Iridium catalysed C-3 alkylation of oxindole with alcohols under solvent free thermal or microwave conditions

Article abstract of DOI:10.1016/j.tet.2009.03.065

Ir-catalysed alkylation of oxindole and N-methyl oxindole with a range of substituted benzyl and heteroaryl alcohols under solvent free thermal or microwave conditions afforded the corresponding C-3-monoalkylated products in high to excellent yield.

Full text of DOI:10.1016/j.tet.2009.03.065

Tetrahedron 65 (2009) 4375–4383
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Iridium catalysed C-3 alkylation of oxindole with alcohols under solvent free
thermal or microwave conditions
,
a
a
b
c
Ronald Grigg a , Simon Whitney , Visuvanathar Sridharan , Ann Keep , Andrew Derrick
*
a Molecular Innovation, Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry, University of Leeds, Woodhouse Lane, Leeds LS2 9JT, UK
b Johnson Matthey, Orchard Road, Royston, Hertfordshire SG8 5HE, UK
c Pfizer Ltd, Chemical Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Ir-catalysed alkylation of oxindole and N-methyl oxindole with a range of substituted benzyl and het-
eroaryl alcohols under solvent free thermal or microwave conditions afforded the corresponding C-3-
monoalkylated products in high to excellent yield.
Received 13 February 2009
Received in revised form 18 March 2009
Accepted 19 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Available online 28 March 2009
Keywords:
Microwave
Ir catalysis
Green chemistry
Regioselective alkylation
Oxindoles
1. Introduction
processes. We have previously reported the alkylation of active
methylene and methine compounds with alcohols catalysed by
Oxindole and its derivatives are of great interest due to their
biological activity and presence in many compounds of pharma-
ceutical interest. These include the dopamine agonist Ropinirole 1
used for the treatment of Parkinson’s disease, the anti-in-
flammatory Tenidap 2 and the anti-cancer kinase inhibitor Suniti-
nib 3.1–3 Oxindoles, specifically those with C-3 functionalisation,
represent an important motif in a number of natural products.4
While the conventional alkylation of oxindoles has been widely
reported many of these processes suffer from poor regioselectivity
and yields are reduced by the formation of bis-alkylated by-prod-
ucts limiting their synthetic utility.5 To increase the molecular
complexity of a simple organic substrate using efficient (high atom
economy), selective, high yielding and environmentally benign
methods is one of the contemporary challenges for synthetic or-
ganic chemists.6 C–C bond formation is a pivotal method for
achieving this goal. Indirect functionalisation of alcohols using
catalytic amounts of a metal complex and base, which generates
only water as a by-product is an attractive green alternative to
standard C–C bond forming reactions. These cascades are termed as
redox neutral, hydrogen autotransfer or ‘borrowing hydrogen’
iridium, rhodium and ruthenium complexes. Thus alkylation of
arylacetonitriles was achieved by using rhodium7 and more re-
cently iridium catalysts.8 We have also reported microwave
assisted redox neutral processes for the selective monoalkylation
of 1,3-dimethylbarbituric acid and tert-butyl cyanoacetate and by
alcohols.9,10 C-3 (methine) alkylation of indoles was also success-
fully carried out utilising alcohols and iridium catalysts.11 Cho et al.
O
N
Cl
S
O
N
O
O
NH2
N
H
Ropinirole, requipTM
1
2 Tenidap, EnablexTM
O
N
N
H
N
H
O
N
H
Sunitinib, sutentTM
3
* Corresponding author. Tel.: þ44 343 6501.
E-mail address: r.grigg@leeds.ac.uk (R. Grigg).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.065

4376
R. Grigg et al. / Tetrahedron 65 (2009) 4375–4383
Table 1
have reported the direct
using a Ru catalyst, to afford saturated alcohols via
a
-alkylation of ketones with alcohols,
-alkylated
ketones.12 The same reaction can be performed in the presence of
Alkylation of oxindole with alcoholsa
a
Entry
1
Alcohol
Product
Yieldb (%)
94 (90)
a sacrificial hydrogen acceptor, such as 1-dodecene, when
a-alky-
lated ketones are obtained.13 Alternative catalysts for the
a
-alkyl-
OH
ation of ketones with alcohols include the use of the phosphine free
O
14
catalyst Ru(DMSO)4Cl4 and palladium nanoparticles.13 Ishi et al.
N
H
5
reported the selective direct a-alkylation of ketones with alcohols
using an Ir catalyst,15 and Williams et al. reported indirect Wittig
reactions with alcohols using [Ir(cod)Cl]216 or a ruthenium carbene
complex17 and variants of the aldol condensation.18 Krische et al.
reported a series of Ir-catalysed C–C coupling via hydrogen auto-
OH
Cl
2
3
83 (76)
80 (77)
O
6
Cl
F
N
H
F
OH
transfer processes involving alcohols and
p-unsaturated reactants
(1,3-dienes, 1,2-dienes, 1,3-enynes or 1,2-diynes).19–22 We and
others reported the N-alkylation of amines with alcohols using
iridium and rhodium catalysts23 whilst Beller et al. achieved the N-
alkylation of anilines with aliphatic amines using Shvo’s catalyst.24
N-acylation of amines with alcohols has been achieved from a ru-
thenium precursor, an N-heterocyclic carbene and a phosphine li-
gand.25 A ruthenium pincer complex catalyst was also utilised for
this transformation.26 N-alkylation of sulfonamides with alcohols
has been achieved using either a homogeneous Ru catalyst or
a heterogeneous nano-Ru/Fe3O4 catalyst.27,28 Aromatic hetero-
cycles such as furans, pyrroles, indoles and quinolines have all been
constructed via redox neutral processes.29–31
O
N
F
F
7
H
I
OH
4
70c (76)d
I
O
N
8
H
OH
OMe
5
6
91 (95)
99 (93)
O
9
MeO
N
H
O
O
O
O
OH
2. Results and discussion
O
`10
N
Early extensive pioneering work by the Maitlis group32 estab-
lished simple routes to a series of halide bridged dimers 4 and
highlighted their catalytic potential. Recently Fujita’s group23c–f and
others have reported applications of 4 in redox neutral processes.
The alkylation of oxindole with alcohols (Scheme 1) is of interest as it
provides a potential ‘green’ route to C-3-substituted oxindole de-
rivatives. We initially surveyed a range of catalysts and identified the
iridium chloro-bridged compound 4 [X¼Cl, M¼Ir(III)] as an effective
catalyst for the selective C-3 alkylation of oxindole (Scheme 1).
The proposed mechanism for this transformation involves de-
hydrogenation of the primary alcohol to generate an aldehyde and
H
O
7
8
98 (94)
90 (96)
OH
O
N
O
11
N
H
OH
N
O
12
N
H
OH
( )
2
9
81 (87)
Cp*
NH
13
N
H
X
X
O
N
M
M
H
X
X
Cp*
4
X = Cl, I or Br
M = Ir, Rh, Ru
10
11
89 (78)
71 (76)
OH
O
N
R
O
14
H
Cp*IrCl2
OH
2
O +
R
N
H
N
H
OH
O
15
N
Scheme 1.
H
82c (74)d
dr 2:1
R
12
OH
R1
OH
O
16
N
+
O
base
H
C
p*Ir
N
H
H
N
O
R
79c,e (76)e
dr 2:1
OH
13
R1
Cp*Ir
H
O
+
+
HO
O
O
17
N
H
Cp*Ir
H
N
H
a
The reaction was carried out at 110 ꢀC for 15 h under solvent free conditions with
OH
base
oxindole (1 mmol), alcohol (3 mmol), [IrCp
*
Cl2]2 (2.5 mol %) and KOH (20 mol %).
