Synthesis of lodopyridone

Article abstract of DOI:10.1016/j.tet.2013.07.033

The total synthesis of the unusual 4-pyridone marine metabolite lodopyridone has been achieved by late stage manipulation of the related 4-pyrone. Key reactions include a Suzuki-Miyaura coupling to form the tetracyclic core and a modified Corey-Ganem-Gilman reaction to install the ethanolamide side-chain.

Full text of DOI:10.1016/j.tet.2013.07.033

Accepted Manuscript
Synthesis of Lodopyridone
Ian R. George, William Lewis, Christopher J. Moody
PII:
S0040-4020(13)01123-X
10.1016/j.tet.2013.07.033
TET 24614
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 20 May 2013
Revised Date: 25 June 2013
Accepted Date: 9 July 2013
Please cite this article as: George IR, Lewis W, Moody CJ, Synthesis of Lodopyridone, Tetrahedron
(2013), doi: 10.1016/j.tet.2013.07.033.
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ACCEPTED MANUSCRIPT
Synthesis of Lodopyridone
Ian R. George, William Lewis and Christopher J. Moody*
School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, U.K.
O
OH
O
MeS
H
N
OMe
N
HO
O
N
Me
Cl
Cl
O
N
S
HO
lodopyridone
Me
N
ABSTRACT
The total synthesis of the unusual 4-pyridone marine metabolite lodopyridone has been achieved
by late stage manipulation of the related 4-pyrone. Key reactions include a Suzuki-Miyaura
coupling to form the tetracyclic core and a modified Corey-Ganem-Gilman reaction to install the
ethanolamide side-chain.
Keywords: natural product; synthesis; pyridone; thiazole; quinoline; pyrone
1. INTRODUCTION
Among the wide structural diversity of pyridine-based alkaloids, those containing the 4-pyridone
nucleus are relatively rare. Examples include leucenol (mimosine), 1 ꢀ5-dehydroalbine,2 and the
recently isolated poronitin B (Figure 1).3 Isolated from a strain of the Actinomycete marine
* Corresponding author. tel.: +44 115 846 8500; fax: +44 115 951 3564; email address:
c.j.moody@nottingham.ac.uk

ACCEPTED MANUSCRIPT
bacterium CNQ490 collected near the mouth of the La Jolla submarine canyon in California by
Fenical and co-workers,4 lodopyridone 1 is one of the more unusual 4-pyridone natural products.
The structure (Figure 1), which was determined by X-ray crystallography, is based on a fully
substituted 4-pyridone nucleus containing unusual substituents such as a thiomethoxy group and
a 6-chloroquinolinylthiazole, and the compound is reported to possess moderate biological
activity against human colon cancer cells. However, in addition to its unusual structure, it was its
reported activity as an inhibitor of human quinone reductase 2 (NQO2, QR2) that attracted our
attention,5 in view of our interest in quinone reductase enzymes.6,7 We now report a total
synthesis of lodopyridone.
O
O
O
O
N
OH
N
H
Me
Me
N
H
CO2H
NH
CO2H
poronitin B
NH2
leucenol
O
O
N
N
MeS
OMe
H
N
N
∆5-dehydroalbine
Me
Cl
O
N
S
HO
lodopyridone 1
Figure 1. Naturally occurring 4-pyridones.
4-Pyridones are usually readily accessible from 4-pyrones,8,9 and indeed poronitin B co-occurs
with the corresponding 4-pyrone.3 Therefore we aimed to install the key biaryl carbon-carbon
bond on the related 4-pyrone system and convert it into the pyridone at a late stage in the
synthesis (Scheme 1). The thiomethoxy group at the pyridone C-3 position could be installed by
displacement of the corresponding bromide, which can be obtained by treatment with a suitable

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electrophilic brominating agent. The pyridone 2 could be made from the pyrone 3, with the amide
being accessed from the corresponding primary alcohol 4. Disconnection of the pyrone-thiazole
bond gives the bromo-4-pyrone fragment 5 and thiazole-quinoline fragment 6 (M =
organometallic coupling partner) that is available by a classical Hantzsch thiazole synthesis.
Whilst these studies were in progress, a synthesis of lodopyridone using a related strategy was
reported by Koert et al.,10 together with an outline of a biomimetic strategy.11
O
O
X
OMe
N
OMe
N
H
H
N
N
HO
N
HO
O
Me
Cl
Cl
O
N
O
N
S
S
3
lodopyridone 1 (X = SMe)
2 (X = H)
O
O
O
Cl
OMe
N
OMe
N
HO
N
M
HO
Cl
O
Br
S
N
S
6
4
5
Scheme 1. Proposed retrosynthetic analysis for lodopyridone 1.
2. RESULTS AND DISCUSSION
The synthesis of the halo-pyrone fragment begins with the previously reported bromination of
commercially available kojic acid 7 (Scheme 2).12 Regioselective bromination of the pyrone at C-
6, was followed by selective protection of the primary alcohol under acidic conditions, and
methylation of the more acidic C-5 alcohol provided the bromopyrone 9 on multi-gram scale.

