Isoquinoline synthesis by C-H activation/annulation using vinyl acetate as an acetylene equivalent

Article abstract of DOI:10.1016/j.tet.2018.05.063

Vinyl acetate is used as an acetylene equivalent in rhodium(III)-catalysed C-H activation/annulation with aryl ketoxime esters. Extension to an aldoxime ester allows for a concise formal synthesis of decumbenine B.

Full text of DOI:10.1016/j.tet.2018.05.063

Accepted Manuscript
Isoquinoline synthesis by C-H activation/annulation using vinyl acetate as an
acetylene equivalent
Nicola J. Webb, Steven A. Raw, Stephen P. Marsden
PII:
S0040-4020(18)30611-2
10.1016/j.tet.2018.05.063
TET 29570
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 2 March 2018
Revised Date: 18 May 2018
Accepted Date: 22 May 2018
Please cite this article as: Webb NJ, Raw SA, Marsden SP, Isoquinoline synthesis by C-H activation/
annulation using vinyl acetate as an acetylene equivalent, Tetrahedron (2018), doi: 10.1016/
j.tet.2018.05.063.
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Isoquinoline synthesis by C-H
activation/annulation using vinyl acetate as
an acetylene equivalent
Leave this area blank for abstract info.
Nicola J. Webb,a Steven A. Raw,b Stephen P. Marsdena,*
a School of Chemistry/Institute of Process Research and Development, University of Leeds, Leeds LS2 9JT, U.K.
b AstraZeneca, Chemical Development, Charter Way, Macclesfield, SK10 2NA, U.K.

1
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Tetrahedron
journal homepage: www.elsevier.com
Isoquinoline synthesis by C-H activation/annulation using vinyl acetate as an
acetylene equivalent
Nicola J. Webba , Steven A. Rawb and Stephen P. Marsdena,
a School of Chemistry and Institute of Process Research and Development, University of Leeds, LS2 9JT, U.K
b AstraZeneca, Chemical Development, Charter Way, Macclesfield, SK10 2NA, U.K.
.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Vinyl acetate is used as an acetylene equivalent in rhodium(III)-catalysed C-H
activation/annulation with aryl ketoxime esters. Extension to an aldoxime ester allows for a
concise formal synthesis of decumbenine B.
2009 Elsevier Ltd. All rights reserved
.
Available online
KKeyrowdseywords:
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———
Corresponding author. Tel.: +44-113-343-6425; e-mail: s.p.marsden@leeds.ac.uk

2
Tetrahedron
1. Introduction
preferences of the reaction of non-symmetrically substituted
ACCEPTED MANUSCRIPT
aroyl oxime esters. We also describe the first application of
aldoxime esters in this transformation, demonstrated in a formal
synthesis of decumbenine B.
Isoquinolines are prevalent scaffolds in pharmaceutical agents,
natural products and other fine chemicals.1-5 Traditional
syntheses of isoquinolines include the well-established Bischler-
Napieraski,6 Pictet-Spengler,7 Pictet-Gams,8 and Pomeranz-
Fritsch9 reactions: in each case the precursors are
monosubstituted aromatic compounds, but the key cyclisation
step proceeds via an SEAr mechanism, which inherently limits
the substrate scope to relatively electron-rich aromatic substrates.
Alternative approaches have been developed which circumvent
this limitation e.g. condensation/cyclisation of 2-azidocinnamates
with α-diazocarbonyl compounds,10 reaction of benzynes with
enamides,11 or cyclisation of aryl imines bearing ortho-alkenyl or
alkynyl functionality,12 but at the expense of more complex or
less readily available starting materials which may require multi-
step syntheses.
2. Results/discussion
To commence our study, the ketoximes 1-4a were examined
using the reaction conditions we previously employed in the
synthesis of isoquinolones, using 1 mol% [Cp*RhCl2]2 with 0.3
o
equivalents of cesium acetate as base in MeOH at 45 C for 24h
(Table 1, entries 1-4).23 After 24 hours the reactions still
contained unreacted starting material, and so were left for 48h.
Disappointingly, all four ketoximes produced <5% of the
corresponding isoquinoline 5a. In the case of substrates 3 and 4,
the remaining starting material had hydrolysed to give the
ketoxime 1.
The recent development of metal-catalysed C-H
activation/annulation cascades13 has enabled the synthesis of
polysubstituted isoquinolines from simple aryl imine derivatives
and alkynes.14-19 The reactions can be carried out under
rhodium,14,15 ruthenium,16 cobalt17,18 or manganese19 catalysis,
and can be run either using N-H imines in the presence of
external oxidants14,17 or alternatively using derivatives (oximes,
oxime ethers and esters, hydrazones or sulfinyl imines) wherein
cleavage of an N-heteroatom bond serves as an internal
oxidant.15,16,18,19 The majority of these methods, however, are
limited to the use of internal alkynes and so generate 3,4-
disubstituted isoquinolines. Alternative strategies utilizing 1,3-
dienes20 or ketoximes21 in place of alkynes have been introduced
which allow access to 4-unsubstituted isoquinolines. However,
many biologically-interesting molecules feature 3,4-unsubstituted
isoquinolines,1-5 which would require either the development of a
method employing acetylene gas (with associated hazards) or the
development of a synthetic equivalent.