-H2O
R
b
Isolated yield.
Reaction time 24 h.
O
c
O
N
d
N
H
Reaction time 60 min, MWI. Numbers in parentheses are isolated yields ob-
tained using MWI, 110 ꢀC, 20 min.
H
e
Toluene (10 mmol) added to the mixture.
Scheme 2.

R. Grigg et al. / Tetrahedron 65 (2009) 4375–4383
4377
metal hydride species. Knoevenagel type condensation occurs fol-
lowed by hydrogenation of the double bond by the in situ formed
metal hydride to give the product (Scheme 2).
13). All the above reactions (Table 1) were also successfully carried
out using microwave irradiation (110 ꢀC, 20 min) in high yield.
Next we explored the alkylation of the commercially available
substituted oxindoles 18a,b with alcohols using microwave irradi-
ation (Table 2, entries 1–6). Substitution was readily tolerated (Cl,
Br) on the aromatic ring. Once again high yields were achieved for
the regioselective C-3 alkylation of substituted oxindole by benzyl,
heteroaryl and aliphatic alcohols (Table 2, entries 1–6).
Further optimisation showed that the reaction could be ach-
ieved under essentially solvent free conditions and identified po-
tassium hydroxide as the base of choice. Initially we carried out the
alkylation reaction of oxindole (1 mmol) with benzyl alcohol
(1.5 mmol), KOH (15–20 mol %) and [Cp
IrCl2]2 (2.5 mol %) at 110 ꢀC
*
for 15 h, which afforded the monoalkylated product 5 in 94% yield
(Table 1, entry 1). Microwave irradiation (MWI) could be used to
achieve a significant rate enhancement. Thus the alkylation of
oxindole with benzyl alcohol at 110 ꢀC for 20 min under microwave
irradiation afforded 5 in 90% yield.
Finally we studied the alkylation of N-methyl oxindole with
a small range of alcohols under thermal conditions. High yields
were achieved using benzyl, heteroaryl and aliphatic alcohols
(Table 3, entries 1–6).
3. Conclusion
Benzyl alcohols substituted with electron-withdrawing or do-
nating groups and aliphatic, primary and secondary alcohols were
readily alkylated to afford the corresponding 3-substituted oxindole
derivatives 5–17 in highyield (Table 1, entries 2–13). The reactionwas
not significantly affected by either the location or the electronic na-
ture of the substituent on the aryl ring. Under the optimised condi-
tions all the additional functional groups (F, Cl, I) were stable. The
reaction of tryptol afforded the alkylated product 13 (Table 1, entry 9)
in 81% yield. The heteroaromatic furfuryl alcohol and 3-pyridyl
methanol were alkylated to the corresponding C-3 substituted
oxindole derivatives (Table 1 entries 7 and 8) in excellent yield.
During all these reactions clean C-3 regioselectivity was observed
with none of the N-alkylated oxindole derivatives. Interestingly with
a slight variation in reaction conditions 1,4-dibenzyl alcohol was
successfully bis-alkylated to 17 in 79% yield (dr 2:1) (Table 1, entry
In conclusion oxindole and substituted oxindoles were suc-
cessfully alkylated with a range of substituted benzyl, heteroaryl
and aliphatic alcohols to afford the corresponding C-3 alkylated
products in high yield.
4. Experimental
4.1. General
Unless otherwise noted all reagents were obtained from
commercial suppliers and used without further purification. Chro-
matography columns were prepared using Fisher Chemicals 60A 35–
70 micron silica gel. Nuclear magnetic resonance spectra were
recorded using Bruker DPX300 and DPX500 MHz spectrometers.
Chemical shifts are reported in parts per million (
d) downfield rela-
Table 2
Alkylation of 18a–b with alcoholsa
tive to the internal reference tetramethylsilane. Unless otherwise
specified NMR spectra were recorded in deuterochloroform at room
temperature. Abbreviations used: Ar¼aromatic, d¼doublet,
X
O
N
H
Table 3
Alkylation of N-methyl oxindole with alcoholsa
a. X = Br
18
b. X = Cl
Entry
1
Alcohol
OH
Product
Yieldb (%)
Entry
1
18
Alcohol
Product
Yieldb (%)
82
64
Br
Cl
Br
O
N
OH
18a
25
Br
O
O
Me
N
H
19
20
21
O
O
O
O
OH
2
76
OH
O
2
3
4
5
18b
18b
18b
18b
75
65
75
76
N
26
Me
N
H
O
OH
OH
O
O
3
4
5
84
87
81
N
27
Cl
Cl
OH
O
O
N
O
M
O
Me
N
H
O
OH
Cl
O
N
28
O
Me
Cl
N
H
22
Cl
OH
O
O
23
OH
N
29
O
O
Me
N
H
Cl
OH
6
18b
81c
OH
O
24
Cl
6
97
N
H
O
30
Cl
N
Me
a
Oxindole (1.1 mmol), alcohol (3 mmol), [IrCp
N2 (1 atm), 110 ꢀC, 20 min, MWI.
*
Cl2]2 (2.5 mol %), KOH (20 mol %),
a
The reaction was carried out at 110 ꢀC for 15 h under solvent free conditions with
oxindole (1 mmol), alcohol (3 mmol), [IrCp
b
Isolated yield.
Ethanol (8 mmol) was used.
*
Cl2]2 (2.5 mol %) and KOH (20 mol %).
c
b
Isolated yield.

4378
R. Grigg et al. / Tetrahedron 65 (2009) 4375–4383
dd¼doublet of doublets, dq¼doublet of quartets, dt¼doublet of
triplets, m¼multiplet, q¼quartet, s¼singlet, t¼triplet. Mass spectra
were recorded using a micromass ZMD 2000 spectrometer employ-
ing the electrospray (ESþ) ionisation technique. Accurate molecular
masses were obtained from Walters LCT or GCT or Bruker MicroTof
spectrometers. Infrared spectra were recorded using a Perkin–Elmer
FT-IR spectrometer. IR spectra of liquids were recorded as thin films
on sodium chloride plates. IR spectra of solids were recorded using
the ‘golden gate’ apparatus. Petrol refers the fraction of petroleum
ether with bp 40–60 ꢀC and ether refers to diethylether. Accurate
masses refer to 35Cl and 79Br isotopes.
procedure A and (0.195 g, 76%) by general procedure B as colourless
needles. Mp 140.0–142.0 ꢀC (Found: C, 69.85; H, 4.80; N, 5.45; Cl,
13.75. C15H12NClO requires: C, 69.91; H, 4.69; N, 5.43; Cl, 13.76%); dH
(500 MHz, CDCl3); 8.25 (br s,1H, NH), 7.19 (d, 2H, J 8.5, H11), 7.18 (t,1H,
0
J 7.7, H6), 7.08 (d, 2H, J 8.5, H12 and H12 ), 6.94 (t, 1H, J 7.7, H5), 6.85 (d,
1H, J 7.7, H4), 6.81 (d,1H, J 7.7, H7), 3.73 (dd,1H, J 4.7, 8.3, CH), 3.41 (dd,
1H, J 4.7,13.7, CHH), 3.01 (dd,1H, J 8.3,13.7 CHH); dC (75 MHz, CDCl3);
179.39 (CO), 141.71 (ArC), 136.41 (ArC), 132.94 (ArC), 131.22 (ArCH),
128.91 (ArC), 128.85 (ArCH), 128.57 (ArCH), 125.12 (ArCH), 122.61
(ArCH),110.16 (ArCH), 47.70 (CH), 36.22 (CH2); nmax/cmꢂ1 (film) 1709
(CO), 1621, 1492, 1471, 1338; HRMS [ESþ] found Mþ1 258.0680.
