Alkaloid inspired spirocyclic oxindoles from 1,3-dipolar cycloaddition of pyridinium ylides

Article abstract of DOI:10.1039/c3ob41415a

Cycloaddition reactions between pyridinium ylides and 3-alkenyl oxindoles that proceed in high yield and with very good regio- and diastereoselectivity are reported. The resulting cycloadducts have the same stereochemistry of biologically active oxindole

Full text of DOI:10.1039/c3ob41415a

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ARTICLE TYPE
Alkaloid inspired spirocyclic oxindoles from 1,3-dipolar cycloaddition of
pyridinium ylides
a
a
a
a
b
Jonathan Day, Maliha Uroos, Richard A. Castledine, William Lewis, Ben McKeever-Abbas, and
a
James Dowden,*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Cycloaddition reactions between pyridinium ylides and 3-alkenyl oxindoles that proceed in high yield and
with very good regio- and diastereoselectivity are reported. The resulting cycloadducts have the same
stereochemistry of biologically active oxindole alkaloids, such as strychnofoline.
cycloadducts and this may have discouraged further investigation
9
1
0
Introduction
40 of these products. The 1,2-dihydropyridine motif embedded
within tetrahydroindolizine cycloadducts is generally regarded as
Natural products and their signature fragments are an enduring
resource for identifying biological modulators. A number of
10
unstable with few exceptions, although there have been exciting
developments in unlocking their synthetic potential.
This report demonstrates that cycloaddition reactions between
pyridinium ylides 2 (Table 1) and 3-alkylidene oxindoles 1
proceed with good selectivity to produce generally isolable
spirotetrahydroindolizineoxindole cycloadducts 3 in good yield.
1
11
biologically active alkaloids, such as strychnofoline and
isorhynchophylline (Figure 1), feature spiroindolizidine
45
2
,3
1
5
oxindoles.
This fragment is considered ‘privileged’ for
potential therapeutic investigation and there is much interest in
developing expedient synthesis of such structures.
4
Results and Discussion
Starting materials for this route are readily accessible by
1
2†
50
olefination of isatin to give 3-alkylidene-2-oxindoles;
1
3†
pyridinium salts were obtained by alkylation. Pyridinium salts
featuring N-methylene groups attached to an electron
withdrawing group can be readily deprotonated using mild base
1
4,15
to give the ylide.
Figure 1 Example spirooxindole alkaloids.
55
Table 1 Optimisation of conditions
2
2
3
3
0
5
0
5
Target spiroindolizidineoxindole structures may be efficiently
accessed by 1,3-dipolar cycloaddition of 3-alkylideneindoline-2-
5
ones. Serov et. al. described reactions between N-phen
6
ylacylquinolinium ylides with 3-alkylidene oxindoles, while
extended studies of this type of reaction have recently been
7
reported. The latter cycloadducts have
a relatively high
molecular weight due to additional aromatic rings and it is not
easy to envisage strategies for their transformation into natural
products or drug-like scaffolds.
a
solvent
Toluene
EtOAc
base
time (h)
yield (%)
Et N
3
4
2
1
4
3
3
2
65
64
88
61
40
73
71
82
There are no literature descriptions of corresponding 1,3-
dipolar cycloadditions of pyridinium ylides to 3-alkylidene
oxindoles, yet such cycloadducts would be attractive for access to
spirooxindole alkaloids and possible therapeutics. Cycloaddition
reactions of pyridinium ylides have previously been reported but
in situ oxidation is commonly used, leading to valuable
3
Et N
3
CH Cl
Et N
3
2
2
DMF
EtOH
Et
Et
N
N
3
3
CH
Cl
DBU
BuOK
NaH
2
2
2
8
t
unsaturated indolizines. Of course, such oxidations destroy the
CH Cl
2
rich stereochemical information accumulated during the
cycloaddition. Early investigation of general pyridinium ylide
cycloadditions noted limited stability of the tetrahydroindolizine
THF
a
Yield after chromatography.
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Initially, we set out to briefly investigate role of solvent and base
Table 2 Cycloaddition with varied oxindoles
on yield. An excess of pyridinium salt 2a relative to
dipolarophiles 1a was used to suppress further cycloaddition onto
9
the initial tetrahydroindolizine product.
5
0
5
0
5
0
Generally, high yields of cycloadduct were obtained using a
variety of solvents and base at room temperature, although
suspending the reagents in dichloromethane, then initiating the
reaction by addition of triethylamine is convenient (Table 1). The
cycloadduct 3a is stable to chromatography and could be stored
under argon in the freezer for no more than a week.
Yield
1
1
2
2
3
Entry
Oxindole
Cycloadduct
a
(%)
Cycloaddition between the ylide derived from 3-
bromopyridinium salt 2a and oxindole 1a appears to be highly
regio- and diastereoselective, giving a single product 3a (Table
1
1
). H-NMR spectroscopy of the cycloadduct revealed an
1
93
apparent triplet for the 5′ proton (J = 7.0 Hz) indicative of
reaction at the C-2 position of the pyridinium salt. Initial NOESY
analysis revealed enhancements between protons corresponding
to 1′ ring junction and 2′ position adjacent to the spirocentre, but
not between the 1′ and 3′ positions adjacent to nitrogen.
Ultimately, single crystal X-ray diffraction of this material
gave unequivocal evidence of the diastereoselectivity of the
2
3
91
82
‡
reaction (Figure 2). The relative stereochemistry of the
spirocentre (position 8a) and the 1′ position is diagnostic of exo
or endo selectivity; co-location of the oxindole carbonyl and 1′
proton on the same face of the cycloadduct is suggestive of an
attractive interaction between the electron rich oxindole aromatic
ring and the electron deficient pyridinium in the transition state.
The trans arrangement of the 1′ and 3′ protons is also confirmed,
indicating that the ylide is S-shaped in the transition state
(Scheme 1). This relative stereochemistry is the same as that
required for alkaloids related to strychnofoline and
isorhynchophylline.
4
5
83
81
a
Yield after chromatography.
1
4
5
stereochemistry similar to cycloadduct 3a as judged by H NMR
spectroscopy. 3-Methylene oxindole 1f is a stable solid that
readily undergoes cycloaddition reactions in good yield (entry 5).
Unfortunately, N-substituted 3-methylene oxindoles are highly
reactive and generally met with polymerisation before
Figure 2 Crystal structure of cycloadduct 3a (CCDC 927103). Ellipsoids
3
5
are drawn at the 50% probability level.
1
6
50
cycloaddition could be attempted. On the other hand, N-
propargyl and N-acetyl substituted oxindoles (entries 3 and 4, 1d
and 1e respectively) bearing an ethyl ester gave good yields of
cycloadducts (3d and 3e respectively).
Scheme 1 Proposed origin of observed diastereoselectivity.
