Si-free enolate Claisen rearrangements of enamido substrates

Article abstract of DOI:10.1039/c2ob06853b

α-Alkyl β-amino esters are available in high diastereoselectivity through a silicon-free Claisen enolate [3,3]-sigmatropic rearrangement of enamide esters. Optimisation studies have probed the crucial role of the initial enolisation and the nature of the enamide N-centre. The demonstration of chirality transfer and the formation of β-proline systems, is also presented.

Full text of DOI:10.1039/c2ob06853b

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PAPER
Si-free enolate Claisen rearrangements of enamido substrates†
Wesley R. R. Harker,a Emma L. Carswellb and David R. Carbery*a
Received 3rd November 2011, Accepted 24th November 2011
DOI: 10.1039/c2ob06853b
a-Alkyl b-amino esters are available in high diastereoselectivity through a silicon-free Claisen enolate
[3,3]-sigmatropic rearrangement of enamide esters. Optimisation studies have probed the crucial role of
the initial enolisation and the nature of the enamide N-centre. The demonstration of chirality transfer
and the formation of b-proline systems, is also presented.
Phosphatases are an important group of proteins with diverse
biological roles.1 The exact pharmacological role played by
the protein phosphatase in these biochemical processes is still
unknown, partly due to a scarcity of selective inhibitors to act
as biological probes.2 Accordingly, the development of efficient
yet flexible syntheses of protein phosphatase inhibitors is of
Scheme 1 Sensitivity of diastereoselectivity to substrate.
synthetic pertinence as crucial structure–activity relationship data
for biological probing should therefore be attainable.
The natural cyclic peptide motuporin 13 (Fig. 1) isolated form
the marine sponge Theonella swinhoei (Gray) is a highly potent
and selective protein phosphatase inhibitor. Motuporin inhibits
protein phosphatase type 1 (PP1, IC50 < 1.0 nM) and displays
cytotoxicity towards a number of human cancer cell lines.4 The
biological activity of 1 is closely linked to the presence of the
unusual b-amino acid residue (2S,3S,8S,9S,4E,6E)-3-amino-9-
methoxy-2,6,8-trimethyl-10-phenyldecadenoic acid, ADDA, 2.5–6
This b-amino acid residue is also found in the structurally related
cyclic peptides nodularin and the microcystins.7
These initial studies uncovered a stark sensitivity of the levels
of observed anti-diastereoselectivity to the nature of the substrate
acyl fragment. Whilst poor levels of diastereocontrol were seen
with propionate 3a, excellent diastereoselectivity was obtainable
with phenylacetate substrate 3b (Scheme 1).
With the targets of motuporin and ADDA in mind, the need to
improve the levels of diastereoselectivity seen in the rearrangement
of propionate substrates was imperative. Accordingly, we have
returned to examine this reaction in greater detail and report
our findings in this article. A more detailed level of optimisation
failed to significantly improve upon the Ireland–Claisen substrate
reported in Scheme 1. Employment of 1.3 equivalents of LiHMDS
and Me3SiCl allowed for a small improvement in yield (72%)
but with an identical level of diastereoselectivity (anti/syn = 2 : 1;
see supporting information for full attempts at re-optimisation†).
This optimisation study had examined variables such as the
loading of base and silylation additive,13 nature of base, soft
enolisation conditions14 and phosphorylative conditions,15 but this
transformation was observed to be invariant.
Fig. 1 Motuporin and ADDA.
Whilst this study did not appear to offer any particular hope
for the development of a useful reaction, it did however mould
our understanding of the problem at hand considerably. We
initially hypothesised that increased stability of intermediate ester
enolates and/or silylketene acetals offered by the presence of the
conjugating phenyl group in 3b in contrast to propionate 3a was
beneficial to the rearrangement of the enamide substrates. In the
context of stabilising intermediate enolates, we became aware of
Collum’s intriguing Si-free [3-3]-sigmatropic rearrangement of
cinnamyl propionate 6 where a Li–enolate rearranges (Scheme 2).16
This protocol immediately offered itself as a potential solution
to the described synthetic problem. Using an adaptation of
Collum’s conditions whereby the reaction was initiated at -95 ◦C,
With a view to developing a flexible route to motuporin, we have
examined a novel Ireland–Claisen8 substrate class9–10 assembled
around a key enamide moiety (Scheme 1).11 On [3,3]-sigmatropic
rearrangement of a silylketene acetal derived from such enamides,
2,3
anti-b -amino esters are formed12 with the flexible synthetic
handle of an N-allylic moiety also present.
