Photochemical synthesis of benz[h]isoquinolines

Article abstract of DOI:10.1016/j.tet.2008.03.066

The synthesis of benz[h]isoquinolines has been achieved using a highly convergent photochemical method. The approach presented provides ready access to biologically active compounds and building blocks not readily available through other methods.

Full text of DOI:10.1016/j.tet.2008.03.066

Tetrahedron 64 (2008) 5072–5078
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Photochemical synthesis of benz[h]isoquinolines
,
Belinda M. Abbott a, Frank D. Ferrari b, Suzannah J. Harnor c, John C. Barnes b, Rodolfo Marquez c
*
a Department of Chemistry, La Trobe University, Melbourne 3086, Australia
b Division of Biological Chemistry and Molecular Microbiology, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom
c WestChem, Department of Chemistry, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of benz[h]isoquinolines has been achieved using a highly convergent photochemical
method. The approach presented provides ready access to biologically active compounds and building
blocks not readily available through other methods.
Received 18 December 2007
Received in revised form 5 March 2008
Accepted 19 March 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Available online 22 March 2008
Keywords:
Benz[h]isoquinoline
Photochemistry
Cyclisation
1. Introduction
An alternative and interesting method was proposed by
Oppolzer, in which the benz[h]isoquinoline framework is accessed
In the last few years a significant amount of work has been
reported on the synthesis of 5-HT3 receptor antagonists as a way to
control and down-regulate cancer chemotherapy-induced emesis.
5-HT3 receptor antagonists have also been shown to be highly
effective in the treatment of animal models of schizophrenia and
anxiety.1
Benz[h]isoquinolines have recently been identified as a new
class of potent 5-HT3 receptor antagonists. As such, a significant
amount of work has been invested in the synthesis of novel
benz[h]isoquinolines as potential new frameworks for drug design
and biological chemistry.2–4
through a thermal 4p electron disrotatory ring opening followed by
a 6p electron conrotatory electrocyclisation.7
Unfortunately, the approaches developed thus far are not easily
amenable for the efficient generation of highly functionalised
benz[h]isoquinoline derivatives without significant synthetic effort.
We would now like to report our convergent method for the
synthesis of polyfunctionalised benz[h]isoquinolines and related
tricyclic derivatives.
2. Results and discussion
The most commonly used approach for the synthesis of benz[h]-
isoquinolines utilises the process developed by Eloy and Deryckere,
in which the pyridone core is generated through the Curtius rear-
rangement of the corresponding a,b-unsaturated cinnamoyl azide
(or the equivalent a,b,g,d-dienoyl azide) followed by the thermally
induced cyclisation of the isocyanate intermediate.5
A different route was reported by Koelsch and Lindquist in which
benz[c]phthalic anhydride is converted to the N-substituted imide.6
A base promoted rearrangement then converts the newly generated
ethyl benz[c]phthalimidoacetate into the corresponding 3-carb-
ethoxy-1,4-dihydroxybenz[f]isoquinoline, which is saponified and
decarboxylated to generate the desired benz[h]isoquinoline.6
In our initial approach, it was envisioned that the benz[h]iso-
quinoline core unit 1 could originate from the photocyclisation of
the bis-aromatic enol 2. Analogous photocyclisations have been
used in the synthesis of quinolines, isoquinolines and benzo-
quinolines.8,2b
The bis-aromatic enol 2, in turn, could then be easily accessed
through the condensation of the pyridine anion 3 with the aromatic
ester 4 (Scheme 1).
Our synthesis began with 2-fluoro-4-methylpyridine 5, which
was deprotonated and the resulting anion was trapped with methyl
4-(trifluoromethyl)benzoate to generate the desired bis-aromatic
ketone 6 in good yield (Scheme 2). Acid hydrolysis of the 2-fluo-
ropyridine unit then afforded the desired pyridone 7 in high yield.
At this point, we hoped to be able to take advantage of the keto–
enol equilibrium to generate the corresponding conjugated enol of
ketone 7, which was expected to cyclise to generate benz[h]iso-
quinoline 8.
* Corresponding author. Tel.: þ44 (0)141 330 5953; fax: þ44 (0)141 330 4888.
E-mail address: r.marquez@chem.gla.ac.uk (R. Marquez).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.066

B.M. Abbott et al. / Tetrahedron 64 (2008) 5072–5078
5073
CHO
CHO
R
R
R
SeO2
TBSCl, TEA
O
OH
OH
Dioxane
52%
CH2Cl2
78%
N
10
OH
N
9
OH
N
11
OTBS
O
O
O
HN
HN
HN
1
2
2A
CO2Me
CO2Me
PhCH2CO2Me
+
O
NaH
35%
NH
HN
R
O
F
13
12
Scheme 3.
N
CO2R
3
4
Scheme 1.
P(OEt)3
neat
CO2Me
CO2Me
O
N
PO(OEt)2
Br
AcOH
89%
(i) NaHMDS, THF, 0 °C
(ii) 4-CF3PhCO2Me
79%
F
14
15
F3C
N
5
F
NaH, 11
CO2Me
CO2Me
6
+
THF
56%
over 3
steps
O
O
HO
F3C
O
HN
NH
OH
hv
E : Z
O
55:45
13
NH
NH
12
Scheme 4.
O
O
F3C
F3C
HN
7
7A
8
Scheme 2.
of the two isomers was corroborated by X-ray crystallography (Figs.
1 and 2).10
Unfortunately, the desired photocyclisation failed to take place
even when acid or base catalysed isomerisation was attempted. We
believe that the failure to obtain any of the desired benz[h]isoqui-
nolines is likely due to lack of ketone enolisation, which then
prevents the photocyclisation from taking place.
Having obtained the desired acyclic precursor, the photochem-
ical cyclisation studies were then undertaken. This included the use
of different solvents (including acetonitrile, benzene, dichloro-
methane, diethyl ether and tetrahydrofuran) and different wave-
lengths (254, 350 and 420 nm).
Therefore it was decided to generate and isolate the corre-
sponding enol ether, which, it was believed, would be more likely to
undergo a successful photocyclisation.
