance of nitrogenous compounds to the manipu-
lation of biological systems in general has meant that the development
of methods for the efficient introduction of this element into organic
compounds continues to occupy a pivotal position in synthetic meth-
odology.1 One only has to consider the impact that the Buchwald–
Hartwig and related amination reactions2 have had, especially in the
Pharmaceutical sector, since their introduction. More generally, al-
though a long established principle, new ways to carry out overall al-
kene hydroamination, the addition of the elements of nitrogen at the
amine oxidation level and hydrogen to an alkene,3 in a selective and
mild manner have come to great prominence of late, by reason of the
significant contribution that such methodology could have to this area.
In principle, one way to multiply the synthetic methods available to
prepare a selected structural featureistoreversethepolarityassociated
with to a particular functional group.4 The nucleophilicity inherent in
a typical alkene bond can be reversed, for example, by epoxidation,
which can allow it then to be attacked by various nucleophilic species.
Closely related are more transient intermediates generated by the
positioning of a halogen or selenium atom across the alkene, thereby
achieving a similar reversal of polarity and hence intramolecular attack
by a suitably positioned nucleophile such as an alcohol or attenuated
amine group. These are, of course, the very familiar halo- or seleno-
During our studies of such cyclisations,6,7 we were stimulated to
search for alternatives to both molecular iodine and selanyl halides for
a number of reasons, not the least of which were the fact that a rela-
tivelylargeexcess(3 equiv) ofiodineisrequired and general limitations
for scale up in both cases, especially when using the selenium-based
reagents, where cost and disposal become limiting considerations.
The idea to attempt to form pyrrolidines and perhaps N-heterocycles
with other ring sizes using such chemistry but with alternative acti-
vating agents for the alkene arose from two observations.
Firstly, we found that overall 5-endo-trig iodocyclisations of
homoallylic sulfonamides 1, which give very largely the 2,5-trans-
iodopyrrolidines 2 under basic conditions (Scheme 1), gave only the
corresponding 2,5-cis diastereomers 3 if the base was omitted.7 By
starting with a single enantiomer of the precursor [1; R1¼Et;
R2¼Bu], we were able to establish that formation of the latter most
likely occurs by cycloreversion of the initially formed and hence
kinetic isomers 2 back to precursor 1 and subsequent cyclisation to
I2 only
I
I
R2
NHTs
I2
I2
R2
R2
R1
K2CO3
N
N
R1
R1
[HI]
Ts
Ts
1
2
3
* Corresponding author. Tel.: þ44 2920 874210; fax: þ44 2920 874030; e-mail
Scheme 1.
address:knightdw@cf.ac.uk (D.W. Knight).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.107

C.M. Griffiths-Jones (ne´e Haskins), D.W. Knight / Tetrahedron 66 (2010) 4150–4166
4151
eventually produce only the thermodynamically more stable 2,5-
cis-isomers 3. Presumably, the trigger for this is protonation of the
trans-pyrrolidines at nitrogen by the hydrogen iodide formed as the
cyclisation proceeds and which is now not removed as no base is
present. A key implication is therefore that at least some of the
regenerated starting material 1 remains unprotonated in the
presence of this strong acid and hence is able to participate as
a nucleophile in subsequent iodocyclisations.
A second significant observation was made during extensions of
this methodology to the formation of highly substituted proline
analogues 4, which, in extreme cases, required prolonged exposure
to excess iodine in order to achieve complete conversion into the
desired iodopyrrolidines 5 (Fig. 1).8 When such cyclisations were
carried out in the absence of base, the products 5 were sometimes
accompanied by small amounts of the de-iodopyrrolidines 6. We
were unsure as to how these were formed, but reasoned that one
possibility was that direct acid-catalysed cyclisation was occurring
to a limited extent. Therefore, when we began to investigate al-
ternative electrophilic triggers for this type of cyclisation in general,
the prospects for using protons, the simplest of electrophiles, for
this purpose was one of the first to be investigated.
incomplete if less than 1 equiv of the acid was used. However, later
trials using less substituted precursors such as those derived from
cinnamyl or crotyl halides failed to produce such cyclisation prod-
ucts (see below). Other trials using acetic acid or trifluoroacetic acid
also failed to produce any cyclisation products as did hydrogen
chloride in methanol. It was only when we turned to a so-called
super acid,12 trifluoromethanesulfonic acid (triflic acid; TfOH,
CF3SO3H) that success was achieved. This then became the reagent
of choice for all subsequent experiments detailed below.
A brief optimisation study soon established that the two model
substrates 7a,b underwent very rapid and clean cyclisations to give the
hoped-for pyrrolidines 9a,b in essentially quantitative yields upon
exposure to around half an equivalent of triflic acid in ice-cold chlo-
roform for no more than 15 min. Using less acid (0.1 and 0.03 equiv)
resulted in much lower conversions under the same conditions (28%
and 8%, respectively). At a very low temperature (ꢁ78 ꢀC), no cyclisa-
tion occurred using up to 1 equiv of acid while at ꢁ40 ꢀC, conversions
into pyrrolidines 9a,b reached around 70% using 0.4 equiv of acid
during up to 6 h. We therefore adopted the initial conditions of
0.4 equiv of triflic acid in chloroform or dichloromethane at 0 ꢀC for
around 15 min as our standard protocol for this type of substrate,
which is expected to give relativelystabilised tertiarycarbenium ions 8.
We next tested the generality of this chemistry by using sub-
stituents that were somewhat less able to provide such stabilisation
of a positive charge. All these and most subsequent substrates were
synthesised using the Stork procedure featuring alkylation of the
carbanion derived from the benzaldehyde Schiff’s base of methyl
glycinate or alaninate 10 (Scheme 3).11 Yields of the intermediate
imines 11 were generally excellent when using allylic bromides;
use of the corresponding iodides was necessary in cases of less
activated, non-allylic alkenyl halides.
R4
R1
R2
I
R3
R3
R3
R1
R2
R1
R2
N
H
N
N
CO2H
CO2Me
CO2Me
Ts
Ts
4
5
6
Figure 1.
Herein, we report in full on the successful outcome of this idea
and on some of its key features. Although the initial concept of this
methodology was that it was a pyrrolidine synthesis, it can of
course also be viewed as an intramolecular hydroamination pro-
cess, as will be discussed later, in which the amine is the nucleo-
phile and the alkene in effect the electrophile.9,10
R1
R1
CO2Me
R1
CO2Me
i)
CO2Me
ii), iii)
N
N
R2
NHTs
R2
Ph
Ph
2. Results and dicussion
10 a) R1 = H
b) R1 = Me
11 a) R1 = H; R2 = Ph
b) R1 = Me; R2 = Ph
c) R1 = H; R2 = Me
d) R1 = R2 = Me
12
Our first experiments were focused not unnaturally on substrates,
which were particularly well set up to undergo such cyclisations, on
the grounds that if these could not be successfully transformed into
pyrrolidines, then the wholeideawas perhaps not aviable proposition
(Scheme 2). We therefore chose the prenyl derivatives 7, which were
readily prepared using the convenient Stork procedure (see below),11
along with the very stable p-toluenesulfonyl (tosyl) groupto attenuate
the reactivity of the amino group. Protonation of the prenyl group was
expected togive the stabilised tertiarycarbenium ions8, whichlooked
well set up to be trapped by the nearby sulfonamide group at least
some of which, as argued above, would not be protonated and hence
would be available to trap the positive ion to give the desired pyrro-
lidines 9. In addition, in the case of precursor 7b, a helpful steric
compression (‘Thorpe–Ingold’ effect) may also contribute.
Scheme 3. (i) LDA, THF, ꢁ78 ꢀC, then add alkyl halide, ꢁ78 ꢀC, 1 h then 20 ꢀC, 1 h; (ii)
1 M HCl, Et2O, 2 h, 20 ꢀC; (iii) p-TsCl, Et3N, DMAP (cat.), CH2Cl2, 20 ꢀC, 16 h.
While the subsequent acid-catalysed imine hydrolysis was simple,
we have great difficulty in obtaining decent yields of the final
N-tosylated derivatives 12, partly due to bis-tosylation.13
After some experimentation, we found conditions under which
cyclisations of all four new precursors 12a–d derived from combi-
nations of glycine and alanine, together with cinnamyl and crotyl
bromides, proceeded very smoothly to give excellent yields of the
expected pyrrolidines 13a–d. The results of these and the foregoing
experiments using the prenyl derivatives 7a,b are collected in
Table 1. These initial cyclisations followed an approximate pattern
expected from the likely carbenium ion stability [cf. ion 8] in the
sense that, while the prenyl derivatives 7a,b underwent rapid cyc-
lisation at 0 ꢀC, the cinnamyl derivatives 12a,b required reactions at
ambient temperature and the crotyl analogues 12c,d reflux tem-
perature. This would seem to roughly equate to tertiary alkyl, ben-
zylic and secondary alkyl carbenium ion stabilities. However, where
relevant (see Experimental section), the reactions shown in Table 1
were not particularly stereoselective. We have briefly examined this
feature and have obtained results, which suggest these initial
products are best regarded as kinetic mixtures (Table 2).
R
R
?
?
R
CO2Me
CO2Me
N
HN
Ts
HN
Ts
CO2Me
Ts
a; R = H;
b; R = Me
7
8
9
Scheme 2.
Initial trials met with success: when the sulfonamides 7 were
refluxed with 1 equiv of p-toluenesulfonic (tosic) acid in chloroform,
ethyl acetate or toluene, complete and reasonably clean conversions
into the hoped-for pyrrolidines 9 were observed. Temperatures in
excess of 70 ꢀC were essential with this acid; in refluxing dichloro-
methane, no cyclisation occurred. Cyclisations were generally
Firstly, the stereochemical assignments shown in Table 2 were
based upon our previous deductions made from both NMR and X-ray

4152
C.M. Griffiths-Jones (ne´e Haskins), D.W. Knight / Tetrahedron 66 (2010) 4150–4166
Table 1
Acid-catalysed cyclisations of the prenyl, cinnamyl and crotyl precursors 7a,b and 12a–d
Precursor
Product
TfOH (equiv)
Time/temp (h/ꢀC)
0.25/0
Convn
100
Yield (%)
97
CO2Me
HN
Ts
N
0.4
CO2Me
CO2Me
CO2Me
Ts
9a
7a
CO2Me
HN
Ts
N
0.4
0.6
0.25/0
4.5/25
100
100
95
95
Ts
9b
7b
Ph
CO2Me
Ph
Ph
HN
N
Ts
Ts
13a
12a
Ph
0.4
0.4
0.6
2/0
6/25
4/25
0
74
100
d
d
96
CO2Me
HN
Ts
N
CO2Me
CO2Me
Ts
13b
12b
CO2Me
HN
Ts
N
0.6
4/62
100
91
Ts
13c
12c
0.4
0.6
24/0–25
4/62
0
100
d
94
CO2Me
HN
Ts
N
CO2Me
Ts
13d
12d
Inview of the successfulcyclisations of the prenyl derivatives 7a,b,
we reasoned that it might well be possible to apply this methodology
to the synthesis of spiro-pyrrolidines, as this would also involve
highly stabilised tertiary alkyl carbenium ions related to ion 8. We
therefore prepared two representative substrates 15 and 18, using the
same Stork methodology11 (Scheme 4). The iodide 14 was necessary
to efficiently alkylate the Schiff’s base derived from alanine methyl
ester; subsequent protecting group exchange then gave the desired
precursor 15. In contrast, the bromide 17 was a sufficiently reactive
electrophile, which smoothly alkylated the corresponding glycinate
carbanion to give, after the same protecting group exchange re-
actions, the exocyclic alkene isomer, the ylidenecyclohexane de-
rivative 18. We were delighted to find that both substrates behaved in
essentially the same fashion as the prenyl derivatives 7 and led to the
hoped-for spiro-compounds16a,b inexcellentyieldsafteronlya brief
exposure to ice-cold triflic acid. In addition to this being a useful
synthetic approach to such spiro-pyrrolidines, the successful cycli-
sation of both precursors, presumably via a common tertiary carbe-
Table 2
Isomerisation characteristics of the cinnamyl derivatives 12
R
R
R
Ph
+
CO2Me
Ph
Ph
HN
Ts
12
12a
N
N
CO2Me
CO2Me
Ts
Ts
'trans'-13
'cis'-13
13a; R = H
12b
13b; R = Me
TfOH (equiv)
Time (h)
cis/trans
TfOH (equiv)
Time (h)
cis/trans
0.6
1.5
2.0
5.0
4.5
2.0
1.5
1.0
1.0:1
1.0:1
>20:1
>20:1
0.6
1.5
2.0
5.0
4.0
2.0
1.5
1.0
2.9:1
3.5:1
4.0:1
9.0:1
data of the corresponding iodocyclisation products and their deiodo
derivatives.7 As can be seen from Table 2, the key to inducing iso-
merisation towards what must be the more thermodynamically sta-
ble isomers is an increase in the amount of acid used rather than an
increase in the reaction time. In the case of the glycine derivative 12a,
the thermodynamically more stable isomer has the 2,5-cis-stereo-
chemistry, ‘cis’-13a, in which the two substituents adopt pseudoe-
quatorial positions and is formed almost exclusively when an excess
of acid is used, according to 1H NMR analysis. Similarly, isomerisation
of the pyrrolidines 13b derived from the alanine derivative 12b gave
up to a 9:1 ratio in favour of ‘cis’-13b, which may well reflect the
thermodynamically more stable ratio of the two isomers, given
the closer similarity in size of the ester and methyl groups. In terms of
the mechanismofisomerisation, therearetwopossibilitiesinthecase
of the glycine derivatives 13a, either acid-catalysed enolisation and
reprotonationor ringopeningand reclosure, triggered presumably by
protonation of the NTs group. While both could operate in the case of
the glycine derivative 13a, only the ringopening pathwaycan occur in
the case of the alanine derivative 13b, as enolisation is blocked. It
therefore seems more likely that this type of cyclisation will often
feature such ring openings on the way to the most thermodynamic
isomer, which may not be the initial major product.
CO2Me
i)
NHTs
I
[40%]
ii) [93% 16a]
14
15
R
CO2Me
N
Ts
16 a) R = Me;
b) R = H
ii) [94% 16b]
CO2Me
NHTs
i)
Br
17
18
Scheme 4. (i) As Scheme 3; (ii) 0.4 equiv TfOH, CHCl3, 0 ꢀC, 0.25 h.

C.M. Griffiths-Jones (ne´e Haskins), D.W. Knight / Tetrahedron 66 (2010) 4150–4166
4153
nium ion, gives this approach a potentially useful flexibility in the
sense that either alkene positional isomer can be used.
R
R
R
OH
O
i)
ii)
Having established the viability of this type of cyclisation, an
immediate concern was the compatibility of this methodology with
substrates containing acid-sensitive functional groups. As a small
contribution to this aspect, we were fortunate to find that reduction
of the hindered ester 7b derived from alanine gave a separable
mixture of the aldehyde 19 and the alcohol 20 (Scheme 5), both of
which were exposed to triflic acid.
Br
24
25
26
PhSO2
a) R = CH2CH2SO2Ph
b) R = CH2CH:CH2
iii)
CO2Me
N
i)
Ts
iv)
iv)
+
R
CO2Me
NHTs
CO2Me
CHO
HN
Ts
7b
HN
Ts
19
HN
Ts
20
28a
OH
27
Scheme 5. (i) 1 M Diisobutylaluminium hydride in ether, ꢁ78 ꢀC, 4.5 h (39% and 50%).
CO2Me
The aldehyde 19 underwent smooth cyclisation to give the corre-
spondingpyrrolidine21 inexcellentyield(Scheme6). Wesuggestthat
this successful cyclisation will be limited to examples such as this,
N
Ts
28b
which do not have a proton
not even synthesise aldehyde precursors related to compound 7b,
which did not have such an -substituent. The approximately 1:1
a to the aldehyde group. Indeed, we could
Scheme 7. (i) 1 M CH2]CHMgBr in THF, ꢁ78 ꢀC/20 ꢀC, w75–85%; (ii) PBr3, pyridine
0
ꢀC; (iii) as Scheme 3; (iv) 0.1–0.3 equiv TfOH, CHCl3, 0 ꢀC, 0.25 h (64–72%).
a
mixture of products 22 and 23 obtained from the alcohol 20 must
reflect a similar reactivity in both nucleophiles, which is presumably
composed of both their inherent nucleophilicity and the strength of
the X–H bond, which is cleaved, i.e., their pKa values.14 Once again, we
speculate that this type of cyclisation will be limited to such highly
substituted examples, which do not allow simple alcohol dehydration
to occur. Althoughnot attempted during thepresentproject, itmay be
possibletoprotectthehydroxylgroupinsuchprecursors, forexample,
by acetate formation as ester groups are stable to the present acidic
conditions (Table 1), and thereby favouring pyrrolidine formation.
us very well, being able to prevent complete protonation of the amine
group as well as proving to be perfectly stable to the acidic conditions.
However, thisverystability wasa causeforconcern, as it was likelyto be
a difficult group to remove. Although there are many methods known
for achieving detosylation,15 in our hands such reactions of represen-
tative pyrrolidines obtained during this project were not very efficient.
This led us to test an alternative strategy that of using one of the three
nitrophenylsulfonyl (nosyl) derivatives introduced by the Fukuyama
group, which are so much easier to remove by ipso attack of a thiolate
under very mild conditions.16 However, the reduced nucleophilicity of
the protonated nitrogen was a concern as was their overall stability to
the acidic conditions. Such concerns proved unfounded whenwe found
that all three such derivatives 29a–c of alanine alkylated by a prenyl
group, underwent very smooth and efficient cyclisations to provide the
nosyl pyrrolidines 30a–c, when exposed tothe mildest setof conditions
employed in this study: 0.5 equiv of triflic acid in ice-cold chloroform
for 0.25 h. The results are collected in Table 3.10
i)
CHO
HN
Ts
N
CHO
Ts
19
21
i)
+
NHTs
N
HN
Ts
20
CHO
O
Ts
OH
Table 3
22
23
Acid-catalysed cyclisation of nitrophenylsulfonyl (nosyl) derivatives
Scheme 6. (i) 0.4 equiv TfOH, CHCl3, 0 ꢀC, 0.25 h [21: 87%; 22: 45%; 23: 45%].
CO2Me
HN
SO2
N
CO2Me
We alsowished to demonstrate that some other useful functional
groups beyond carboxylic acid esters (see Table 1) were compatible
with this highly acidic methodology. To this end, we prepared the
functionalised amino-ester precursors 27 using a similar approach
for both compounds, starting with the corresponding 2-phenyl-
sulfonylethyl- or 2-allyl-cyclohexanone 24 (Scheme 7). Each was
condensed with vinylmagnesium bromide followed by brominative
rearrangement of the resulting tertiary alcohols 25 to give the allylic
bromides 26, which were then used to alkylate the Schiff base 10a
derived from glycine.11 We were delighted to find that both of the
resulting substrates 27, obtained using the usual protecting group
exchange, underwent smooth cyclisation to give the hoped-for
spiro-pyrrolidines upon exposure to sub-stoichiometric amounts
of triflic acid in ice-cold chloroform. Unoptimised isolated yields
were in the region of 70%. Both products 28 were isolated as 2–3:1
mixtures of only two diastereomers whose structures were tenta-
tively assigned on steric grounds, arising from approach of the in-
coming sulfonamide nucleophile to the intermediate carbenium ion
transtothe ring substituent, leaving a mixtureat the carboxylic ester
centre. Further studies will be necessary to confirm this.
SO2
R
R
29
30
R
TfOH (equiv)
Temp (ꢀC)
Time (h)
Yield 30
(a) 2-NO2
(b) 4-NO2
(c) 2,4-Di-NO2
0.5
0.5
0.6
0
0
0
0.25
0.25
0.25
89
87
87
CO2Me
+
CO2Me
CO2Me
HN
SO2
N
N
SO2
SO2
R
R
R
31
cis-32
trans-32
R
TfOH (equiv)
Temp (ꢀC)
Time (h)
Yield 32 (cis/trans)
(a) 2-NO2
(b) 4-NO2
(c) 2,4-Di-NO2
1.0
1.0
1.4
62
62
62
4
4
4
86 (3:1)
86 (3:1)
83 (3:1)
Another aspect that we were anxious to address was the nature of
the nitrogen protecting group. Clearly the tosylated function had served