aDepartment of Chemistry, University of Bath, Bath, United Kingdom, BA2
7AY. E-mail: d.carbery@bath.ac.uk; Tel: 44 1225 386144
bMSD, Newhouse, Motherwell, United Kingdom
† Electronic supplementary information (ESI) available: Full exper-
imental data and NMR spectra of novel compounds. See DOI:
10.1039/c2ob06853b
1406 | Org. Biomol. Chem., 2012, 10, 1406–1410
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Table 1 Silicon-free rearrangement optimisation
may affect leaving group ability and alter the electronic nature
of the enamide. The preparation of alcohols 5b–e for subsequent
acylation was attempted through a NaBH4 mediated reduction of
the corresponding ketone (Fig. 2).
Entry
M
8a (%)a
dr (anti/syn) 8a
9a (%)a
1
2
4
5
6
7
8
9
Li
46b
21
0
0
2
>25 : 1
>25 : 1
—
—
—
—
2 : 1
—
38
40
0
Lic
Na
K
Fig. 2 Key enamido allylic alcohols studied.
0
We were unable to prepare 5b cleanly due to competing
phthalimide carbonyl reduction. Enecarbamate alcohols 5c and
5d proved particularly prone to dehydration, with crotonaldehyde
and the parent N–H carbamate observed in crude 1H NMR analy-
ses. In contrast, enesulfonamide 5e proved stable enough to convert
via EDCI-mediated esterification to the corresponding propionate.
When conducting these Si-free Claisen rearrangements using the
Collum protocol on the ester derivatives of 5c, we have observed a
minor improvement in recovered yield on utilising a higher loading
of LiHMDS and Et3N (4.5 and 45 equivalents respectively), pos-
sibly due to competitive N-allyl lithiation. These new conditions
now lead to improved outcomes with high diastereoselectivity
observed with no subsequent elimination (Entry 1, Table 2). The
improvement when using the Collum-based protocol for this N-
allyl enamide is unambiguous when compared with the silylation
protocol which offers poor yield and diastereoselectivity (Entry 2).
On examining the substrate scope from the original commu-
nication, an improvement in dr is seen with the exception of
the O-benzyl glycolate 10d. We feel the Si-free protocol for alkyl
Lid
Lie
Lif
Lih
80
80
0
3
42g
0
0
a Assayed by 1H NMR analysis of crude reaction mixture. b Ester 4a
isolated (45%) after treatment with CH2N2 in Et2O. c LiHMDS (4 equiv.),
Et3N (40 equiv.) used. d Base added to substrate and Me3SiCl (6 equiv.).
e Me3SiCl (6 equiv.) added to base and substrate. f Warmed to quenching
temperature of -10 ◦C. g Starting material 3a recovered (35%). h Reaction
conducted in THF, intractable mixture formed.
Scheme 2 Collum Si-free ester enolate Claisen rearrangement.
anti-4a was isolated after methylation in unexceptional yield
however with excellent levels of diastereoselectivity (Entry 1,
Table 1).
An increase in the loading of base proved detrimental with
a reduction in the amount 8a present in the crude mixture
(Entry 2). The addition of silyl chloride to this protocol leads
to an unfavourable outcome (Entries 6–7). The data presented
suggests that a subsequent elimination of 2-oxazolidinone occurs
after rearrangement. Furthermore, it had been noticed that a
colour change occurred on warming to >-10 ◦C. When quenching
a rearrangement at -10 ◦C a striking change in diastereoselectivity
(Entry 8, dr = 2 : 1 anti/syn) is observed. Therefore, we believe a
kinetic resolution occurs with the syn-isomer preferentially elimi-
nating to diene 9a after an initial poorly selective rearrangement.
Further support for this hypothesis was obtained when isolated
acid 8a was re-subjected to reaction conditions with dienyl acid 9a
and an enrichment of the anti-diastereomer observed (Scheme 3).