However, despite extensive experimentation, it was not possible
to control the regiochemistry of enolisation. All attempts at con-
verting keto pyridone 7 into the desired enol ether were un-
successful, with various ratios of pyridone protection (both O and N
protections) observed. Photocyclisation of the pyridone protected
product was attempted without success.
After considerable experimentation, the mixture of E and Z
conjugated esters 12 and 13 was successfully cyclised to the desired
benz[h]isoquinoline 16 when exposed to a 254 nm light source in
tetrahydrofuran (Scheme 5).11 Only a small amount of photo-
cyclisation was observed at the longer wavelengths.
Treatment of the pure Z isomer 13 under the same photo-
chemical conditions cleanly isomerised the internal double bond
This prompted us to re-consider our cyclisation strategy and to
generate a cyclisation precursor in which the enol unit was
replaced by a more stable alkene unit.
Our revised synthesis began with 2-hydroxy-4-methylpyridine
9, which was selectively oxidised under Ren’s conditions (Scheme
3).9 An Aldol type condensation of the protected aldehyde 11 with
methyl phenylacetate then proceeded to generate the E and Z
conjugated esters 12 and 13 in moderate yield. The TBS group was
cleanly cleaved under the reaction conditions.
In an attempt to improve the yield of this coupling, a Horner–
Wadsworth–Emmons approach was then attempted. Hence, com-
mercially available methyl bromo(phenyl)acetate 14 was subjected
to an Arbuzov reaction with triethylphosphite to generate the
desired phosphonate 15 (Scheme 4).
Gratifyingly, the Horner–Wadsworth–Emmons olefination of
carbaldehyde 11 with phosphonate 15 proceeded to generate the
desired E and Z conjugated esters 12 and 13 as a 55:45 mixture in
good overall yield over the three steps. The double bond geometry
Figure 1. Crystal structure of E isomer 12.

5074
B.M. Abbott et al. / Tetrahedron 64 (2008) 5072–5078
On a side note, the photocyclisation of alkenoate esters 33 and
34 also yielded a small amount of dihydrobenz[h]isoquinoline 38
(Scheme 7).
F
CO2Me
O
HN
38
Scheme 7.
The structure of ester 38 was determined by NMR analysis and
subsequently corroborated through X-ray crystallography (Fig. 3).12
Compound 38 is consistent with the six electron photocyclisation of
olefins 33 and 34, which then fail to be oxidised to the desired
benz[h]isoquinoline 37. However, the mechanism for the formation
of benz[h]isoquinoline 37 is not clear.
In conclusion, we have successfully developed a four-step syn-
thesis for the generation of benz[h]isoquinolines core unit and
related analogues. These results provide an efficient approach to
the synthesis of these important building blocks, and significantly
improve on existing methodologies.2–7
Figure 2. Crystal structure of Z isomer 13.
CO2Me
CO2Me
CO2Me
hv
+
O
O
254 nm
18%
NH
HN
HN
O
13
12
16
hv
254 nm
Scheme 5.
before undergoing the desired photocyclisation to also generate
benz[h]isoquinoline 16.
Having successfully demonstrated the potential of this pro-
cedure, the synthesis of the methoxy-, trifluoromethyl- and fluoro-
substituted benz[h]isoquinolines was then undertaken.
4-Methoxyphenylacetic acid 17, 4-trifluoromethylphenylacetic
acid 18 and 4-fluorophenylacetic acid 19 were esterified and then
brominated to afford the benzyl bromides 23–25 (Scheme 6). The
corresponding phosphonates 26–28 were then generated in situ,
and coupled with the previously described carbaldehyde 11 to
afford the desired bis-aryl olefins 29–34 in excellent yields over the
entire sequence.
As expected, photolysis of E/Z mixtures of bis-aryl olefins
29–34 at 254 nm afforded the desired methoxy-, trifluoromethyl-
and fluoro-substituted benz[h]isoquinolines 35–37, respectively.
Figure 3. Crystal structure of reduced analogue 38.
R
R
R
R
H2SO4
MeOH
89-96%
NBS
CCl4
88-89%
P(OEt)3
CO2H
CO2Me
CO2Me
CO2Me
PO(OEt)2
Br
17 X = OCH3
18 X = CF3
19 X= F
20 X = OCH3
21 X = CF3
22 X = F
23 R = OCH3
24 R = CF3
25 R = F
26 R = OCH3
27 R = CF3
28 R = F
R
O
R
R
CO2Me
CO2Me
+
CO2Me
hv
NaH, 11
14-31%
THF
60-89%
over 3 steps
O
HN
HN
NH
O
E : Z
65:35
61:39
64:36
30 R = OCH3
32 R = CF3
34 R = F
29 R = OCH3
31 R = CF3
33 R = F
35 R = OCH3
36 R = CF3
37 R = F
Scheme 6.

B.M. Abbott et al. / Tetrahedron 64 (2008) 5072–5078
5075
We are currently working on the expansion of the chemical
diversity around the benz[h]isoquinoline core structure and the
biological assessment of this series of compounds.
were then combined, dried over sodium sulfate and then concen-
trated in vacuo to afford the expected silyl ether 11 (1.88 g,
7.92 mmol, 78%) as an oil. 1H (300 MHz, CDCl3) d 9.99 (s, 1H, CHO),
8.31 (d, 1H, J¼5.1 Hz, Ar), 7.26 (d, 1H, J¼5.2 Hz, Ar), 7.08 (s, 1H, Ar),
0.99 (s, 9H, 3ꢀMe), 0.33 (s, 6H, 2ꢀMe). 13C (75 MHz, CDCl3) d 197.1,
169.6, 154.3, 150.6, 120.5, 119.7, 31.0, 1.6.
3. Experimental
3.1. General
3.1.3. 3-(2-Hydroxypyridin-4-yl)-2-phenylacrylic acid methyl
esters 12 and 13
All reactions were performed in oven-dried glassware under an
inert argon atmosphere unless otherwise specified. Tetrahydrofu-
ran, diethyl ether and dichloromethane were distilled before use.
All other reagents were used as-received unless specified other-
wise. 1H NMR spectra were obtained at 300 or 500 MHz using
Bruker DPX300 or Bruker Avance 500 instruments, respectively.
