Iridium catalysed alkylation of 4-hydroxy coumarin, 4-hydroxy-2-quinolones and quinolin-4(1H)-one with alcohols under solvent free thermal conditions

Article abstract of DOI:10.1016/j.tet.2009.07.027

Ir catalysed alkylation of 4-hydroxy coumarin, 4-hydroxy-2-quinolones and quinolin-4(1H)-one with a range of substituted benzyl and aliphatic alcohols under solvent free thermal conditions afforded the corresponding monoalkylated products in high to excel

Full text of DOI:10.1016/j.tet.2009.07.027

Tetrahedron 65 (2009) 7468–7473
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Iridium catalysed alkylation of 4-hydroxy coumarin, 4-hydroxy-2-quinolones and
quinolin-4(1H)-one with alcohols under solvent free thermal 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, Leeds LS2 9JT, UK
b Johnson Matthey, Orchard Road, Royston, Hertfordshire SG8 5HE, UK
c PfizerLtd, 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:
Received 15 May 2009
Received in revised form 18 June 2009
Accepted 2 July 2009
Available online 24 July 2009
Ir catalysed alkylation of 4-hydroxy coumarin, 4-hydroxy-2-quinolones and quinolin-4(1H)-one with
a range of substituted benzyl and aliphatic alcohols under solvent free thermal conditions afforded the
corresponding monoalkylated products in high to excellent yield and in certain cases produced bis-(3,30-
1-methyl-4-hydroxy)methenes.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Microwave
Ir catalysis
Green chemistry
Regioselective alkylation
4-Hydroxy coumarin
4-Hydroxy-1-methyl 2(1H)-quinoline
1. Introduction
O
OH
Coumarins and quinolones are of great interest due to their roles
in natural product chemistry, their biological activity and presence
in many compounds of pharmaceutical interest.1 3-(Benzyl/alkyl)-
substituted 4-hydroxycoumarins include a range of bioactive
compounds such as warfarin 1 and also serve as useful scaffolds.1a
The latter include the Hsp90 inhibitor novobiocin 2 a member of
the coumermycin family of antibiotics and laquinimod 3, a novel
oral immunomodulator, developed as a disease-modifying drug for
relapsing-remitting multiple sclerosis (RRMS)2 is a further topical
example.
Environmental legislation has highlighted the need for pro-
cesses using efficient (high atom economy), selective, high yielding
and environmentally benign methods.3 C–C bond formation is
a pivotal method in organic synthesis and the indirect functional-
isation 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 redox-neutral, hydrogen autotransfer or
‘borrowing hydrogen’ processes. We have previously reported the
alkylation of active methylene and methine compounds with
N
O
O
N
O
O
Cl OH
1. Warfarin
3. Laquinimod
OH
OH
O
H
N
O
O
O
O
MeO
O
2. Novobiocin
OH
H2N
O
alcohols catalysed by iridium, rhodium and ruthenium complexes.
Thus alkylation of arylacetonitriles was achieved by using rho-
dium4 and more recently iridium catalysts.5 We have also reported
microwave assisted redox-neutral processes for the selective C-
monoalkylation of 1,3-dimethylbarbituric acid, oxindole and tert-
butyl cyanoacetate by alcohols.5–7 C-3 (Methine) alkylation of
indoles was also successfully carried out utilising alcohols and
iridium catalysts as was cascade indole ring formationdC-3
* Corresponding author. Tel.: þ44 (0)113 3436501.
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.2009.07.027

R. Grigg et al. / Tetrahedron 65 (2009) 7468–7473
7469
alkylation.8 This general approach is attracting much current in-
terest with many thoughtful contributions. Cho et al. have reported
the direct -alkylation of ketones with alcohols, using a Ru catalyst,
to afford saturated alcohols via
-alkylated ketones.9 The same
reaction can be performed in the presence of a sacrificial hydrogen
OH
X
R1
R
OH
a
+
C
base
O
p*Ir
a
path a
R
O
X
acceptor, such as 1-dodecene, when
a
a
-alkylated ketones are
-alkylation of ketones
R1
obtained.10 Alternative catalysts for the
Cp*Ir
H
O
+
+
O
with alcohols include the use of the phosphine free catalyst
Cp*Ir
H
OH
Ru(DMSO)4Cl211 and palladium nanoparticles.12 Ishi et al. reported
the selective direct a-alkylation of ketones with alcohols using an Ir
path b
-H2O
O
OH
base
OH
catalyst,13 and Williams et al. reported indirect Wittig reactions
R
X
O
14
with alcohols using [Ir(cod)Cl]2 or a ruthenium carbene com-
plex15 and variants of the aldol condensation.16 Krische et al.
reported a series of Ir catalysed C–C coupling processes via hy-
X
O
OH
X
R
OH
X
O
X = O, NMe, NH
drogen autotransfer processes involving alcohols and
p-un-
saturated reactants (1,3-dienes, 1,2-dienes, 1,3-enynes, 1,2
diynes).17–20 Milstein et al. have reported the direct conversion of
alcohols to acetals by the use of a ruthenium pincer complex cat-
alyst.21 Reddy et al. 1a have reported solid supported acid catalysed
C-3 alkylation of 4-hydroxycoumarins with secondary benzyl al-
cohols. This process however failed to work with primary benzyl
alcohols. We and others reported the N-alkylation of amines with
alcohols using iridium and rhodium catalysts22 whilst Beller et al.
achieved the N-alkylation of anilines with aliphatic amines using
Shvo’s catalyst.23 N-Acylation of amines with alcohols has been
achieved from a ruthenium precursor catalyst, an N-heterocyclic
carbene and a phosphine ligand.24 A ruthenium pincer complex
catalyst was also utilised for this transformation.25 N-Alkylation of
sulfonamides with alcohols has been achieved using either a ho-
mogeneous Ru catalyst or a heterogeneous nano-Ru/Fe3O4 cata-
lyst.26,27 Aromatic heterocycles such as furans, pyrroles, indoles,
quinolines and benzazoles have all been constructed via redox-
neutral processes.8,28–31
O
X
O
Scheme 2.