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O
O
O
1. DHP, p-TSA,
OH
X
OMe
THF, RT
HO
THPO
2. Me2SO4, DMF, RT
55% (2 steps)
O
Br
9
kojic acid 7 (X = H)
8 (X = Br)
Br2, NaH2PO4
aq H3PO4, 0-4 °C
45-55%
Scheme 2. Synthesis of bromopyrone fragment.
The thiazole-quinoline fragment was readily built up from 6-chloro-2-methylquinoline 10.
Oxidation of the methyl group with selenium(IV) oxide to the aldehyde, followed by Pinnick
oxidation to the carboxylic acid 11 was achieved in excellent overall yield, and conversion into
the amide via the acid chloride, followed by treatment with Lawesson’s reagent (LR) gave the
thioamide 12. Stirring thioamide 12 in neat methyl bromoacetate gave the thiazolone 13 in
quantitative yield. Attempts to convert thiazolone 13 into the corresponding triflate proceeded in
a disappointing 31% yield, a result subsequently noted by Koert et al. during their synthesis.10
Fortunately the corresponding nonaflate 14, could be synthesized in a greatly improved 61%
yield. Model studies on the bromopyrone 9 showed Stille coupling to be highly effective, but
when it came to test the transmetallation of the nonoflate 14, coupling with
bis(pinacolato)diboron proved to be more effective. A number of palladium based catalyst
systems were investigated and it was found that the (diphenylphosphino)ferrocene ligand was
highly effective for the metallation of nonaflate. Provided the potassium acetate base is
thoroughly dried, the nonaflate 14 undergoes smooth conversion into the pinacolboronic ester 15
which was coupled following partial purification. Gratifyingly the Suzuki-Miyaura coupling of
the bromopyrone 9 and the boronato 15 proceeded in excellent yield, and the structure of the
tetracycle 16 was confirmed unambiguously by X-ray crystallography (Figure 2).

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1. SeO2, 1,4-dioxane, reflux
2. NaClO2, tBuOH, H2O, RT
1) SOCl2, reflux
2) NH4OH (aq.), CH2Cl2
Cl
Cl
Cl
HO
H2N
Me
N
N
N
98% (2 steps)
3) LR, THF, reflux
49% (3 steps)
O
S
10
11
12
O
Br
MeO
RT, 99%
Cl
Cl
Cl
(BPin)2, KOAc
(dppf)PdCl2·CH2Cl2
NfF, NEt3
DME, RT
O
S
O
B
N
N
N
C4F9
N
N
O
N
O
1,4-dioxane, 80 °C
87%
O
61%
O
S
S
S
15
13
14
9, KOAc, (dppf)PdCl2·CH2Cl2
1,4-dioxane/H2O, 10:1, 80 °C
92%
O
OMe
N
THPO
O
Cl
N
S
16
Scheme 3. Synthesis of quinoline-thiazole-pyrone.

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Figure 2. X-ray crystal structure of quinoline-thiazole-pyrone 16.
With the key C-6 biaryl bond in place, the insertion of the amide side chain was the next task
(Scheme 4). Although the deprotection of the THP ether was trivial, the oxidation of the primary
alcohol to the carboxylic acid proved problematic, Jones oxidation, for example, being
unsuccessful. We suspect that poor solubility of the pyrone 17 and the presence of the basic
quinoline may have contributed to this failure. Fortunately the modified Corey-Ganem-Gilman
conditions developed by Taylor et al. allowed the amide side chain to be installed in a single
reaction,13 achieving both oxidation and amide coupling. It was necessary to use ethanol as a
solvent due to the inherent insolubility of the pyrone 17 but despite, this none of the
corresponding ethyl ester was observed. Furthermore, upon formation of the silyl protected
ethanolamide the solubility of the compound in organic solvents was greatly enhanced.

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Conversion of pyrone 18 into pyridone 19 also proved problematic; anhydrous ethanolic or THF
solutions of methylamine returned only the starting pyrone, whilst in the presence of water
competing transamination of the amide was observed, and the pyridone 19 was only isolated in a
dissapointing 27% yield. With the pyridone 19 in hand the next step was to introduce the
methanethiolate group at the pyridone C-3 position which we planned to achieve via the
displacement of the corresponding bromide. Bromination of the pyridone 19 required relatively
forcing conditions, necessitating more than 6 hours with pyridinium tribromide in pyridine at
reflux. This is in contrast to the related work that showed when the C-6 position is unsubstituted,
the pyridone underwent selective C-3 bromination at room temperature in the presence of N-
bromosuccinimide.10 Nevertheless displacement of the bromide occurred easily by heating with
sodium methanethiolate to give 20 as the sole product. No side reactions were observed and
copper(I) catalysts were necessary in contrast to the conditions described in the literature for a
related transformation.10 Finally, deprotection of the silyl protecting group by treatment with
hydrogen fluoride/pyridine complex in pyridine gave lodopyridone 1. Comparison of the NMR
data with those reported for the natural product by Fenical et al.4 confirmed the successful
completion of the synthesis.

ACCEPTED MANUSCRIPT
O
O
O
O
OMe
N
OMe
N
NH2
H
TBDPSO
, NaCN, MnO2
N
RO
TBDPSO
Cl
Cl
EtOH, reflux
O
N
N
S
S
92%
18
16 R = THP
17 R = H
HCl, MeOH
99%
MeNH2
THF/H2O 2:1, 4 °C
27%
O
O
1. PyH•Br3, pyridine, reflux
2. NaSMe, 1,4-dioxane, 90 °C
OMe
N
MeS
H
N
OMe
N
H
N
N
TBDPSO
RO
N
33% over 2 steps
Cl
Me
Me
Cl
N
O
O
S
N
S
20 R = TBDPS
1 R = H
HF•pyridine
pyridine, RT
99%
19
Scheme 4. Completion of the synthesis of lodopyridone.
We have successfully completed the second total synthesis of lodopyridone. We have developed
a Suzuki coupling strategy for the synthesis of the key pyrone-thiazole bond and demonstrated
that the corresponding pyrone can be converted into lodopyridone after the biaryl bond is formed.
Finally we have shown that the amide side chain can be installed in one step from the primary
alcohol, overcoming the inherent solubility problems associated with this compound.
3. EXPERIMENTAL SECTION
3.1 General information
Commercially available reagents were used throughout without purification unless otherwise
stated. All anhydrous solvents were used as supplied, except tetrahydrofuran and
dichloromethane that were freshly distilled according to standard procedures. Reactions were
routinely carried out under an argon atmosphere unless otherwise stated, and all glassware was