Table 1
Optimisation of the C-H activation/annulation
Entrya Oxime
R
X(eq.) Conc. (M)
Temp. (oC) Yield (%)b
1
1
H
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
5
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
2.0
2.0
2.0
2.0
1.0
45
45
45
45
60
60
60
60
60
60
60
60
60
60
60
5
2
2
Me
Piv
Ac
H
0
3
3
5
4
4a
1
3
5
4
6
2
Me
Piv
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
0
7
3
4
8
4a
4a
4a
4a
4a
4a
4a
4a
24
2c
0d
19
48
79
30
56
We
recently
reported
that
rhodium-catalysed
C-H
activation/annulation of benzoyl hydroxamic esters22 with vinyl
acetate generated 3,4-unsubstituted isoquinolones,23 wherein the
vinyl acetate had acted as a convenient acetylene equivalent
(Scheme 1a).24-26
9
10
11
12
13
14
15
10
20
10
a Standard conditions: [Cp*RhCl2]2 (1 mol%), CsOAc (0.3 eq.), MeOH, 48
h. b 1H NMR yield using trimethoxybenzene as an internal standard. c using
CsOAc (1 eq.) as base. d using K2CO3 (1 eq.) as base.
Increasing the temperature to 60 °C improved the yield of the
reaction of the O-acetylated oxime 4a from 3% to 24% (entry 8).
Proceeding with O-acetylated ketoxime 4a, increasing the
equivalents of caesium acetate base to one equivalent had a
detrimental effect on yield, as did use of potassium carbonate
which had been successfully employed by Fagnou in related
annulations (entries 9 and 10).22a Increasing the concentration of
the reaction and equivalents of vinyl acetate resulted in an
increase in yield, with the optimum yield of 5a of 79% obtained
with ten equivalents at 2M (entry 13). Further increasing the
amount of vinyl acetate (entry 14) or lowering the reaction
concentration (entry 15) were deleterious. Comparing our
optimized conditions with those of Yu and Cheng,27 significantly
we are operating at a fourfold lower loading ot the precious metal
catalyst, and also employing a more economic base (caesium
versus silver(I) acetate) and operating at a lower temperature,
albeit at a longer reaction time.
Scheme 1. Vinyl acetate as an acetylene surrogate in C-H
activation/annulation reactions.
Subsequently, Yu and Cheng reported that internally-substituted
vinyl acetates react with acetophenone oxime esters under
rhodium catalysis facilitating access to 3-substituted quinolines.27
In this paper, they also disclosed that vinyl acetate itself could be
used as a reagent, generating 3,4-unsubstituted isooquinolines,
exemplified in a synthesis of the alkaloid papaverine. This
prompts us to report our own work on the use of vinyl acetate as
an acetylene equivalent in the synthesis of isquinolines (Scheme
1b). Specifically, under complementary conditions to those
employed by Yu and Cheng, we probe the regiochemical

3
We next probed regioselectivity with meta-substituted
ACCEPTED MANUSCRIPT
substrates. The meta-methyl substrate 4k returned a 52% yield
of a 10:1 mixture of the C7/C5-isomers 5k/5k’, presumably
driven by steric effects. However, the meta-methoxy substrate 4l
produced a 1.4:1 mixture in favour of the C5 isomer of 5l’ in
58% yield. In this case, it is likely that the acidifying effect of
the methoxy group on the ortho-hydrogens compensates for the
steric effects.22a,23 In line with this observation, the meta-bromo
substrate 4m favoured production of the C7 isomer (2.7:1) with
steric effects dominating, whereas the smaller, more strongly
acidifying fluoride substituent in 4n returned a 5:1 mixture in
favour of the C5 product. We reasoned that reducing the steric
influence of the oxygen substituent by constraining it as part of a
methylenedioxy unit would allow the electronic influence to
dominate, and were gratified to find that isoquinoline 5o was
formed as a single isomer in 36% yield. Finally, the presence of
additional ring fusion was tolerated, with the naphthyl substrate
4p generating benzoisoquinoline 5p, albeit in modest yield.
Table 2
Scope of the C-H activation/annulation
Entry Product
1
Yield Entry Product
Yield
83
57
82
60
2
4
6
3
5
44
72
Encouraged by the formation of a single regioisomer in the case
of the methylenedioxy-substituted 5o, we were interested to
apply the methodology to the corresponding aldoxime 6 in the
hope of preparing the isoquinoline intermediate 7. Compound 7
has previously been prepared as an intermediate28 in the synthesis
of decumbenine B, a naturally occurring alkaloid used for the
treatment of hypertension, rheumatoid arthritis and sciatic
neuraligia.29 The five step route developed by Orito et al.28
involves a key Pictet-Gams cyclisation to afford the isoquinoline
7 in a yield of 25% over five steps. However, to our knowledge,
aldoxime derivatives have not yet been employed in direct
isoquinoline annulation reactions, and this provided an ideal
opportunity to test their suitability. By application of our
standard conditions, we were able to convert the aldoxime 6 to
the corresponding isoquinoline as a single regioisomer, with a
yield of 26% (21% over three steps from piperonal; Scheme 2).
