4-Substituted 5-nitroisoquinolin-1-ones from intramolecular Pd-catalysed reaction of N-(2-alkenyl)-2-halo-3-nitrobenzamides

Article abstract of DOI:10.1016/j.tet.2009.04.007

4-Methyl- and 4-benzyl-5-aminoisoquinolin-1-ones are close analogues of the water-soluble PARP-1 inhibitor 5-AIQ. Their synthesis was approached through Pd-catalysed cyclisations of N-(2-alkenyl)-2-iodo-3-nitrobenzamides. Reaction of N,N-diallyl-2-iodo-3-nitrobenzamide with Pd(PPh₃)₄ gave a mixture of 2-allyl-4-methyl-5-nitroisoquinolin-1-one and 2-allyl-4-methylene-5-nitro-3,4-dihydroisoquinolin-1-one. N-Benzhydryl-N-cinnamyl-2-iodo-3-nitrobenzamide similarly gave 2-benzhydryl-4-benzyl-5-nitroisoquinolin-1-one and 2-benzhydryl-4-benzylidene-5-nitro-3,4-dihydroisoquinolin-1-one. The isomeric products are not interconvertible. A deuterium-labelling study indicated that the isomers were formed by different pathways: a π-allyl-Pd route and the classical Heck route. The corresponding secondary amides N-allyl-2-iodo-3-nitrobenzamide and N-((substituted)-cinnamyl)-2-iodo-3-nitrobenzamide gave good yields of the required 4-methyl- and 4-((substituted)-benzyl)-5-nitroisoquinolin-1-ones, respectively, under optimised conditions (Pd(PPh₃)₄, Et₃N, Bu₄NCl, 150 °C, rapid heating). Hydrogenation of the nitro groups gave 4-methyl- and 4-benzyl-5-aminoisoquinolin-1-ones, which were potent inhibitors of PARP-1 activity.

Full text of DOI:10.1016/j.tet.2009.04.007

Tetrahedron 65 (2009) 4751–4765
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
4-Substituted 5-nitroisoquinolin-1-ones from intramolecular Pd-catalysed
reaction of N-(2-alkenyl)-2-halo-3-nitrobenzamides
,
Archana Dhami a, Mary F. Mahon b, Matthew D. Lloyd a, Michael D. Threadgill a
*
a Medicinal Chemistry, Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK
b X-ray Crystallography Unit, Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
4-Methyl- and 4-benzyl-5-aminoisoquinolin-1-ones are close analogues of the water-soluble PARP-1 in-
hibitor 5-AIQ. Their synthesis was approached through Pd-catalysed cyclisations of N-(2-alkenyl)-2-iodo-
3-nitrobenzamides. Reaction of N,N-diallyl-2-iodo-3-nitrobenzamide with Pd(PPh3)4 gave a mixture of
2-allyl-4-methyl-5-nitroisoquinolin-1-one and 2-allyl-4-methylene-5-nitro-3,4-dihydroisoquinolin-1-
one. N-Benzhydryl-N-cinnamyl-2-iodo-3-nitrobenzamide similarly gave 2-benzhydryl-4-benzyl-5-nitro-
isoquinolin-1-one and 2-benzhydryl-4-benzylidene-5-nitro-3,4-dihydroisoquinolin-1-one. The isomeric
products are not interconvertible. A deuterium-labelling study indicated that the isomers were formed by
Received 14 January 2009
Received in revised form 13 March 2009
Accepted 2 April 2009
Available online 9 April 2009
different pathways: a p-allyl-Pd route and the classical Heck route. The corresponding secondary amides
N-allyl-2-iodo-3-nitrobenzamide and N-((substituted)-cinnamyl)-2-iodo-3-nitrobenzamide gave good
yields of the required 4-methyl- and 4-((substituted)-benzyl)-5-nitroisoquinolin-1-ones, respectively,
under optimised conditions (Pd(PPh3)4, Et3N, Bu4NCl, 150 ꢀC, rapid heating). Hydrogenation of the nitro
groups gave 4-methyl- and 4-benzyl-5-aminoisoquinolin-1-ones, which were potent inhibitors of PARP-1
activity.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Poly(ADP-ribose)polymerase-1 (PARP-1; EC 2.4.2.30) is a consti-
tutively expressed enzyme that is located in the nuclei of most cell
types. It is an essential component of the system, which detects
damaged sites on DNA and initiates repair of single-strand breaks.1–3
Inhibition of PARP-1 activity (and, indeed, of other PARP isoforms)
has a large number of potential therapeutic applications.4 Inhibitors
of PARP-1 activity act as radiosensitising5,6 and chemosensitising7–9
agents in cancer therapy and there are recent indications that PARP-1
inhibitors may have activity against cancer as single agents in BRCA-
2-deficient tumours10,11 and as antimetastatic agents.12,13
No substituent
permitted
Conformation
of amide
O
H
N
R
Bulky group
tolerated /
preferred
1
O
O
O
O
H
N
H
N
H
H
The consensus pharmacophore for inhibition of PARP-1,4 de-
veloped by classical structure–activity relationship (SAR) studies
and by modelling using the X-ray crystal structure of the catalytic
(NADþ-binding) domain, is a primary or secondary benzamide, with
the amide N–H and carbonyl conformationally constrained relative
to the benzene ring (1, Fig. 1). Examples of potent inhibitors include
the isoquinolin-1-ones 2 (and their 3,4-dihydro analogues),5 the 4-
benzylphthalazin-1-ones 4,14,15 the tricyclic lactams 57,8 and the
benzimidazole-4-carboxamides 6.16 In 6, the carboxamide is held in
N
N
R
NH2
3
Ar
2
4
O
H
N
N
H
N
N
R
N
HN
R
5
6
* Corresponding author. Tel.: þ44 1225 386840; fax: þ44 1225 386114.
E-mail address: m.d.threadgill@bath.ac.uk (M.D. Threadgill).
Figure 1. Structures of the consensus pharmacophore for PARP-1 inhibition 1 and of
types of potent inhibitor 2–6. Compound 3 is the potent water-soluble inhibitor 5-AIQ.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.007

4752
A. Dhami et al. / Tetrahedron 65 (2009) 4751–4765
an intramolecularly hydrogen-bonded ring, rather than in a het-
erocyclic covalently bonded ring. Many inhibitors conforming to
that pharmacophore have very limited solubility in water but we
have shown 5-aminoisoquinolin-1(2H)-one (5-AIQ, 3) to be highly
soluble,17 as its hydrochloride salt, and to have potent activity
in a wide range of disease models in ischaemia–reperfusion in-
jury,18–20 inflammation21,22 and metastasis.12 We therefore wished
to explore the SAR around the 4-position of this lead compound
through synthesis and preliminary biochemical evaluation of the
4-methyl and 4-benzyl analogues of 5-AIQ.
Three synthetic routes have been reported for the preparation of
5-AIQ 3. All proceed via reduction of the 5-nitro analogue 9 as the
final step (Scheme 1). Wenkert et al.23 and Suto et al.5 used a rather
unreliable Polonowski rearrangement of 5-nitroisoquinoline-1-
oxide 8 (formed by oxidation of 7) to generate 9 in modest overall
yield. Radical bromination of the Ar–Me of 10 followed by dis-
placement of the bromine of 11 with cyanide and selective low-
temperature reduction of the nitrile of 12 led to 9 in 15% overall
yield.24 The most efficient synthesis of 9, and thence 3, reported to
date comprises condensation of 10 with dimethylformamide
dimethylacetal, with hydrolysis of the intermediate enamine and
cyclisation during chromatography on wet silica, to form the iso-
coumarin 13, which can be readily converted into 9 with ammonia;
the overall yield is 39%.18 However, none of these routes is adapt-
able for synthesis of analogues carrying substituents on the het-
erocyclic ring24,25 and it was necessary to devise a novel route to
such compounds. Our studies on development of such a route to
5-amino-4-methylisoquinolin-1-one and 5-amino-4-benzylisoqui-
nolin-1-one are reported below.
The intramolecular version of the Heck reaction has been used to
assemble a variety of carbocycles and oxygen- and nitrogen-het-
erocycles.26 In the formation of isoquinolin-1-ones, cyclisation of N-
allyl-2-iodobenzamides with Pd catalysts has been reported to give
the direct Heck products (4-alkylidine-3,4-dihydroisoquinolin-1-
ones) or products of Heck coupling preceded or succeeded by
migration of the C]C double bond either away from the heterocycle
(4-ethenyl-3,4-dihydroisoquinolin-1-ones) or into the heterocycle
(3-alkylisoquinolin-1-ones). Examples are shown in Scheme 2;
the secondary amide 14 gives the dihydroisoquinolin-1-one 15 with
the exocyclic double bond, without double bond migration;27 the N-
allyl imide 16 gives a mixture of 17, where the C]C remains in situ,
and 18, where the C]C has migrated away from the ring;28 the
tertiary amide 19 gives a very high yield of the 3-methylisoquinolin-
1-one 20 with C]C migration into the ring.29 Interestingly, in the
latter case, the authors suggest that the ‘unmigrated’ direct Heck
product is formed first and that migration of the C]C into the ring
occurs from an intermediate 3-methylene-3,4-dihydroisoquinolin-
1-one.
O
Me
Me
O
O
O
O
i
N
H
NH
Me
I
CO2Me
CO2Me
14
15
O
Boc
N
ii
N
Boc
I
Me
Me
Me
16
17
+
Boc
N
Me
18
t
t
O
I
CONHBu
iii
CONHBu
N
Ar
N Ar
Me
20
19
Scheme 2. Literature examples of formation of the isoquinolin-1-one ring by intra-
molecular Pd-catalysed cyclisation of N-allyl-2-iodobenzamides. Reagents and condi-
tions: (i) Pd(OAc)2, PPh3, Et3N, MeCN, 70 ꢀC; (ii) Pd(OAc)2, PPh3, TPAB, DMF, 80 ꢀC; (iii)
Pd(OAc)2, PCy3, DMA, 100 ꢀC.
None of the reported studies use N-allyl-3-substituted-2-iodo-
benzamides; the presence of an electron-withdrawing and bulky
nitro group (required for synthesis of the 5-AIQ derivatives)
flanking the iodine was thought to be likely to influence the out-
come of the Pd-catalysed reactions. Moreover, the literature pre-
cedents were not consistent as to the ability of the C]C double
bond to migrate into the ring (as required for the 5-AIQ derivatives).
Thus we undertook a study on the Pd-catalysed reactions of N-allyl-
2-iodo-3-nitrobenzamides with a view to develop a synthesis of
4-alkyl-5-nitroisoquinolin-1-ones and hence 4-alkyl-5-amino-
isoquinolin-1-ones.
2. Chemistry
2.1. Pd-catalysed cyclisation of tertiary N-allyl-2-iodo-
3-nitrobenzamides
Initially, we predicted that the ring-closure reaction would
proceed more efficiently from an N-allyl tertiary amide than from
a secondary amide, since the conformational preference would be
for a Z (trans) amide in the latter, which places the alkene remote
from the iodoarene. 2-Iodo-3-nitrobenzoic acid 21a (prepared from
O
O
CO2Me
CN
CO2Me
Br
N
N
i
ii
vi
v
NH
NH
NO2
NO2
NO2
12
NO2
11
NO2
9
7
8
iii
viii
iv
O
O
O
CO2Me
vii
Me
NH2
NO2
13
NO2
10
3
Scheme 1. Reported syntheses of 5-AIQ 3. Reagents and conditions: (i) H2O2, AcOH; (ii) Ac2O, D; (iii) H2, Pd/C, EtOH, HCl; (iv) Br2, (PhCO2)2, hn, D
; (v) Et4NCN; (vi), iBu2AlH, CH2Cl2,
ꢁ78 ꢀC; (vii) DMFDMA, DMF,
D; (viii) NH3, MeOCH2CH2OH, D.

A. Dhami et al. / Tetrahedron 65 (2009) 4751–4765
4753
3-nitrobenzene-1,2-dioic acid)30 was converted to its acid chloride
22a, from which the N,N-diallyl amide 23 was formed by treatment
with diallylamine (Scheme 3). This tertiary amide is an ideal test
substrate, since it carries two allyl groups; thus one will always be
in an apposite conformation for Pd-catalysed cyclisation. However,
a preliminary MM2 energy minimisation on the structure of 23
indicated a conformation in which the amide carbonyl should be
approximately orthogonal to the benzene ring (Fig. 2), owing to
steric interactions with the large adjacent iodine. This would make
the molecule chiral, with the asymmetric centre located in the
centre of the Ar–C bond. This chirality means that not only are
the two allyl groups inequivalent (owing to restricted amide C–N
bond rotation) but also the two aliphatic methylenes are each
diastereotopic. This was evident in the 1H NMR spectrum, which
showed different chemical shifts for each of the four
N(CH2CH]CH2)2 protons with appropriate geminal couplings.
Treatment of 23 with tetrakis(triphenylphosphine)palladium(0)
(5 mol %) and triethylamine in boiling acetonitrile (80 ꢀC) for 2 days
gave a high yield (79%) of an inseparable mixture of the isomers 24
and 25 in the molar ratio 1:2. The latter is derived from direct Heck
cyclisation of 23, without prior C]C bond migration, and it was
proposed that the former, required, isomer may be formed by Pd-
catalysed migration of the double bond into conjugation with the
amide nitrogen before or after cyclisation. None of the alternative
product (2-allyl-5-nitro-2,3-dihydrobenzo[c]azepin-1-one) of Heck
cyclisation of 23 at the terminal alkene carbon (which is less ste-
rically hindered) was observed. To test whether 24 may have been
formed from 25 by migration of the double bond into a doubly
conjugated system after cyclisation, the mixture of isomers 24 and
25 was exposed to the cyclisation reaction conditions for a pro-
longed period. Examination of the products by 1H NMR revealed
that there was no change in the ratio of isomers, suggesting either
that the isomers were not interconvertible (i.e., 24 was not formed
from 25) or that the 1:2 ratio of isomers with endocyclic or exo-
cyclic C]C was the ratio at equilibrium. Furthermore, several other
sets of catalyst/ligand conditions were investigated but all failed to
effect a change in the ratio. Even treatment of the isomeric mixture
with Pd(PPh3)4 in tetraglyme at increasing temperatures also failed
to change the ratio of isomers, up to ca. 250 ꢀC when decomposition
set in. This contrasts with the very recent proposal of Ardizzoia
et al.31 that 2-allyl-4-methylene-3,4-dihydroisoquinolin-1-one
may isomerise to 2-allyl-4-methylisoquinolin-1-one under similar
Figure 2. MM2-minimised structures of tertiary amides 23 and 30, showing predicted
orthogonality of the amide and the aromatic ring caused by the bulky ortho-iodo
substituent.
Pd-catalysed conditions. These workers reported that the major
product when N,N-diallyl-2-iodobenzamide was treated with
methanol and PdCl2(PPh3)2 in acetonitrile under 100 bar pressure
of carbon monoxide was ꢂ-2-allyl-4-(methoxycarbonylmethyl)-
3,4-dihydroisoquin-1-one.
To approach the 4-benzylisoquinolin-1-one series, an alterna-
tive N-protecting group, benzhydryl, was selected to provide major
steric bulk. As shown in Scheme 3, the required secondary amine 28
was prepared by condensation of cinnamaldehyde 26 with diphe-
nylmethylamine 27. Subsequent reaction with the acid chloride 22a
provided the N-cinnamyl-N-diphenylmethyl tertiary amide 30.
MM2 minimisation studies of the structure of 30 suggested two
low-energy rotamers arising from rotation about the amide C–N
bond (Fig. 2). Both rotamers are also chiral, as the amide is again
orthogonal to the iodobenzene ring. The 1H NMR spectrum of 30
also showed the presence of these rotamers in the ratio 3:4, with
appropriate magnetic inequivalence of the cinnamyl diastereotopic
CH2 protons in each rotamer. Reaction of 30 with Pd(PPh3)4
O
I
O
O
CO2H
I
COCl
I
N
N
N
i
ii
iii
+
NO2
NO2
NO2
NO2 Me
NO2
25
21a
22a
23
24
Ph
Ph
O
Ph
Ph
O
N
Ph
HN
Ph
N
Ph
v
H2N
Ph
iv
vi
O
27
I
NO2
30
Ph
Ph
Ph
Ph
26
28
29
vii
Ph
O
Ph
N
Ph
N
Ph
+
NO2
31
NO2
32
Ph
Ph
Scheme 3. Pd-catalysed cyclisation of N-allyl and N-cinnamyl tertiary amides 23 and 30. Reagents and conditions: (i) SOCl2, DMF, CH2Cl2, 94%; (ii) diallylamine, Et3N, CH2Cl2, 75%;
(iii) (Ph3P)4Pd, Et3N, MeCN, 80 ꢀC, 48 h, 26% (24), 63% (25); (iv) PhMe, Dean–Stark, 110 ꢀC, 24 h, 97%; (v) NaBH4, MeOH, 95%; (vi) 22a, Et3N, CH2Cl2, 54%; (vii) (Ph3P)4Pd, Et3N, EtCN,
100 ꢀC, 48 h, 10% ( ), 31% (32).