However there is the potential for a competing Michael addition
process leading to the 3,30-bis(heterocyclyl)methenes (Scheme 2,
path b).
Further optimisation showed that the reaction could be ach-
ieved under essentially solvent free conditions and identified
potassium hydroxide as the base of choice. Initially we carried out
the alkylation reaction of 4-hydroxy-1-methyl-2(1H)-quinoline
(1 mmol) with benzyl alcohol (5 mmol), KOH (20 mol %) and
[Cp
IrCl2]2 (2.5 mol %) at 110 ꢀC for 48 h in a sealed tube, which
*
afforded the monoalkylated product 5 in 68% yield (Table 1, entry 1).
The conversion and the yield of C-alkylated product varied greatly
depending on the alcohol in question. Electron rich aromatic al-
cohols (Table 1, entries 2, 3) and aliphatic alcohols (Table 1, entries
6, 7) gave high conversion and high yields of the desired C(3)-
alkylated products. However aromatic benzylic alcohols with
inductively withdrawing substituents such as 3-bromo or 4-
chlorobenzyl alcohol gave very poor yields of the desired C-3
alkylated products (Table 1, entries 3, 4). In these cases the major
products isolated were the 3,30 bis-(heterocyclyl) methene prod-
ucts 8 and 10 arising from addition of 4-hydroxy-1-methylquinolin-
2(1H)-one to the Michael acceptor intermediate (Scheme 2, path b).
The formation of two different products demonstrates that the rate
of hydrogenation of the Michael acceptor is affected by the nature
of the alcohol. In the case of electron rich alcohols it appears that
hydrogenation of the Michael acceptor is fast and therefore the
expected 3-substituted product is observed. However, in the case of
electron deficient alcohols, hydrogenation of the Michael acceptor
is slow indicating this intermediate is longer lived and therefore
prone to nucleophilic attack.
Next we briefly studied the alkylation of 4-hydroxy coumarin
and 4-hydroxy-2(1H)-quinolone with benzyl alcohol. In both
cases C-3 alkylated products were obtained in excellent yield
(Table 1, entries 8, 9) but excess benzyl alcohol (7–10 mol equiv)
was required in both cases. Finally, quinolin-4-(1H)-one was also
investigated in the alkylation cascade with benzyl alcohol under
more forcing conditions using an excess of benzyl alcohol
(5 mol equiv). After heating for 48 h at 120 ꢀC the C-3 alkylated
product 15 was isolated in 37% yield (Table 1, entry 10).
With longer reactions times (>72 h) the reaction remained
incomplete.
2. Results and discussion
Early extensive pioneering work by the Maitlis group32 estab-
lished simple routes to a series of halide bridged dimers 3 and
highlighted their catalytic potential. Recently Fujita’s group22c–f and
others have reported applications of 3 in redox-neutral processes.
The alkylation of 4-hydroxy coumarin/quinolone with alcohols
(Scheme 1) is of interest as it provides a potential ‘green’ route to
C-3 substituted derivatives of 4-hydroxy coumarin and 4-hydroxy
1-methyl quinolone. We initially surveyed a range of catalysts and
identified the iridium chloro-bridged compound 3 [X¼Cl, M¼Ir(III)]
as an effective catalyst for this transformation (Scheme 1).
Cp*
X
X
M
M
X
X
Cp*
3
X = Cl, I or Br
M = Ir, Rh, Ru
OH
X
OH
X
Cp*IrCl2
2
R
+
R
OH
O
O
X = O, NMe, NH
Scheme 1.
The proposed mechanism for this transformation involves de-
hydrogenation of the primary alcohol to generate an aldehyde and
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 C-3 alkylated product (Scheme 2, path a).
3. Conclusion
In conclusion 4-hydroxy-quinolones, coumarin and 4-(1H)-
quinolone were successfully C-alkylated with a range of substituted

7470
R. Grigg et al. / Tetrahedron 65 (2009) 7468–7473
Table 1
Table 1 (continued)
Alkylation of 4-hydroxy coumarin and 4-hydroxy-quinolones with alcoholsa
Entry
9
Alcohol
Product
Yieldb (%)
Entry
Alcohol
Product
Yieldb (%)
OH
OH
OH
87c
Ph
OH
1
68
O
O
N
Me
O
14
4
OH
O
OH
2
3
88
OH
MeO
N
Me
O
OMe
O
10
37
5
N
H
15
OH
a
Heterocycle (1.1 mmol), alcohol (5 mmol), [IrCp
(20 mol %), N2 (1 atm), 110 ꢀC, 48 h.
*
Cl2]2 (2.5 mol %), KOH
O
O
OH
b
71
11
Isolated yield.
c
Alcohol (10 mmol) was used.
N
Me
O
6
benzyl and aliphatic alcohols to afford the corresponding C-3
alkylated products in high yield. In certain cases 3,30-bis (hetero-
cyclyl) methane products arising via a Michael addition pathway
were also observed.