4154
C.M. Griffiths-Jones (ne´e Haskins), D.W. Knight / Tetrahedron 66 (2010) 4150–4166
Overall, there was surprisingly little difference between the
39 were obtained with undiminished levels of optical activity
(Scheme 10). Similar methodology has also been applied success-
fully to examples of spiro-pyrrolidine synthesis, in much the same
fashion as shown in Schemes 4 and 7, but again with carbonyl
rather than sulfonyl groups protecting the amine function.18
tosyl and nosyl derivatives 29, all of which cyclised under much the
same conditions; the returns from the nosyl derivatives were
slightly lower and the 2,4-dinitro derivatives in particular respon-
ded slightly better when a little more triflic acid was used. Of
course, the substrates 29 are the most easily cyclised and so we also
tested the suitability of the nosyl groups in cyclisations of the
corresponding crotyl derivatives, which are amongst the most
difficult to cyclise, requiring relatively prolonged refluxing in
chloroform to achieve complete conversions.
i)
ii)
H
H
H
CO2Me
N
HN
N
CO2Me
CO2H
.HCl
H
O
O
37
39
38
Once again, the results (Table 3) from these cyclisations were
very comparable with those found for the related tosyl compounds;
again, yields using the nosyl precursors were marginally lower but
otherwise the overall outcomes were very similar. In terms of
product stereochemistry, this too was similar in that there was
a distinct preference for formation of the cis-diastereomers (see
Table 2). Perhaps all of these results reflect a balance between the
lower nucleophilicity of the nitrophenylsulfonyl groups and their
lower pKa values relative to the toluenesulfonyl group; the latter
feature would facilitate the cyclisations on the assumption that
N–H bond cleavage is a rate-determining step. In contrast, we found
that carbamate derivatives were much less suited to this type of
cyclisation. Again we first examined the prenyl derivative 33 of
alanine now modified by a relatively acid-stable methoxycarbonyl
function on nitrogen, as this was the most likely to undergo smooth
cyclisation. However, this did not cyclise at ice temperature and
only gave the anticipated pyrrolidine 34 in our hands in 69% yield
when exposed to 2 equiv of triflic acid at ambient temperature.
As these were not the most extreme conditions, we pursued the
use of this carbamate group by attempting to cyclise both the cin-
namyl and crotyl derivatives 35, but neither of these led to the
formation of pyrrolidines 36, even after very prolonged exposure to
excess acid in refluxing chloroform (Scheme 9).
Scheme 10. (i) 1 M HCl, reflux, 1.5 h (60%); (ii) 20% TfOH, toluene, 100 ꢀC, 4 h (96%).
Repositioning the carbonyl group of such derivatives on the ‘inside’
of the precursor, as in N-aryl-4-pentenamides, has also been shown
to be a viable and highly efficient tactic in a new approach to 2-
pyrrolidinones but which requires rather brutal conditions (1 equiv
TfOH, toluene, 100 ꢀC, 5–30 h), reflecting the requirement for the
generation of a secondary carbenium ion, at least in the examples
reported.10 Remarkably, an isolated but efficient example of an
acid-catalysed intramolecular cyclisation of an isoxazolone, effec-
tively an O-acyl hydroxylamine, onto a tertiary carbenium ion has
been reported, although the fact that the nitrogen atom can also be
regarded as being part of a vinylogous amide probably means it has
considerable similarity to the foregoing examples.14
The seemingly clear intermediacy of carbenium ions in these
types of cyclisation stimulated the thought that suitably placed
sulfonamide groups could act as terminators to polyene cascade
cyclisations, especially when the latter were similar to those en-
countered in terpene biosynthesis or related biomimetic synthe-
ses.19 Fortunately, this idea was relatively easy to test: using the
Stork method (Scheme 3),11 both Schiff’s bases 10a,b were smoothly
alkylated using geranyl bromide 40; following protecting group
exchange, the first two test substrates 41a,b were readily obtained
(Scheme 11).
i)
CO2Me
CO2Me
33
N
HN
CO2Me
CO2Me
34
i)
R
CO2Me
Scheme 8. (i) 2.0 equiv TfOH, CHCl3, 25 ꢀC, 2 h (69%).
Br
NHTs
40
41
a) R = H;
b) R = Me.
i)
R
CO2Me
R
CO2Me
HN
CO2Me
35
N
H
R
CO2Me
R = Ph, Me
CO2Me
R
ii)
36
CO2Me
NHTs
N
Scheme 9. (i) 1.0–2.0 equiv TfOH, CHCl3, 62 ꢀC, 24 h (0%).
Ts
43
42
Scheme 11. (i) As Scheme 3, using Schiff’s bases 10a and 10b; (ii) 0.4 equiv TfOH,
CHCl3, 0 ꢀC, 0.25 h (w90%).
It would therefore appear that the inclusion of sulfonyl groups is
generally necessary for achieving this type of cyclisation, with the
exception of very acid-stable carbamates (NHCO2Me or acet-
amides) but only when the intermediate is a relatively favoured
tertiary carbenium ion. The conversion of the prenyl derivative 33
into the pyrrolidines 34 (Scheme 8) is not strictly an original ob-
servation, as a very closely related conversion has recently been
reported by Jackson et al. for the synthesis of 5,5-dimethylproline
38 from the acetylated precursor 37 (Scheme 10).17 Quite forcing
conditions were used to obtain the free acid 38 directly, while ex-
posure to the much more vigorous conditions of triflic acid in hot
toluene initially introduced by Schlummer and Hartwig10 gave an
excellent return of the fully protected proline derivative 39. An
additional and significant finding made by the Jackson group dur-
ing this study is that the stereogenic centre adjacent to the ester
group is not scrambled during such acid-induced cyclisations, de-
spite the more demanding conditions used; both products 38 and
We were delighted and even surprised to find that both sub-
strates 42a,b were very readily transformed into the octahy-
droindoles 43a,b using the mildest set of conditions, both in
excellent yields and as 3:1 and 3:2 mixtures of diastereomers, re-
spectively. Evidence for these complete cyclisations came from 1H
NMR analysis, which showed the complete disappearance of the
two olefinic protons in precursors 42 and distinct upfield shifts of
the three aliphatic methyl groups, together with separation of
many of the high field protons into much more complex patterns,
suggestive of cyclic structures. While all other spectroscopic and
analytical data also supported the proposed structures 43a,b, we
were fortunate to be able to separate a sample of the major di-
astereoisomer 43a.maj derived from glycine, which showed a key
NOE enhancement between the proton
a to the ester group and the
methyl group at the new ring junction suggestive of conformation

C.M. Griffiths-Jones (ne´e Haskins), D.W. Knight / Tetrahedron 66 (2010) 4150–4166
4155
44. Presumably, the isomer ratio is a balance of A1,3 strain between
the ester group and the ring junction proton when the former is
axial as shown (45) and steric repulsion between the ester and tosyl
groups if the former is equatorial. Evidently, the axial ester position
is favoured in this substrate and most likely also in the product 43b
derived from alanine where the 3:2 ratio probably reflects the
closer size similarity of the ester and methyl groups. The close
similarity of the spectroscopic data supports these structural as-
signments (Fig. 2).
successful cascades, although the complexity of the spectra in
which all resonances except those associated with the ester and
tosyl functions appeared above dH 2.20 provided neither structural
proof nor definite isomer ratios. The most compelling evidence for
the structures 51a,b came from very detailed analyses of the mass
spectrometric fragmentation patterns and comparisons of these
with those displayed by the lower homologues 43a,b and 48a,b, the
full details of which have been published elsewhere.21 Clearly,
although arguably probably correct, this possible approach to the
azasteroid skeleton requires more optimisation, especially to try
and control the stereoselectivity as well as to carry out separation
and more complete characterisation of those isomers, which
are formed.
H
H
CO2Me
H
H
N
CO2Me
CO2Me
N
NHTs
Ts
Ts
H
44
45
43a.maj
3. Conclusions
Figure 2. Likely three-dimensional shape 44 of the major diastereoisomer 43a.maj
derived from geranyl bromide and glycine and a likely transition state conformation 45.
In conclusion, we suggest that this type of acid-catalysed
intramolecular hydroamination will provide a valuable method
for the synthesis of many substituted pyrrolidines in a very rapid
and efficient manner. Of course, there will be limitations, especially
associated with the presence of acid-sensitive functionalities. Cur-
rent efforts are aimed at a much fuller definition of exactly what
these are. For example, it is assumed that all acid-labile alcohol
protecting groups will probably not survive the present acidic
conditions, but this may not be entirely true. In addition, triflic acid
is not a particularly attractive reagent, is expensive and very hy-
groscopic and hence requires very careful handling. Many of the
conditions reported herein are considerably milder than those used
by Schlummer and Hartwig for inducing very similar cyclisations,
specifically heating in toluene at 100 ꢀC for a number of hours.10
Mostly, their examples consisted of cyclisations of sulfonamides
onto benzylic carbenium ions unassisted by any substituents on the
connecting chain, whereas all of the present substrates carry at
least one, usually an ester group, which will provide assistance to
the cyclisations by adding some steric compression. However, the
difference between around an hour at ambient temperature and
a few hours at 100 ꢀC of otherwise relatively similar benzylic car-
benium ions is considerable, even though the present cases are
triggered by 40 mol % triflic acid, twice as much as was used in the
Schlummer–Hartwig cases. In contrast and in line with the results
published by Schlummer and Hartwig,10 we have very recently
examined the effectiveness of using concentrated sulfuric acid in its
place. Preliminary findings suggest this may be a great improve-
ment, obviating most if not all of the foregoing drawbacks associ-
ated with triflic acid. For example, a 2–3 M mixture of concentrated
H2SO4 in dichloromethane is successful in cyclising the ‘favourable’
substrates 7a,b (Scheme 2) at ice temperature with only a slight
increase in reaction time; use of this reagent in such cases certainly
does not require the much more brutal conditions of prolonged
reflux in toluene as originally reported.10,17 Subsequent to these
initial reports of acid-catalysed intramolecular hydroamination,
a number of groups have defined conditions for related acid-
catalysed intermolecular hydroaminations of alkenes and
alkynes.3,22,23
In no experiment did we observe any intermediate(s) arising
from cyclisation onto only the central alkene group.20 It would
therefore seem that protonation takes place entirely at the distal
alkene leading to complete cyclisation to the bicyclic systems 43.
We then focussed on the more extended farnesyl derivatives
47a,b, which were prepared in exactly the same manner from (E,E)-
farnesyl bromide 46 (Scheme 12). This too underwent very smooth
conversion into the completely cyclised tricyclic products 48a,b
under the mildest set of conditions and were both isolated as
3:3:1:1 mixtures of four stereoisomers in approximately 85% yields.
The isomer ratios were determined from integrations of the methyl
ester resonances in the 1H NMR spectra. Although not proven, we
speculate that there is a similar 3:1 ratio of epimers at the ester site,
which then suggests that both trans- and cis-ring fusion were
formed as shown, given the outcomes of such cyclisations of the
related geranyl derivatives 42.
Ts
N
NHTs
R
R
i)
ii)
H
CO2Me
CO2Me
H
Br
a) R = H;
b) R = Me
46
47
48
Scheme 12. (i) and (ii) as Scheme 11 (85%).
In view of this success, we then went one step further and
attempted to cyclise the geranylgeranyl derivatives 50, again de-
rived from the corresponding bromide 49, prepared from natural
geranylgeraniol. We were delighted to observe that, under the
same set of conditions as those used in the foregoing cascades, the
substrates 50a,b were rapidly transformed into what appeared to
be the azasteroid derivatives 51a,b in 80% and 83% yields, re-
spectively (Scheme 13). The proposed structures 51 are somewhat
tentative. The complete disappearance of all olefinic resonances in
the 1H NMR spectra of the products provided good indications of
In an interesting caveat to the present work, Mun˜oz and Lloyd-
Jones have very recently reported that triflic acid is capable of in-
ducing dealkylative lactonisation in the formation of butyrolactones
54 from the unsaturated esters 52 and have even observed the
oxonium intermediates 53 during 1H NMR analysis (Scheme 14).24
NHTs
R
i)
CO2Me
Br
a) R = H;
b) R = Me
ii)
49
50
Ts
N
R
R
R
R
CO2Me
OTf
CO2Me
+ MeOTf
O
CO2Me
O
CO2Me
i)
O
O
O
O
51
52
53
54
Scheme 14. (i) 2.TfOH, CHCl3, 20 ꢀC, 24 h (79%; 1.7:1 ratio of diastereomers).
Scheme 13. (i) and (ii) as Scheme 11 (80–83%).

4156
C.M. Griffiths-Jones (ne´e Haskins), D.W. Knight / Tetrahedron 66 (2010) 4150–4166
Evidently, in our examples, the sulfonamide group is much the more
reactive with the initially formed carbenium ion as, in no cases, did
wedetectanylactone formation. However, this may notbe the case if
alternative esters, such as benzyl or 4-methoxybenzyl were used,
which are much more reactive in a dealkylative sense.
This ability of the sulfonyl group to prevent complete pro-
tonation of the sulfonamides and hence allow cyclisation to occur,
or at least to provide crucial assistance to proton transfer onto the
alkene,10 echoes the only other commonly encountered reaction
wherein a nitrogen atom retains its nucleophilicity under acidic
conditions, the Ritter reaction, which even today continues to at-
tract attention, applications and further developments.25
vacuum at 0.1 mmHg to leave the imine 10a (20.1 g, 95%) as a yellow
oil. dH (400 MHz, CDCl3) 8.22 (s, 1H, N]CH), 7.72–7.69 (m, 2H),
7.36–7.33 (m, 3H), 4.36 (s, 2H, CH2), 3.70 (s, 3H, OMe).11
4.2.2. Methyl 2-(benzylideneamino)propanoate (10b). By the same
procedure, reaction between alanine methyl ester hydrochloride
(5.0 g, 36 mmol) and benzaldehyde (3.64 mL, 36 mmol) in
dichloromethane (70 mL) gave the imine 10b (6.6 g, 98%) also as
a yellow oil. dH (400 MHz, CDCl3) 8.25 (s, 1H, N]CH), 7.79–7.76 (m,
2H), 7.38–7.36 (m, 3H), 4.11 (q, J¼6.8 Hz, 1H, H2), 3.67 (s, 3H, OMe),
1.45 (d, J¼6.8 Hz, 3-Me).
4.2.3. General procedure A: synthesis of unsaturated p-toluene-
sulfonamides (7, 12, etc.)11. Lithium diisopropylamide was prepared
by the dropwise addition of butyl lithium (1.2 equiv of a 2.5 M solu-
tion in hexanes) to a solution of diisopropylamine (1.2 equiv) in tet-
rahydrofuran (2 mL mmolꢁ1 ofdiisopropylamine) maintained at0 ꢀC.
After 0.5 h, the solution was cooled to ꢁ78 ꢀC. A solution of an
N-(benzylideneamino) ester 10 (1.0 equiv) in tetrahydrofuran
(2 mL mmolꢁ1) was added dropwise by syringe and the resulting
deep red solution stirred for 0.5 h at ꢁ78 ꢀC. An allylic bromide or
alkenyl iodide (1.1 equiv) in tetrahydrofuran (1 mL mmolꢁ1) was
then added dropwise and the resulting solution stirred at ꢁ78 ꢀC
for 1 h, after which the now orange solution was allowed to warm
to ambient temperature, stirred for an additional 1 h then
quenched by the addition of saturated aqueous ammonium chlo-
ride (4 mL mmolꢁ1) and diluted with ether (2 mL mmolꢁ1). The
layers were separated and the aqueous layer extracted with ether
(3ꢂ4 mL mmolꢁ1). The combined organic solutions were dried,
filtered and evaporated to leave the imine 11, together with
varying amounts of the hydrolysis products, the corresponding
free amine and benzaldehyde.
4. Experimental section
4.1. General remarks
NMR spectra were recorded using a Bruker DPX spectrometer
operating at 400 MHz for 1H spectra and at 100.6 MHz for 13C
spectra, respectively. Unless stated otherwise, NMR spectra were
measured using dilute solutions in deuteriochloroform. All NMR
measurements were carried out at 30 ꢀC and chemical shifts are
reported as parts per million on the delta scale downfield from
tetramethylsilane (TMS:
d
¼0.00) or relative to the resonances of
CHCl3
(dH¼7.27 in proton spectra and dC¼77.0 ppm for the central
line of the triplet in carbon spectra, respectively). Coupling con-
stants (J) are reported in hertz. Infrared spectra were recorded as
thin films on sodium chloride plates for liquids and as KBr disks for
solids, using a Perkin–Elmer 1600 series FTIR spectrophotometer
and sodium chloride plates. Low resolution mass spectra were
obtained using a VG Platform II Quadrupole spectrometer operating
in the electron impact (EI; 70 eV) or atmospheric pressure chemical
ionisation (ApcI) modes, as stated. High resolution mass spectro-
metric data was obtained from the EPSRC Mass Spectrometry Ser-
vice, University College, Swansea, using the electrospray ionisation
(ES) mode unless otherwise stated. Melting points were de-
termined using a Kofler hot stage apparatus and are uncorrected.
Elemental analyses were obtained using a Perkin Elmer 240C Ele-
mental Microanalyser.
Following brief characterisation by 1H NMR, the crude imine 11
(1 equiv) was dissolved in ether (8 mL mmolꢁ1) and 1 M hydro-
chloric acid (8 mL mmolꢁ1) was added slowly to the resulting so-
lution. The two-phase mixture was stirred vigorously at ambient
temperature until TLC monitoring indicated complete hydrolysis of
the imine (ca. 2 h). The organic layer was separated and discarded
and the aqueous layer washed with ether (2ꢂ8 mL mmolꢁ1), then
adjusted to pH 9 using 2 M aqueous sodium hydroxide and
extracted with dichloromethane (3ꢂ4 mL mmolꢁ1). The combined
extracts were dried, filtered and evaporated to leave the crude
amine. After weighing, this was dissolved in dichloromethane
(5 mL mmolꢁ1) at ambient temperature and treated with p-tolue-
nesulfonyl chloride (1.2 equiv), triethylamine (1.2 equiv) and a few
crystals of 4-(dimethylamino)pyridine. The resulting solution was
stirred overnight at ambient temperature then quenched by the
addition of 2 M hydrochloric acid (4 mL mmolꢁ1) and the phases
separated. The aqueous phase was further extracted with
dichloromethane (2ꢂ4 mL mmolꢁ1) and the combined dichloro-
methane extracts washed with brine, then dried, filtered and
evaporated. The residue was either separated by column chroma-
tography (EtOAc/petrol mixtures) or purified by crystallisation from
ethyl acetate/hexanes mixtures to give the sulfonamides 12.
All reactions were conducted in oven-dried apparatus under an
atmosphere of dry nitrogen unless otherwise stated. All organic
solutions from aqueous work-ups were dried by brief exposure to
dried magnesium sulfate, followed by gravity filtration. The result-
ing dried solutions were evaporated using a Bu¨chi rotary evaporator
under water aspirator pressure and at ambient temperature unless
otherwise stated. Column chromatography was carried out using
Merck Silica Gel 60 (230–400 mesh). TLC analyses were carried out
using Merck silica gel 60 F254 pre-coated, aluminium-backed plates,
which were visualised using ultraviolet light or potassium per-
manganate or ammonium molybdenate sprays.
Ether refers to diethyl ether and petrol to the fraction boiling
60–80 ꢀC unless stated otherwise.
4.2. Precursor synthesis
4.2.1. Methyl (benzylideneamino)acetate (10a). Glycine methyl es-
ter hydrochloride (15.0 g, 120 mmol) and dried magnesium sulfate
(14.0 g) were stirred together in dry dichloromethane (200 mL) at
ambient temperature for 20 min then benzaldehyde (12.1 mL,
120 mmol) and dry triethylamine (26.8 mL, 220 mmol) were added
sequentially and dropwise. The resulting mixture was stirred for
30 h at the same temperature then filtered and the solvent evap-
orated. The residue was dissolved in ether (100 mL) and water
(100 mL) and the separated aqueous layer extracted with ether
(2ꢂ100 mL). The combined ether solutions were washed with brine
then dried, filtered and evaporated and finally dried under high
4.2.4. Methyl 5-methyl-2-(p-toluenesulfonylamino)hex-4-enoate (7a).
Methyl 2-(benzylideneamino)-acetate 10a (4.00 g, 23 mmol) was
alkylated using prenyl bromide according to general procedure A to
give the imine 11a: dH (400 MHz, CDCl3) 8.12 (s,1H, N]CH), 7.68–7.65
(m, 2H), 7.33–7.31 (m, 3H), 5.00 (t, J¼7.5 Hz, 1H, H4), 3.89–3.87 (m,
1H, H2), 3.68 (s, 3H, OMe), 2.64 (ddd, J¼14.8, 7.5, 6.4 Hz, 1H, H3a), 2.47
(ddd, J¼14.8, 7.5, 6.4 Hz, 1H, H3b), 1.59 (s, 3H), 1.50 (s, 3H).
This was hydrolysed and tosylated to give the sulfonamide 7a
(2.60 g, 38%) as a colourless, crystalline solid, mp 97–99 ꢀC; Rf 0.43
(40% EtOAc/petrol); C15H21NO4S: calcd C 57.9, H 6.8, N 4.5; found: C
57.8, H 6.6, N 4.7%; dH (400 MHz, CDCl3) 7.65 (d, J¼8.2 Hz, 2H,