C15H13NO35Cl requires 258.0680.
4.2. General procedure for the alkylation of oxindoles
with alcohols
4.5. 3-(3,5-Difluorobenzyl)indolin-2-one (7)
4.2.1. General procedure A
F
H11
The oxindole (1.0 mmol), [Cp IrCl2]2 (0.020 g, 2.5 mol %), KOH
*
H13
(0.011 g, 0.2 mmol) and the alcohol (3.0 mmol) were combined in
a thick walled glass tube. The tube was sealed with a rubber septum,
purged with nitrogen and magnetically stirred at 110 ꢀC for 15 h then
allowed to cool to room temperature. The reaction mixture was
analysed by 1H NMR and thereafter purified by chromatography.
H4
H5
H6
F
N
H
O
H7
4.2.2. General procedure B
Alkylation of oxindoles with alcohols with MWI. As for general
procedure A but with microwave heating for 20 min at 110 ꢀC.
Prepared by general procedures A and B from oxindole (0.133 g,
1.0 mmol) and 3,5-difluorobenzyl alcohol (0.432 g, 3.0 mmol).
Chromatography eluting with 1:1 v/v ether and petrol followed by
crystallisation from DCM and hexane gave the product (0.207 g,
80%) by general procedure A and (0.199 g, 77%) by general pro-
cedure B as pale yellow prisms. Mp 105.0–106.0 ꢀC (Found: C,
69.35; H, 4.25; N, 5.20; F, 14.55. C15H11NF2O requires: C, 69.49; H,
4.28; N, 5.40; F, 14.66%); dH (500 MHz, CDCl3); 8.88 (br s, 1H, NH),
7.20 (t, 1H, J 7.7, H6), 6.99 (t, 1H, J 7.7, H5), 6.86 (d, 1H, J 7.7, H4), 6.86
4.2.3. General procedure C
N-Methyl oxindole with alcohols under thermal conditions. As
for general procedure A, but employing N-methyl oxindole (0.147 g,
1.0 mmol).
4.3. 3-Benzylindolin-2-one (5)
3
(d, 1H, J 7.7, H7), 6.73–6.68 (m, 2H, H11), 6.65 (tt, 1H, JHF 9.0, 2.1,
H
13), 3.74 (dd, 1H, J 4.7, 8.6, CH), 3.42 (dd, 1H, J 4.7, 13.7, CHH), 3.00
H4
(dd, 1H, J 8.6, 13.7 CHH); dC (75 MHz, CDCl3); 179.59 (CO), 163.19
H5
H6
1
3
3
(dd, JCF 248.3, JCF 12.7, 2ꢁArCF), 141.98 (t, JCF 9.2, ArC), 141.81
(ArC), 128.79 (ArCH), 128.58 (ArC), 124.94 (ArCH), 122.78 (ArCH),
N
H
O
0
112.67 (dd, JCF 16.7 and JCF 7.5, ArCH11 ), 110.44 (ArCH), 102.74 (t,
2JCF 25.3, ArCH13), 47.41 (CH), 36.52 (CH2); nmax/cmꢂ1 (film) 1712
(CO), 1624, 1596, 1471, 1339, 1225, 1118, 752; HRMS [ESþ] found
Mþ1 260.0878. C15H12NF2O requires 260.0881.
2
4
H7
Prepared by general procedures A and B from oxindole (0.133 g,
1.0 mmol) and benzyl alcohol (0.324 g, 3.0 mmol). Chromatography
eluting with 1:1 v/v petrol–ether followed by crystallisation from
DCM and hexane gave the product (0.210 g, 94%) by general pro-
cedure A and (0.201 g, 90%) by general procedure B as a colourless
solid. Mp 129.0–130.0 ꢀC (lit.33 mp 129.0–131.0 ꢀC); dH (500 MHz,
CDCl3); 7.27–7.20 (m, 3H, 3ꢁArH), 7.19–7.14 (m, 3H, 3ꢁArH), 6.89 (t,
1H, J 7.7, H5), 6.83 (d, 1H, J 7.7, H4), 6.74 (d, 1H, J 7.7, H7), 3.75 (dd,1H, J
9.4, 4.7, CH), 3.50 (dd, 1H, J 13.7, 4.7, CHH), 2.94 (dd, 1H, J 13.7, 9.4,
CHH); nmax (film)/cmꢂ11707 (CO),1621,1470,1338,1230; HRMS [ESþ]
found MþNa 246.0885. C15H13NONa requires 246.0889.
4.6. 3-(2-Iodobenzyl)-indolin-2-one (8)
H12
I
H13
H4
H5
H14
H15
H6
N
H
O
H7
4.4. 3-(4-Chlorobenzyl)indolin-2-one (6)
Prepared by general procedure A with heating for 24 h and general
procedure B with heating for 1 h from oxindole (0.133 g,1.0 mmol) and
2-iodobenzyl alcohol (0.702 g, 3.0 mmol). Chromatography eluting
with 1:1 v/v petrol–ether followed by crystallisation of the residue
gave the product (0.244 g, 70%) by general procedure A and (0.265 g,
76%) by general procedure B as colourless microprisms. Mp 148.0–
149.0 ꢀC (Found: C, 51.30; H, 3.35; N, 4.25; I, 36.60. C15H12NOI requires:
C, 51.60; H, 3.46; N, 4.01; I, 36.34%); dH (500 MHz, CDCl3); 7.90 (dd,1H, J
7.7, 0.9, H12), 7.79 (br s,1H, NH), 7.31 (dt,1H, J 0.9, 7.7, H14), 7.24 (dd,1H, J
1.7, 7.7, H15), 7.19 (t,1H, J 7.7, H6), 6.99 (dt, 1H, J 7.7, 1.7, H13), 6.88 (t, 1H, J
7.7, H5), 6.88 (d,1H, J 7.7, H4), 6.63 (d,1H, J 7.7, H7), 3.92 (dd,1H, J 5.6, 9.8,
CH), 3.56 (dd, 1H, J 5.6, 14.1, CHH), 3.00 (dd, 1H, J 9.8, 14.1, CHH); dC
(75 MHz, CDCl3); 178.62 (CO), 141.06 (ArC), 140.60 (ArC), 139.82
(ArCH), 131.31 (ArCH), 128.73 (ArCH), 128.59 (ArC), 128.17 (ArCH),
H12
H11
Cl
H4
H5
H6
N
H
O
H7
Prepared by general procedures A and B from oxindole (0.133 g,
1.0 mmol) and 4-chlorobenzyl alcohol (0.426 g, 3.0 mmol). Chroma-
tography eluting with 1:1 v/v ether–petrol followed by crystallisation
from DCM and hexane gave the product (0.213 g, 83%) by general

R. Grigg et al. / Tetrahedron 65 (2009) 4375–4383
4379
128.04 (ArCH), 125.29 (ArCH), 122.05 (ArCH), 109.48 (ArCH), 100.98
(ArC), 45.22 (CH), 41.78 (CH2); nmax/cmꢂ1 (film) 1707 (CO), 1620, 1470,
1338, 1230; HRMS [ESþ] found Mþ1 350.0026. C15H13NOI requires
350.0036.