4754
A. Dhami et al. / Tetrahedron 65 (2009) 4751–4765
(5 mol %) and triethylamine in boiling propanenitrile (100 ꢀC) for 2
days gave a moderate yield of an inseparable mixture of the isomers
31 and 32 in the molar ratio 1:3, an outcome similar to that of the
cyclisation of 23. As for the diallyl case, the required 4-benzyl-5-
nitroisoquinolin-1-one 31 isomer was the minor product. Minor
changes to the reaction conditions gave similar results, with small
modifications to the ratios of isomers.
has been lost, were not formed. These observations are consistent
with Heck cyclisation by the classical mechanism directly from the
amide 34a to form 35. Interestingly, the 4-benzylisoquinolin-1-ones
observed by 1H NMR were the monodeutero compound 37 with the
deuterium located at the 3-position (i.e., unmigrated with respect to
its initial location in the cinnamyl group in 34) and the undeuterated
isotopomer 31; the isomer 38, which would be one product of Pd-
catalysed C]C migration (and thus H/D migration in the opposite
direction) was not formed. Thus the 4-benzylisoquinolin-1-ones are
not formed by initial double bond migration to intermediates 39
and 40, prior to cyclisation. The remaining plausible mechanism is
loss of D or H from the allylic position in the N-cinnamyl amide to
2.2. Deuterium-labelling studies
To test the hypotheses that the 4-alkylidine-3,4-dihy-
droisoquinolin-1-ones 25 and 32, the major products, had been
formed by Heck cyclisation before C]C bond migration could take
place and that the required 4-alkylisoquinolin-1-ones 24 and 31 were
formed by Pd-catalysed migration of the C]C before Pd-catalysed
coupling/cyclisation, a series of deuterium-labelling experiments
were carried out (Scheme 4). Firstly, one deuterium was introduced
into the methylene of the N-benzhydryl cinnamylamine 33 by re-
duction of the unlabelled imine 28 with sodium borodeuteride. Re-
action with 2-iodo-3-nitrobenzoyl chloride 22a gave the tertiary
amide 34a carrying one deuterium. Recalling that the methylenes of
the two rotamers of the unlabelled analogue 30 are each diaster-
eotopic and inequivalent in the 1H NMR spectrum, the racemic nature
of 34a with respect to the CHD centre was demonstrated in that each
of the methylene 1H signals was diminished by 50% in intensity in the
spectrum of 34a, with respect to that of 30.
generate
p-allyl-Pd species such as 41 and 42, respectively, as in-
termediates. Once formed, these intermediates are committed to
cyclise to 31 and 37, respectively, capturing an H from a source other
than the starting material. Isotopomers 31 and 37 are formed in
equimolar amounts, showing that there is no kinetic deuterium
isotope effect in the breaking of the C–H/D bond in going to
intermediates 41 and 42. These experiments point to two
independent Pd-catalysed reaction pathways leading from the
N-allyl-2-iodobenzamides to the 4-alkylidene-3,4-dihydroiso-
quinolin-1-ones and to the 4-alkylisoquinolin-1-ones. These two
pathways may have different rates and activation energies, in-
dicating that modification of the reaction conditions may modulate
the ratio of the products formed and allow production of a single
(required) isomer.
To investigate this further, iodine was replaced by bromine in the
starting2-halo-3-nitrotertiarybenzamides(Scheme 4). 2-Bromo-3-
nitrobenzoic acid 21b32 was converted to its acid chloride 22b,
which was then coupled with the monodeutero secondary amine 33
to form the tertiary amide 34b. Bromoarenes often undergo classical
Heck couplings more slowly than do iodoarenes33 and it was pro-
posed that this effect may slow the direct Heck cyclisation suffi-
Reaction of 34a with Pd(PPh3)4 and Et3N in refluxing MeCN for 2 h
gave an equimolar mixture of isotopomers 31 and 37 of the 4-ben-
zylisoquinolin-1-ones (minor products) and a single isotopomer 35
of the 4-benzylidene-3,4-dihydroisoquinolin-1-ones (major prod-
uct). The lower temperature and shorter reaction time were chosen
such that unreacted tertiary amide starting material could be re-
covered and its isotopic composition determined; all the recovered
tertiary amide was shown by 1H NMR to be 34a, i.e., it contained one
deuterium at the original position. This demonstrates that molecules
are committed to cyclisation once they had reacted initially with Pd,
as no exchange or migration of the deuterium had occurred in mole-
cules where the cyclisation was aborted. All the 4-benzylidene-3,4-
dihydroisoquinolin-1-one product contained one deuterium which
was shown by 1H NMR to be located at the 3-position and was thus
identified as 35. The isomer 36, where the deuterium has migrated
prior to cyclisation, and the isotopomer 32, where the deuterium
ciently to allow formation of the p-allyl intermediates and thus lead
to greater yields of the 4-benzylisoquinolin-1-one. However, re-
action of 34b with Pd(PPh3)4 and triethylamine in boiling acetoni-
trile (80 ꢀC) again gave 35 as the major product, with equimolar
amounts of the isotopomers 31 and 37 as very minor products. The
similarity of the outcomes of the reactions of 34a and 34b suggests
that the reaction of the Ar–Hal bond may not be rate-limiting or that
breaking of this bond (with insertion of Pd) may be the common first
step in both reaction pathways.
Ph
O
Ph
O
O
O
Ph
O
Ph
O
Ph
H
iii
i
HN
Ph ii
N
Ph
Ph
N
Ph
Ph
Ph
Ph
N
N
Ph
28
D
D
X D
O2N
O2N
O2N
O2N
Ph
Ph
Ph
Ph
D
33
34
35
36 (not formed)
32 (not formed)
Ph
D
O
Ph
O
Ph
CO2H
Br
COCl
Br
iv
N
N
Ph
N
H
H
NO2
NO2
2b
O2N
O2N
O2N
Ph
Ph
Ph
D
21
b
2
37
31
38 (not formed)
O
Ph
O
Ph
Ph
O
Ph
O
Ph
N
D
Ph
N
Ph
N
Ph
Ph
N
Ph
Ph
N
Ph
Ph
X
H
X
X
X D
34
X
X
H
D
H
Pd
H
Pd
H
O2N
O2N
O2N
O2N
O2N
Ph
Ph
D
42
41
39
40
Scheme 4. Deuterium-labelling experiments to study the mechanism of the Pd-catalysed cyclisations: (a) X¼I; (b) X¼Br. Reagents and conditions: (i) NaBD4, MeOH, 99%; (ii) 22a or
22b, Et3N, CH2Cl2, 61% (34a), 54% (34b); (iii) (Ph3P)4Pd, Et3N, EtCN, various conditions; (iv) SOCl2, DMF, CH2Cl2, 86%.

A. Dhami et al. / Tetrahedron 65 (2009) 4751–4765
4755
2.3. Pd-catalysed cyclisation of secondary N-allyl-2-iodo-
3-nitrobenzamides
a mixture of 45 and 46 in which the required 4-methyl-5-nitro-
isoquinolin-1-one 46 predominated (7.3:1 ratio of products) (entry
3). The trend to increase the proportion of 45 in the product mix-
ture was continued to 150 ꢀC, at which temperature the sole iso-
lable product was 45 (entry 4). This effect was only evident when
the reaction mixture was heated rapidly to 150 ꢀC during <1 min;
slower heating to 150 ꢀC led to the formation of significant amounts
of the isomer 46.
As a further investigation of the mechanistic pathways to the
isomeric products, the migration of the C]C double bond in 43
into conjugation with the amide was achieved by treatment with
RuClH(CO)(PPh3)3 in boiling benzene (Scheme 5); this provides
a potential intermediate in a pathway from 43 whence conven-
tional Heck coupling would furnish 45. However, subjection of
this putative intermediate to the optimised Pd-catalysed cycli-
sation conditions gave the reductively deiodinated material 49 as
the sole isolable product, along with a trace of 3-nitrobenzamide
50 arising from decomposition of 49. Since 49 arises from abor-
ted coupling reactions, this observation demonstrates that 48
cannot cyclise under these conditions and is, therefore, not an
intermediate in the reaction pathway from 43 to 45. As with the
In the light of the unfavourable distribution of isomeric products
from the Pd-catalysed cyclisations of the tertiary N-allyl-2-iodo-3-
nitrobenzamides and the later difficulty in removing the N-allyl and
N-benzhydryl protecting groups from 24/25 and 31, respectively,
Pd-catalysed cyclisation of the corresponding secondary amides
was explored. Treatment of the acid chloride 22a with allylamine
under mild conditions gave the expected N-allyl secondary amide
43, along with a minor yield of 44, in which the highly activated
iodine has been lost in an SNAr displacement by another molecule
of allylamine. The structure of 44 was confirmed by an X-ray crystal
structure determination (Fig. 3). Examination of the supramolec-
ular array revealed that molecules link together via intermolecular
hydrogen bonding, involving the hydrogen atom attached to N3 in
one molecule and O3 of a lattice neighbour.
Pd-catalysed cyclisation of the N-allyl tertiary amides, a
p-allyl-
Pd species is therefore likely to be involved in the formation of
the required isomer 45.
Schemes 6 and 7 show the extension of this optimisation of the
conditions to the Pd-catalysed cyclisation of secondary N-cinnamyl
2-iodo-3-nitrobenzamides 63a–d. The four cinnamylamines 53a–
d required for this study are not commercially available. The 4-
unsubstituted cinnamylamine 53a was prepared by displacement
of the bromine of cinnamyl bromide 51 with the anion derived from
trifluoroacetamide, followed by cleavage of the amide in 52 by
hydrolysis or reductively with sodium borohydride (Scheme 6). The
substituted analogues 53b–d were assembled in a different manner
by Heck coupling of a protected allylamine to an appropriate
iodoarene. Thus N-allylphthalimide 54 was coupled in high yields
with 4-iodotoluene and with 4-iodomethoxybenzene to afford the
N-cinnamylphthalimides 55b,c. Hydrazinolysis of the phthalimide
then formed the 4-methyl- and 4-methoxy-cinnamylamines 53b,c.
Reaction of 53a–c with the acid chloride 22a then provided the N-
cinnamyl secondary amides 63a–c. The route to the 3-succinimido
compounds started with condensation of 3-iodoaniline 56 with
succinic anhydride at 190 ꢀC in the absence of solvent to give the
imide 57. The phthalimide protection was not appropriate in this
series, as the hydrazinolysis would also cleave the succinimide.
Thus N-Boc allylamine 59 (prepared from allylamine 58 and di-tert-
butyl dicarbonate) was then Heck coupled with 57, using palladium(II)
acetate. Interestingly, this process did not proceed regiospecifically,
affording a chromatographically inseparable mixture (4:1) of the
required N-Boc cinnamylamine 60 and the isomer 61 where the
coupling has taken place at the more sterically hindered end of the
alkene. This mixture was taken forward into acidolytic deprotection
(giving amines 53d and 62) and reaction with the acid chloride 22a
to give an inseparable 4:1 mixture of the required benzamide 63d
and the isomer 64.
Figure 3. Crystal structure of 44, with crystallographic numbering. Ellipsoids are
represented at the 30% probability level.
Reaction of 43 with Pd(PPh3)4 under the conditions used for
cyclisation of the tertiary amides (Et3N, EtCN, 100 ꢀC) gave the two
cyclised products 45 (4-methyl-5-nitroisoquinolin-1-one) and 46
(4-methylene-5-nitro-3,4-dihydroisoquinolin-1-one) in a 1:1 ratio,
along with the dehalogenated amide 47 (Table 1, entry 1). We have
previously observed reductive dehalogenation as a major side re-
action of attempted Pd-catalysed couplings to the closely related
ester methyl 2-iodo-3-nitrobenzoate, arising from aborted cou-
plings to the severely hindered aryl carbon.34 Moreover, Majumder
et al. very recently found that dehalogenation was the sole outcome
of treatment of the secondary amide N-allyl-2-iodobenzamide
under similar conditions.35 Tetrabutylammonium chloride was
added to modify the reaction conditions for later experiments and
the solvent was changed to DMF to allow a greater range of tem-
peratures to be explored. Running the reaction at 50 ꢀC for 2 days
(entry 2) gave a similar 1:1 ratio of the cyclised products 45 and 46.
Raising the reaction temperature to 100 ꢀC for 2 days led to
Application of the modified cyclisation conditions (Pd(PPh3)4,
Et3N, Bu4NCl, DMF, with rapid heating to 150 ꢀC) to the cyclisation
Table 1
Pd-catalysed cyclisations of 43 under different conditions
Entry
Reagents
Reaction temp
Reaction time
Yield of 45
Yield of 46
Yield of 47
1
2
3
4
Pd(PPh3)4 (5 mol %), Et3N (2 equiv), EtCN
100 ꢀ
C
24 h
48 h
48 h
16 h
29%
27%
51%
65%
29%
27%
7%
23%
27%
13%
0%
Pd(PPh3)4 (5 mol %), Et3N (2 equiv), Bu4NCl, DMF
Pd(PPh3)4 (5 mol %), Et3N (2 equiv), Bu4NCl, DMF
Pd(PPh3)4 (5 mol %), Et3N (2 equiv), Bu4NCl, DMF
50 ꢀ
C
100 ꢀ
C
150 ꢀCa
0%
a
Rapid heating.

4756
A. Dhami et al. / Tetrahedron 65 (2009) 4751–4765
O
I
O
O
COCl
I
i
ii
N
H
NH
NH
NO2
22a
NO2
43
NO2 Me
45
NO2
46
O
O
N
H
N
H
N
H
NO2
44
NO2
47
O
O
I
O
O
Me
Me
iii
iv
N
H
N
H
N
H
NH2
I
NO2
43
NO2
48
NO2
49
NO2
50
Scheme 5. Formation and Pd-catalysed cyclisation of secondary N-allyl amide 43 and effect of migration of C]C before reaction with Pd catalyst. Reagents and conditions: (i)
H2C]CHCH2NH2, Et3N, CH2Cl2, 71% (43), 10% (44); (ii) various Pd catalysts, various conditions (see Table 1); (iii) RuClH(CO)(PPh3)3, benzene, 80 ꢀC, 96%; (iv) Pd(PPh3)4, Et3N, Bu4NCl,
DMF, reflux, 52% (49), trace (50).
dehalogenation) and 3-amino-2-chloro-N-cinnamylbenzamide 68.
R
The latter appears to have been formed by SNAr displacement of
iodine by chloride from the Bu4NCl additive, with subsequent re-
duction of the nitro group to an amine. Of course, the Ar–Cl in-
termediate is much less likely to undergo Pd-catalysed coupling
than the Ar–I starting material but it is unclear why this in-
termediate (putatively 2-chloro-N-cinnamyl-3-nitrobenzamide)
should be selectively reduced at the nitro group. In view of this
unwanted SNAr side reaction, tetrabutylammonium chloride was
replaced by the corresponding iodide for the Pd-catalysed cyclisa-
tions of the N-(4-substituted cinnamyl)benzamides 63b–d, making
the displacement a futile reaction. The 4-(substituted benzyl)iso-
quinolin-1-ones 65b–d and the 4-(substituted benzylidene)-3,4-
dihydroisoquinolin-1-ones 66b–d were again formed in moderate
overall yield, with the ratios of these products ca. 1:1. Significant
amounts of reduced side-products were isolated. N-Cinnamyl-
amides 67b–d were formed by the usual reductive dehalogenation;
unexpected hydrogenation of the C]C double bond then led to the
3-nitro N-(3-phenylpropyl)benzamides 69b,c in two of the exam-
ples. Interestingly, the contaminating starting material 64 in the
succinimido reaction, which formally carries an N-allyl-2-iodo-
benzamide, failed to cyclise and formed only the reductively
dehalogenated product 70. The conventional Heck route is, of
course, blocked owing to the presence of the Ar group at the 2-
position of the N-allyl unit; presumably the presence of this Ar
51: R = Br
i
52: R = F3CCOHN
53a: R = H2N
ii or iii
iv
63a: R = 2-I-3-O2N-benzoylHN
O
v
R
N
R4
O
55b,c: R = PhthHN
54
vi
iv
53b,c: R = H2N
b: R4 = Me
63b,c: R = 2-I-3-O2N-benzoylHN
c: R4 = OMe
O
I
NH2
I
N
vii
O
56
57
58: R = H
59: R = Boc
viii
RHN
RHN
ix
O
O
group also inhibits the formation of
studies are illustrated in Scheme 7.
p-allyl-Pd intermediates. These
N
N
+
O
O
RHN
+
+
+
60
61 R = Boc
62 R = H
64 R = 2-I-3-O2N-benzoyl
x
iv
2.4. Pd-catalysed cyclisation of an N-allylimide
53d
63d
Scheme 8 shows the outcome of a short study on an alternative
approach to favour a conformation suitable for Pd-catalysed cycli-
sation, use of an N-allyl imide. The Boc group was introduced in
high yield at the amide nitrogen of substrate 43 by treatment with
di-tert-butyl dicarbonate and DMAP. Subjection of the imide 71 to
the cyclisation conditions optimised for the formation of 45 from
43 (Pd(PPh3)4, Et3N, Bu4NCl, DMF, 150 ꢀC, rapid heating) gave a 1:1
mixture of the isomeric cyclised products 45 and 46, which lack the
Boc group. Since direct cyclisation of 43 under these conditions
gives 45 as the sole cyclised product, i.e., a different outcome, it is
proposed that cyclisation of the N-allylimide occurs prior to ther-
mal loss of the Boc group.
Scheme 6. The three synthetic routes to N-cinnamyl secondary 2-iodo-3-nitro-
benzamides 63a–c: (a) R4¼H; (b) R4¼Me; (c) R4¼OMe. Reagents and conditions: (i)
H2NCOCF3, KOtBu, THF, 33%; (ii) NH3, aq EtOH, 4 days, 88%; (iii) NaBH4, EtOH, 16 h, 90%;
(iv) 22a, Et3N, CH2Cl2, 74% (63a), 82% (63b), 75% (63b), 25.6% (63d), 6.4% (64); (v) 4-
iodotoluene or 4-iodomethoxybenzene, Pd(OAc)2, Et3N,
D, 82% (55b), 94% (55c); (vi)
N2H4$H2O, EtOH, 65% (53b), 89% (53c); (vii) succinic anhydride, 190 ꢀC, 74%; (viii)
Boc2O, CH2Cl2, 83%; (ix) Pd(OAc)2, Et3N, 29% (60), 7% (61); (x) HCl, CH2Cl2.
of 63a afforded a chromatographically separable mixture of the 4-
benzylisoquinolin-1-one 65a and the isomer 66a in approximately
1:1 ratio in moderate overall yield. Interestingly, two side-products
were also formed, 67a (the expected product of reductive