C.M. Griffiths-Jones (ne´e Haskins), D.W. Knight / Tetrahedron 66 (2010) 4150–4166
4157
2ꢂArH), 7.20 (d, J¼8.2 Hz, 2H, 2ꢂArH), 5.06 (d, J¼8.6 Hz, 1H, NH),
4.86 (t, J¼7.3 Hz, H4), 3.89 (td, 9.4, 8.6 Hz,1H, H2), 3.44 (s, 3H, OMe),
2.38–2.35 (m, 2H, 3-CH2), 2.36 (s, 3H, ArMe), 1.51 (s, 3H), 1.40 (s,
3H); dC (100.6 MHz, CDCl3) 173.4 (CO), 143.4 (s), 139.6 (s), 139.0 (5-
C), 129.7 (4-CH), 128.0 (2ꢂd), 126.3 (2ꢂd), 117.3 (5-CH), 67.3 (2-CH),
52.5 (OMe), 41.4 (3-CH2), 29.3 (q), 28.2 (q), 27.7 (q); nmax (KBr)/cmꢁ1
3253, 3241, 1734, 1430, 1328, 1254; HRMS: m/z: calcd for
C15H22NO4S: 312.1270; found: 312.1261 [MþH]þ.
1598, 1421, 1370; HRMS: m/z: calcd for C20H24NO4S: 374.1426;
found: 374.1428 [MþH]þ.
4.2.8. Methyl (E)-2-(p-toluenesulfonylamino)hex-4-enoate (12c).
Methyl 2-(benzylideneamino)acetate 10a (1.50 g, 8.5 mmol) was
alkylated using crotyl bromide according to general procedure A
to give the imine 11c: dH (400 MHz, CDCl3) 8.12 (s, 1H, N]CH),
7.67–7.65 (m, 2H), 7.37–7.36 (m, 3H), 5.46 (dq, J¼14.3, 6.2 Hz, 1H,
H5), 5.18 (dt, J¼14.3, 7.6 Hz, 1H, H4), 3.92–3.90 (m, 1H, H2), 3.64 (s,
3H, OMe), 2.64–2.58 (m, 2H, 3-CH2), 1.59 (d, J¼6.2 Hz, 3H, 5-Me).
This was hydrolysed and tosylated to give the sulfonamide 12c
(1.10 g, 51%) as a colourless, crystalline solid, mp 68–70 ꢀC; Rf 0.33
(25% EtOAc/petrol); C14H19NO4S: calcd C 56.6, H 6.4, N 4.7; found: C
56.5, H 6.3, N 4.9%; dH (400 MHz, CDCl3) 7.68 (d, J¼8.2 Hz, 2H, 2ꢂArH),
7.28 (d, J¼8.2 Hz, 2H, 2ꢂArH), 5.45 (dq, J¼15.2, 6.5 Hz, 1H, H5), 5.18
(ddd, J¼15.2, 7.2, 7.0 Hz,1H, H4), 5.10 (d, J¼8.8 Hz,1H, NH), 3.97–3.96
(m,1H, H2), 3.53 (s, 3H, OMe), 2.39 (s, 3H, ArMe), 2.37–2.32 (m, 2H, 3-
CH2), 1.62 (d, J¼6.5 Hz, 3H, 5-Me); dC (100.6 MHz, CDCl3) 172.1 (CO),
143.7 (s), 137.1 (s), 136.3 (4(5)-CH), 129.4 (2ꢂd), 127.7 (2ꢂd), 122.4
(5(4)-CH), 57.5(2-CH), 52.6(OMe), 38.4(3-CH2),22.3(q),19.7(q);nmax
(KBr)/cmꢁ1 3261, 2955, 1743, 1431, 1331; HRMS: m/z: calcd for
C14H20NO4S: 298.1113; found: 298.1109 [MþH]þ.
4.2.5. Methyl 2,5-dimethyl-2-(p-toluenesulfonylamino)hex-4-enoate
(7b). Methyl
2-(benzylideneamino)-propanoate
10b
(3.80 g,
20 mmol) was alkylated using prenyl bromide according to general
procedure A to give the expected imine:dH (400 MHz, CDCl3)8.15(s,1H,
N]CH), 7.69–7.67 (m, 2H), 7.36–7.34 (m, 3H), 5.03 (t, J¼7.5 Hz,1H, H4),
3.65 (s, 3H, OMe), 2.58–2.55 (m, 2H, 3-CH2),1.61 (s, 3H),1.54 (s, 3H),1.40
(s, 3H).
This was hydrolysed and tosylated to give the sulfonamide 7b
(2.40 g, 38%) as a colourless, crystalline solid, mp 84–87 ꢀC; Rf 0.45
(40% EtOAc/petrol); C16H23NO4S: calcd C 59.1, H 7.1, N 4.3; found: C
59.3, H 7.1, N 4.6%; dH (400 MHz, CDCl3) 7.67 (d, J¼8.2 Hz, 2H,
2ꢂArH), 7.19 (d, J¼8.2 Hz, 2H, 2ꢂArH), 5.30 (br s, 1H, NH), 4.84 (t,
J¼7.8 Hz, H4), 3.52 (s, 3H, OMe), 2.32 (dd, J¼14.4, 7.8 Hz, 1H, H3a),
2.49 (dd, J¼14.4, 7.8 Hz, 1H, H3b), 2.32 (s, 3H, ArMe), 1.58 (s, 3H),
1.50 (s, 3H), 1.32 (s, 3H); dC (100.6 MHz, CDCl3) 174.1 (CO), 143.5 (s),
139.9 (s), 137.4 (5-C), 129.8 (2ꢂd), 127.4 (2ꢂd), 117.1 (4-CH), 62.6 (2-
C), 53.0 (OMe), 39.1 (3-CH2), 26.4 (q), 21.9 (q), 21.4 (q), 14.6 (q); nmax
(KBr)/cmꢁ1 3253, 2942, 1733, 1463, 1377; HRMS: m/z: calcd for
C16H24NO4S: 326.1426; found: 326.1421 [MþH]þ.
4.2.9. Methyl (E)-2-methyl-2-(p-toluenesulfonylamino)hex-4-enoate
(12d). Methyl 2-(benzylideneamino)propanoate 10b (3.80 g,20 mmol)
was alkylated using crotyl bromide according to general procedure
A to give the imine 11d: dH (400 MHz, CDCl3) 8.11 (s, 1H, N]CH),
7.67–7.64 (m, 2H), 7.40–7.38 (m, 3H), 5.41 (dq, J¼13.5, 6.5 Hz, 1H,
H5), 5.23 (ddd, J¼13.5, 7.6, 7.1 Hz, 1H, H4), 3.61 (s, 3H, OMe), 2.54–
2.40 (m, 2H, 3-CH2), 1.55 (d, J¼6.5 Hz, 3H, 5-Me), 1.36 (s, 3H).
This was hydrolysed and tosylated to give the sulfonamide 12d
(2.20 g, 36%) as a colourless, crystalline solid, mp 98–99 ꢀC; Rf 0.35
(25% EtOAc/petrol); C15H21NO4S: calcd C 57.9, H 6.8, N 4.5; found: C
57.5, H 7.0, N 4.6%; dH (400 MHz, CDCl3) 7.97 (d, J¼8.3 Hz, 2H,
2ꢂArH), 7.50 (d, J¼8.3 Hz, 2H, 2ꢂArH), 5.75 (dq, J¼13.2, 6.5 Hz, 1H,
H5), 5.45 (br s,1H NH), 5.43 (ddd, J¼13.2, 7.6, 7.1 Hz,1H, H4), 3.91 (s,
3H, OMe), 2.73–2.57 (m, 2H, 3-CH2), 2.63 (s, 3H, ArMe), 1.86 (d,
J¼6.5 Hz, 3H, 5-Me), 1.62 (s, 3H); dC (100.6 MHz, CDCl3) 173.4 (CO),
143.6 (s), 139.9 (s), 131.7 (4(5)-CH), 129.9 (2ꢂd), 127.5 (2ꢂd), 123.9
(5(4)-CH), 62.5 (2-C), 53.0 (OMe), 43.8 (3-CH2), 22.4 (q), 21.9 (q),
18.5 (q); nmax (KBr)/cmꢁ1 3350, 3032, 2953, 1734, 1597, 1431; m/z
[APCI] 312 (MþþH, 100%), 252 (MþꢁCO2Me, 37); HRMS: m/z: calcd
for C15H22NO4S: 312.1270; found: 312.1262 [MþH]þ.
4.2.6. Methyl (E)-5-phenyl-2-(p-toluenesulfonylamino)pent-4-enoate
(12a). Cinnamyl bromide was used to alkylate methyl 2-(benzylide-
neamino)acetate 10a (3.70 g, 21 mmol) according to general pro-
cedure A to give the imine 11a: dH (400 MHz, CDCl3) 8.13 (s, 1H,
N]CH), 7.66–7.65 (m, 2H), 7.31–7.02 (m, 7H), 6.34 (d, J¼15.8 Hz, 1H,
H5), 6.08 (dt, J¼15.8, 7.3 Hz, 1H, H4), 3.61 (s, 3H, OMe), 3.58–3.62
(obscured, 1H, H2), 2.70–2.68 (m, 2H, 3-CH2), 1.41 (s, 3H).
This was hydrolysed and tosylated to give the sulfonamide 12a
(2.70 g, 36%) as a colourless, crystalline solid, mp 96–99 ꢀC;
C19H21NO4S: calcd C 63.5, H 5.9, N 3.9; found: C 63.6, H 6.0, N 4.0%; dH
(400 MHz, CDCl3) 7.74 (d, J¼8.2 Hz, 2H, 2ꢂArH), 7.34–7.23 (m, 7H),
6.40 (d, J¼15.5 Hz, 1H, H5), 5.96 (dt, J¼15.5, 7.6 Hz, 1H, H4), 5.10 (d,
J¼8.8 Hz, 1H, NH), 4.11 (dt, J¼8.8, 5.9 Hz, 1H, H2), 3.57 (s, 3H, OMe),
2.70–2.64 (m, 2H, 3-CH2), 2.41 (s, 3H, ArMe); dC (100.6 MHz, CDCl3)
172.6 (CO),144.1 (s),135.6 (s),134.9 (s), 130.1 (d),128.9 (d),128.1 (d),
127.6 (d),126.7 (d),126.3 (d),122.9 (d), 55.9 (2-CH), 53.0 (OMe), 37.3
(3-CH2), 22.0 (q); nmax (KBr)/cmꢁ1 3274, 3031,1734,1597; HRMS: m/
z: calcd for C19H22NO4S: 360.1264; found: 360.1268 [MþH]þ.
4.3. General procedure for acid-catalysed cyclisations
4.3.1. General procedure B: acid-catalysed cyclisations of sulfon-
amides (7, 12, etc.). The sulfonamide was dissolved in dry, ethanol-
free chloroform (2 mL mmolꢁ1) and the solution stirred and cooled
to 0 ꢀC. The desired amount of trifluoromethanesulfonic (triflic)
acid was added as a 10% (v/v) solution in dry, ethanol-free chloro-
form [This is a 1 mmol solution; hence 1 ml contains 150 mg of
triflic acid.]. The resulting solution was stirred at the desired tem-
perature for the necessary length of time then cooled in ice, if
heated, before being quenched with excess saturated aqueous so-
dium carbonate. The separated aqueous layer was extracted with
dichloromethane (2ꢂ) and the combined organic solutions dried,
filtered and evaporated. The crude product was purified usually by
passage through a small plug of silica gel eluted with dichloro-
methane and/or by crystallisation from hexanes/ethyl acetate.
4.2.7. Methyl (E)-2-methyl-5-phenyl-2-(p-toluenesulfonylamino)pent-
4-enoate (12b). Cinnamyl bromide was used to alkylate methyl
2-(benzylideneamino)propanoate 10b (1.90 g, 10 mmol) according
to general procedure A to give the imine 11b: dH (400 MHz, CDCl3)
8.13 (s, 1H, N]CH), 7.66–7.64 (m, 2H), 7.31–7.02 (m, 8H), 6.34 (d,
J¼15.8 Hz,1H, H5), 6.08 (dt, J¼15.8, 7.3 Hz,1H, H4), 3.61 (s, 3H, OMe),
2.69 (d, J¼7.3 Hz, 2H, 3-CH2), 1.41 (s, 3H, 2-Me).
This was hydrolysed and tosylated to give the sulfonamide 12b
(1.30 g, 33%) as a colourless, crystalline solid, mp 131–133 ꢀC; Rf
0.33 (25% EtOAc/petrol); C20H23NO4S: calcd C 64.3, H 6.2, N 3.8;
found: C 64.0, H 6.3, N 3.7%; dH (400 MHz, CDCl3) 7.72 (d, J¼8.2 Hz,
2H, 2ꢂArH), 7.22–7.11 (m, 7H), 6.29 (d, J¼15.8 Hz, 1H, H5), 5.87 (dt,
J¼15.8, 7.4 Hz, 1H, H4), 5.47 (br s, 1H, NH), 3.58 (s, 3H, OMe), 2.68
(dd, J¼15.0, 7.4 Hz, 1H, H3a), 2.55 (dd, J¼15.0, 7.4 Hz, 1H, H3b), 2.32
(s, 3H, ArMe), 1.39 (s, 3H); dC (100.6 MHz, CDCl3) 174.6 (CO), 144.3
(s), 139.8 (s), 135.0 (s), 132.4 (d), 130.0 (2ꢂd), 128.9 (2ꢂd), 128.0 (d),
127.5 (2ꢂd), 126.7 (2ꢂd), 123.0 (d), 62.8 (2-C), 53.3 (OMe), 43.2 (3-
CH2), 23.0 (q), 21.9 (q); nmax (KBr)/cmꢁ1 3354, 3055, 2990, 1738,
4.4. Model acid-catalysed cyclisations
4.4.1. Methyl 5,5-dimethyl-1-(p-toluenesulfonyl)pyrrolidine-2-car-
boxylate (9a). The sulfonamide 7a (115 mg, 0.37 mmol) was treated
with triflic acid (22 mg, 0.15 mmol) at 0 ꢀC for 0.25 h according to

4158
C.M. Griffiths-Jones (ne´e Haskins), D.W. Knight / Tetrahedron 66 (2010) 4150–4166
general procedure B and gave the pyrrolidine 9a (105 mg, 91%) as
a colourless, crystalline solid, mp 94–96 ꢀC; C15H21NO4S: calcd C
57.9, H 6.8, N 4.5; found: C 58.2, H 6.9, N 4.5%; dH (400 MHz, CDCl3)
7.67 (d, J¼8.2 Hz, 2H, 2ꢂArH), 7.24 (d, J¼8.2 Hz, 2H, 2ꢂArH), 4.32
(dd, J¼7.9, 2.4 Hz, 1H, H2), 3.49 (s, 3H, OMe), 2.30 (s, 3H, ArMe),
2.09–2.07 (m, 1H), 1.93–1.90 (m, 1H), 1.77–1.75 (m, 1H), 1.64–1.62
(m, 1H), 1.41 (s, 3H), 1.30 (s, 3H); dC (100.6 MHz, CDCl3) 178.5 (CO),
144.1 (s), 139.8 (s), 130.2 (2ꢂd), 128.9 (2ꢂd), 68.8 (2-CH), 63.9 (5-C),
53.6 (OMe), 41.2 (t), 38.4 (t), 28.7 (q), 26.8 (q), 22.8 (q); nmax (KBr)/
cmꢁ1 2986, 1732, 1494; HRMS: m/z: calcd for C15H22NO4S:
312.1270; found: 312.1272 [MþH]þ.
Me); nmax (KBr)/cmꢁ1 1732, 1598, 1451, 1151; HRMS: m/z: calcd for
C21H24NO4S: 374.1426; found: 374.1418 [MþH]þ.
4.4.5. Methyl (2RS,5RS)- and (2RS,5SR)-5-methyl-1-(p-toluenesulfo-
nyl)pyrrolidine-2-carboxylate (13c). The sulfonamide 12c (102 mg,
0.34 mmol), derived from crotyl bromide, was exposed to triflic acid
(51 mg,0.34 mmol)inchloroformat62 ꢀCfor4 haccordingtogeneral
procedure B and gave the pyrrolidine 13c (93 mg, 91%) as a colourless,
crystalline solid, in a ratio of 2.5:1 (2RS,5SR)/(2RS,5RS) of inseparable
diastereoisomers, mp 130–132 ꢀC; C14H19NO4S: calcd C 56.6, H 6.4, N
4.7; found: C 56.8, H 6.6, N 4.6%; dH (400 MHz, CDCl3) (major isomer)
7.68 (d, J¼8.2 Hz, 2H, 2ꢂArH), 7.17 (d, J¼8.2 Hz, 2H, 2ꢂArH), 4.30 (dd,
J¼7.8, 2.3 Hz,1H, H2), 3.79–3.76 (m,1H, H5), 3.72 (s, 3H, OMe), 2.35 (s,
3H, ArMe), 2.35–1.34 (m, 4H), 1.26 (d, J¼6.5 Hz, 3H, 5-Me); dC
(100.6 MHz, CDCl3) 174.4 (CO), 148.7 (s), 142.6 (s), 128.8 (2ꢂd), 127.0
(2ꢂd), 66.5 (2-CH), 58.2 (5-CH), 52.7 (OMe), 38.6 (t), 31.2 (t), 24.3 (q),
21.9 (q); dH (400 MHz, CDCl3) (minor isomer) 7.72 (d, J¼8.2 Hz, 2H,
2ꢂArH), 7.12 (d, J¼8.2 Hz, 2H, 2ꢂArH), 4.39 (dd, J¼7.4, 2.8 Hz,1H, H2),
4.07–4.05 (m,1H, H5), 3.68 (s, 3H, OMe), 2.34 (s, 3H, ArMe), 2.27–1.31
(m, 4H),1.12 (d, J¼6.6 Hz, 3H, 5-Me);dC (100.6 MHz, CDCl3) 174.8 (CO),
148.9 (s),142.8 (s),128.6 (2ꢂd), 127.3 (2ꢂd), 68.4 (2-CH), 57.6 (5-CH),
52.8 (OMe), 38.3 (t), 31.5 (t), 23.9 (q), 21.7 (q); nmax (KBr)/cmꢁ1 2954,
1732, 1338, 1150; m/z: [APCI] 298 (100%, [MþH]þ).
4.4.2. Methyl 2,5,5-trimethyl-1-(p-toluenesulfonyl)pyrrolidine-2-
carboxylate (9b). The sulfonamide 7b (92 mg, 0.28 mmol), derived
from prenyl bromide, was exposed to triflic acid (17 mg, 0.11 mmol)
in chloroform at 0 ꢀC for 0.25 h according to general procedure B
and gave the pyrrolidine 9b (85 mg, 92%) as a colourless, crystalline
solid, mp 87–89 ꢀC; C16H23NO4S: calcd C 59.1, H 7.1, N 4.3; found: C
59.4, H 6.8, N 4.0%; dH (400 MHz, CDCl3) 7.69 (d, J¼8.0 Hz, 2H,
2ꢂArH), 7.26 (d, J¼8.0 Hz, 2H, 2ꢂArH), 3.70 (s, 3H, OMe), 2.34 (s,
3H, ArMe), 2.20 (ddd, J¼11.4, 7.9, 5.0 Hz, 1H, H3a), 1,79–1.77 (m, 3H,
H3b and 4-CH2), 1.70 (s, 3H), 1.33 (s, 3H), 1.21 (s, 3H); dC (100.6 MHz,
CDCl3) 177.3 (CO), 144.2 (s), 140.6 (s), 130.6 (2ꢂd), 129.4 (2ꢂd), 71.8
(s), 66.8 (s), 54.0 (OMe), 42.0 (t), 38.2 (t), 30.0 (q), 28.9 (q), 27.1 (q),
22.9 (q); nmax (KBr)/cmꢁ1 1741, 1598, 1454, 1142; HRMS: m/z: calcd
for C16H24NO4S: 326.1426; found: 326.1428 [MþH]þ.
4.4.6. Methyl (2RS,5RS)- and (2RS,5SR)-2,5-dimethyl-1-(p-toluene-
sulfonyl)pyrrolidine-2-carboxylate (13d). The sulfonamide 12d
(0.316 g, 1.00 mmol), derived from crotyl bromide, was exposed to
triflic acid (0.151 g, 1.00 mmol) in chloroform at 62 ꢀC for 4 h
according to general procedure B and gave the pyrrolidine 13d
(0.297 g, 94%) as a colourless, crystalline solid, in a ratio of 1.3:1
(2RS,5SR)/(2RS,5RS) of inseparable diastereoisomers, mp 133–
135 ꢀC; C15H21NO4S: calcd C 57.9, H 6.8, N 4.5; found: C 58.1, H 6.9, N
4.5%; dH (400 MHz, CDCl3) (major isomer) 7.69 (d, J¼8.2 Hz, 2H,
2ꢂArH), 7.12 (d, J¼8.2 Hz, 2H, 2ꢂArH), 3.87–3.86 (m, 1H, H5), 3.74 (s,
3H, OMe), 2.34 (s, 3H, ArMe), 2.32–1.39 (m, 4H), 1.52 (s, 3H, 2-Me),
1.15 (d, J¼6.5 Hz, 3H, 5-Me); dC (100.6 MHz, CDCl3) 174.6 (CO), 149.2
(s), 143.9 (s), 129.8 (2ꢂd), 127.9 (2ꢂd), 67.4 (2-C), 57.8 (5-CH), 52.9
(OMe), 39.1 (t), 31.7 (t), 26.5 (q), 21.9 (q), 21.7 (q); dH (400 MHz,
CDCl3) (minor isomer) 7.72 (d, J¼8.2 Hz, 2H, 2ꢂArH), 7.10 (d,
J¼8.2 Hz, 2H, 2ꢂArH), 4.07–4.06 (m, 1H, H5), 3.66 (s, 3H, OMe), 2.34
(s, 3H, ArMe), 2.21–1.27 (m, 4H), 1.70 (s, 3H, 2-Me), 1.03 (d, J¼6.5 Hz,
3H, 5-Me); dC (100.6 MHz, CDCl3) 175.2 (CO),149.2 (s),143.6 (s),129.7
(2ꢂd), 127.3 (2ꢂd), 70.4 (2-C), 57.9 (5-CH), 52.8 (OMe), 38.3 (t),
32.0 (t), 27.3 (q), 22.2 (q), 21.8 (q); nmax (KBr)/cmꢁ11727,1326; HRMS:
m/z: calcd for C15H22NO4S: 312.1270; found: 312.1260 [MþH]þ.
4.4.3. Methyl (2RS,5RS)- and (2RS,5SR)-5-phenyl-1-(p-toluenesulfo-
nyl)pyrrolidine-2-carboxylate (13a)26. The sulfonamide 12a (117 mg,
0.33 mmol), derived from cinnamyl bromide, was exposed to triflic
acid (30 mg, 0.20 mmol) in chloroform at 20 ꢀC for 4 h according to
general procedure B and gave the pyrrolidine 13a (111 mg, 95%) as
a colourless, crystalline solid, in a ratio of 1.2:1 (2RS,5SR)/(2RS,5RS),
mp 100–103 ꢀC; C19H21NO4S: calcd C 63.5, H 5.9, N 3.9; found: C 63.8,
H 6.4, N 4.0%; dH (400 MHz, CDCl3) (major cis-isomer) 7.53 (d,
J¼8.2 Hz, 2H, 2ꢂArH), 7.45–7.38 (m, 2H, 2ꢂArH), 7.24–7.10 (m, 5H),
4.77 (app. t, J¼ca. 6.7 Hz, 1H, H5), 4.56 (app. t, J¼ca. 6.5 Hz, 1H, H2),
3.78 (s, 3H, OMe), 2.36 (s, 3H, ArMe), 2.16–2.06 (m, 1H), 2.06–2.00
(m, 2H), 1.96–1.87 (m, 1H); dC (100.6 MHz, CDCl3) 173.2 (CO), 143.9
(s),141.7 (s),135.9 (s),129.7 (2ꢂd),128.6 (2ꢂd),128.1 (2ꢂd),127.6 (d),
127.4 (2ꢂd), 65.3 (d), 62.4 (d), 52.9 (OMe), 36.2 (t), 29.8 (t), 21.9 (q);
the minor trans-isomer could be identified and quantified by reso-
nances at dH (400 MHz, CDCl3) 5.11 (app. d, J¼8.8 Hz, 1H, H2(5)), 4.58
(app. d, J¼8.6 Hz, 1H, H5(2)), 3.73 (s, 3H, OMe), 2.66–2.55 (m, 1H),
2.31 (s, 3H, ArMe), 1.78–1.68 (m, 1H); nmax (KBr)/cmꢁ1 1751, 1598,
1453; HRMS: m/z: calcd for C19H25N2O4S: 377.1535; found: 377.1532
[MþNH4]þ.
4.5. Spiro-pyrrolidines
4.4.4. Methyl (2RS,5RS)- and (2RS,5SR)-2-methyl-5-phenyl-1-(p-tol-
uenesulfonyl)pyrrolidine-2-carboxylate (13b). The sulfonamide 12b
(134 mg, 0.36 mmol), derived from cinnamyl bromide, was exposed
to triflic acid (33 mg, 0.22 mmol) in chloroform at 20 ꢀC for 4 h
according to general procedure B to give the pyrrolidine 13b
(129 mg, 96%) as a colourless, crystalline solid, in a ratio of 2:1
(2RS,5SR)/(2RS,5RS), mp 142–144 ꢀC; C20H23NO4S: calcd C 64.3, H
6.2, N 3.8; found: C 64.0, H 6.3, N 3.8%; dH (400 MHz, CDCl3) (major
isomer) 7.36 (d, J¼8.2 Hz, 2H, 2ꢂArH), 7.11–7.09 (m, 2H, 2ꢂArH),
6.94–6.93 (m, 3H, 3ꢂArH), 6.85 (d, J¼8.2 Hz, 2H, 2ꢂArH), 4.85 (dd,
J¼9.2, 1.5 Hz, 1H, H5), 3.82 (s, 3H, OMe), 2.60–2.48 (m, 1H), 2.37–
2.28 (m, 1H), 2.16 (s, 3H, ArMe), 1.82–1.67 (m, 2H), 1.77 (s, 3H, 2-
Me); dC (100.6 MHz, CDCl3) 175.4 (CO), 142.8 (s), 142.2 (s), 139.2 (s),
129.1 (d), 128.6 (d), 127.5 (d), 127.3 (d), 126.9 (d), 70.4 (2-C), 65.9 (5-
CH), 53.1 (OMe), 39.0 (t), 33.4 (t), 24.6 (q), 21.8 (q); dH (400 MHz,
CDCl3) (minor isomer) 7.12–6.79 (m, 9H), 5.22 (dd, J¼9.1, 2.6 Hz, 1H,
H5), 3.72 (s, 3H, OMe), 2.57–2.46 (m, 1H, H3a), 2.21 (s, 3H, ArMe),
2.13–2.04 (m, 2H, H3b, H4a), 1.66–1.57 (m, 1H, H4b), 1.80 (s, 3H, 2-
4.5.1. Methyl 4-(cyclohex-1-en-1-yl)-2-methyl-2-(p-toluenesulfonyl-
amino)butanoate (15). Methyl 2-(benzylideneamino)propanoate
10b (3.80 g, 20 mmol) was alkylated using 1-(2-iodoethyl)cyclo-
hexene 14 [4.96 g, 21 mmol; dH (400 MHz, CDCl3) 5.50 (br res.,
1H,:CH), 3.22 (t, J¼7.5 Hz,2H,1-CH2), 2.51 (td, J¼7.5 and ca. 1 Hz, 2H, 2-
CH2), 2.04–1.96 (m, 2H), 1.96–1.90 (m, 2H), 1.70–1.50 (m, 4H); dC
(100.6 MHz, CDCl3) 136.2 (s),124.2 (d), 42.4 (t), 27.8(t), 25.9(t), 23.2 (t),
22.5 (t), 4.9 (t)]27 according to general procedure A to give an imine,
which was immediately hydrolysed and tosylated to give the sulfon-
amide 15 (2.92 g, 40%) as an oil: dH (400 MHz, CDCl3) 7.75 (d, J¼8.1 Hz,
2H, 2ꢂArH), 7.22 (d, J¼8.2 Hz, 2H, 2ꢂArH), 5.61 (s,1H, NH), 5.28 (app.
brs,1H, ]CH),3.62(s,3H,OMe), 2.35(s, 3H, ArMe),1.98–1.44(m,12H),
1.42 (s, 3H, 2-Me); nmax (film)/cmꢁ1 3240, 1730, 1460, 1380; HRMS:
m/z: calcd for C19H28NO4S: 366.1734; found: 366.1734 [MþH]þ.
4.5.2. Methyl1-aza-2-methyl-1-toluenesulfonyl-spiro-[4.5]decane-2-car-
boxylate (16a). The foregoing sulfonamide 15 (182 mg, 0.50 mmol),
derived from cyclohexenyl iodide 14, was exposed to triflic acid

