Tandem Horner-Wadsworth-Emmons/Heck procedures for the preparation of 3-alkenyl-oxindoles: The synthesis of Semaxanib and GW441756

Article abstract of DOI:10.1016/j.tet.2010.03.018

A tandem sequence involving Horner-Wadsworth-Emmons (HWE) olefination followed by a palladium-catalysed intramolecular Heck reaction has been developed to provide rapid access to 3-alkenyl-oxindoles from α-halo-anilides. This one-pot microwave accelerated process proceeds with catalytic palladium(II) acetate or tetrakis(triphenylphosphine)palladium, and has been used to prepare a range of adducts derived from aromatic, heteroaromatic and aliphatic aldehydes. The procedures can be used to prepare N-unprotected oxindoles directly and the applicability of the process has been established by carrying out one-pot syntheses of Semaxanib, an angiogenesis signalling inhibitor, and GW441756, an aza-oxindole Trk A inhibitor.

Full text of DOI:10.1016/j.tet.2010.03.018

Tetrahedron 66 (2010) 6606–6612
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Tandem Horner–Wadsworth–Emmons/Heck procedures for the preparation
of 3-alkenyl-oxindoles: the synthesis of Semaxanib and GW441756
*
Jana Lubkoll, Alessia Millemaggi, Alexis Perry, Richard J.K. Taylor
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A tandem sequence involving Horner–Wadsworth–Emmons (HWE) olefination followed by a palladium-
catalysed intramolecular Heck reaction has been developed to provide rapid access to 3-alkenyl-ox-
Received 4 February 2010
Received in revised form 3 March 2010
Accepted 3 March 2010
indoles from
a-halo-anilides. This one-pot microwave accelerated process proceeds with catalytic
palladium(II) acetate or tetrakis(triphenylphosphine)palladium, and has been used to prepare a range of
adducts derived from aromatic, heteroaromatic and aliphatic aldehydes. The procedures can be used to
prepare N-unprotected oxindoles directly and the applicability of the process has been established by
carrying out one-pot syntheses of Semaxanib, an angiogenesis signalling inhibitor, and GW441756, an
aza-oxindole Trk A inhibitor.
Available online 10 March 2010
Dedicated to Professor Steve Ley to cele-
brate the award of the Tetrahedron Prize
and to acknowledge his scientific
inspiration – and his enduring friendship
and support
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Heck
Horner–Wadsworth–Emmons
Phosphonates
Palladium catalysis
Oxindoles
Tandem reactions
Semaxanib
GW441756
1. Introduction
employed as building blocks in natural product and target
synthesis.10
3-Alkenyl-oxindoles and 3-alkenyl-aza-oxindoles are present
in many compounds of medicinal and biological importance as
well as in a number of natural products.1–3 In terms of pharma-
ceuticals, mention should be made of the anti-angiogenic/anti-
cancer pyrrolylidene oxindoles Semaxanib (SU5416) 14 and Suni-
tinib (SU11248) 2,5 Tenidap 3, a cyclooxygenase inhibitor used for
the treatment of rheumatoid arthritis and osteo-arthritis,6 and the
aza-oxindole GW441756 4, a potent and highly selective, orally
active tyrosine kinase (Trk) A inhibitor.7 In terms of natural
products, Soulieotine 58 and Ammosamide B 69 are representative
examples (Fig. 1). Soulieotine 5 was isolated from Souliea vaginata,
which is employed as an anti-inflammatory in traditional Chinese
medicine8 and Ammosamide B 6 was recently obtained from the
marine-derived Streptomyces strain CNR-698 and shown to inhibit
myosin.9 In addition, 3-alkenyl-oxindoles have been widely
As part of a programme to develop efficient and practical tan-
dem/telescoped procedures to heterocyclic systems,11,12 we recently
designed a telescoped, one-pot procedure for the streamlined
conversion of
a-halo-anilides 7 into 3-alkenyl-oxindoles 9, as
shown in Scheme 1.11 The amidophosphonates 7 were subjected to
palladium-catalysed intramolecular enolate arylation to give the
cyclised intermediates 8; subsequent addition of an aldehyde in the
presence of base then initiated Horner–Wadsworth–Emmons
(HWE) olefination to generate the target alkenyl-oxindoles 9 in
a regiocontrolled manner. This procedure was successfully utilised
to prepare a range of 3-alkenyl-oxindoles 9 derived from aromatic,
heteroaromatic and aliphatic aldehydes and formaldehyde and
employed for the first synthesis of Soulieotine 5.11
Although successful, the sequence illustrated in Scheme 1 still
possesses some drawbacks:
i. It did not prove possible to carry out the process in a tandem
manner – the aldehyde had to be added after the arylation
process had reached completion.
* Corresponding author. E-mail address: rjkt1@york.ac.uk (R.J.K. Taylor).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.018

J. Lubkoll et al. / Tetrahedron 66 (2010) 6606–6612
NEt
6607
O
2
Me
Me
N
H
S
OH
O
Me
N
H
Cl
Me
N
H
F
O
O
N
H
N
H
N
H
Tenidap 3
cyclooxygenase inhibitor
rheumatoid arthritis
osteo-arthritis
Semaxanib 1
anti-angiogenic
anti-cancer
Sunitinib 2
anti-angiogenic
anti-cancer
Me
N
CONH
Me
2
Me
H N
2
N
O
O
O
N
Cl
N
H
MeO
N
H
Me
NH
2
GW441756 4
orally active Trk A inhibitor
Soulieotine 5
Souliea vaginata
Ammosamide B 6
Streptomyces strain
inhibits myosin
anti-inflammatory
Figure 1. Representative 3-alkenyl-oxindoles.