A. Dhami et al. / Tetrahedron 65 (2009) 4751–4765
4757
O
O
I
O
O
i
N
H
NH
NH
N
H
R4
R4
NO2
O2N
65a-c
O2N
R4
NO2
R4
67a-c
63a-c
66a-c
O
O
I
a: R4 = H
N
H
N
H
b: R4 = Me
c: R4 = OMe
Cl
R4
NO2
NO2
68
69b,c
O
O
O
N
H
N
N
O
O
I
NO2
N
O2N
N
O2N
66d
N
O
O
O
O
O
i
63d
65d
O
O
O
O
N
H
N
H
N
N
H
N
I
O
O
NO2
N
NO2
NO2
O
O
70
67d
70
Scheme 7. Pd-catalysed cyclisations of N-cinnamyl secondary 2-iodo-3-nitrobenzamides 63a–d: (a) R4¼H; (b) R4¼Me; (c) R4¼OMe. Reagents and conditions: (i) e.g. Pd(PPh3)4, Et3N,
Bu4NCl, DMF, reflux, rapid heating (see text and Experimental).
O
I
O
I
NO2
71
iii
O
O
O
O
O
Boc
N
H
N
NH i
NH
NH
Ph
NH
Ph
i
ii
NO2
43
NO2 Me
NH2 Me
NO2
NH2
73
45
72
65a
O
O
O
O
O
NH
NH
Ph
NH
Ph
NH
Ph
ii
+
NH
NH
+
NO2
66a
NH2
NH2
NH2
Ph
NO2 Me
NO2
46
73
74
75 (not formed)
45
Scheme 9. Hydrogenation of 45, 65a and 66a. Reagents: (i) H2, Pd/C, EtOH, aq, HCl,
70%; (ii) H2, Pd/C, EtOH, aq, HCl, 51% (73 from 65a).
Scheme 8. Effect of N-Boc substitution on outcome of Pd-catalysed cyclisation. Reagents
and conditions: i, Boc2O, Et3N, DMAP, CH2Cl2, 92%; ii, Pd(PPh3)4, Et3N, Bu4NCl, DMF,150 ꢀC.
2.5. Reduction of the 5-nitro group
3. Biochemistry
Catalytic hydrogenation was used to convert the 5-nitro groups
of the 4-substituted isoquinolin-1-ones 45 and 65a to provide the
target 5-aminoisoquinolin-1-ones 72 and 73, respectively (Scheme
9). Reduction of the 4-methyl-5-nitro compound 45 to 5-amino-4-
methylisoquinolin-1-one 72 was uneventful and high yielding.
Application of the same procedure to the 4-benzyl analogue 65a
furnished the 5-amino-4-benzylisoquinolin-1-one 73. However,
application of this apparently straightforward process to the 4-
benzylidene-3,4-dihydroisoquinolin-1-one 66a gave only two un-
expected products, 73 and 74. Compound 74 results from reduction
of both the C]C double bond and the nitro group. Interestingly, 73
is a product of reduction of the nitro group and C]C bond migra-
tion. It is not clear whether the bond migration occurs before or
after the reduction but it is catalysed by the Pd metal surface. Un-
fortunately, it was not possible to reduce the nitro groups of 65b–
d cleanly, as the products always comprise inseparable mixtures of
the 5-aminoisoquinolin-1-ones and over-reduced materials.
The 4-substituted 5-AIQ analogues 72 and 73 were evaluated for
inhibition of the enzymatic activity of recombinant human PARP-1
using the Trevigen kit with a protocol modified slightly from the
manufacturer’s instructions.36 5-AIQ 3 was also tested as a positive
control for comparison. The IC50 values are presented in Table 2.
Both 4-substituted 5-AIQs were more potent in this assay than was
the parent 5-AIQ, the 4-methyl compound 73 being 7-fold more
active and the 4-benzyl analogue 74 being 3.5 times more potent.
Table 2
Inhibition of PARP-1 activity by 4-substituted 5-AIQs
a
Compound
IC50
(
mM)
log IC50
3
72
73
1.8
0.25
0.50
0.26ꢂ0.14
ꢁ0.60ꢂ0.28
ꢁ0.34ꢂ0.11
a
Data are the mean of three experiments and are reported as meanꢂSEM.

4758
A. Dhami et al. / Tetrahedron 65 (2009) 4751–4765
These data suggest that substitution in the 4-position with lipo-
philic groups enables the compounds to bind more tightly to the
active site of the enzyme, consistent with the pharmacophore and
with modelling studies.
5.3. 2-Bromo-3-nitrobenzoyl chloride (22b)
2-Bromo-3-nitrobenzoic acid 21b32 (1.0 g, 4.5 mmol) and DMF
(100 mL) were boiled under reflux in SOCl2 (10 mL) for 24 h. Evap-
oration and recrystallisation (Et2O) yielded 22b (1.02 g, 86%) as
white solid: mp 65–67 ꢀC (lit.38 mp 66–66.5 ꢀC); IR nmax 1756, 1534,
4. Conclusion
1345 cmꢁ1; 1H NMR (CD3)2SO
d
7.62 (1H, t, J¼7.9 Hz, 5-H), 7.87 (1H,
dd, J¼8.1, 1.7 Hz, 4-H), 8.03 (1H, dd, J¼8.0, 1.5 Hz, 6-H).
In this paper, we have reported the Pd-catalysed cyclisations of
tertiary and secondary N-allyl and N-cinnamyl 2-iodo-3-nitro-
benzamides to two isomeric products, the 4-alkyl-5-nitroisoquinolin-
1-ones 24, 31, 45 and 65a–c and the 4-alkyl-5-nitro-3,4-dihy-
droisoquinolin-1-ones 25, 32, 46 and 66a–c. A deuterium-labelling
study indicated that the two products may arise from different types of
5.4. N,N-Di(prop-2-enyl)-2-iodo-3-nitrobenzamide (23)
Di(prop-2-enyl)amine (310 mg, 3.2 mmol) was stirred with 2-
iodo-3-nitrobenzoyl chloride 22a (1.0 g, 3.2 mmol) and Et3N
(646 mg, 6.4 mmol) in CH2Cl2 (5 mL) for 30 min. Washing (5% aq
HCl, 5% aq NaHCO3), drying, evaporation and chromatography
(CH2Cl2/EtOAc 20:1) gave 23 (890 mg, 75%) as a pale buff wax: IR
Pd-containing intermediates,
p-allyl-Pd and conventional s-aryl-Pd
species, respectively. Secondary N-allyl-2-iodobenzamides cyclised as
efficientlyas did the tertiaryamides. The ratios of the isomeric products
from the secondary amides 43 and 63a–d varied with the reaction
conditions. In particular, optimum yields of the 4-alkyl-5-nitro-
isoquinolin-1-ones were obtained in the presence of tetrabutyl-
ammonium chloride and with rapid heating to the reaction
temperature of 150 ꢀC, suggesting that the required reaction through
(film) nmax 1733, 1532, 1360 cmꢁ1
;
1H NMR
d
3.63 (1H, dd, J¼16.3,
3.9 Hz, propenyl 1-H), 3.75–3.77 (2H, m, 2ꢃpropenyl 1-H), 4.60
(1H, dd, J¼14.9, 4.3 Hz, propenyl 1-H), 5.12 (1H, dq, J¼17.2, 1.6 Hz,
propenyl 3-H), 5.20 (1H, dq, J¼10.2, 1.2 Hz, propenyl 3-H), 5.30 (1H,
dq, J¼10.6, 1.2 Hz, propenyl 3-H), 5.35 (1H, dq, J¼17.2, 1.2 Hz, pro-
penyl 3-H), 5.64–5.66 (1H, m, propenyl 2-H), 5.94–5.96 (1H, m,
propenyl 2-H), 7.34 (1H, dd, J¼7.6, 1.5 Hz, 6-H), 7.49 (1H, t, J¼7.8 Hz,
the p-allyl-Pd intermediate may need high temperatures and that the
conventional Heck coupling (giving the C]C unmigrated isomers) was
favoured at lower temperatures. A 2-iodo-N-(prop-1-enyl)benzamide
did not cyclise, confirming that it is not an intermediate. Interestingly,
the proportion of the 4-alkylidene-3,4-dihydroisoquinolin-1-one
products was higher when the starting material was an N-cinnamyl
amide than when N-allyl amides were used; this may reflect more
5-H), 7.68 (1H, dd, J¼7.9, 1.5 Hz, 4-H); 13C NMR
d 46.76 (propenyl 1-
C), 50.16 (propenyl 1-C), 85.22 (2-C), 118.46 (propenyl 3-C), 119.06
(propenyl 3-C), 124.63 (4-C), 129.47 (5-C), 129.75 (6-C), 131.78
(propenyl 2-C), 131.95 (propenyl 3-C), 145.88 (1-C), 154.34 (3-C),
169.13 (C]O); MS (EI) m/z 371.9958 (M) (C13H13IN2O3 requires
371.9970).
difficult formation of the
minal aryl group.
p-allyl-Pd species in the presence of the ter-
This Pd-catalysed cyclisation is now available, with careful
control of the reaction conditions, for the future preparation of
a range of 4-substituted-5-nitroisoquinolin-1-ones and thence to
analogues of the potent water-soluble PARP-1 inhibitor, 5-AIQ. Two
4-substituted 5-AIQs do show significantly increased potency for
inhibition of human PARP-1.
5.5. Pd-catalysed cyclisation of23in MeCN: 4-methyl-5-nitro-2-
(prop-2-enyl)isoquinolin-1(2H)-one (24) and 4-methylene-5-
nitro-2-(prop-2-enyl)-3,4-dihydroisoquinolin-1(2H)-one (25)
Compound 23 (310 mg, 0.81 mmol) was boiled under reflux in
dry MeCN (10 mL) with (Ph3P)4Pd (40.3 mg, 35 mmol) and Et3N
(175 mg, 1.7 mmol) for 48 h. The evaporation residue, in EtOAc, was
washed (5% aq HCl, 5% aq NaHCO3) and dried. Evaporation and
chromatography (hexane/EtOAc 4:1) yielded an inseparable mix-
ture of 24 and 25 (1:2) (150 mg, 79%) as a buff oil. IR (film) nmax
5. Experimental
5.1. General
1658, 1531, 1365 cmꢁ1
;
1H NMR (24)
d
2.10 (3H, d, J¼1.2 Hz, Me),
1H NMR spectra were recorded on Varian GX270 or EX400
spectrometer of samples in CDCl3, unless otherwise stated. HMQC
and HMBC were used in each case to assign the 13C NMR spectra. IR
spectra were recorded on a Perkin–Elmer 782 spectrometer as KBr
discs, unless otherwise stated. Mass spectra were obtained using
fast atom bombardment (FAB) ionisation in the positive ion mode,
unless otherwise stated. The chromatographic stationary phase
was silica gel. DMF refers to dimethylformamide. THF (tetrahy-
drofuran) was dried over Na. Solutions in organic solvents were
dried over MgSO4. Solvents were evaporated under reduced pres-
sure. The aq NaHCO3 was saturated. Experiments were conducted
at ambient temperature, unless otherwise stated. Melting points
were measured with a Thermo Galen Kofler block and are
uncorrected.
4.60 (2H, dt, J¼5.7, 1.5 Hz, propenyl 1-H2), 5.18–5.20 (2H, m, pro-
penyl 3-H2), 5.95–5.96 (1H, m, propenyl 2-H), 6.93 (1H, q, J¼1.2 Hz,
3-H), 7.53 (1H, t, J¼7.9 Hz, 7-H), 7.74 (1H, dd, J¼7.8, 1.5 Hz, 6-H),
8.66 (1H, dd, J¼7.8, 1.5 Hz, 8-H); 1H NMR (25)
d 4.12 (2H, s, 3-H2),
4.20 (2H, dt, J¼5.9, 1.5 Hz, propenyl 1-H2), 5.25–5.26 (2H, m, pro-
penyl 3-H2), 5.29 (1H, br s, 4-]CH), 5.45 (1H, s, 4-]CH), 5.81–5.82
(1H, m, propenyl 2-H), 7.47 (1H, t, J¼7.9 Hz, 7-H), 7.70 (1H, dd, J¼8.1,
1.5 Hz, 6-H), 8.31 (1H, dd, J¼7.8, 1.3 Hz, 8-H); 13C NMR (24)
d 15.81
(Me), 50.67 (propenyl 1-C), 108.36 (4-C), 118.74 (propenyl 3-C),
125.95 (7-C), 127.18 (6-C), 131.86 (8-C), 131.99 (propenyl 2-C),
132.60 (10-C), 133.18 (3-C), 133.87 (9-C), 147.33 (5-C), 159.87 (1-C);
13C NMR (25)
d 49.33 (propenyl 1-C), 52.18 (3-C), 118.12 (propenyl
3-C), 119.39 (4-]CH2), 126.60 (6-C), 128.69 (7-C), 129.13 (10-C),
130.68 (9-C),131.55 (4-C),131.78 (8-C),131.89 (propenyl 2-C),147.51
(5-C), 161.05 (1-C).
5.2. 2-Iodo-3-nitrobenzoyl chloride (22a)
5.6. E-N-(Diphenylmethyl)-3-phenylpropenaldimine (28)
2-Iodo-3-nitrobenzoic acid 21a25 (3.0 g, 10 mmol) was boiled
under reflux with DMF (0.2 mL) and SOCl2 (30 mL) for 24 h. Evap-
oration and recrystallisation (hexane) yielded 22a (3.0 g, 94%) as
yellow crystals: mp 71–73 ꢀC (lit.37 mp 70–71 ꢀC); IR nmax (KBr)
Diphenylmethylamine 27 (6.9 g, 38 mmol) and E-3-phenyl-
propenal 26 (5.0 g, 38 mmol) were boiled in toluene (50 mL) in
a Dean–Stark apparatus for 24 h. Evaporation and recrystallisation
(Et2O) gave 28 (11.0 g, 97%) as yellow crystals: Mp 115–117 ꢀC (lit.39
1348 and 1530 (NO2), 1758 (C]O) cmꢁ1 1H NMR (CDCl3)
; d 7.64
(1H, t, J¼7.8 Hz, 5-H), 7.79 (1H, dd, J¼7.8, 1.6 Hz, 4-H), 7.95 (1H, dd,
mp 116–118 ꢀC); IR nmax 1598, 1489, 1444 cmꢁ1; 1H NMR
d
5.48 (1H,
J¼7.8, 1.6 Hz, 6-H).
s, Ph2CH), 6.96 (1H, br d, J¼16.1 Hz, 3-H), 7.06 (1H, dd, J¼16.0,