C.M. Griffiths-Jones (ne´e Haskins), D.W. Knight / Tetrahedron 66 (2010) 4150–4166
4159
(34 mg, 0.22 mmol) in chloroform at 0 ꢀC for 0.25 h according to
general procedure B and gave the spiro-pyrrolidine 16a (169 mg, 93%)
as a pale yellow oil: dH (400 MHz, CDCl3) 7.85 (d, J¼8.3 Hz, 2H,
2ꢂArH), 7.23 (d, J¼8.3 Hz, 2H, 2ꢂArH), 3.77 (s, 3H, OMe), 2.39 (s, 3H,
ArMe), 2.27–1.03 (m, 14H), 1.77 (s, 3H, 2-Me); dC (100.6 MHz, CDCl3)
175.8 (CO), 143.1 (s), 141.6 (s), 129.6 (2ꢂd), 128.2 (2ꢂd), 71.8 (s), 70.3
(s), 52.9 (OMe), 38.1 (t), 37.2 (t), 34.8 (t), 34.0 (t), 26.3 (q), 25.4 (t), 24.8
(t), 21.9 (q); nmax (film)/cmꢁ11740,1600,1456,1140; HRMS: m/z: calcd
for C19H28NO4S: 366.1734; found: 366.1739 [MþH]þ.
4.6.2. 1-(p-Toluenesulfonyl)-2,5,5-trimethylpyrrolidine-2-carbox-
aldehyde (21). The aldehyde 19 (0.324 g, 1.1 mol) was cyclised
according to general procedure
B using triflic acid (66 mg,
0.44 mmol) for 0.25 h at 0 ꢀC, to give an oily solid. Crystallisation
from ethyl acetate/hexanes gave the pyrrolidine-2-carboxaldehyde
21 (0.283 g, 87%) as a colourless, crystalline solid, mp 86–88 ꢀC;
C15H21NO3S: calcd C 61.0, H 7.2, N 4.7; found: C 61.2, H 7.2, N 4.7%;
dH (400 MHz, CDCl3) 9.51 (s, 1H, CHO), 7.69 (d, J¼8.2 Hz, 2H,
2ꢂArH), 7.18 (d, J¼8.2 Hz, 2H, 2ꢂArH), 2.32 (s, 3H, ArMe), 2.00 (ddd,
J¼10.5, 6.8, 2.1 Hz, 1H, H3a), 1.83 (ddd, J¼10.5, 6.4, 2.3 Hz, 1H, H3b),
1.68 (ddd, J¼10.3, 6.8, 2.3 Hz, 1H, H4a), 1.47 (ddd, J¼10.3, 6.4, 2.1 Hz,
1H, H4b), 1.45 (s, 3H), 1.36 (s, 3H),1.28 (s, 3H); dC (100.6 MHz, CDCl3)
179.6 (CHO), 142.8 (s), 140.6 (s), 129.4 (2ꢂd), 128.6 (2ꢂd), 70.2 (s),
66.9 (s), 40.3 (t), 39.4 (t), 28.7 (q), 24.2 (q), 23.6 (q), 21.8 (q); nmax
(KBr)/cmꢁ1 2972, 1731, 1600, 1454, 1322; HRMS: m/z: calcd for
C15H22NO3S: 296.1320; found: 296.1318 [MþH]þ.
4.5.3. Methyl 1-aza-1-toluenesulfonyl-spiro-[4.5]decane-2-carboxyl-
ate (16b). Methyl 2-(p-toluenesulfonylamino)-4-cyclohexylidene-
butanoate 18 was prepared using general procedure A from methyl
2-(benzylideneamino)-acetate 10a and bromoethylidenecyclohex-
ane 1728 on an 11 mmol scale. Subsequent exposure to triflic acid, in
exactly the same manner and scale as in the foregoing reaction gave
the spiro-pyrrolidine 16b (165 mg, 94%) as a colourless solid, mp
121–124 ꢀC; C18H25NO4S: calcd C 62.8, H 6.9, N 3.9; found: C 62.7, H
7.0, N 4.1%; dH (400 MHz, CDCl3) 7.76 (d, J¼8.3 Hz, 2H, 2ꢂArH), 7.24
(d, J¼8.3 Hz, 2H, 2ꢂArH), 4.38 (dd, J¼8.6, 2.7 Hz, 1H, H2), 3.57 (s,
3H, OMe), 2.36 (s, 3H, ArMe), 2.43–1.14 (m, 14H); dC (100.6 MHz,
CDCl3) 173.5 (CO), 144.0 (s), 138.7 (s), 129.7 (2ꢂd), 127.9 (2ꢂd), 72.1
(5-C), 62.2 (2-CH), 52.6 (OMe), 38.4 (t), 35.0 (t), 34.8 (t), 28.3 (t),
25.5 (t), 25.4 (q), 25.0 (t), 21.9 (t); nmax (KBr)/cmꢁ1 1749, 1588, 1458,
1376, 1140; m/z: [APCI] 352 (100%, [MþH]þ), 292 (49). HRMS: m/z:
calcd for C18H26NO4S: 352.1582; found: 352.1586 [MþH]þ.
4.6.3. 1-(p-Toluenesulfonyl)-2,5,5-trimethylpyrrolidine-2-methanol
(22) and 5-(p-toluenesulfonylamino)-2,2,5-trimethyltetrahydropyran
(23). The sulfonamide alcohol 20 (0.276 g, 0.93 mmol) when
treated with triflic acid (56 mg, 0.37 mmol) for 0.25 h at 0 ꢀC as
described in general procedure B, followed by column chroma-
tography (20% ethyl acetate/petrol) gave:
(i) the pyrrolidine-2-methanol 22 (0.121 g, 45%) as a colourless,
crystalline solid, mp 92–95 ꢀC; C15H23NO3S: calcd C 60.6, H 7.8,
N 4.7; found: C 60.9, H 8.0, N 4.9%; dH (400 MHz, CDCl3) 7.72 (d,
J¼8.2 Hz, 2H, 2ꢂArH), 7.25 (d, J¼8.2 Hz, 2H, 2ꢂArH), 3.26 (s,
2H, CH2OH), 2.42 (s, 1H, OH), 2.34 (s, 3H, ArMe), 1.61–1.33 (m,
4H), 1.17 (s, 3H), 1.12 (s, 3H), 1.03 (s, 3H); dC (100.6 MHz, CDCl3)
142.9 (s), 140.6 (s), 129.5 (2ꢂd), 126.8 (2ꢂd), 71.6 (s), 70.3
(CH2OH), 67.8 (s), 31.8 (t), 31.4 (t), 28.6 (q), 23.3 (q), 22.5 (q),
22.2 (q); nmax (KBr)/cmꢁ1 3527, 2972, 1496, 1368; HRMS: m/z:
calcd for C15H24NO3S: 298.1477; found: 298.1476 [MþH]þ;
(ii) the tetrahydropyran 23 (0.123 g, 45%) as a colourless, crystal-
line solid, mp 89–94 ꢀC; dH (400 MHz, CDCl3) 7.72 (d, J¼8.2 Hz,
2H, 2ꢂArH), 7.26 (d, J¼8.2 Hz, 2H, 2ꢂArH), 5.17 (s, 1H, NH),
3.80 (d, J¼12.2 Hz, 1H, H6a), 3.32 (d, J¼12.2 Hz, 1H, H6b), 2.34
(s, 3H, ArMe), 1.80–1.34 (m, 4H), 1.49 (s, 3H), 1.42 (s, 3H), 0.87
(s, 3H); dC (100.6 MHz, CDCl3) 143.0 (s), 140.6 (s), 129.5 (2ꢂd),
127.6 (2ꢂd), 70.6 (s), 68.6 (t), 54.0 (s), 39.2 (t), 34.4 (t), 29.5
(q), 28.9 (q), 22.2 (q), 21.5 (q); nmax (KBr)/cmꢁ1 3279, 2970,
1598, 1457; HRMS: m/z: calcd for C15H24NO3S: 298.1477;
found: 298.1473 [MþH]þ.
4.6. Functionalised pyrrolidines
4.6.1. 2,5-Dimethyl-2-(p-toluenesulfonylamino)hex-4-enal (19) and
2,5-dimethyl-2-(p-toluenesulfonylamino)hex-4-en-1-ol (20). The sul-
fonamide 7b (2.00 g, 7.19 mmol) was dissolved in dry ether (100 mL)
and the resulting solution stirred and cooled to ꢁ78 ꢀC. Diisobuty-
laluminium hydride (18.4 mL of
a 1 M solution in hexanes,
18.4 mmol) was added dropwise and the resulting mixture stirred at
the same temperature for 4.5 h, then allowed to warm to ambient
temperature and quenched by the careful addition of saturated
aqueous citric acid (100 mL). The resulting two layers were sepa-
rated and the aqueous layer extracted with dichloromethane
(2ꢂ50 mL). The combined organic solutions were dried, filtered and
evaporated. Column chromatography (20% ethyl acetate/petrol) of
the residue (1.8 g) gave:
(i) the aldehyde 19 (0.70 g, 39%) as a colourless solid, mp 83–
86 ꢀC; C15H21NO3S: calcd C 61.0, H 7.2, N 4.7; found: C 61.2, H
7.0, N 4.7%; dH (400 MHz, CDCl3) 9.32 (s, 1H, CHO), 7.68 (d,
J¼8.2 Hz, 2ꢂArH), 7.22 (d, J¼8.2 Hz, 2ꢂArH), 5.15 (s, 1H, NH),
4.82 (t, J¼7.5 Hz, 1H, H4), 2.34–2.31 (m, 5H, 3-CH2, ArMe), 1.63
(s, 3H, Me), 1.56 (s, 3H, Me), 1.20 (s, 3H, 2-Me); dC (100.6 MHz,
CDCl3) 179.6 (CHO), 147.3 (s), 142.8 (s), 136.4 (5-C), 128.9 (2ꢂd),
126.7 (2ꢂd),117.4 (4-CH), 66.4 (2-C), 36.8 (3-CH2), 26.8 (q), 21.7
(q), 20.3 (q), 19.8 (q); nmax (KBr)/cmꢁ1 2927, 1730, 1453, 1327;
HRMS: m/z: calcd for C15H22NO3S: 296.1320; found: 296.1322
[MþH]þ;
4.6.4. 2-(2-Benzenesulfonylethyl)cyclohexanone
(24a)29. Toluene
(20 mL), cyclohexanone (10.3 mL, 100 mmol), morpholine (11.5 mL,
130 mmol) and p-toluenesulfonic acid (0.10 g) were refluxed to-
gether under a Dean and Stark water separator for 1 h then cooled
to ambient temperature. Phenyl vinyl sulfone (16.8 g, 100 mmol)
was then added and the resulting mixture refluxed for a further 4 h
after which the toluene was evaporated to leave a crude enamine as
a brown oil.
(ii) the alcohol 20 (0.90 g, 50%) as a colourless, crystalline solid, mp
91–93 ꢀC; C15H23NO3S: calcd C 60.6, H 7.7, N 4.8; found: C 60.6,
H 7.6, N 4.9%; dH (400 MHz, CDCl3) 7.80 (d, J¼8.2 Hz, 2ꢂArH),
7.31 (d, J¼8.2 Hz, 2ꢂArH), 5.07 (br t, J¼ca. 7.6 Hz, 1H, H4), 4.75
(s, 1H, NH), 3.57 (dd, J¼11.7, 6.2 Hz, 1H, H1a), 3.50 (dd, J¼11.7,
6.2 Hz, 1H, H1b), 2.45 (s, 3H, ArMe), 2.30 (dd, J¼14.3, 7.9 Hz, 1H,
H3a), 2.12 (dd, J¼14.3, 7.4 Hz, 1H, H3b), 1.73 (s, 3H, Me), 1.66 (br
s, 1H, OH), 1.65 (s, 3H, Me), 1.13 (s, 3H, 2-Me); dC (100.6 MHz,
CDCl3) 143.7 (s), 140.1 (s), 137.2 (s, 5-C), 130.0 (2ꢂd), 127.4
(2ꢂd), 118.0 (d, 4-CH), 68.6 (t, 1-CH2), 61.3 (s, 2-C), 37.1 (t, 3-
CH2), 26.5 (q), 21.9 (q), 21.5 (q), 18.4 (q); nmax (KBr)/cmꢁ1 3277,
2926, 1598, 1483; m/z: [APCI] 298 (100%, [MþH]þ).
This was added to a stirred mixture of glacial acetic acid (48 mL),
sodium acetate (16 g) and water (48 mL), which was then refluxed
for 2 h. The cooled mixture was then neutralised using aqueous
ammonia and filtered through Celite. The brown filtrate was
extracted with dichloromethane (3ꢂ100 mL) and the combined
organic extracts dried, filtered and evaporated. The residue was
separated by column chromatography (25% EtOAc/petrol) to give
the keto-sulfone 24a (12.2 g, 46%) as an off-white solid, mp 87–90 ꢀC
[lit.29 mp 71–71 ꢀC]; dH (400 MHz, CDCl3) 7.88–7.80 (m, 2H), 7.64–
7.50 (m, 3H), 3.46 (t, J¼7.0 Hz, 2H, 20-CH2), 3.10–3.00 (m, 1H, H2),
2.45–1.20 (m, 10H); dC (100.6 MHz, CDCl3) 193.2 (CO), 140.5 (s),
134.1 (d), 129.6 (d), 128.4 (d), 52.1 (d), 49.3 (t), 42.6 (t), 34.8 (t), 28.3