ACCEPTED MANUSCRIPT
flame-dried before use. Light petroleum refers to the fraction with bp 40-60 ºC. Ether refers to
diethyl ether.
Analytical thin layer chromatography was carried out on aluminum backed plates coated with
silica gel, and visualized under UV light at 254 and/or 360 nm and/or by chemical staining. Flash
chromatography was carried out using silica gel, with the eluent specified.
Infrared spectra were recorded using an FT-IR spectrometer over the range 4000-600 cm-1. NMR
spectra were recorded at 400 or 500 MHz (1H frequency, 100 or 125 MHz 13C frequency).
Chemical shifts are quoted in parts per million (ppm), and are referenced to residual H in the
deuterated solvent as the internal standard. Coupling constants, J, are quoted in Hz. In the 13C
NMR spectra, signals corresponding to CH, CH2, or CH3 groups are assigned from DEPT. Mass
spectra were recorded on a time-of-flight mass spectrometer using electrospray ionization (ESI),
or an EI magnetic sector instrument.
3.2 6-Bromo-5-hydroxy-2-hydroxymethyl-4H-pyran-4-one 8
A solution of bromine (2.25 mL, 43.91 mmol) and monobasic sodium phosphate (26.78 g, 0.22
mol) in water (74 mL) was added slowly to a stirred suspension of kojic acid 7 (5.25 g, 37.21
mmol) in orthophosphoric acid (27 mL) at 0 °C, the suspension was warmed to 4 ˚C and stirred
for 72 h. The suspension was filtered and the solid obtained was dried azeotropically with toluene
to give the title compound 8 as a colorless solid (4.36 g, 53%); mp 168-170 °C (lit.,12 mp 169-170
79
+
°C); (Found: [M+Na]+, 242.9269. C6H5 BrNaO4 requires 242.9269); νmax (CHCl3) 3043, 2927,
1602, 1240 cm-1; δH (400 MHz; DMSO-d6) 9.88 (1H, s), 6.37 (1H, br t, J 0.6), 5.74 (1H, t, J 6.2),
4.31 (2H, dd, J 6.2, 0.6); δc (100 MHz; DMSO-d6) 172.2 (C), 168.9 (C), 144.1 (C), 129.2 (C),
109.5 (CH), 59.2 (CH2).

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3.3 6-Bromo-5-hydroxy-2-[(tetrahydro-2H-pyran-2-yloxy)methyl]-4H-pyran-4-one
para-Toluenesulfonic acid (9 mg, 0.46 mmol) was added to a suspension of alcohol 8 (512 mg,
2.33 mmol) and 2,3-dihydropyran (0.41 mL, 4.49 mmol) in dichloromethane (22 mL) and the
mixture was stirred at room temperature for 2 h then concentrated in vacuo. The residue was
purified by chromatography on silica eluted with 75 - 100% ethyl acetate in light petroleum to
give the title compound as a pale yellow oil (703 mg, 99%); (Found: [M+Na]+, 326.9822.
+
C11H1379BrNaO5 requires 326.9844); νmax (CHCl3) 3632, 3410, 3009, 2946, 1640, 1017 cm-1; δH
(400 MHz; CDCl3) 7.01 (1H, br s), 6.54 (1H, s), 4.73 (1H, t, J 3.1), 4.55 (1H, d, J 14.8), 4.38
(1H, d, J 14.8), 3.83 (1H, td, J 9.1, 3.1), 3.28 - 3.63 (1H, m), 1.05 - 1.99 (6H, m); δC (100 MHz;
CDCl3) 172.3 (C), 166.7 (C), 144.3 (C), 128.0 (C), 110.0 (CH), 98.3 (CH), 64.1 (CH2), 62.0
(CH2), 30.0 (CH2), 25.1 (CH2), 18.7 (CH2).
3.4 6-Bromo-5-methoxy-2-[(tetrahydro-2H-pyran-2-yloxy)methyl]-4H-pyran-4-one 9
Potassium hydroxide (2.23 g, 39.74 mmol) was added in one portion to a stirred solution of the
above THP protected pyrone (6.03 g, 19.82 mmol) and iodomethane (2.47 mL, 39.68 mmol) in
dimethyl sulfoxide (20 mL), and the solution was stirred at room temperature for 10 h. The
mixture was diluted with water (100 mL) and dichloromethane (50 mL), the aqueous phase was
extracted with dichloromethane (5 × 20 mL) and the combined organic extracts washed with
water (15 mL), brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by
chromatography on silica, eluted with 50 - 100% ethyl acetate in light petroleum to give the title
+
compound 9 as a red oil (3.45 g, 55%); (Found: [M+Na]+, 340.9991. C12H1579BrNaO5 requires
341.0001; νmax (CHCl3) 3004, 2946, 1653, 1441, 1036 cm-1; δH (400 MHz; CDCl3) 6.48 (1H, t, J