OH
Br
N
O
Me
7
82
Br
OH
4. Experimental
4.1. General
4
OH
OH
Br
Unless otherwise noted all reagents were obtained from com-
mercial suppliers and used without further purification. Chroma-
tography columns were prepared using Fisher Chemicals 60A
N
Me
O
N
Me
O
8
˚
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
19
59
OH
relative to the internal reference tetramethylsilane. Unless other-
wise specified NMR spectra were recorded in deuterochloroform at
room temperature. Abbreviations used: Ar¼aromatic, d¼doublet,
dd¼doublet of doublets, dq¼doublet of quartets, dt¼doublet of
triplets, m¼multiplet, q¼quartet, s¼singlet, t¼triplet. Mass spectra
N
Me
O
Cl
9
Cl
OH
5
were recorded using
a micromass ZMD 2000 spectrometer
Cl
employing the electrospray (ESþ) ionisation technique. Accurate
molecular masses were obtained from Walters LCT, GCT or Bruker
MicroTof spectrometers. Infra-red 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 re-
fers to the fraction of petroleum ether with bp 40–60 ꢀC and ether
refers to diethyl ether. Accurate masses refer to 35Cl and 79Br
isotopes.
OH
OH
N
O
N
Me
O
Me
10
OH
OH
6
7
8
92
82
N
Me
O
11
4.2. General procedure for the alkylation
of oxindoles with alcohols
OMe
OMe
12
OH
MeO
MeO
OH
4.2.1. General procedure
N
O
The heterocycle (1.0 mmol), [Cp IrCl2]2 (0.020 g, 2.5 mol %),
*
Me
KOH (0.011 g, 0.2 mmol) and the alcohol (5.0 mmol) were com-
bined in a thick walled glass tube. The tube was sealed with
a rubber septum, purged with nitrogen and the mixture was
magnetically stirred at 110 ꢀC with conventional heating for 48 h
then allowed to cool to room temperature. The reaction mixture
was analysed by 1H NMR and thereafter purified by silica gel col-
umn chromatography.
OH
OH
94c
N
H
O
13

R. Grigg et al. / Tetrahedron 65 (2009) 7468–7473
7471
4.2.2. 3-Benzyl-4-hydroxy-1-methylquinolin-2(1H)-one (4)
6.76 (d,1H, J 7.7, H15), 6.74 (d,1H, J 7.7, H16), 5.92 (s, 2H, OCH2O), 3.90
(s, 2H, CH2), 3.60 (s, 3H, CH3); dC (75 MHz, DMSO-d6); 163.00 (CO),
156.60 (ArC), 147.24 (ArC), 145.44 (ArC), 138.83 (ArC), 134.92 (ArC),
130.83 (ArCH), 123.48 (ArCH), 121.61 (ArCH), 121.33 (ArCH), 116.48
(ArC), 114.70 (ArCH), 111.19 (ArC), 109.24 (ArCH), 108.16 (ArCH),
100.85 (CH2), 29.56 (CH3), 29.323 (CH2); nmax/cmꢂ1 (solid) 1639,
1609, 1569, 1486, 1442, 1331, 1037, 931; HRMS [ESþ] found MþNa,
332.0891. C18H15NO4Na requires 332.0893.
H5
OH
H6
H7
N
O
H8
Prepared by the general procedure from 4-hydroxy-1-methyl-
quinolin-2(1H)-one (0.161 g, 1.0 mmol) and benzyl alcohol (0.540 g,
5.0 mmol). Chromatography, eluting with 3:97 v/v methanol and
DCM followed by crystallisation of the residue from methanol gave
the product (0.184 g, 68%) as colourless prisms. Mp 226.0–228.0 ꢀC
(lit. mp 219.0–220.0 ꢀC);33 dH (500 MHz, CDCl3); 7.92 (d, 1H, J 7.8,
H8), 7.57 (appar t, 1H, J 7.8, H7), 7.36–7.21 (m, 7H, 7ꢁArH), 5.96 (s,
1H, OH), 4.14 (s, 2H, CH2), 3.74 (s, 3H, CH3); nmax/cmꢂ1 (solid) 1627,
1583, 1498, 1455, 1093, 1011, 913, 818; HRMS [ESþ] found Mþ1,
266.1171. C17H16NO2 requires 266.1176.
4.2.5. 3-(3-Bromobenzyl)-4-hydroxy-1-methylquinolin-
2(1H)-one (7)
H15
H16
H14
H5
OH
H6
H7
Br
H12
N
O
H8
4.2.3. 3-(4-Methoxybenzyl)-4-hydroxy-1-methylquinolin-
2(1H)-one (5)
Prepared by the general procedure from 4-hydroxy-1-methyl-
2(1H)-quinolone (0.175 g, 1.0 mmol) and 3-bromobenzyl alcohol
(0.935 g, 5.0 mmol). Chromatography eluting with DCM followed by
crystallisation from methanol gave the product (0.39 g, 11.0%) as
colourless micro needles. Mp >230.0 ꢀC; dH (500 MHz, DMSO-d6);
10.55 (br s, 1H, OH), 8.08 (d, 1H, J 8.1, ArH), 7.62 (appar t, 1H, J 7.7,
ArH), 7.50 (d, 1H, J 8.1, ArH), 7.44 (s, 1H, H12), 7.34 (d, 1H, J 7.7, ArH),
7.30–7.26 (m, 2H, 2ꢁArH), 7.21 (appar t, 1H, J 7.7, ArH), 3.98 (s, 2H,
CH2), 3.60 (s, 3H, CH3); dC (75 MHz, DMSO-d6); 162.94 (CO), 157.08
(ArC), 144.05 (ArC), 138.93 (ArC), 131.26 (ArCH), 131.03 (ArCH),
130.57 (ArCH), 128.84 (ArCH), 127.78 (ArCH), 123.57 (ArCH), 121.71
(ArCH), 121.67 (ArC), 116.38 (ArC), 114.81 (ArCH), 110.16 (ArC), 29.60
(CH3), 29.59 (CH2); nmax/cmꢂ1 (solid) 1639, 1608, 1508, 1421, 1394,
1329, 951, 753; HRMS [ESþ] found MþNa, 366.0108. C17H14BrNO2Na
requires 366.0100.