A selection of pyridinium salts (2g-l) were also evaluated
We next carried out investigation into the generality of the 55 (Table 3). Cycloadducts arising from reaction with unsubstituted
1
1†
reaction using various 3-alkylideneoxindoles 1b-f (Table 2).
pyridinium salt (2l) could be detected by mass spectrometry of
the reaction mixture but were not stable to purification by
chromatography, however the saturated indolizidine 3l could
obtained by in situ reduction using Raney nickel in good yield.
4
0
Cycloaddition with the ylide derived from 3-bromopyridinium
salt 2a generally proceeded to give good yields (80-90%) of
cycloadducts 3b-f as single diastereoisomers with relative
2
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Table 3 Cycloaddition with various pyridinium salts
in the 3-position gave good overall yields of spiroindolizidine
Yield (%)
Entry
Pyridinium salt
Cycloadduct
a
[
ratio]
Scheme 2 Reagents and conditions: a, NaH (2 eqiuv.), THF, rt.
oxindoles arising from reaction at the C-6 position of the
20 pyridinium ring, i.e. opposite to the electron withdrawing
substituent. These products (3g-i) were obtained as a mixture of
two diastereoisomers in varying ratios.
b
b
b
1
77 [2:1]
95 [7:3]
81 [1:1]
Crystals were obtained from the 3-cyanopyridine derived
cycloadduct 3g that X-ray diffraction revealed to feature the 1′
‡
25
proton on the opposite face to the oxindole carbonyl (Figure 3).
2
3
This product was later confirmed as the minor diastereoisomer
1
3
g′ by H NMR spectroscopy.
4
5
6
76
87
3
0
Figure 3 Crystal structure of the minor diastereoisomer of cycloadduct
3
g′ (CCDC 927102). Ellipsoids are drawn at the 50% probability level.
There are two possible explanations for these observed results.
One is that pyridinium resonance stabilising groups influence the
orientation of the transition state. Alternatively, interconversion
of cycloadducts via ring opening to restore the pyridinium ring,
then rotation about the former 2′-8′a bond and rejoining of the
3
4
4
5
5
0
5
0
1
7
c
enolate with the pyridinium may proceed. An analogous
reversible Mannich reaction mechanism is well known to occur in
either acidic or basic media, leading to interchange between
related spirocyclic oxindole alkaloid diastereoisomers, such as
63
a
b
18
Yield after chromatography. Inseparable mixture of two
diastereoisomers, ratio in parenthesis from relative integration of H NMR
spectrum. Crude cycloadduct subject to H
EtOAc.
isorhynchnophylline and rhynchnophylline. Diastereoisomer
1
3
g′ remained unchanged when exposed to the same cycloaddition
c
2
/Raney nickel (~10 mol%) in
1
9
conditions for 14 hours, however.
5
A recent paper described reactions of very closely related
pyridinium ylides and 3-alkylideneoxindoles in ethanol with 20
mol% triethylamine at 50°C, but alkene products arising from
Pyridinium salts featuring methyl, or phenyl substituents at the 3-
or 4-pyridinium position (not shown) did not give observable
products in their respective cycloaddition reactions using these
condition, which we presume to be due to their instability.
Pleasingly, less acidic pyridinium salts featuring either nitrile
20
elimination of pyridine were the exclusive reported products.
Similar elimination products were obtained when the
cycloaddition reaction between pyridinium ylide 2l with 3-
alkylideneoxindole 1a was performed in ethanol at room
temperature, resulting in clean conversion to the elimination
product 5 in 60% yield (Scheme 3). Presumably, the reaction
proceeds via 1,4-conjugate addition and not cycloaddition, with
1
0
(
2m) or phenyl (2n) ylide stabilising groups could be
deprotonated with sodium hydride, leading to good yields of the
corresponding cycloadducts 3m and 3n respectively as single
diastereoisomers (Scheme 2).
1
5
Pyridinium salts featuring resonance stabilising groups (2g-i)
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Page 4 of 7
2
1,22
6
subsequent elimination of pyridine.
1372, 1340, 1249, 1191; NMR  (400 MHz, d -DMSO) 10.68
H
(1H, br s, NH), 7.26-7.22 (1H, m, ArH), 7.17 (1H, d, J= 7.4 Hz,
ArH), 6.91 (1H, m, ArH), 6.86 (1H, d, J= 7.4 Hz, ArH), 6.61 (1H,
d, J= 7.0 Hz, N-CH=CH), 6.10 (1H, d, J= 7.0 Hz, CH-CH=CBr),
4
5
5
6
6
7
5
0
5
0
5
0
5.06 (1H, d, J= 7.0 Hz, NCH(CO Et), 5.00 (1H, s, NCHC-Br),
2
4
.45 (1H, app t, J= 7.0 Hz, NCH=CH), 4.21 (2H, q, J= 7.1 Hz,
NCHCO CH CH ), 3.65 (2H, q, J= 7.1 Hz, CCH(CO CH CH )),
2
2
3
2
2
3
3
.45 (1H, d, J= 7.0 Hz, CCH(CO Et), 1.23 (3H, t, J= 7.1 Hz,
2
NCHCOCH CH ), 0.62 (3H, t, J= 7.1 Hz, CCO CH CH ); NMR
2
3
2
2
3
6
 (100 MHz, d -DMSO) 176.2 (C), 171.4 (C), 168.4 (C), 144.0
C
(
1
(
1
C), 134.9 (CH), 129.5 (CH), 128.9 (CH), 126.5 (C), 124.7 (CH),
21.5 (CH), 109.9 (CH), 106.9 (C), 93.2 (CH), 72.6 (CH), 64.8
CH), 64.2 (C), 62.0 (CH ), 61.4 (CH ), 52.8 (CH), 14.5 (CH ),
2
2
3
7
9
3.5 (CH ); m/z (HRMS-ESI+) 461.0697 (M+H C H BrN O
3 21 22 2 5
8
1
requires 461.0712), 463.0700 (M+H C H BrN O requires
2
1
22
2
5
4
(
63.0692).
1'R*,2'S*,3'S*,8a'S*)-Diethyl
5,8'-dibromo-2-oxo-3',8a'-
Scheme 3 Reagents and conditions: a, Et
3
N (2 equiv.), ethanol, rt, 60%;
Cl , rt.
dihydro-2'H-spiro[indoline-3,1'-indolizine]-2',3'-
b, Et N (2 equiv.), CH
3
2
2
dicarboxylate (3b). Brown solid; 85mg (93 %); m.p. 68-70 C;
-
1
IR (νmax/cm , CHCl ) 3437, 2982, 1732, 1639, 1618, 1564, 1465,
3
5
Significantly, crude cycloadduct 4 obtained from cycloaddition in
dichloromethane at room temperature did not undergo
elimination when stirred in ethanol with triethylamine. This
result, when considered alongside the observation for cycloadduct
6
1
373, 1309, 1130; NMR  (400 MHz, d -acetone) 9.84 (1H, br s,
H
NH), 7.45-7.41 (2H, m, ArH), 6.95 (1H, dd, J= 8.2, 0.4 Hz, ArH),
6
.61 (1H, d, J= 7.1 Hz, N-CH=CH), 6.14 (1H, app dt, J= 6.4, 1.0
Hz, CH-CH=CBr), 5.20 (1H, d, J= 1.0 Hz, NCHCBr), 5.05 (1H,
3
g′ above, suggests that the reversible mechanism is not
d, J= 6.6 Hz, NCH(CO Et), 4.58 (1H, dd, J= 7.1, 6.4 Hz,
2
1
0
occurring in these cases. Overall, these studies underline that, for
these reagents, cycloaddition and 1,4-conjugate addition reaction
outcomes are under the subtle influence of solvent.