ACCEPTED MANUSCRIPT
0.7), 4.73 (1H, t, J 3.1), 4.52 (1H, dd, J 14.7, 0.7), 4.34 (1H, dd, J 14.7 0.7), 3.91 (3H, s), 3.73 -
4.05 (1H, m), 3.27 - 3.62 (1H, m), 1.42 - 1.89 (6H, m); δC (100 MHz; CDCl3) 173.9 (C), 165.0
(C), 146.2 (C), 139.3 (C), 113.7 (CH), 98.0 (CH), 63.5 (CH2), 61.7 (CH2), 59.8 (CH3), 29.7
(CH2), 24.8 (CH2), 18.4 (CH2).
3.5 6-Chloroquinoline-2-carbaldehyde
6-Chloro-2-methylquinoline (2.00 g, 11.26 mmol) was added to a suspension of selenium(IV)
oxide (7.50 g, 67.56 mmol) in 1,4-dioxane (113 mL) in one portion at 50 °C, and the stirred
suspension was heated to reflux for 1.5 h. The mixture was filtered hot through Celite and
concentrated in vacuo. The residue was suspended in ethyl acetate (40 mL) with sonication, and
the selenium impurities precipitated by addition of light petroleum (30 mL). The suspension was
filtered through a short pad of silica, washed with 30% ethyl acetate in light petroleum and
concentrated in vacuo to give the title compound as a yellow solid (2.11 g, 98 %); mp 135-136 °C
35
(lit.,14 mp 140 °C); (Found: [M+Na+], 214.0034. C10H6 ClNNaO+ requires 214.0036); νmax
(CHCl3) 2989, 1713, 1458, 1185 cm-1; δH (400 MHz; CDCl3) 10.24 (1H, d, J 0.7), 8.26 (1H, d, J
8.5), 8.22 (1H, dt, J 9.0, 0.7,), 8.08 (1H, d, J 8.5), 7.93 (1H, d, J 2.3), 7.79 (1H, dd, J 9.0, 2.3); δC
(100 MHz; CDCl3) 193.3 (CH), 152.7 (C), 146.3 (C), 136.5 (CH), 135.3 (C), 132.0 (CH), 131.6
(CH), 130.6 (C), 126.6 (CH), 118.3 (CH).
3.6 6-Chloroquinoline-2-carboxylic acid 11
A solution of monobasic sodium phosphate (3.87 g, 32.22 mmol) and sodium chlorite (3.87 g,
42.76 mmol) in water (39 mL) was added slowly to a solution of 6-chloroquinoline-2-
carbaldehyde (852 mg, 4.45 mmol) in tert-butanol (89 mL). The solution was stirred at room

ACCEPTED MANUSCRIPT
temperature for 2 h, concentrated in vacuo, diluted with water (68 mL) and ethyl acetate (50 mL),
then acidified to pH 4. The precipitate was collected by filtration to give a colorless solid (870
mg, 95 %). The aqueous layer was extracted with ethyl acetate (5 × 15 mL) and the combined
organic extracts washed with brine (2 × 15 mL), dried (Na2SO4) and concentrated in vacuo to
give more colourless solid (80 mg, 7%) giving the title compound (>99% combined yield); mp
35
+
234-236 °C (lit.,15 mp 227-228 °C); (Found: [M+Na+], 229.9996. C10H6 ClNNaO2 requires
229.9985); νmax (CHCl3) 3691, 3002, 1769, 1602, 1334 cm-1; δH (300 MHz; DMSO-d6) 8.53 (1H,
d, J 8.5, CH), 8.25 (1H, d, J 2.4, CH), 8.18 (1H, d, J 9.0, CH), 8.15 (1H, d, J 8.5, CH) 7.87 (1H,
dd, J 9.0, 2.4, CH); δC (75 MHz; DMSO-d6) 166.1 (C), 149.3 (C), 145.2 (C), 137.0 (CH), 132.9
(C), 131.8 (CH), 130.1 (CH), 129.5 (C), 126.7 (CH), 121.7 (CH).
3.7 6-Chloroquinoline-2-carboxamide
A suspension of 6-chloroquinoline-2-carboxylic acid 11 (1.00 g, 4.82 mmol) in thionyl chloride
(10 mL) was heated to reflux for 40 min. The reaction mixture was concentrated in vacuo, and
the residue dissolved in dichloromethane (48 mL) and cooled to 0 °C. Ammonium chloride (1.29
g, 24.08 mmol) was added, followed by dropwise addition of triethylamine (6.70 mL, 48.15
mmol) and the reaction mixture stirred for 15 min at 0 °C. Aqueous sodium hydroxide solution (2
M; 30 mL) was added and the suspension filtered to give an orange solid. The organic phase was
washed with sodium hydroxide (2 M; 2 × 30 mL), brine (14 mL), dried (Na2SO4) and
concentrated in vacuo before purification by chromatography on silica, eluting with 50 - 100 %
ethyl acetate in light petrol to give the title compound as a colorless solid (730 mg, 73 %); mp
35
228-230 °C; (Found: [M+Na+], 229.0142. C10H7 ClN2NaO requires 229.0145); νmax (CHCl3)
3517, 3394, 3011, 1692, 1562 cm-1; δH (400 MHz; CDCl3) 8.36 (1H, d, J 8.5), 8.27 (1H, d, J 8.5),