OMe
H5
OH
H6
H13
H12
H7
N
O
H8
Prepared by the general procedure from 4-hydroxy-1-methyl-
2(1H)-quinolone (0.175 g, 1.0 mmol) and 4-methoxy benzyl alcohol
(0.414 g, 5.0 mmol). Chromatography eluting with 1:1 v/v ethyl
acetate and hexane gave the product (0.260 g, 88%) as colourless
micro needles. Mp 194.0–195.0 ꢀC; (Found: C, 73.20; H, 5.70; N,
4.80. C18H17NO3 requires: C, 73.20; H, 5.80; N, 4.74%.) dH (500 MHz,
CDCl3); 7.94 (d, 1H, J 7.3, H8), 7.56 (appar t, 1H, J 7.3, H7), 7.34 (d, 1H, J
8.5, H5), 7.23 (d, 2H, J 8.6, H12), 7.22 (appar t, 1H, J 7.7, H6), 6.80 (d,
2H, J 8.6, H13), 6.42 (br s, 1H, OH), 4.07 (s, 2H, CH2), 3.74 (s, 3H, CH3),
3.72 (s, 3H, CH3); dC (75 MHz, CDCl3); 163.66 (CO), 158.42 (ArC),
156.86 (ArC), 138.76 (ArC), 130.66 (ArCH), 130.42 (2ꢁArCH), 129.45
(ArCH), 123.20 (ArCH), 121.71 (ArCH), 116.01 (ArC), 114.38
(2ꢁArCH), 113.90 (ArCH), 110.28 (ArC), 55.23 (OCH3), 29.85 (NCH3),
29.32 (CH2); nmax/cmꢂ1 (solid) 1607 (CO), 1511, 1463, 1301, 1038,
940, 820, 748; HRMS [ESþ] found Mþ1, 296.1282. C18H18NO3 re-
quires 296.1281.
4.2.6. 3,30-Bis(3-bromobenzylidene)2,20-dioxo-4,40-hydroxyl-1,10-
dimethylquinolyl methane (8)
H14
H15
Br
H16
OH
H12
OH
H5'
H5
H8
H6
H7
H6'
H7'
4.2.4. 3-(Benzo[d][1,3]dioxol-5-ylmethyl)-4-hydroxy-1-
methylquinolin-2(1H)-one (6)
N
O O
N
H8'
O
H12
Prepared by the general procedure from 4-hydroxy-1-methyl-
2(1H)-quinolone (0.175 g, 1.0 mmol) and 3-bromobenzyl alcohol
(0.935 g, 5.0 mmol). Chromatography eluting with DCM followed
by crystallisation from methanol gave the product (0.212 g, 82%) as
a colourless solid. Mp >230.0 ꢀC; dH (500 MHz, CDCl3); 8.25 (d, 1H, J
8.1, ArH), 8.21 (d, 1H, J 7.7, ArH), 7.65–7.60 (m, 2H, 2ꢁArH), 7.42 (d,
2H, J 8.6, 2ꢁArH), 7.36–7.29 (m, 4H, 4ꢁArH), 7.13 (d, 2H, J 4.7,
2ꢁArH), 6.40 (s, 1H, CH), 3.82 (s, 3H, CH3), 3.72 (s, 3H, CH3); dC
(75 MHz, DMSO-d6); 166.66 (CO), 164.78 (CO), 162.32 (ArC), 161.19
(ArC),140.55 (ArC),138.61 (ArC),138.46 (ArC),131.38 (ArCH),129.63
(ArCH), 129.58 (ArCH), 129.11 (ArCH), 125.33 (ArCH), 124.98 (ArCH),
124.85 (ArCH), 122.73 (ArCH), 122.67 (ArCH), 122.46 (ArC), 118.05
(ArC),117.74 (ArC),114.28 (ArCH),114.14 (ArCH),110.91 (ArC),109.15
(ArC), 37.05 (CH), 30.52 (CH3), 30.06 (CH3); nmax/cmꢂ1 (solid) 1624
(CO), 1554, 1496, 1373, 1344, 1176, 866, 755; HRMS [ESþ] found
Mþ1, 517.0785. C27H22BrN2O4 requires 517.0757.