NCH=CH), 4.27 (2H, q, J= 7.1 Hz, NCHCO CH CH ), 3.76 (2H,
2
2
3
q, J= 7.1 Hz, CCHCO CH CH ), 3.69 (1H, d, J= 6.6 Hz,
2
2
3
CCHCO Et), 1.29 (3H, t, J= 7.1 Hz, NCHCOCH CH ), 0.78 (3H,
2
2
3
6
t, J= 7.1 Hz, CCHCO CH CH ); NMR  (100 MHz, d -acetone)
2
2
3
C
Conclusions
175.3 (C), 170.6 (C), 168.0 (C), 143.0 (C), 134.0 (CH), 131.9
(CH), 129.0 (C), 128.8 (CH), 127.5 (CH), 113.3 (C), 111.3 (CH),
106.8 (C), 93.3 (CH), 72.8 (CH), 64.8 (CH), 64.4 (C), 61.6
(CH ), 61.1 (CH ), 52.8 (CH), 13.6 (CH ), 12.9 (CH ); m/z
In summary, 1,3-dipolar cycloadditions between pyridinium
ylides and 3-alkenyloxidinoles that give spiroindolizidine
oxindole products in high yield and with excellent
regioselectivity and diastereoselectivity are reported for the first
1
5
2
2
3
7
3
9
(HRMS-ESI+) 538.9808 (M+H C H Br N O requires
2
1
21
2
2
5
8
1
time. These cycloadducts are highly reminiscent of biologically 75 538.9812), 540.9806 (M+H C H Br N O requires 540.9792).
2
1
21
2
2
5
active
alkaloids,
especially
isorhynchophylline
and
(1'R*,2'S*,3'S*,8a'S*)-Diethyl 8'-bromo-5-nitro-2-oxo-3',8a'-
dihydro-2'H-spiro[indoline-3,1'-indolizine]-2',3'-
2
0
strychnofoline. Specific modification of this general
cycloaddition route to facilitate highly convergent access to such
alkaloids and related targets is underway.
dicarboxylate (3c). Yellow solid; 88mg (91 %); m.p. 83-85 C;
-
1
IR (νmax/cm , CHCl ) 3249, 2981, 1745, 1626, 1603, 1455, 1343,
3
6
8
8
9
9
0
5
0
5
1125; NMR  (400 MHz, d -acetone) 10.30 (1H, br s, NH), 8.28
H
Experimental
(1H, dd, J= 8.7, 2.3 Hz, ArH), 8.17 (1H, d, J= 2.3 Hz, ArH), 7.22
(1H, d, J= 8.7 Hz, ArH), 6.70 (1H, d, J= 7.1 Hz, N-CH=CH),
General Information
Experimental describing precursor preparation is included within
the Supporting Information.
6
5
.15 (1H, d, J= 6.4 Hz, CH-CH=CBr), 5.27 (1H, s, NCHC-Br),
2
3
3
4
5
0
5
0
.15 (1H, d, J= 6.5 Hz, NCH(CO Et)), 4.62 (1H, dd, J= 7.1, 6.4
2
Hz, NCH=CH), 4.28 (2H, q, J= 7.1 Hz, NCHCO CH CH ), 3.77
2
2
3
General Procedure for preparation of cycloadducts (3). Base
(
1H, d, J= 6.5 Hz, CCH(CO Et)), 3.76 (2H, q, J= 7.1 Hz,
2
(2 equiv.) was added to pyridinium salt (2 equiv.) in dry solvent,
CCH(CO CH CH )), 1.30 (3H, t, J= 7.1 Hz, NCHCOCH CH ),
2
2
3
2
3
under argon and the mixture stirred at room temperature for 5
minutes. Oxindole (1 equiv.) was added and the mixture stirred at
room temperature for 2-4 hours. Water was added and the organic
layer separated, washed with water (2x), brine, dried over
Na SO , filtered and evaporated. The crude products were
0
.77 (3H, t, J= 7.1 Hz, CCH(CO CH CH )); NMR  (100 MHz,
2 2 3 C
6
d -acetone) 176.0 (C), 170.4 (C), 167.9 (C), 149.9 (C), 142.4 (C),
134.0 (CH), 129.1 (CH), 127.5 (C), 126.3 (CH), 120.2 (CH),
1
09.7 (CH), 106.4 (C), 93.6 (CH), 73.2 (CH), 65.0 (CH), 64.2
2
4
(
C), 61.7 (CH ), 61.4 (CH ), 52.8 (CH), 13.6 (CH ), 12.9 (CH );
2
2
3
3
purified by column chromatography on silica gel (using either
MeOH/CH Cl ; 1/10 or EtOAc/Petrol; 1/1 as eluent) or
79
m/z (HRMS-ESI+) 506.0569 (M+H C H BrN O requires
5
2
1
21
3
7
2
2
81
06.0558), 508.0552 (M+H C H BrN O requires 508.0537).
21 21 3 7
recrystallised with ethanol.
1'R*,2'S*,3'S*,8a'S*)-Diethyl 8'-bromo-2-oxo-3',8a'-dihydro-
'H-spiro[indoline-3,1'-indolizine]-2',3'-dicarboxylate (3a).