Chemical shifts (d) are reported in parts per million (ppm) and
referenced to the residual solvent peak. The order in citation in
parentheses is: (1) multiplicity (s¼singlet, br s¼broad singlet,
d¼doublet, t¼triplet, q¼quartet, m¼multiplet, br¼broad); (2)
number of equivalent nuclei (by integration); (3) coupling con-
stant (J) quoted in Hertz to the nearest 0.1 Hz. 13C NMR spectra
were recorded at 75.5 or 125.7 MHz using Bruker DPX300 or
Bruker Avance 500 instruments. Chemical shifts (d) are quoted in
parts per million and referenced to the residual solvent peak. Mass
Spectra (MS) were completed using a PerSeptive Biosystems
Mariner ES1-TOF spectrometer. High-Resolution Mass Spectra
(HRMS) were realised with a Bruker MicroTOF spectrometer by
electrospray ionisation mass spectrometry operating at a resolu-
tion of 15,000 full widths at half height. Photochemical reactions
were carried out using a LuzChem Photoreactor fitted with
10ꢀ8 W low-pressure germicidal lamps (UVC l¼254 nm). IR
spectra were recorded on a JASCO FT/IR410 Fourier transform
spectrometer. Only significant absorptions (nmax) are reported in
wavenumbers (cmꢁ1). Flash column chromatography was per-
formed using Silica Gel 60 A C.C. 35–70 mm (SDS ref. 2000027). TLC
was performed on aluminium sheets ore-coated with silica (Merck
Silica Gel 60 F254) and visualised by the quenching of UV fluo-
A suspension of washed and dried sodium hydride (31.5 mg,
0.79 mmol) in tetrahydrofuran (1 mL) was cooled to 0 ꢂC and
treated with a solution of phenylacetic acid methyl ester (118 mg,
113 mL, 0.79 mmol) in tetrahydrofuran (1 mL). The resulting
mixture was then stirred at 0 ꢂC for 15 min and then treated
with 2-(tert-butyldimethylsilanyloxy)-pyridine-4-carbaldehyde
11 (170 mg, 0.72 mmol). The reaction mixture was allowed to warm
up to room temperature overnight. The reaction mixture was
quenched with brine (2 mL) and extracted with ethyl acetate
(2ꢀ10 mL). The combined organic phases were dried over sodium
sulfate and the solvent removed in vacuo. The crude residue was
purified by flash column chromatography (silica gel, elution gra-
dient: 100% petroleum ether to 100% ethyl acetate) to give the
desired alkene as a pale yellow solid (70.0 mg, 0.27 mmol, 35%) as
ca. 1:1 mixture of E and Z isomers.
Alternative procedure: Neat methyl a-bromophenylacetate
(460 mg, 2.00 mmol) was stirred while triethylphosphite (415 mg,
2.50 mmol) was carefully added drop-wise at room temperature.
The resulting mixture was then heated at 160 ꢂC for 1 h before
being cooled slightly and then treated with a second portion of
triethylphosphite (415 mg, 2.5 mmol). The reaction mixture was
then heated up to 160 ꢂC for an extra 1 h and then cooled to room
temperature. The excess triethylphosphite was then removed
through vacuum distillation and the clean crude residue was dis-
solved in anhydrous THF (5 mL) under argon. The freshly generated
solution was added drop-wise to a cooled (0 ꢂC) suspension of
sodium hydride (60% oil dispersion, 80.0 mg, 2.00 mmol) in anhy-
drous THF (2.5 mL). The suspension was stirred for 15 min before
a solution of 2-(tert-butyldimethylsilanyloxy)-pyridine-4-carbal-
dehyde 11 (450 mg, 2.00 mmol) in anhydrous THF (2.5 mL) was
added slowly. The resulting reaction mixture was then stirred
overnight at room temperature, the solvent was concentrated
under vacuum and the crude residue was partitioned between
ethyl acetate and water (50 mL, 1:1). The organic layer was sepa-
rated, dried over sodium sulfate and concentrated in vacuo. Puri-
fication of the crude residue was completed using flash column
chromatography (silica gel, elution gradient: 100% petroleum spirit
to 100% ethyl acetate). The desired alkenes were obtained in 56%
(288 mg) yield as white amorphous solids and an overall ratio of
55:45 E/Z isomers.
rescence (l
254 nm).
max
3.1.1. 2-Hydroxypyridine-4-carbaldehyde 109
To a mixture of 2-hydroxy-4-methylpyridine (2.10 g, 19.2 mmol)
and selenium dioxide (2.50 g, 22.5 mmol) was added anhydrous
dioxane (35 mL). The heterogeneous solution was then refluxed
under argon for 48 h before being cooled down to room tempera-
ture, treated with sodium hydrogen carbonate (1.5 g) and stirred for
3 h to neutralise acidic by-products. The resulting dark brown
suspension was filtered through a pad of magnesium sulfate (2.5 g),
Florisil (2.5 g) and Celite (2.5 g) to remove insoluble residues. The
yellow filtrate was concentrated in vacuo to obtain the crude
compound (1.40 g). Purification of the crude product was com-
pleted using silica column chromatography in ethyl acetate, fol-
lowed by 9:1 ethyl acetate/methanol then 8:2 ethyl acetate/
methanol to give the desired aldehyde 10 (1.23 g, 9.99 mmol, 52%)
as a yellow solid. 1H (500 MHz, DMSO-d6) d 11.93 (s,1H, NH), 9.87 (s,
1H, CHO), 7.52 (d, 1H, J¼7.0 Hz, Ar), 6.95 (s, 1H, Ar), 6.42 (d, 1H,
J¼6.5 Hz, Ar). 13C (125 MHz, DMSO-d6) d 193.5, 162.8, 145.8, 137.0,
125.6, 99.7. Mp: 79–81ꢂC (lit. 83 ꢂC).8,2b
3.1.3.1. (E)-3-(2-Hydroxypyridin-4-yl)-2-phenylacrylic acid methyl
ester 12. 1H (300 MHz, CDCl3) d 12.62 (br s, 1H, NH), 7.58 (s, 1H, Ar),
7.37–7.35 (m, 3H, Ar), 7.20–7.16 (m, 2H, Ar), 7.07 (d, 1H, J¼6.9 Hz,
Ar), 6.42 (s, 1H, ]CH), 5.71 (d, 1H, J¼6.8 Hz, Ar), 3.82 (s, 3H, Me). 13
C
(75 MHz, CDCl3) d 167.4, 165.3,148.4, 137.7, 137.0, 134.3,133.9, 129.6,
128.6, 121.7, 107.5, 52.8. Mp: 191–194 ꢂC. MS: m/z¼256.1069
([MþH]þ). HRMS: calcd for C15H13NO3þH 256.0968, found
256.0958.