Chromatography eluting with 1:1 v/v ether–petrol followed by
crystallisation from DCM and hexane gave the product (0.209 g,
98%) by general procedure A and (0.200 g, 94%) by general pro-
cedure B as colourless needles. Mp 150.0–152.0 ꢀC (Found: C, 73.00;
H, 5.25; N, 6.65. C13H11NO2 requires: C, 73.23; H, 5.20; N, 6.57%); dH
(500 MHz, CDCl3); 8.75 (br s, 1H, NH), 7.34 (d, 1H, J 1.3, H14), 7.19 (t,
1H, J 7.7, H6), 6.94 (t, 1H, J 7.7, H5), 6.89 (d, 1H, J 7.7, H4), 6.79 (d, 1H, J
7.7, H7), 6.29 (dd, 1H, J 3.4, 1.3, H13), 6.03 (d, 1H, J 3.4, H12), 3.81 (dd,
1H, 9.4, 4.7), 3.47 (dd, 1H, J 4.7, 15.0, CHH), 2.99 (dd, 1H, J 9.4, 15.0,
CHH); dC (75 MHz, CDCl3); 179.80 (CO), 152.32 (ArC), 141.98 (ArCH),
141.78 (ArH), 129.16 (ArH), 128.52 (ArCH), 125.10 (ArCH), 122.69
(ArCH), 110.78 (ArCH), 110.16 (ArCH), 107.74 (ArCH), 45.57 (CH),
29.47 (CH2); nmax/cmꢂ1 (film) 1702 (CO), 1619, 1506, 1470, 1343,
1231; HRMS [ESþ] found Mþ1 214.0862. C13H12NO2 requires
214.0863.
4.7. 3-(4-Methoxybenzyl)indolin-2-one (9)
H12
H11
OMe
H4
H5
H6
N
H
O
H7
Prepared by general procedures A and B from oxindole (0.133 g,
1.0 mmol) and 4-methoxybenzyl alcohol (0.414 g, 3.0 mmol).
Chromatography eluting with 1:1 v/v petrol–ether followed by
crystallisation from DCM and hexane gave the product (0.229 g,
91%) by general procedure A and (0.240 g, 95%) by general pro-
cedure B as colourless microneedles. Mp 114.0–115.0 ꢀC (Found: C,
75.70; H, 5.95; N, 5.45: C16H15NO2 requires: C, 75.87; H, 5.97; N,
5.53%); dH (500 MHz, CDCl3); 9.16 (br s, 1H, NH), 7.15 (t, 1H, J 7.5,
ArH), 7.07 (d, 2H, J 8.6, H11), 6.90 (t, 1H, J 7.5, ArH), 6.85 (d, 1H, J 7.7,
H7), 6.78 (d, 1H, J 7.7, H4), 6.76 (d, 2H, J 8.6, H12), 3.75 (s, 3H, CH3),
3.70 (dd, 1H, J 4.7, 9.0, CH), 3.41 (dd, 1H, J 4.7, 13.7, CHH), 2.90 (dd,
1H, J 9.0, 13.7, CHH); dC (75 MHz, CDCl3); 180.48 (CO), 158.74 (ArC),
142.04 (ArC), 130.82 (ArCH), 130.17 (ArC), 129.53 (ArC), 128.34
(ArCH), 125.22 (ArCH), 122.39 (ArCH), 114.12 (ArCH), 110.24 (ArCH),
55.58 (CH3), 48.23 (CH), 36.17 (CH2); nmax/cmꢂ1 (film) 1708 (CO),
1619, 1513, 1471, 1248, 1178, 1035, 828; HRMS [ESþ] found Mþ1
254.1171. C16H16NO2 requires 254.1176.
4.10. 3-(Pyridin-3-ylmethyl)indolin-2-one (12)
H14
H15
H13
H4
N
H5
H6
H11
N
H
O
H7
Prepared by general procedures A and B from oxindole
(0.133 g, 1.0 mmol) and pyridine 3-methanol (0.327 g, 3.0 mmol).
Chromatography eluting with 95:5 v/v DCM–methanol gave the
product (0.202 g, 90%) by general procedure A and (0.215 g, 96%)
by general procedure B as a colourless solid. Mp 140.0–142.0 ꢀC
(lit.35 mp 139.0–141.0 ꢀC); dH (500 MHz, C6D6); 8.44 (d, 1H, J 1.7,
H
11), 8.35 (dd, 1H, J 1.3, 4.7, H13), 8.26 (br s, 1H, NH), 7.05 (ddd, 1H,
4.8. 3-(Benzo[d][1,3]dioxol-5-ylmethyl)indolin-2-one (10)
J 1.3, 1.7, 7.7, H15), 6.88 (t, 1H, J 7.7, H6), 6.70 (t, 1H, J 7.7, H5), 6.60
(dd, 1H, J 4.7, 7.7 H14), 6.57 (d, 1H, J 7.7, H4), 6.35 (d, 1H, J 7.7, H7),
3.25 (dd, 1H J 5.1, 7.7, CH), 2.95 (dd, 1H, J 5.1, 13.7, CHH), 2.78 (dd,
1H, J 7.7, 13.7, CHH); nmax/cmꢂ1 (film) 1704 (CO), 1622, 1471, 1426,
1338; HRMS [ESþ] found Mþ1 225.1021. C14H13N2O requires
225.1022.
H4
H12
H5
H6
H13
H14
O
O
N
H
H7
4.11. 3-(2-(1H-Indol-3-yl)ethyl)indolin-2-one (13)
Prepared by general procedures A and B from oxindole (0.133 g,
1.0 mmol) and 3,4-methylenedioxybenzyl alcohol (0.456 g,
3.0 mmol). Chromatography eluting with 1:1 v/v ether–petrol fol-
lowed by crystallisation from DCM and hexane gave the product
(0.264 g, 99%) by general procedure A and (0.248 g, 93%) by general
procedure B as a colourless amorphous solid. Mp 138–139.0 ꢀC
(lit.34 mp 138.0–139.0); dH (500 MHz, CDCl3); 8.60 (1H, br s, NH),
7.15 (t, 1H, J 7.7, H6), 6.93 (t, 1H, J 7.7, H5), 6.85 (d, 1H, J 7.7, H4), 6.83
(d, 1H, J 8.1, H14), 6.68 (d, 1H, J 7.7, H7), 6.67 (d, 1H, J 1.3, H11), 6.60
(dd, 1H, J 1.3, 8.1 H15), 5.91 (s, 2H, OCH2O), 3.69 (dd, 1H, J 4.7, 9.0,
CH), 3.39 (dd, 1H, J 4.7, 13.7, CHH), 2.89 (dd, 1H, J 9.0, 13.7, CHH);
nmax/cmꢂ1 (film) 1708 (CO), 1620, 1502, 1489, 1470, 1444; HRMS
[ESþ] found MþNa 290.0775. C16H13NO3Na requires 290.0788.