A. Dhami et al. / Tetrahedron 65 (2009) 4751–4765
4759
8.1 Hz, 2-H), 7.20–7.40 (13H, m, 2ꢃPh0–H5þPh 3,4,5-H3), 7.47 (2H,
d, J¼9.4 Hz, Ph 2,6-H2), 8.18 (1H, dd, J¼8.2, 0.8 Hz, 1-H).
137.95, 147.94 (5-C), 161.52 (1-C). MS (EI) m/z 447.1703 (MþH)
(C29H23N2O3 requires 447.1707).
5.10. -E-1-Deuterio-N-diphenylmethyl-3-phenylprop-2-en-
1-amine (33)
5.7. E-N-Diphenylmethyl-3-phenylprop-2-en-1-amine (29)
NaBH4 (770 mg, 20 mmol) was added to 28 (6.0 g, 20 mmol) in
MeOH (250 mL) at 45 ꢀC for 20 min. The evaporation residue, in
Et2O, was washed (5% aq NaHCO3) and dried. Evaporation gave 2940
(5.8 g, 95%) as a pale yellow semi-solid: IR (film) nmax 3332, 1598,
Compound 28 was treated with NaBD4, as for the synthesis of
29, to give 33 (99%) as a pale yellow semi-solid: IR (film) nmax 3325,
2248, 1599, 1493, 1451 cmꢁ1 1H NMR
; d 2.09 (1H, br s, N–H), 3.61
1492, 1451 cmꢁ1; 1H NMR
d
1.94 (1H, br, N–H), 3.52 (2H, dd, J¼6.2,
(1H, d, J¼6.0 Hz, 1-H), 5.19 (1H, s, Ph2CH), 6.57 (1H, dd, J¼15.8,
6.0 Hz, 2-H), 6.81 (1H, d, J¼15.8 Hz, 3-H), 7.41–7.81 (15H, m, 3ꢃPh–
1.0 Hz, CH2), 5.07 (1H, s, Ph2CH), 6.47 (1H, dt, J¼15.8, 6.0 Hz, 2-H),
H5); 13C NMR
128.27, 128.36, 128.44, 128.46, 131.26, 137.05, 143.82.
d
49.41 (1:1:1t, J¼20 Hz, 1-C), 126.18, 126.96, 127.25,
6.65 (1H, d, J¼15.8 Hz, 3-H), 7.34–7.61 (15H, m, 3ꢃPh–H5).
5.8. N-Diphenylmethyl-2-iodo-3-nitro-N-(3-phenylprop-
2-enyl)benzamide (30)
5.11. -N-(1-Deuterio-3-phenylprop-2-enyl)-N-
diphenylmethyl-2-iodo-3-nitrobenzamide (34a)
Compound 22 (1.5 g, 4.8 mmol) was stirred with 29 (1.43 g,
4.8 mmol) and Et3N (0.97 g, 9.6 mmol) in CH2Cl2 (10 mL) for 30 min.
Washing (5% aq HCl, 5% aq NaHCO3), drying, evaporation and
chromatography (hexane/EtOAc 4:1) gave 30 (1.49 g, 54%) as a pale
buff solid: mp 134–136 ꢀC; IR nmax 1636, 1530, 1360 cmꢁ1; 1H NMR
Compound 22a was treated with 33, as for the synthesis of 30
except that the chromatographic eluant was hexane/EtOAc 6:1, to
give 34a (61%) as pale yellow crystals: mp 135–137 ꢀC; IR nmax 1634,
1529, 1339 cmꢁ1; 1H NMR (
a rotamer) d 3.93–3.94 (1H, m, propenyl
1-H), 5.16 (1H, dd, J¼16.0, 7.0 Hz, propenyl 2-H), 5.40 (1H, d,
showed the presence of two rotamers,
a
and
b
, about the amide
J¼16.0 Hz, propenyl 3-H), 7.29 (1H, s, Ph2CH), 6.90–7.65 (18H, m,
bond, in the ratio 3:4. 1H NMR (
a
rotamer)
d 3.91–4.06 (2H, m,
3ꢃPh–H5þAr 4,5,6-H3); 13C NMR (
a
rotamer)
d
49.25 (t, J¼20.7 Hz,
propenyl 1-H2), 5.20 (1H, dt, J¼15.5, 6.5 Hz, propenyl 2-H), 5.42 (1H,
propenyl 1-C), 61.34 (Ph2CH), 86.08 (2-C), 124.06 (propenyl 2-C),
124.56 (4-C), 126.21, 127.24, 127.26, 127.87, 128.35, 128.46, 128.62,
128.82, 128.84, 129.47, 132.64, 132.69 (propenyl 3-C), 135.61, 138.28,
d, J¼16.0 Hz, propenyl 3-H), 7.31 (1H, s, Ph2CH), 6.9–7.65 (18H, m,
3ꢃPh–H5þAr 4,5,6-H3); 1H NMR (
b rotamer) d 3.99–4.00 (1H, m,
138.84, 146.27 (1-C), 154.30 (3-C), 168.66 (C]O); 1H NMR (
b
propenyl 1-H), 4.81 (1H, dd, J¼14.5, 5.5 Hz, propenyl 1-H), 5.83 (1H,
s, Ph2CH), 5.88 (1H, d, J¼16.0 Hz, propenyl 3-H), 6.0 (1H, dt, J¼16.0,
6.0 Hz, propenyl 2-H), 6.90–7.65 (18H, m, 3ꢃPh–H5þAr 4,5,6-H3);
rotamer)
d
3.89–3.90 (0.5H, m, propenyl 1-H), 4.8 (0.5H, d, J¼5.4 Hz,
propenyl 1-H), 5.78 (1H, s, Ph2CH), 5.84 (1H, dd, J¼16.0, 5.0 Hz,
propenyl 3-H), 5.96 (1H, dd, J¼16.0, 7.5 Hz, propenyl 2-H), 6.9–7.65
13C NMR (
a rotamer) d 49.33 (propenyl 1-C), 61.21 (Ph2CH), 85.89 (2-
(18H, m, 3ꢃPh–H5þAr 4,5,6-H3); 13C NMR (
b rotamer) 46.68 (t,
C),123.91 (propenyl 2-C),124.34 (4-C),126.03,127.16,127.32,127.66,
127.76, 128.26, 128.38, 128.54, 128.84, 129.25, 130.66, 132.73 (pro-
penyl 3-C), 135.45, 138.16, 138.60, 145.95 (1-C), 154.19 (3-C), 168.80
J¼20.7 Hz, propenyl 1-C), 66.84 (Ph2CH), 85.43 (2-C), 123.44 (pro-
penyl 2-C), 124.69 (4-C), 126.21, 126.36, 127.37, 127.89, 128.48,
128.54, 128.74,128.89, 129.38, 130.91,132.95 (propenyl 3-C),136.83,
137.68, 139.53, 145.45 (1-C), 154.48 (3-C), 170.03 (C]O).
(C]O); 13C NMR (
b rotamer) d 46.72 (propenyl 1-C), 66.63 (Ph2CH),
85.18 (2-C), 123.42 (propenyl 2-C), 124.49 (4-C), 126.15, 127.08,
127.58, 127.68, 127.72, 128.16, 128.24, 128.35, 128.63, 128.79, 129.22,
132.36 (propenyl 3-C), 136.63, 137.51, 139.25, 145.17, 154.26, 169.42;
MS (EI) m/z 575.0821 (MþH) (C29H24IN2O3 requires 575.0826).
5.12. Pd-catalysed reaction of 34 in boiling EtCN: 2-
diphenylmethyl-5-nitro-4-phenylmethylisoquinolin-1(2H)-
one (31), 3-deutero-2-diphenylmethyl-5-nitro-4-
phenylmethylisoquinolin-1(2H)-one (37) and -Z-4-
benzylidene-3-deutero-2-diphenylmethyl-5-nitro-
3,4-dihydroisoquinolin-1(2H)-one (35)
5.9. Pd-catalysed cyclisation of 30 in EtCN: 2-diphenylmethyl-
5-nitro-4-phenylmethylisoquinolin-1(2H)-one (31) and Z-4-
benzylidene-2-diphenylmethyl-5-nitro-3,4-
dihydroisoquinolin-1(2H)-one (32)
Compound 34 was treated with (Ph3P)4Pd and Et3N in EtCN, as
for the reaction of 30 except that the reaction time was 2 h, to give
a mixture of 31, 37 and 35 (1H NMR ratio 1:1:40) (85%) as a pale
Compound 30 (500 mg, 0.87 mmol) was boiled under reflux
with (Ph3P)4Pd (50 mg, 44 mmol) and dry Et3N (170 mg, 1.7 mmol)
in dry EtCN (15 mL) for 48 h. The evaporation residue, in EtOAc, was
washed (5% aq HCl, 5% aq NaHCO3) and dried. Evaporation and
chromatography (hexane/EtOAc 4:1) yielded a chromatographi-
cally inseparable mixture of 31 and 32 (160 mg, 41%) (1H NMR
showed the ratio 31/32 to be 1:3) as yellow crystals. Careful ex-
amination of the melting behaviour revealed that the isomers
formed different crystals, one with mp 75–77 ꢀC and one with mp
yellow solid: IR nmax 1654, 1523, 1347 cmꢁ1 1H NMR (31) data as
;
above; 1H NMR (37)
d
3.73 (2H, s, CH2), 6.86–7.30 (15H, m, 3ꢃPh–
H5), 7.42 (1H, s, Ph2CH), 7.53 (1H, t, J¼7.9 Hz, 7-H), 7.81(1H, dd,
J¼7.7, 1.5 Hz, 6-H), 8.74 (1H, dd, J¼7.9, 1.4 Hz, 8-H); 1H NMR (35)
d
4.19 (1H, br s, 3-H), 6.80 (1H, s, ]CH), 7.23 (1H, s, Ph2CH), 6.86–
7.30 (15H, m, 3ꢃPh–H5), 7.52 (1H, t, J¼8.0 Hz, 7-H), 7.77 (1H, dd,
J¼8.0, 1.2 Hz, 6-H), 8.39 (1H, dd, J¼7.9, 1.2 Hz, 8-H); 13C NMR (35)
121–123 ꢀC; IR nmax 1654, 1524, 1347 cmꢁ1; 1H NMR (31)
d
3.75 (2H,
d
43.43 (t, J¼20.7 Hz, 3-C), 60.73 (Ph2CH), 124.87 (4-C), 127.11 (6-C),
s, CH2), 6.54 (1H, s, 3-H), 6.86–7.30 (15H, m, 3ꢃPh-H5), 7.44 (1H, s,
127.52, 127.56, 128.28, 128.34, 128.36, 128.41, 128.43, 128.64, 128.81,
129.07, 132.01 (8-C), 134.61, 134.74 (]CH), 137.92, 137.95, 147.91 (5-
C), 161.48 (1-C). MS (ESI þve) (35/37) m/z 470.1527 (MþNa)
(C129H221H1N2NaO3 requires 470.1591).
Ph2CH), 7.52 (1H, t, J¼7.8 Hz, 7-H), 7.79 (1H, dd, J¼7.5, 1.4 Hz, 6-H),
8.75 (1H, dd, J¼8.2,1.7 Hz, 8-H); 1H NMR (32)
4.24 (2H, d, J¼1.1 Hz,
d
3-CH2), 6.82 (1H, s, ]CH), 7.24 (1H, s, Ph2CH), 6.86–7.30 (15H, m,
3ꢃPh–H5), 7.51 (1H, t, J¼8.2 Hz, 7-H), 7.78 (1H, dd, J¼7.8, 1.3 Hz, 6-
H), 8.41 (1H, dd, J¼7.8, 1.3 Hz, 8-H); 13C NMR (31)
d
35.45 (CH2),
5.13. -2-Bromo-N-(1-deuterio-3-phenylprop-2-enyl)-N-
diphenylmethyl-3-nitrobenzamide (34b)
60.72 (Ph2C), 112.07 (4-C), 125.96 (7-C), 126.59 (6-C), 128.16, 128.39,
128.62, 128.69, 129.05, 131.27, 132.76 (8-C), 133.47 (3-C), 133.38,
137.54, 147.88 (5-C), 159.95 (1-C); 13C NMR (32)
d
43.66 (CH2), 60.77
Compound 22b was treated with 33, as for the synthesis of 30, to
give 34b (54%) as pale buff crystals: mp 114–116 ꢀC; IR nmax 1638,
(Ph2C), 124.93 (4-C), 127.14 (6-C), 127.48, 127.56, 128.30 (7-C),
128.38, 128.42, 128.44, 128.74, 131.15, 131.33, 134.63, 134.75 (]CH),
1532, 1359 cmꢁ1 1H NMR showed the presence of two rotamers,
;

4760
A. Dhami et al. / Tetrahedron 65 (2009) 4751–4765
a
d
and
b
, about the amide bond, in the ratio 2:3; 1H NMR (
a
rotamer)
MS (ESI þve) m/z 205.0608 (MþH) (C10H9N2O3 requires 205.0613).
Further elution gave a mixture of 45 (21 mg, 18%) and 46 (9 mg, 8%)
3.93–3.94 (1H, m, propenyl 1-H), 5.10 (1H, dd, J¼15.9, 6.8 Hz,
propenyl 2-H), 5.41 (1H, d, J¼15.9 Hz, propenyl 3-H), 7.29 (1H, s,
Ph2CH), 6.80–7.46 (17H, m, 3ꢃPh–H5þAr 5,6-H2), 7.74 (1H, dd,
as a pale buff semi-solid: 1H NMR (46)
d
4.22 (2H, d, J¼1.2 Hz, CH2),
5.34 (1H, s, ]CH), 5.50 (1H, s, ]CH), 7.06 (1H, br s, NH), 7.52 (1H, t,
J¼8.2 Hz, 7-H), 7.76 (1H, dd, J¼8.2, 1.4 Hz, 6-H), 8.32 (1H, dd, J¼8.2,
J¼7.35, 2.1 Hz, Ar 4-H); 1H NMR (
b rotamer) d 3.90–3.92 (0.5H, m,
propenyl 1-H), 4.75 (0.5H, d, J¼5.0 Hz, propenyl 1-H), 5.81 (1H, s,
Ph2CH), 5.81–5.88 (2H, m, propenyl 2,3-H2), 6.9–7.65 (16H, m,
3ꢃPh-H5þAr 5-H), 6.98 (1H, dd, J¼8.2, 1.8 Hz, Ar 4-H), 7.71 (1H, dt,
1.4 Hz, 8-H); 13C NMR (46)
d 47.45 (NCH2), 119.57 (]CH2), 127.19
(6-C), 128.81 (7-C), 129.77 (10-C), 129.76 (9-C), 131.46 (8-C), 131.51
(4-C), 147.92 (5-C), 163.25 (1-C). Further elution gave 3-nitro-N-
(prop-2-enyl)benzamide 47 (16 mg, 13%) as a yellow semi-solid: IR
J¼7.9, 1.8 Hz, Ar 6-H); 13C NMR (
a
rotamer)
d
48.96 (t, J¼22.2 Hz,
propenyl 1-C), 111.79 (2-C), 124.00 (propenyl 2-C), 125.16 (4-C),
126.11, 128.04, 128.12, 128.17, 128.44, 128.74, 128.84, 130.14 (Ar 6-C),
131.62,132.60 (propenyl 3-C),135.59 (Ph 1-C),138.79,139.26,141.67
nmax (film) 3468, 3349,1639,1528, 1350 cmꢁ1; 1H NMR
d 4.09 (2H, t,
J¼5.9 Hz, propenyl 1-H2), 5.20 (1H, dt, J¼10.1, 1.6 Hz, propenyl 3-H),
5.27 (1H, dd, J¼17.2, 1.9 Hz, propenyl 3-H), 5.86–5.96 (1H, m, pro-
penyl 2-H), 6.73 (1H, br s, NH), 7.62 (1H, t, J¼8.2 Hz, 5-H), 8.15 (1H,
dd, J¼7.8, 1.6 Hz, 6-H), 8.33 (1H, ddd, J¼8.2, 2.4, 1.2 Hz, 4-H), 8.60
(Ar 1-C), 152.53 (Ar 3-C), 168.22 (C]O); 13C NMR (
b rotamer)
d
46.33 (t, J¼22.2 Hz, propenyl 1-C), 66.72 (Ph2CH), 111.49 (Ar 2-C),
123.42 (propenyl 2-C), 125.29 (Ar 4-C), 126.35, 127.88, 128.30,
128.48, 128.57, 128.78, 129.16 (Ar 6-C), 130.57, 132.85 (propenyl 3-
C), 136.75 (Ph 1-C), 137.59, 138.24, 141.01 (Ar 1-C), 150.61 (Ar 3-C),
167.77 (C]O); MS (EI) m/z 527.0945 (M) (C29H222HN2O3Br requires
527.0949).
(1H, t, J¼1.9 Hz, 2-H); 13C NMR
d 42.70 (propenyl 1-C), 117.23
(propenyl 3-C),121.77 (2-C),126.04 (4-C),129.82 (5-C),130.29 (6-C),
133.44 (propenyl 2-C), 135.96 (1-C), 148.06 (3-C), 164.97 (C]O); MS
(ESI þve) m/z 207.077 (MþH) (C10H11N2O3 requires 207.0764).
5.16. E-2-Iodo-3-nitro-N-(prop-1-enyl)benzamide (48)
5.14. 2-Iodo-3-nitro-N-(prop-2-enyl)benzamide (43) and 2-
iodo-N-(prop-2-enyl)-2-(prop-2-enylamino)benzamide (44)
Compound 43 (100 mg, 0.3 mmol) was heated to 80 ꢀC with
RuClH(CO)(PPh3)3 (1.4 mg, 1.5 mmol) in benzene (200 mL) for 3 h
Compound 22a (1.65 g, 5.3 mmol) was stirred with prop-2-
enylamine (300 mg, 5.3 mmol) and Et3N (1.07 g, 10.6 mmol) in
CH2Cl2 (20 mL) for 1 h. Washing (5% aq HCl, 5% aq NaHCO3), drying,
evaporation and chromatography (CH2Cl2/EtOAc 4:1) gave 43
(1.25 g, 71%) as pale yellow crystals: mp 108–110 ꢀC; IR nmax 3264,
under Ar. EtOAc (25 mL) was added. The mixture was cooled to 0 ꢀC
and filtered. Evaporation of the filtrate and chromatography (hex-
ane/EtOAc 4:1) gave 46 (96 mg, 96%) as a pale yellow solid: mp
169–172 ꢀC; IR nmax 3245, 3067, 1644, 1586, 1528, 1349 cmꢁ1 1H
;
NMR
propenyl 2-H), 6.83–6.92 (1H, tq, J¼10.5, 1.8 Hz, propenyl 1-H), 7.20
(1H, br, NH), 7.51–7.56 (2H, m, 5,6-H2), 7.69–7.70 (1H, m, 4-H); 13
NMR 14.94 (propenyl 3-C), 84.89 (2-C), 110.99 (propenyl 2-C),
d
1.76 (3H, dd, J¼6.8, 1.8 Hz, propenyl 3-H3), 5.37–5.38 (1H, m,
3077, 1643, 1588, 1529, 1349 cmꢁ1
;
1H NMR
d
3.95 (2H, dt, J¼5.9,
1.5 Hz, propenyl 1-H2), 5.11 (1H, dq, J¼10.4, 1.3 Hz, propenyl 3-H),
5.25 (1H, dq, J¼17.1, 1.5 Hz, propenyl 3-H), 5.77–5.90–5.91 (1H, m,
propenyl 2-H), 6.28 (1H, br, NH), 7.41 (1H, dd, J¼7.7, 1.8 Hz, 4-H),
7.49 (1H, t, J¼7.5 Hz, 5-H), 7.62 (1H, dd, J¼7.7, 1.8 Hz, 6-H); 13C NMR
C
d
122.50 (propenyl 1-C), 125.44 (4-C), 129.55 (6-C), 130.65 (5-C),
130.83 (1-C), 154.99 (3-C), 164.91 (C]O); MS (EI) m/z 331.9672 (M)
(C10H9IN2O3 requires 331.9658).
d
42.48 (propenyl 1-C), 84.86 (2-C), 117.42 (propenyl 3-C), 125.00
(6-C), 129.40 (5-C), 130.30 (4-C), 132.99 (propenyl 2-C), 146.03 (1-
C), 154.75 (3-C), 168.24 (C]O); MS (FABþ) m/z 331.9677 (M)
(C10H9IN2O3 requires 371.9657); Anal. Calcd for C10H9IN2O3: C,
36.17; H, 2.73; N, 8.44; Found: C, 36.6; H, 2.85; N, 8.36. Further
elution gave 44 (140 mg, 10%) as bright yellow crystals: mp 54–
5.17. E-3-Nitro-N-(prop-1-enyl)benzamide (49)
Compound 48 (200 mg, 0.6 mmol) was boiled under reflux with
(Ph3P)4Pd (17.3 mg, 12 mmol), dry Et3N (151 mg, 1.5 mmol) and
57 ꢀC; IR nmax 3468, 3334, 1639, 1578, 1516, 1345 cmꢁ1
;
1H NMR
Bu4NCl (210 g, 0.75 mmol) in dry DMF (1.0 mL) for 7 days. The
evaporation residue, in CHCl3, was washed (5% aq HCl, 5% aq
NaHCO3) and dried. Evaporation and chromatography (hexane/
EtOAc 2:1) yielded 49 (42 mg, 52%) as a buff semi-solid: IR nmax
d
3.75 (2H, s, amide propenyl 1-H2), 4.01 (2H, tt, J¼6.0, 1.4 Hz,
arylamino propenyl 1-H2), 5.13–5.25 (4H, m, 2ꢃpropenyl 3-H2),
5.78–5.92 (2H, m, 2ꢃpropenyl 2-H), 6.77 (1H, t, J¼8.2 Hz, 5-H), 6.82
(1H, br, NH), 7.66 (1H, dd, J¼7.4, 1.7 Hz, 4-H), 7.72 (1H, br, NH), 8.10
3306, 3078, 1654, 1638, 1528, 1350 cmꢁ1 1H NMR
; d 1.76 (3H, dd,
(1H, dd, J¼8.2, 1.7 Hz, 6-H); 13C NMR
d
42.41 (amide propenyl 1-C),
J¼6.6, 1.6 Hz, Me), 5.36–5.45 (1H, m, propenyl 2-H), 6.94–6.95 (1H,
m, propenyl 1-H), 7.66 (1H, t, J¼8.2 Hz, 5-H), 7.70 (1H, br s, NH), 8.17
(1H, dt, J¼7.8, 1.2 Hz, 6-H), 8.36 (1H, ddd, J¼8.2, 2.4, 1.2 Hz, 4-H),
50.24 (arylamino propenyl 1-C), 117.21 (5-C), 117.31 (propenyl 3-C),
117.40 (propenyl 3-C), 126.31 (2-C), 128.63 (6-C), 133.30 (propenyl
2-C), 133.72 (propenyl 2-C), 136.30 (4-C), 137.23 (1-C), 143.58 (3-C),
167.37 (C]O).
8.60 (1H, t, J¼1.9 Hz, 2-H); 13C NMR
d 14.99 (Me), 110.47 (propenyl
2-C), 121.65 (2-C), 123.04 (propenyl 1-C), 126.35 (4-C), 130.04 (5-C),
133.33 (6-C), 135.44 (1-C), 148.50 (3-C), 161.64 (C]O); MS (ESI þve)
m/z 229.0579 (MþNa) (C10H10N2O3Na requires 229.0589). Further
elution gave a trace of 3-nitrobenzamide 50, identical with a com-
mercial sample.
5.15. Pd-catalysed cyclisation of 43 in DMF: 5-nitro-4-
methylisoquinolin-1(2H)-one (45), 5-nitro-4-
methylisoquinolin-1(2H)-one (46) and 3-
nitro-N-(prop-2-enyl)benzamide (47)
5.18. E-N-(3-Phenylprop-2-enyl)-2,2,2-trifluoro-
Compound 43 (200 mg, 0.6 mmol) was heated to reflux in dry
acetamide (52)
DMF (0.7 mL) with (Ph3P)4Pd (14 mg, 12 mmol), dry Et3N (152 mg,
0.75 mmol) and Bu4NCl (170 mg, 0.6 mmol) for 48 h. The evapo-
ration residue, in CHCl3, was washed (5% aq HCl, 5% aq NaHCO3) and
dried. Evaporation and chromatography (hexane/EtOAc 2:1) yiel-
ded 43 (40 mg, 33%) as a pale buff powder: mp 209–211 ꢀC; IR nmax
KOtBu (2.84 g, 25.4 mmol) was stirred with trifluoroacetamide
(2.86 g, 25.4 mmol) in dry THF (25 mL) for 30 min. (3-Bromoprop-1-
enyl)benzene 51 (5.03 g, 25.4 mmol) was added and the mixture was
stirred for 2 h. The evaporation residue, in CH2Cl2, was washed (H2O)
and dried. Evaporation and chromatography (hexane/EtOAc 4:1)
yielded 52 (1.89 g, 33%) as white powder: mp 101–103 ꢀC (lit.41 mp
3448, 3173, 1639, 1529, 1350 cmꢁ1; 1H NMR
d 2.16 (3H, s, Me), 7.05
(1H, s, 3-H), 7.52 (1H, t, J¼7.9 Hz, 7-H), 7.82 (1H, dd, J¼7.8, 1.4 Hz, 6-
H), 8.68 (1H, dd, J¼7.8, 1.4 Hz, 8-H), 10.72 (1H, br s, NH); 13C NMR
100–102 ꢀC); IR nmax 3299, 3116, 1704, 1556, 1179 cmꢁ1
4.13 (2H, t, J¼6.5 Hz, propenyl 1-H2), 6.17 (1H, dt, J¼15.4, 6.9 Hz,
propenyl 2-H), 6.52 (1H, br, NH), 6.60 (1H, d, J¼15.4 Hz, propenyl 2-
;
1H NMR
d
15.80 (Me), 109.03 (4-C), 126.08 (7-C), 127.79 (6-C), 127.87 (10-C),
d
129.47 (3-C), 129.74 (9-C), 131.37 (8-C), 147.50 (5-C), 161.83 (1-C);