3.1.2. 2-(tert-Butyldimethylsilanyloxy)-pyridine-4-carbaldehyde 1113
A solution of 2-hydroxypyridine-4-carbaldehyde 10 (1.24 g,
10.1 mmol) in dry dichloromethane (40 mL) was treated with
triethylamine (3.60 mL, 25.8 mmol) and tert-butyldimethylsilyl
chloride (1.66 g, 11.0 mmol). The reaction mixture was stirred at
room temperature overnight and then quenched with methanol
(5 mL). The solvent was then removed in vacuo and the crude
residue triturated with petroleum spirit. The solvent washings
3.1.3.2. (Z)-3-(2-Hydroxypyridin-4-yl)-2-phenylacrylic acid methyl
ester 13. 1H (300 MHz, CDCl3) d 12.70 (br s, 1H, NH), 7.47–7.36 (m,
6H, Ar), 6.80 (s, 1H, Ar), 6.55 (s, 1H, ]CH), 6.28 (d, 1H, J¼6.7 Hz, Ar),
3.83 (s, 3H, Me). 13C (75 MHz, CDCl3) d 168.9, 165.6, 149.2, 139.5,
135.7, 134.5, 129.4, 129.0, 128.0, 126.7, 118.9, 106.6, 52.7. Mp: 182–
184 ꢂC. MS: m/z¼256.1095 ([MþH]þ). HRMS: calcd for
C15H13NO3þH 256.0968, found 256.0962.

5076
B.M. Abbott et al. / Tetrahedron 64 (2008) 5072–5078
3.1.4. 1-Hydroxy-benz[h]isoquinoline-6-carboxylic methyl ester 16
A solution of methyl esters 12 and 13 (100 mg, 0.39 mmol) in
THF (100 mL) was placed in a in a quartz vessel and stirred inside
the UV photoreactor for 75 min. The solvent was concentrated in
vacuo to obtain the crude residue, which was purified using flash
column chromatography (silica gel, elution gradient 100%
dichloromethane to 99:1 dichloromethane/methanol). The semi-
crude product obtained (27.7 mg) was then recrystallised from
methanol to obtain 17.4 mg (18%) of analytically pure benz[h]iso-
quinoline 16 as a pale solid. 1H (300 MHz, DMSO-d6) d 11.90 (br s,
1H, NH), 10.29 (d, 1H, J¼8.5 Hz, Ar), 8.54 (d, 1H, J¼8.3 Hz, Ar), 8.23
(s, 1H, Ar), 7.80–7.68 (m, 2H, Ar), 7.52 (d, 1H, J¼6.5 Hz, Ar), 6.88 (d,
1H, J¼6.8 Hz, Ar), 4.00 (s, 3H, Me). 13C (75 MHz, DMSO-d6) d 166.9,
161.8, 138.0,132.3,131.6, 131.2, 127.8, 127.6,126.5,126.2,125.1, 120.2,
acetate and water (30 mL, 1:1). The organic layer was washed with
water (15 mL), dried over sodium sulfate and concentrated under
vacuum. Flash column chromatography (silica gel, elution gradient
100% petroleum spirit to 100% ethyl acetate) generated 405 mg of the
expected methyl esters 29 and 30 (1.42 mmol, 60%) as a white solid
containing a mixture of E and Z isomers (65:35).
3.1.7.1. (E)-3-(2-Hydroxypyridin-4-yl)-2-(4-methoxyphenyl)-acrylic
acid methyl ester 29. 1H (300 MHz, CDCl3) d 12.62 (br s, 1H, NH),
7.52 (s, 1H, Ar), 7.11 (d, 2H, J¼8.4 Hz, Ar), 7.04 (d, 1H, J¼6.6 Hz, Ar),
6.87 (d, 2H, J¼8.4 Hz, Ar), 6.43 (s, 1H, ]CH), 5.72 (d, 1H, J¼6.9 Hz,
Ar), 3.87 (s, 6H, OMe). 13C (75 MHz, CDCl3) d 167.8, 165.3, 159.9,
148.8, 137.4, 136.4, 133.7, 131.2, 126.4, 121.7, 114.1, 107.6, 55.3, 52.8.
Mp: 168–170 ꢂC. MS: m/z¼286.1172 ([MþH]þ). HRMS: calcd for
105.3, 52.4. n
(film)/cmꢁ1 3271, 3124, 2877, 2793, 1720, 1631,
C16H15NO4þH 286.1074, found 286.1067.
max
1600, 1539, 1500, 1253. Mp: 226–228 ꢂC. MS: m/z¼254.1007
([MþH]þ). HRMS: calcd for C15H11NO3þH 254.0812, found
254.0818.
3.1.7.2. (Z)-3-(2-Hydroxypyridin-4-yl)-2-(4-methoxyphenyl)-acrylic
acid methyl ester 30. 1H (300 MHz, CDCl3) d 12.69 (br s, 1H, NH),
7.39 (d, 2H, J¼8.7 Hz, Ar), 7.31 (d, 1H, J¼6.9 Hz, Ar), 6.92 (d, 2H,
J¼9.0 Hz, Ar), 6.71 (s, 1H, Ar), 6.52 (s, 1H, ]CH), 6.24 (d, 1H,
J¼6.8 Hz, Ar), 3.84 (s, 6H, OMe). 13C (75 MHz, CDCl3) d 168.2, 164.5,
159.7, 148.4, 133.3, 130.2, 127.1, 124.8, 117.7, 113.4, 1þ13.2, 105.7, 54.5,
51.7. Mp: 208–211 ꢂC. MS: m/z¼286.1082 ([MþH] ). HRMS: calcd
for C16H15NO4þH 286.1074, found 286.1083.