R3
P(O)(OEt)2
R1
R1
R1
X
P(O)(OEt)2
O
R3CHO
base
Pd(0)
base
O
O
N
R2
N
R2
N
R2
8
7
9
Scheme 1.
ii. It was not possible to carry out the enolate arylation/HWE
procedure on unprotected anilides 7 (R2¼H); this necessi-
tated the use of N-protected oxindoles (9, R2sH) and an
additional deprotection step was required to produce the free
oxindoles.
N-methyl phosphonate 11, excess benzaldehyde and a number of
different bases to promote the HWE reaction. A smaller excess of
the aldehyde could be employed but longer reaction times were
then required.
The use of potassium 3,7-dimethyl-3-octylate (KDMO)11 and
KOtBu in THF (entries i and ii) gave the expected alkene 12 albeit in
disappointing yield with a number of side-products being evident.
However, with Cs2CO3 as base the required reaction proceeded in
essentially quantitative yield (entry iii). The optimum conditions
used 6 equiv of Cs2CO3 and 5 equiv of benzaldehyde at high con-
centration (300 mM with respect to phosphonate) with microwave
acceleration.
In the search for an improved procedure for the overall annu-
lation we investigated the complementary HWE/Heck approach to
3-alkenyl-oxindoles 9 (Scheme 2) in a ‘one-pot’ microwave irra-
diation process. Heck reactions leading to 3-alkenyl-oxindoles 9
are well known13–18 but, to our knowledge, they have not been
combined with in situ generation of the cyclisation precursors
10.17 In addition, in some cases, Heck routes to oxindoles have
been shown to be compatible with unprotected nitrogen
substituents.18
Encouraged by these results, we next investigated the second
step of the one-pot sequence, the Heck reaction (Table 2). Several
different palladium sources were screened unsuccessfully but the
expected 3-alkenyl-oxindole 13a was observed using tetrakis
(triphenylphosphine)palladium (entry i), Pd2(dba)3 (entry ii), and
palladium(II) acetate (entry iii). However, the best yield by far was
In order to evaluate the sequence shown in Scheme 2, we ini-
tially investigated the individual steps (Table 1) before moving on
to the one-pot process. These initial investigations used the
R3
R3
R3CHO
base
R1
R1
R1
X
P(O)(OEt)2
O
X
Pd(0)
Heck
O
HWE
N
R2
N
N
O
R2
R2
7
9
10
Scheme 2.

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J. Lubkoll et al. / Tetrahedron 66 (2010) 6606–6612
Table 1
Table 3
HWE reactions of the N-methylated phosphonate 11
The tandem HWE/Heck route to 3-alkenyl-oxindoles 13a–j
Ph
O
5 eq. RCHO
5 eq. PhCHO
x eq. base, THF
Br P(O)(OEt)
2
6 eq. Cs CO , THF
R
2
3
Br
5 mol% Pd(OAc)
Br
P(O)(OEt)
O
2
2
11 mol% PPh
3
N
O
100 C, 30 min, MW
N
Me
O
N
Me
Me
30 min, 100 C, MW
N
11
Me
13a-13k
12
11
Entry
Base
Eq. base
Conc. 11 [mM]
Yield 12a [%]
Entry
Aldehyde
PhCHO
4-NO2–C6H4–CHO
4-Cl–C6H4–CHO
4-CF3–C6H4–CHO
4-MeO–C6H4–CHO
Product, Yield (%)
E/Z ratio
i
ii
iii
KDMO
KOtBu
Cs2CO3
2.5
2.5
6
100
100
300
61
13a, 83a
13b, 45
13c, 58
13d, 57
13e, 25
1:1
1:1
E-only
E-only
1.3:1
40
i
98b,c
ii
iii
iv
v
a
E/Z >95:5.
b
c
Repeating this reaction but with 2.5 equiv Cs2CO3 gave 12 in 22% yield.
Repeating this reaction with 2.5 equiv Cs2CO3 at a concentration of 100 mM
gave 12 in 80% yield.
vi
vii
Pyridine-3-CHO
2-Furaldehyde
13f, 98
13g, 99
1.6:1
E-only
viiib
ixb
3-Methylbutyraldehyde
CyCHO
13h, 71
13i, 71
1:1
2.6:1
observed using 5 mol % Pd(OAc)2 and 11 mol % triphenylphosphine.
With these conditions the N-methylated oxindole 13a was isolated
in 91% yield (entry iv).
With the parameters for the individual reactions defined, the
one-pot tandem HWE/Heck reactions of N-methylated phospho-
nate 11 was explored (Table 3). Starting with benzaldehyde (entry i),
we were delighted to observe that on mixing all of the reagents for
both processes together, the desired 3-alkenyl-oxindole 13a was
a
Other solvents can also be employed: THF–PhMe (1:1, 35%), DME (61%), CH3CN
(70%).
b
No 3-alkenyl-oxindole was observed using pivaldehyde and HCHO gave
a complex mixture of products; hexanal gave the expected product in >60% yield
but it was not possible to obtain an analytically pure sample.
reactions of this type producing 3-alkenyl-oxindoles,19 mixtures of
stereoisomers (often rich in the E-isomers) were normally obtained
(unless intramolecular hydrogen bonding is present to favour the
Z-isomer – see compound 1 in Scheme 3). The E/Z ratio was also
sensitive to solvent, choice of phosphine and palladium catalyst,
catalyst concentration and reaction time.