The removal of the Lewis basic solvent THF from the system is
seen to be important as shown by unsuccessfully attempting the
rearrangement in this solvent (Entry 9).
Table 2 [3,3]-Sigmatropic rearrangements of N-allyl enesulfonamides
Entry
R
11
dra
12
13
1
Me (10a)
51 (11a)
<5
65 (11b)
70 (11c)
0
30 (11d)
67
67 (11e)
73 (11f)
40 (11g)
68 (11h)
>25 : 1
1 : 1
>25 : 1
10 : 1
0
53
0
0
41
0
27
21
18
15
22
71 (13a)
—
86 (13b)
—
—
—
92 (13c)
51c (13d)
89 (13e)
96 (13f)
83c (13g)
2b
3
Me
iPr (10b)
4
5
6
Allyl (10c)
OBn (10d)
Ph (10e)
—
>25 : 1
>25 : 1
>25 : 1
>25 : 1
20 : 1
7b
8b
9b
10b
11b
Ph
o-IC6H4 (10f)
p-OMeC6H4 (10g)
p-NO2C6H4 (10h)
>25 : 1
12b
55 (11i)
>25 : 1
25
89 (13h)
Scheme 3 Kinetic resolution mechanism for high diastereocontrol in
Si-free rearrangement.
a anti/syn ratio measured by 1H NMR analysis of crud◦e reaction mixtures.
b LiHMDS (2.5 equiv.), Me3SiCl (6 equiv.), THF, -95 C → 20 ◦C. c Ring
closing diene metathesis conducted at 65 ◦C.
Whilst these studies were disappointing it in turn led us to
examine the influence of the enamide nitrogen centre as this
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esters actually compliments a traditional silylation approach for
arylacetate esters as we find a silylation approach is better for
arylacetate substrates as seen when examining 10e (Entries 6–7). It
should be pointed out that methyl arylacetates 12 are also isolated
and we believe this is due to methylation of the parent acid after
hydrolysis of unconverted substrate at the end of the reaction. It is
worth commenting on the sensitivity of these enamide esters. The
substrates under discussion will not withstand chromatography
andeventhenature of the acylfragmentcan have aprofound effect.
We endeavoured to study an a-amino ester substrate, with a view
to synthesising a,b-diamino acid systems. However, attempted
carbodiimide coupling of 5e with N-phthaloyl glycine proved
unsuccessful, even though we have published the synthesis and
rearrangement of structurally homologous enol ether substrates.17
Furthermore, these previous studies also support our belief that
the inability to form a rearranged product from 10d is not due to a
lack of reactivity but due electronic issues with a substrate bearing
multiple electron donating heteroatoms.
The amino dienes prepared through this sigmatropic approach
lend themselves for subsequent elaboration, in particular a ring-
closing diene metathesis to pyrrolines.18 Accordingly, such a
metathesis ring-closure was smoothly achieved using Grubb’s 1st
generation catalyst in a number of instances (Table 2, Entries 1,
3, 7–12). The products from these metatheses offer themselves
as intriguing exocyclic carboxyl b-prolines. The olefin synthetic
handle and the excellent diastereocontrol suggest this strategy
may offer some future synthetic value. For example, pyrroline 13d
was smoothly converted through an intramolecular Heck reaction,
forming the tricyclic b-amino ester 14 in good yield (Scheme 4).19
Conclusions
In conclusion, optimization studies have led to the development of
new substrates for the [3,3]-sigmatropic rearrangements of enam-
ido allylic esters. These developments include the use of N-allyl
enesulfonamides for the highly diastereoselective rearrangementof
alkyl esters using a Si-free, enolate Claisen protocol. The electronic
control offered by the new enamide has also provided suitable
substrate stability to allow the rearrangement of enantiopure
substrates. We are currently looking to expand the synthetic
application of these b-amino esters.