3.1.5. 4-Methoxyphenylacetic acid methyl ester 2014
A solution of 4-methoxyphenylacetic acid (4.15 g, 25.0 mmol) in
methanol (10 mL) was treated by the careful addition of concen-
trated sulfuric acid (0.5 mL). The resulting mixture was heated to
reflux overnight, then cooled to room temperature and concen-
trated in vacuo. The crude residue was dissolved in diethyl ether
(100 mL) to which water (50 mL) was added. The phases were
separated, and the organic layer was washed with satd aq sodium
hydrogen carbonate (50 mL), dried over sodium sulfate and con-
centrated under vacuum to yield 4.02 g of the required ester 20 as
a pale yellow oil (22.3 mmol, 89%), which was used without any
further purification. 1H (300 MHz, CDCl3) d 7.28 (d, 2H, J¼9.0 Hz,
Ar), 6.94 (d, 2H, J¼9.0 Hz, Ar), 3.86 (s, 3H, OMe), 3.76 (s, 3H, OMe),
3.64 (s, 2H, CH2). 13C (75 MHz, CDCl3) d 172.4, 158.8, 130.3, 126.1,
114.1, 55.3, 52.0, 40.3.
3.1.8. 1-Hydroxy-9-methoxy-benz[h]isoquinoline-6-carboxylic acid
methyl ester 35
A solution of the methyl esters 29 and 30 (353 mg,1.24 mmol) in
THF (100 mL) was stirred in the photoreactor for 1 h in a quartz
container and placed in the UV photoreactor. The solvent was then
concentrated in vacuo to obtain a crude residue, which was purified
through flash column chromatography (silica gel, elution gradient:
100% dichloromethane to 99:1 dichloromethane/methanol) to
produce 80 mg of the desired cyclisation product 35 as a white solid
(0.282 mmol, 23%). 1H (300 MHz, DMSO-d6) d 11.80 (br s, 1H, NH),
9.88 (d, 1H, J¼2.7 Hz, Ar), 8.49 (d, 1H, J¼9.3 Hz, Ar), 8.06 (s, 1H, Ar),
7.48 (t, 1H, J¼6.3 Hz, Ar), 7.37 (dd, 1H, J¼9.3, 2.7 Hz, Ar), 6.83 (d, 1H,
J¼6.8 Hz, Ar), 3.98 (s, 3H, OMe), 3.93 (s, 3H, OMe). 13C (75 MHz,
DMSO-d6) d 167.7, 162.7, 159.2, 139.2, 134.3, 132.7, 131.8, 127.2, 125.8,
3.1.6. a-Bromo-(4-methoxyphenyl) acetic acid methyl ester 2315
A solution of 4-methoxyphenylacetic acid methyl ester 20
(1.00 g, 5.55 mmol) in carbon tetrachloride (20 mL) was treated with
N-bromosuccinimide (1.06 g, 5.95 mmol) and benzoyl peroxide
(24.0 mg, 0.100 mmol). The reaction mixture was refluxed under UV
light for 4 h before being cooled down to room temperature and
filtered through Celite. The filtrate was concentrated under vacuum
to obtain 1.26 g of the desired bromide 23 (88%) as a yellow oil. 1H
(300 MHz, CDCl3) d 7.49 (d, 2H, J¼9.0 Hz, Ar), 6.88 (d, 2H, J¼9.0 Hz,
Ar), 5.36 (s,1H, CH), 3.80 (s, 3H, OMe), 3.78 (s, 3H, OMe).13C (75 MHz,
CDCl3) d 169.0, 160.4, 130.2, 127.8, 114.3, 55.4, 53.4, 46.6.
123.3, 120.2, 117.9, 107.5, 106.1, 55.5, 53.0. n
(film)/cmꢁ1 3117,
max
2855, 2835,1728,1639,1597, 1516,1438, 1253. Mp: 259–260 ꢂC. MS:
m/z¼284.1123 ([MþH]þ). HRMS: calcd for C16H13NO4þH 284.0917,
found 284.0922.
3.1.9. 4-Trifluoromethylphenylacetic acid methyl ester 2116
4-Trifluorophenylacetic acid (1.00 g, 4.89 mmol) was treated
under the same conditions as 4-methoxyphenylacetic acid to yield
941 mg of the desired methyl ester 21 (4.31 mmol, 90%) as a clear oil.
1H (300 MHz, CDCl3) d 7.59 (d, 2H, J¼8.1 Hz, Ar), 7.41 (d, 2H, J¼8.1 Hz,
Ar), 3.72 (s, 3H, OMe), 3.70 (s, 2H, CH2). 13C (75 MHz, CDCl3) d 171.3,
138.1, 129.8, 129.3, 126.0, 125.6, 125.5, 122.5, 118.9, 52.2, 40.9.
3.1.7. 3-(2-Hydroxypyridin-4-yl)-2-(4-methoxyphenyl)-acrylic acid
methyl ester 29 and 30
a-Bromo-(4-methoxyphenyl)-acetic acid methyl ester 23
(617 mg, 2.38 mmol) was stirred while triethylphosphite (495 mg,
2.98 mmol) was added carefully. The reaction mixture was heated
to 160 ꢂC for 1 h, before being cooled slightly and treated with
a further portion of triethylphosphite (495 mg, 2.98 mmol). The
reaction mixture was then heated again for 1 h at 160 ꢂC, cooled
down to room temperature and the excess triethylphosphite was
removed under vacuum. The residue, essentially constituting the
phosphonyl ester 26, was dissolved in anhydrous THF (5 mL) under
argon. This solution was then added drop-wise to a cooled (0 ꢂC)
suspension of sodium hydride (60% oil dispersion, 95 mg,
2.38 mmol) in anhydrous THF (4 mL). The suspension was stirred
for 15 min before being treated with a solution of 2-(tert-butyldi-
methylsilanyloxy)-pyridine-4-carbaldehyde 11 (565 mg, 2.38 mmol)
in anhydrous THF (4 mL) at 0 ꢂC. The reaction mixture was then
stirred overnight at room temperature. Solvent was concentrated
under vacuum and the crude residue partitioned between ethyl
3.1.10. a-Bromo-(4-trifluoromethylphenyl)-acetic acid methyl
ester 2417
4-Trifluoromethylphenylacetic acid methyl ester 21 (520 mg,
2.83 mmol) was reacted with N-bromosuccinimide (424 mg,
2.83 mmol) under the same conditions as methyl ester 20 to obtain
748 mg of bromide 24 (2.52 mmol, 89%) as a yellow oil. 1H
(300 MHz, CDCl3) d 7.68 (d, 2H, J¼8.4 Hz, Ar), 7.63 (d, 2H, J¼8.4 Hz,
Ar), 5.38 (s, 1H, CH), 3.80 (s, 3H, OMe). 13C (75 MHz, CDCl3) d 168.4,
139.7, 134.4, 126.0, 125.9, 53.7, 45.1.