(1'R*,2'S*,3'S*,8a'S*)-Diethyl 8'-bromo-5-methoxy-2-oxo-1-
(
2
(prop-2-yn-1-yl)-3',8a'-dihydro-2'H-spiro[indoline-3,1'-
indolizine]-2',3'-dicarboxylate (3d). Grey solid; 74 mg (82 %);
-
1
Brown solid; 121mg (88 %); m.p. 76-78 C; IR (νmax/cm ,
-1
m.p. 125-127 C (ethanol); IR (νmax/cm , CHCl ) 3309, 3011,
3
CHCl ) 3442, 3136, 2984, 2482, 1734, 1639, 1622, 1563, 1471,
3
4
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Organic & Biomolecular Chemistry
1
738, 1718, 1639, 1605, 1495, 1370, 1339, 1192; NMR  (400
spiro[indoline-3,1'-indolizine]-3'-carboxylate
6'-cyano-2-oxo-3',8a'-dihydro-2'H-
spiro[indoline-3,1'-indolizine]-3'-carboxylate (3g′). Yellow
(3g)
and
H
6
MHz, d -acetone) 7.07 (1H, d, J= 8.5 Hz, ArH), 6.99 (1H, d, J= 60 (1'R*,3'R*,8a'S*)-Ethyl
2
7
.4 Hz, ArH), 6.94 (1H, dd, J= 8.5, 2.4 Hz, ArH), 6.61 (1H, d, J=
.1 Hz, N-CH=CH), 6.08 (1H, dt, J= 6.4, 0.9 Hz, CH-CH=CBr),
-
1
solid; 90 mg (77%); m.p. 188-190 C; IR (νmax/cm , CHCl )
3
5
0
5
0
5
0
5
0
5
0
5
5.21 (1H, d, J= 0.9 Hz, NCHC-Br), 5.06 (1H, d, J= 6.9 Hz,
NCH(CO Et)), 4.63 (1H, d, J= 17.8, 2.6 Hz, NCH H ), 4.57 (1H,
dd, J= 7.1, 6.4 Hz, NCH=CH), 4.50 (1H, d, J= 17.8, 2.5 Hz, 65 diastereoisomers, *indicates minor where different from major)
3203. 2981, 2938, 2203, 1731, 1643, 1621, 1574, 1485, 1469,
1391, 1133; NMR H (400 MHz, d -Acetone, 2:1 mixture of
6
2
a
b
NCH H ), 4.27 (2H, q, J= 7.1 Hz, NCHCO CH CH ), 3.74 (3H,
9.65 (1H, br s, NH), 9.50 (1H, br s, NH*), 7.35-7.20 (3H, m,
ArH, NCC=CH), 7.07-6.95 (2H, m, ArH), 5.80 (1H, app dt, J =
10.0, 1.5 Hz, CNC-CH*=CH), 5.67 (1H, app dt, J = 10.1, 1.5 Hz,
CNC-CH=CH), 5.06 (1H, t, J = 2.1 Hz, NCH*), 4.98-4.93 (2H,
a
b
2
2
3
s, OCH ), 3.73 (1H, d, J= 6.9 Hz, CCH(CO Et), 3.72 (2H, q, J=
3
2
1
1
2
2
3
3
4
4
5
5
7.1 Hz, CCH(CO CH CH )), 2.80 (1H, dd, J= 2.6, 2.5 Hz,
2 2 3
C≡CH), 1.30 (3H, t, J= 7.1 Hz, NCHCOCH CH ), 0.73 (3H, t, J=
2
3
6
7
1
.1 Hz, CCH(CO CH CH )); NMR  (100 MHz, d -acetone) 70 m, CHCO Et, NCH), 4.86 (1H, app t, J= 7.7 Hz, CH*CO Et),
72.8 (C), 170.7 (C), 167.9 (C), 155.6 (C), 137.0 (C), 133.9
2 2 3 C 2 2
4.60 (1H, ddd, J= 10.0, 2.1, 1.0 Hz, CH=CH*-CH), 4.52 (1H,
ddd, J= 10.1, 2.1, 0.8 Hz, CH=CH-CH), 4.35-4.24 (2H, m,
CH CH ), 2.57 (1H, dd, J= 13.4, 8.6 Hz, CH *), 2.48-2.43 (2H,
(CH), 128.5 (CH), 126.9 (C), 113.3 (CH), 111.8 (CH), 109.3
(CH), 106.4 (C), 93.3 (CH), 76.9 (C), 72.8 (CH), 72.7 (C), 64.8
2
3
a
(
CH), 61.5 (CH ), 61.0 (CH ), 52.3 (CH), 55.1 (CH), 52.3 (CH ),
m, CH CHCO Et), 2.37 (1H, dd, J= 13.4, 7.7 Hz, CH *), 1.30
2 2 b
2
2
3
6
2
9.2 (CH ), 13.6 (CH ), 12.9 (CH ); m/z (HRMS-ESI+) 529.0957 75 (3H, t, J= 7.1 Hz, CH CH ); NMR  (100 MHz, d -Acetone)
2
3
3
2
3
C
7
9
(M+H C H BrN O requires 529.0969), 531.0951 (M+H
179.3 (C), 176.5 (C), 171.8 (C), 171.6 (C), 147.8 (CH), 146.6
(CH), 143.5 (C), 142.3 (C), 132.1 (C), 129.8 (CH), 129.4 (CH),
127.9 (C), 126.4 (C), 124.7 (CH), 124.0 (CH), 123.7 (CH), 123.2
(CH), 123.0 (CH), 120.9 (C), 120.7 (C) 111.9 (CH), 111.5 (CH),
2
5
26
2
6
8
1
C H BrN O requires 531.0949).
2
5
26
2
6
(1'R*,2'S*,3'S*,8a'S*)-Diethyl
1-acetyl-8'-bromo-2-oxo-
3
',8a'-dihydro-2'H-spiro[indoline-3,1'-indolizine]-2',3'-
dicarboxylate (3e). Yellow solid; 80 mg (83 %); m.p. 108-110 80 110.7 (CH), 110.2 (CH), 78.6 (C), 78.4 (C), 67.8 (CH), 67.4
-
1

1
C; IR (νmax/cm , CHCl ) 2981, 1744, 1710, 1636, 1561, 1466,
(CH), 63.9 (CH), 63.2 (CH), 62.4 (CH ), 62.3 (CH ), 37.2 (CH ),
2 2 2
34.9 (CH ), 14.5 (CH ); m/z (HRMS-ESI+) 358.1162 (M+Na
2 3
C H N NaO requires 358.1162).
19 17 3 3
(1'R*,3'S*,8a'R*)-Ethyl 6'-carbamoyl-2-oxo-3',8a'-dihydro-
3
6
370, 1308, 1272, 1191, 1023; NMR  (400 MHz, d -acetone)
H
8.22 (1H, d, J= 8.2 Hz, ArH), 7.45-7.39 (2H, m, ArH), 7.21 (1H,
td, J= 8.2, 1.4 Hz, ArH), 6.63 (1H, d, J= 7.1 Hz, N-CH=CH),
6
5
.11 (1H, d, J= 6.5 Hz, CH-CH=CBr), 5.37 (1H, s, NCHC-Br), 85 2'H-spiro[indoline-3,1'-indolizine]-3'-carboxylate (3h) and
.05 (1H, d, J= 7.3 Hz, NCH(CO Et)), 4.58 (1H, dd, J= 7.1, 6.5 (1'R*,3'S*,8a'S*)-Ethyl 6'-carbamoyl-2-oxo-3',8a'-dihydro-
2'H-spiro[indoline-3,1'-indolizine]-3'-carboxylate (3h′).