Experimental procedures
(E)-4-(N-Allyl-4-methylphenylsulfonamido)but-3-en-2-yl
propionate (10a)
To a solution of EDCI (0.54 g, 2.81 mmol) in CH2Cl2 (100 mL),
was added triethylamine (0.39 mL, 2.81 mmol), DMAP (0.02 g,
0.14 mmol) and propionic acid (0.22 mL, 2.81 mmol). This
solution was cooled to 0 ◦C before adding 5e (0.40 g, 1.41 mmol) in
CH2Cl2 (10 mL) and stirring for 15 h at room temperature. Citric
acid (10%, 30 mL) was added and the organic layer separated
before washing with further citric acid (10%, 2 ¥ 30 mL), NaHCO3
(sat., 3 ¥ 30 mL), brine (30 mL). The organic layer was dried over
MgSO4, filtered and solvent removed in vacuo to afford (E)-4-(N-
allyl-4-methylphenylsulfonamido)but-3-en-2-yl propionate 10a as
a yellow oil (0.40 g, 84%). FTIR (film/cm-1) umax: 3082 (m), 3039
(m), 2980 (m), 2931 (m), 2861 (m), 1727 (s), 1656 (s), 1597 (s); 1H
NMR (500 MHz, (CD3)2CO) d: 1.10 (t, 3H, J = 7.6 Hz, CH3CH2–
), 1.29 (d, 3H, J = 6.6 Hz, CH3CH(CH–)O–), 2.25 (q, 2H, J =
7.6 Hz, CH3CH2–), 2.45 (s, 3H, –C6H4CH3), 3.96 (qd, 2H, J =
15.0, 5.4 Hz, –NCH2CHCH2), 4.80 (dd, 1H, J = 14.2, 6.6 Hz,
–NCHCH–), 5.09–5.17 (m, 2H, CH2CHCH2N–), 5.34 (app. quin,
1H, J = 6.6 Hz, CH3CH(CH–)O–), 5.79 (ddt, 1H, J = 17.0, 10.3,
5.4 Hz, –NCH2CHCH2), 6.96 (d, 1H, J = 14.2 Hz, –NCHCH–),
7.29 (app. d, 2H, J = 7.6 Hz, ArH Ts), 7.65 (d, 2H, J = 7.6 Hz,
ArH Ts); 13C NMR (125 MHz, (CDCl3) d: 9.1, 21.0, 21.5, 27.9,
48.0, 69.8, 110.1, 117.9, 127.0, 129.5, 129.8, 131.3, 136.1, 143.9,
173.6; HRMS (ESI, +ve) m/z calcd. for C23H27NNaO4S 436.1558,
found 436.1679 (M + Na)+.
Scheme 4 Heck elaboration to tricyclic b-proline systems.
Finally, the development and examination of new enamide
substrates has allowed us to fulfil a long-term goal of preparing
an enantioenriched substrate with a view to performing asym-
metric versions of these enamide Ireland–Claisen rearrangements.
The development of the N-allyl enamide class has allowed the
transformation of commercial enantiopure butyn-2-ol through the
protocol of Meyer.20 It is worth mentioning the non-trivial matter
of cleanly forming such a substrate. However, we have ascertained
that high levels of diastereo- (dr > 25 : 1) and enantiocontrol
(er > 95 : 5) are achievable in this proof-of-concept study by the
rearrangement of phenylacetate (S)-10f to (2R,3R)-11f using the
silylation protocol (Scheme 5).
(anti-E)-Methyl 3-(N-allyl-4-methylphenylsulfonamido)-2-
methylhex-4-enoate (11a)
To a solution of LiHMDS (1 M in toluene, 1.34 mL, 1.34 mmol)
and triethylamine (1.81 mL, 13.4 mmol) at -95 ◦C was added
10a (0.10 g, 0.30 mmol) in toluene (1 mL) via syringe (4 mL
h-1) down the side of the reaction vessel. The reaction was
slowly warmed to room temperature over 1 h before the ad-
dition of HCl (1 M)/brine (1 : 1, 5 mL). The organics were
extracted with Et2O (5 ¥ 15 mL) before immediate methylation
with diazomethane (generated from N-nitrosomethyl urea in a
diazomethane generator). Further purification by flash chro-
matography (EtOAc/petroleum ether 40–60 ◦C/triethylamine;
20 : 80 : 1 → 40 : 60 : 1) afforded (anti-E)-methyl 3-(N-allyl-4-
methylphenylsulfonamido)-2-methylhex-4-enoate 11a as a white
solid (0.06 g, 55%, dr >25 : 1). M.p. 88–90 ◦C; FTIR (film/cm-1)
u
max: 2966 (m), 2916 (m), 1735 (s), 165 s (m); 1H NMR (500 MHz,
CDCl3) d: 1.06 (d, 3H, J = 6.9 Hz), 1.51 (dd, 3H, J = 6.4, 1.5 Hz),
Scheme 5 Absolute stereocontrol in [3,3]-sigmatropic rearrangement of
enamides.