3.1.11. 3-(2-Hydroxypyridin-4-yl)-2-(4-trifluoromethylphenyl)-
acrylic acid methyl esters 31 and 32
a-Bromo methyl ester 24 (619 mg, 2.08 mmol) was reacted with
triethylphosphite (2ꢀ433 mg, 2.60 mmol) under the same

B.M. Abbott et al. / Tetrahedron 64 (2008) 5072–5078
5077
conditions as bromide 23 to produce phosphonyl ester 27. Phos-
phonyl ester 27 was reacted with carbaldehyde 11 (565 mg,
2.38 mmol) under identical conditions as phosphonyl ester 26 to
generate 305 mg of alkenes 31 and 32 (0.945 mmol, 45%) as a white
solid containing a mixture of both E and Z isomers (61:39).
3.1.15.1. (E)-2-(4-Fluorophenyl)-3-(2-hydroxypyridin-4-yl)-acrylic acid
methyl ester 33. 1H (300 MHz, CDCl3) d 12.61 (br s, 1H, NH), 7.58 (s,
1H, Ar), 7.19–7.01 (m, 5H, Ar), 6.40 (s, 1H, ]CH), 5.72 (d, 1H,
J¼6.8 Hz, Ar), 3.82 (s, 3H, OMe). 13C (75 MHz, CDCl3) d 167.2, 165.3,
164.5, 161.2, 148.3, 137.4, 136.6, 134.1, 131.6, 130.2, 121.7, 115.8, 115.7,
107.5, 52.9. Mp: 190–193 ꢂC. MS: m/z¼274.1003 ([MþH]þ). HRMS:
calcd for C15H12FNO3þH 274.0874, found 274.0872.
3.1.11.1. (E)-3-(2-Hydroxypyridin-4-yl)-2-(4-trifluoromethylphenyl)-
acrylic acid methyl ester 31. 1H (300 MHz, CDCl3) d 12.93 (br s, 1H,
NH), 7.75 (s, 1H, Ar), 7.68 (d, 2H, J¼8.1 Hz, Ar), 7.42 (d, 2H, J¼6.8 Hz,
Ar), 7.21 (d, 1H, J¼6.8 Hz, Ar), 6.34 (s, 1H, ]CH), 5.88 (d, 1H,
J¼6.9 Hz, Ar), 3.81 (s, 3H, OMe). 13C (75 MHz, CDCl3) d 166.7, 165.1,
147.9, 138.2, 137.8, 136.7, 136.3, 134.3, 130.6, 130.3, 128.6, 125.7,
125.6, 122.2, 121.9, 121.8, 107.3, 53.0. Mp: 167–172 ꢂC. MS: m/z¼
324.1006 ([MþH]þ). HRMS: calcd for C16H12F3NO3þNa 346.0661,
found 346.0653.
3.1.15.2. (Z)-2-(4-Fluorophenyl)-3-(2-hydroxypyridin-4-yl)-acrylic acid
methyl ester 34. 1H (300 MHz, CDCl3) d 12.91 (br s, 1H, NH), 7.46–
7.41 (m, 2H, Ar), 7.37 (d, 1H, J¼6.8 Hz, Ar), 7.10 (t, 2H, J¼8.6 Hz, Ar),
6.75 (s, 1H, Ar), 6.54 (s, 1H, ]CH), 6.26 (dd, 1H, J¼6.8, 1.5 Hz, Ar),
3.83 (s, 3H, OMe). 13C (75 MHz, MeOD) d 168.7, 165.2, 165.1, 161.8,
149.2, 138.5, 134.4, 131.7, 128.8, 128.7, 128.1, 119.0, 116.3, 116.0, 106.8,
52.9. Mp: 238–240 ꢂC. MS: m/z¼274.1045 ([MþH]þ). HRMS: calcd
for C15H12FNO3þH 274.0874, found 274.0874.
3.1.11.2. (Z)-3-(2-Hydroxypyridin-4-yl)-2-(4-trifluoromethylphenyl)-
acrylic acid methyl ester 32. 1H (300 MHz, CDCl3) d 13.15 (br s, 1H,
NH), 7.68–7.56 (m, 4H, Ar), 7.39 (d, 1H, J¼6.9 Hz, Ar), 6.86 (s, 1H, Ar),
3.1.16. 9-Fluoro-1-hydroxy-benz[h]isoquinoline-6-carboxylic
methyl ester 37
6.57 (s, 1H, ]CH), 6.29 (d, 1H, J¼6.6 Hz, Ar), 3.84 (s, 3H, OMe). 13
C
Methyl esters 33 and 34 (300 mg, 1.10 mmol) were cyclised
under the same conditions as esters 29 and 30 to produce 92.9 of
the desired cyclic ester 37 as a white solid (0.34 mmol, 31%). 1H
(300 MHz, DMSO-d6) d 11.99 (br s, 1H, NH), 10.02 (d, 1H, J¼13.4 Hz,
Ar), 8.65 (t, 1H, J¼7.8 Hz, Ar), 8.20 (s, 1H, Ar), 7.60 (t, 1H, J¼8.1 Hz,
Ar), 7.55 (d, 1H, J¼6.5 Hz, Ar), 6.87 (d, 1H, J¼6.5 Hz, Ar), 3.99 (s, 3H,
OMe). 13C (75 MHz, DMSO-d6) d 166.9, 162.9, 162.1, 159.7, 139.2,
133.6, 133.4,132.2, 132.1, 128.2, 128.1, 127.9, 125.1, 120.0, 119.9, 116.2,
(75 MHz, MeOD) d 170.1, 166.0, 151.3, 136.3, 135.9, 131.9, 131.5,
131.1, 128.8, 127.7, 126.9, 119.8, 118.3, 108.3, 107.7, 76.4, 53.6. Mp:
224–226 ꢂC. MS: m/z¼324.0881 ([MþH]þ). HRMS: calcd for
C
16H12F3NO3þH 324.0842, found 324.0833.