N
Br
5f
7
64
14
8
41
9a
9
10
11
52% 12
(10:1)
58%
(1:1.4)
[RhCp*Cl2]2 (1 mol%)
vinyl acetate (10 eq)
CsOAc (30 mol%)
O
O
O
O
N
N
MeOH (2 M),
60 oC, 72 h
26%
OAc
13
50% 14
(2.7:1)
47%
(1:5)
6
7
ref. 28
O
O
O
O
N
OH
decumbenine B
15
36
16
24
Scheme 2. C-H activation/annulation reaction of aldoxime esters.
Attempts to optimize the conditions further by increasing the
catalyst and base loading proved unsuccessful, with elimination
of acetic acid to give the corresponding nitrile being a significant
competing process. Employing the pivaloyl oxime ester (in the
hope that the less acidic pivalic acid would prove a worse leaving
group and slow elimination) was also unsuccessful.
Nevertheless, the formation of 7 shows for the first time that
aldoxime esters are capable directing groups for rhodium-
catalysed C-H activation and that the electronic directing effect
of the methylenedioxy group translates from the ketoxime series.
a reaction run for 24h
With our optimized conditions in hand, we sought to establish the
scope of the reaction utilizing a broad range of substrates, the
results of which are summarized in Table 2. The isolated yield of
the parent 2-methylisoquinoline 5a was 57%. Electron-
withdrawing substituents had a beneficial effect on yield, with
the p-nitro- and p-trifluoromethyl substrates giving 83% and 82%
yields of 5b/c respectively. In contrast, the presence of an
electron-donating p-methyl group returned a lower yield of 44%.
Halogens were well tolerated, with 8-fluoro- and 6-chloro-,
bromo-, and iodoisoquinolines 5e-h being formed in reasonable
to good yields (41-72%).
3. Conclusion
In conclusion, a C-H activation protocol has been developed for
the synthesis of seventeen 3,4-unsubstituted isoquinolines. The
synthetic utility of vinylic esters as acetylene synthons continues

4
Tetrahedron
to find applicability in C-H activation chemistry. A three-step
1,6-Dimethylisoquinoline (5d) The desired compound was
ACCEPTED MANUSCRIPT
synthesis of a known intermediate 7 in the synthesis of
decumbenine B has additionally demonstrated that aldoximes are
viable substrates for such C-H activation/annulation processes.
isolated as a brown oil (69 mg, 44%) from (E)-1-(p-
tolyl)ethanone O-acetyl oxime (191 mg, 1.00 mmol) following
the general procedure. δH (300 MHz, CDCl3) 8.32 (1H, d, J 5.9),
8.00 (1H, d, J 8.6), 7.56 (1H, s), 7.47-7.39 (2H, m), 2.95 (3H, s),
2.53 (3H, s); δC (75 MHz, CDCl3) 158.0 (C), 141.0 (CH), 140.6
(C), 136.4 (CH), 129.6 (C), 126.2 (CH), 125.8 (C), 125.6 (CH),
119.2 (CH), 21.9 (CH3), 21.7 (CH3); HRMS (ESI+): m/z
calculated for formula C11H12N [MH+] 158.0964; found
158.0962; IR (vmax, solid, cm-1) 1643, 1631, 1403, 1258, 1037.
4. Experimental
The ketoximes 4 were made according to the procedure outlined
by Chiba et al.15a Chromatography: Column chromatography was
peformed with Fischer Matrix silica gel (35-70 µm particles).
SCX catridges: Biotage Isolute SPE Columns 5g SCX-2 25 mL
columns were used. Chemical shifts (δ) and coupling constants
(J) were expressed as parts per million and Hertz, respectively.
Proton (1H) and carbon (13C{1H}) nuclear magnetic resonance
spectra were recorded using a Bruker DPX 300, a Bruker DRX
500 or a Bruker Avance 500 spectrometer using an internal
deuterium lock. High resolution electrospray mass spectra (ESI-
MS) were measured on a Bruker MicroTOF-Q or Bruker MaXis
Impact spectrometer in positive mode.
6-Chloro-1-methylisoquinoline (5e) The desired compound was
isolated as a brown oil (106 mg, 60%) from (E)-1-(4-
chlorophenyl)ethanone O-acetyl oxime (211 mg, 1.00 mmol)
following the general procedure. δH (300 MHz, CDCl3) 8.40 (1H,
d, J 5.8), 8.04 (1H, d, J 9.0), 7.77 (1H, d, J 2.1), 7.52 (1H, dd, J
9.0, 2.1), 7.41 (1H, d, J 5.8), 2.93 (3H, s); δC (75 MHz, CDCl3)
158.7 (C), 143.0 (CH), 136.8 (C), 136.1 (C), 128.0 (CH), 127.4
(CH), 125.9 (CH), 125.7 (C), 118.4 (CH), 22.4 (CH3); HRMS
(ESI+): m/z calculated for formula C10H935ClN [MH+] 178.0418;
found 178.0421; IR (vmax, solid, cm-1) 3390, 3056, 1616, 1562,
1089.