Having developed a satisfactory tandem procedure for pre-
paring N-methylated 3-alkenyl-oxindoles, we proceeded to in-
vestigate the use of the N-unprotected phosphonate 14 in the
tandem HWE/Heck sequence. Analysis of the individual steps as
before revealed that the HWE reaction was slower in the un-
Table 2
Heck reactions of the N-methylated alkene 12a
5 mol% [Pd]
Ph
Ph
11 mol% Ligand
Br
6 eq. Cs CO , THF
2
3
O
100 C, 30 min, MW
300 mM in 12
N
Me
O
N
Me
12
13a
Entry
[Pd]b
Ligand
Yield 13a (%)
E/Z ratio
i
ii
iii
iv
Pd(PPh3)4
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
d
d
d
41
31
22
91
4:1
3:1
4:1
1:1
Me
c
PPh3
Me
5 eq.
Me
CHO
N
H
a
The chloride and iodide corresponding to bromide 12 were also investigated.
The chloride proved unreactive in the Heck reaction whereas the iodide underwent
smooth cyclisation; however, the iodide proved to be unstable to storage and so
bromide 12 was used preferentially.
5 mol% Pd(PPh )
6 eq. Cs CO , THF
3 4
Me
N
H
X
P(O)(OEt)
O
2
2
3
O
b
With PdCl2, [Pd(PPh3)2Cl2] and [Pd(CH3CN)2Cl2] no reaction was observed.
Repeating this reaction but with P(o-Tol)3 or P(C6F5)3 gave 13a in 85% and 21%
N
H
N
H
60 min, 100 C, MW
c
yield, respectively.
14, X = Br
15, X = I
Semaxanib, 1
X = Br; 20%
X = I; 64%
Scheme 3.
obtained in 83% overall yield. It should be noted that, in the absence
of microwave irradiation, oxindole formation was not observed
using a 30 min reaction time.
This tandem HWE/Heck sequence was then applied to a range of
aromatic and heteroaromatic aldehydes (entries ii–vii). As can be
seen, electron-deficient aryl compounds reacted moderately well
(entries ii–iv) but with 4-methoxybenzaldehyde the yield of
3-alkenyl-oxindole 13e was disappointing under these standard
conditions (entry v), presumably due to mesomeric deactivation of
the aldehyde group. It is worth emphasising that the reaction
conditions employed in Table 3 were optimised for benzaldehyde
and the yields with the other aldehydes could well be improved by
further study (the Heck cyclisation is always the difficult step).
With pyridine-3-carboxaldehyde and 2-furaldehyde good yields of
the oxindole products were obtained under the standard condi-
tions (entries vi and vii). Aliphatic aldehydes also gave good results
in this tandem sequence (entries viii and ix). As is normal in
protected system, that the best catalyst for the Heck reaction was
tetrakis(triphenylphosphine)palladium, and that the iodo-
phosphonate 15 often gave higher yields than the corresponding
bromide 14. It was also established that the one-pot process was
more efficient than the two step sequence, possibly due to syner-
gistic effects.20
With the knowledge gleaned from the above investigations,
a range of aldehydes were studied in this N-unprotected HWE/Heck
sequence (Table 4). As before, benzaldehyde and electron-deficient
analogues gave 3-alkenyl-oxindoles in good to excellent yields (en-
tries i and ii) but, by contrast to the N–Me system, 4-methoxy-
benzaldehyde also gave an excellent 82% yield of oxindole 16c under
these standard conditions (entry iii, presumably a reflection of the
longer reaction time). However, 4-chloro-benzaldehyde reacted

J. Lubkoll et al. / Tetrahedron 66 (2010) 6606–6612
6609
sluggishly in the sequence using bromide 14 and the iodide 15 was
needed to obtain a reasonable yield of adduct 16d (entry iv). With
pyridine-3-carboxaldehyde and 2-furaldehyde, good yields of the
oxindole products were also obtained starting from iodide 15 (entries
v and vi). However, in the N–H series, reactions with aliphatic alde-
hydes gave only poor conversion (entry vii); the N–Me procedure is
preferred for these processes. In terms of stereoselectivity, the E/Z
ratios for the NMe (Table 3) and NH (Table 4) examples vary but in an
unpredictable manner (some reaction are more selective, some less,
in the NH systems). We ascribe these differences to the small changes
in product structures (NMe vs NH), and the longer reaction times in
the NH examples.
angiogenesis signalling inhibitor, was designed to block the VEGF-R
in blood vessels, thereby inhibiting the blood supply to the tu-
mour.4 Thus, in the optimum procedure, using the standard HWE/
Heck sequence, iodide 15 was converted into Semaxanib 1 in a one-
pot process in 64% yield solely as the required Z-stereoisomer
(intramolecular H-bonding being responsible for the high
stereoselectivity).
Buoyed by the successful preparation of Semaxanib 1, we moved
on to explore the use of the tandem HWE/Heck process for one-pot
approaches to 3-alkenyl-aza-oxindoles, as exemplified by the Trk A
inhibitor GW441756 4 (Scheme 4). Aza-oxindoles display a wide
range of biological properties including anti-viral, anti-arthritis and
anti-tumour activities.3,7
The bromopyridine precursor 17 was readily prepared and
proved to be an excellent substrate for the HWE/Heck sequence.