3.1.12. 1-Hydroxy-9-trifluoromethyl-benz[h]isoquinoline-6-
carboxylic acid methyl ester 36
Methyl esters 31 and 32 (80 mg, 0.25 mmol) were cyclised un-
der the same conditions and wavelength as esters 29 and 30 to
yield 11.2 mg of the desired cyclic product 36 as a white solid
(0.035 mmol, 14%). 1H (300 MHz, DMSO-d6) d 12.13 (br s, 1H, NH),
10.72 (s, 1H, Ar), 8.81 (d, 1H, J¼8.7 Hz, Ar), 8.45 (s, 1H, Ar), 7.99 (d,
1H, J¼8.9 Hz, Ar), 7.61 (t, 1H, J¼6.3 Hz, Ar), 6.96 (d, 1H, J¼6.7 Hz, Ar),
4.01 (s, 3H, OMe). 13C (75 MHz, DMSO-d6) d 166.6, 162.0, 139.2,
132.7, 131.9, 131.3, 131.1, 129.9, 128.5, 128.1, 127.7, 127.3, 126.3, 123.9,
115.9, 111.1, 110.7, 105.7, 52.8. n
(film)/cmꢁ1 3128, 3105, 2835,
max
2812, 1724, 1658, 1632, 1604, 1550, 1512, 1415, 1249, 1269, 1192. Mp:
280–281 ꢂC. MS: m/z¼272.0899 ([MþH]þ). HRMS: calcd for
C
15H10FNO3þH 272.0717, found 272.0726.
A side product was also isolated as a white solid (108 mg,
39.5 mmol) and identified as tetrahydro-benz[h]isoquinoline 38.
3.1.17. 9-Fluoro-1-oxo-1,2,5,6-tetrahydro-benz[h]isoquinoline-6-
carboxylic acid methyl ester 38
123.8, 122.7, 122.3, 119.1, 106.2, 52.9. n
(film)/cmꢁ1 3155, 3109,
max
2839, 1724, 1647, 1635, 1604, 1546, 1516, 1311, 1253. Mp: 262–
1H (300 MHz, CDCl3) d 13.29 (br s,1H, NH), 8.71 (d,1H, J¼11.1 Hz,
Ar), 7.41 (d, 1H, J¼5.8 Hz, Ar), 7.26 (d, 1H, J¼7.5 Hz, Ar), 6.99 (s, 1H,
Ar), 6.37 (d, 1H, J¼5.7 Hz, Ar), 4.02 (s, 1H, CH), 3.63 (s, 3H, OMe),
3.04–2.97 (m, 2H, CH2). 13C (75 MHz, CDCl3) d 172.7, 163.9, 163.0,
160.7, 150.0, 133.9, 133.1, 132.9,129.6, 129.5, 128.4,121.1, 114.6, 114.3,
114.2, 114.0,108.9, 52.4, 42.9, 31.8. 13C DEPT (75 MHz, CDCl3) d 134.1,
129.9, 129.8, 114.9, 114.7, 114.6, 114.4, 109.3, 52.7, 43.2, 32.1. nmax
(film)/cmꢁ1 3405, 2950, 2839, 1646, 1450, 1411, 1111. Mp: 171–
173 ꢂC. MS: m/z¼296.0739 ([MþNa]þ). HRMS: calcd for
264 ꢂC. MS: m/z¼322.0968 ([MþH]þ). HRMS: calcd for
C
16H10F3NO3þH 322.0686, found 322.0676.
3.1.13. 4-Fluorophenylacetic acid methyl ester 2214
4-Fluorophenylacetic acid (2.50 g, 16.2 mmol) was esterified
under the same conditions as 4-methoxyphenylacetic acid to yield
2.61 g of methyl ester 22 (15.5 mmol, 96%) as a pale yellow oil. 1H
(300 MHz, CDCl3) d 7.15–7.13 (m, 2H, Ar), 6.92 (t, 2H, J¼8.7 Hz, Ar),
3.60 (s, 3H, OMe), 3.51 (s, 2H, CH2). 13C (75 MHz, CDCl3) d 172.0,
163.7, 160.5, 131.0, 130.9, 129.8, 115.6, 115.4, 52.1, 40.3.
C15H13FNO3þH 274.0874, found 274.0886.
Acknowledgements
3.1.14. a-Bromo-(4-fluorophenyl)-acetic acid methyl ester 2514
Methyl ester 22 (4.10 g, 24.4 mol) was brominated with N-bro-
mosuccinimide (4.34 g, 24.4 mmol) and benzoyl peroxide (24.6 mg,
0.106 mmol) under the same conditions as ester 20 to afford 5.39 g
of the brominated methyl ester 25 (89%) as a yellow oil. 1H
(300 MHz, CDCl3) d 7.54 (dd, 2H, J¼8.8, 5.2 Hz, Ar), 7.05 (t, 2H,
J¼8.6 Hz, Ar), 5.34 (s,1H, CH), 3.79 (s, 3H, OMe). 13C (75 MHz, CDCl3)
d 168.8, 164.8, 161.5, 131.8, 130.9, 116.1, 115.8, 53.5, 45.5.
The financial support for this work was provided by the Medical
Research Council Technology Gap Fund and the University of
Dundee. R.M. is grateful to Dr. Ian Sword and the University of
Glasgow for financial support. We would also like to thank Dr.
Richard Hartley for very helpful discussions.
References and notes
3.1.15. 2-(4-Fluorophenyl)-3-(2-hydroxypyridin-4-yl)-acrylic acid
methyl esters 33 and 34
1. Matsui, M.; Sugiura, T.; Nakai, H.; Iguchi, S.; Shigeoka, S.; Takada, H.; Odagaki,
Y.; Nagao, Y.; Ushio, Y.; Ohmoto, K.; Iwamura, H.; Yamazaki, S.; Arai, Y.;
Kawamura, M. J. Med. Chem. 1992, 35, 3307.