General procedure for the synthesis of isoquinolines: Vinyl
acetate (922 µL, 10.0 mmol) was added to a solution of the
acetylated oxime (1 mmol) in MeOH (0.5 mL, 2 M) with CsOAc
(58 mg, 0.3 mmol) and [Cp*RhCl2]2 (6 mg, 0.01 mmol) in a
septum-topped vial under nitrogen. The reaction vials were
sealed and heated to 60 °C for 48 hours. The crude reaction
mixture was loaded on to a 5 g SCX column that was
subsequently washed with MeOH (2 × 25 mL). The product
eluted with the secondary wash using 0.7 M NH3 in MeOH (2 ×
25 mL) to give the clean product (>90% purity). Products
containing impurities were purified using flash silica
chromatography.
6-Bromo-1-methylisoquinoline (5f) The desired compound was
isolated as a brown oil (159 mg, 72%) from (E)-1-(4-
bromophenyl)ethanone O-acetyl oxime (256 mg, 1.00 mmol)
following the general procedure. δH (300 MHz, CDCl3) 8.38
(1H, d, J 5.8), 7.96-7.90 (2H, m), 7.63 (1H, dd, J 9.0, 1.9), 7.38
(1H, d, J 5.8), 2.91 (3H, s); δC (75 MHz, CDCl3) 158.8 (C), 142.7
(CH), 137.1 (C), 130.6 (CH), 129.3 (CH), 127.4 (CH), 125.9 (C),
124.7 (C), 118.3 (CH), 22.3 (CH3); HRMS (ESI+): m/z calculated
for formula C10H979BrN [MH+] 221.9913; found 221.9915; IR
(vmax, solid, cm-1) 1611, 1560, 1393, 1077.
6-Iodo-1-methylisoquinoline (5g) The desired compound was
isolated as a tan crystalline solid (172 mg, 64%) from (E)-1-(4-
iodophenyl)ethanone O-acetyl oxime (303 mg, 1.00 mmol)
following the general procedure. The product was crystallized
from EtOAc–hexane. M.p. 132-134 °C (EtOAc–hexane); δH
(300 MHz, CDCl3) 8.41 (1H, d, J 5.9), 8.24 (1H, d, J 1.1), 7.88-
7.84 (2H, m), 7.42 (1H, d, J 5.8), 2.96 (3H, s); δC (75 MHz,
CDCl3) 158.8 (C), 142.7 (CH), 137.5 (C), 136.1 (CH), 136.0
(CH), 127.2 (CH), 126.3 (C), 118.2 (CH), 97.1 (C), 21.6 (CH3);
HRMS (ESI+): m/z calculated for formula C10H9IN [MH+]
269.9774; found 269.9774; IR (vmax, solid, cm-1) 1607, 1558,
1392, 1072.
1-Methylisoquinoline (5a) The desired compound was isolated
as a brown oil (82 mg, 57%) from (E)-acetophenone O-acetyl
oxime (177 mg, 1.00 mmol) following the general procedure. δH
(300 MHz, CDCl3) 8.37 (1H, d, J 5.7), 8.08 (1H, d, J 7.6), 7.77
(1H, d, J 7.8 Hz), 7.68-7.60 (1H, m), 7.60-7.52 (1H, m, H), 7.48
(1H, d, J 5.8), 2.94 (3H, s); δC (75 MHz, CDCl3) 158.6 (C), 141.8
(CH), 135.8 (C), 129.9 (CH), 127.2 (2 signals, C and CH), 127.0
(CH), 125.6 (CH), 119.3 (CH), 22.4 (CH3); LRMS (ESI+): m/z
144.0 [MH+]; IR (vmax, film, cm-1) 2968, 1623, 1563, 1391. Data
consistent with the literature.30
1-Methyl-6-nitroisoquinoline (5b) The desired compound was
isolated as a brown oil (156 mg, 83%) from (E)-1-(4-
nitrophenyl)ethanone O-acetyl oxime (222 mg, 1.00 mmol)
following the general procedure. δH (300 MHz, CDCl3) 8.72 (1H,
d, J 2.0), 8.56 (1H, d, J 5.8), 8.36-8.24 (2H, m), 7.69 (1H, d, J
5.8), 3.02 (3H, s); δC (75 MHz, CDCl3) 159.3 (C), 148.0 (C),
143.9 (CH), 135.2 (C), 129.1 (C), 127.8 (CH), 123.5 (CH), 120.4
(2 signals, 2 x CH), 22.7 (CH3); HRMS (ESI+): m/z calculated for
8-Fluoro-1-methylisoquinoline (5h) The desired product was
isolated as
a brown oil (66 mg, 41%) from (E)-1-(2-
fluorophenyl)ethanone O-acetyl oxime (195 mg, 1.00 mmol)
following the general procedure. The material was purified by
column chromatography using 0-100% EtOAc in hexane without
the use of an SCX column. RF 0.73 (50% EtOAc in pentane); δH
(300 MHz, CDCl3) 8.37 (1H, d, J 5.8), 7.56-7.52 (2H, m), 7.45
(1H, dd, J 5.8, 2.7), 7.22-7.14 (1H, m), 3.05 (3H, d, J 7.0); δC (75
MHz, CDCl3) 160.0 (d, J 256.8, C), 156.8 (d, J 5.9, C), 142.3 (d,
J 1.8, CH), 138.5 (d, J 3.5, C), 130.4 (d, J 9.3, CH), 123.3 (d, J
4.5, CH), 118.7 (d, J 3.7, CH), 118.4 (d, J 14.1, C), 112.4 (d, J
23.2, CH), 26.8 (d, J 10.7, CH3); HRMS (ESI+): m/z calculated
formula C10H9N2O2 [MH+] 189.0659; found 189.0660; IR (vmax
,
solid, cm-1) 3074, 1535, 1344, 906.