H4
H13
H5
H6
H14
H15
11
O
N
H
N
H
H
H7
H16
Prepared by general procedures A and B from oxindole (0.133 g,
1.0 mmol) and tryptophol (0.483 g, 3.0 mmol). Chromatography
eluting with 1:1 v/v petrol–ether gave the product (0.224 g, 81%)
by general procedure A and (0.240 g, 87%) by general procedure B
as a colourless solid. Mp 80.0–82.0 ꢀC; dH (500 MHz, CDCl3); 8.47
(br s, 1H, NH), 7.97 (br s, 1H, NH), 7.58 (d, 1H, J 7.3, H13), 7.33 (d, 1H,
J 7.7, H4), 7.28 (d, 1H, J 7.3, H16), 7.22 (t, 1H, J 7.7, H6), 7.17 (t, 1H, J
7.3, H15), 7.09 (t, 1H, J 7.7, H5), 7.05 (t, 1H, J 7.3, H14), 6.99 (d, 1H, J
1.7, H11), 6.89 (d, 1H, J 7.7, H7), 3.58 (t, 1H, J 6.0, CH), 2.98–2.90 (m,
1H, CHCHH), 2.87–2.80 (m, 1H, CHCHH), 2.41–2.34 (m, 2H,
CHCH2CH2); dC (75 MHz, CDCl3); 180.82 (CO), 142.01 (ArC), 136.71
(ArC), 130.15 (ArC), 128.30 (ArCH), 127.80 (ArC), 124.58 (ArCH),
122.77 (ArCH), 122.38 (ArCH), 121.98 (ArCH), 119.66 (ArCH), 119.29
(ArCH), 115.84 (ArC), 111.50 (ArCH), 110.13 (ArCH), 46.00 (CH),
31.52 (CH2), 21.81 (CH2); nmax/cmꢂ1 (film) 1699, 1620, 1470, 741;
HRMS [ESþ] found MþNa 299.1148. C18H16N2ONa requires
299.1155.
4.9. 3-(Furan-2-ylmethyl)indolin-2-one (11)
H4
H12
H5
H6
H13
H14
O
N
H
O
H7
Prepared by general procedures A and B from oxindole (0.133 g,
1.0 mmol) and furfuryl alcohol (0.294 g, 3.0 mmol).

4380
R. Grigg et al. / Tetrahedron 65 (2009) 4375–4383
4.12. 3-Ethylindolin-2-one (14)
a colourless solid. 1H NMR showed that the product was a 2:1
mixture of diastereoisomers; dH (500 MHz, CDCl3); 8.49 (br s, 1H,
MAJNH), 8.14 (br s, 1H, MINNH), 7.42–7.30 (m, 7H, 7ꢁArH), 7.24–
7.18 (m, 4H, 2ꢁMINArH and 2ꢁMAJArH), 7.14–7.09 (m, 2H, MINArH
and MAJArH), 7.00 (t, 1H, J 7.5, MINH5), 6.93–6.88 (m, 2H, MAJH5 and
MAJH7), 6.79 (d, 1H, J 8.1, MINH4), 6.57 (d, 1H, J 7.3, MAJH4), 1.69 (d,
3H, J 7.3, MINCH3), 1.25 (d, 3H, J 8.6, MAJCH3); dC (75 MHz, CDCl3);
179.53 (CO), 179.131 (CO), 143.15, 142.51, 142.25, 141.99, 128.75,
128.5, 128.38, 128.35, 128.27, 127.37, 127.13, 127.08, 125.57, 122.30,
122.30, 122.27, 109.85, 53.32, 52.76, 42.26, 39.93, 19.64, 13.93;
nmax/cmꢂ1 (solid) 1705 (CO), 1620, 1470, 1339, 1227, 1020, 751,
699; HRMS [ESþ] found Mþ1 238.1226. C16H16NO requires
238.1226.
H4
H5
H6
N
H
O
H7
Prepared by general procedures
A and B from oxindole
(0.133 g, 1.0 mmol) and ethanol (1.0 mL). Chromatography eluting
with 1:1 v/v ether–petrol followed by crystallisation from DCM
and hexane gave the product (0.142 g, 89%) by general procedure
A and (0.126 g, 78%) by general procedure B as colourless mi-
croprisms. Mp 99.0–101.0 ꢀC (lit.36 mp 104.0 ꢀC); dH (500 MHz,
CDCl3); 8.16 (br s, 1H, NH), 7.23 (d, 1H, J 7.7, H4), 7.22 (t, 1H, J 7.7,
H6), 7.04 (t, 1H, J 7.7, H5), 6.88 (1H, d, J 7.7, H7), 3.46 (1H, t, J 5.8,
CH), 2.04 (m, 2H, CH2), 0.93 (t, 3H, J 7.5, CH3); dC (75 MHz,
CDCl3); 180.13 (CO), 141.61 (ArC), 129.50 (ArC), 127.82 (ArCH),
124.16 (ArCH), 122.27 (ArCH), 109.52 (ArCH), 47.04 (CH), 23.59
(CH2), 9.99 (CH3); nmax/cmꢂ1 (film) 1708 (CO), 1621, 1471, 1338,
1220; HRMS [ESþ] found Mþ1 162.0918. C10H12NO requires
162.0913.
4.15. 1,4-Bis(3-methylindolin-2-one) benzene (17)
H4
H7
H4'
H7'
H
N
H5
H6
O
H5'
H6'
N
H
O
4.13. 3-Isobutylindolin-2-one (15)
Prepared by general procedures
A and B from oxindole
(0.146 g, 1.1 mmol) and 1,4-dibenzyl alcohol (0.069 g, 0.5 mmol)
but with the addition of toluene (1.0 mL). Chromatography eluting
with 19:1 v/v DCM–methanol gave the product (0.145 g, 79%) as
a pale yellow solid as a 2:1 mixture of diastereoisomers. dH
(500 MHz, DMSO-d6); 10.24 (br s, 2H, NHM2 AJ), 10.23 (br s, 2H,
NHM2 IN), 7.05–6.99 (m, 2H), 6.93 (s, 4H, 4ꢁPhHMAJ), 6.92 (s, 4H,
4ꢁPhHMIN), 6.74–6.64 (m, 4H), 6.57–6.52 (m, 2H), 3.69 (m, 2H,
2ꢁCH), 3.23–3.17 (m, 2H, 2ꢁCHH), 2.78–2.70 (m, 2H, 2ꢁCHH); dC
(75 MHz, DMSO-d6); 178.46 (CO), 142.96 (ArC), 136.39 (ArC),
136.34 (ArC), 129.29 (ArCH), 129.22 (ArC), 127.86 (ArCH), 124.65
(ArCH), 121.18 (ArCH), 109.38 (ArCH), 46.82 (CH), 35.40 (CH2);
nmax/cmꢂ1 (solid) 1702 (CO), 1764, 1615, 1468, 1336, 1230, 1017,
959; HRMS [ESþ] found MþNa 391.1413. C24H20N2O2Na requires
391.1417.
H4
H5
H6
N
H
O
H7
Prepared by general procedures
A and B from oxindole
(0.133 g, 1.0 mmol) and 2-methyl propanol (1.0 mL). Chromatog-
raphy eluting with 1:1 v/v ether–petrol followed by crystal-
lisation of the residue from DCM and hexane gave the product
(0.135 g, 71%) by general procedure A and (0.148 g, 76%) by
general procedure
B
as colourless prisms. Mp 96.0–97.0 ꢀC
(Found: C, 75.95; H, 8.05; N, 7.35. C12H15NO requires: C, 76.16; H,
7.99; N, 7.40%); dH (500 MHz, CDCl3); 8.51 (br s, 1H, NH), 7.22 (m,
2H, H6 and H7), 7.01 (t, 1H, J 7.7, H5), 6.90 (d, 1H, J 7.7, H4), 3.48 (t,
1H, J 7.3, H3), 2.09–2.01 (m, 1H, CH3CHCH3), 1.90–1.84 (m, 1H,
CHH), 1.73–1.67 (m, 1H, CHH), 1.01 (d, 3H, J 6.4, CH3), 0.96 (d, 3H, J
6.4, CH3); dC (75 MHz, CDCl3); 181.28 (CO), 141.73 (ArC), 130.71
(ArC), 128.15 (ArCH), 124.80 (ArCH), 122.53 (ArCH), 110.07 (ArCH),
44.66 (CH), 40.36 (CH2), 25.73 (CH), 23.33 (CH3), 22.54 (CH3);
nmax/cmꢂ1 (film) 1705, 1620, 1471, 1332, 1230, 1102, 1018, 749,
668; HRMS [EIþ] found Mþ1 190.1233. C12H16NO requires
190.1226.