2
Hz, NCH=CH), 4.29 (2H, q, J= 7.1 Hz, NCHCO CH CH ), 3.86
2
2
3
-
1
(1H, d, J= 7.3 Hz, CCH(CO Et), 3.69 (2H, q, J= 7.1 Hz,
Yellow solid; 109 mg (95 %); m.p. 138-140 C; IR (νmax/cm ,
2
CCH(CO CH CH )), 2.66 (3H, s, NCOCH ), 1.31 (3H, t, J= 7.1
CHCl ) 3352. 2926, 2359, 2340, 1710, 1648, 1620, 1585, 1471,
2
2
3
3
3
6
Hz, NCHCOCH CH ), 0.69 (3H, t, J= 7.1 Hz, 90 1382, 1290, 1196, 1104; NMR H (400 MHz, d -DMSO, 7:3
2
3
6
CCH(CO CH CH )); NMR  (100 MHz, d -acetone) 175.3 (C),
mixture of diastereoisomers, *indicates minor where different
from major) 10.63 (1H, s, NH), 10.40 (1H, s, NH*), 7.38 (2H, s,
2
2
3
C
1
70.4 (C), 170.3 (C), 167.4 (C), 141.5 (C), 133.8 (CH), 129.4
(CH). 129.1 (CH), 125.4 (C), 124.7 (CH), 123.9 (CH), 115.9
CH=CCONH ), 7.27-7.16 (4H, m, ArH), 7.02-6.84 (4H, m, ArH),
2
(
(
(
CH), 106.3 (C), 93.5 (CH), 74.3 (CH), 64.5 (CH), 63.8 (C), 61.7
6.54 (4H, br s, NH ), 6.28 (1H, dt, J= 10.2, 2.1 Hz, NH COC-
2
2
CH ), 61.2 (CH ), 53.6 (CH), 25.8 (CH ), 13.5 (CH ), 12.7 95 CH*=CH), 6.14 (1H, dt, J= 10.2, 2.1 Hz, NH COC-CH=CH),
2
2
3
3
2
7
9
CH ); m/z (HRMS-ESI+) 503.0800 (M+H C H BrN O
4.95 (1H, dd, J= 8.8, 7.4 Hz, CHCO Et), 4.92 (1H, dd, J= 8.8, 7.4
3
23 24
2
6
2
8
1
requires 503.0813), 505.0788 (M+H C H BrN O6 requires
Hz, CH*CO Et), 4.78 (2H, app dd, J= 2.1, 0.6 Hz, NCH), 4.38
2
3
24
2
2
505.0792).
1'S*,3'R*,8a'S*)-Ethyl 8'-bromo-2-oxo-3',8a'-dihydro-2'H-
(1H, ddd, J= 10.2, 2.1, 0.6 Hz, CH=CH*-CH), 4.35 (1H, ddd,
J=10.2, 2.1, 0.6 Hz, CH=CH-CH), 4.24 (4H, m, CH CH ), 2.47
(
2
3
spiro[indoline-3,1'-indolizine]-3'-carboxylate (3f). Brown 100 (1H, dd, J= 13.3, 8.8 Hz, CH *H ), 2.35-2.17 (2H, m, CH *,
a
b
b
-
1
solid; 107 mg (81 %); m.p. 144-146 C; IR (νmax/cm , CHCl )
CH H ), 1.29 (3H, t, J= 7.1 Hz, CH CH *), 1.27 (3H, t, J= 7.1
a b 2 3
3
6
3
434, 2962, 2361, 1732, 1621, 1472, 1374, 1261, 1106; NMR H
Hz, CH CH ); NMR  (100 MHz, d -DMSO) 179.3 (C), 176.6
2 3 C
(400 MHz, CDCl ) 8.55 (1H, s, NH), 7.33-7.28 (2H, m, ArH),
(C), 172.2 (C), 172.1 (C), 167.4 (C), 167.3 (C), 143.0 (C), 142.6
(CH), 141.9 (C), 141.5 (CH), 132.0 (C) 129.0 (CH), 128.7 (CH),
3
7
.09-7.04 (1H, m, ArH), 6.97 (1H, d, J= 7.3 Hz, ArH), 6.25 (1H,
d, J= 7.2 Hz, NCH=CH), 6.07 (1H, d, J= 7.2 Hz, CH=CBr), 5.38 105 128.0 (C) 124.8 (CH), 124.2 (CH), 124.1 (CH), 123.2 (CH),
(1H, s, CH), 4.62 (1H, app.t, J= 7.2 Hz, NCH=CH), 4.44 (1H, dd,
122.1 (CH), 122.0 (CH) 110.0 (CH), 109.9 (CH), 109.1 (CH),
107.5 (CH), 101.1 (C), 101.0 (C), 68.1 (CH), 67.5 (CH), 63.5
(CH), 62.6 (CH), 61.8 (CH ), 61.7 (CH ), 55.6 (C), 55.4 (C),
J= 8.4, 7.9 Hz, CHCO Et), 4.29 (2H, q, J= 7.1 Hz, CH CH ),
2
2
3
2.52 (1H, dd, J= 13.4, 7.9 Hz, CH H ), 2.22 (1H, dd, J= 13.4, 8.4
a
b
2
2
Hz, CH H ), 1.35 (3H, t, J= 7.1 Hz, CH CH ); NMR  (100
36.5 (CH ), 34.3 (CH ), 14.6 (CH ), 14.5 (CH ); m/z (HRMS-
2 2 3 3
a
b
2
3
C
MHz, CDCl ) 178.0 (C), 171.7 (C), 141.1 (C), 132.8 (CH), 130.6 110 ESI+) 354.1442 (M+H C H N O requires 354.1454).
3
19 20
3
4
(C), 128.6 (CH), 127.4 (CH), 123.6 (CH), 122.5 (CH), 110.0
(1'R*,3'S*,8a'R*)-Ethyl
spiro[indoline-3,1'-indolizine]-3'-carboxylate
(1'R*,3'S*,8a'S*)-Ethyl 6'-acetyl-2-oxo-3',8a'-dihydro-2'H-
6'-acetyl-2-oxo-3',8a'-dihydro-2'H-
(CH), 109.3 (C), 94.9 (CH), 71.5 (CH), 64.1 (CH), 61.8 (CH2),
(3i) and
60.9 (C), 37.7 (CH ), 14.2 (CH ); m/z (HRMS-ESI+) 389.0494
2
3
7
9
(
M+H C H BrN O requires 389.0501), 391.0476 (M+H
spiro[indoline-3,1'-indolizine]-3'-carboxylate (3i′). Brown
1
8
18
2
3
8
1
-1
C H BrN O requires 391.0480).
115 solid, 97 mg (81 %); M.p. 118-120 C; IR (νmax/cm , CHCl )
1
8
18
2
3
3
(1'S*,3'R*,8a'S*)-Ethyl 6'-cyano-2-oxo-3',8a'-dihydro-2'H-
3434, 3010, 2447, 1731, 1621, 1573, 1472, 1373, 1251, 1180;
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 5

View Article Online
DOI: 10.1039/C3OB41415A
Organic & Biomolecular Chemistry
Page 6 of 7
NMR H (400 MHz, CDCl , 1:1.3 mixture of diastereoisomers,
hexahydro-2'H-spiro[indoline-3,1'-indolizine]-2',3'-
3
*indicates minor where different from major) 8.35 (1H, s, NH*), 60 dicarboxylate (3l). Following the general procedure described
8
.21 (1 H, s, NH), 7.47 (1H, s, NCH*=CCOCH ), 7.42 (1H, s,
above but the product was not stable to chromatography on silica
gel, so the crude cycloadduct 4 was reduced without purification
using the following procedure.