O
H5
OH
H6
H15
H16
H7
N
O
H8
Prepared by the general procedure from 4-hydroxy-1-methyl-
2(1H)quinolone (0.175 g, 1.0 mmol) and 3,4-(methylenedioxy)
benzyl alcohol (0.760 g, 5.0 mmol). Chromatography, eluting with
1:1 v/v petroleum ether and diethyl ether, followed by crystal-
lisation from methanol gave the product (0.220 g, 71%) as colour-
less micro needles. Mp 207.0–208.0 ꢀC; (Found: C, 69.90; H, 4.85; N,
4.4. C18H15NO4 requires: C, 69.89; H, 4.89; N, 4.53%.) dH (500 MHz,
DMSO-d6); 10.40 (s, 1H, OH), 8.03 (d, 1H, J 7.9, H8), 7.60 (appar t, 1H,
J 8.6, H6), 7.48 (d, 1H, J 8.6, H5), 7.27 (1H, J 7.9, H7), 6.84 (s, 1H, H12),

7472
R. Grigg et al. / Tetrahedron 65 (2009) 7468–7473
4.2.7. 3-(4-Chlorobenzyl)-4-hydroxy-1-methylquinolin-2(1H)-
one (9)
(1.0 mL, 5.0 mmol). Chromatography eluting with 1:1 v/v ethyl
acetate and hexane followed by crystallisation of the residue from
DCM and methanol gave the product (0.260 g, 88%) as colourless
micro prisms. Mp 186.0–187.0 ꢀC; dH (500 MHz, CDCl3); 8.05 (d, 1H,
J 8.1, H8), 7.61 (appar t, 1H, J 8.6, H6), 7.51 (d, 1H, J 8.6, H5), 7.29
(appar t, 1H, J 7.5, H7), 4.90 (br s, 1H, OH), 3.71 (s, 1H, NCH3), 2.59 (d,
2H, J 7.7, CH2), 2.05–1.95 (m, 1H, CH), 0.95 (d, 6H, J 6.7, 2ꢁCH3); dC
(75 MHz, CDCl3); 166.23 (CO), 159.39 (ArC), 140.00 (ArC), 131.84
(ArCH), 124.66 (ArCH), 123.28 (ArCH), 118.34 (ArC), 115.68 (ArCH),
111.95 (ArC), 34.03 (CH2), 30.43 (CH3), 29.20 (CH), 22.98 (2ꢁCH3);
nmax/cmꢂ1 (solid) 1581 (CO), 1395, 1252, 1164, 1085, 987, 876, 758;
HRMS [ESþ] found Mþ1, 232.1333. C14H18NO2 requires 232.1332.
Cl
H5
OH
H6
H13
H12
H7
N
O
H8
Prepared by the general procedure from 4-hydroxy-1-methyl-
2(1H)-quinolone (0.175 g, 1.0 mmol) and 4-chlorobenzyl alcohol
(0.710 g, 5.0 mmol). Chromatography eluting with 1:1 v/v ethyl
acetate and hexane followed by crystallisation from methanol gave
the product (0.057 g, 19.0%) as colourless micro needles. Mp 227.0–
228.0 ꢀC; dH (500 MHz, DMSO-d6); 10.5 (br s, 1H, OH), 8.04 (d, 1H, J
8.1, ArH), 7.62 (appar t, 1H, J 8.1, ArH), 7.50 (d, 1H, J 8.1, ArH), 7.30–
7.26 (m, 5H, 5ꢁArH), 3.97 (s, 2H, CH2), 3.60 (s, 3H, CH3); dC (75 MHz,
DMSO-d6); 162.95 (CO), 156.96 (ArC), 140.15 (ArC), 138.90 (ArC),
130.96 (ArCH), 130.48 (2ꢁArCH), 128.25 (2ꢁArCH), 123.54 (ArCH),
121.66 (ArCH), 116.42 (ArC), 114.76 (ArCH), 110.41 (ArC), 29.56
(CH3), 29.15 (CH2); nmax/cmꢂ1 (solid) 1609 (CO), 1494, 1428, 1017,
965, 898, 749, 552; HRMS [ESþ] found MþNa, 322.0595.
C17H14NClO2Na requires 322.0605.
4.2.10. 3-(3,4-Dimethoxyphenethyl)-4-hydroxy-1-methylquinolin-
2(1H)-one (12)
H15
H16
OMe
H5
OH
H6
OMe
H12
H7
N
O
H8
4.2.8. 3,30-Bis(4-chlorobenzylidene)-1,10-methylquinolin-2,20-(1H)-
one (10)
Prepared by the general procedure from 4-hydroxy-1-methyl-
2(1H)-quinolone (0.175 g, 1.0 mmol) and 3,4-dimethoxyphenyl
ethyl alcohol (0.910 g, 5.0 mmol). Chromatography, eluting with
ether, followed by crystallisation of the residue from DCM and
methanol gave the product (0.278 g, 82%) as colourless micro
needles. Mp 173.0–174.0 ꢀC; (Found: C, 70.70; H, 6.25; N, 4.0.
C20H21NO4 requires: C, 70.78; H, 6.24; N, 4.13%); dH (500 MHz,
DMSO-d6); 10.20 (br s, 1H, OH), 8.01 (d, 1H, J 7.9, H8), 7.59 (appar
t, 1H, J 8.6, H7), 7.48 (d, 1H, J 8.6, H5), 7.26 (appar t, 1H, J 7.7, H6),
6.91 (d, 1H, J 1.6, H12), 6.86 (d, 1H, J 8.2, H15), 6.79 (dd, 1H, J 1.6,
8.2, H16), 3.75 (s, 3H, OCH3), 3.73 (s, 3H, OCH3), 3.62 (s, 3H,
NCH3); dC (75 MHz, CDCl3); 160.68 (CO), 153.89 (ArC), 146.56
(ArC), 144.98 (ArC), 136.37 (ArC), 132.77 (ArC), 128.28 (ArCH),
121.09 (ArCH), 119.22 (ArCH), 118.12 (ArCH), 114.27 (ArC), 112.24
(ArCH), 110.33 (ArCH), 109.89 (ArCH), 108.65 (ArC), 53.58 (OCH3),
53.39 (OCH3), 31.44 (CH2), 27.14 (NCH3), 24.30 (CH2); nmax/cmꢂ1
(solid) 1637 (CO), 1516, 1330, 1388, 1224, 1024, 927, 800, 645;
HRMS [ESþ] found MþNa, 262.1355. C20H21NNaO4 requires
262.1362.