ACCEPTED MANUSCRIPT
8.09 (1H, d, J 9.0), 8.05 (1H, br s), 7.91 (1H, d, J 2.3), 7.74 (1H, dd, J 9.0, 2.3), 5.63 (1H, br s);
δC (100 MHz; CDCl3) 166.4 (C), 149.6 (C), 145.0 (C), 136.7 (CH), 134.1 (C), 131.4 (CH), 131.3
(CH), 130.0 (C), 126.5 (CH), 119.8 (CH); m/z (ESI) 231/229 (M+Na+, 29/90%)
3.8 6-Chloroquinoline-2-thiocarboxamide 12
Lawesson’s reagent (2.43 g, 5.98 mmol) was added to a stirred solution of 6-chloroquinoline-2-
carboxamide (336 mg, 1.77 mmol) in tetrahydrofuran (35 mL) and the mixture was then heated to
reflux for 2.5 h. After concentration in vacuo, the residue was purified by chromatography on
silica, eluting with 30 - 100 % dichloromethane in light petroleum to give the title compound as a
yellow solid (258 mg, 67 %); mp 170-172 °C; (Found: C, 53.93; H, 3.17; N, 12.32. C10H7ClN2S
35
requires C, 53.93; H, 3.17; N, 12.58); (Found: [M+H+], 223.0102. C10H8 ClN2S requires
223.0097); νmax (CHCl3) 3482, 3335, 2993, 1576, 1492, 1305, 836 cm-1; δH (400 MHz; CDCl3)
9.71 (1H, br s), 8.89 (1H, d, J 8.7), 8.24 (1H, d, J 8.7, CH), 8.10 (1H, d, J 9.0, CH), 7.90 (1H, d, J
2.1), 7.74 (1H, dd, J 9.0, 2.3), 7.72 (1H, br s); δC (100 MHz; CDCl3) 195.6 (C), 149.7 (C), 143.9
(C), 135.9 (CH), 134.2 (C), 131.5 (CH), 131.4 (CH), 129.6 (C), 126.4 (CH), 122.2 (CH).
3.9 2-(6-Chloroquinolin-2-yl)thiazol-4-ol 13
A suspension of 6-chloroquinoline-2-thiocarboxamide 12 (1.16 g, 5.22 mmol) in methyl
bromoacetate (60 mL) was stirred at room temperature for 1 h. The mixture was diluted with
dichloromethane (150 mL), the suspension filtered and the solid washed with dichloromethane (3
× 50 mL) to give the title compound 13 as a yellow solid (1.35 g, 99%); mp 137-129 °C; (Found
35
[M+H+], 263.0039. C12H7 ClN2OS+ requires 263.0041); νmax (ATR) 2870, 1717, 1602, 1310 cm-
1; δH (300 MHz; DMSO-d6) 8.48 (1H, d, J 8.5), 8.20 (1H, d, J 8.5), 8.19 (1H, d, J 2.5), 8.04 (1H,

ACCEPTED MANUSCRIPT
d, J 9.0), 7.81 (1H, dd, J 9.0, 2.5), 6.49 (1H, s); δC (75 MHz; DMSO-d6) 163.3 (C), 163.1 (C),
150.9 (C), 145.5 (C), 137.1 (CH), 131.4 (C), 131.0 (CH), 130.7 (CH), 128.9 (C), 126.9 (CH),
118.0 (CH), 94.3 (CH).
3.10 Nonofluorobutanesulfonyl 2-(6-chloroquinolin-2-yl)thiazol-4-ol 14
Triethylamine (0.86 mL, 6.26 mmol) and nonofluorobutanesulfonyl fluoride (1.3 mL, 7.24
mmol) was added to a suspension of 2-(6-chloroquinolin-2-yl)thiazol-4-ol 13 (1.26 g, 4.81 mmol)
in 1,2-dimethoxyethane (48 mL) and the mixture stirred for 2 h at room temperature under an
argon atmosphere. Additional triethylamine (0.86 mL, 6.26) and nonofluorobutanesulfonyl
fluoride (1.3 mL, 7.24 mmol) were added and the mixture stirred for a further 10 h. The mixture
was concentrated in vacuo and the residue purified by chromatography on silica, eluting with 5 -
10% ethyl acetate in light petroleum to give 14 as a pale yellow solid (1.59 g, 61%); mp 132-134
°C; νmax (CHCl3) 3130, 3001, 1491, 1242, 1146, 982 cm-1; δH (300 MHz; CDCl3) 8.27 (1H, d, J
8.6), 8.19 (1H, d, J 8.6), 8.07 (1H, d, J 9.0), 7.85 (1H, d, J 2.3), 7.70 (1H, dd, J 9.0, 2.3), 7.26
(1H, s); δC (75 MHz; CDCl3) 167.0 (C), 151.0 (C), 149.7 (C), 145.9 (C), 136.5 (CH), 133.6 (C),
131.4 (CH), 131.0 (CH), 129.5 (C), 126.5 (CH), 118.2 (CH), 109.7 (CH); nonaflate carbons not
observed; δF (282 MHz; CDCl3) –80.6 (3F, tt, J 9.9, 2.2, CF3), –108.3 (2F, ttq, J 13.6, 4.5, 2.4,
CF2), –120.8 (2F, m, CF2), –125.7 (2F, m, CF2); m/z (MALDI) 545 (M+H+, 100%)
3.11 6-[2-(6-Chloroquinolin-2-yl)thiazol-4-yl]-5-methoxy-2-[(tetrahydro-2H-pyran-2-
yloxy)methyl]-4H-pyran-4-one 16
(a) Potassium acetate (361 mg, 3.68 mmol) and bis(diphenylphosphino)ferrocenepalladium
dichloride dichloromethane adduct (75 mg, 92 µmol) were added to a degassed solution of