A. Dhami et al. / Tetrahedron 65 (2009) 4751–4765
4761
H), 7.25–7.37 (5H, m, Ph-H5); 13C NMR
d
41.91 (propenyl 1-C), 117.22
1704 cmꢁ1
;
1H NMR
d
3.77 (3H, s, Me), 4.39 (2H, dd, J¼6.6, 1.1 Hz,
(q, J¼288.3 Hz, CF3),122.62 (propenyl 2-C),126.48 (Ph 2,6-C2),128.24
CH2), 6.13 (1H, dt, J¼15.9, 6.6 Hz, propenyl 2-H), 6.56 (1H, d,
J¼16.0 Hz, propenyl 3-H), 6.80 (2H, d, J¼8.0 Hz, Ph 3,5-H2), 7.28 (2H,
d, J¼8.0 Hz, Ph 2,6-H2), 7.68–7.72 (2H, m, Phth 3,6-H2), 7.84–7.87
(2H, m, Phth 4,5-H2).
(Ph 4-C), 128.68 (Ph 3,5-C2), 134.18 (propenyl 3-C), 135.78 (Ph 1-C),
157.23 (q, J¼37.6 Hz, C]O); 19F NMR (CDCl3)
ꢁ75.81 (s, CF3).
d
5.19. E-3-Phenylprop-2-enamine (53a): method A
5.25. 1-(3-Iodophenyl)pyrrolidine-2,5-dione (57)
Compound 52 (1.2 g, 5.2 mmol) was stirred with aq NH3 (35%,
1.0 mL) in EtOH (15 mL), for 4 days. The evaporation residue, in
CH2Cl2, was washed (H2O) and dried. Evaporation and chroma-
tography (CH2Cl2/MeOH 10:1) gave 53a42 (616 mg, 88%) as a pale
Succinic anhydride (1.0 g, 10 mmol) and 3-iodoaniline 56 (2.19 g,
10 mmol) were heated at 190 ꢀC for 6 h. Recrystallisation (EtOAc)
afforded 57 (2.23 g, 74%) as pale buff crystals: mp 167–169 ꢀC; IR nmax
yellow oil: IR (film) nmax 3390, 1598 cmꢁ1
;
1H NMR
d
3.47 (2H, d,
1714 cmꢁ1 1H NMR
; d 2.82 (4H, s, succinimide 3,4-H4), 7.19 (1H, t,
J¼6.7 Hz, CH2), 6.10 (1H, dt, J¼15.8, 6.9 Hz, propenyl 2-H), 6.39 (2H,
J¼8.2 Hz, Ph 5-H), 7.28 (1H, dt, J¼7.8, 1.2 Hz, Ph 6-H), 7.71 (1H, t,
br, NH2), 6.54 (1H, d, J¼15.8 Hz, HCPh), 7.20–7.31 (5H, m, Ph–H5).
J¼1.9 Hz, Ph 2-H), 7.73 (1H, dt, J¼7.8,1.6 Hz, Ph 4-H); 13C NMR
d 28.35
(succinimide 3,4-C2), 93.69 (Ph 3-C),125.79 (Ph 6-C),130.52 (Ph 5-C),
132.84 (Ph 1-C),135.23 (Ph 2-C),137.65 (Ph 4-C),175.70 (2ꢃC]O); MS
(ESI þve) m/z 301.9658 (MþH) (C10H8NO2 requires 301.9678).
5.20. E-3-Phenylprop-2-enamine (53a): method B
Compound 52 (810 mg, 3.52 mmol) was stirred with NaBH4
(1.06 g, 28.2 mmol) in EtOH (10 mL) for 16 h. The evaporation res-
idue, in CH2Cl2, was washed (H2O) and dried. Evaporation and
chromatography (CH2Cl2/MeOH 10:1) gave 53a42 (422 mg, 90%) as
a pale yellow oil with properties as above.
5.26. 1,1-Dimethylethyl N-(prop-2-enyl)carbamate (59)
Prop-2-en-1-amine 58 (570 mg, 10 mmol) was added slowly to
Boc2O (2.18 g, 10.0 mmol) in CH2Cl2 (5 mL) at 0 ꢀC and the mixture
was stirred at this temperature for 3 h. Evaporation gave 59 (1.3 g,
83%) as colourless prisms: mp 33–35 ꢀC (lit.47 mp 35–36 ꢀC); IR nmax
5.21. E-3-(4-Methylphenyl)prop-2-en-1-amine (53b)
3354, 1684, 1531 cmꢁ1 1H NMR
; d 1.42 (9H, s, Me3), 3.72 (2H, t,
Compound 55b (270 mg, 1.0 mmol) was boiled under reflux
with N2H4$H2O (32 mg,1.0 mmol) in EtOH (10 mL) for 3 h. The solid
was filtered, washed with ethanol and then suspended in aq NaOH
(5%, 10 mL). This mixture was extracted with Et2O (2ꢃ10 mL) and
with CH2Cl2 (1ꢃ10 mL). The combined extracts were washed (H2O)
and dried. Evaporation gave 53b43 (150 mg, 65%) as a pale yellow
J¼5.2 Hz, propenyl 1-H2), 4.60 (1H, br, NH), 5.05 (1H, dq, J¼10.2,
1.6 Hz, propenyl 3-H), 5.19 (1H, dq, J¼17.1, 1.7 Hz, propenyl 3-H),
5.80–5.81 (1H, m, propenyl 2-H).
5.27. E-1,1-Dimethylethyl N-(3-(3-(2,5-dioxopyrrolidin-1-
yl)phenyl)prop-2-enyl)carbamate (60) and 1,1-dimethylethyl
N-(2-(3-(2,5-dioxopyrrolidin-1-yl)phenyl)prop-2-
enyl)carbamate (61)
oil: IR (film) nmax 3460 cmꢁ1; 1H NMR
d 2.32 (3H, s, Me), 3.43 (2H, d,
J¼5.8 Hz, CH2), 6.19–6.29 (1H, dt, J¼16.0, 6.0 Hz, CHCH2), 6.48 (1H,
d, J¼15.9 Hz, CHPh), 7.08 (2H, d, J¼8.0 Hz, Ph 2,6-H2), 7.24 (2H, d,
J¼7.9 Hz, Ph 3,5-H2).
Compound 59 (1.57 g, 10 mmol) was boiled under reflux with 57
(3.0 g, 10 mmol), Et3N (2.02 g, 20 mmol) and Pd(OAc)2 (22.5 mg,
5.22. E-3-(4-Methoxyphenyl)prop-2-en-1-amine (53c)
10 mmol) under N2 for 48 h. The evaporation residue, CHCl3, was
washed (5% aq HCl, aq NaHCO3) and dried. Evaporation gave
a chromatographically inseparable mixture of 60 (960 mg, 29%) and
61 (240 mg, 7%) as a pale buff semi-solid: IR (film) nmax 3370,
Compound 55c was treated with hydrazine, as for the synthesis
of 53b, to give 53c44 (89%) as a pale yellow oil: IR (film) nmax 3460,
1518 cmꢁ1; 1H NMR
d
1.35 (2H, br, NH2), 3.44 (2H, dd, J¼5.8, 1.4 Hz,
1709 cmꢁ1; 1H NMR (60)
d 1.44 (9H, s, Me3), 2.87 (4H, s, succinimide
propenyl 1-H2), 3.79 (3H, s, Me), 6.16 (1H, dt, J¼16.0, 5.8 Hz, pro-
penyl 2-H), 6.45 (1H, d, J¼15.7 Hz, propenyl 3-H), 6.86 (2H, d,
J¼8.8 Hz, Ph 3,5-H2), 7.31 (2H, d, J¼8.8 Hz, Ph 2,6-H2).
3,4-H4), 3.87–3.89 (2H, m, propenyl 1-H2), 4.71 (1H, br, NH), 6.22
(1H, dt, J¼16.0, 5.9 Hz, propenyl 2-H), 6.5 (1H, d, J¼16.0 Hz, pro-
penyl 3-H), 7.13 (1H, dt, J¼7.4, 1.6 Hz, Ar 6-H), 7.24 (1H, s, Ar 2-H),
7.36 (1H, dd, J¼7.8, 1.6 Hz, Ar 4-H), 7.41 (1H, t, J¼7.8 Hz, Ar 5-H); 1H
5.23. E-2-(3-(4-Methylphenyl)prop-2-enyl)isoindoline-1,3-
NMR (61) d 1.43 (9H, s, Me3), 2.87 (4H, s, succinimide 3,4-H4), 4.15
dione (55b)
(2H, d, J¼5.4 Hz, propenyl 1-H2), 4.5 (1H, br, NH), 5.26 (1H, s, pro-
penyl 3-H), 5.43 (1H, s, propenyl 3-H), 7.13–7.41 (4H, m, Ar 2,4,5,6-
4-Iodotoluene (220 mg, 1.1 mmol) was heated with E-2-(prop-2-
enyl)isoindoline-1,3-dione 5445 (200 mg, 1.1 mmol), Et3N (222 mg,
2.2 mmol) and Pd(OAc)2 (2.5 mg, 0.1 mmol) in DMF (5 mL) under N2
at 90 ꢀC for 24 h. The evaporation residue, in EtOAc, was washed (5%
aq HCl, 5% aq NaHCO3) and dried. Evaporation and chromatography
(hexane/EtOAc 2:1) gave 55b (240 mg, 82%) as a pale buff solid: mp
H4); 13C NMR (60)
d 28.34 (succinimide 3,4-C2), 28.37 (Me3), 42.47
(propenyl 1-C), 79.48 (CMe3), 124.29 (Ar 2-C), 125.37 (Ar 4-C),
126.55 (Ar 6-C), 127.89 (propenyl 2-C), 129.32 (Ar 5-C), 130.14
(propenyl 3-C), 132.13 (Ar 3-C), 138.01 (Ar 1-C), 155.68 (carbamate
C]O), 176.15 (2ꢃsuccinimide C]O); 13C NMR (61)
d 28.16 (succin-
imide 3,4-C2), 28.22 (Me3), 44.14 (propenyl 1-C), 79.48 (C–CMe3),
114.39 (propenyl 3-C),124.38 (Ar 2-C),125.88 (Ar 4-C),126.36 (Ar 6-
C), 129.40 (Ar 5-C), 129.46 (propenyl 2-C), 129.87 (Ar 3-C), 132.03
(Ar 1-C), 155.68 (carbamate C]O), 176.04 (2ꢃsuccinimide C]O);
MS (ESI þve) m/z 331.1652 (MþH) (C18H23N2O4 requires 331.1658).
164–166 ꢀC (lit.43 mp 165–166 ꢀC); IR nmax 1704 cmꢁ1; 1H NMR
d 2.29
(3H, s, Me), 4.42 (2H, dd, J¼6.6, 1.1 Hz, CH2), 6.19 (1H, dt, J¼16.0,
6.3 Hz, CHCH2), 6.64 (1H, d, J¼16.0 Hz, CHPh), 7.08 (2H, d, J¼8.0 Hz,
Ph 2,6-H2), 7.24 (2H, d, J¼8.0 Hz, Ph 3,5-H2), 7.68–7.72 (2H, m, Phth
3,6-H2), 7.83–7.86 (2H, m, Phth 4,5-H2).
5.28. E-2-Iodo-3-nitro-N-(3-phenylprop-2-enyl)benzamide
5.24. E-2-(3-(4-Methoxyphenyl)prop-2-enyl)isoindoline-1,3-
(63a)
dione (55c)
Compound 22a (1.55 g, 5.0 mmol) was stirred with 53a (660 mg,
5.0 mmol) and Et3N (1.01 g mL, 10 mmol) in CH2Cl2 (20 mL) for 2 h.
Washing (5% aq HCl, aq NaHCO3), drying, evaporation and chro-
matography (hexane/EtOAc 4:1) gave 63a (1.51 g, 74%) as yellow
Compound 5445 was treated with 1-iodo-4-methoxybenzene,
Et3N and Pd(OAc)2, as for the synthesis of 55b, to give 55c (94%) as
a pale yellow solid: mp 137–139 ꢀC (lit.46 mp 139.7–140 ꢀC); IR nmax