Cl
H13
H12
H5
OH
N
OH
N
H6
H7
O O
H8
Prepared by the general procedure from 4-hydroxy-1-methyl-
2(1H)-quinolone (0.175 g, 1.0 mmol) and 4-chlorobenzyl alcohol
(0.710 g, 5.0 mmol). Chromatography eluting with 1:1 v/v ethyl
acetate and hexane gave the product (0.140 g, 59%) as a colourless
solid. Mp 174.0–175.0 ꢀC. (Found: C, 68.65; H, 4.75; N, 5.75; Cl, 7.55.
C27H20ClN2O4 requires: C, 68.57; H, 4.48; N, 5.92; Cl, 7.50%.) dH
(500 MHz, CDCl3); 8.25 (d, 1H, J 7.7, ArH), 8.19 (d, 1H, J 7.7, ArH),
7.65–7.60 (m, 2H, 2ꢁArH), 7.42 (d, 2H, J 8.5, 2ꢁArH), 7.37–7.30 (m,
2H, 2ꢁArH), 7.22 (d, 2H, J 8.6, H13), 7.11 (d, 2H, J 8.6, H12), 6.38 (s,
1H, CH), 3.83 (s, 3H, CH3), 3.71 (s, 3H, CH3); dC (75 MHz, CDCl3);
166.70 (CO), 164.82 (CO), 162.32 (ArC), 161.12 (ArC), 138.58 (ArC),
138.44 (ArC), 136.47 (ArC), 131.65 (ArC), 131.35 (ArCH), 128.25
(ArCH), 128.02 (ArCH), 124.91 (ArCH), 124.84 (ArCH), 122.74 (ArCH),
122.66 (ArCH), 118.06 (ArC), 117.77 (ArC), 114.25 (ArCH), 114.15
(ArCH), 111.08 (ArC), 109.50 (ArC), 36.99 (CH), 30.52 (CH3), 30.06
(CH3); nmax/cmꢂ1 (solid) 1627 (CO), 1490, 1366, 1217, 1116, 1014,
827, 756; HRMS [ESþ] found Mþ1, 473.1262. C27H22ClN2O4 requires
473.1263.
4.2.11. 3-Benzyl-4-hydroxyquinolin-2(1H)-one (13)
H5
OH
H6
H7
N
H
O
H8
4-Hydroxyquinolin-2(1H)-one (0.161 g, 1.0 mmol), [Cp IrCl2]2
*
(0.02 g, 2.5 mol %), KOH (0.011 g, 0.2 mmol) and benzyl alcohol
(0.756 g, 7.0 mmol) were combined in a thick walled glass tube.
The tube was sealed with a rubber septum and purged with ni-
trogen. The reaction mixture was heated with stirring at 110 ꢀC for
48 h. Chromatography eluting with 1:1 v/v ethyl acetate and
hexane gave the product (0.234 g, 94%) as a colourless solid. Mp
214.0–216.0 ꢀC (lit. Mp 218.0–220.0 ꢀC);34 dH (500 MHz, DMSO-d6);
11.36 (br s, 1H, NH), 7.94 (d, 1H, J 7.7, H8), 7.46 (appar t, 1H, J 7.3, H7),
7.30–7.20 (m, 5H, 5ꢁArH), 7.18–7.10 (m, 2H, 2ꢁArH), 3.94 (s, 2H,
CH2); nmax/cmꢂ1 (solid) 1629, 1603, 1498, 1382, 1273, 1098, 914,
756; HRMS [ESþ] found MþNa, 274.0846. C16H13NO2Na requires
274.0838.
4.2.9. 4-Hydroxy-3-isobutyl-1-methylquinolin-2(1H)-one (11)
H5
OH
H6
H7
N
O
H8
Prepared by the general procedure from 4-hydroxy-1-methyl-
2(1H)-quinolone (0.175 g, 1.0 mmol) and 2-methyl propanol

R. Grigg et al. / Tetrahedron 65 (2009) 7468–7473
2. Sorbera, L. A.; Castaner, J. Drugs Future 2003, 28, 1059–1063.
7473
4.2.12. 3-Benzyl-4-hydroxy-2H-chromen-2-one (14)
3. (a) Schreiber, S. L. Science 2000, 287, 1964–1969; (b) Spring, D. R. Org. Biomol.
Chem. 2003, 1, 3867–3870; (c) Itami, K.; Yoshida, J. I. Chem.dEur. J. 2006, 12,
3966–3974.
4. Grigg, R.; Mitchell, T. R. B.; Sutthivaiyakit, S.; Tongpenyai, N. Tetrahedron Lett.
1981, 22, 4107–4711.
5. (a) Motokura, K.; Nishimura, D.; Mori, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K. J.
Am. Chem. Soc. 2004, 126, 5662–5663; (b) Lofberg, C.; Grigg, R.; Whittaker, M.
A.; Keep, A.; Lofberg, C.; Grigg, R.; Keep, A.; Derrick, A.; Sridharan, V,; Kilner, C.
Chem. Commun. 2006, 5000–5002.
H5
OH
H6
H7
O
O
6. Grigg, R.; Lofberg, C.; Whitney, S.; Sridharan, V.; Keep, A.; Derrick, A. Tetrahe-
dron 2009, 65, 849–854.
H8
7. (a) Grigg, R.; Whitney, S.; Sridharan, V.; Keep, A.; Derrick, A. Tetrahedron, 2009,
65, 4375–4383; (b) Jensen, T.; Madsen, R. J. Org. Chem. 2009.