2. (a) McKay, R. D.; Androutsellis-Theotokis, A. PCT Int. Appl., WO 2007030693 A2
20070315, 2007; 109 pp; (b) Wilks, A. F.; Burns, C. J.; Fantino, E.; Lucet, I.;
Rossjohn, J.; Styles, M. L. PCT Int. Appl., WO 2006119542 A1 20061116, 2006;
140 pp.
3. (a) Chang, T.-H.; Lee, S.-J.; Yang, C.-W.; Wu, P.-L. Org. Biomol. Chem. 2006, 4, 860;
(b) Saito, I.; Okamoto, A.; Tanaka, K.; Fukuta, T.; Tainaka, K.; Iida, M.; Kato, T. PCT
Int. Appl., WO 2004046147 A1 20040603, 2004; 77 pp; (c) Arrington, K. L.;
Dudkin, V. Y.; Fraley, M. E.; Garbaccio, R. M.; Hartman, G. D.; Huang, S. Y.;
a-Bromo ester 25 (513 mg, 2.08 mmol) reacted with tri-
ethylphosphite (2ꢀ431 mg, 2.605 mmol) to produce phosphonyl
ester 28. Phosphonyl ester 28 was then coupled with carbalde-
hyde 11 (493 mg, 2.08 mmol) under the same conditions as
phosphonyl ester 26 to afford 503 mg of alkenes 33 and 34
(1.84 mmol, 89%) as a white solid and a mixture of the E and Z
isomers (64:36).

5078
B.M. Abbott et al. / Tetrahedron 64 (2008) 5072–5078
Kreatsoulas, C.; Tasber, E. S. PCT Int. Appl., WO 2007008502 A2 20070118, 2007;
163 pp.
4. (a) Gerster, M.; Wicki, R. Synthesis 2004, 2, 249; (b) Okamoto, A.; Tainaka, K.;
Saito, I. Tetrahedron Lett. 2003, 44, 6871.
5. Eloy, F.; Deryckere, A. Chim. Ther. 1970, 5, 121.
10. The atomic coordinates for 12 and 13 (CCDC deposition numbers CCDC265923
and CCDC265922, respectively) are available upon request from the Cambridge
Crystallographic Centre, University Chemical Laboratory, Lensfield Road, Cam-
bridge CB2 1EW, United Kingdom. The crystallographic numbering system
differs from that used in the text, therefore, any request should be accompanied
by the full literature citation of this paper.
6. Koelsch, C. F.; Lindquist, R. M. J. Org. Chem. 1956, 21, 657.
7. Oppolzer, W. Ger. Offen., DE 1963226 19700709, 1970; 20 pp.
8. For photochemical approaches to the synthesis of quinolines, isoquinolines and
benzooquinolines, please see: (a) Arai, S.; Nakamura, N.; Yamaguchi, H.;
Okasaki, M.; Hida, M. Bull. Chem. Soc. Jpn. 1991, 64, 1996; (b) Pattabiraman, M.;
Natarajan, A.; Kaliappan, R.; Mague, J. T.; Ramamurthy, V. Chem. Commun. 2005,
4542; (c) Lewis, F. D.; Kalgutkar, R. S.; Yang, J.-S. J. Am. Chem. Soc. 2001, 123,
3878; (d) Harrowven, D. C.; Sutton, B. J.; Coulton, S. Org. Biomol. Chem. 2003, 1,
4047; (e) Hewlins, M. J. E.; Salter, R. Synthesis 2007, 2164; (f) Harrowven, D. C.;
Nunn, M. I. T.; Blumire, N. J.; Fenwick, D. R. Tetrahedron 2001, 57, 4447; (g)
Abbate, S.; Bazzini, C.; Caronna, T.; Fontana, F.; Gambarotti, C.; Gangemi, F.;
Longhi, G.; Mele, A.; Sora, I. N.; Panzeri, W. Tetrahedron 2006, 62, 139; (h) Arai,
S.; Yafune, T.; Okubo, M.; Mida, M. Tetrahedron Lett. 1989, 30, 7217; (i)
Harrowven, D. C.; Nunn, M. I. T.; Blumire, N. J.; Fenwick, D. R. Tetrahedron Lett.
2000, 41, 6681; (j) Dyke, S. F.; Sainsbury, M. Tetrahedron 1967, 23, 3161; (k)
Pierce, M. E.; Fortunak, J. M. D.; Islam, Q. Synth. Commun. 1996, 26, 3645; (l)
Sato, K.; Nakajima, K.; Arai, S.; Yamagishi, T. Liebigs Ann. 1996, 4, 439.
9. Ren, R. X.-F.; Sakai, N.; Nakanishi, K. J. Am. Chem. Soc. 1997, 119, 3619.
11. (a) Wigglesworth, T. J.; Sud, D.; Norsten, T. B.; Lekhi, V. S.; Branda, N. R. J. Am.
Chem. Soc. 2005, 127, 7272; (b) Rice, J. E.; Cai, Z. W.; He, Z. M.; LaVoie, E. J. J. Org.
Chem. 1995, 60, 8101.
12. The atomic coordinates for 38 (CCDC deposition number CCDC 290038) are
available upon request from the Cambridge Crystallographic Centre, University
Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
The crystallographic numbering system differs from that used in the text,
therefore, any request should be accompanied by the full literature citation of
this paper.
13. Kubota, R.; Palczewski, K.; Gall, A. PCT Int. Appl., WO 2006091796 A2 20060831,
2006; 167 pp.
14. Mohan, R. J. Org. Chem. 1984, 49, 1238.
15. Sweeney, J. B.; Tavassoli, A.; Carter, N. B.; Hayes, J. F. Tetrahedron 2002, 58, 10113.
16. Durandetti, M. Tetrahedron 2006, 63, 1146.
17. Epstein, J. W.; Brabander, H. J.; Fanshawe, W. J.; Hofmann, C. M.; McKenzie, T. C.;
Safir, S. R.; Osterberg, A. C.; Cosulich, D. B.; Lovell, F. M. J. Med. Chem. 1981,
24, 481.