4.16. 3-Benzyl-5-bromo-indolin-2-one (19)
H12
H11
H4
Br
H6
N
H
O
H7
Prepared by general procedure B from 5-bromo oxindole
(0.212 g, 1.0 mmol) and benzyl alcohol (0.324 g, 3.0 mmol).
Chromatography eluting with 1:1 v/v ether–petrol followed by
crystallisation from DCM and hexane gave the product (0.248 g,
82%) as colourless prisms. Mp 138.0–140.0 ꢀC (Found: C, 59.85;
H, 4.00; N, 4.65; Br, 26.15. C15H12BrNO requires: C, 59.62; H,
4.00; N, 4.64; Cl, 26.44%); dH (500 MHz, CDCl3); 8.68 (br s, 1H,
NH), 7.32–7.14 (m, 6H, 6ꢁArH), 6.86 (s, 1H, H4), 6.72 (d, 1H, J
8.1, H6), 3.73 (dd, 1H, J 4.5, 8.8, CH), 3.45 (dd, 1H, J 4.5, 13.7,
CHH), 2.95 (dd, 1H, J 8.8, 13.7, CHH); dC (75 MHz, CDCl3); 179.45
(CO), 140.81 (ArC), 137.52 (ArC), 131.41 (ArC), 131.29 (ArCH),
129.78 (2ꢁArCH), 128.91 (2ꢁArCH), 128.44 (ArCH), 127.39
(ArCH), 115.14 (ArC), 111.54 (ArCH), 48.02 (CH), 36.85 (CH2);
nmax/cmꢂ1 (film) 1709 (CO), 1616, 1473, 1313, 1228, 1117, 812,
698; HRMS [ESþ] found Mꢂ1 300.0029. C15H11BrNO requires
300.0030.
4.14. 3-(1-Phenylethyl)indolin-2-one (16)
H12
H11
H13
H4
H7
H3C
H5
H6
N
H
O
Prepared by general procedures
A and B from oxindole
(0.133 g, 1.0 mmol) and 1-phenyl ethanol (0.366 g, 3.0 mmol).
Chromatography eluting with 1:1 v/v petrol–ether followed by
crystallisation from DCM–hexane gave the product (0.237 g, 82%)
by general procedure A and (214 g, 74%) by general procedure B as

R. Grigg et al. / Tetrahedron 65 (2009) 4375–4383
4381
4.17. 3-Benzyl-5-chloro-indolin-2-one (20)
3.0 mmol). Chromatography eluting with 1:1 v/v petrol–ether
followed by crystallisation from DCM and hexane gave the
product (0.219 g, 75%) as colourless needles. Mp 157.5–158.5 ꢀC
(Found: C, 61.50; H, 3.70; N, 4.80; Cl, 24.10. C15H11Cl2NO2 re-
quires: C, 61.67; H, 3.79; N, 4.79; Cl, 24.27%); dH (500 MHz,
CDCl3); 8.91 (1H, br s, NH), 7.21 (2H, d, J 8.3, H12), 7.16 (1H, dd, J
1.7, 8.6, H6), 7.06 (2H, d, J 8.3, H11), 6.87 (1H, d, J 1.7, H4), 6.75 (1H,
d, J 8.6, H7), 3.72 (1H, dd, J 4.7, 8.1, CH), 3.45 (1H, dd, J 4.7, 13.7,
CHH), 3.03 (1H, dd, J 8.1, 13.7, CHH); dC (75 MHz, CDCl3); 178.81
(CO), 139.91 (ArC), 135.37 (ArC), 132.79 (ArC), 130.70 (ArCH),
130.19 (ArC), 128.57 (ArCH), 128.19 (ArC), 127.58 (ArCH), 125.00
(ArCH), 110.76 (ArCH), 47.46 (CH), 36.58 (CH2); nmax/cmꢂ1 (film)
1712 (CO), 1619, 1489, 1478, 1439; HRMS [ESꢂ] found Mꢂ1
290.0136. C15H10NCl2O requires 290.0145.
H12
H11
H13
H4
H7
Cl
H6
N
H
O
Prepared by general procedure B from 5-chloro oxindole
(0.167 g, 1.0 mmol) and benzyl alcohol (0.324 g, 3.0 mmol). Chro-
matography eluting with 1:1 v/v petrol–ether followed by crystal-
lisation from DCM and hexane gave the product (0.193 g, 75%) as
colourless plates. Mp 115.0–116.0 ꢀC (Found: C, 69.70; H, 4.55; N,
5.40; Cl, 13.65%. C15H12ClNO requires: C, 69.91; H, 4.69; N, 5.43; Cl,
13.76%); dH (500 MHz, CDCl3); 8.71 (1H, br s, NH), 7.29–7.21 (3H, m),
7.18–7.13 (3H, m), 6.76 (1H, d, J 8.6, H7), 6.73 (1H, s, H4), 3.74 (1H, dd,
J 4.7, 9.0, CH), 3.46 (1H, dd, J 4.7, 13.7, CHH), 2.96 (1H, dd, J 9.0, 13.7,
CHH); dC (75 MHz, CDCl3); 179.18 (CO), 139.91 (ArC), 137.13 (ArC),
130.59 (ArC), 129.34 (ArCH), 128.49 (ArCH), 127.97 (ArCH), 127.41
(ArC), 126.95 (ArCH), 125.23 (ArCH), 110.61 (ArCH), 47.66 (CH),
36.42 (CH2); nmax/cmꢂ1 (film) 1710 (CO), 1619, 1476, 1454,1313.
4.20. 3-Furfuryl-5-chloro-indolin-2-one (23)
H4
H12
Cl
H6
H13
H14
O
N
H
O
H7
Prepared by general procedure B from 5-chloro oxindole
(0.167 g, 1.0 mmol) and furfuryl alcohol (0.294 g, 3.0 mmol).
Chromatography eluting with 1:1 v/v ether–petrol-ether fol-
lowed by crystallisation from DCM and hexane gave the product
(0.188 g, 76%) as colourless microneedles. Mp 150.5–152.5 ꢀC
(Found: C, 62.75; H, 4.00; N, 5.60; Cl, 14.30. C13H10ClNO2 re-
quires: C, 63.04; H, 4.07; N, 5.66; Cl, 14.31%); dH (500 MHz,
CDCl3); 9.09 (br s, 1H, NH), 7.34 (d, 1H, J 1.5, H4), 7.17 (1H, dd, J
1.5, 8.3, H6), 6.82 (d, 1H, J 8.3, H7), 6.77 (d, 1H, J 1.7, H14), 6.30 (dd,
1H, J 1.7, 3.0, H13), 6.06 (d, 1H, J 3.0, H12), 3.80 (dd, 1H, J 4.7, 9.4,
CH), 3.45 (dd, 1H, J 4.7, 15.0, CHH), 2.99 (1H, dd, J 9.4, 15.0, CHH);
dC (75 MHz, CDCl3); 179.54 (CO), 151.71 (ArC), 142.18 (ArCH),
140.36 (ArC), 130.80 (ArC), 128.53 (ArCH), 128.07 (ArC), 125.54
(ArCH), 111.16 (ArCH), 110.90 (ArCH), 108.01 (ArCH), 45.79 (CH),
29.27 (CH2); nmax/cmꢂ1 (film) 1712 (CO), 1619, 1478, 1442, 1316;
HRMS [ESþ] found Mþ1 248.0472. C13H11NO2Cl requires
248.0473.