4160
C.M. Griffiths-Jones (ne´e Haskins), D.W. Knight / Tetrahedron 66 (2010) 4150–4166
(t), 25.5 (t), 23.5 (t); nmax (KBr)/cmꢁ1 1700, 1350, 1310; m/z: [APCI]
267 (100%; MþH)þ.
(400 MHz, CDCl3) (minor isomer) 7.70–7.62 (m, 4H), 7.54–7.50 (m,
3H), 7.25 (d, J¼8.2 Hz, 2H), 4.15–4.11 (m, 1H, H2), 3.82–3.76 (m, 2H),
3.61 (s, 3H, OMe), 2.34 (s, 3H, ArMe), 2.08–2.03 (m, 2H), 1.95–1.88
(m, 4H), 1.74–1.00 (m, 9H); dC (100.6 MHz, CDCl3) 174.1 (CO), 141.1
(s), 138.8 (s), 136.2 (s), 133.5 (d), 130.1 (d), 129.6 (d), 126.3 (d), 124.2
(d), 66.5 (s), 63.2 (d), 53.7 (OMe), 52.9 (t), 35.8 (d), 31.0 (t), 26.8 (t),
25.5 (t), 24.7 (t), 21.1 (q), 20.4 (t), 18.3 (t), 17.6 (t); nmax (KBr)/cmꢁ1
1740; m/z: [APCI] 520 (100%; MþH)þ; HRMS: m/z: calcd for
C26H34NO6S2: 520.1822; found: 520.1822 [MþH]þ.
4.6.5. (E)-1-(2-Benzenesulfonylethyl)-2-(2-bromoethylidene)cyclo-
hexane (26a). The foregoing sulfone 24a (2.60 g, 10 mmol) was
dissolved in dry tetrahydrofuran (50 mL) and the solution cooled to
ꢁ78 ꢀC. Vinylmagnesium bromide (20 mL of a 1 M solution in tet-
rahydrofuran, 20 mmol) was added dropwise and the solution
allowed to warm slowly to ambient temperature then stirred
overnight. Saturated aqueous ammonium chloride (50 mL) and
ether (50 mL) were then carefully added, the two layers separated
and the aqueous layer extracted with ether (50 mL). The combined
ether extracts were dried, filtered and evaporated to leave 2-(2-
benzenesulfonylethyl)-1-ethenylcyclohexanol 25a (2.5 g, 87%) as
a pale yellow oil: dH (400 MHz, CDCl3) 7.89–7.80 (m, 3H), 7.50–7.40
(m, 2H), 5.68 (dd, J¼17.2, 10.7 Hz, 1H, ]CH), 5.09 (app. d, J¼17.2 Hz,
1H, ]CH), 4.99 (app. d, J¼10.7 Hz, 1H, ]CH), 3.08–2.89 (m, 2H),
1.80–1.15 (m, 11H); nmax (film)/cmꢁ1 3400, 2936, 1447, 1304; m/z:
[APCI] 295 (100%; MþH)þ, 278 (54; MþꢁOH).
4.6.8. 2-Allyl-1-ethenylcyclohexanol (25b). Vinylmagnesium bro-
mide (40 mL of a 1 M solution in tetrahydrofuran, 40 mmol) was
added dropwise to a solution of 2-allylcyclohexanone 24b (3.0 g,
22 mmol) in dry tetrahydrofuran (100 mL), stirred and cooled in an
ice-water bath. The resulting mixture was stirred overnight without
further cooling then carefully diluted with saturated aqueous am-
monium chloride (100 mL) and ether (50 mL). The separated aqueous
layer was extracted with ether (100 mL) and the combined organic
solutions dried, filtered and evaporated to leave the alcohol 25b (2.6 g,
72%) as a pale yellow oil: dH (400 MHz, CDCl3) 5.68–5.63 (m, 2H),
5.05–4.95 (m, 4H), 2.33–2.28 (m, 2H),1.90–1.84 (m, 3H),1.80–1.10 (m,
6H); dC (100.6 MHz, CDCl3) 140.0 (d),138.3 (d),115.5 (t),113.5 (t), 74.9
(s), 46.8 (d), 40.4 (t), 34.7 (t), 28.4 (t), 25.2 (t), 23.3 (t); nmax (film)/cmꢁ1
3364, 2923, 1346; m/z: [APCI] 167 (53%; MþH)þ, 149 [100; MꢁOH]þ.
The alcohol 25a (2.5 g, 8.5 mmol) was dissolved in pyridine
(1 mL) and the resulting solution added dropwise to phosphorus
tribromide (0.32 mL, 3.4 mmol), protected from light. After stirring
for 5 min, excess reagents were removed under reduced pressure to
leave the crude bromide 26a (2.5 g, 82%) as a pale yellow oil, which
was separated from solid products using a pipette and used im-
mediately in the next step: dH (400 MHz, CDCl3) 7.70–7.60 (m, 2H),
7.55–7.48 (m, 3H), 5.31 (t, J¼7.2 Hz, 1H, ]CH), 4.12 (d, J¼7.2 Hz, 2H,
CH2Br), 3.00–2.95 (m, 2H), 2.10–1.22 (m, 11H).
4.6.9. Methyl
(E)-4-(2-allylcyclohexylidene)-2-(p-toluenesulfonyl-
amino)butanoate (27b). A solution of the foregoing alcohol 25b
(1.0 g, 6.1 mmol) and pyridine (0.07 mL) in tetrahydrofuran was
added dropwise to a stirred mixture of phosphorus tribromide
(0.23 mL) containing pyridine (one drop) and protected from light.
After 5 min, the solvent was evaporated to leave the crude bromide
26b (0.98 g, 71%), after separation from solid products by removal
by pipette: dH (400 MHz, CDCl3) 5.64–5.61 (m,1H), 5.41 (t, J¼8.5 Hz,
1H), 5.01 (d, J¼17.6 Hz, 1H), 4.98 (d, J¼10.6 Hz, 1H), 3.98 (d,
J¼8.5 Hz, 2H), 2.30–1.25 (m, 11H).
4.6.6. Methyl (E)-4-[2-(2-benzenesulfonylethyl)cyclohexylidene]-2-
(p-toluenesulfonylamino)butanoate (27a). Methyl 2-(benzylidenea-
mino)acetate 10a (2.00 g, 11.3 mmol) was alkylated using the fore-
going bromide 26a according to general procedure A to give an
imine: dH (400 MHz, CDCl3) 8.17 (s, 1H, N]CH), 7.75–7.60 (m, 4H),
7.55–7.50 (m, 3H), 7.40–7.33 (m, 3H), 4.43 (dd, J¼7.2, 6.8 Hz,1H, H4),
3.72 (dd, J¼7.3, 6.9 Hz,1H, H2), 3.58 (s, 3H, OMe), 3.02–2.97 (m, 2H),
2.45–2.40 (m, 2H), 2.10–1.25 (m, 11H). This imine was hydrolysed
and tosylated and the crude product purified by column chroma-
tography (20% EtOAc/petrol)togive the sulfonamide 27a (1.41 g, 24%)
as a colourless solid, mp 67–69 ꢀC; C26H33NO6S2: calcd C 60.1, H 6.4,
N 2.7; found: C 60.1, H 6.4, N 2.6%; dH (400 MHz, CDCl3) 7.86 (d,
J¼8.2 Hz, 2H), 7.65–7.61 (m, 3H), 7.52–7.48 (m, 2H), 7.23 (d, J¼8.2 Hz,
2H), 5.17 (t, J¼9.4 Hz,1H, H4), 4.82 (br res.,1H, NH), 3.86 (ddd, J¼9.4,
7.4, 6.8 Hz, 1H, H2), 3.42 (s, 3H, OMe), 2.81–2.95 (m, 2H, CH2SO2),
2.37–2.32 (m, 5H, including 2.33, s, Me), 1.98–1.20 (m, 10H); dC
(100.6 MHz, CDCl3) 171.6 (CO),144.8 (s),143.7 (s),139.2 (s),136.7 (s),
133.7 (d), 129.7 (2ꢂd), 129.3 (2ꢂd), 128.1 (2ꢂd), 127.2 (2ꢂd), 114.9
(d), 55.6 (d), 54.5 (t), 52.6 (OMe), 43.5 (d), 33.6 (t), 31.1 (t), 27.8 (t),
25.9 (t), 24.3 (t), 22.8 (t) 21.6 (q); nmax (KBr)/cmꢁ1 2928, 1743, 1598,
1447; m/z: [APCI] 519 (25%; MþH)þ, 256 (100); HRMS: m/z: calcd for
C26H37N2O6S2: 537.2088; found: 537.2092 [MþNH4]þ.
Methyl 2-(benzylideneamino)acetate 10a (0.6 g, 3.5 mmol) was
alkylated using the foregoing bromide 26b according to general
procedure A to give an imine, which was hydrolysed and tosylated
and the crude product purified by column chromatography (20%
EtOAc/petrol) to give the sulfonamide 27b (0.36 g, 27%) as a colour-
less solid in a 1.2:1 ratio of diastereoisomers, mp 91–94 ꢀC;
C21H29NO4S: calcd C 64.5, H 7.4, N 3.6; found: C 64.3, H 7.6, N 3.7%; dH
(400 MHz, CDCl3) (major isomer) 7.62 (d, J¼8.2 Hz, 2H), 7.22 (d,
J¼8.2 Hz, 2H), 5.67–5.58 (m, 1H), 5.10–4.75 (m, 4H), 3.95–3.88 (m,
1H), 3.45 (s, 3H, OMe), 2.45–2.35 (m, 5H), 2.25–2.20 (m, 2H), 2.00–
1.30 (m, 9H); dC (100.6 MHz, CDCl3) 171.2 (CO), 147.3 (s), 143.6 (s),
138.0 (d),137.7 (d),136.3 (s),129.6 (2ꢂd),127.2 (2ꢂd),115.5 (t),112.8
(d), 112.6 (d), 55.6 (d), 52.4 (OMe), 44.4 (d), 36.6 (t), 33.1 (t), 30.9 (t),
28.0 (t), 27.3 (t), 23.5 (t), 21.6 (q); dH (400 MHz, CDCl3) (minor iso-
mer) 7.63 (d, J¼8.2 Hz, 2H), 7.21 (d, J¼8.2 Hz, 2H), 5.67–5.58 (m,1H),
5.10–4.75 (m, 4H), 3.95–3.88 (m, 1H), 3.44 (s, 3H, OMe), 2.45–2.35
(m, 5H), 2.25–2.20 (m, 2H), 2.00–1.30 (m, 9H); nmax (KBr)/cmꢁ1 2928,
1744, 1446, 1162; m/z: [APCI] 392 (100%; MþH)þ; HRMS: m/z: calcd
for C21H30NO4S: 392.1895; found: 392.1898 [MþH]þ.
4.6.7. Methyl
6-(2-benzenesulfonylethyl)-1-(p-toluenesulfonyl)-1-
azaspiro[4.5]decane-2-carboxylate (28a). Sulfonamide 27a (0.40 g,
0.80 mmol) was cyclised for 0.25 h at 0 ꢀC using triflic acid (46 mg,
0.30 mmol) according to general procedure B to give the spiro-
pyrrolidine 28a (0.34 g, 84%) as a colourless, crystalline solid as a 3:1
ratio of diastereoisomers, mp 127–129 ꢀC (EtOAc/hexane);
C26H33NO6S2: calcd C 60.1, H 6.4, N 2.7; found: C 60.0, H 6.3, N 2.9%;
dH (400 MHz, CDCl3) (major isomer) 7.70–7.62 (m, 4H), 7.48–7.42
(m, 3H), 7.22 (d, J¼8.2 Hz, 2H), 4.12–4.08 (m, 1H, H2), 3.82–3.76 (m,
2H), 3.68 (s, 3H, OMe), 2.33 (s, 3H, ArMe), 2.05–2.00 (m, 2H), 1.95–
1.88 (m, 4H), 1.74–1.05 (m, 9H); dC (100.6 MHz, CDCl3) 172.0 (CO),
140.9 (s), 138.5 (s), 136.3 (s), 133.5 (d), 129.5 (d), 128.7 (d), 126.6 (d),
125.4 (d), 68.1 (s), 62.4 (d), 53.8 (OMe), 52.7 (t), 36.7 (d), 31.0 (t),
27.2 (t), 25.2 (t), 24.5 (t), 20.9 (q), 20.4 (t), 18.9 (t), 17.8 (t); dH
4.6.10. Methyl 6-allyl-1-(p-toluenesulfonyl)-1-azaspiro[4.5]decane-
2-carboxylate (28b). Sulfonamide 27b (0.27 g, 0.69 mmol) was
cyclised for 0.25 h at 0 ꢀC using triflic acid (24
mL, 0.28 mmol)
according to general procedure B to give the spiro-pyrrolidine 28b
(0.34 g, 84%) as a colourless, crystalline solid in a 3:1 ratio of di-
astereoisomers, mp 81–84 ꢀC (EtOAc/hexane); C21H29NO4S: calcd C
64.5, H 7.4, N 3.6; found: C 64.4, H 7.6, N 3.7%; dH (400 MHz, CDCl3)
(major isomer) 7.67 (d, J ¼ 8.2 Hz, 2H), 7.21 (d, J 8.2 Hz, 2H),
5.70ꢁ5.66 (m,1H), 5.06 (app. d, J 17.3 Hz,1H; H3c), 4.98 (app. d, J 10.2
Hz, 1H; H3t), 3.74–3.71 (m, 1H; H2), 3.65 (s, 3H; OMe), 2.34 (s, 3H;
ArMe), 2.00–1.97 (m, 2H),1.95–1.91(m, 2H),1.85–1.00ppm (m,11H);

C.M. Griffiths-Jones (ne´e Haskins), D.W. Knight / Tetrahedron 66 (2010) 4150–4166
4161
dC (100 MHz, CDCl3) 173.3 (CO), 143.1 (s), 138.4 (s), 137.2 (d), 129.3
(2 ꢂ d),128.2 (2 ꢂ d),127.0 (d),116.2 (t), 76.1 (s), 62.1 (d), 52.1 (OMe),
43.0 (d), 40.4 (t), 35.8 (t), 32.4 (t), 30.1 (t), 28.8 (t), 25.5 (t), 21.5 ppm
(q); dH (400 MHz, CDCl3) (minor isomer) 7.64 (d, J ¼ 8.2 Hz, 2H), 7.21
(d, J 8.2 Hz, 2H), 5.66–5.62 (m,1H; 2’-:CH), 5.02 (app. d, J 17.3 Hz,1H;
H3c), 4.91 (app. d, J 10.2 Hz, 1H; 3Ht), 3.69-3.66 (m, 1H; H2), 3.57 (s,
3H; OMe), 2.34 (s, 3H; ArMe), 2.00–1.97 (m, 2H), 1.95–1.91 (m, 2H),
1.85–1.00 ppm (m, 11H); dC (100.6 MHz, CDCl3) 172.8 (CO), 143.2 (s),
138.4 (s), 137.2 (d), 129.6 (2ꢂd), 127.9 (2ꢂd), 127.6 (d), 116.2 (t), 76.1
(s), 61.4 (d), 52.0 (OMe), 45.7 (d), 42.0 (t), 35.1 (t), 29.9 (t), 28.3 (t),
27.6 (t), 25.2 (t), 21.5 (q); nmax (KBr)/cmꢁ1 1742; m/z: [APCI] 392
(100%; MþH)þ; HRMS: m/z: calcd for C21H30NO4S: 392.1895; found:
392.1898 [MþH]þ.
(OMe), 39.6 (3-CH2), 25.6 (q), 21.1 (q), 18.0 (q); nmax (KBr)/cmꢁ1
3371, 3106, 1738, 1595, 1442, 1348; m/z [APCI] 402 (100%, [MþH]þ).
4.7.5. Methyl (E)-2-(2-nitrobenzenesulfonylamino)hex-4-enoate (31a).
Colourless solid (0.37 g, 56%), mp 83–85 ꢀC; C13H16N2O6S: calcd C 47.6,
H 4.9, N 8.5; found: C 47.4, H 4.9, N 8.3%; dH (400 MHz, CDCl3) 7.97–
7.96 (m, 1H), 7.83–7.82 (m, 1H), 7.66–7.65 (m, 2H), 5.95 (d, J¼8.7 Hz,
1H, NH), 5.46 (dt, J¼15.2, 7.5 Hz, 1H, H4), 5.15 (dq, J¼15.2, 6.5 Hz, 1H,
H5), 4.17 (dt, J¼8.7, 7.5 Hz, 1H, H2), 3.43 (s, 3H, OMe), 2.40 (t, J¼7.5 Hz,
2H, 3-CH2), 1.53 (d, J¼6.5 Hz, 3H, 5-Me); dC (100.6 MHz, CDCl3) 172.5
(CO), 147.9 (s), 135.2 (s), 133.7 (d), 133.5 (d), 131.6 (d), 131.3 (d), 130.9
(d), 124.1 (d), 62.8 (2-CH), 52.6 (OMe), 32.0 (3-CH2), 21.0 (5-Me); nmax
(KBr)/cmꢁ1 3291, 2955, 1737, 1586, 1437; m/z [APCI] 327 (100%), 269
(52); HRMS: m/z: calcd for C13H17N2O6S: 329.0799; found: 329.0802
[MþH]þ.
4.7. Nitrophenylsulfonyl (nosyl) derivatives
4.7.1. General procedure C: synthesis of nitrosulfonamides (nosyl
derivatives) (29 and 31)16. Crude amines were prepared as de-
scribed in general procedure A. The crude amine was weighed and
immediately dissolved in dry, ethanol-free chloroform
(4 mL mmolꢁ1) at ambient temperature and treated with nitro-
benzenesulfonyl chloride (1.2 equiv), dry pyridine (1.2 equiv) and
a few crystals of 4-(dimethylamino)pyridine. The resulting solution
was stirred at ambient temperature overnight then quenched by
the addition of 2 M aqueous hydrochloric acid (4 mL mmolꢁ1). The
resulting two layers were separated and the aqueous layer extrac-
ted with dichloromethane (2ꢂ2 mL mmolꢁ1). The combined or-
ganic solution was washed with brine, then dried, filtered and
evaporated. The residue was purified by column chromatography
(EtOAc/petrol) or crystallisation (EtOAc/hexanes).
4.7.6. Methyl (E)-2-(4-nitrobenzenesulfonylamino)hex-4-enoate (31b).
Colourless solid (0.583 g, 61%), mp 81–85 ꢀC; dH (400 MHz, CDCl3)
8.28 (d, J¼8.0 Hz, 2H, 2ꢂArH), 8.04 (d, J¼8.0 Hz, 2H, 2ꢂArH), 5.45 (dq,
J¼15.0, 6.6 Hz, 1H, H5), 5.36 (d, J¼8.4 Hz, 1H, NH), 5.11 (dt, J¼15.0,
6.5 Hz, 1H, H4), 4.02–4.00 (m, 1H, H2), 3.51 (s, 3H, OMe), 2.37 (t,
J¼6.5 Hz, 2H, 3-CH2), 1.55 (d, J¼6.6 Hz, 3H, 5-Me); dC (100.6 MHz,
CDCl3) 172.8 (CO), 150.3 (s), 146.7 (s), 129.2 (d), 128.9 (2ꢂd), 124.9 (d),
124.4 (2ꢂd), 62.2 (2-CH), 58.3 (OMe), 32.4 (3-CH2), 21.9 (q); nmax
(KBr)/cmꢁ1 3274, 2957,1736,1538,1442; m/z [APCI] 329 (56%, MþHþ),
269 (100); HRMS: m/z: calcd for C13H20N3O6S: 346.1067; found:
346.1065 [MþNH4]þ.
4.7.7. Methyl (E)-2-(2,4-dinitrobenzenesulfonylamino)hex-4-enoate
(31c). Colourless solid (0.612 g, 47%), mp 78–79 ꢀC; dH (400 MHz,
CDCl3) 8.65 (d, J¼2.0 Hz, 1H), 8.44 (dd, J¼8.6, 2.0 Hz, 1H), 7.87 (d,
J¼8.6 Hz, 1H), 6.03 (br d, J¼7.8 Hz, 1H, NH), 5.56–5.54 (m, 1H, H4),
5.15–5.12 (m, 1H, H5), 4.23–4.21 (m, 1H, H2), 3.49 (s, 3H, OMe),
2.49–2.47 (m, 2H, 3-CH2), 1.34 (d, J¼7.2 Hz, 3H, 5-Me); dC
(100.6 MHz, CDCl3) 171.1 (CO),149.6 (s), 147.7 (s),140.1 (s),132.2 (d),
132.0 (d), 127.1 (d), 122.9 (d), 121.0 (d), 56.4 (2-CH), 52.7 (OMe), 35.9
(3-CH2), 18.0 (q); nmax (KBr)/cmꢁ1 3112, 2928, 1743, 1606, 1539,
1429, 1350; m/z [APCI] 374 (83%, MþHþ), 314 (100); HRMS: m/z:
calcd for C13H16N3O8S: 374.0658; found: 374.0654 [MþH]þ.
All of the following preparations of nosyl derivatives were car-
ried out on 2.0–3.5 mmol scales.
4.7.2. Methyl 2,5-dimethyl-2-(2-nitrobenzenesulfonylamino)hex-4-
enoate (29a). Colourless solid (0.521 g, 61%), mp 88–90 ꢀC;
C15H20N2O6S: calcd C 50.6, H 5.7, N 7.9; found: C 50.4, H 5.7, N 7.7%; dH
(400 MHz, CDCl3) 8.03 (dd, J¼6.5, 1.8 Hz, 1H), 7.82 (dd, J¼6.5, 2.1 Hz,
1H), 7.70–7.60 (m, 2H), 6.06 (s,1H, NH), 4.93 (t, J¼7.6 Hz,1H, H4), 3.75
(s, 3H, OMe), 2.61–2.47(m, 3-CH2),1.79(s, 3H),1.74(s, 3H),1.71(s, 3H);
dC (100.6 MHz, CDCl3) 174.2 (CO),148.8 (s),138.1 (5-C),136.6 (s),133.7
(d),130.6 (d),129.4 (d),123.6 (d),118.1 (4-CH), 60.8 (2-C), 52.8 (OMe),
40.4 (3-CH2), 25.7 (q), 21.6 (q), 18.9 (q); nmax (KBr)/cmꢁ1 3334, 2951,
1738, 1539, 1441, 1344; m/z [APCI] 357 (80%), 155 (100); HRMS: m/z:
calcd for C15H21N2O6S: 357.1114; found: 357.1117 [MþH]þ.
4.7.8. Methyl 1-(2-nitrobenzenesulfonyl)-2,5,5-trimethylpyrrolidine-
2-carboxylate (30a). The sulfonamide 29a (67 mg, 0.19 mmol) was
cyclised at 0 ꢀC for 0.25 h using triflic acid (14 mg, 0.10 mmol)
according to general procedure B to yield the pyrrolidine 30a
(58 mg, 87%) as a colourless, crystalline solid, mp 123–126 ꢀC;
C15H20N2O6S: calcd C 50.6, H 5.6, N 7.9; found: C 50.4, H 5.7, N 7.6%;
dH (400 MHz, CDCl3) 8.00–7.99 (m,1H), 7.55–7.54 (m, 2H), 7.43–7.42
(m, 1H), 3.68 (s, 3H, OMe), 2.28–2.26 (m, 1H, H3a), 1.87–1.85 (m, 3H,
H3b and 4-CH2), 1.71 (s, 3H), 1.40 (s, 3H), 1.17 (s, 3H); dC (100.6 MHz,
CDCl3) 174.5 (CO), 148.9 (s), 136.2 (s), 133.1 (d), 130.9 (d), 129.6 (d),
123.9 (d), 71.2 (2(5)-C), 68.1 (5(2)-C), 40.4 (3(4)-CH2), 36.9 (4(3)-
CH2), 27.8 (q), 27.3 (q), 25.8 (q); nmax (KBr)/cmꢁ1 1742, 1554, 1441,
1346; HRMS: m/z: [APCI] 357 (MþHþ).
4.7.3. Methyl 2,5-dimethyl-2-(4-nitrobenzenesulfonylamino)hex-4-
enoate (29b). Colourless solid (0.750 g, 63%), mp 97–100 ꢀC; dH
(400 MHz, CDCl3) 8.45 (d, J¼8.2 Hz, 2H, 2ꢂArH), 8.17 (d, J¼8.2 Hz,
2H, 2ꢂArH), 5.60 (s, 1H, NH), 5.01 (dd, J¼7.6, 7.2 Hz, 1H, H4), 3.81 (s,
3H, OMe), 2.68 (dd, J¼14.5, 7.6 Hz, 1H, H3a), 2.55 (dd, J¼14.5, 7.2 Hz,
1H, H3b), 1.78 (s, 3H), 1.70 (s, 3H), 1.54 (s, 3H); dC (100.6 MHz, CDCl3)
173.2 (CO), 149.5 (s), 149.1 (s), 137.6 (5-C), 129.1 (d), 123.6 (d), 117.4
(4-CH), 61.9 (2-C), 52.7 (OMe), 38.9 (3-CH2), 26.2 (q), 20.8 (q), 18.5
(q); nmax (KBr)/cmꢁ1 3288, 2954, 1738, 1607, 1537, 1435; m/z [APCI]
357 (85%), 297 (100); HRMS: m/z: calcd for C15H21N2O6S: 357.1114;
found: 357.1115 [MþH]þ.
4.7.9. Methyl 1-(4-nitrobenzenesulfonyl)-2,5,5-trimethylpyrrolidine-
2-carboxylate (30b). The sulfonamide 29b (60 mg, 0.17 mmol) was
cyclised at 0 ꢀC for 0.25 h using triflic acid (13 mg, 0.09 mmol)
according to general procedure B to yield the pyrrolidine 30b
(53 mg, 89%) as a colourless, crystalline solid, mp 126–128 ꢀC;
C15H20N2O6S: calcd C 50.6, H 5.6, N 7.9; found: C 50.8, H 5.8, N
7.5%; dH (400 MHz, CDCl3) 8.24 (d, J¼8.0 Hz, 2ꢂArH), 8.07 (d,
J¼8.0 Hz, 2ꢂArH), 3.69 (s, 3H, OMe), 2.22 (ddd, J¼10.8, 7.2, 4.4 Hz,
1H, H3a), 1.83–1.80 (m, 3H, H3b and 4-CH2), 1.69 (s, 3H), 1.66 (s,
3H), 1.22 (s, 3H); dC (100.6 MHz, CDCl3) 174.1 (CO), 143.5 (s), 139.9
(s), 130.0 (2ꢂd), 127.4 (2ꢂd), 62.6 (s), 60.4 (s), 53.0 (OMe), 39.1
(3(4)-CH2), 32.3 (4(3)-CH2), 26.4 (q), 22.3 (q), 21.9 (q); nmax (KBr)/
4.7.4. Methyl 2,5-dimethyl-2-(2,4-dinitrobenzenesulfonylamino)hex-
4-enoate (29c). Colourless solid (0.598 g, 52%), mp 75–78 ꢀC;
C15H19N3O8S: calcd C 44.9, H 4.8, N 10.5; found: C 44.5, H 4.7, N
11.0%; dH (400 MHz, CDCl3) 8.65 (s, 1H, ArH), 8.48 (d, J¼8.6 Hz, 1H,
ArH), 8.26 (d, J¼8.6 Hz, 1H, ArH), 6.10 (s, 1H, NH), 4.85 (app. t, J¼ca.
7.3 Hz, 1H, H4), 3.61 (s, 3H, OMe), 2.18 (dd, J¼7.3, 6.7 Hz, 1H, H3a),
2.07 (dd, J¼7.3, 6.7 Hz,1H, H3b),1.59 (s, 3H),1.55 (s, 3H),1.50 (s, 3H);
dC (100.6 MHz, CDCl3) 172.5 (CO), 149.4 (s), 146.5 (s), 140.0 (s), 138.5
(5-C), 132.2 (d), 132.0 (d), 127.2 (d), 119.3 (4-CH), 60.4 (2-C), 52.7