4762
A. Dhami et al. / Tetrahedron 65 (2009) 4751–4765
crystals: mp 146–148 ꢀC; IR nmax 3263, 3066,1645,1537,1377 cmꢁ1
1H NMR
;
7.85 (1H, dd, J¼7.8, 1.6 Hz, Ar 6-H), 8.88 (1H, t, J¼5.5 Hz, NH); 13C
d
4.22 (2H, t, J¼6.3 Hz, propenyl 1-H2), 6.08 (1H, br, NH),
NMR ((CD3)2SO) d 28.55 (succinimide 3,4-C2), 40.89 (propenyl 1-C),
6.26 (1H, dt, J¼15.9, 6.3 Hz, propenyl 2-H), 6.64 (1H, d, J¼15.6 Hz,
86.77 (Ar 2-C), 124.03 (Ar 4-C), 124.83 (Ar0 2-C), 126.09 (Ar0 6-C),
126.21 (Ar0 4-C), 127.42 (propenyl 2-C), 129.19 (Ar0 5-C), 129.57
(propenyl 3-C), 129.77 (Ar 6-C), 130.34 (Ar 5-C), 133.19 (Ar0 1-C),
137.44 (Ar0 3-C), 146.39 (Ar 1-C), 155.26 (Ar 3-C), 168.13 (amide
C]O), 177.60 (2ꢃsuccinimide C]O); MS (ESI þve) m/z 506.0207
(MþH) (C20H17IN3O5 requires 506.0213). NMR data for 64: 1H
propenyl 3-H), 7.22–7.36 (5H, m, Ph–H5), 7.42–7.50 (2H, m, Ar 5,6-
H2), 7.63–7.74 (1H, m, Ar 4-H); 13C NMR
d 42.24 (propenyl 2-C),
84.91 (Ar 2-C), 124.05 (propenyl 2-C), 125.14 (Ar 4-C), 126.40 (Ph
2,6-C2), 127.97 (Ph 4-C), 128.65 (Ph 3,5-C2), 129.46 (Ar 6-C), 130.35
(Ar 5-C), 133.23 (propenyl 1-C), 136.15 (Ph 1-C), 146.06 (Ar 1-C),
154.85 (Ar 3-C), 168.24 (C]O); MS (ESI þve) m/z 409.0035 (MþH)
(C16H14IN2O3 requires 409.0049). Anal. Calcd for C16H13IN2O3: C,
47.08; H, 3.21; N, 6.86. Found: C, 47.58; H, 3.19; N, 6.93%.
NMR ((CD3)2SO)
d 2.82 (4H, s, succinimide 3,4-H4), 4.48 (2H, d,
J¼5.0 Hz, CH2), 5.38 (1H, br s, ]CH), 5.40 (1H, br s, ]CH), 7.01–
7.73 (5H, m, 5-HþPh–H4), 8.19–8.20 (1H, m, 4-H), 8.28–8.29 (1H,
m, 6-H); 13C NMR ((CD3)2SO)
d 27.38, 51.63, 121.02, 127.47, 129.54,
5.29. E-2-Iodo-3-nitro-N-(3-(4-methylphenyl)prop-2-
enyl)benzamide (63b)
129.81, 131.99, 132.14, 132.52, 133.37, 142.66, 149.00, 162.00,
171.16.
Compound 53b was treated with 22a and Et3N, as for the syn-
thesis of 63a, to give 63b (82%) as yellow crystals: mp 159–162 ꢀC;
5.32. Pd-catalysed cyclisation of 63a: 4-benzyl-5-
nitroisoquinolin-1(2H)-one (65a), Z-4-benzylidene-5-nitro-
3,4-dihydroisoquinolin-1(2H)-one (66a), E-3-nitro-N-(3-
phenylprop-2-enyl)benzamide (67a) and E-3-amino-2-
chloro-N-(3-phenylprop-2-enyl)benzamide (68)
IR nmax 3468, 3268, 1644, 1589, 1530, 1361 cmꢁ1 1H NMR
; d 2.34
(3H, s, Me), 4.23 (2H, t, J¼5.9 Hz, CH2), 5.99 (1H, br, NH), 6.23 (1H,
dt, J¼16.0, 6.6 Hz, CHCH2), 6.63 (1H, d, J¼16.0 Hz, CHPh), 7.14 (2H, d,
J¼7.8 Hz, Ph 3,5-H2), 7.27 (2H, d, J¼7.8 Hz, Ph 2,6-H2), 7.51–7.53 (2H,
m, Ar 5,6-H2), 7.68–7.69 (1H, m, 4-H); 13C NMR
d
21.21 (Me), 42.34
Compound 63a (100 mg, 0.24 mmol) was heated rapidly (<1 min)
to 150 ꢀC with Pd(PPh3)4 (6.0 mg, 5
mmol), Et3N (63 mg, 0.62 mmol)
(CH2), 84.94 (Ar 2-C), 124.94 (propenyl 2-C), 125.15 (Ar 4-C), 126.32
(Ph 2,6-C2), 129.35 (Ph 3,5-C2), 129.47 (Ar 5-C), 130.37 (Ar 6-C),
133.27 (propenyl 3-C),133.36 (Ph 1-C),137.93 (Ph 4-C), 146.13 (Ar 1-
C), 154.89 (Ar 3-C), 168.19 (C]O); Anal. Calcd for C17H15IN2O3: C,
48.36; H, 3.58; N, 6.63. Found: C, 47.84; H, 3.37; N, 6.54%.
and Bu4NCl (70 mg, 0.25 mmol) in dry DMF (0.5 mL) and stirred at
reflux for 48 h. The evaporation residue, in CHCl3, was washed (5% aq
HCl, 5% aq NaHCO3) and dried. Evaporation and chromatography
(hexane/EtOAc 2:1) gave 67a (8 mg, 11%) as a yellow solid: mp 108–
110 ꢀC; IR nmax 3468, 3283,1638,1530,1345 cmꢁ1; 1H NMR
d 4.24 (2H,
5.30. E-2-iodo-N-(3-(4-methoxyphenyl)prop-2-enyl)-3-
nitrobenzamide (63c)
t, J¼6.7 Hz, propenyl 1-H2), 6.25(1H, dt, J¼15.6, 6.3 Hz, propenyl 2-H),
6.57 (1H, d, J¼16.0 Hz, propenyl 3-H), 7.06 (1H, t, J¼5.5 Hz, NH), 7.20–
7.33 (5H, m, Ph-H5), 7.57 (1H, t, J¼7.8 Hz, Ar 5-H), 8.20 (1H, dd, J¼7.8,
1.6 Hz, Ar 6-H), 8.29 (1H, ddd, J¼8.2, 2.4, 1.2 Hz, Ar 4-H), 8.63 (1H, t,
Compound 53c was treated with 22a and Et3N, as for the syn-
thesis of 63a, to give 63c (75%) as yellow crystals: mp 124–127 ꢀC;
J¼1.6 Hz, Ar 2-H); 13C NMR
d 42.38 (propenyl 1-C), 121.81 (Ar 2-C),
IR nmax 3468, 3259, 1640, 1588, 1529, 1348 cmꢁ1
;
1H NMR
d
3.79
124.56 (propenyl 2-C), 125.98 (Ar 4-C), 126.29 (Ph 2,6-C2), 127.84 (Ph
4-C),128.54 (Ph 3,5-C2),129.73 (Ar 5-C),132.78 (propenyl 3-C),133.33
(Ar 6-C),135.84(Ar 1-C),136.14 (P 1-C),147.98 (Ar 3-C),165.00 (C]O);
MS (ESI þve) m/z 283.1077 (MþH) (C16H15N2O3 requires 283.1083).
(3H, s, Me), 4.21 (2H, t, J¼6.7 Hz, propenyl 1-H2), 6.01 (1H, br, NH),
6.11 (1H, dt, J¼16.0, 6.6 Hz, propenyl 2-H), 6.59 (1H, d, J¼16.0 Hz,
propenyl 3-H), 6.83 (2H, d, J¼8.6 Hz, Ph 3,5-H2), 7.28 (2H, d,
J¼8.9 Hz, Ph 2,6-H2), 7.48–7.51 (2H, m, Ar 5,6-H5), 7.65–7.66 (1H, m,
Further elution gave 68 (10 mg, 14%) as a yellow semi-solid: IR (film)
Ar 4-H); 13C NMR
d
42.40 (propenyl 2-C), 55.28 (Me), 84.94 (Ar 2-C),
nmax 3340, 3061, 1644 cmꢁ1; H NMR
d
4.20 (2H, s, NH2), 4.22–4.24
1
114.02 (Ph 3,5-C2), 121.68 (propenyl 2-C), 125.13 (Ar 4-C), 127.62 (Ph
2,6-C2), 128.88 (Ph 1-C), 129.45 (5-C), 130.36 (6-C), 132.91 (propenyl
3-C), 146.12 (Ar 1-C), 154.86 (Ar 3-C), 159.44 (Ph 4-C), 168.19 (C]O).
Anal. Calcd for C17H15IN2O4: C, 46.59; H, 3.45; N, 6.39. Found: C,
46.48; H, 3.33; N, 6.31%.
(2H, m, propenyl 1-H2), 6.11 (1H, br, NH), 6.26 (1H, dt, J¼15.7, 6.3 Hz,
propenyl 2-H), 6.58 (1H, d, J¼16.0 Hz, propenyl 3-H), 6.80 (1H, dd,
J¼8.2, 1.6 Hz, Ar 4-H), 6.88 (1H, dd, J¼7.8, 1.6 Hz, Ar 6-H), 7.07 (1H, t,
J¼7.8 Hz, Ar 5-H), 7.23–7.37 (5H, m, Ph–H5); 13C NMR
d 41.97 (pro-
penyl 1-C), 115.36 (Ar 2-C), 116.99 (Ar 4-C), 118.28 (Ar 6-C), 124.95
(propenyl 2-C), 126.38 (Ph 2,6-C2), 127.52 (Ph 4-C), 127.76 (Ar 5-C),
128.58 (Ph 3,5-C2), 132.44 (propenyl 3-C), 136.37 (Ar 1-C), 136.42 (Ph
1-C), 143.64 (Ar 3-C), 167.29 (C]O); MS (ESI þve) m/z 287.0946
(MþH) (C16H16ClN2O requires 287.0951). Further elution gave 65a
5.31. E-N-(3-(3-(2,5-Dioxopyrrolidin-1-yl)phenyl)prop-2-
enyl)-2-iodo-3-nitrobenzamide (63d) and N-(2-(3-(2,5-
dioxopyrrolidin-1-yl)phenyl)prop-2-enyl)-2-iodo-3-
nitrobenzamide (64)
(12 mg,17%) as an orange solid: mp 210–212 ꢀC; 1H NMR
d 3.88 (2H, s,
CH2), 6.75 (1H, s, 3-H), 7.11 (2H, d, J¼7.0 Hz, Ph 2,6-H2), 7.23–7.31 (3H,
m, Ph 3,4,5-H3), 7.56 (1H, t, J¼7.8 Hz, 7-H), 7.82 (1H, dd, J¼7.8, 1.2 Hz,
6-H), 8.68 (1H, dd, J¼7.8, 1.2 Hz, 8-H), 11.07 (1H, br, NH); 13C NMR
A mixture of 60 and 61 (4:1, 1.2 g, 3.6 mmol) in CH2Cl2 (15 mL)
was treated with excess HCl for 30 min. Evaporation gave a mixture
of 53d and 62 (4:1), which was used without further purification or
characterisation. This mixture (1.65 g, 5.0 mmol) was stirred with
22a (1.5 g, 5.0 mmol) and Et3N (1.01 g, 10 mmol) in CH2Cl2 (15 mL)
for 6 h. Washing (5% aq HCl, aq NaHCO3), drying, evaporation and
d
35.45 (CH2),113.27 (4-C),126.11 (7-C),126.94 (Ph 4-C), 127.94 (8-C),
128.71 (5-C), 128.81 (Ph 3,5-C2), 129.39 (Ph 2,6-C2), 129.59 (8a-C),
130.93 (3-C),131.85 (7-C),137.71 (Ph 1-C),147.65 (4a-C),161.89 (1-C);
MS (ESI þve) m/z 281.0921 (MþH) (C16H13N2O3 requires 281.0926).
Further elution gave 66a (10 mg, 14%) as a yellow solid: mp 183–
chromatography (hexane/EtOAc 4:1) gave
a mixture of 63d
(640 mg, 25.6%) and 64 (160 mg, 6.4%). Further careful chroma-
tography allowed the isolation of a very small sample of pure 63d
for characterisation: yellow crystals, mp 147–149 ꢀC; IR nmax 3467,
185 ꢀC; 1H NMR
d
4.50 (2H, d, J¼1.4 Hz, 3-CH2), 6.74 (1H, br, NH), 6.79
(1H, s, ]CH), 7.18 (2H, d, J¼7.2 Hz, Ph 2,6-H2), 7.30–7.41 (3H, m,
Ph 3,4,5-H3), 7.50 (1H, t, J¼7.9 Hz, 7-H), 7.82 (1H, dd, J¼8.2, 1.4 Hz,
3313, 1702, 1631, 1534, 1391 cmꢁ1; 1H NMR ((CD3)2SO)
d
2.78 (4H, s,
6-H), 8.30 (1H, dd, J¼7.9, 1.4 Hz, 8-H); 13C NMR
d 41.99 (3-C),
succinimide 3,4-H4), 4.06 (2H, t, J¼5.5 Hz, propenyl 1-H2), 6.38 (1H,
dt, J¼15.7, 5.9 Hz, propenyl 2-H), 6.69 (1H, d, J¼16.0 Hz, propenyl 3-
H), 7.12 (1H, dt, J¼7.4, 1.6 Hz, Ar0 6-H), 7.33 (1H, d, J¼1.6 Hz, Ar0 2-H),
7.45 (1H, t, J¼7.4 Hz, Ar0 5-H), 7.49 (1H, dt, J¼7.8, 1.6 Hz, Ar0 4-H),
7.59 (1H, dd, J¼7.8, 1.6 Hz, Ar 4-H), 7.64 (1H, t, J¼7.8 Hz, Ar 5-H),
124.34 (4-C), 127.65 (5-C), 128.34 (6-C), 128.58 (Ph 3,4,5-C3),
129.14 (Ph 2,6-C2), 130.31 (8-C), 131.21 (7-C), 131.66 (8a-C), 134.72
(]CH), 134.80 (Ph 1-C), 148.39 (4a-C), 162.89 (1-C). Anal. Calcd
for C16H12N2O3: C, 68.56; H, 4.32; N, 9.99. Found: C, 68.43; H,
4.07; N, 9.99.