4.18. 3-(Piperonyl)-5-chloro-indolin-2-one (21)
O
H11
O
H4
Cl
H14
H15
H6
N
H
O
H7
Prepared by general procedure B from 5-chloro oxindole
(0.167 g, 1.0 mmol) and 3,4-methylenedioxybenzyl alcohol
(0.456 g, 3.0 mmol). Chromatography eluting 1:1 v/v petrol–ether
followed by crystallisation from DCM and hexane gave the
product (0.196 g, 65%) as colourless microneedles. Mp 159.0–
160.0 ꢀC (Found: C, 63.75; H, 3.95; N, 4.60; Cl, 11.75. C16H12NO3Cl
requires: C, 63.69; H, 4.01; N, 4.64; Cl, 11.75%); dH (500 MHz,
CDCl3); 8.54 (1H, br s, NH), 7.16 (1, dd, J 1.7, 8.1, H6), 6.83 (1H, d, J
1.7, H4), 6.76 (1H, d, J 8.1, H7), 6.69 (1H, d, J 8.1, H14), 6.66 (1H, d, J
1.3, H11), 6.58 (1H, dd, J 1.3, 7.7, H15), 5.92 (1H, d, J 2.1, OCH2O),
3.68 (1H, dd, J 4.7, 8.6, CH), 3.35 (1H, dd, J 4.7, 13.7, CHH), 2.91
(1H, dd, J 8.6, 13.7, CHH); dC (75 MHz, CDCl3); 179.35 (CO), 148.09
(ArC), 146.88 (ArC), 140.30 (ArC), 131.16 (ArCH), 130.95 (ArC),
128.42 (ArCH), 127.87 (ArC), 125.60 (ArCH), 122.97 (ArCH), 111.03
(ArCH), 109.87 (ArCH), 108.56 (ArCH), 101.38 (OCH2O), 48.16 (CH),
36.52 (CH2); nmax/cmꢂ1 (film) 1710 (CO), 1618, 1502, 1478, 1443;
HRMS [ESþ] found MþCl 324.0391. C16H12NClO3Na requires
324.0398.
4.21. 3-Ethyl-5-chloro-indolin-2-one (24)
H4
Cl
H6
N
H
O
H7
Prepared by general procedure B from 5-chloro oxindole
(0.167 g, 1.0 mmol) and ethanol (1.0 mL). Chromatography eluting
with 1:1 v/v petrol–ether followed by crystallisation from DCM and
hexane gave the product (0.158 g, 81%) as colourless prisms. Mp
128.0–129.0 ꢀC (Found: C, 61.20; H, 5.05; N, 7.25; Cl, 17.95.
C10H10ClNO requires: C, 61.39; H, 5.15; N, 7.16; Cl, 18.12%); dH
4.19. 3-(4-Chlorobenzyl)-5-chloro-indolin-2-one (22)
H12
H11
Cl
d
9.45 (1H, br s, NH), 7.21 (1H, s, H4), 7.19 (1H, d, J
H4
(500 MHz, CDCl3);
8.1, H6), 7.85 (1H, d, J 8.1, H7), 3.47 (1H, t, J 5.6, CH), 2.03 (2H, dq, J 5.6,
7.5, CH2), 0.92 (3H, t, J 7.5, CH3); dC (75 MHz, CDCl3); 180.66 (CO),
140.47 (ArC), 131.22 (ArC), 127.84 (ArCH), 127.64 (ArC), 124.48
Cl
d
H6
N
H
O
H7
(ArCH), 110.77 (ArCH), 47.40 (CH), 23.44 (CH2), 9.91 (CH3); nmax
/
cmꢂ1 (film) 1709 (CO), 1620, 1479, 1458, 1313, 1220, 1172, 813;
HRMS [ESþ] found MþNa 218.0340. C10H10NONa requires
218.0343.
Prepared by general procedure B from 5-chloro oxindole
(0.167 g, 1.0 mmol) and 4-chlorobenzyl alcohol (0.426 g,

4382
R. Grigg et al. / Tetrahedron 65 (2009) 4375–4383
4.22. 3-(3-Bromobenzyl)-1-methylindolin-2-one (25)
8.43 (d, 1H, J 3.4, H13), 8.34 (s, 1H, H11), 7.47 (d, 1H, J 7.7, H15), 7.23 (t,
1H, J 7.5, H6), 7.15 (dd, 1H, J 7.5, 3.4, H14), 6.97 (t, 1H, J 7.5, H5), 6.91
(d, 1H, J 7.5, H4), 6.73 (d, 1H, J 7.7, H7), 3.73 (dd, 1H, J 4.5, 7.5 CH),
3.41 (dd, 1H, J 4.5, 14.1 CHH), 3.12 (s, 3H, CH3), 3.06 (dd, 1H, J 7.5,
14.1 CHH); dC (75 MHz, CDCl3); 176.86 (CO), 151.06 (ArCH), 148.57
(ArCH), 144.59 (ArC), 137.26 (ArCH), 133.43 (ArC), 128.73 (ArCH),
127.88 (ArC), 124.64 (ArCH), 123.54 (ArCH), 122.77 (ArCH), 108.56
(ArCH), 47.00 (CH), 34.14 (CH2), 26.53 (CH3); nmax (film)/cmꢂ1 1709
(CO), 1612, 1493, 1469, 1424, 1375, 1126, 1088; HRMS [ESþ] found
Mþ1 239.1186. C15H15N2O requires 239.1186.
Br
H11
H13
H14
H4
H5
H15
H6
N
O
H7
Prepared by general procedure C from N-methyl oxindole
(0.147 g, 1.0 mmol) and 3-bromobenzyl alcohol (0.280 g, 1.5 mmol).
Chromatography eluting with 1:1 v/v petrol–ether gave the product
(0.202 g, 64%) as a colourless solid. Mp 108.0–109.0 ꢀC (Found: C,
60.55; H, 4.45; N, 4.35; Br, 25.05. C16H14BrNO requires: C, 60.78; H,
4.46; N, 4.43; Br, 25.27%); dH (500 MHz, CDCl3); 7.34 (d,1H, J 7.3, H4),
7.31 (s, 1H, H11), 7.24 (t, 1H, J 7.6, H6), 7.14–7.07 (m, 2H, H13 and H14),
6.95 (appar t,1H, J 7.5, H5), 6.79 (d,1H, J 7.5, H15), 6.76 (d,1H, J 7.6, H7),
3.69 (dd, 1H, J 3.8, 9.2, CH), 3.43 (dd, 1H, J 3.8, 13.7, CHH), 3.16 (s, 3H,
CH3), 2.88 (dd, 1H, J 9.2, 13.7, CHH); dC (75 MHz, CDCl3); 176.66 (CO),
144.16 (ArC), 140.25 (ArC) 132.35 (ArCH), 129.79 (ArCH), 128.16
(ArCH), 128.06 (ArCH), 127.88 (ArC), 124.38 (ArCH), 122.27 (ArC),
122.19 (ArCH), 108.06 (ArCH), 46.73 (CH), 36.36 (CH2), 26.15 (CH3);
nmax/cmꢂ1 (film) 2925, 1708 (CO), 1612, 1567, 1470, 1375, 1087, 750;
HRMS [ESþ] found Mþ1 316.0336. C16H15BrNO requires 316.2001.