ACCEPTED MANUSCRIPT
Nonofluorobutanesulfonyl 2-(6-chloroquinolin-2-yl)thiazol-4-ol 14 (1.00 g, 1.84 mmol) and
bis(pinacolato)diboron (514 mg, 2.02 mmol) in 1,4-dioxane (18 mL) and the mixture degassed
with argon and sonication for a second time before heating to 80 °C for 4 h. The mixture was
concentrated in vacuo before purification by chromatography on silica, eluting with 50% ethyl
acetate in light petroleum to give a ca. 1:1 mixture of the 2-(6-chloroquinolin-2-yl)-4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole 15 and pinacol (770 mg total) as a yellow residue
(600 mg, 87%) that was used without further purification; δH (300 MHz; CDCl3) 8.53 (1H, d, J
8.6), 8.14 (1H, s), 8.14 (1H, d, J 8.6), 8.06 (1H, d, J 8.9), 7.81 (1H, d, J 2.4), 7.66 (1H, dd, J 8.9,
2.2), 1.41 (12H, s); δC (75 MHz; CDCl3) 170.2 (C), 151.6 (C), 146.1 (C), 135.7 (CH), 134.6
(CH), 132.7 (C), 131.0 (CH), 130.8 (CH), 129.2 (C), 126.4 (CH), 119.6 (CH), 84.5 (CH), 24.9
(CH3); one carbon unobserved;
(b) Potassium acetate (376 mg, 3.83 mmol) and bis(diphenylphosphino)ferrocenepalladium
dichloride dichloromethane adduct (52 mg, 64 µmol) was added to a degassed solution of 2-(6-
chloroquinolin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole 15 (475 mg, 1.28
mmol) and bromopyrone 9 (1.97 mg, 6.20 mmol) in 1,4-dioxane (13 mL) and the mixture
degassed with argon and sonication for a second time before heating to 80 °C for 3 h. The
mixture was concentrated in vacuo and purified by chromatography on silica, eluting with 50%
ethyl acetate in light petroleum to give the title compound 17 as a pale yellow solid (571 mg,
92%); mp 159-161 °C; (Found: [M+H+], 485.0941. C24H2235ClN2O5S+ requires 485.0933); νmax
(CHCl3) 3007, 2947, 1652, 1620, 1413, 1389 cm-1; δH (300 MHz; CDCl3) 8.40 (1H, d, J 8.7),
8.32 (1H, s), 8.20 (1H, d, J 8.6), 8.08 (1H, d, J 9.0), 7.84 (1H, d, J 2.3), 7.69 (1H, dd, J 9.0, 2.3),
6.60 (1H, t, J 0.8), 4.85 (1H, t, J 3.4), 4.71 (1H, dd, J 14.8, 0.8), 4.54 (1H, dd, J 14.8, 0.8), 4.05
(3H, s), 3.82-3.96 (1H, m), 3.56-3.67 (1H, m), 1.48-1.94 (6H, m); δC (75 MHz; CDCl3) 176.2

ACCEPTED MANUSCRIPT
(C), 168.9 (C), 164.0 (C), 150.8 (C), 150.4 (C), 146.2 (C), 146.1 (C), 144.9 (C), 136.2 (CH),
133.2 (C), 131.1 (CH), 131.1 (CH), 129.3 (C), 126.4 (CH), 126.1 (CH), 118.6 (CH), 113.5 (CH),
98.2 (CH), 64.1 (CH2), 61.9 (CH2), 59.8 (CH3), 30.1 (CH2), 25.2 (CH2), 18.7 (CH2); m/z (ESI)
487/485 (M+H+, 37/100%), 509/507 (M+Na+, 12/33%).
3.12 2-(2-(6-Chloroquinolin-2-yl)thiazol-4-yl)-6-(hydroxymethyl)-3-methoxy-4H-pyran-4-
one 17
Methanolic hydrogen chloride (2 M; 20 mL, 40 mmol) was added to a suspension of 6-[2-(6-
chloroquinolin-2-yl)thiazol-4-yl]-5-methoxy-2-[(tetrahydro-2H-pyran-2-yloxy)methyl]-4H-
pyran-4-one 16 (296 mg, 611 µmol) and the mixture stirred at room temperature for 40 min under
an argon atmosphere. The mixture was concentrated in vacuo, and the residue triturated with
methanol and the suspension filtered to give the title compound 17 as a pale yellow solid (245
mg, 99%) which was used without further purification; mp 137-139 °C; δH (300 MHz; CDCl3)
8.58 (1H, s), 8.58 (1H, d, J 8.6), 8.37 (1H, d, J 8.6), 8.24 (1H, d, J 2.4), 8.12 (1H, d, J 9.2), 7.86
(1H, dd, J 9.1, 2.4), 6.44 (1H, s), 4.45 (2H, s), 3.94 (3H, s); δC (75 MHz; CDCl3) 175.2 (C), 168.1
(C), 167.8 (C), 150.5 (C), 149.7 (C), 145.7 (C), 145.6 (C), 144.2 (C), 137.5 (CH), 132.1 (C),
131.3 (CH), 130.9 (CH), 129.3 (C), 127.3 (CH), 127.0 (CH), 118.4 (CH), 111.9 (CH), 59.6
(CH2), 59.5 (CH3).
3.13 N-[2-(tert-Butyldiphenylsiloxy)ethyl]-6-[2-(6-chloroquinolin-2-yl)thiazol-4-yl]-5-
methoxy-4-oxo-4H-pyran-2-carboxamide 18
Sodium cyanide (25 mg, 500 µmol) and manganese(IV) oxide (326 mg, 3.75 mmol) were added
to a stirred suspension of 2-(2-(6-chloroquinolin-2-yl)thiazol-4-yl)-6-(hydroxymethyl)-3-