4162
C.M. Griffiths-Jones (ne´e Haskins), D.W. Knight / Tetrahedron 66 (2010) 4150–4166
cmꢁ1 1739, 1529, 1348, 1143; m/z [APCI] 357 (100%, MþHþ), 297
(42); HRMS: m/z: calcd for C15H21N2O6S 357.1120; found: 357.1115
[MþH]þ.
for 4 h in gently refluxing chloroform using triflic acid (20 mg,
0.13 mmol) according to general procedure B to give the pyrrolidine
32c (48 mg, 83%) as a colourless, crystalline solid, in a 3:1 ratio of
(2SR,5RS) and (2RS,5RS) diastereoisomers, as an inseparable mix-
ture, mp 80–86 ꢀC; C13H16N3O8S: calcd C 41.7, H 4.3, N 11.2; found: C
41.6, H 4.4, N 11.4%; dH (400 MHz, CDCl3) (major isomer) 8.65 (d,
J¼2.1 Hz, 1H, ArH3), 8.39 (dd, J¼8.6, 2.1 Hz, 1H, ArH5), 8.23 (d,
J¼8.6 Hz, 1H, ArH6), 4.52 (app. d, J¼8.5 Hz, 1H, H2), 4.31–4.27 (m,
1H, H5), 3.58 (s, 3H, OMe), 2.29–2.25 (m, 1H, 3Ha), 2.16–2.12 (m, 1H,
3Hb), 1.96 (ddd, J¼12.0, 6.7, 1.3 Hz, 1H, H4a), 1.59–1.56 (m, 1H, H4b),
1.10 (d, J¼6.4 Hz, 3H, 5-Me); dC (100.6 MHz, CDCl3) 174.8 (CO), 149.2
(s), 146.4 (s), 139.6 (s), 132.3 (d), 132.1 (d), 129.3 (d), 68.6 (d), 59.0
(d), 52.9 (OMe), 38.9 (t), 31.3 (t), 20.2 (q); dH (400 MHz, CDCl3)
(minor isomer) 8.65 (d, J¼2.1 Hz, 1H, ArH3), 8.40 (dd, J¼8.6, 2.1 Hz,
1H, ArH5), 8.24 (d, J¼8.4 Hz, 1H, ArH6), 4.56 (dd, J¼8.2, 4.4 Hz, 1H,
H2), 4.10–4.07 (m, 1H, H5), 3.66 (s, 3H, OMe), 2.34–2.29 (m, 1H,
H3a), 2.14–2.11 (m, 1H, H3b), 2.04–2.00 (m, 1H, H4a), 1.61–1.58 (m,
1H, H4b), 1.28 (d, J¼6.3 Hz, 3H, 5-Me); dC (100.6 MHz, CDCl3) 174.7
(CO), 149.2 (s), 146.3 (s), 139.5 (s), 132.3 (d), 132.1 (d), 129.6 (d), 68.6
(d), 59.0 (d), 52.9 (OMe), 38.9 (t), 31.3 (t), 20.2 (q); nmax (KBr)/cmꢁ1
2956, 1747, 1538, 1462, 1352; m/z [APCI] 374 (100%, MþHþ), 314
(64); HRMS: m/z: calcd for C13H19N4O8S 391.0924; found: 391.0921
[MþNH4]þ.
4.7.10. Methyl 1-(2,4-dinitrobenzenesulfonyl)-2,5,5-trimethylpyrro-
lidine-2-carboxylate (30c). The sulfonamide 29c (88 mg, 0.22 mmol)
was cyclised at 0 ꢀC for 0.25 h using triflic acid (20 mg, 0.13 mmol)
according to general procedure B to yield the pyrrolidine 30c (77 mg,
87%) as a colourless, crystalline solid, mp 118–120 ꢀC; dH (400 MHz,
CDCl3)8.63(s,1H),8.46(d, J¼8.4 Hz,1H), 7.88(d,J¼8.4 Hz,1H), 3.68(s,
3H, OMe), 2.29–2.26 (m, 2H), 2.14–2.11 (m, 2H), 1.51 (s, 3H), 1.48 (s,
3H),1.46 (s, 3H); dC (100.6 MHz, CDCl3) 175.2 (CO),149.2 (s),146.5 (s),
139.8 (s), 132.4 (d), 132.1 (d), 127.4 (d), 63.0 (s), 60.9 (s), 52.8 (OMe),
39.6 (t), 32.1 (t), 26.6 (q), 22.8(q),18.9 (q);nmax (KBr)/cmꢁ1 2956,1738,
1606, 1538, 1462, 1350; m/z [APCI] 402 (100%, MþHþ); HRMS: m/z:
calcd for C15H23N4O8S 419.1237; found: 419.1236 [MþNH4]þ.
4.7.11. Methyl (2RS,5RS)- and (2SR,5RS)-5-methyl-1-(2-nitro-
benzenesulfonyl)pyrrolidine-2-carboxylate (32a). The sulfonamide
31a (86 mg, 0.25 mmol), derived from crotyl chloride, was cyclised
for 4 h in gently refluxing chloroform using triflic acid (22 mg,
0.15 mmol) according to general procedure B to give the pyrroli-
dine 32a (74 mg, 86%) as a colourless, crystalline solid, in a 3:1
ratio of (2SR,5RS) and (2RS,5RS) diastereoisomers, as an in-
separable mixture, mp 99–104 ꢀC; dH (400 MHz, CDCl3) (major
isomer) 8.06–8.05 (m, 1H), 7.63–7.61 (m, 2H), 7.55–7.54 (m, 1H),
4.52 (app. d, J¼9.2 Hz, 1H, H2), 4.31–4.28 (m, 1H, H5), 3.58 (s, 3H,
OMe), 2.40–1.63 (m, 4H, 2ꢂCH2), 1.02 (d, J¼6.4 Hz, 3H, 5-Me); dC
(100.6 MHz, CDCl3) 175.6 (CO), 148.6 (s), 135.9 (s), 132.8 (d), 131.0
(d), 129.5 (d), 123.7 (d), 66.5 (d), 57.8 (d), 52.8 (OMe), 38.1 (t), 30.8
(t), 20.3 (q); dH (400 MHz, CDCl3) (minor isomer) 8.07–8.06 (m,
1H), 7.64–7.62 (m, 2H), 7.55–7.53 (m, 1H), 4.51–4.47 (m, 1H, H2),
4.01 (dq, J¼8.9, 6.4 Hz, 1H, H5), 3.68 (s, 3H, OMe), 2.40–1.63 (m,
4H, 2ꢂCH2), 1.32 (d, J¼6.4 Hz, 3H, 5-Me); dC (100.6 MHz, CDCl3)
174.8 (CO), 148.9 (s), 136.1 (s), 133.0 (d), 130.9 (d), 129.6 (d), 123.8
(d), 67.7 (d), 56.6 (d), 52.9 (OMe), 38.8 (t), 30.2 (t), 20.7 (q); nmax
(KBr)/cmꢁ1 1740, 1552, 1444, 1359, 1148; m/z [APCI] 329 (100%,
MþHþ), 269 (84); HRMS: m/z: calcd for C13H17N2O6S 329.0807;
found: 329.0806 [MþH]þ.
4.8. Carbamates
4.8.1. Methyl 2,5-dimethyl-2-(methoxycarbonylamino)hex-4-enoate
(33). Methyl 2-amino-2,5-dimethylhex-4-enoate (2.30 g, 13 mmol;
see Schemes 2 and 3), prepared according to general procedure A,
was immediately dissolved in methanol (10 mL) containing anhy-
drous potassium carbonate (2.48 g, 18 mmol) and methyl chlor-
oformate (1.25 mL, 16 mmol) added dropwise. The resulting
solution was refluxed for 2 h then cooled and evaporated. The
residue was dissolved in ether (30 mL) and water (20 mL) and the
separated organic solution washed with water (50 mL) and brine
(50 mL), then dried, filtered and evaporated. Crystallisation of the
residue from ethyl acetate/hexanes then gave the carbamate 33
(2.20 g, 64%) as a yellowish solid, mp 64–66 ꢀC; dH (400 MHz,
CDCl3) 5.33 (s, 1H, NH), 4.91 (t, J¼7.4 Hz, 1H, H4), 3.68 (s, 3H, OMe),
3.58 (s, 3H, OMe), 2.64 (dd, J¼14.4, 7.4 Hz,1H, H3a), 2.43 (dd, J¼14.4,
7.4 Hz, 1H, H3b), 1.64 (s, 3H), 1.54 (s, 3H), 1.46 (s, 3H); dC (100.6 MHz,
CDCl3) 174.6 (CO), 164.2 (NCO), 136.6 (5-C), 117.4 (4-CH), 59.8 (2-C),
52.6 (OMe), 51.9 (OMe), 36.0 (3-CH2), 26.1 (q), 23.0 (q),17.9 (q); nmax
(KBr)/cmꢁ1 3354, 2952, 1728, 1724, 1524, 1453, 1376; m/z [APCI] 230
(69%, MþHþ), 170 (100, MþꢁCO2Me); HRMS: m/z: calcd for
C11H20NO4: 230.1387; found: 230.1387 [MþH]þ.
4.7.12. Methyl (2RS,5RS)- and (2SR,5RS)-5-methyl-1-(4-nitro-
benzenesulfonyl)pyrrolidine-2-carboxylate (32b). The sulfonamide
31b (44 mg, 0.13 mmol), derived from crotyl chloride, was cyclised
for 4 h in gently refluxing chloroform using triflic acid (11 mg,
0.075 mmol) according to general procedure B to give the pyrroli-
dine 32b (38 mg, 86%) as a colourless, crystalline solid, in a 3:1 ratio
of (2SR,5RS) and (2RS,5RS) diastereoisomers, as an inseparable
mixture, mp 87–93 ꢀC; C13H16N2O6S: calcd C 47.6, H 4.9, N 8.5;
found: C 47.3, H 5.0, N 8.6%; dH (400 MHz, CDCl3) (major isomer)
8.34 (d, J¼7.9 Hz, 2H, 2ꢂArH), 8.06 (d, J¼7.9 Hz, 2H, 2ꢂArH), 4.54
(dd, J¼8.6, 1.3 Hz, 1H, H2), 4.08 (app. pent., J¼6.4 Hz, 1H, H5), 3.68
(s, 3H, OMe), 2.40–1.60 (m, 4H, 2ꢂCH2), 1.27 (d, J¼6.4 Hz, 3H, 5-
Me); dC (100.6 MHz, CDCl3) 174.4 (CO), 148.7 (s), 142.6 (s), 128.8
(2ꢂd), 127.0 (2ꢂd), 66.5 (d), 58.2 (d), 52.7 (OMe), 38.6 (t), 31.2 (t),
20.3 (q); dH (400 MHz, CDCl3) (minor isomer) 8.36 (d, J¼7.9 Hz, 2H,
2ꢂArH), 8.11 (d, J¼7.9 Hz, 2H, 2ꢂArH), 4.41 (dd, J¼7.7, 5.7 Hz, 1H,
H2), 3.97–3.90 (m, 1H, H5), 3.76 (s, 3H, OMe), 2.40–1.60 (m, 4H,
2ꢂCH2), 1.30 (d, J¼6.4 Hz, 3H, 5-Me); dC (100.6 MHz, CDCl3) 174.6
(CO), 143.7 (s), 140.1 (s), 129.7 (2ꢂd), 127.3 (2ꢂd), 68.1 (d), 59.2 (d),
53.0 (OMe), 37.9 (t), 32.4 (t), 19.8 (q); nmax (KBr)/cmꢁ1 1737, 1533,
1344, 1150; m/z [APCI] 329 (100%, MþHþ); HRMS: m/z: calcd for
C13H17N2O6S 329.0807; found: 329.0810 [MþH]þ.
4.8.2. Dimethyl 2,5,5-trimethylpyrrolidine-1,2-dicarboxylate (34).
The carbamate 33 (140 mg, 0.61 mmol) was cyclised at ambient
temperature for 2 h using triflic acid (174 mg, 1.22 mmol, 2 equiv)
according to general procedure B to give the pyrrolidine 34 (96 mg,
69%) as a colourless, crystalline solid, mp 88–91 ꢀC; C11H19NO4:
calcd C 57.6, H 8.3, N 6.1; found: C 57.5, H 8.0, N 6.3%; dH (400 MHz,
CDCl3) 3.60 (s, 3H, OMe), 3.50 (s, 3H, OMe), 2.05 (ddd, J¼11.6, 7.8,
4.6 Hz, 1H, H3a), 1.76–1.73 (m, 3H, H3b and 4-CH2), 1.42 (s, 3H), 1.35
(s, 3H), 1.31 (s, 3H); dC (100.6 MHz, CDCl3) 175.3 (CO), 153.6 (CO),
67.3 (s), 63.4 (s), 52.6 (OMe), 51.9 (OMe), 39.3 (t), 36.0 (t), 27.8 (q),
24.5 (q), 23.5 (q); nmax (KBr)/cmꢁ1 2955, 1745, 1694, 1442, 1360; m/z
[APCI] 230 (33%, MþHþ), 170 (100; MþꢁCO2Me); HRMS: m/z: calcd
for C11H20NO4 230.1387; found: 230.1384 [MþH]þ.
4.8.3. Methyl (E)-2-(methoxycarbonylamino)-5-phenylpent-4-eno-
ate (35a). By the foregoing procedure, reaction between methyl
(E)-2-amino-5-phenylpent-4-enoate (1.30 g, 6.1 mmol) and methyl
chloroformate (0.57 mL, 7.3 mmol) gave, after crystallisation from
ethyl acetate/hexanes, the carbamate 35a (0.96 g, 51%) as
4.7.13. Methyl (2RS,5RS)- and (2SR,5RS)-1-(2,4-dinitrobenzenesul-
fonyl)-5-methylpyrrolidine-2-carboxylate (32c). The sulfonamide
31c (59 mg, 0.16 mmol), derived from crotyl chloride, was cyclised