1408 | Org. Biomol. Chem., 2012, 10, 1406–1410
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2.39 (3H, s), 3.02 (ddt, 2H, J = 10.1, 7.8, 6.9 Hz), 2.83 (s, 3H),
3.69–3.85 (s, 2H), 4.27 (app. t, 1H, J = 10.1 Hz), 5.07–5.18 (m,
2H), 5.41 (ddq, 1H, J = 15.1, 10.1, 1.5 Hz), 5.55 (dq, 1H, J = 15.1,
6.4 Hz), 5.71 (ddt, 1H, J = 17.3, 10.2, 6.5 Hz), 7.26 (app. d, 2H,
J = 8.2 Hz), 7.69 (app. d, 2H, J = 8.2 Hz); 13C NMR (125 MHz,
CDCl3) d: 15.6, 17.7, 21.4, 43.4, 49.4, 51.7, 64.1, 117.6, 126.2,
127.7, 129.1, 132.1, 135.3, 137.8, 142.9, 175.0; HRMS (ESI, +ve)
m/z calcd. for C18H25NO4S 352.1582, found 352.1577 (M + H)+.
extracted with Et2O (5 ¥ 15 mL) before immediate methylation
with diazomethane (generated from N-nitrosomethyl urea in a
diazomethane generator). Further purification by flash chro-
matography (EtOAc/petroleum ether 40–60 ◦C/triethylamine;
20 : 80 : 1 → 40 : 60 : 1) afforded (anti-E)-methyl 3-(N-allyl-4-
methylphenylsulfonamido)-2-(2-iodophenyl)hex-4-enoate 11e as
a white solid (0.05 g, 67%, dr >25 : 1). M.p. 97–99 ◦C; FTIR
(film/cm-1) umax: 3179 (w), 2953 (m), 2922 (m), 1734 (s), 1597 (m);
1H NMR (500 MHz, CDCl3) d: 1.35 (d, 3H, J = 6.5 Hz), 2.41 (s,
3H), 3.63 (s, 3H), 3.83 (app. d, 1H, J = 17.3, 6.7 Hz), 3.93 (app.
d, 1H, J = 7.3, 6.7 Hz), 4.75 (d, 1H, J = 11.7 Hz), 4.91 (d, 1H,
J = 11.7 Hz), 5.14–5.23 (m, 2H), 5.25–5.37 (m, 2H), 5.79 (ddt,
1H, J = 17.0, 10.8, 6.7 Hz), 6.92 (app. t, 1H, J = 7.9 Hz), 7.26
(app. d, 2H, J = 8.7 Hz), 7.27–7.33 (m, 1H), 7.51 (app d, 1H, J =
7.9 Hz), 7.74 (app. d, 2H, J = 8.7 Hz), 7.82 (d, 1H, J = 7.9 Hz);
13C NMR (125 MHz, CDCl3) d: 17.6, 21.4, 49.2, 52.2, 57.8, 64.2,
118.1, 124.7, 127.9, 128.5, 128.9, 129.0, 129.2, 129.3, 132.1, 135.0,
137.7, 138.9, 139.6, 143.1, 171.8; HRMS (ESI, +ve) m/z calcd. for
C25H32NO6S 474.1950, found 474.1948 (M + H)+.