Withbenzaldehyde astrapping agent, aza-oxindole 1821 was formed
in 70% yield. With N-methylindole-3-carboxaldehyde, the reaction
gavetheTrkA inhibitor4 in upto 78%yield (DMEgaveslightlyhigher
yields than THF in this case) as a mixture of isomers (the compound
is marketed as an E/Z-mixture). Toourknowledge, this is the shortest
synthesis of GW441756 4 published to date.
To illustrate the value of the tandem HWE/Heck sequence, it was
applied to a simple, one-pot preparation of the anti-cancer agent
Semaxanib 1 as shown in Scheme 3. Semaxanib, a small molecule
Table 4
The tandem HWE/Heck route to unprotected 3-alkenyl-oxindoles 16a–g
5 eq. RCHO
R
6 eq. Cs CO , THF
2
3
5 mol% Pd(PPh )
X
P(O)(OEt)
O
3 4
2
In summary, we have developed a new tandem sequence
involving HWE olefination followed by a palladium-catalysed
intramolecular Heck reaction which provides rapid access to
O
N
60 min, 100 C, MW
N
H
H
3-alkenyl-oxindoles from readily available a-halo-anilides and al-
dehydes. The one-pot, MW accelerated process is fast (30–60 min)
and can be employed with a range of aldehyde trapping reagents.
N-Alkylated and NH oxindoles can be prepared using this sequence,
which can also be extended to prepare 3-alkenyl-aza-oxindoles.
The applicability of the tandem HWE/Heck sequence has been
demonstrated by carrying out one-pot syntheses of the anti-cancer
agent Semaxanib, and of GW441756, a potent aza-oxindole Trk A
inhibitor.
14, X = Br
15, X = I
16a-16g
Entry
X
Aldehyde
Product, yield (%)
E/Z ratio
i
ii
iii
iv
Br
Br
Br
I
PhCHO
16a, 82a
16b, 91
16c, 82
16d, 78b
2:1
5:1
3:1
E-only
4-CF3–C6H4–CHO
4-MeO–C6H4CHO
4-Cl–C6H4–CHO
v
vi
I
I
Pyridine-3-CHO
2-Furaldehyde
16e, 88
16f, 62
2.3:1
2:1
2. Experimental
vii
Br
CyCHOc
16g, 12
1:1
a
A 54% yield was obtained using the Pd(OAc)2 conditions as in Table 3 in a one-
step process; in a two step process the overall yield was 73% with a combined re-
action time of 90 min.
2.1. General details
All reagents were purchased from commercial sources and
used without further purification. All reactions were carried out in
oven-dried or flame-dried glassware under a nitrogen or argon
atmosphere using standard syringe and septum techniques unless
otherwise stated. THF were freshly distilled from sodium/
b
Yield of 16d from 14 was 35%.
Pivaldehyde and hexanal underwent efficient HWE elaboration but gave low
c
yields of oxindole products (10–40%) and the hexanal product could not be fully
purified; no oxindole products were observed with acetaldehyde and formaldehyde
(which gave a polymeric material).
5 eq. PhCHO
5 mol% Pd(PPh )
6 eq. Cs CO , THF
2 3
Ph
3 4
N
N
Br P(O)(OEt)
2
O
N
H
60 min, 100 C, MW
N
H
O
18, 70% (E:Z = 3.8:1)
17
CHO
5 eq.
Me
N
N
Me
5 mol% Pd(PPh )
3 4
N
N
Br P(O)(OEt)
6 eq. Cs CO , DME
2 3
2
O
N
H
60 min, 130 C, MW
N
H
O
GW441756 4, 72-78% (E:Z = 2:1)
17
Scheme 4.

6610
J. Lubkoll et al. / Tetrahedron 66 (2010) 6606–6612
benzophenone. Thin layer chromatography was performed on
pre-coated 0.2 mm Merck Kieselgel 60 F254 silica plates and
compounds were visualized under 245 nm ultraviolet irradiation
followed by staining in alkaline potassium permanganate. Flash
column chromatography was performed using Fluka Kieselgel 60
F (220–440 mesh) with the indicated solvents. Petroleum ether
refers to the fractions with boiling range 40–60 ꢀC. Melting points
were determined on a Gallenkamp melting point apparatus and
are uncorrected. Infrared spectra were recorded with a Thermo-
Nicolet IR100 spectrophotometer as thin films between sodium
chloride plates. 1H and 13C NMR spectra were obtained using ei-
ther a JEOL 400 MHz spectrometer operating at either 400 MHz or
the aqueous layer was extracted with EtOAc (3ꢁ3 mL). The com-
bined organic layers were dried over Na2SO4, filtered, concentrated
in vacuo and purified by flash chromatography (SiO2, petrol/EtOAc,
10:1).