C.M. Griffiths-Jones (ne´e Haskins), D.W. Knight / Tetrahedron 66 (2010) 4150–4166
4163
a yellowish solid, mp 99–105 ꢀC; dH (400 MHz, CDCl3) 7.29–7.27 (m,
2H), 7.15–7.12 (m, 3H), 6.32 (d, J¼15.3 Hz, 1H, H5), 5.97 (dt, J¼15.3,
7.5 Hz, 1H, H4), 5.34 (d, J¼9.0 Hz, 1H, NH), 4.24–4.22 (m, 1H, H2),
3.65 (s, 3H, OMe), 3.62 (s, 3H, OMe), 2.56–2.53 (m, 2H, 3-CH2); dC
(100.6 MHz, CDCl3) 174.3 (CO), 160.0 (NCO), 136.7 (s), 130.5 (d),
127.9 (d), 127.2 (d), 125.8 (d), 123.2 (d), 56.5 (2-CH), 52.7 (OMe), 51.8
(OMe), 35.9 (3-CH2); nmax (KBr)/cmꢁ1 3299, 2967, 1729, 1726, 1537,
1150; m/z [APCI] 264 (100%, MþHþ), 206 (92, MþꢁCO2Me).
(2ꢂd), 65.9 (s), 58.4 (d), 55.0 (d), 51.9 (OMe), 40.3 (t), 38.0 (t), 32.9
(q), 28.6 (t), 21.7 (q), 20.5 (q), 20.3 (t), 19.5 (q); nmax (KBr)/cmꢁ1
2942, 1752, 1459, 1322, 1152; m/z: [APCI] 380 (100%; MþH)þ;
HRMS: m/z: calcd for C20H29NO4S: 379.1800; found: 379.1802 [M]þ.
Careful column chromatography (silica gel, 20% EtOAc in petrol)
separated a fraction enriched in the major isomer 43a.maj, crys-
tallisation of which from EtOAc/hexane gave prisms, mp 132–
135 ꢀC, of approximately 90% purity in terms of isomer ratio.
4.8.4. Methyl (E)-2-(methoxycarbonylamino)hex-4-enoate (35b). By
the foregoing procedure, reaction between methyl (E)-2-amino-
hex-4-enoate (0.70 g, 4.9 mmol) and methyl chloroformate
(0.46 mL, 5.9 mmol) gave, after crystallisation from ethyl acetate/
hexanes, the carbamate 35b (0.712 g, 58%) as an off-white solid, mp
57–59 ꢀC; C9H15NO4: calcd C 53.7, H 7.5, N 7.0; found: C 53.7, H 7.8,
N 6.6%; dH (400 MHz, CDCl3) 5.36 (d, J¼8.8 Hz, 1H, NH), 5.32 (dq,
J¼14.8, 6.5 Hz, 1H, H5), 4.98 (ddd, J¼14.8, 7.6, 7.4 Hz, 1H, H4), 4.36–
4.35 (m, 1H, H2), 3.67 (s, 3H, OMe), 3.58 (s, 3H, OMe), 2.59 (dt,
J¼14.5, 7.4 Hz, H3a), 2.47 (ddd, J¼14.5, 7.6, 7.4 Hz, 1H, H3b), 1.52 (d,
J¼6.5 Hz, 3H, 5-Me); dC (100.6 MHz, CDCl3) 175.2 (CO), 162.3 (NCO),
121.4 (d), 117.4 (d), 57.5 (2-CH), 51.8 (OMe), 50.7 (OMe), 35.1 (3-
CH2), 19.9 (q); nmax (KBr)/cmꢁ1 3353, 2956, 1732, 1728, 1554, 1432;
m/z [APCI] 202 (88%, MþHþ), 142 (100, MþꢁCO2Me).
4.9.3. Methyl (E)-2-(p-toluenesulfonylamino)-2,5,9-trimethyldeca-
4,8-dienoate (41b). Geranyl bromide 40 (2.9 mL, 14 mmol) was
used to alkylate methyl 2-(benzylideneamino)propanoate 10b
(2.50 g, 13 mmol) according to general procedure A to give an
intermediate imine: dH (400 MHz, CDCl3) 8.12 (s, 1H, N]CH),
7.71–7.66 (m, 2H), 7.38–7.35 (m, 3H), 5.46 (t, J¼8.5 Hz, 1H), 5.05–
5.00 (m, 1H), 3.66 (s, 3H, OMe), 2.57 (t, J¼7.8 Hz, 2H), 2.00–1.95 (m,
4H), 1.66 (s, 3H), 1.53 (s, 3H), 1.41 (s, 3H), 1.36 (s, 3H).
The crude imine was hydrolysed and tosylated followed by
column chromatography (25% ethyl acetate/petrol) to give the
geranyl sulfonamide 41b (1.90 g, 44%) as a pale yellow oil; Rf 0.38
(25% EtOAc/petrol); dH (400 MHz, CDCl3) 7.68 (d, J¼8.2 Hz, 2H), 7.24
(d, J¼8.2 Hz, 2H), 5.22 (s, 1H, NH), 5.00 (t, J¼8.1 Hz, 1H), 4.86 (t,
J¼7.5 Hz, 1H), 3.56 (s, 3H, OMe), 2.44 (dd, J¼14.3, 8.1 Hz, 1H, H3a),
2.34 (dd, J¼14.3, 7.5 Hz, 1H, H3b), 2.34 (s, 3H, ArMe), 1.98–1.90 (m,
4H), 1.62 (s, 3H), 1.53 (s, 3H), 1.51 (s, 3H), 1.35 (s, 3H); dC (100.6 MHz,
CDCl3) 174.2 (CO),143.7 (s),142.9 (s),139.6 (s),137.2 (s),129.8 (2ꢂd),
129.0 (2ꢂd), 127.1 (d), 118.5 (d), 60.0 (s), 48.2 (OMe), 42.0 (t), 40.6
(t), 39.6 (t), 28.9 (q), 21.5 (q), 20.7 (q), 19.8 (q), 14.1 (q); nmax (film)/
cmꢁ1 3518, 3272, 2950, 1738, 1598; m/z: [APCI] 394 (100%; MþH)þ;
HRMS: m/z: calcd for C21H31NO4S: 393.1974; found: 393.1976 [M]þ.
4.9. Cascade cyclisations
4.9.1. Methyl (E)-5,9-dimethyl-2-(p-toluenesulfonylamino)deca-4,8-
dienoate (41a). Geranyl bromide 40 (3.2 mL, 16 mmol) was used
to alkylate methyl 2-(benzylideneamino)acetate 10a (2.50 g,
14 mmol) according to general procedure A to give an intermediate
imine: dH (400 MHz, CDCl3) 8.07 (s, 1H, N]CH), 7.65–7.60 (m, 2H),
7.30–7.26 (m, 3H), 4.95–4.90 (m, 2H), 3.83 (dd, J¼8.3, 5.4 Hz, 1H,
H2), 3.63 (s, 3H, OMe), 2.52–2.48 (m, 2H), 1.90–1.80 (m, 4H), 1.52 (s,
3H), 1.46 (s, 3H), 1.42 (s, 3H).
The crude imine was hydrolysed and tosylated followed by
column chromatography (25% ethyl acetate/petrol) to give the
geranyl sulfonamide 41a (1.72 g, 39%) as a pale yellow oil; Rf 0.40
(25% EtOAc/petrol); dH (400 MHz, CDCl3) 7.62 (d, J¼8.2 Hz, 2H), 7.22
(d, J¼8.2 Hz, 2H), 5.01 (d, J¼9.3 Hz, 1H, NH), 4.97 (t, J¼6.7 Hz, 1H),
4.88 (t, J¼6.9 Hz, 1H), 3.92 (dt, J¼9.3, 5.7 Hz, 1H, H2), 3.56 (s, 3H,
OMe), 2.35–2.31 (m, 2H), 2.32 (s, 3H, ArMe), 1.95–1.85 (m, 4H), 1.53
(s, 3H), 1.51 (s, 3H), 1.49 (s, 3H); dC (100.6 MHz, CDCl3) 172.7 (CO),
143.6 (s),143.1 (s),139.4 (s),137.3 (s),129.7 (2ꢂd),129.0 (2ꢂd),127.4
(d), 118.1 (d), 59.2 (d), 51.3 (OMe), 42.0 (t), 40.9 (t), 39.2 (t), 28.2 (q),
21.1 (q), 19.6 (q), 14.8 (q); nmax (film)/cmꢁ1 3526, 3259, 2939, 1737;
m/z: [APCI] 380 (100%; MþH)þ; HRMS: m/z: calcd for C20H29NO4S:
379.1817; found: 379.1813 [M]þ.
4.9.4. Methyl (2RS/SR,3aRS,7aRS)-2,4,4,7a-tetramethyl-1-(p-tolue-
nesulfonyl)octahydroindole-2-carbxylate (43b). The foregoing sul-
fonamide 41b (0.63 g, 1.9 mmol) was cyclised for 0.25 h at 0 ꢀC
using triflic acid (0.11 g, 0.77 mmol) as described in general pro-
cedure B followed by crystallisation from dichloromethane gave the
octahydroindole 43b (0.57 g, 91%) as a colourless solid and a mixture
of two diastereoisomers in a 3:2 ratio, mp 87–89 ꢀC; C21H31NO4S:
calcd C 64.1, H 7.7, N 3.6; found: C 64.2, H 7.9, N 3.7%; dH (400 MHz,
CDCl3) (major isomer) 7.65 (d, J¼8.2 Hz, 2H), 7.18 (d, J¼8.2 Hz, 2H),
3.78 (s, 3H, OMe), 2.34 (s, 3H, ArMe), 2.15–2.10 (m, 2H), 1.80–1.74
(m, 5H), 1.71 (s, 3H), 1.32 (s, 3H), 0.80 (s, 3H), 0.75 (s, 3H); dC
(100.6 MHz, CDCl3) 174.7 (CO), 141.8 (s), 141.4 (s), 128.1 (2ꢂd),
126.5 (2ꢂd), 67.7 (s), 65.7 (s), 54.7 (d), 51.6 (OMe), 39.3 (d), 37.2 (t),
36.6 (t), 31.7 (q), 24.7 (t), 20.5 (q), 19.5 (q), 19.4 (q), 13.1 (q); dH
(400 MHz, CDCl3) (minor isomer) 7.80 (d, J¼8.2 Hz, 2H), 7.18 (d,
J¼8.2 Hz, 2H), 3.71 (s, 3H, OMe), 2.34 (s, 3H, ArMe), 2.15–2.10 (m,
2H), 1.80–1.74 (m, 5H), 1.32 (s, 3H), 1.11 (s, 3H), 0.77 (s, 3H), 0.73 (s,
3H); dC (100.6 MHz, CDCl3) 174.1 (CO), 140.8 (s), 139.7 (s), 127.3
(2ꢂd), 126.0 (2ꢂd), 66.9 (s), 66.8 (s), 53.8 (d), 51.6 (OMe), 41.0 (t),
39.1 (t), 37.1 (t), 31.8 (q), 26.2 (t), 20.4 (q), 19.8 (q), 19.4 (q), 19.0
(q); nmax (KBr)/cmꢁ1 2950, 1740, 1598, 1459, 1092; m/z: [APCI] 394
(100%; MþH)þ; HRMS: m/z: calcd for C21H31NO4S: 393.1974;
found: 393.1978 [M]þ.
4.9.2. Methyl (2RS/SR,3aRS,7aRS)-4,4,7a-trimethyl-1-(p-toluenesulf-
onyl)octahydroindole-2-carboxylate (43a). The foregoing sulfon-
amide 41a (0.55 g, 1.8 mmol) was cyclised for 0.25 h at 0 ꢀC using
triflic acid (0.11 g, 0.77 mmol) as described in general procedure B
followed by crystallisation from EtOAc/hexanes gave the octahy-
droindole 43a (0.48 g, 88%) as a colourless solid and a mixture of
two diastereoisomers in a 3:1 ratio, mp 92–94 ꢀC; C20H29NO4S:
calcd C 63.3, H 7.7, N 3.6; found: C 63.3, H 7.7, N 3.8%; dH (400 MHz,
CDCl3) (major isomer) 7.76 (d, J¼8.2 Hz, 2H), 7.19 (d, J¼8.2 Hz, 2H),
4.34 (app. d, J¼9.3 Hz, 1H, H2), 3.53 (s, 3H, OMe), 2.34 (s, 3H, ArMe),
2.30–1.10 (m, 9H), 1.55 (s, 3H), 1.22 (s, 3H), 0.80 (s, 3H); dC
(100.6 MHz, CDCl3) 173.4 (CO),143.2 (s),138.9 (s),129.2 (2ꢂd),128.1
(2ꢂd), 67.8 (s), 58.2 (d), 55.0 (d), 52.2 (OMe), 40.2 (t), 38.3 (t), 32.8
(q), 28.1 (t), 21.6 (q), 20.6 (q), 20.4 (t), 19.2 (q); dH (400 MHz, CDCl3)
(minor isomer) 7.71 (d, J¼8.2 Hz, 2H), 7.19 (d, J¼8.2 Hz, 2H), 4.29
(app. d, J¼8.9 Hz, 1H, H2), 3.73 (s, 3H, OMe), 2.35 (s, 3H, ArMe),
2.30–0.90 (m, 9H), 1.52 (s, 3H), 1.25 (s, 3H), 0.76 (s, 3H); dC
(100.6 MHz, CDCl3) 172.7 (CO),143.2 (s),138.8 (s),129.4 (2ꢂd),127.8
4.9.5. (2E,6E)-1-Bromo-3,7,11-trimethyldodeca-2,6,10-trienoate (far-
nesyl bromide)30 (46). (E,E)-Farnesol (2.50 g, 8.6 mmol) was dis-
solved in ether (30 mL) and the solution cooled in ice-water and
protected from light. Pyridine (4.3 mL, 66 mmol) was added fol-
lowed by phosphorus tribromide (1.0 mL, 14 mmol). The resulting
mixture was then stirred for 3 h without further cooling and the
solvent evaporated. The bromide 46 (6.2 g, 72%), a pale yellow oil,
was removed by pipette from the solid residue and used immedi-
ately in the next step: dH (400 MHz, CDCl3) 5.47 (t, J¼7.8 Hz, 1H),
5.05–5.00 (m, 2H), 3.94 (br d, J¼7 Hz, 2H, CH2Br), 2.10–1.90 (m, 8H),
1.61 (s, 6H), 1.53 (s, 6H); dC (100.6 MHz, CDCl3) 144.0 (s), 136.0 (s),

4164
C.M. Griffiths-Jones (ne´e Haskins), D.W. Knight / Tetrahedron 66 (2010) 4150–4166
131.8 (s), 124.7 (d), 123.8 (d), 120.9 (d), 40.2 (t), 32.4 (t), 30.1 (t), 27.1
(t), 26.5 (t), 26.1 (q), 23.8 (q), 18.1 (q).30
1.52 (s, 6H), 1.22 (s, 3H); nmax (film)/cmꢁ1 3162, 2984, 1721, 1398; m/
z: [APCI] 462 (100%; MþH)þ; HRMS: m/z: calcd for C26H39NO4S:
461.2600; found: 461.2622 [M]þ.
4.9.6. Methyl (4E,8E)-5,9,13-trimethyl-2-(p-toluenesulfonylamino)-
tetradeca-4,8,12-trienoate (47a). Farnesyl bromide 46 (see above;
1.8 g, 6.2 mmol) was used to alkylate methyl 2-(benzylideneami-
no)acetate 10a (1.0 g, 5.6 mmol) according to general procedure A
to give the expected imine: dH (400 MHz, CDCl3) 8.13 (s,1H, N]CH),
7.86–7.82 (m, 2H), 7.35–7.30 (m, 3H), 5.35 (t, J¼7.6 Hz, 1H), 5.04–
5.00 (m, 2H), 3.88 (dd, J¼8.3, 5.5 Hz, 1H, H2), 3.69 (s, 3H, OMe), 2.66
(dd, J¼14.2, 5.5 Hz, 1H, H3a), 2.51 (dd, J¼14.2, 8.3 Hz, 1H, H3b), 2.10–
1.90 (m, 8H), 1.60 (s, 6H), 1.52 (s, 6H). This crude imine was
hydrolysed and tosylated as usual and the crude product purified
by column chromatography (25% ethyl acetate/petrol) to give the
farnesyl sulfonamide 47a (0.78 g, 36%) as a pale yellow oil; Rf 0.38
(25% EtOAc/petrol); dH (400 MHz, CDCl3) 7.82 (d, J¼8.2 Hz, 2H), 7.39
(d, J¼8.2 Hz, 2H), 5.21 (d, J¼8.8 Hz, 1H, NH), 5.20–5.16 (m, 2H), 5.06
(t, J¼7.1 Hz, 1H), 4.10–4.07 (m, 1H, H2), 3.62 (s, 3H, OMe), 2.67–
2.51 (m, 2H), 2.51 (s, 3H, ArMe), 2.20–2.00 (m, 8H), 1.78 (s, 6H),
1.72 (s, 6H); dC (100.6 MHz, CDCl3) 173.2 (CO), 143.5 (s), 143.0 (s),
139.8 (s), 138.6 (s), 137.7 (s), 129.5 (2ꢂd), 128.6 (2ꢂd), 126.3 (d),
118.9 (d), 115.2 (d), 61.4 (2-CH), 52.0 (OMe), 43.1 (t), 42.7 (t), 41.3
(t), 40.8 (t), 39.4 (t), 28.6 (q), 21.7 (q), 20.4 (q), 19.3 (q), 15.8 (q);
nmax (film)/cmꢁ1 3278, 2975, 1735, 1451, 1273; m/z: [APCI] 448
(100%; MþH)þ; HRMS: m/z: calcd for C25H37NO4S: 447.2443;
found: 447.2452 [M]þ.
4.9.9. Methyl 2,3a,6,6,9a-pentamethyl-3-(p-toluenesulfonyl)dodeca-
hydro-1H-benzo[e]indole-2-carboxylate (48b). The foregoing far-
nesyl sulfonamide 47b (0.39 g, 0.85 mmol) was cyclised for 0.25 h
at 0 ꢀC by the general procedure B using triflic acid (51 mg,
0.34 mmol). The crude product was purified by column chroma-
tography (dichloromethane) to give the tricycle 48b (0.33 g, 86%) as
a pale yellow oil and as a 1:1:3:3 mixture of diastereoisomers. dH
(400 MHz, CDCl3) (major isomers) 7.78 (d, J¼8.2 Hz, 2H), 7.19 (d,
J¼8.2 Hz, 2H), 3.75 (s, 3H, OMe), 3.63 (s, 3H, OMe), 2.34 (s, 3H,
ArMe), 2.33 (s, 3H, ArMe), 2.20–0.90 (m, 14H), 1.80 (s, 3H), 1.79 (s,
3H), 1.62 (s, 3H), 1.56 (s, 3H), 1.54 (s, 3H), 1.35 (s, 3H), 1.34 (s, 3H),
1.08 (s, 3H), 1.00 (s, 3H); dH (400 MHz, CDCl3) (minor isomers) 7.76
(d, J¼8.2 Hz, 2H), 7.72 (d, J¼8.2 Hz, 2H), 7.20 (d, J¼8.2 Hz, 2H), 7.18
(d, J¼8.2 Hz, 2H), 3.77 (s, 3H, OMe), 3.50 (s, 3H, OMe), 2.34 (s, 3H,
ArMe), 2.20–0.90 (m, 14H), 1.68 (s, 3H), 1.61 (s, 3H), 1.59 (s, 3H), 1.51
(s, 3H), 1.48 (s, 3H), 1.21 (s, 3H), 1.09 (s, 3H); dC (100.6 MHz, CDCl3)
(whole sample) 173.5 (CO), 171.2 (CO), 170.8 (CO), 143.7 (s), 143.6
(s), 139.3 (s), 139.1 (s), 139.0 (s), 130.6 (d), 129.6 (d), 129.5 (d), 128.7
(d), 128.6 (d), 127.5 (d), 71.0 (s), 69.4 (s), 68.2 (s), 66.7 (s), 66.1 (s),
52.4 (OMe), 52.2 (OMe), 52.1 (OMe), 41.2 (d), 39.7 (d), 39.3 (t),
39.2 (t), 39.0 (t), 38.6 (d), 38.4 (d), 38.1 (t), 37.9 (t), 37.6 (t), 37.4
(t), 36.9 (t), 36.7 (t), 35.8 (t), 35.2 (t), 31.6 (t), 31.3 (t), 25.6 (q),
25.0 (t), 24.9 (t), 21.2 (t), 20.9 (t), 20.5 (s), 20.1 (s), 20.0 (s), 19.9
(t), 19.8 (t), 19.8 (s), 19.6 (s), 19.5 (q), 19.4 (q), 19.2 (q), 19.1 (q),
18.8 (q), 18.4 (q), 18.3 (q), 18.0 (q), 17.9 (q), 17.5 (q), 17.2 (q); nmax
(film)/cmꢁ1 2923, 2852, 1744, 1462, 1262; m/z: [APCI] 462 (100%;
MþH)þ; HRMS: m/z: calcd for C26H39NO4S: 461.2600; found:
461.2609 [M]þ.
4.9.7. Methyl 3a,6,6,9a-tetramethyl-3-(p-toluenesulfonyl)dodecahy-
dro-1H-benzo[e]indole-2-carboxylate (48a). The foregoing farnesyl
sulfonamide 47a (0.60 g, 1.60 mmol) was cyclised for 0.25 h at 0 ꢀC
by the general procedure B using triflic acid (95 mg, 0.60 mmol).
The crude product was purified by column chromatography
(dichloromethane) to give the tricycle 48a (0.52 g, 86%) as a pale
yellow oil: dH (400 MHz, CDCl3) (whole sample) 7.80–7.60 (m, 2H),
7.15–7.05 (m, 2H), 4.32–4.25 (m, 1H), 3.68–3.60 (m, 1H), 3.47, 3.45,
3.44, 3.42 (all s, total 3H, OMe), 2.33–2.27 (m, 3H, ArMe), 2.10–0.70
(m, 14H), 1.55, 1.53 1.48, 1.46, 1.33, 1.24, 0.92, 0.90, 0.88, 0.77, 0.75,
0.74 (all s, total 12H, Me); dC (100.6 MHz, CDCl3) (whole sample)
174.5 (CO), 172.3 (CO), 172.1 (CO), 170.9 (CO), 145.6 (s), 144.2 (s),
143.7 (s), 139.9 (s), 139.8 (s), 131.0 (d), 130.5 (d), 130.4 (d), 129.9
(d), 129.1 (d), 128.7 (d), 69.9 (d), 68.9 (d), 68.1 (d), 67.2 (s), 66.5
(s), 66.4 (s), 52.4 (OMe), 52.2 (OMe), 39.8 (d), 39.6 (d), 38.7 (d),
36.2 (t), 36.0 (t), 35.7 (t), 35.0 (t), 34.8 (t), 34.6 (t), 34.5 (t), 32.3
(s), 31.8 (s), 29.8 (t), 29.6 (t), 29.4 (t), 28.7 (t), 28.3 (t), 27.2 (t),
27.0 (t), 26.9 (t), 26.5 (q), 26.3 (q), 26.2 (q), 25.9 (q), 24.6 (s), 24.0
(s), 23.3 (s), 23.3 (q), 22.9 (q), 22.4 (q), 21.8 (q), 21.2 (t), 20.7 (t),
20.6 (t), 19.9 (q), 19.5 (q), 19.2 (q), 18.8 (q), 18.4 (q), 17.9 (q); nmax
(film)/cmꢁ1 2928, 1743, 1598, 1477; m/z: [APCI] 448 (100%;
MþH)þ; HRMS: m/z: calcd for C25H37NO4S: 447.2443; found:
447.2450 [M]þ.
4.9.10. (2E,6E,10E)-1-Bromo-2,6,10,14-tetramethylhexadeca-
2,6,10,14-tetraene31 (49). Geranylgeraniol (0.88 g, 3 mmol) was
dissolved in dry ether (5 mL) and the solution stirred, protected
from light and cooled in an ice-water bath. Pyridine (0.48 mL,
6 mmol) was added followed by phosphorus tribromide
(0.11 mL, 1.1 mmol). The resulting solution was allowed to warm
to ambient temperature for 3 h then passed through a plug of
silica gel and the filtrate evaporated. The crude geranylgeranyl
bromide 49 (0.68 g, 64%) was used immediately: dH (400 MHz,
CDCl3) 5.47 (t, J¼8.4 Hz, 1H), 5.05–4.95 (m, 3H), 4.09 (d, J¼6.9 Hz,
2H, 1-CH2), 2.15–1.85 (m, 12H), 1.74 (s, 3H), 1.69 (s, 3H), 1.53 (s,
9H).31
4.9.11. Methyl (4E,8E,12E)-5,9,13,17-tetramethyl-2-(p-toluenesulfo-
nylamino)octadeca-4,8,12,16-tetraenoate (50a). Geranylgeranyl bro-
mide 49 was used to alkylate methyl 2-(benzylideneamino)acetate
10a (0.34 g, 1.9 mmol) according to general procedure A to give the
expected imine: dH (400 MHz, CDCl3) 8.12 (s, 1H, N]CH), 7.70–7.66
(m, 2H), 7.38–7.33 (m, 3H), 5.00–4.95 (m, 4H), 3.91 (dd, J¼7.3, 5.6 Hz,
1H, H2), 3.63 (s, 3H, OMe), 2.65 (dd, J¼14.1, 5.6 Hz, 1H, H3a), 2.51 (dd,
J¼14.1, 7.3 Hz, 1H, H3b), 2.05–1.85 (m, 12H), 1.60 (s, 3H), 1.52 (s, 9H),
1.48 (s, 3H). This crude imine was hydrolysed and tosylated as usual
and thecrudeproductpurifiedbycolumnchromatography (25% ethyl
acetate/petrol) to give the geranylgeranyl sulfonamide 50a (1.50 g,
28%) as a pale yellow oil: dH (400 MHz, CDCl3) 7.69 (d, J¼8.2 Hz, 2H),
7.23 (d, J¼8.2 Hz, 2H), 5.11 (d, J¼9.1 Hz, 1H, NH), 5.05–4.95 (m, 4H),
4.91 (t, J¼7.0 Hz, 1H, H4), 3.95–3.90 (m, 1H, H2), 3.48 (s, 3H, OMe),
2.42–2.33 (m, 2H), 2.35 (s, 3H, ArMe), 2.00–1.82 (m,12H),1.61 (s, 3H),
1.53 (s, 9H), 1.49 (s, 3H); dC (100.6 MHz, CDCl3) 172.1 (CO), 144.0 (s),
141.0 (s), 137.2 (s), 135.8 (s), 135.4 (s), 131.7 (s), 129.9 (2ꢂd), 127.6
(2ꢂd), 124.8 (d), 124.6 (d), 124.2 (d), 116.9 (d), 55.9 (d), 52.7 (OMe),
40.1 (t), 40.0 (t), 35.6 (t), 32.2 (t), 27.1 (t), 27.0 (t), 26.9 (t), 26.1 (q), 21.9
(q), 20.1 (q), 18.2 (q), 16.7 (q), 16.4 (q); nmax (film)/cmꢁ1 3508, 3276,
4.9.8. Methyl (4E,8E)-2,5,9,13-tetramethyl-2-(p-toluenesulfonylami-
no)tetradeca-4,8,12-trienoate (47b). The foregoing bromide 46
(2.5 g, 8.6 mmol) was used to alkylate methyl 2-(benzylideneami-
no)propanoate 10b (1.5 g, 7.9 mmol) according to general pro-
cedure A to give the expected imine: dH (400 MHz, CDCl3) 8.14 (s,
1H, N]CH), 7.70–7.65 (m, 2H), 7.30–7.25 (m, 3H), 5.35–5.30 (m,
1H), 5.02–4.95 (m, 2H), 3.73 (s, 3H, OMe), 2.50–2.40 (m, 2H), 2.00–
1.85 (m, 4H),1.60 (s, 3H), 1.57 (s, 3H),1.39 (s, 3H), 1.35 (s, 3H), 1.21 (s,
3H). This crude imine was hydrolysed and tosylated as usual and
the crude product purified by column chromatography (25% ethyl
acetate/petrol) to give the farnesyl sulfonamide 47b (0.95 g, 31%) as
a pale yellow oil; Rf 0.38 (25% EtOAc/petrol); dH (400 MHz, CDCl3)
7.79 (d, J¼8.2 Hz, 2H), 7.28 (d, J¼8.2 Hz, 2H), 5.25 (s, 1H, NH), 5.20–
5.15 (m, 2H), 5.05–5.00 (m, 1H), 3.69 (s, 3H, OMe), 2.65–2.50 (m,
2H), 2.41 (s, 3H, ArMe), 2.20–2.00 (m, 8H), 1.68 (s, 3H), 1.61 (s, 3H),