8. Whitney, S.; Grigg, R.; Derrick, A.; Keep, A. Org. Lett. 2007, 9, 3299–3302.
9. Cho, C. S.; Kim, B. T.; Kim, T. J.; Shim, S. C. J. Organomet. Chem. 2001, 6,
9020–9022.
10. Cho, C. S.; Kim, T. J.; Shim, S. C. Tetrahedron Lett. 2002, 43, 7987–7990.
11. (a) Martinez, R.; Brand, G. J.; Ramon, D. J.; Yus, M. Tetrahedron Lett. 2005, 46,
3683–3686; (b) Martinez, R.; Ramon, D. J.; Yus, M. Tetrahedron 2006, 62, 8982–
8987; (c) Martinez, R.; Ramon, D. J.; Yus, M. Tetrahedron 2006, 240, 8988–9001;
(d) Guillena, G.; Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2007, 46, 2–9.
12. Yamada, Y. M. A.; Uozumi, Y. Org. Lett. 2006, 8, 1375–1378.
13. Tauchi, K.; Nakagawa, H.; Hirabayashi, T.; Sakauchi, S.; Ishii, Y. J. Am. Chem. Soc.
2004, 126, 72–73.
14. Edwards, M. G.; Williams, J. M. J. Angew. Chem., Int. Ed. 2002, 41, 4740–4743.
15. (a) Edwards, M. G.; Jazzar, R. F. R.; Paine, B. M.; Shermer, D. J.; Whittlesey, M. K.;
Williams, J. M. J.; Edney, D. D. Chem. Commun. 2004, 90–91; (b) Burling, S.; Pain,
B. M.; Nama, D.; Brown, V. S.; Mahon, M. F.; Prior, T. J.; Pregosin, P. S.; Whit-
tlesey, M. K.; Williams, J. M. J. J. Am. Chem. Soc. 2007, 129, 1987–1995.
16. Slatford, P. A.; Whittlesey, M. K.; Williams, M. J. Tetrahedron Lett. 2006, 47,
6787–6789.
17. (a) Shibahara, F.; Bower, J. F.; Krische, M. J. J. Am. Chem. Soc. 2008, 130, 6338–
6339; (b) Bower, J. F.; Patman, R. L.; Krische, M. J. Org. Lett. 2008, 10, 1033–1035.
18. (a) Bower, J. F.; Skucas, E.; Patman, R. L.; Krische, M. J. J. Am. Chem. Soc. 2007,
129, 15134–15135; (b) Ngai, M. Y.; Skucas, E.; Krische, M. J. Org. Lett. 2008, 10,
2705–2708.
4-Hydroxy coumarin (0.162 g, 1.0 mmol), [Cp IrCl2]2 (0.020 g,
*
2.5 mol %), KOH (0.011 g, 0.2 mmol) and benzyl alcohol (1.08 g,
10.0 mmol) were combined in a thick walled glass tube. The tube
was sealed with a rubber septum and purged with nitrogen. The
reaction mixture was heated with stirring at 110 ꢀC for 48 h.
Chromatography eluting with 1:99 v/v methanol and DCM gave the
product (0.219 g, 87%) as a colourless solid. Mp 207.0–208.0 ꢀC (lit.
Mp 207.0–209.0 ꢀC);35 dH (500 MHz, CDCl3); 7.74 (dd, 1H, J 1.3, 8.1,
H5), 7.54 (ddd,1H, J 1.3, 7.3, 8.5, H7), 7.37–7.33 (m, 5H, 5ꢁArH), 7.31–
7.27 (m, 2H, 2ꢁArH), 6.12 (br s,1H, OH), 4.04 (s, 2H, CH2); nmax/cmꢂ1
(solid) 1662, 1614, 1567, 1494, 1392, 1185, 1108, 750; HRMS [ESþ]
found MþNa, 275.0679. C16H12O3Na requires 275.0679.
4.2.13. 3-Benzylquinolin-4(1H)-one (15)
H5
O
H6
19. Patman, R. L.; Williams, V. M.; Bower, J. F.; Krische, M. J. Angew. Chem., Int. Ed.
2008, 47, 1–5.
H7
20. Patman, R. L.; Chaulagin, M. R,; Williams, V. M.; Krische, M. J. J. Am. Chem. Soc.
2009, 131, 2066–2067.
21. Gunanathan, C.; Shimon, L. J. W.; Milstein, D. J. Am. Chem. Soc. 2009, 131,
3146–3147.
H2
N
H
H8
22. (a) Grigg, R.; Mitchell, T. R. B.; Sutthivaiyakit, S.; Tongpenyai, N. J. Chem. Soc.,
Chem. Commun. 1981, 611–612; (b) Watanabe, Y.; Tsuji, Y.; Ige, H.; Ohsugi, Y.;
Ohta, T. J. Org. Chem. 1984, 49, 3359–3363; (c) Fujita, K.; Fujii, T.; Yamaguchi, R.
Org. Lett. 2004, 6, 3525–3528; (d) Fujita, K.; Yamaguchi, R. Synlett 2005, 560–
571; (e) Fujita, K.; Asai, C.; Yamaguchi, T.; Hanasaka, F. Org. Lett. 2005, 7, 4017–
4019; (f) Fujita, K.; Enkoi, R.; Yamaguchi, T. Org. Synth. 2006, 83, 217–221; (g)
Haniti, M.; Hamid, S. A.; Slatford, P. A.; Williams, J. M. Adv. Synth. Catal. 2007,
349, 1555–1575.