ACCEPTED MANUSCRIPT
methoxy-4H-pyran-4-one 17 (100 mg, 250 µmol) and tert-butyldiphenylsiloxyethanamine (374
mg, 1.25 mmol) in ethanol (8 mL) and the mixture stirred and heated to reflux for 1 h under an
argon atmosphere. The mixture was concentrated in vacuo, triturated with 30% ethyl acetate in
light petroleum and the solid filtered to give 18 an orange solid (109 mg, 64%). The filtrate was
concentrated in vacuo and purified by chromatography on silica, eluting with 2% methanol in
dichloromethane to give the title compound as an orange oil (48 mg, 28%, total yield 92%). On a
120 mg scale (300 µmol) the yield reduced to 50%; (Found: [M+H+], 696.1754.
C36H32ClN3O5SSi+ requires 696.1750); νmax (CHCl3) 3014, 2934, 2860, 1689, 1650, 1472, 1320
cm-1; δH (300 MHz; CDCl3) 8.39 (1H, s), 8.20 (1H, d, J 8.4), 8.07 (1H, d, J 9.0), 7.85 (1H, d, J
8.4), 7.78 (1H, d, J 2.3), 7.71 (1H, dd, J 9.0, 2.3), 7.57-7.63 (4H, m), 7.39-7.48 (1H, m), 7.24-
7.39 (6H, m), 4.13 (3H, s), 3.96 (2H, t, J 5.4), 3.72 (2H, q, J 5.4), 0.97 (9H, s); δC (75 MHz;
CDCl3) 175.9 (C), 172.2 (C), 169.3 (C), 158.7 (C), 153.4 (C), 150.4 (C), 146.1 (C), 136.2 (CH),
135.5 (C), 135.3 (CH), 133.3 (C), 133.2 (C), 131.2 (CH), 131.0 (CH), 129.8 (CH), 129.2 (C),
127.8 (C), 127.8 (CH), 126.9 (CH), 126.4 (CH), 118.4 (CH), 116.4 (CH), 62.6 (CH2), 59.8 (CH3),
42.2 (CH2), 26.8 (CH3), 19.2 (C).
3.14 N-[2-(tert-Butyldiphenylsilyloxy)ethyl]-6-[2-(6-chloroquinolin-2-yl)thiazol-4-yl]-5-
methoxy-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxamide 19
Aqueous methylamine (25-30%, 1 mL, 5.63-6.76 mmol) was added to a stirred solution of N-[2-
(tert-butyldiphenylsilyloxy)ethyl]-6-[2-(6-chloroquinolin-2-yl)thiazol-4-yl]-5-methoxy-4-oxo-
4H-pyran-2-carboxamide 18 (32 mg, 47 µmol) in THF (2 mL) at 0 °C and the mixture warmed
slowly to 4 °C and stirred for 8 h under an argon atmosphere. The mixture was concentrated in
vacuo and purified by chromatography on silica, eluting with 3-5% methanol in dichloromethane

ACCEPTED MANUSCRIPT
to give the title compound 19 as a yellow oil (9 mg, 27%); (Found: [M+H+], 709.2067.
C38H3935ClN4O4SSi+ requires 709.2080); νmax (CHCl3) 3011, 2932, 2859, 1678, 1610, 1472 cm-1;
δH (300 MHz; CDCl3) 8.28 (1H, d, J 8.7), 8.18 (1H, d, J 8.7), 8.08 (1H, d, J 9.1), 7.83 (1H, d, J
2.3), 7.75 (1H, s), 7.69 (1H, dd, J 9.1, 2.3), 7.65-7.69 (4H, m), 7.34-7.48 (6H, m,), 6.61 (1H, s),
3.89 (2H, t, J 5.2), 3.74 (3H, s), 3.60 (2H, q, J 5.2), 3.48 (3H, s), 1.08 (9H, s); δC (75 MHz;
CDCl3) 173.6 (C), 169.3 (C), 163.5 (C), 150.7 (C), 149.0 (C), 146.0 (C), 145.9 (C), 145.3 (C),
138.9 (C), 136.2 (CH), 135.5 (CH), 133.2 (C), 131.2 (CH), 130.9 (CH), 129.8 (CH), 129.2 (C),
127.8 (CH), 127.5 (CH), 126.4 (CH), 125.5 (CH), 118.5 (CH), 117.3 (CH), 62.3 (CH2), 59.9
(CH3), 42.3 (CH2), 39.6 (CH3), 26.8 (CH3), 19.2 (C); m/z (ESI) 711/709 (M+H+, 52/100%).
3.15 3-Bromo-N-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-6-(2-(6-chloroquinolin-2-yl)thiazol-4-
yl)-5-methoxy-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxamide
A stirred solution of N-[2-(tert-butyldiphenylsilyloxy)ethyl]-6-[2-(6-chloroquinolin-2-yl)thiazol-
4-yl]-5-methoxy-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxamide 19 (3 mg, 4 µmol) and
pyridinium tribromide (26 mg, 146 µmol) in pyridine (3 mL) was heated to reflux for 3 h. The
mixture was concentrated in vacuo and purified by chromatography on silica eluting with 4%
methanol in dichloromethane to give the title compound as an orange residue (3 mg, 99%);
(Found: [M+H+], 787.1179. C38H3779Br35ClN4O4SSi+ requires 787.1172); νmax (CHCl3) 3008,
2960, 1673, 1592, 1489, 1144 cm-1; δH (400 MHz; CDCl3) 8.62 (1H, br s), 8.28 (1H, d, J 8.6),
8.18 (1H, d, J 8.6), 8.10 (1H, d, J 9.1), 7.85 (1H, d, J 2.1), 7.73 (2H, dd, J 9.1), 7.67-7.70 (4H,
m), 7.34-7.44 (6H, m), 3.96 (2H, t, J 4.9), 3.70 (3H, s), 3.65-3.69 (2H, m), 3.96 (3H, br s); 1.07
(1H, s); δC (75 MHz; CDCl3) 169.3 (C), 161.9 (C), 150.7 (C), 149.1 (C), 147.0, (C), 146.1 (C),
145.2 (C), 144.7 (C), 141.0 (C), 136.4 (CH), 135.5 (CH), 134.8 (CH), 133.4 (C), 133.2 (C), 131.3