C.M. Griffiths-Jones (ne´e Haskins), D.W. Knight / Tetrahedron 66 (2010) 4150–4166
4165
2921,1743,1481;m/z: [APCI] 516 (100%; MþH)þ; HRMS:m/z: calcd for
References and notes
C30H45NO4S: 515.1976; found: 515.1987 [M]þ.
1. For reviews of pyrrolidine synthesis, see Lewis, J. R. Nat. Prod. Rep. 2001, 18, 95;
O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435; Fischer, G. Chem. Soc. Rev. 2000, 29,
119; Parsons, A. F. Tetrahedron 1996, 52, 4149; Wolfe, J. P. Eur. J. Org. Chem. 2007,
571; Bellina, F.; Rossi, R. Tetrahedron 2006, 62, 7213; Coldham, I.; Hufton, R.
Chem. Rev. 2005, 105, 2765 and references therein.
2. For reviews, see Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046; Wolfe, J. P.;
Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805; Yang, B.
Y.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125; Shekhar, S.; Ryberg, P.;
Hartwig, J. L.; Mathew, J. S.; Blackmond, D. G.; Strieter, E. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2006, 128, 3584.
3. Mueller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108,
3795; Doye, S. Hydroamination, in Science of Synthesis; 2009; Vol. 40a p 111
(Volume date 2008); For a review of the catalytic hydroamination of alkynes,
see Severin, R.; Doye, S. Chem. Soc. Rev. 2007, 36, 1404.
4. Warren, S. Organic Synthesis: The Disconnective Approach; Wiley and Sons:
Chichester, UK, 1982.
4.9.12. Methyl 17-aza-4,4,8,10,13,-pentamethyl-17-(p-toluenesulfo-
nyl)hexadecahydrocyclopenta[a]-phenanthrene-16-carboxylate
(51a). The foregoing geranylgeranyl sulfonamide 50a (0.101 g,
0.20 mmol) was cyclised for 0.25 h at 0 ꢀC using triflic acid (12 mg,
0.08 mmol) as described in general procedure B. The crude product
was purified by column chromatography (dichloromethane) to give
the cyclised product 51a (0.083 g, 83%) as a pale yellow oil: dH
(400 MHz, CDCl3) 7.80–7.65 (m, 2H), 7.25–7.15 (m, 2H), 4.38–4.27 (m,
1H, H16), 3.70–3.67 (m, OMe), 2.38–2.30 (m, 3H, ArMe), 2.20–0.65
(m, 34H); nmax (film)/cmꢁ1 2964, 2891, 1742, 1477; m/z: [APCI] 516
(100%; MþH)þ; HRMS: m/z: calcd for C30H45NO4S: 515.1976; found:
515.1990 [M]þ.
5. Knight, D. W. Prog. Heterocycl. Chem. 2002, 14, 19; French, A. N.; Bissmire, S.;
Wirth, T. Chem. Soc. Rev. 2004, 33, 354; Browne, D. M.; Wirth, T. Curr. Org. Chem.
2006, 10, 1893; Freudendahl, D. M.; Shahzad, S. A.; Wirth, T. Eur. J. Org. Chem.
2009, 1649.
4.9.13. Methyl (4E,8E,12E)-2,5,9,13,17-pentamethyl-2-(p-toluenesul-
fonylamino)octadeca-4,8,12,16-tetraenoate (50b). The foregoing
bromide 49 was used to alkylate methyl 2-(benzylideneamino)-
propanoate 10b (0.27 g, 1.4 mmol) according to general procedure
A to give the expected imine: dH (400 MHz, CDCl3) 8.21 (s, 1H,
N]CH), 7.75–7.68 (m, 2H), 7.30–7.22 (m, 3H), 5.05–4.95 (m, 4H),
3.69 (s, 3H,OMe), 2.68 (dd, J¼14.2, 7.4 Hz, 1H, H3a), 2.61 (dd, J¼14.2,
7.6 Hz, 1H, H3b), 2.10–1.80 (m, 12H), 1.61 (s, 3H), 1.56 (s, 3H), 1.53 (s,
3H), 1.51 (s, 6H), 1.40 (s, 3H). This crude imine was hydrolysed and
tosylated as usual and the crude product purified by column
chromatography (25% ethyl acetate/petrol) to give the geranylger-
anyl sulfonamide 50b (0.25 g, 32%) as a pale yellow oil: dH (400 MHz,
CDCl3) 7.68 (d, J¼8.2 Hz, 2H), 7.20 (d, J¼8.2 Hz, 2H), 5.22 (s, 1H, NH),
5.05–5.00 (m, 3H), 4.89 (t, J¼7.6 Hz, 1H), 3.64 (s, 3H, OMe), 2.45 (dd,
J¼14.4, 7.6 Hz, 1H, H3a), 2.35 (dd, J¼14.4, 7.6 Hz, 1H, H3b), 2.34 (s,
3H, ArMe), 2.05–1.90 (m, 12H), 1.61 (s, 3H), 1.54 (s, 6H), 1.53 (s, 3H),
1.52 (s, 3H), 1.35 (s, 3H); dC (100.6 MHz, CDCl3) 174.2 (CO), 143.7 (s),
142.5 (s), 141.6 (s), 139.8 (s), 139.6 (s), 138.2 (s), 129.8 (2ꢂd), 127.9
(2ꢂd), 126.3 (d), 124.4 (d), 122.3 (d), 117.2 (d), 60.8 (d), 53.4 (OMe),
43.0 (t), 42.1 (t), 41.8 (t), 41.3 (t), 40.7 (t), 40.0 (t), 39.6 (t), 27.5 (q),
26.2 (q), 24.3 (q), 21.8 (q), 19.9 (q), 18.1 (q); nmax (film)/cmꢁ1 1730;
m/z: [APCI] 530 (100%; MþH)þ; HRMS: m/z: calcd for C31H47NO4S:
529.1366; found: 529.1382 [M]þ.
6. Bedford, S. B.; Bell, K. E.; Bennett, F.; Hayes, C. J.; Knight, D. W.; Shaw, D. E. J.
Chem. Soc., Perkin Trans. 1 1999, 2143; Tiecco, M.; Testaferri, L.; Marini, F.;
Sternativo, S.; Bagnoli, L.; Santi, C.; Temperini, A. Tetrahedron: Asymmetry 2001,
12, 1493; Jones, A. D.; Knight, D. W.; Morgan, I. R.; Redfern, A. L.; Williams, A. C.
Tetrahedron 2006, 62, 9247 and references therein; For the formation of spiro-
pyrrolidines by intramolecular nucleophilic attack by sulfonamides onto ep-
oxides, see Nuhrich, A.; Moulines, J. Tetrahedron 1991, 47, 3075.
7. Jones, A. D.; Knight, D. W.; Hibbs, D. E. J. Chem. Soc., Perkin Trans. 1 2001, 1182.
8. Amjad, M.; Knight, D. W. Tetrahedron Lett. 2006, 47, 2825.
9. Haskins, C. M.; Knight, D. W. Chem. Commun. 2002, 2724.
10. Schlummer, B.; Hartwig, J. F. Org. Lett. 2002, 4, 1471.
11. Stork, G.; Leong, A. Y.; Touzin, A. M. J. Org. Chem. 1976, 41, 3491.
12. Olah, G.A.;Prakash,G. K.S.;Sommer, J.Superacids; Wiley: New York, NY,1985; Lewis
Acids in Organic Synthesis; Yamamoto, Y., Ed.; Wiley-VCH: Weinheim, 2000; Vol. 2.
13. In a separate study, such N-tosylations were found to be somewhat more ef-
ficient if the reactants were mixed at ꢁ78 ꢀC, prior to slowly warming to am-
bient tempertaure during a few hours: Proctor, A. J., unpublished observation.
14. For a review of intramolecular carbenium ion trapping by hydroxyl groups,
when generated using super Lewis acids, see Coulombei, L.; Grau, F.; Weiwer,
M.; Favier, I.; Chaminade, X.; Heumann, A.; Bayo´ n, J. C.; Aguirre, P. A.; Dun˜ach, E.
Chem. Biodivers. 2008, 5, 1070; For related examples, see Linder, S. M.; Reichlin,
D.; Simmons, D. P.; Snowden, R. L. Tetrahedron Lett. 1993, 34, 4791.
15. Single electron transfer methods: Roemmele, R. C.; Rapoport, H. J. Org. Chem.
1988, 53, 2367 (this paper compares this method with electrolysis and HBr/
HOAc for the deprotection of N-tosylthreonine) Li or Na naphthalenide: Alonso,
´
E.; Ramon, D. J.; Yus, M. Tetrahedron 1997, 53, 14355; buffered Na amalgam:
Birkinshaw, T. N.; Holmes, A. B. Tetrahedron Lett. 1987, 28, 813; SmI2: Vedejs, E.;
Lin, S. J. Org. Chem. 1994, 59, 1602; photo-induced electron transfer: Hamada, T.;
Nishida, A.; Yonemitsu, O. J. Am. Chem. Soc. 1986, 108, 140; HBr/HOAc: Opalka,
C. J.; D’ambra, T. E.; Faccone, J. J.; Bolson, G.; Cossement, E. Synthesis 1995, 766;
LiAlH4: Bradshaw, J. S.; Krakowiak, K. E.; Izatt, R. M. Tetrahedron 1992, 48, 4475;
Red-Al: Gold, E. H.; Babad, E. J. Org. Chem. 1972, 37, 2208; Me2PhSiLi: Fleming, I.;
Frackenpohl, J.; Ila, H. J. Chem. Soc., Perkin Trans. 1 1998, 1229; fluoride: Op-
polzer, W.; Bienayme´, H.; Genevois-Borella, A. J. Am. Chem. Soc. 1991, 113, 9660;
Grignard reagent and a nickel salt: Snieckus, V., Personal communication.
16. Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373; Fukuyama,
T.; Cheung, M.; Jow, C.-K.; Hadai, Y.; Kan, T. Tetrahedron Lett. 1997, 38, 5831; Fu-
kuyama, T.; Cheung, M.; Kan, T. Synlett 1999, 1301; Fujiwara, A.; Kan, T.; Fu-
kuyama, T. Synlett 2000, 1667; Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.;
Kuboyama, T.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 2137; Kan,
T.; Fujiwara, A.; Kobayashi, H.; Fukuyama, T. Tetrahedron 2002, 58, 626.
17. Elaridi, J.; Jackson, W. R.; Robinson, A. J. Tetrahedron: Asymmetry 1995, 16, 2025.
18. Jackson, W. R., Personal communication.
19. For recent contributions, see Fish, P. V.; Johnson, W. S.; Jones, G. S.; Thu, F. S.;
Kullnig, R. K. J. Org. Chem. 1994, 59, 6150; Fish, P. V.; Johnson, W. S. J. Org. Chem.
1994, 59, 2324; Herring, S. R.; Livinghouse, T. Tetrahedron 1994, 50, 9229;
Johnson, W. S.; Bartlett, W. R.; Czaskis, B. A.; Gautier, A.; Lee, C. H.; Lemoine, R.;
Leopold, E. J.; Luedtke, G. R.; Bancroft, K. J. J. Org. Chem. 1999, 64, 9587; Frank-
Neumann, M.; Geoffrey, P.; Hans, D. Tetrahedron Lett. 2002, 43, 2277 and ref-
erences cited therein.
4.9.14. Methyl 17-aza-4,4,8,10,13,16-hexamethyl-17-(p-toluenesulfo-
nyl)hexadecahydrocyclopenta[a]-phenanthrene-16-carboxylate
(51b). The foregoing geranylgeranyl sulfonamide 50b (0.118 g,
0.22 mmol) was cyclised for 0.25 h at 0 ꢀC using triflic acid (13 mg,
0.10 mmol) as described in general procedure B. The crude prod-
uct was purified by column chromatography (dichloromethane) to
give the cyclised product 51b (0.095 g, 80%) as a pale yellow oil: dH
(400 MHz, CDCl3) 7.80–7.60 (m, 2H), 7.30–7.15 (m, 2H), 3.70–3.58
(m, OMe), 2.45–2.30 (m, 3H, ArMe), 2.20–0.65 (m, 37H); nmax
(film)/cmꢁ1 2936, 2945, 1746, 1448; m/z: [APCI] 530 (100%;
MþH)þ; HRMS: m/z: calcd for C31H47NO4S: 529.1366; found:
529.1374 [M]þ.
Acknowledgements
We thank the EPSRC Mass Spectrometry Service, University
College, Swansea for the provision of some high resolution mass
spectrometric data, Professor G. Pattenden (University of Not-
tingham) for a generous gift of all-E-geranylgeraniol, the Uni-
versity of Melbourne and Professor A.B. Holmes for the award of
a Wilsmore Fellowship (to D.W.K.) during which this paper was
written, Professor W. Roy Jackson (Monash University) for
a helpful and civilised exchange of results, Gilles Yzambart for
carrying out some additional experiments on the cascade cycli-
sations and the EPSRC for financial support through the DTA
scheme.
20. Cyclisations followed by continual NMR analysis showed no resonances other
than those of the precursors 42 and the products 43. We thank Mr. Gilles
Yzambart for carrying out these experiments.
21. Haskins, N. J.; Haskins, C. M.; Knight, D. W. Rapid Commun. Mass Spectrom. 2004,
18, 1.
22. Anderson, L. L.; Arnold, J.; Bergman, R. G. J. Am. Chem. Soc. 2005, 127, 14542; Li,
Z.; Zhang, J.; Brouwer, C.; Yang, C.-G.; Reich, N. W.; He, C. Org. Lett. 2006, 8,
4175; Rosenfeld, D. C.; Shekhar, S.; Takemiya, A.; Utsunomiya, M.; Hartwig, J. F.
Org. Lett. 2006, 8, 4179; Motokura, K.; Nakagiri, N.; Mori, K.; Mizugaki, T.;
Ebitani, K.; Jitsukawa, K.; Kaneda, K. Org. Lett. 2006, 8, 4617.
23. For a review of the intramolecular amidopalladation of alkenes leading to
pyrrolidines, see Minatti, A.; Muniz, K. Chem. Soc. Rev. 2007, 36, 1142; For
a recent contribution to gold-assisted hydroamination, see Hesp, K. D.; Stra-
diotto, M. Org. Lett. 2009, 11, 1449; For a review of platinum(II) activation of

4166
C.M. Griffiths-Jones (ne´e Haskins), D.W. Knight / Tetrahedron 66 (2010) 4150–4166
alkenes to nucleophilic attack, see Chianese, A. R.; Lee, S. J.; Gagne, M. R. Angew.
24. Mun˜oz, M. P.; Lloyd-Jones, G. C. Eur. J. Org. Chem. 2009, 516.
25. For a review, see Krimen, L. I.; Cota, D. J. Org. React. 1969, 17, 213; For recent
contributions, see Wang, Z. D.; Sheikh, S. O.; Cox, S.; Zhang, Y.; Massey, K. Eur. J.
Org. Chem. 2007, 2243; Baum, J. C.; Milne, J. E.; Murry, J. E.; Thiel, O. R. J. Org.
Chem. 2009, 74, 2207 and; Santos, M. D.; Crousse, B.; Bonnet-Delpon, D. Tet-
rahedron Lett. 2009, 50, 857.
26. van Esseveldt, B. C. J.; van Delft, F. L.; Smits, J. M. M.; De Gelder, R.; Rutjes, F. P. J.
T. Synlett 2003, 2354.
27. Jackson, A. C.; Goldman, B. E.; Snider, B. B. J. Org. Chem. 1984, 49, 3988; Ghorai,
P.; Dussault, P. H.; Hu, C. Org. Lett. 2008, 10, 2401.
Chem., Int. Ed. 2007, 46, 4042 and of palladium-catalysed asymmetric hydro-
amination; Hii, K. K. Pure Appl. Chem. 2006, 78, 341; For a recent contribution to
copper-catalysed hydroamination leading to pyrrolidines, see Zeng, W.;
Chembler, S. R. J. Am. Chem. Soc. 2007, 129, 12948 to gold-catalysed cyclisations
of sulfonamides onto dienes leading to pyrrolidines; Yeh, M.-C. P.; Pai, H.-F.; Lin,
Z.-J.; Lee, B.-R. Tetrahedron 2009, 65, 4789 to intramolecular hydroamination
catalysed by palladium(II) see; Cochran, B. M.; Michael, F. E. J. Am. Chem. Soc.
2008, 130, 2786 and by iron(III) chloride, see; Komeyama, K.; Morimoto, T.;
Takaki, K. Angew. Chem., Int. Ed. 2006, 45, 2938; For the intermolecular hy-
droaminomethylationation of unactivated alkenes by secondary amines using
a tantalum complex, see Herzon, S. B.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130,
14940 and using indium(III) bromide, see; Huang, J.-M.; Wong, C.-M.; Xu, F.-X.;
Loh, T.-P. Tetrahedron Lett. 2007, 48, 3375.
28. Larock, R. C.; Oertle, K.; Potter, G. F. J. Am. Chem. Soc. 1980, 102, 190.
29. Risalti, A.; Fatutta, S.; Forduassin, M. Tetrahedron 1967, 23, 1451.
30. Jin, Y.; Roberts, F. G.; Coates, R. M. Org. Synth. 2007, 84, 43.
31. Tanaka, H.; Noguchi, H.; Abe, I. Org. Lett. 2005, 7, 5873.