A. Dhami et al. / Tetrahedron 65 (2009) 4751–4765
4763
5.33. Pd-catalysed cyclisation of 63b: 4-(4-methylbenzyl)-5-
nitroisoquinolin-1(2H)-one (65b), Z-4-(4-methylbenzylidene)-
5-nitro-3,4-dihydroisoquinolin-1(2H)-one (66b), E-N-(3-(4-
methylphenyl)prop-2-enyl)-3-nitrobenzamide (67b) and
N-(3-(4-methylphenyl)propyl)-3-nitrobenzamide (69b)
J¼16.0, 6.3 Hz, propenyl 2-H), 6.48 (1H, d, J¼16.0 Hz, propenyl 3-H),
6.79 (2H, d, J¼8.6 Hz, Ph 3,5-H2), 7.21 (2H, d, J¼9.0 Hz, Ph 2,6-H2),
7.33 (1H, br, NH), 7.56 (1H, t, J¼8.2 Hz, Ar 5-H), 8.18 (1H, dt, J¼8.2,
1.6 Hz, Ar 6-H), 8.27 (1H, ddd, J¼8.2, 2.4, 1.2 Hz, Ar 4-H), 8.64 (1H, t,
J¼1.9 Hz, Ar 2-H); 1H NMR (69c)
d
1.90 (2H, qn, J¼7.4 Hz, propyl 2-
H2), 2.63 (2H, t, J¼7.4 Hz, propyl 3-H2), 3.48–3.49 (2H, m, propyl 1-
H2), 3.76 (3H, s, Me), 6.90 (1H, t, J¼5.4 Hz, NH), 6.79 (2H, J¼8.6 Hz,
Ph 3,5-H2), 7.06 (2H, d, J¼8.9 Hz, Ph 2,6-H2), 7.50 (1H, t, J¼7.8 Hz, Ar
5-H), 8.02 (1H, dt, J¼7.8, 1.2 Hz, Ar 6-H), 8.23 (1H, ddd, J¼8.2, 2.4,
Compound 63b (150 mg, 0.35 mmol) was boiled under reflux
with Pd(PPh3)4 (8.2 mg, 7 mmol), Et3N (90 mg, 0.89 mmol) and Bu4NI
(129 mg, 0.35 mmol) in dry DMF (0.7 mL) for 48 h. The evaporation
residue, in CHCl3, was washed (5% aq HCl, 5% aq NaHCO3) and dried.
Evaporation and chromatography (hexane/EtOAc 2:1) yielded an
inseparable mixture of 67b (12 mg, 12%) and 69b (5 mg, 5%) as pale
1.2 Hz, Ar 4-H), 8.48 (1H, t, J¼1.9 Hz, Ar 2-H); 13C NMR (67c)
d 42.44
(propenyl 1-C), 55.14 (Me), 113.88 (Ph 3,5-C2), 121.88 (Ar 2-C),
122.24 (propenyl 2-C), 125.84 (Ar 4-C), 127.42 (Ph 2,6-C2), 128.88
(Ph 1-C), 129.61 (Ar 5-C), 132.16 (propenyl 3-C), 133.29 (Ar 6-C),
135.88 (Ar 1-C), 147.91 (Ar 3-C), 159.20 (Ph 4-C), 164.99 (C]O); 13C
yellow semi-solid: IR (film) nmax 3467, 3312, 1641, 1524, 1350 cmꢁ1
;
1H NMR (67b)
d
2.33 (3H, s, Me), 4.23 (2H, t, J¼6.3 Hz, propenyl 1-H2),
6.24 (1H, dt, J¼15.6, 6.6 Hz, propenyl 2-H), 6.55 (1H, d, J¼16.0 Hz,
propenyl 3-H), 6.61 (1H, br, NH), 7.10–7.11 (2H, m, Ph 3,5-H2), 7.26
(2H, d, J¼7.8 Hz, Ph 2,6-H2), 7.64 (1H, t, J¼8.2 Hz, Ar 5-H), 8.18 (1H, d,
J¼8.2, 1.6 Hz, Ar 6-H), 8.34 (1H, ddd, J¼8.2, 2.4, 1.2 Hz, Ar 4-H), 8.63
NMR (69c) d 30.85 (propyl 2-C), 32.45 (propyl 3-C), 40.09 (propyl 1-
C), 55.08 (Me), 113.78 (Ph 3,5-C2), 121.64 (Ar 2-C), 125.70 (Ar 4-C),
129.10 (Ph 2,6-C2), 129.52 (Ar 5-C), 133.19 (Ph 1-C), 133.11 (Ar 6-C),
136.03 (Ar 1-C), 147.83 (Ar 3-C), 157.76 (Ph 4-C), 165.05 (C]O); MS
(ESI þve) m/z 335.0996 (MþNa) ((67c) C17H16N2NaO4 requires
335.1008), 315.1320 (MþH) ((69c) C17H19N2O4 requires 315.1345).
Further elution gave 65c (17%) as a pale orange powder: mp 121–
(1H, t, J¼1.9 Hz, Ar 2-H); 1H NMR (69b)
1.96 (2H, quintet, J¼7.0 Hz,
d
propyl 2-H2), 2.29 (3H, s, Me), 2.71 (2H, t, J¼7.4 Hz, propyl 3-H2), 3.54
(2H, q, J¼6.6 Hz, propyl 1-H2), 7.10–7.11 (2H, m, Ph 3,5-H2), 7.26 (2H,
d, J¼8.2 Hz, Ph 2,6-H2), 7.60 (1H, t, J¼7.8 Hz, Ar 5-H), 7.98 (1H, dt,
J¼7.4, 1.9 Hz, Ar 6-H), 8.30 (1H, ddd, J¼8.2, 2.4, 1.2 Hz, Ar 4-H), 8.44
124 ꢀC; IR nmax 3119, 3042, 1661, 1604, 1527, 1367 cmꢁ1
;
1H NMR
d
3.79 (3H, s, Me), 3.81 (2H, s, CH2), 6.76 (1H, s, 3-H), 6.82 (2H, d,
(1H, t, J¼1.9 Hz, Ar 2-H), 8.54 (1H, br, NH); 13C NMR (67b)
d
21.18 (Me),
J¼8.6 Hz, Ph 3,5-H2), 7.02 (2H, d, J¼8.6 Hz, Ph 2,6-H2), 7.52 (1H, t,
J¼7.8 Hz, 7-H), 7.83 (1H, dd, J¼7.8, 1.2 Hz, 6-H), 8.65 (1H, dd, J¼7.8,
42.50 (propenyl 1-C), 121.75 (Ar 2-C), 123.38, 126.06 (Ar 4-C), 126.28
(Ph 2,6-C2),129.31 (Ph 3,5-C2), 129.85 (Ar 5-C), 133.11 (propenyl 3-C),
133.29 (Ar 6-C), 135.73 (Ph 1-C), 135.97 (Ar 1-C), 137.85 (Ph 4-C),
1.6 Hz, 8-H), 11.68 (1H, br, NH); 13C NMR
d 34.52 (Me), 55.23 (CH2),
113.77 (4-C), 114.18 (Ph 3,5-C2), 125.98 (6-C), 127.81 (8-C), 128.66
(5-C), 129.52 (8a-C), 130.41 (Ph 2,6-C2), 130.93 (3-C), 131.75 (7-C),
147.61 (4a-C), 158.47 (Ph 4-C), 162.21 (1-C); MS (ESI þve) m/z
311.1026 (MþH) (C17H15N2O4 requires 311.1032). Further elution
gave 66c (15%) as a pale yellow solid: mp 203–204 ꢀC; 1H NMR
148.10 (Ar 3-C), 164.86 (C]O); 13C NMR (69b)
d 20.94 (Me), 30.81
(propyl 2-C), 33.19 (propyl 3-C), 40.26 (propyl 1-C), 121.54 (Ar 2-C),
125.88 (Ar 4-C), 126.28 (Ph 2,6-C2),129.31 (Ph 3,5-C2),129.68 (Ar 5-C),
133.36 (Ar 6-C), 135.02 (Ph 1-C), 136.11 (Ar 1-C), 138.14 (Ph 4-C),
148.10 (Ar 3-C), 164.86 (C]O); MS (ESI þve) m/z 321.1207 (MþNa)
((69b) C17H18N2NaO3 requires 321.1215), 297.1240 (MþH) ((67b)
C17H17N2O3 requires 297.1239). Further elution gave 65b (16 mg,15%)
as a pale orange powder: mp 186–188 ꢀC; IR nmax 3392, 3118, 1660,
d
3.83 (3H, s, Me), 4.52 (2H, s, 3-H2), 6.24 (1H, br, NH), 6.72 (1H, s,
]CH), 6.92 (2H, d, J¼8.9 Hz, Ph 2,6-H2), 7.12 (2H, d, J¼8.2 Hz, Ph
3,5-H2), 7.52 (1H, t, J¼8.2 Hz, 7-H), 7.80 (1H, dd, J¼8.2, 1.2 Hz, 6-H),
8.31 (1H, dd, J¼7.8, 1.2 Hz, 8-H); 13C NMR
d 42.14 (3-C), 55.37 (Me),
1526, 1367 cmꢁ1; 1H NMR
d
2.33 (3H, s, Me), 3.82 (2H, s, CH2), 6.75
114.00 (Ph 3,5-C2), 122.58 (4-C), 127.48 (Ph 1-C), 127.67 (5-C),
128.02 (6-C), 130.15 (8-C), 130.73 (Ph 2,6-C2), 131.21 (7-C), 131.95
(8a-C), 134.56 (]CH), 148.43 (4a-C), 159.83 (Ph 4-C), 162.63 (1-C);
MS (ESI þve) m/z 311.1001 (MþH) (C17H15N2O4 requires 311.1032).
(1H, s, 3-H), 6.98 (2H, d, J¼7.9 Hz, Ph 3,5-H2), 7.10 (2H, d, J¼7.9 Hz, Ph
2,6-H2), 7.54 (1H, t, J¼7.9 Hz, 7-H), 7.83 (1H, dd, J¼7.9, 1.1 Hz, 6-H),
8.67 (1H, d, J¼7.9, 1.1 Hz, 8-H), 11.32 (1H, br s, NH); 13C NMR
d 21.07
(Me), 34.98 (CH2), 113.56 (4-C), 126.01 (6-C), 127.85 (8-C), 128.67 (5-
C), 129.26 (Ph 3,5-C2), 129.49 (Ph 2,6-C2), 126.62 (8a-C), 130.91 (3-C),
131.77 (7-C), 134.54 (Ph 1-C), 136.51 (Ph 4-C), 147.63 (4a-C), 162.03
(1-C); MS (ESI þve) m/z 295.1077 (MþH) (C17H15N2O3 requires
295.1083). Furtherelution gave 66b(14 mg,13%) as a yellow solid: mp
5.35. Pd-catalysed cyclisation of 63d: E-N-(3-(3-(2,5-
dioxopyrrolidin-1-yl)phenyl)prop-2-enyl)-3-nitrobenzamide
(67d), N-(2-(3-(2,5-dioxopyrrolidin-1-yl)phenyl)prop-2-
enyl)-3-nitrobenzamide (70), 1-(3-((5-nitro-1-oxo-1,2-
dihydroisoquinolin-4-yl)methyl)phenyl)pyrrolidine-2,5-dione
(65d) and Z-1-(3-((5-nitro-1-oxo-2,3-dihydroisoquinolin-4-
ylidene)methyl)phenyl)pyrrolidine-2,5-dione (66d)
152–154 ꢀC; IR nmax 3042,1662,1529,1352 cmꢁ1; 1H NMR
d 2.30 (3H,
s, Me), 4.50 (2H, d, J¼1.6 Hz, CH2), 6.75 (1H, s, ]CH), 6.84 (1H, br, NH),
7.09 (2H, d, J¼7.8 Hz, Ph 2,6-H2), 7.19–7.21 (2H, m, Ph 3,5-H2), 7.50
(1H, t, J¼8.2 Hz, 7-H), 7.80 (1H, dd, J¼8.12, 1.2 Hz, 6-H), 8.30 (1H, dd,
J¼7.8, 1.2 Hz, 8-H); 13C NMR
d
21.32 (Me), 42.04 (3-C), 123.51 (4-C),
A mixture of 63d and 64 (4:1) was treated with Pd(PPh3)4, Et3N
and Bu4NI in DMF, as for the synthesis of 65b and 66b, to give an
inseparable mixture of 67d (12 mg, 15%) and 70 (2 mg, 3%) as
a yellow semi-solid: IR (film) nmax 3351, 3078, 1709, 1658, 1528,
127.64 (5-C), 128.15 (6-C), 129.15 (Ph 2,6-C2), 129.25 (Ph 3,5-C2),
130.24 (8-C), 131.14 (7-C), 131.85 (8a-C), 132.01 (Ph 4-C), 134.83
(]CH),138.74 (Ph 1-C), 148.41 (4a-C), 162.96 (1-C); MS (ESI þve) m/z
295.1066 (MþH) (C17H15N2O3 requires 295.1083).
1350 cmꢁ1 1H NMR (67d)
; d 2.87 (4H, s, succinimide 3,4-H4), 4.17
(2H, t, J¼6.3 Hz, propenyl 1-H2), 6.20 (1H, dt, J¼16.0, 6.3 Hz, pro-
penyl 2-H), 6.69 (1H, d, J¼16.0 Hz, propenyl 3-H), 7.10 (1H, dt, J¼8.2,
1.6 Hz, Ar0 6-H), 7.19 (1H, t, J¼1.9 Hz, Ar0 2-H), 7.27 (1H, d, J¼8.2 Hz,
Ar0 4-H), 7.49 (1H, dt, J¼7.8, 1.6 Hz, Ar0 5-H), 7.59 (1H, t, J¼7.8 Hz, Ar
5-H), 8.20 (1H, dt, J¼7.8, 1.6 Hz, Ar 6-H), 8.29 (1H, ddd, J¼8.2, 2.4,
5.34. Pd-catalysed cyclisation of 63c: E-N-(3-(4-
methoxyphenyl)prop-2-enyl)-3-nitrobenzamide (67c), N-(3-
(4-methoxyphenyl)propyl)-3-nitrobenzamide (69c), 4-(4-
methoxybenzyl)-5-nitroisoquinolin-1(2H)-one (65c) and Z-4-
(4-methoxybenzylidene)-5-nitro-3,4-dihydroisoquinolin-
1(2H)-one (66c)
1.2 Hz, Ar 4-H), 8.66 (1H, t, J¼1.9 Hz, Ar 2-H); 1H NMR (70)
d 2.88
(4H, s, succinimide 3,4-H4), 4.48 (2H, d, J¼5.0 Hz, NCH2), 5.36 (1H, s,
]CH), 5.49 (1H, s, ]CH), 7.08–7.63 (5H, m, Ar 5-HþAr0 2,4,5,6-H4),
8.19–8.20 (1H, m, Ar 6-H), 8.28–8.29 (1H, m, Ar 4-H), 8.56 (1H, s, Ar
Compound 63c was treated with Pd(PPh3)4, Et3N and Bu4NI in
DMF, as for the synthesis of 65b and 66b, to give an inseparable
mixture of 67c (8%) and 69c (12%) as a pale yellow semi-solid: IR
2-H); 13C NMR (67d)
d 28.38 (succinimide 3,4-C2), 42.20 (propenyl
1-C), 121.92 (Ar0 2-C), 124.22 (Ar 4-C), 125.62 (Ar 2-C), 125.98 (Ar0 6-
C), 126.36 (Ar0 4-C), 126.56 (propenyl 2-C), 129.35 (Ar0 5-C), 129.67
(propenyl 3-C), 131.37 (Ar 6-C), 131.89 (Ar 5-C), 133.51 (Ar0 1-C),
(film) nmax 3300, 3095, 1637, 1539, 1357 cmꢁ1; 1H NMR (67c)
d
3.76
(3H, s, Me), 4.17 (2H, t, J¼6.7 Hz, propenyl 1-H2), 6.07 (1H, dt,