1-Methyl-6-(trifluoromethyl)isoquinoline (5c) The desired
compound was isolated as a brown oil (174 mg, 82%) from (E)-
1-(4-(trifluoromethyl)-phenyl)ethanone O-acetyl oxime (245 mg,
1.00 mmol) following the general procedure. δH (300 MHz,
CDCl3) 8.49 (1H, d, J 5.8), 8.22 (1H, d, J 8.8), 8.09 (1H, dt, J 1.9,
1.0), 7.75 (1H, dd, J 8.8, 1.8), 7.57 (1H, d, J 5.8), 2.99 (3H, s); δC
(75 MHz, CDCl3) δ 158.9 (C), 143.2 (CH), 135.0 (C), 131.6 (q, J
32.6, C), 128.3 (C), 126.9 (CH), 124.9 (q, J 4.4, CH), 123.9 (q, J
271.0, C), 122.7 (q, J 3.1, CH), 119.6 (CH), 22.4 (CH3); HRMS
(ESI+): m/z calculated for formula C11H9F3N [MH+] 212.0682;
found 212.0690; IR (vmax, solid, cm-1) 3060, 1590, 1574, 1340,
1237, 1127.
for formula C10H9FN [MH+] 162.0714; found 162.0709; IR (νmax
,
film, cm-1): 2932, 1629, 1565, 1385, 1346, 1325, 1260, 1223,
1118, 1017.
8-Methoxy-1-methylisoquinoline (5i) The desired product was
isolated as
a brown oil (23 mg, 14%) from (E)-1-(2-
methoxyphenyl)ethanone O-acetyl oxime (207 mg, 1.00 mmol)
following general procedure E. The material was purified by
column chromatography using 0-100% EtOAc in hexane without
the use of an SCX column. RF 0.65 (50% EtOAc in pentane); δH
(300 MHz, CDCl3) 8.31 (1H, d, J 5.7), 7.53 (1H, t, J 8.0), 7.40

5
(1H, d, J 5.7), 7.32 (1H, d, J 7.6), 6.88 (1H, d, J 7.8), 3.97 (3H,
2936, 2837, 1625, 1588, 1563, 1506, 1411, 1273, 1262, 1241,
1222, 1183, 1055, 1027.
ACCEPTED MANUSCRIPT
s), 3.10 (3H, s); δC (75 MHz, CDCl3) 158.6 (C), 158.2 (C), 142.1
(CH), 138.9 (C), 130.3 (CH), 120.6 (C), 119.5 (CH), 119.1 (CH),
106.4 (CH), 55.6 (CH3), 28.9 (CH3); HRMS (ESI+): m/z
calculated for formula C11H12NO [MH+] 174.0913; found
174.0910; IR (νmax, film, cm-1): 2970, 2934, 1619, 1561, 1457,
1359, 1344, 1327, 1272, 1231, 1067.
7-Bromo-1-methylisoquinoline
(5m)
and
5-bromo-1-
methylisoquinoline (5m’) The regioisomeric compounds were
isolated as an inseparable 1:2.7 mixture of 5-bromo-1-
methylisoquinoline 5m and 7-bromo-1-methylisoquinoline 5m’
in the form of a brown oil (131 mg, 50%) from (E)-1-(3-
bromophenyl)ethanone O-acetyl oxime (256 mg, 1.00 mmol)
following the general procedure. The material was purified by
column chromatography using 0-100% EtOAc in hexane without
the use of an SCX column. RF 0.58 (50% EtOAc in pentane); δH
(300 MHz, CDCl3) 8.38 (1H, d, J 5.8), 8.20 (0.73H, d J 1.7), 8.03
(0.27H, dd, J 8.4, 0.9), 7.89 (0.27H, dd, J 7.5, 0.9), 7.81 (0.27H,
d, J 6.0, H4), 7.69 (0.73H, dd, J 8.7, 1.8), 7.61 (0.73H, d, J 8.7),
7.42 (0.73H, d, J 5.8), 7.37 (0.27H, t, J 8.0), 2.93 (0.81H, s), 2.88
(2.19H, s); δC (75 MHz, CDCl3) 159.0 (C, minor), 157.8 (C,
major), 143.0 (CH, minor), 142.1 (CH, major), 135.1 (C, minor),
134.4 (C, major), 133.8 (CH, minor), 133.5 (CH, major), 129.0
(CH, major), 128.6 (C, minor), 128.5 (C, major), 128.1 (CH,
major), 127.4 (CH, minor), 125.4 (CH, minor), 122.3 (C, minor),
120.8 (C, major), 119.0 (CH, major), 118.2 (CH, minor), 22.5
(CH3, minor), 22.3 (CH3, major); HRMS (ESI+): m/z calculated
for formula C10H979BrN [MH+] 221.9913; found 221.9912; IR
(νmax, film, cm-1): 2919, 1579, 1557, 1488, 1400, 1365, 1346,
1299, 1070.