2.4. (E)-3-(4-Chlorobenzylidene)-1-methylindolin-2-one 13c
Yellow solid (21.3 mg, 58%, E-isomer only), mp 107–109 ꢀC; Rf
0.27 (petrol/EtOAc, 10:1); IR (neat) 3424, 1704, 1608, 1488, 1377,
1339, 1092, 743 cmꢂ1
;
1H NMR (400 MHz, CDCl3)
d
¼7.77 (s, 1H),
7.58 (m, 3H), 7.44 (m, 2H), 7.28 (ddd, J¼1.1, 7.7, 7.7 Hz, 1H), 6.90
(ddd, J¼1.1, 7.7, 7.7 Hz, 1H), 6.86 (br d, J¼7.7 Hz, 1H), 3.27 (s, 3H, N–
100 MHz or
a
Bruker AMX 500 spectrometer operating at
Me) ppm; 13C NMR (100 MHz, CDCl3)
d
¼168.7, 144.7, 135.8, 133.7,
500 MHz or 125 MHz, respectively. Data are expressed in parts per
million downfield shift from tetramethylsilane as an internal
standard or relative to CDCl3. All J values are given in Hertz. As-
signments are made with the aid of DEPT 135, COSY and HSQC
experiments. Mass spectra were recorded using a Fisons Analyti-
cal VG Autospec spectrometer operating in chemical ionization
(CI), electron ionisation (EI) or fast atom bombardment (FAB)
mode or on a Bruker Daltronics microTOF spectrometer operating
in electrospray ionisation (ESI) mode. All microwave reactions
were performed in a CEM Discover system (50 W, closed vessel
mode, 100 ꢀC; the set temperature was reached in 10 min and
maintained for the remainder of the experiment). 2-Bromo-ani-
lides 1111 and 1522 were prepared using literature procedures. The
following products are known: 13a,23 13b,23 13d,23 13e,23 13f,24
16a,25 16b,26 16c,25 16d,25 16e,25 16e27 and 16f.19 With 3-alkenyl-
oxindoles 13 and 16, the E/Z ratios were determined using NMR
spectroscopy on the unpurified reaction mixtures. The individual
E- and Z-isomers were easily distinguished using NMR spectros-
copy (the chemical shift of the vinyl ]CH is observed at higher
parts per million values for the E-isomer compared to the Z-iso-
mer).11,23 In addition, the Z-isomer is usually less polar and is
eluted first during column chromatography.11,23
130.9, 130.3, 129.2, 128.7, 127.9, 122.9, 122.2, 121.0, 108.5, 25.9 (N–
Me) ppm; MS (ESI) 270 ([MþNa]þ, 100); HRMS (ESI): Found,
270.0680. C16H1335ClNO requires 270.0674 (2.2 ppm error).
2.5. (E)-3-(Furan-2-ylmethylene)-1-methylindolin-2-one 13g
Yellow solid (28 mg, 99%, E-isomer only), mp 124–128 ꢀC; Rf 0.42
(petrol/EtOAc, 5:1); IR (neat) 3116, 1702, 1629, 1604, 1470, 1489,
1420, 1379, 1341,1254, 1127, 1106, 1021, 745 cmꢂ1
;
1H NMR
(400 MHz, DMSO-d6)
d
¼8.42 (d, J¼7.5 Hz,1H), 8.18 (d, J¼1.8 Hz,1H),
7.43 (s, 1H), 7.36 (ddd, J¼1.1, 7.5, 7.5 Hz, 1H), 7.30 (d, J¼3.5 Hz, 1H),
7.09 (ddd, J¼1.1, 7.5, 7.5 Hz), 7.05 (br d, J¼7.5 Hz,1H), 6.81 (dd, J¼1.8,
3.5 Hz, 1H), 3.21 (s, 3H, N–Me) ppm; 13C NMR (100 MHz, CDCl3)
d
¼169.7, 151.8, 146.0, 144.2, 129.6, 125.1, 122.5, 122.3, 121.7, 120.6,
119.9, 113.3, 107.9, 25.9 (N–Me) ppm; MS (ESI) 326 ([MþH]þ, 100);
HRMS (ESI): Found, 326.0863. C14H12NO2 requires 326.0866
(ꢂ1.0 ppm error).
2.6. (E/Z)-1-Methyl-3-(3-methylbutylidene)indolin-2-one 13h
Colourless oil (44.8 mg, 71%, E/Z¼1:1, separated by column
chromatography, petrol/EtOAc), Rf 0.38 (E)/0.61 (Z) (petrol/EtOAc,
9:1); IR (neat) 3406, 1696, 1650, 1613, 1469, 1380, 1335, 1257, 1122,
2.2. (E)-N-(2-Bromophenyl)-N-methylcinnamamide 12
1090, 1022, 745 cmꢂ1
.
E-isomer: 1H NMR (400 MHz, CDCl3)
d¼7.41 (d, J¼7.7 Hz, 1H),
A
solution of the 2-bromo-N-methylanilide 11 (100 mg,
0.27 mmol), Cs2CO3 (373 mg, 1.64 mmol) and benzaldehyde
(160 L, 1.37 mmol) in THF (1 mL) under an Ar atmosphere was
7.26 (ddd, J¼1.2, 7.7, 7.7 Hz, 1H), 7.02 (ddd, J¼1.0, 7.7, 7.7 Hz, 1H),
6.90 (t, J¼7.9 Hz, 1H), 7.09 (br d, J¼7.7, 1H), 3.22 (s, 3H, N–Me), 2.92
(dd, J¼6.9, 7.9 Hz, 2H), 1.87 (m, 1H), 1.01 (d, J¼6.7 Hz, 6H) ppm.
m
heated with MW irradiation at 100 ꢀC (CEM Discover, 50 W max.)
for 30 min. The reaction mixture was treated with dist. H2O (3 mL)
and the aqueous layer was extracted with EtOAc (3ꢁ3 mL). The
combined organic layers were dried over Na2SO4, filtered, con-
centrated in vacuo and purified by flash chromatography (SiO2,
petrol/EtOAc, 10:1) to give the title compound 12 (85 mg, 98%, E-
isomer only), as a colourless oil, Rf 0.47 (petrol/EtOAc, 10:1); IR
(neat) 3437, 3005, 2925, 2853, 1658, 1616, 1582, 1477, 1450, 1420,
Z-isomer: 1H (400 MHz, CDCl3)
d
¼7.56 (d, J¼7.5 Hz, 1H), 7.27 (m,
1H), 7.09–7.02 (m, 2H), 6.82 (br d, J¼7.8 Hz, 1H), 3.23 (s, 3H, N–Me),
2.56 (t, J¼7.3 Hz, 1H), 1.96 (m, 1H), 1.03 (d, J¼6.7 Hz, 6H) ppm; 13C
NMR (100 MHz, CD3CN, Z-isomer)
d¼169.4, 144.6, 143.7, 130.8,
129.6, 125.1, 123.8, 121.1, 110.1, 37.8, 30.4, 26.7, 23.5 ppm; MS (ESI)
216 ([MþH]þ, 100); HRMS (ESI): Found, 216.1383. C14H17NO re-
quires 216.1382 (0.2 ppm error).