ACCEPTED MANUSCRIPT
(CH), 131.0 (CH), 129.9 (CH), 129.6 (C), 129.3 (C), 127.9 (CH), 126.5 (CH), 118.5 (CH), 62.0
(CH2), 60.0 (CH3), 42.3 (CH2), 40.4 (CH3), 26.9 (CH3), 19.2 (C); m/z (ESI)
787/788/789/790/791/792 (M+H+, 29/13/39/20/16/7%).
3.16 N-(2-((tert-Butyldiphenylsiloxy)ethyl)-6-(2-(6-chloroquinolin-2-yl)thiazol-4-yl)-5-
methoxy-1-methyl-3-(methylthio)-4-oxo-1,4-dihydropyridine-2-carboxamide 20
Sodium thiomethoxide (3 mg, 43 µmol) was added to a stirred suspension of 3-bromo-N-(2-
((tert-butyldiphenylsiloxy)ethyl)-6-(2-(6-chloroquinolin-2-yl)thiazol-4-yl)-5-methoxy-1-methyl-
4-oxo-1,4-dihydropyridine-2-carboxamide (3 mg, 4 µmol) in 1,4-dioxane (3 mL) and the mixture
heated to 90 °C for 3 h. The mixture was concentrated in vacuo and partitioned between
dichloromethane (5 mL) and water (3 mL), the aqueous phase was extracted with
dichloromethane (3 × 5 mL) and the combined organic extracts washed with brine (3 mL), dried
(Na2SO4), concentrated in vacuo and purified by chromatography on silica, eluting with
dichloromethane-10% methanol in dichloromethane to give the title compound 20 as a yellow
residue (1 mg, 33%); (Found: [M+H+], 755.1922. C39H4035ClN4O4S2Si+ requires 755.1944); νmax
(CHCl3) 3002, 2956, 1661, 1592, 1262 cm-1; δH (300 MHz; CDCl3) 8.30 (1H, d, J 8.6), 8.19 (1H,
d, J 8.6), 8.11 (1H, d, J 9.1), 7.85 (1H, d, J 2.3), 7.81 (1H, s), 7.72 (1H, dd, J 9.1, 2.3), 7.65-7.70
(4H, m), 7.35-7.46 (6H, m), 3.96 (2H, t, J, 5.2), 3.75 (3H, s), 3.65 (2H, t, J 5.2), 3.46 (3H, s),
2.35 (3H, s), 1.08 (9H, s); δC (126 MHz; CDCl3) 171.2 (C), 169.4 (C), 162.5 (C), 150.8 (C),
148.3 (C), 147.7 (C), 146.2 (C), 145.3 (C), 137.4 (C), 136.3 (CH), 135.5 (CH), 133.4 (CH), 133.1
(C), 131.3 (CH), 131.1 (CH), 130.0 (C), 129.3 (C), 127.9 (CH), 126.5 (CH), 125.8 (CH), 121.8
(C), 118.5 (CH), 62.1 (CH2), 60.0 (CH3), 42.3 (CH2), 39.6 (CH3), 26.9 (CH3), 19.2 (C), 17.3
(CH3); m/z (ESI) 755/757 (M+H+, 42/25%). Data consistent with the literature.10

ACCEPTED MANUSCRIPT
3.17 Lodopyridone 1
A solution of hydrogen fluoride pyridine complex in pyridine (30%, 0.1 mL, 1.50 mmol) was
added to a stirred solution of N-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-6-(2-(6-chloroquinolin-2-
yl)thiazol-4-yl)-5-methoxy-1-methyl-3-(methylthio)-4-oxo-1,4-dihydropyridine-2-carboxamide
20 (2 mg, 3 µmol) in pyridine (2 mL) and the mixture stirred for 2 h at room temperature. The
mixture was quenched with saturated aqueous potassium carbonate solution (3 mL), concentrated
in vacuo partitioned between dichloromethane (5 mL) and water (3 mL). The aqueous phase was
extracted with dichloromethane (3 × 3 mL) and the combined organic extracts washed with brine,
dried (Na2SO4), concentrated in vacuo and purified by chromatography on silica, eluting with 3-
5% methanol in dichloromethane to give lodopyridone (1) as a colorless gum (1 mg, 99%); νmax
(CHCl3) 3073, 2958, 2929, 2857, 1661, 1592, 1488, 1280, cm-1; δH (500 MHz; CDCl3) 8.63 (1H,
br s) 8.24 (1H, d, J 8.6, CH) 8.11 (1H, d, J 8.6) 8.03 (1H, d, J 9.1) 7.79 (1H, s) 7.78 (1H, d, J 2.2)
7.69 (1H, dd, J 9.0, 2.4) 3.99 (2H, br s) 3.77 (3H, s) 3.72 (2H, br s) 3.57 (3H, s) 2.36 (3H, s); δC
(126 MHz; CDCl3) 172.3 (C), 169.5 (C), 162.5 (C), 150.7 (C), 149.8 (C), 147.6 (C), 146.1 (C),
144.9 (C), 138.6 (C), 136.3 (CH), 133.4 (C), 131.3 (CH), 131.0 (CH), 129.2 (C), 126.4 (CH),
125.8 (CH), 122.0 (C), 118.5 (CH), 61.4 (CH2), 60.4 (CH3), 43.2 (CH2), 40.0 (CH3), 18.0 (CH3);
δH (500 MHz; DMSO-d6) 8.95 (1H, t, J 5.7) 8.55 (1H, d, J 8.5) 8.33 (1H, d, J 8.5) 8.27 (1H, s)
8.25 (1H, d, J 2.4) 8.13 (1H, d, J 9.0) 7.87 (1H, dd, J 9.0, 2.4) 4.73 (1H, t, J 5.0), 3.67 (3H, s)
3.54 (2H, br s) 3.36 (3H, s) 2.29 (3H, s); δC (126 MHz; DMSO-d6) 170.9 (C), 168.5 (C), 161.9
(C), 150.6 (C), 149.1 (C), 147.0 (C), 145.6 (C), 145.2 (C), 137.5 (CH), 136.9 (CH), 132.0 (C),
131.3 (CH), 130.9 (CH), 129.2 (C), 127.0 (CH), 126.4 (CH), 119.9 (C), 118.4 (C), 59.3 (CH3),
59.2 (CH2), 41.7 (CH2), 38.9 (CH3), 16.2 (CH3). Data consistent with the literature.4

ACCEPTED MANUSCRIPT
ACKNOWLEDGEMENTS
We thank the EPSRC for a studentship to I.G.
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