6-Methoxy-1-methylisoquinoline (5j) The desired compound
was isolated as a brown oil (16 mg, 9%) from (E)-1-(4-
methoxyphenyl)ethanone O-acetyl oxime (207 mg, 1.00 mmol)
following the general procedure. δH (300 MHz, CDCl3) 8.32 (1H,
d, J 5.8), 8.02 (1H, d, J 9.2), 7.44 (1H, d, J 5.9), 7.23 (1H, dd, J
9.2, 2.6), 7.06 (1H, d, J 2.5), 3.95 (3H, s), 2.92 (3H, s); δC (75
MHz, CDCl3) 160.9 (C), 157.7 (C), 141.4 (CH), 138.2 (C), 127.6
(CH), 120.0 (CH), 119.0 (CH), 104.9 (CH), 55.5 (CH3), 21.6
(CH3) (one Cq not observed); HRMS (ESI+): m/z calculated for
formula C11H12NO [MH+] 174.0913; found 174.0919; IR (vmax
,
solid, cm-1) 3249, 1619, 1514, 1251, 1179, 1029.
1,7-Dimethylisoquinoline (5k) and 1,5-dimethylisoquinoline
(5k’) The regioisomeric compounds were isolated as an
inseparable 1:10 mixture of 1,5-dimethylisoquinoline (X) and
1,7-dimethylisoquinoline (X) in the form of a brown oil (82 mg,
52%) from (E)-1-(3-methylphenyl)ethanone O-acetyl oxime (193
mg, 1.00 mmol) following the general procedure. The material
was purified by column chromatography using 0-100% EtOAc in
hexane without the use of an SCX column. RF 0.56 (50% EtOAc
in pentane); δH (300 MHz, CDCl3) 8.40 (0.09H, d, J 6.0, H3
minor), 8.31 (0.91H, d, J 5.8, H3), 7.96-7.91 (0.09H, m, H8
minor), 7.84 (0.91H, d, J 1.5, H8), 7.67 (0.91H, d, J 8.3, H5), 7.60
(0.09H, d, J 6.1, H4 minor), 7.47 (1H, dd, J 8.4, 1.5, H6 and H6 or
H7 minor), 7.44 (1H, d, J 5.7, H4 and H6 or H7 minor), 2.94
(0.27H, s, 1-Me minor), 2.91 (2.73H, s, 1-Me), 2.63 (0.27H, s, 5-
Me minor), 2.54 (2.73H, s, 7-Me); δC (75 MHz, CDCl3) Signals
for major isomer only: 157.8 (C), 140.8 (CH), 137.0 (C), 134.2
(C), 132.3 (CH), 127.7 (C), 127.1 (CH), 124.6 (CH), 119.2 (CH),
22.2 (CH3), 22.1 (CH3); HRMS (ESI+): m/z calculated for
7-Fluoro-1-methylisoquinoline
(5n)
and
5-fluoro-1-
methylisoquinoline (5n’) The regioisomeric compounds were
isolated as an inseparable 5:1 mixture of 5-fluoro-1-
methylisoquinoline 5n and 7-fluoro-1-methylisoquinoline 5n’ in
the form of a brown oil (76 mg, 47%) from (E)-1-(3-
fluorophenyl)ethanone O-acetyl oxime (195 mg, 1.00 mmol)
following the general procedure. The material was purified by
column chromatography using 0-100% EtOAc in hexane without
the use of an SCX column. RF 0.56 (50% EtOAc in pentane); δH
(300 MHz, CDCl3) 8.42 (0.83H, d, J 5.9), 8.35 (0.17H, d, J 5.8,
H), 7.85 (0.83H, d, J 8.5), 7.80-7.74 (0.34H, m), 7.71 (0.83H, d,
J 5.9), 7.66 (0.17H, dd, J 9.9, 2.4), 7.52-7.44 (0.83H, m), 7.43-
7.37 (0.17H, m), 7.30 (0.83H, dd, J 9.8, 7.8), 2.93 (2.49H, s),
2.88 (0.51H, s); δC (75 MHz, CDCl3) 160.8 (d, J 248.8, C,
minor), 158.4 (d, J 2.7, C, major), 158.0 (d, J 5.7, C, minor),
158.0 (d, J 253.3, C, major), 141.9 (d, J 1.7, CH, major), 141.0
(d, J 2.6, CH, minor), 133.0 (C, CH, minor), 129.8 (d, J 8.5, CH<
minor), 128.3 (d, J 7.9, C, minor), 128.6 (d, J 4.6, C, major),
126.8 (d, J 7.9, CH, major), 126.6 (d, J 17.5, C, major), 121.4 (d,
J 4.4, CH, major), 120.5 (d, J 25.3, CH, minor), 119.0 (CH,
minor), 113.5 (d, J 19.2, CH, major), 111.9 (d, J 4.6, CH, major),
109.2 (d, J 21.1, CH, minor), 22.5 (CH3, major), 22.1 (CH3,
minor); HRMS (ESI+): m/z calculated for formula C10H9FN
[MH+] 162.0714; found 162.0718; IR (νmax, film, cm-1): 2970,
2926, 1632, 1591, 1498, 1414, 1389, 1356, 1237, 1156.
formula C11H12N [MH+] 158.0964; found 158.0961; IR (νmax
,
film, cm-1): 2919, 1589, 1561, 1434, 1411, 1366, 1309, 1239.