1370, 1289, 1248, 1216, 1133, 1060, 1030, 758 cmꢂ1
(400 MHz, CDCl3)
¼7.73–7.69 (m, 2H), 7.42 (ddd, J¼1.5, 7.3, 7.8 Hz,
1H), 7.34–7.27 (m, 7H), 6.12 (d, J¼15.5 Hz, 1H,), 3.31 (s, 3H, N–
Me) ppm; 13C NMR (100 MHz, CDCl3)
;
1H NMR
2.7. (E/Z)-3-(Cyclohexylmethylene)-1-methylindolin-
2-one 13i
d
d¼166.0, 142.4, 142.2, 135.0,
Yellow solid (45.7 mg; 71%, E/Z¼2.6:1, separated by column
chromatography, petrol/EtOAc), mp 115–117 ꢀC; Rf 0.31 (E)/0.17 (Z)
(petrol/EtOAc, 10:1); IR (neat) 2924, 2851, 1704, 1612, 1470, 1380,
133.9, 130.2, 129.8, 129.6, 128.9, 128.6, 127.8, 123.5, 117.8, 36.2 (N–
Me) ppm MS (ESI) 316 ([MþH]þ, 100); HRMS (ESI): Found,
316.0332. C16H1579BrNO requires 316.0333 (ꢂ0.4 ppm error).
1257, 1089, 745 cmꢂ1
.
E-isomer: 1H NMR (400 MHz, CDCl3)
d
¼7.38 (d, J¼7.4 Hz, 1H),
2.3. General procedure for the HWE/Heck sequence using
N–Me protected phosphonates
7.25 (ddd, J¼1.2, 7.7, 7.7 Hz, 1H), 7.01 (ddd, J¼1.0, 7.7, 7.7 Hz, 1H),
6.78 (br d, J¼7.7 Hz, 1H), 6.68 (d, J¼10.0 Hz, 1H), 3.84 (m, 1H), 3.28
(s, 3H, N–Me), 1.83–1.70 (m, 4H), 1.53–1.37 (m, 2H), 1.29–1.11
(m, 4H) ppm.
A
solution of 2-bromo-N-methylanilide 1111 (100 mg,
0.27 mmol), Cs2CO3 (373 mg, 1.64 mmol), Pd(OAc)2 (3.1 mg,
0.014 mmol), PPh3 (7.9 mg, 0.03 mmol) and benzaldehyde (160 L,
Z-isomer: 1H NMR (400 MHz, CDCl3)
d
¼7.51 (d, J¼7.7 Hz, 1H),
m
7.27 (ddd, J¼1.0, 7.7, 7.7 Hz, 1H), 7.04 (ddd, J¼1.0, 7.7, 7.7 Hz, 1H),
6.91 (d, J¼9.8 Hz, 1H), 6.82 (br d, J¼7.8 Hz, 1H), 3.23 (s, 3H, N–Me),
2.94 (m, 1H), 1.83–1.70 (m, 4H), 1.53–1.37 (m, 2H), 1.29–1.11 (m,
1.37 mmol) in THF (1 mL) under an Ar atmosphere was heated
under MW irradiation at 100 ꢀC (CEM Discover, 50 W max.) for
30 min. The reaction mixture was treated with dist. H2O (3 mL) and
4H) ppm; 13C NMR (100 MHz, CDCl3)
d¼168.8, 147.4, 143.9, 128.9,

J. Lubkoll et al. / Tetrahedron 66 (2010) 6606–6612
6611
126.0, 123.5, 122.3, 122.2, 108.2, 37.9, 31.4, 25.8, 25.5, 25.3 ppm; MS
1672, 1556, 1464, 1340, 1289, 784, 734 cmꢂ1
DMSO-d6)
;
1H NMR (400 MHz,
(ESI) 242 ([MþH]þ, 100); HRMS (ESI): Found, 242.1539. C16H20NO
d
¼13.38 (s, 1H), 10.80 (s, 1H), 7.72 (d, J¼7.7 Hz, 1H), 7.56
requires 242.1536 (1.2 ppm error).