Methyl 2-(1-tosyl-2,5-dihydro-1H-pyrrol-2-yl)propanoate (13a)
To a solution of 11a (0.02 g, 0.05 mmol) in CH2Cl2 (5 mL) was
added Grubbs I catalyst (5 mol%) and stirred at room temperature
for 6 h. When the reaction was judged complete by TLC, the
reaction was concentrated in vacuo and further purified by flash
chromatography (EtOAc/petroleum ether 40–60 ◦C; 10 : 90 →
20 : 80) to afford 13a as a white solid (0.01 g, 79%). M.p. 95–97 ◦C;
FTIR (film/cm-1) umax: 2960 (m), 2928 (m), 2878 (m), 1730 (s),
1597 (m); 1H NMR (500 MHz, CDCl3) d: 1.12 (d, 3H, J = 7.1 Hz),
2.44 (s, 3H), 3.31 (qd, 1H, J = 7.1, 3.96 Hz), 3.72 (s, 3H), 4.06–4.19
(m, 2H), 4.84–4.89 (m, 1H), 5.55 (app dq, 1H, J = 5.5, 2.2 Hz),
5.72 (app. dq, 1H, J = 5.5, 2.2 Hz), 7.33 (app. d, 2H, J = 8.1 Hz),
7.74 (app. d, 2H, J = 8.1 Hz); 13C NMR (125 MHz, CDCl3) d: 10.1,
21.5, 43.9, 51.8, 56.1, 67.9, 126.5, 126.8, 127.4, 129.8, 134.1, 143.6,
174.5; HRMS (ESI, +ve) m/z calcd. for C15H20NO4S 310.1130,
found 310.1108 (M + H)+.
Methyl 2-(2-iodophenyl)-2-(1-tosyl-2,5-dihydro-1H-
pyrrol-2-yl)acetate (13d)
To a solution of 11e (0.09 g, 0.17 mmol) in toluene (5 mL)
was added Grubbs I catalyst (5 mol%) and stirred at 65 ◦C
for 6 h. When the reaction was judged complete by TLC, the
reaction was concentrated in vacuo and further purified by flash
chromatography (EtOAc/petroleum ether 40–60 ◦C; 10 : 90 →
20 : 80) to afford 13d as a white solid (0.04 g, 51%). M.p. 186–
(E)-4-(N-Allyl-4-methylphenylsulfonamido)but-3-en-2-yl
2-(2-iodophenyl)acetate (10f)
◦
188 C; FTIR (film/cm-1) umax: 3026 (m), 2952 (m), 2878 (m),
To a solution of EDCI (0.54 g, 2.81 mmol) in CH2Cl2 (100 mL),
was added triethylamine (0.39 mL, 2.81 mmol), DMAP (0.02 g,
0.14 mmol), 2-iodo phenylacetic acid (0.74 g, 2.81 mmol). This
solution was cooled to 0 ◦C before adding 5e (0.40 g, 1.41 mmol)
in CH2Cl2 (20 mL) and stirring for 15 h at room temperature.
Citric acid (10%, 30 mL) was added and the organic layer separated
before washing with further citric acid (10%, 2 ¥ 30 mL), NaHCO3
(sat., 3 ¥ 30 mL), brine (30 mL). The organic layer was dried over
MgSO4, filtered and solvent removed in vacuo to afford 10f as a
yellow oil (0.64 g, 86%). FTIR (film/cm-1) umax: 2978 (m), 2922
(m), 1727 (s), 1655 (s), 1596 (w); 1H NMR (500 MHz, (CD3)2CO)
d: 1.31 (d, 3H, J = 6.6 Hz), 2.44 (s, 3H), 3.77 (app. d, 2H), 3.97–4.08
(m, 2H), 4.91 (dd, 1H, J = 14.2, 6.6 Hz), 5.12 (app. dq, 1H, J = 10.4,
1.4 Hz), 5.20 (app. dq, 1H, J = 17.3, 1.7 Hz), 5.39 (app. quin, 1H, J
= 6.6 Hz), 5.65 (ddt, 1H, J = 17.3, 10.4, 5.0 Hz), 7.00–7.08 (m, 2H),
7.35–7.43 (m, 4H), 7.72 (app. d, 2H, J = 8.2 Hz), 7.88 (d, 1H, J =
7.8 Hz); 13C NMR (125 MHz, (CD3)2CO) d: 20.4, 20.5, 46.0, 47.6,
70.6, 100.6, 109.9, 117.1, 127.0, 128.4, 128.8, 129.8, 129.9, 131.0,
131.8, 136.4, 138.5, 139.2, 144.0, 169.0; HRMS (ESI, +ve) m/z
calcd. for C22H24INNaO4S 548.0368, found 548.0407 (M + Na)+.