7-Methoxy-1-methylisoquinoline (5l) and 5-methoxy-1-
1
methylisoquinoline (5l’) The H NMR spectrum of the crude
reaction indicated a 1:1.2 mixture of the 7-:5-methoxy-1-
methylisoquinolines.
Mixed fractions of 5-methoxy-1-
methylisoquinoline 5l and 7-methoxy-1-methylisoquinoline 5l’
(51 mg, 29%, 1:5) and pure fractions of 5-methoxy-1-
methylisoquinoline 5l (49 mg, 29%) were isolated in the form of
brown oils (combined yield: 100 mg, 58%, 1:1.4 ratio of 7-:5-)
from (E)-1-(3-methoxyphenyl)ethanone O-acetyl oxime (207 mg,
1.00 mmol) following the general procedure. The material was
purified by column chromatography using 0-100% EtOAc in
hexane without the use of an SCX column. 7-Methoxy-1-
methylisoquinoline (5l): RF 0.5 (50% EtOAc in pentane); δH
(300 MHz, CDCl3) 8.27 (1H, d, J 5.7), 7.68 (1H, d, J 8.9), 7.41
(1H, d, J 5.7), 7.30 (1H, dd, J 8.9, 2.5), 7.25 (1H, d, J 2.5), 3.93
(3H, s), 2.89 (3H, s); δC (75 MHz, CDCl3) 158.2 (C), 156.9 (C),
134.0 (CH), 131.4 (C), 128.8 (CH), 128.6 (C), 122.7 (CH), 119.1
(CH), 103.5 (CH), 55.5 (CH3), 22.4 (CH3); IR (νmax, film, cm-1):
2957, 2935, 2836, 1621, 1585, 1495, 1446, 1412, 1389, 1353,
1261, 1248, 1181, 1041. 5-Methoxy-1-methylisoquinoline (5l’):
RF 0.3 (50% EtOAc in pentane); δH (300 MHz, CDCl3) 8.38 (1H,
d, J 5.9), 7.88 (1H, d, J 5.9), 7.65 (1H, d, J 8.5, 0.7), 7.47 (1H, t,
J 8.1), 6.97 (1H, dd, J 7.7, 0.7), 3.98 (3H, s), 2.93 (3H, s); δC (75
MHz, CDCl3) 158.0 (C), 155.0 (C), 141.5 (CH), 128.7 (C), 128.3
(C), 127.0 (CH), 117.5 (CH), 113.6 (CH), 107.4 (CH), 55.8
(CH3), 22.8 (CH3); HRMS (ESI+): m/z calculated for formula
C11H12N [MH+] 174.0913; found 174.0908; IR (νmax, film, cm-1):
6-Methyl-[1,3]dioxolo[4,5-f]isoquinoline (5o) The desired
compound was isolated as a brown oil (58 mg, 36%) after
column chromatography using 10-30% EtOAc in hexane, from
(E)-1-(benzo[d][1,3]dioxol-5-yl)ethanone O-acetyl oxime (221
mg, 1.00 mmol) following the general procedure. δH (300 MHz,
CDCl3) 8.31 (1H, d, J 5.9), 7.74 (1H, d, J 8.7), 7.47 (1H, d, J
5.9), 7.26 (1H, d, J 8.7), 6.22 (2H, s), 2.92 (3H, s); δC (75 MHz,
CDCl3) 158.9 (C), 146.5 (C), 141.6 (CH), 140.8 (C), 123.9 (C),
122.0 (C), 120.6 (CH), 111.4 (CH), 110.9 (CH), 102.3 (CH2),
23.0 (CH3); HRMS (ESI+): m/z calculated for formula C11H10NO2
[MH+] 188.0706; found 188.0700; IR (vmax, solid, cm-1) 1646,
1594, 1471, 1428, 1284, 1052.