3
NCH=CCOCH ), 7.27-6.94 (8H, m, ArH), 6.53 (1H, d, J= 10.3
Hz, (COCH )CH=CH-CH), 6.36 (1H, d, J= 10.3 Hz,
3
5
0
5
0
5
0
5
0
5
0
5
3
(
(
(
(
COCH )CH*=CH-CH), 5.18 (1H, t, J= 1.8 Hz,
Crude cycloadduct 4 (75 mg) and Raney nickel (10 mol%)
3
COCH )CH=CH-CH*), 5.05 (1H, t, J= 1.8 Hz, 65 were dissolved in anhydrous ethyl acetate (4 mL), under argon.
3
COCH )CH=CH-CH), 4.81 (1H, t, J= 7.8 Hz, CHCO Et), 4.67
The atmosphere was replaced with H2 and the mixture stirred
until reduction was complete by TLC analysis and then filtered
through a pad of Celite. The filtrate was concentrated in vacuo
and purified via column chromatography (EtOAc/Petrol; 1/4) to
3
2
1H, dd, J= 10.3, 1.8 Hz, (COCH )CH=CH-CH) 4.61 (1H, t, J=
3
1
1
2
2
3
3
4
4
5
5
7.8 Hz, CH*CO Et) 4.53 (1H, dd, J= 10.3, 1.8 Hz,
2
(
(
(
COCH )CH=CH*-CH), 4.38-4.30 (4H, m, CH CH ), 2.70-2.58
2H, m, CH-CH CH ), 2.45-2.33 (2H, m, CH-CH CH ), 2.18 70 give spiroindolizidine 3l as a yellow oil; 48 mg (63 %); IR
3H, s, COCH *), 2.13 (3H, s, COCH ), 1.41-1.34 (3H, m,
3
2
3
a
b
a
b
-
1
(νmax/cm , CHCl ) 3440, 3198, 2942, 1732, 1621, 1471, 1373,
3
3
3
CH CH ); NMR  (100 MHz, CDCl ) 191.8 (C), 179.6 (C),
176.8 (C), 171.2 (C), 170.6 (C), 146.2 (CH), 144.3 (CH), 141.6
1339, 1319, 1184, 1097; NMR  (400 MHz, CDCl ) 8.66 (1H,
2
3
C
3
H
3
br s, NH), 7.31 (1H, d, J= 7.6 Hz, ArH), 7.22 (1H, td, J= 7.6, 1.0
Hz, ArH), 7.00 (1H, t, J= 7.6 Hz, ArH), 6.92 (1H, d, J= 7.6 Hz,
(C), 140.3 (C), 130.7 (C), 129.2 (CH), 128.9 (CH), 126.8 (C),
1
1
6
23.9 (CH), 123.7 (CH), 123.5 (CH), 123.2 (CH), 122.9 (CH), 75 ArH), 4.59 (1H, d, J= 5.6 Hz, NCHCO Et), 4.35-4.20 (2H, m,
2
22.8 (CH), 122.6 (CH), 110.4 (CH), 110.3 (CH), 108.7 (CH),
NCH(COCH CH )), 4.00 (1H, d, J= 5.6 Hz, NCH(CO Et)CH),
2 3 2
3.81-3.61 (2H, m, CH(COCH CH )), 3.41 (1H, dd, J= 10.9, 2.4
2 3
Hz, NCHC)), 3.09 (1H, d, J= 9.5 Hz, CH H ), 2.45 (1H, t, J= 9.5
a b
Hz, CH H ), 1.64-1.53 (2H, m, CH H , CH H ), 1.42-1.12 (6H,
a b a b a b
80 m, CH H , CH H , CH CH , CH CH ), 0.74-0.64 (4H, m,
a b a b a b 2 3
CH CH CH CH ); NMR  (100 MHz, CDCl ) 178.4 (C), 172.4
2 3, a b C 3
(C), 143.1 (C), 131.7 (C), 128.2 (CH), 126.5 (C), 125.8 (CH),
8.1 (CH), 67.1 (CH), 63.3 (CH), 62.8 (CH), 62.4 (CH ), 62.2
2
(CH ), 58.8 (C), 58.4 (C), 36.9 (CH ), 34.4 (CH ), 14.2 (CH );
m/z (HRMS-ESI+) 353.1498 (M+H C H N O requires
2
2
2
3
2
0
21
2
4
3
(
53.1501).
1'R*,3'S*,8a'S*)-3'-Acetyl-8'-bromo-3',8a'-dihydro-2'H-
spiro[indoline-3,1'-indolizin]-2-one (3j). Brown solid; 63 mg
-
1
(76 %); m.p. 126-128 C; IR (νmax/cm , CHCl ) 3438, 3011,
2
NMR H (400 MHz, d -DMSO) 10.53 (1H, s, NH), 7.27-7.19 85 22.6 (CH ), 14.4 (CH ), 13.3 (CH ); m/z (HRMS-ESI+) 387.1908
122.2 (CH), 109.4 (CH), 67.7 (CH), 64.1 (CH), 60.9 (CH ), 60.6
3
2
928, 2437, 1780, 1721, 1622, 1471, 1426, 1390, 1240, 1170;
(CH ), 60.0 (C), 54.2 (CH), 47.5 (CH ), 25.9 (CH ), 25.3 (CH ),
2
2
2
2
6
2
3
3
(2H, m, 2xArH), 6.96 (1H, td, J= 7.6, 1.0 Hz, ArH), 6.86 (1H, d,
(M+H C H N O requires 387.1920).
21 27 2 5
J= 7.6 Hz, ArH), 6.43 (1H, d, J= 7.0 Hz, CH-CH=CBr), 6.09
(1H, d, J= 7.0 Hz, N-CH=CH), 4.88 (1H, s, NCH), 4.70 (1H, t, J=
7
(1'S*,2'R*,3'R*,8a'R*)-Ethyl 8'-bromo-3'-cyano-2-oxo-3',8a'-
dihydro-2'H-spiro[indoline-3,1'-indolizine]-2'-carboxylate
.0 Hz, NCH=CH), 4.49 (1H, t, J= 6.8 Hz, CHCOCH ), 2.19 (3H,
(3m). White solid; 145 mg (72 %); m.p. 159-161 C (acetone); IR
3
6
-1
s, COCH ), 2.11-2.06 (2H, m, CH H ); NMR  (100 MHz, d - 90 (νmax/cm , CHCl ) 3691, 3439, 3009, 2482, 2245, 1735, 1640,
3
a
b
C
3
6
DMSO) 207.3 (C), 177.7 (C), 142.8 (C), 135.2 (CH), 131.3 (C),
28.7 (CH), 128.2 (CH), 123.8 (CH), 121.8 (CH), 109.9 (CH),
108.0 (C), 93.3 (CH), 71.7 (CH), 70.5 (CH), 61.3 (C), 36.4
CH2), 26.7 (CH3); m/z (HRMS-ESI+) 359.0370 (M+H
1621, 1569, 1485, 1378, 1191; NMR  (400 MHz, d -acetone)
H
1
9.74 (1H, br s, NH), 7.28 (1H, app t, J= 7.6 Hz, ArH), 7.22 (1H,
d, J= 7.3 Hz, ArH), 7.01-6.91 (2H, m, ArH), 6.67 (1H, d, J= 7.2,
N-CH=CH), 6.12 (1H, d, J= 6.4 Hz, CH-CH=CBr), 5.48 (1H, d,
(M+H 95 J= 6.4 Hz, NCHCN, 5.25 (1H, s, NCHC-Br), 4.72 (1H, app t, J=
6.4 Hz, NCH=CH), 3.77 (1H, d, J= 6.4 Hz, CHCO CH CH ),
(
7
9
C H BrN O
C H BrN O requires 361.0375).