4.25. 3-(Furan-2-ylmethyl)-1-methylindolin-2-one (28)
H4
H12
H5
H13
O
H6
N
O
H14
H7
Prepared by general procedure C from N-methyl oxindole
(0.147 g, 1.0 mmol) and furfuryl alcohol (0.147 g, 1.5 mmol). Chro-
matography eluting with 1:1 v/v petrol–ether gave the product
(0.185 g, 75%) as a colourless oil. dH (500 MHz, CDCl3); 7.34 (s, 1H,
H
14), 7.25 (appar t, 1H, J 7.3, H6), 6.96 (appar t, 1H, J 7.3, H5), 6.80 (d,
1H, J 6.8, H4), 6.42 (d, 1H, J 6.4, H7), 6.28 (s, 1H, H13), 6.01 (s, 1H, H12),
3.77 (dd, 1H, J 3.9, 9.6, CH), 3.47 (dd, 1H, J 3.9, 15.0, CHH), 3.20 (s, 3H,
CH3), 2.90 (dd, 1H, J 9.6, 15.0, CHH); dC (75 MHz, CDCl3); 177.14 (CO),
152.52 (ArC), 144.55 (ArC), 141.91 (ArCH), 128.59 (ArC), 128.50
(ArCH), 124.81 (ArCH), 122.71 (ArCH), 110.77 (ArCH), 108.35 (ArCH),
107.66 (ArCH), 45.06 (CH), 29.66 (CH2), 26.65 (CH3); nmax (film)/
cmꢂ1 1710 (CO), 1612, 1493, 1469, 1376, 1350; HRMS [ESþ] found
Mþ1 228.1020. C14H14NO2 requires 228.1019.
4.23. 3-(Benzo[d][1,3]dioxol-5-ylmethyl)-1-methylindolin-
2-one (26)
O
H11
O
H4
H5
H14
H15
H6
N
O
4.26. 3-iso-Butyl-1-methylindolin-2-one (29)
H7
H4
Prepared by general procedure C from N-methyl oxindole
(0.147 g,1.0 mmol) and 3,4-methylenedioxy benzyl alcohol (0.228 g,
1.5 mmol). Chromatography eluting with 1:1 v/v petrol–ether gave
the product (0.213 g, 76%) as a pale yellow oil; dH (500 MHz, CDCl3);
7.22 (t,1H, J 7.5, H5), 6.93 (appar t,1H, J 7.5, H6), 6.81 (d,1H, J 7.5, H4),
6.76 (d, 1H, J 7.5, H7), 6.68 (d, 1H, J 7.3, H14), 6.66 (s, 1H, H11), 6.59 (d,
1H, J 7.3, H15), 5.90 (d, 2H, J 1.7, OCH2O), 3.64 (dd, 1H, J 4.3, 9.2, CH),
3.39 (dd,1H, J 4.3,13.7, CHH), 3.16 (s, 3H, CH3), 2.81 (dd,1H, J 9.2,13.7,
CHH); dC (75 MHz, CDCl3); 177.36 (CO), 147.92 (ArC), 146.63 (ArC),
144.60 (ArC), 132.06 (ArC), 128.70 (ArC), 128.38 (ArCH), 124.93
(ArCH), 122.93 (ArCH) 122.50 (ArCH), 110.01 (ArCH), 108.43 (ArCH),
108.36 (ArCH), 101.28 (CH2), 47.59 (CH), 36.89 (CH2), 26.56 (CH3);
nmax (film)/cmꢂ11709(CO),1612,1490,1470,1443,1376; HRMS [ESþ]
found Mþ1 282.1135. C17H16NO3 requires 282.1125.
H5
H6
N
H
O
H7
PreparedbygeneralprocedureC fromN-methyloxindole(0.147 g,
1.0 mmol) and 2-methyl propanol (1.0 mL). Chromatography eluting
with 1:1 v/v ether–petrol gave the product (0.165 g, 81%) as a col-
ourless oil. dH (500 MHz, CDCl3); 7.27 (t,1H, J 7.7, H6), 7.24 (d,1H, J 7.7,
H4), 7.04 (t,1H, J 7.7, H5), 6.82 (d,1H, J 7.7, H7), 3.44 (t,1H, J 7.3), 3.20 (s,
3H, NCH3), 2.10–1.99 (m, 1H, CH), 1.85 (ddd, 1H, J 6.0, 7.9, 14.1, CHH),
1.64 (ddd,1H, J 6.8, 8.1,14.1, CHH) 1.00 (d, 3H, J 6.4, CH3), 0.94 (d, 3H, J
6.4, CH3); dC (75 MHz, CDCl3); 178.35 (CO),144.17 (ArC),129.70 (ArC),
127.73 (ArCH), 124.05 (ArCH), 122.11 (ArCH), 107.93 (ArCH), 43.70
(CH), 40.06 (CH2), 26.14 (CH3), 25.29 (CH), 22.90 (CH3), 22.10 (CH3);
nmax (film)/cmꢂ1 3054, 2956, 2869, 1712 (CO), 1613, 1494; HRMS
[ESþ] found MþNa 226.1202. C13H17NONa requires 226.2763.
4.24. 1-Methyl-3-(pyridin-3-ylmethyl)indolin-2-one (27)
H14
H15
H13
4.27. 3-(4-Chlorobenzyl)-1-methylindolin-2-one (30)
H4
H12
N
H5
H11
H11
Cl
H4
H6
N
O
H5
H7
H6
N
O
Prepared by general procedure
C from N-methyl oxindole
(0.147 g, 1.0 mmol) and pyridine 3-methanol (0.163 g, 1.5 mmol).
Chromatography eluting with 19:1 v/v DCM–methanol followed by
crystallisation from DCM and hexane gave the product (0.200 g,
84%) as colourless needles. Mp 107.0–108.0 ꢀC; dH (500 MHz, CDCl3);
H7
Prepared by general procedure C from N-methyl oxindole
(0.147 g, 1.0 mmol) and 4-chlorobenzyl alcohol (0.213 g, 1.5 mmol).

R. Grigg et al. / Tetrahedron 65 (2009) 4375–4383
4383
16. Edwards, M. G.; Williams, J. M. J. Angew. Chem., Int. Ed. 2002, 41, 4740–4743.
Chromatography eluting with 1:1 v/v petrol–ether gave the prod-
uct (0.264 g, 97%) as colourless prisms. Mp 115.0–116.0 ꢀC (Found:
C, 70.55; H, 5.15; N, 5.15; Cl, 13.05. C16H14ClNO requires: C, 70.72; H,
5.19; N, 5.15; Cl, 13.05%); dH (500 MHz, CDCl3); 7.23 (t, 1H, J 7.7, H5),
7.19 (d, 2H, J 8.1, H12), 7.06 (d, 2H, J 8.1, H11), 6.94 (t,1H, J 7.5, H6), 6.84
(d,1H, J 7.3, H4), 6.74 (d,1H, J 8.1, H7), 3.69 (dd,1H, J 4.7, 8.6, CH), 3.41
(dd, 1H, J 4.7, 13.7, CHH), 3.14 (s, 3H, CH3), 2.95 (dd, 1H, J 8.55, 13.7,
CHH); dC (75 MHz, CDCl3); 177.12 (CO), 144.64 (ArC), 136.62 (ArC),
132.87 (ArC), 131.16 (ArCH), 128.76 (ArCH), 128.53 (ArCH), 128.35
(ArC), 124.73 (ArCH), 122.55 (ArCH), 108.45 (ArCH), 47.28 (CH),
36.40 (CH2), 26.51 (CH3); nmax/cmꢂ1 (film) 2925, 1704 (CO), 1610,
1490, 1467, 1373, 1346, 1086; HRMS [ESþ] found Mþ1 272.0841.
C16H15ClNO requires 272.0837.
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