1-Methylbenzo[h]isoquinoline (5p) The desired product was
isolated as a brown amorphous solid (46 mg, 24%) from (E)- and
(Z)-1-(naphthalene-1-yl)ethanone O-acetyl oxime (229 mg, 1.00

6
Tetrahedron
ACCEPTED MANUSCRIPT
10. Yang Y-Y, Shou W-G, Chen Z-B, Hong D, Wang Y-G J. Org.
mmol) (E:Z, 3:1) following the general procedure. The material
Chem. 2008; 73: 3928-3930.
was purified by column chromatography using 0-100% EtOAc in
hexane without the use of an SCX column. RF 0.61 (50% EtOAc
in pentane); δH (500 MHz, CDCl3) 8.89 (1H, d, J 8.5), 8.59 (1H,
d, J 5.3), 7.96 (1H, dd, J 7.8, 1.5), 7.91 (1H, d, J 8.7), 7.74 (1H,
ddd, J 8.6, 7.0, 1.6), 7.67 (1H, d, J 8.7), 7.67 (1H, ddd, J 8.0, 7.1,
1.1), 7.60 (1H, d, J 5.3), 3.35 (3H, s); δC (75 MHz, CDCl3) 157.0
(C), 143.1 (CH), 138.0 (C), 133.6 (C), 131.9 (CH), 130.5 (C),
129.3 (CH), 127.2 (CH), 126.8 (CH), 126.0 (CH), 125.5 (C),
120.4 (CH), 30.3 (CH3); HRMS (ESI+): m/z calculated for
11. Gilmore CD, Allan KM, Stoltz BM J. Am. Chem. Soc. 2008;130:
1558-1559.
12. (a) Obika S, Kono H, Yasui Y, Yanada R, Takemoto Y J. Org.
Chem. 2007; 72: 4462-4468;
(b) Hui BW-Q, Chiba S Org. Lett. 2009; 11: 729-732;
(c) Yang D, Burugupalli S, Daniel D, Chen Y J. Org. Chem. 2012;
77: 4466-4472;
(d) Fischer D, Tomeba H, Pahadi NK, Patil NT, Huo Z,
Yamamoto Y J. Am. Chem. Soc. 2008, 130, 15720-15721;
(e) Niu Y-N, Yan Z-Y, Gao G-L, Wang H-L, Shu X-Z, Ji K-G,
Liang Y-M J. Org. Chem. 2009; 74: 2893-2896;
(f) Parthasarathy K, Cheng C-H J. Org. Chem. 2009; 74: 9359-
9364;
formula C14H12N [MH+] 194.0964; found 194.0961; IR (νmax
,
film, cm-1): 2969, 2929, 1675, 1588, 1448, 1416, 1382, 1248.
(E)-Benzo[d][1,3]dioxole-5-carbaldehyde O-acetyl oxime (6)
Acetyl chloride (1.85 mL, 15.0 mmol) was added to a solution of
(E)-benzo[d][1,3]dioxole-5-carbaldehyde oxime31 (1.65 g, 10.0
mmol) in pyridine (10 mL, 2.0 M) with catalytic DMAP (5 mg).
After 4 hours, water (30 mL) was added to quench the reaction
and the product was extracted with EtOAc (2 × 50 mL). The
organic layers were combined and washed with 1 N HCl (50
mL), brine (50 mL), dried with MgSO4, filtered and concentrated
in vacuo. The crude material was crystallised from Et2O–pentane
to afford a colourless crystalline solid (1.94 g, 73%). M.p. 107-
109 °C (EtOAc–pentane); δH (300 MHz, CDCl3) 8.24 (1H, s),
7.35 (1H, d, J 1.6), 7.08 (1H, dd, J 8.0, 1.6), 6.83 (1H, d, J 8.0),
6.03 (2H, s), 2.22 (3H, s); δC (75 MHz, CDCl3) 168.9 (C), 155.6
(CH), 151.0 (C), 148.6 (C), 125.3 (CH), 124.4 (C), 108.6 (CH),
106.7 (CH), 101.9 (CH2), 19.8 (CH3); HRMS (ESI+): m/z
calculated for formula C10H10NO4 [MH+] 208.0604; found
208.0601; IR (νmax, solid, cm-1): 2914, 2855, 1757, 1596, 1508,
1493, 1439, 1359, 1338, 1253, 1209, 1100, 1035, 1001.
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[1,3]Dioxolo[4,5-f]isoquinoline (7) The desired compound was
isolated as a brown amorphous solid (45 mg, 26%) from (E)-
benzo[d][1,3]dioxole-5-carbaldehyde O-acetyl oxime (207 mg,
1.00 mmol) following the general procedure. The remaining
material contained benzo[d][1,3]dioxole-5-carbonitrile. δH (300
MHz, CDCl3) 9.16 (1H, s), 8.43 (1H, d, J 5.8), 7.60-7.57 (2H,
m), 7.29 (1H, d, J 8.7), 6.23 (2H, s); δC (75 MHz, CDCl3) 152.9
(CH), 147.1 (C), 142.8 (C), 140.3 (CH), 125.3 (C), 122.9 (CH),
121.8 (C), 112.7 (CH), 111.8 (CH), 102.5 (CH2); LRMS (ESI+):
m/z 174.1 [MH+]; IR (νmax, solid, cm-1): 2897, 1648, 1549, 1466,
1431, 1369, 1287, 1261, 1070, 1050, 1020. Spectral data
consistent with the literature.28
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Acknowledgments
25. For other uses of vinyl acetate in C-H activation reactions, see: (a)
Otley KD, Ellman JA Org. Lett. 2015; 17: 1332-1335;
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We thank AstraZeneca and the EPSRC for financial support
(CASE award to NJW).
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