requires
359.0395),
361.0359
1
7
16
2
2
8
1
1
7
16
2
2
2
2
3
(2'S*,3'S*,8a'S*)-Diethyl 8'-fluoro-2-oxo-3',8a'-dihydro-2'H-
3.72 (2H, q, J= 7.1 Hz, CCH(CO CH CH )), 0.74 (3H, t, J= 7.1
2 2 3
6
spiro[indoline-3,1'-indolizine]-2',3'-dicarboxylate (3k). Yellow
oil; 80 mg (87 %); IR (νmax/cm , CHCl ) 3691, 3440, 3010, 1736,
1
Hz, NCHCOCH CH ); NMR  (100 MHz, d -DMSO) 176.1
2
3
C
-
1
(C), 167.9 (C), 144.6 (C), 132.8 (CH), 130.3 (CH), 129.1 (CH),
3
620, 1597, 1472, 1391, 1314, 1192, 1025; NMR  (400 MHz, 100 126.7 (C), 125.5 (CH), 122.3 (CH), 119.1 (C), 110.6 (CH), 109.1
H
6
d -acetone) 9.66 (1H, br s, NH), 7.26-7.22 (2H, m, ArH), 6.97-
.91 (2H, m, ArH), 6.35-6.32 (1H, m, N-CH=CH), 5.39-5.34
(1H, m, CH-CH=CF), 5.17 (1H, s, NCHC-F), 5.03 (1H, dd, J=
.4, 1.2 Hz, NCH(CO Et)), 4.54-4.49 (1H, m, NCH=CH), 4.27
(C), 96.7 (CH), 72.9 (CH), 63.8 (C), 62.3 (CH ), 55.6 (CH), 54.9
2
6
(CH), 13.7 (CH3); m/z (HRMS-ESI+) 436.0273 (M+Na
7
9
C H BrN NaO requires 436.0273), 438.0256 (M+Na
1
9
16
3
3
8
1
7
C H BrN NaO requires 438.0256).
19 16 3 3
2
(2H, q, J= 7.1 Hz, NCHCO CH CH ), 3.81-3.66 (3H, m, 105 (1'S*,2'R*,3'R*,8a'R*)-Ethyl 8'-bromo-2-oxo-3'-phenyl-3',8a'-
2 2 3
NCH(CO Et)CH(CO Et), NCH(CO Et)CH(CO CH CH )), 1.29
dihydro-2'H-spiro[indoline-3,1'-indolizine]-2'-carboxylate
2
2
2
2
2
3
(3H, t, J= 7.1 Hz, NCHCOCH CH ), 0.70 (3H, t, J= 7.1 Hz,
(3n). White solid; 149 mg (70 %); m.p. 176-178 C (acetone); IR
2
3
6
-1
NCH(CO Et)CH(CO CH CH )); NMR  (100 MHz, d -acetone)
1
(νmax/cm , CHCl ) 3692, 3441, 3009, 1731, 1601, 1562, 1484,
2
2
2
3
C
3
C-F
6
74.9 (C), 170.9 (C), 168.1 (C), 149.3 (d, J = 252 Hz, C), 143.0
1379, 1247, 1117, 1027; NMR H (400 MHz, d -acetone) 9.71
C-F
(
(
(
C), 130.5 (d, J = 4 Hz, CH), 129.0 (CH), 126.6 (C), 124.6 110 (1H, br s, NH), 7.51-7.41 (5H, m, ArH), 7.36-7.25 (2H, m, ArH),
CH), 121.3 (CH), 109.6 (CH), 103.1 (d, J = 14 Hz, CH), 91.1
d, J = 5 Hz, CH), 68.0 (d, J = 33 Hz, CH), 65.3 (d, J = 1
C-F
7.01 (1H, td, J= 7.7, 0.8 Hz, ArH), 6.97 (1H, d, J= 7.7 Hz, ArH),
6.32 (1H, d, J= 6.7 Hz, N-CH=CH), 6.07 (1H, d, J= 6.7 Hz, CH-
CH=CBr), 5.43 (1H, d, J= 8.5 Hz, NCHPh, 4.51 (1H, app t, J=
6.7 Hz, CH=CHN), 3.78 (1H, dq, J= 10.8, 7.1 Hz, CH H ), 3.67
C-F
C-F
C-F
C-F
Hz, CH), 62.6 (d, J = 3 Hz, C), 61.5 (CH ), 60.9 (CH ), 52.9
2
2
(
(
(
CH), 13.6 (CH ), 12.8 (CH ); m/z (HRMS-ESI+) 401.1507
M+H C H FN O requires 401.1507).
1'R*,2'S*,3'S*,8a'R*)-Diethyl
3 3
a
b
115 (1H, dq, J= 10.8, 7.1 Hz, CH H ), 3.4 (1H, d, J= 8.5 Hz,
a b
2
1
22
2
5
6
2-oxo-3',5',6',7',8',8a'-
CHCO Et), 0.77 (3H, t, J= 7.1 Hz, CH ); NMR  (100 MHz, d -
2 3 C
6
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

View Article Online
DOI: 10.1039/C3OB41415A
Page 7 of 7
Organic & Biomolecular Chemistry
acetone) 176.6 (C), 169.3 (C), 144.5 (C), 143.2 (C), 134.6 (CH),
8
9
B. X. Wang, X. C. Zhang, J. Li, X. Jiang, Y. F. Hu and H. W. Hu, J.
Chem. Soc. Perkin Trans. 1, 1999, 1571-1575. See ref 22 also.
S. Kanemasa, S. Takenaka, H. Watanabe and O. Tsuge, J. Org.
Chem., 1989, 54, 420-424.