(s, 1H), 7.10 (ddd, J¼1.1, 7.7, 7.7 Hz, 1H), 6.98 (ddd, J¼1.1, 7.7, 7.7 Hz,
1H), 6.87 (br d, J¼7.7 Hz, 1H), 6.01 (d, J¼2.5 Hz, 1H), 2.32 (s, 3H),
2.8. 1,3-Diethyl 2-(2-bromophenylamino)-
2-oxoethylphosphonate 14
2.30 (s, 3H) ppm; 13C (100 MHz, DMSO-d6)
d
¼169.3, 138.0, 135.5,
131.5, 126.5, 125.8, 125.6, 123.3, 120.7, 117.9, 112.6, 112.4, 109.2,
13.4, 11.2 ppm; MS (ESI) 239 ([MþH]þ, 100); HRMS (ESI): Found,
239.1179. C15H15N2O requires 239.1179 (ꢂ0.1 ppm error). These
data were consistent with those published.19
A solution of 2-bromoaniline (2 g, 11.8 mmol) in dry dichloro-
methane (15 mL) was cooled to 0 ꢀC, and then 2-chloro-1-methyl-
pyridinium iodide (9 g, 35.4 mmol), triethylamine (6 g, 59 mmol)
and 2-(diethoxyphosphoryl)acetic acid (3.5 g, 17.7 mmol) were
added. After 30 min the reaction mixture was treated with 10%
HCl (10 mL), extracted with dichloromethane (3ꢁ30 mL) and the
organic layers were washed with brine (3ꢁ10 mL). The combined
organic layers were dried over Na2SO4, filtered, concentrated in
vacuo and purified by flash chromatography (SiO2, 5% MeOH/
EtOAc) to give the title compound 14 (3.36 g, 81%) as a colourless
oil, Rf 0.57 (EtOAc/MeOH, 10:1); IR (neat) 3444, 2985, 1692, 1592,
2.12. Diethyl 2-(2-bromopyridin-3-ylamino)-
2-oxoethylphosphonate 17
White solid (3.36 g, 81%), mp 68–70 ꢀC; Rf 0.42 (MeOH/EtOAc,
10:1); IR (neat) 3230, 2985,1688,1578,1529,1452,1392,1300,1229,
1053, 1025, 975, 799 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
¼8.98 (br s,
1H), 8.62 (dd, J¼1.8, 8.2 Hz, 1H), 8.11 (dd, J¼1.8, 4.6 Hz, 1H), 7.27 (m,
1H), 4.25–4.17 (m, 4H), 3.07 (d, J¼20.7 Hz, 2H), 1.36 (t, J¼7.1 Hz,
1531, 1438, 1304, 1246, 1026, 973, 755 cmꢂ1
CDCl3)
;
1H NMR (400 MHz,
6H) ppm; 13C NMR (100 MHz, CDCl3)
d
¼163.4 (d, J(C-P)¼4.2 Hz),
d
¼8.83 (br s, 1H), 8.28 (d, J¼8.3 Hz, 1H), 7.55 (m, 1H), 7.32–
145.2, 133.9, 133.5, 129.5, 123.5, 63.0 (d, J(C-P)¼6.5 Hz), 37.2 (d, J(C-
P)¼130.7 Hz), 16.0 (d, J(C-P)¼5.9 Hz) ppm; MS (ESI) 352 ([MþH]þ,
100); HRMS (ESI): Found, 351.0104. C11H1779BrN2O4P requires
351.0107 (ꢂ1.0 ppm error).
7.26 (m, 1H), 7.01–6.97 (m, 1H), 4.24–4.16 (m, 4H), 3.06 (d,
J¼8.3 Hz, 2H), 1.35 (t, J¼7.0 Hz, 6H) ppm; 13C NMR (100 MHz,
CDCl3)
d
¼162.8 (d, J(C-P)¼4.1 Hz), 135.9, 132.7, 128.3, 125.7, 122.5,
113.8, 63.8 (d, J(C-P)¼6.5 Hz), 36.6 (d, J(C-P)¼130.4 Hz), 15.9 (d,
J(C-P)¼6.0 Hz) ppm; MS (ESI) 350 ([MþH]þ, 100); HRMS (ESI):
Found, 350.0151. C12H1879BrNO4P requires 350.0145 (1.9 ppm
error).
2.13. (E/Z)-3-Benzylidene-1H-pyrrolo[3,2-b]pyridin-
2(3H)-one 18
Yellow solid (70%, E/Z¼3.8:1, inseparable), mp 212–214 ꢀC lit.21
(mixture) mp 206–208 ꢀC; Rf 0.43 (petrol/EtOAc, 1:1); IR (neat)
2919, 1704, 1610, 1569, 1409, 1176, 768 cmꢂ1; 1H (400 MHz, DMSO-
2.9. General procedure for the HWE/Heck sequence using
N–H unprotected phosphonates
d6, E/Z mixture)
d
¼10.85 (s, 1H, E), 10.79 (s, Z), 8.81 (m, 2H, Z), 8.52
A solution of 2-bromo-anilide 14 (100 mg, 0.29 mmol), Cs2CO3
(390 mg, 1.72 mmol), Pd(PPh3)4 (16.5 mg, 0.014 mmol) and benz-
aldehyde (145 mL, 1.43 mmol) in THF (1 mL) under an Ar atmo-
sphere was heated using MW irradiation at 100 ꢀC (CEM Discover,
50 W max.) for 60 min. The reaction mixture was treated with dist.
H2O (3 mL) and the aqueous layer was extracted with EtOAc
(3ꢁ3 mL). The combined organic layers were dried over Na2SO4,
filtered, concentrated in vacuo and purified by flash chromatogra-
phy (SiO2, petrol/EtOAc, 5:1). A similar procedure was employed
using the iodo-anilide 15.