4764
A. Dhami et al. / Tetrahedron 65 (2009) 4751–4765
135.70 (Ar0 3-C), 137.60 (Ar 1-C), 147.99 (Ar 3-C), 164.96 (amide
(2H, s, CH2), 6.87 (1H, d, J¼7.4 Hz, 6-H), 6.9 (1H, s, 3-H), 7.22 (1H, t,
J¼7.4 Hz, 7-H), 7.25–7.35 (5H, m, Ph–H5), 8.02 (1H, d, J¼7.8 Hz, 8-H),
C]O),176.36 (2ꢃsuccinimide C]O); 13C NMR (70)
d 28.38 (succini-
mide 3,4-C2), 50.66 (NCH2), 122.02, 128.45, 128.57, 129.41, 129.61,
131.99, 132.04, 132.14, 132.52, 133.37, 142.66,149.00 (Ar 3-C), 165.00
(amide C]O), 171.26 (2ꢃsuccinimide C]O); MS (ESI þve) m/z
380.1246 (MþH) (C20H18N3O5 requires 380.1240).
11.51 (1H, br s, NH); 13C NMR
d 38.39 (CH2), 113.34 (4-C), 119.11 (8-
C), 120.92 (6-C), 126.64 (4a-C), 126.93 (Ph 4-C), 127.23 (3-C), 127.43
(7-C), 128.09 (Ph 2,6-C2), 128.16 (8a-C), 129.16 (Ph 3,5-C2), 140.05
(Ph 1-C), 143.50 (5-C), 163.99 (1-C); MS (ESI þve) m/z 251.1179
(MþH) (C16H15N2O requires 251.1184).
Also isolated was an inseparable mixture of 65d (8 mg, 10.5%)
and 66d (8 mg, 10.5%) as a pale yellow gum: IR (film) nmax 3351,
3078, 1658, 1528, 1350 cmꢁ1 1H NMR (65d)
; d 2.85 (4H, s, succin-
5.39. 5-Amino-4-phenylmethylisoquinolin-1-one (73) and -5-
amino-4-phenylmethyl-3,4-dihydroisoquinolin-1-one (74)
imide 3,4-H4), 4.48 (2H, s, 4-CH2), 7.04 (1H, s, 3-H), 7.15–7.43 (4H,
m, Ph-H4), 7.53 (1H, t, J¼7.8 Hz, 7-H), 7.81 (1H, dd, J¼8.2, 1.2 Hz, 6-
H), 8.65 (1H, dd, J¼7.8, 1.6 Hz, 8-H), 10.34 (1H, br, NH); 1H NMR
Compound 66a was treated with H2 and Pd/C, as for the syn-
thesis of 73 from 65a, to give an inseparable mixture of 73 (14%) and
74 (54%). Careful examination of the melting behaviour revealed
that the compound formed different crystals, one (73) with mp
121–123 ꢀC and one (74) with mp 169–170 ꢀC; Data for 74: 1H NMR
(66d) d 2.91 (4H, s, succinimide 3,4-H4), 4.49 (2H, s, 3-H2), 6.14 (1H,
br, NH), 6.78 (1H, s, ]CH), 7.15–7.16 (1H, m, Ph 2-H), 7.22–7.23 (1H,
m, Ph 4-H), 7.31–7.32 (1H, m, Ph 6-H), 7.51 (1H, t, J¼7.8 Hz, Ph 5-H),
7.54 (1H, t, J¼7.8 Hz, 7-H), 7.83 (1H, dd, J¼8.2, 1.2 Hz, 6-H), 8.33 (1H,
dd, J¼7.8, 1.2 Hz, 8-H); 13C NMR (65d)
d 28.38, 35.15, 60.39, 125.02,
126.19, 126.97, 128.64, 129.17, 129.60, 131.37, 132.04, 132.22, 139.11,
d
2.92 (2H, d, J¼3.5 Hz, PhCH2), 2.99 (1H, dd, J¼9.4, 3.5 Hz, 4-H),
3.35 (1H, ddd, J¼12.5, 5.1, 1.2 Hz, 3-H), 3.61 (1H, dd, J¼12.5, 3.9 Hz,
3-H), 6.64 (1H, br s, NH), 6.82 (1H, dd, J¼7.8, 1.2 Hz, 6-H), 7.16 (2H, d,
J¼7.4 Hz, Ph 2,6-H2), 7.18 (1H, t, J¼7.8 Hz, 7-H), 7.20–7.35 (3H, m, Ph
148.27, 161.20, 176.15; 13C NMR (66d)
d 30.93, 41.82, 59.27, 125.91,
126.29, 127.65, 128.69, 129.45, 129.72, 131.04, 131.97, 133.14, 135.78,
147.51, 162.67, 176.02.
3,4,5-H3), 7.62 (1H, dd, J¼7.8, 1.2 Hz, 8-H); 13C NMR
d 35.08 (4-C),
37.55 (CH2Ph), 42.82 (3-C). 119.25 (8-C), 119.94 (6-C), 126.66 (Ph 4-
C), 127.71 (4a-C), 127.61 (7-C), 128.71 (8a-C), 128.75 (Ph 3,5-C2),
129.03 (Ph 2,6-C2), 139.29 (Ph 1-C), 142.81 (5-C), 166.67 (1-C); MS
(ESI þve) m/z 253.1328 (MþH) (C16H17N2O requires 253.1335).
5.36. N-(1,1-Dimethylethoxycarbonyl)-2-iodo-3-nitro-N-
(prop-2-enyl)benzamide (71)
Boc2O (100 mg, 0.45 mmol) was added slowly to 43 (100 mg,
0.3 mmol) in CH2Cl2 (5.0 mL) at 0ꢀC. Et3N (45 mg, 0.45 mmol) and
4-(dimethylamino)pyridine (7.4 mg, 60 mmol) were added and the
5.40. Crystal data for 44
mixture was stirred for 3 h. Washing (5% aq citric acid, aq NaHCO3,
H2O), drying and evaporation gave 71 (120 mg, 92%) as a yellow
Crystal Data for 44: C13H14N3O3, M¼260.27, ¼0.71073 Å, mono-
l
clinic, space group P21, a¼11.1000(5), b¼5.0730(2), c¼11.9100(6) Å,
semi-solid: IR (film) nmax 1739, 1672, 1535, 1347 cmꢁ1
;
1H NMR
b
¼101.651(2)ꢀ, V¼656.84(5) Å3, Z¼2, Dc 1.316 g cmꢁ3
,
m
¼0.096 mmꢁ1
,
t
d
1.19 (9H, s, Bu), 4.46 (2H, d, J¼5.5 Hz, propenyl 1-H2), 5.11–5.23
F(000)¼274, crystal size 0.50ꢃ0.10ꢃ0.10 mm, unique reflections
(1H, dd, J¼10.2, 1.4 Hz, propenyl 3-H), 5.27–5.35 (1H, dq, J¼17.1,
1.4 Hz, propenyl 3-H), 5.87–6.02 (1H, m, propenyl 2-H), 7.27 (1H,
dd, J¼7.4,1.4 Hz, 4-H), 7.49 (1H, t, J¼7.7 Hz, 5-H), 7.66 (1H, dd, J¼8.0,
¼2887 [R(int)¼0.0555], observed I>2 (I)¼2417, data/restraints/
s
parameters¼2887/1/173, R1¼0.0457 wR2¼0.1019 (obsd data),
R1¼0.0603 wR2¼0.1092 (all data), max peak/hole 0.534 and
ꢁ0.169 e Åꢁ3, software used: SHELXS,48 SHELXL49 and ORTEX.50 The
Flack parameter had no credibility for assignment of the absolute
configuration in this structure. The stereochemistry as presented was
dictated by chemical information.
1.3 Hz, 6-H); 13C NMR
d 27.46 (Me3), 46.66 (propenyl 1-C), 83.95 (2-
C), 84.45 (CMe3), 117.94 (propenyl 3-C), 124.05 (4-C), 128.86 (6-C),
129.10 (5-C), 132.05 (propenyl 2-C), 148.45 (1-C), 151.04 (carbamate
C]O), 154.16 (3-C), 169.64 (amide C]O); MS (ESI þve) m/z
455.0048 (MþNa) (C15H17IN2NaO5 requires 455.0080).
Crystallographic data for 44 have been deposited with the
Cambridge Crystallographic Data Centre as Supplementary data
(CCDC 702633). Requests for data should be addressed to CCDC, 12
Union Road, Cambridge, CB2 1EZ, UK.
5.37. 5-Amino-4-methylisoquinolin-1-one hydrochloride (72)
A slurry of 10% Pd/C (100 mg) in EtOH (2 mL) was added to 45
(58 mg, 0.28 mmol) in EtOH (5 mL) and concd aq HCl (0.2 mL). The
mixture was stirred under H2 for 2 h. The suspension was then
filtered (CeliteÒ). The CeliteÒ pad and residue were suspended in
water (100 mL) and heated. The hot suspension was filtered
through a second CeliteÒ pad. Concentration of the filtrate and
drying gave 72 (42 mg, 70%) as pale buff crystals: mp 227–229 ꢀC;
Acknowledgements
We thank Dr. Timothy J. Woodman (University of Bath) for the
NMR spectra, Mr. James Amato and Dr. Anneke Lubben (University
of Bath) for the MS spectra and the University of London School of
Pharmacy Microanalysis Service for the microanalytical data. A.D.
was supported by an Overseas Research Studentship.
IR nmax 3421, 1654 cmꢁ1; 1H NMR (D2O)
d 2.37 (3H, s, Me), 6.94 (1H,
s, 3-H), 7.42 (1H, t, J¼8.2 Hz, 7-H), 7.63 (1H, d, J¼7.8 Hz, 6-H), 8.14
(1H, d, J¼8.2 Hz, 8-H); 13C NMR
d 18.41 (Me),110.74 (4-C),126.89 (5-
References and notes
C), 127.04 (8a-C), 127.24 (7-C), 128.48 (8-C), 128.64 (3-C), 129.55 (6-
C), 132.52 (4a-C), 162.72 (1-C); MS (ESI þve) m/z 175.0866 (MþH)
(C10H11N2O1 requires 175.0871).
1. Lindahl, T.; Satoh, M. S.; Poirier, G. G.; Klungland, A. Trends Biochem. Sci. 1995,
20, 405–411.
2. Petrucco, S.; Percudani, R. FEBS J. 2008, 275, 883–893.
3. Bu¨rkle, A. FEBS J. 2005, 272, 4576–4589.
5.38. 5-Amino-4-phenylmethylisoquinolin-1-one (73)
4. Woon, E. C. Y.; Threadgill, M. D. Curr. Med. Chem. 2005, 12, 2373–2392.
5. Suto, M. J.; Turner, W. R.; Arundel-Suto, C. M.; Werbel, L. M.; Sebolt-Leopold, J. S.
Anti-Cancer Drug Des. 1991, 7, 107–117.
6. Weltin, D.; Holl, V.; Hyun, J. W.; Dufour, P.; Marchal, J.; Bischoff, P. Int. J. Radiat.
Biol. 1997, 72, 685–692.
7. Skalitzky, D. J.; Marakovits, J. T.; Maegley, K. A.; Ekker, A.; Yu, X. H.; Hostomsky, Z.;
Webber, S. E.; Eastman, B. W.; Almassy, R.; Li, J.; Curtin, N. J.; Newell, D. R.; Calvert,
A. H.; Griffin, R. J.; Golding, B. T. J. Med. Chem. 2003, 46, 210–213.
8. Canan Koch, S. S.; Thoresen, L. H.; Tikhe, J. G.; Maegley, K. A.; Almassy, R.; Li, J.;
Yu, X.-H.; Zook, S. E.; Kumpf, R. A.; Zhang, C.; Boritzki, T. J.; Mansour, R. N.;
Zhang, K. E.; Ekker, A.; Calabrese, C. R.; Curtin, N. J.; Kyle, S.; Thomas, H. D.;
A slurry of 10% Pd/C (50 mg) in EtOH (2 mL) was added to 65a
(20 mg, 70 mmol) in EtOH (5 mL). The mixture was stirred under H2
for 1 h. The suspension was then filtered (CeliteÒ). The CeliteÒ pad
and residue were suspended in water (100 mL) and heated. The hot
suspension was filtered through a second CeliteÒ pad. Concentra-
tion of the filtrate and drying gave 73 (9 mg, 51%) as a pale buff
powder: 121–123 ꢀC; IR nmax 3407, 3337, 1623 cmꢁ1; 1H NMR
d 4.32

A. Dhami et al. / Tetrahedron 65 (2009) 4751–4765
4765
Wang, L.-Z.; Calvert, A. H.; Golding, B. T.; Griffin, R. J.; Newell, D. R.; Webber,
S. E.; Hostomsky, Z. J. Med. Chem. 2002, 45, 4961–4974.
9. Tentori, L.; Leonetti, C.; Scarsella, M.; d’Amati, G.; Vergati, M.; Portarena, I.;
Xu, W. Z.; Kalish, V.; Zupi, G.; Zhang, J.; Graziani, G. Clin. Cancer Res. 2003, 9,
5370–5379.
10. Evers, B.; Drost, R.; Schut, E.; de Bruin, M.; van der Burg, E.; Derksen, P. W. B.;
Holstege, H.; Liu, X.; van Drunen, E.; Beverloo, H. B.; Smith, G. C. M.; Martin, N.
M. B.; Lau, A.; O’Connor, M. J.; Jonkers, J. Clin. Cancer Res. 2008, 14, 3916–3925.
11. Farmer, H.; McCabe, N.; Lord, C. J.; Tutt, A. N. J.; Johnson, D. A.; Richardson, T. B.;
Santarosa, M.; Dillon, K. J.; Hickson, I.; Knights, C.; Martin, N. M. B.; Jackson, S. P.;
Smith, G. C. M.; Ashworth, A. Nature 2005, 434, 917–921.
25. Wong, S.-M.; Shah, B.; Shah, P.; Butt, I. C.; Woon, E. C. Y.; Wright, J. A.;
Thompson, A. S.; Upton, C.; Threadgill, M. D. Tetrahedron Lett. 2002, 43, 2299–
2302.
26. Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106, 4644–4680.
27. Sanchez-Sancho, F.; Mann, E.; Herradon, B. Adv. Synth. Catal. 2001, 343,
360–368.
28. Tietze, L. F.; Burkhardt, O. Liebigs Ann. Chem. 1995, 1153–1157.
29. Xiang, Z.; Luo, T.; Lu, K.; Cui, J.; Shi, X.; Fathi, R.; Chen, J.; Yang, Z. Org. Lett. 2004,
6, 3155–3158.
30. Woon, E. C. Y.; Dhami, A.; Mahon, M. F.; Threadgill, M. D. Tetrahedron 2006, 62,
4829–4837.
12. Wang, Y.-L.; Hao, L.-X. Chin. J. Cancer Res. 2007, 19, 119–123.
13. Cai, L.; Threadgill, M. D.; Wang, Y.-L.; Li, M. Pathol. Oncol. Res., in press.
14. Loh, V. M.; Cockcroft, X. L.; Dillon, K. J.; Dixon, L.; Drzewiecki, J.; Eversley, P. J.;
Gomez, S.; Hoare, J.; Kerrigan, F.; Matthews, I. T. W.; Menear, K. A.; Martin, N.
M. B.; Newton, R. F.; Paul, J.; Smith, G. C. M.; Vile, J.; Whittle, A. J. Bioorg. Med.
Chem. 2005, 15, 2235–2238.
15. Cockcroft, X. L.; Dillon, K. J.; Dixon, L.; Drzewiecki, J.; Kerrigan, F.; Loh, V. M.;
Martin, N. M. B.; Menear, K. A.; Smith, G. C. M. Bioorg. Med. Chem. 2006, 16,
1040–1044.
16. White, A. W.; Almassy, R.; Calvert, A. H.; Curtin, N. J.; Griffin, R. J.; Hostomsky,
Z.; Maegley, K.; Newell, D. R.; Srinavasan, S.; Golding, B. T. J. Med. Chem. 2000,
43, 4084–4097.
17. Watson, C. Y.; Whish, W. J. D.; Threadgill, M. D. Bioorg. Med. Chem. 1998, 6,
721–734.
31. Ardizzoia, G. A.; Becccalli, E. M.; Borsini, E.; Brenna, S.; Broggini, G.; Rigamonte,
M. Eur. J. Org. Chem. 2008, 5590–5596.
32. Lamm, B.; Liedholm, B. Acta Chem. Scand. 1967, 21, 2679–2688.
33. Plevyak, J. E.; Dickerson, J. E.; Heck, R. F. J. Org. Chem. 1979, 44, 4078–4080.
34. Woon, E.C.Y. Ph.D. thesis, University of Bath, 2004.
35. Majumdar, K. C.; Chakravorty, S.; Ray, K. Synthesis 2008, 2991–2995.
36. Lord, A. M.; Mahon, M. F.; Lloyd, M. D.; Threadgill, M. D J. Med. Chem. 2009, 52,
868–877.
37. Ames, D. E.; Hansen, K. J.; Griffith, N. D. J. Chem. Soc., Perkin Trans. 1 1973, 2818–
2824.
38. Burger, A.; Schmalz, A. C. J. Org. Chem. 1954, 19, 1841–1846.
39. Bakibaev, A. A.; Filimonov, V. D.; Kuzheleva, G. I.; Gorshkova, V. K.; Saratikov, A.
S.; Novozheeva, T. P.; Akhmedzhanov, R. R.; Krauinsh, M. P. Khim. Farm. Zh. 1993,
27, 36–39.
18. McDonald, M. C.; Mota-Filipe, H.; Wright, J. A.; Abdelrahman, M.; Threadgill, M.
D.; Thompson, A. S.; Thiemermann, C. Br. J. Pharmacol. 2000, 130, 843–850.
19. Wayman, N.; McDonald, M. C.; Thompson, A. S.; Threadgill, M. D.; Thie-
mermann, C. Eur. J. Pharmacol. 2001, 430, 93–100.
20. Chatterjee, P. K.; Chatterjee, B. E.; Pedersen, H.; Sivarajah, A.; McDonald, M. C.;
Mota-Filipe, H.; Brown, P. A. J.; Stewart, K. N.; Cuzzocrea, S.; Threadgill, M. D.;
Thiemermann, C. Kidney Int. 2004, 65, 499–509.
40. Stutz, A.; Georgopoulos, A.; Granitzer, W.; Petranyi, G.; Berney, D. J. Med. Chem.
1986, 29, 112–125.
41. Landini, D.; Penso, M. Synth. Commun. 1988, 18, 791–800.
42. McManus, S. P.; Pitman, C. U.; Fanta, P. E. J. Org. Chem. 1972, 37, 2353–2354.
43. Brewbaker, J. L.; Hart, H. J. Am. Chem. Soc. 1969, 91, 711–715.
44. Cimino, G.; Gavagnin, M.; Sodano, G.; Spinella, A.; Strazzullo, G. J. Org. Chem.
1987, 52, 2301–2303.
`
45. Baker, B. R.; Schaub, R. E.; Joseph, J. P.; McEvoy, F. J.; Williams, J. H. J. Org. Chem.
1952, 17, 149–157.
46. Meyers, A. I.; Lawson, J. P.; Carver, D. R. J. Org. Chem. 1981, 46, 3119–3123.
47. De Amici, M.; De Micheli, C.; Misani, V. Tetrahedron 1990, 46, 1975–1986.
48. Sheldrick, G. M. Acta Crystallogr. 1990, A46, 467–473.
21. Cuzzocrea, S.; Mazzon, E.; Di Paola, R.; Genovese, T.; Patel, N. S. A.; Muia, C.;
Threadgill, M. D.; De Sarro, A.; Thiemermann, C. Naunyn Schmiedebergs Arch.
Pharmacol. 2004, 370, 464–473.
22. Genovese, T.; Mazzon, E.; Di Paola, R.; Muia, C.; Threadgill, M. D.; Caputi, A. P.;
Thiemermann, C.; Cuzzocrea, S. J. Pharmacol. Exp. Ther. 2005, 313, 529–538.
23. Wenkert, E.; Johnston, D. B. R.; Dave, K. G. J. Org. Chem. 1964, 29, 2534–2542.
24. Woon, E. C. Y.; Dhami, A.; Sunderland, P. T.; Chalkley, D. A.; Threadgill, M. D.
Lett. Org. Chem. 2006, 3, 619–621.
`
49. Sheldrick, G. M. SHELXL-97,
a Computer Program for Crystal Structure Re-
finement; University of Go¨ttingen: Go¨ttingen, 1997.
50. McArdle, P. J. Appl. Crystallogr. 1995, 28, 65.