1
1728 (s), 1597 (m); H NMR (500 MHz, CDCl3) d: 2.42 (s, 3H),
3.66–3.75 (m, 1H), 3.75 (s, 3H), 3.97 (app. dq, 1H J = 15.7, 1.9 Hz),
4.78 (d, 1H, J = 5.6 Hz), 5.19–5.24 (m, 1H), 5.50–5.59 (m, 2H), 6.95
(app. t, 1H, J = 7.4 Hz), 7.24–7.34 (m, 4H), 7.73 (app. d, 2H, J =
8.3 Hz), 7.89 (app. d, 1H, J = 7.4 Hz); 13C NMR (125 MHz, CDCl3)
d: 21.5, 52.3, 55.5, 59.9, 68.7, 127.5, 127.6 (¥2), 127.7, 129.1, 129.7,
129.9, 134.2, 136.3, 138.0, 140.2, 143.6, 172.2; HRMS (ESI, +ve)
m/z calcd. for C22H21INO4S 498.0235, found 498.0259 (M + H)+.
anti-Methyl 1-tosyl-1,2,8,8a-tetrahydroindeno[2,1-b]pyrrole-8-
carboxylate (14)
To a solution of Pd(OAc)2 (3.00 mg, 0.01 mmol, 0.2 eq.), PPh3
(3.67 mg, 0.01 mmol, 0.2 eq.), Ag2CO3 (29.1 mg, 0.11 mmol,
1.5 eq.) in MeCN was added 11e (35.0 mg, 0.07 mmol, 1.0 eq.).
The reaction mixture was refluxed for 4 h, concentrated in vacuo
before being subjected to flash column chromatography using
ethyl acetate/petroleum ether 40–60 ◦C (20 : 80) to yield 14 as an
amorphous clear solid (22.0 mg, 84%). FTIR (film/cm-1) umax
:
2958 (m), 2919 (m), 2849 (m), 1734 (s), 1597 (m); 1H NMR
(500 MHz, CD3Cl) d: 2.47 (s, 3H, –C6H4CH3), 3.80 (s, 3H, –
CO2CH3), 4.92 (br. d, 1H, J = 9.5 Hz, –NCHHCH–), 4.63 (br. s,
1H, –CHCO2CH3), 4.90 (dd, 1H, J = 9.5, 2.0 Hz, –NCHHCH–),
5.31 (app. dd, 1H, J = 4.1, 2.8 Hz, –NCH(CH–)CH–), 6.36 (app.
dd, 1H, J = 4.1, 2.8 Hz, –NCH2CH–), 7.10–7.15 (m, 1H, ArH),
7.23–7.27 (m, 2H, ArH), 7.36 (app. d, 2H, J = 8.2 Hz, ArH, Ts),
7.45–7.51 (m, 1H, ArH), 7.75 (app. d, 2H, J = 8.2 Hz, ArH, Ts);
13C NMR (125 MHz, CDCl3) d: 21.6, 52.5, 54.5, 58.3, 66.1, 112.9,
125.1, 126.1, 127.8, 127.9, 128.6, 129.9, 130.5, 132.9, 137.8, 142.9,
(anti-E)-Methyl 3-(N-allyl-4-methylphenylsulfonamido)-2-
(2-iodophenyl) hex-4-enoate (11e)
To a solution of LiHMDS (1 M in THF, 0.34 mL, 0.34 mmol),
TMSCl (0.10 mL, 1.57 mmol) at -95 ◦C was added 10f
(0.07 g, 0.26 mmol) in THF (0.7 mL) via syringe (4 mL
h-1) down the side of the reaction vessel. The reaction was
slowly warmed to room temperature over 1 h before the ad-
dition of HCl (1 M)/brine (1 : 1, 5 mL). The organics were
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144.2, 172.3; HRMS (ESI, +ve) m/z calcd. for C20H20N1O4S1
Wipf, Claisen Rearrangements; Comprehensive Organic Synthesis, ed.
B. M. Trost, I. Fleming, L. A. Paquette, Pergamon: Oxford, 1991;
Vol 5, p827; (e) E. A. Ilardi, C. E. Stivala and A. Zakarian, Chem. Soc.
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370.1148, found 370.1113 (M + H)+.
9 P. M. Ylioja, A. D. Mosley, C. E. Charlot and D. R. Carbery,
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1410 | Org. Biomol. Chem., 2012, 10, 1406–1410
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