(m, 2H, E), 8.30 (dd, J¼2.6, 3.8 Hz, 1H, Z), 8.16 (dd, J¼1.8, 4.4 Hz, 1H,
E), 8.06 (s, 1H, E), 7.73 (s, 1H, Z), 7.53 (m, 3H, E), 7.28 (m, 3H, Z), 7.21
(m, 2H, E), 7.05 (m, 3H, Z) ppm (data consistent with those pub-
lished21); 13C (100 MHz, DMSO-d6, E/Z mixture)
d¼168.3 (C2), 166.3
(C20), 144.6 (C7a0), 142.8 (C7a), 142.3 (C70), 142.2 (C7), 140.8 (C3a),
139.7 (C3a0), 138.9 (C5), 136.3 (C50), 134.3 (C6), 133.8 (C60), 133.7
(C14, 10), 133.1 (C140, 100), 131.9 (C3), 131.9 (C30), 129.0 (C13, 11),
128.8 (C130,110), 125.9 (C120), 125.4 (C12), 124.3 (Cþ9), 123.9 (C90),
116.7 (C8), 116.0 (C80) ppm; MS (ESI) 223 ([MþH] , 100); HRMS
(ESI): Found, 223.0866. C14H11N2O requires 223.0863 (1.4 ppm
error).
2.10. (E/Z)-3-(Cyclohexylmethylene)indolin-2-one 16g
2.14. (E/Z)-3-((1-Methyl-1H-indol-3-yl)methylene)-1H-
pyrrolo[3,2-b]pyridin-2(3H)-one 4
Yellow film (8 mg, 12%, E/Z¼1:1, separated by column chroma-
tography, petrol/EtOAc), mp 92–94 ꢀC, Rf 0.30, 0.35 (petrol/EtOAc,
10:1); IR (neat) 3238, 2926, 2849, 1703, 1641, 1614, 1463, 1332, 1216,
Yellow film (56.5 mg, 72%, E/Z¼2:1, inseparable), mp 181–
183 ꢀC; Rf 0.35 (petrol/EtOAc, 1:2); IR (neat) 3402, 2923, 1685,
741 cmꢂ1
.
E-isomer: 1H NMR (400 MHz, CD3CN)
d
¼9.10 (br s, 1H), 7.44 (d,
1597, 1515,1472, 1389, 1333, 1195, 1122 cmꢂ1 1H NMR (400 MHz,
;
J¼7.7 Hz, 1H), 7.15 (ddd, J¼1.1, 7.7, 7.7 Hz, 1H), 6.96 (ddd, J¼1.0, 7.7,
7.7 Hz, 1H), 6.85 (m, 2H), 2.88 (m, 1H), 1.83–1.79 (m, 5H), 1.37–1.22
(m, 5H) ppm.
MeOD-d4, E/Z mixture)
d
¼10.13 (s, 1H), 9.48 (s, 1H), 8.64 (s, 1H),
8.39 (dd, J¼1.5, 5.1 Hz, 1H), 8.29 (s, 1H), 8.14 (dd, J¼1.5, 5.1 Hz, 1H),
8.06 (m, 1H), 7.98 (m, 1H), 7.57 (m, 2H), 7.36 (m, 4H), 7.28 (m, 2H),
7.20–7.14 (m, 2H), 4.03 (s, 3H), 4.00 (s, 3H) ppm; 13C NMR
Z-isomer: 1H NMR (400 MHz, CD3CN)
d¼8.40 (br s, 1H), 7.58 (m,
1H), 7.23 (ddd, J¼1.2, 7.7, 7.7 Hz,1H), 7.01 (ddd, J¼1.1, 7.7, 7.7 Hz,1H),
6.90 (d, J¼9.8 Hz, 1H), 6.70 (br d, J¼7.7 Hz, 1H), 2.97 (m, 1H), 1.85–
1.77 (m, 4H), 1.51–1.41 (m, 3H), 1.35–1.28 (m, 3H) ppm; 13C NMR
(100 MHz, CDCl3, E/Z mixture)
d
¼190.7, 179.0, 145.0, 142.6, 142.2,
140.8, 140.7, 139.8, 135.1, 132.6, 132.4, 132.3, 132.2, 132.0, 131.6,
128.8, 128.7, 123.5, 123.4, 123.3, 122.4, 122.3, 121.1, 120.9, 119.1,
118.9, 116.8, 115.0, 112.4, 110.3, 33.8, 33.7 ppm; MS (ESI) 276
([MþH]þ, 100); HRMS (ESI): Found, 276.1131. C17H14N3O requires
276.1129 (ꢂ2.0 ppm error).
(100 MHz, CD3CN)
d
¼168.6, 145.9, 141.8, 128.9, 126.4, 123.8, 122.3,
121.8, 119.8, 37.7, 31.4,25.6, 25.3 ppm; MS (ESI) 228 ([MþH]þ, 100);
HRMS (ESI): Found, 228.1383. C15H18NO requires 228.1375
(3.6 ppm error).
For further characterization, 4$HCl salt (E/Z ratio 2:1) was pre-
pared, mp 260–262 ꢀC; Sigma–Aldrich (E/Z ratio 8:1) mp ꢃ270 ꢀC.
2.11. (Z)-3-((3,5-Dimethyl-1H-pyrrol-2-yl)methylene)indolin-
2-one 119
Acknowledgements
Yellow solid (38.5 mg, 64%, Z-isomer only), mp 220–222 ꢀC,
lit.19 mp 221–222 ꢀC; Rf 0.29 (petrol/EtOAc, 1:1); IR (neat) 3170,
We thank the SNF (J.L.) and EPSRC (A.M. and A.P.; EP/029841/1)
for funding.

6612
J. Lubkoll et al. / Tetrahedron 66 (2010) 6606–6612
12. (a) Perry, A.; Taylor, R. J. K. Chem. Commun. 2009, 3249; (b) Beltra´n-Rodil, S.;
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