1
1
30.0 (CH), 129.9 (CH), 129.4 (CH), 128.7 (CH), 127.5 (C),
27.2 (CH), 125.6 (CH), 122.2 (CH), 110.4 (CH), 108.3 (C), 94.1
6
7
5
0
(
CH), 73.7 (CH), 68.1 (CH), 64.8 (C), 61.6 (CH ), 59.4 (CH),
2
10 S. J. Taylor, A. M. Taylor and S. L. Schreiber, Angew. Chem. Int.
Ed., 2004, 43, 1681-1685
1
7
9
5
0
5
0
13.8 (CH ); m/z (HRMS-ESI+) 465.0800 (M+H C H BrN O
3 24 22 2 3
requires 465.0808), 467.0786 (M+H C H BrN O3 requires
8
1
1
For recent developments: M. A. Ischay, M. K. Takase, R. G.
Bergman, and J. A. Ellman, J. Am. Chem. Soc., 2013, 135,
2478−2481 and references therein.
(a) For Wittig olefination for 1a-e: S. W. Duan, Y. Li, Y. Y. Liu, Y.
Q. Zou, D. Q. Shi and W. J. Xiao, Chem. Commun., 2012, 48, 5160-
5162. (b) For Peterson route to 1f: T. Watanabe, M. Arisawa, K.
Narusuye, M. S. Alam, K. Yamamoto, M. Mitomi, Y. Ozoe and A.
Nishida, Bioorg. Med. Chem., 2009, 17, 94-110.
2
4
22
2
4
65.0793).
Diethyl 2-(2-oxoindolin-3-ylidene)succinate 5. Method as
cycloaddition, but ethanol was used as solvent and reaction
performed at 50 °C. Yellow oil (60 %); NMR H (400 MHz,
CDCl3, 5:1 mixture of diastereoisomers, only major
1
2
1
1
2
-
1
75
diastereoisomer peaks are quoted) (νmax/cm , CHCl ) 3446,
3
1
3
A. R. Katritzky, N. E. Grzeskowiak and J. Alvarezbuilla, J. Chem.
Soc. Perkin Trans. 1, 1981, 1180-1185.
3
011, 2986, 1726, 1617, 1470, 1370, 1334, 1295, 1192; NMR
H (400 MHz, CDCl ) 8.38 (1H, s, NH), 7.66 (1H, d, J= 8.0 Hz,
14 W. G. Phillips and K. W. Ratts, J. Org. Chem., 1970, 35, 3144-3147.
15 X.-M. Zhang, F. G. Bordwell,. M. Van Der Puy, and H. E. Fried, J.
Org. Chem. 1993,58, 3060-3066.
3
ArH), 7.29 (1H, td, J= 8.0, 1.2 Hz, ArH), 6.98 (1H, td, J= 8.0, 1.2
Hz, ArH), 6.85 (1H, d, J= 8.0 Hz, ArH), 4.43 (2H, q, J= 7.2 Hz,
CH CH ), 4.41 (2H, s, CH CO Et), 4.22 (2H, q, J= 7.2 Hz,
8
0
1
1
6
7
R. L. Hinman, C. P. Bauman, J. Org. Chem. 1964, 29, 2431-2437.
For a related synthetic process: B. Viswambharan, K. Selvakumar, S.
Madhavan, and P. Shanmugam, Org. Lett, 2010, 12, 2108-2111.
2
3
2
2
CH CH ), 1.40 (3H, t, J= 7.2 Hz, CH CH ), 1.29 (3H, t, J= 7.2
2
3
2
3
Hz, CH CH ); NMR  (100 MHz, CDCl ) 169.7 (C), 169.2 (C),
18 G. Laus, J. Chem. Soc. Perkin Trans. 2, 1998, 315-317.
2
3
C
3
167.4 (C), 141.0 (C), 135.0 (C), 130.9 (CH), 129.4 (C), 125.1 85 19 Diastereoisomers, such as 3g:3g′ could not be separated by column
chromatography on silica gel. No change was observed to the
(
CH), 122.3 (CH), 120.8 (C), 109.9 (CH), 61.9 (CH ), 61.2
2
diastereomeric ratio in the crude product obtained from cycloaddition
reactions performed in various solvents at a range of temperatures.
20 Q. Fu and C-G. Yan, Tetrahedron, 2013, 69, 5841-5849.
21 For related solvent effects: N. E. Dontsova, V. N. Nesterov, A. M.
Shestopalov, Tetrahedron, 2013, 69, 5016-5021.
(
3
CH ), 34.7 (CH ), 14.2 (CH ), 14.0 (CH ); m/z (HRMS-ESI+)
26.0982 ([M+Na] 100%) requires C H NO Na 326.0999.
16 17 5
2
2
3
3
+
9
9
0
5
Acknowledgements
2
2
A very recent paper describing stepwise reaction of pyridinium ylides
2
5
This work was supported by the EPSRC (MU, EP/J021008/1),
AstraZeneca (JD) and the University of Nottingham (RAC).
with Michael acceptors: Eur. J. Org. Chem. 2013, DOI:
1
0.1002/ejoc.201300784.
Notes and references
a
School of Chemistry, University of Nottingham, University Park,
Nottingham, UK NG7 2RD. E-mail: james.dowden@nottingham.ac.uk;
Fax: +44 115 9513565; Tel: +44 115 9513566
Pharmaceutical Development, AstraZeneca, Silk Road Business Park,
3
3
4
4
5
5
6
0
5
0
5
0
5
0
b
Macclesfield, U.K.
†
Electronic Supplementary Information (ESI) available: Full
experimental and spectroscopic information.
DOI: 10.1039/b000000x/
See
‡
8
1
Crystal data for 3a. C21H21BrN O , M = 507.38, triclinic, a =
.5537(12), b = 9.0560(14), c = 16.2097(17) Å, U = 1147.4(3) Å . T =
20(2)K, space group P -1, Z = 2, 8522 reflections measured, 4490
2 5
3
unique. with R = 0.0804 wR
Crystal data for 3g′ (not shown).† C19
2
= 0.2241. CCDC 927103.
, M = 335.35, triclinic, a =
17 3 3
H N O
3
8
1
.8865(5), b = 9.3125(3), c = 10.9460(5) Å, U = 826.26(7) Å . T =
20(2)K, space group P -1, Z = 2, 15441 reflections measured, 3480
= 0.0903. CCDC 927102.
Footnotes should appear here. These might include comments relevant
unique. with R = 0. 0346 wR
‡
2
to but not central to the matter under discussion, limited experimental and
spectral data, and crystallographic data.
1
B. Over, S. Wetzel, C. Grutter, Y. Nakai, S. Renner, D. Rauh and H.
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C. V. Galliford and K. A. Scheidt, Angew. Chem. Int. Ed., 2007, 46,
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C. Marti and E. M. Carreira, Eur. J. Org. Chem., 2003, 2209-2219.
G. S. Singh and Z. Y. Desta, Chem. Rev., 2012, 112, 6104-6155.
For recent examples and references: a) A. P. Antonchick, C. Gerding-
Reimers, M. Catarinella, M. Schürmann, H. Preut, S. Ziegler, D.
Rauh and H. Waldmann, Nature Chem, 2010, 2, 735-740; b) T.-L.
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011, 9, 1980-1986.
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A. B. Serov, V. G. Kartsev, Y. A. Aleksandrov and F. M. Dolgushin,
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