Quinolin-4(1H)-one (0.145 g, 1.0 mmol), [Cp IrCl2]2 (0.02 g,
*
2.5 mol %), KOH (0.112 g, 2.0 mmol) and benzyl alcohol (0.540 g,
5.0 mmol) were combined in a thick walled glass tube and sealed
with a rubber septum. The reaction vessel was purged with nitro-
gen and heated with stirring at 110 ꢀC for 48 h. The reaction mix-
ture was allowed to cool. Chromatography eluting with 3:97 v/v
methanol and DCM followed by crystallisation from methanol gave
the product (0.087 g, 37%) as colourless micro plates. Mp 218.0–
219.0 ꢀC; dH (500 MHz, DMSO-d6); 11.69 (br s, 1H, NH), 8.12 (d, 1H, J
7.7, H5), 7.86 (s, 1H, H2), 7.62 (appar t, 1H, J 7.7, H6), 7.52 (d, 1H, J 8.3,
H8), 7.32–7.23 (m, 4H, 4ꢁArH), 7.15 (appar t, 1H, J 7.5, H7), 3.78 (s,
2H, CH2); dC (75 MHz, DMSO-d6); 176.25 (CO), 141.72 (ArC), 140.01
(ArC), 137.81 (ArCH), 131.60 (ArCH), 128.90 (2ꢁArCH), 128.43
(2ꢁArCH), 125.96 (ArCH), 125.44 (ArCH), 125.05 (ArC), 123.08
(ArCH), 120.74 (ArC), 118.43 (ArCH), 33.32 (CH2); nmax/cmꢂ1 (solid)
1629, 1549, 1526, 1474, 1455, 1367, 1208, 761; HRMS [ESþ] found
Mþ1, 236.1079. C16H14NO requires 236.1070.
23. (a) Hollmann, D.; Bahn, S.; Tillack, A.; Beller, M. Angew. Chem., Int. Ed. 2007, 46,
8291–8294; (b) Hollmann, D.; Bahn, S.; Tillack, A.; Beller, M. Chem. Commun.
2008, 3199–3201.
24. Nordstrom, L. U.; Vogt, H.; Madsen, R. J. Am. Chem. Soc. 2008, 130, 17672–17673.
25. Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007, 317, 790–792.
26. Haniti, M.; Hamid, S. A.; Liana Allen, C.; Lamb, G. W.; Maxwell, A. C.; Maytum,
H. C.; Watson, A. J. A.; Williams, M. J. J. Am. Chem. Soc. 2009, 131, 1766–1774.
27. Shi, F.; Tse, M. K.; Zhou, S.; Pohl, M. M.; Radnik, J.; Hubner, S.; Jahnisch, K.;
Bruckner, A.; Beller, M. J. Am. Chem. Soc. 2009, 131, 1775–1779.
28. Pridmore, S. J.; Slatford, P. A.; Williams, J. M. J. Tetrahedron Lett. 2007, 48,
5111–5114.
29. (a) Tsuji, Y.; Yokoyama, Y.; Huh, K. T.; Watanabe, Y. Bull. Chem. Soc. Jpn. 1987, 60,
3456–3458; (b) Pridmore, S. J.; Slatford, P. A.; Daniel, A.; Whittlesey, M. K.;
Williams, J. M. J. Tetrahedron Lett. 2007, 48, 5115–5120.
30. (a) Tsuji, Y.; Huh, K. T.; Watanabe, Y. Tetrahedron Lett.1986, 27, 377–380; (b) Tsuji,
Y.; Huh, K. T.; Watanabe, Y. J. Org. Chem.1987, 52,1673–1680; (c) Cho, C. S.; Lim, H.
K.; Shim, S. C.; Kim, T. J.; Choi, H. J. Chem. Commun.1998, 995–996; (d) Taguchi, K.;
Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 2005, 46, 4539–4542; (e) Igarashi, T.; Inda,
T.; Sekioka, T.; Nakajima, T.; Shimizu, I. Chem. Lett. 2005, 106–109; (f) Aramoto,
H.; Obora, Y.; Ishii, Y. J. Org. Chem. 2009, 74, 628–633.
Acknowledgements
We thank Leeds University, Pfizer and Johnson Matthey for
support.
31. Blacker, A. J.; Farah, M. M.; Hall, M. I.; Marsden, S. P.; Saidi, O.; Williams, M. J.
Org. Lett. 2009, 11, 2039–2042.
32. (a) Cook, J.; Hamlin, J. E.; Nutton, A.; Maitlis, P. M. J. Chem. Soc., Dalton Trans.
1981, 2342–2352; (b) Gill, D. S.; White, C.; Maitlis, P. M. J. Chem. Soc., Dalton
Trans. 1978, 617–626; (c) Maitlis, P. M. Acc. Chem. Res. 1978, 11, 301–307.
33. Huffman, J. W. J. Org. Chem. 1961, 26, 1470–1471.
References and notes
34. Ukrainets, I. V.; Taran, S. G.; Evtifeeva, O. A.; Gorokhova, O. V.; Benzuglyi, P. A.
Chem. Heterocycl. Compd. (Engl. Transl.) 1994, 30, 591–596.
35. Toth, G.; Molnar, S.; Tamas, T.; Borbely, I. Org. Prep. Proced. Int. 1999, 31, 222–225.
1. (a) Reddy, Ch. R.; Srikantha, B.; Rao, N. N.; Shim, D. S. Tetrahedron 2008, 64,
11666–11672; (b) Burlison, J. A.; Neckers, L.; Smith, A. B.; Maxwell, A.; Blagg, B.
S. J. Am. Chem. Soc. 2006, 128, 15529–15536.