Synthesis of N-substituted isoindolinones via a palladium catalysed three-component carbonylation - amination - Michael addition cascade

Article abstract of DOI:10.1139/v05-111

We herein describe a novel palladium catalysed three-component cascade process involving carbonylation of an aryl iodide to generate an acyl palladium(II) species that is intercepted by a primary aliphatic or aromatic amine, amide, or sulfonamide followed

Full text of DOI:10.1139/v05-111

990
Synthesis of N-substituted isoindolinones via a
palladium catalysed three-component
carbonylation – amination – Michael addition
cascade1
Ronald Grigg, Xinjie Gai, Tossapol Khamnaen, Shuleewan Rajviroongit,
Visuvanathar Sridharan, Lixin Zhang, Simon Collard, and Ann Keep
Abstract: We herein describe a novel palladium catalysed three-component cascade process involving carbonylation of
an aryl iodide to generate an acyl palladium(II) species that is intercepted by a primary aliphatic or aromatic amine,
amide, or sulfonamide followed by intramolecular Michael addition to furnish N-substituted isoindolinones in good
yield. Overall, the cascade results in the formation of one C—C and two C—N bonds, one ring and one stereocentre.
Key words: isoindolinone, palladium, cascade, amidation, sulfonamidation.
Résumé : On décrit un nouveau processus en cascade, à trois composants et catalysé par le palladium qui permet de
procéder à la carbonylation d’un iodure d’aryle pour générer une espèce palladium(II) acyle qui peut être interceptée
par une amine, un amide ou un sulfonamide primaire, aliphatique ou aromatique, suivie d’une addition intramoléculaire
de Michael qui permet d’obtenir des isoindolinones N-substituées avec de bons rendements. La cascade globale conduit
à la formation d’une liaison C—C et de deux liaisons C—N, d’un cycle et d’un stéréocentre.
Mots clés : isoindolinone, palladium, cascade, amidation, sulfonamidation.
[Traduit par la Rédaction] Grigg et al. 1005
Introduction
one-step process for the synthesis of N-substituted isoin-
dolones (14) from o-phthalaldehyde that did not access
1(3)-substituted derivatives. Naming and numbering of
isoindolones using ACD/I-Lab version 8.0 software results
in interchange of the 1- and 3-positions depending upon the
1(3)-substituent. This simple protocol was subsequently ex-
tended by others (15, 16) for accessing more complex poly-
substituted isoindolinones (17–22). Additionally, we have
described a range of catalytic processes that exploit the ver-
satility of carbon monoxide and allene as powerful relay
switches in palladium catalysed cyclisation – anion capture
cascades (23). Our ongoing interest in designing palladium
catalysed atmospheric pressure carbonylation processes in a
tactical combination with core reactions led us to explore
combinations with Michael addition processes as a novel ap-
proach to isoindolinone derivatives (Scheme 1) (24). Alter-
Nitrogen heterocycles containing isoindolinone skeletons
have attracted much interest in recent years owing to their
biological activity. N-Substituted isoindolinones of general
structure 1 (Fig. 1) possess anxiolytic activity and are of in-
terest as sedatives, hypnotics, and muscle relaxants (1). Typ-
ical examples are the anxiolytics pazinaclone (2), pagoclone
(3) (Aventis/Pfizer, phase III clinical trials) (2), and the
anxiolytic and anticonvulsant zopiclone (4) (3, 4). The
isoindolinone moiety also features in anti-cancer drug candi-
dates including protein kinase inhibitors.
Current syntheses of isoindolinones are often unsatisfac-
tory because of severe reaction conditions (5–7), substituent
restrictions (8–10), multi-step protocols, or even product pu-
rification difficulties (11–13). We earlier described a simple
Received 7 January 2005. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 27 August 2005.
R. Grigg,2 X. Gai, V. Sridharan, and L. Zhang. Molecular Innovation Diversity and Automated Synthesis (MIDAS) Centre,
School of Chemistry, Leeds University, Leeds LS2 9JT, UK.
T. Khamnaen. Molecular Innovation Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry, Leeds University,
Leeds LS2 9JT, UK and Department of Chemistry, Faculty of Science, Mahidol University, Rama VI Road, Rajthevee, Bangkok
10400, Thailand.
S. Rajviroongit. Department of Chemistry, Faculty of Science, Mahidol University, Rama VI Road, Rajthevee, Bangkok 10400,
Thailand.
S. Collard and A. Keep. Johnson Matthey, Orchard Road, Royston, Herts SG8 5HE, UK.
1This article is part of a Special Issue dedicated to Professor Howard Alper.
2Corresponding author (e-mail: r.grigg@chem.leeds.ac.uk).
Can. J. Chem. 83: 990–1005 (2005)
doi: 10.1139/V05-111
© 2005 NRC Canada

Grigg et al.
991
Fig. 1. Examples of biologically active N-substituted isoindolinones.
O
O
O
R
N
O
N
Ar
N
N
O
N
O
Cl
1
2
O
O
N
N
Me
N
N
N
Cl
N
N
N
O
N
O
Cl
3
4
Scheme 1. R = alkyl, aryl, heteroaryl, amido, sulphonamido.
EWG
NHR
Ar
X
path a
EWG
EWG
CO –NH2
Pd(0)
NR
Ar
Ar
X
O
5
EWG
NHR
7
path b
Ar
X = I, Br, OTf, etc.
EWG = Electron Withdrawing Group
O
6
cascade allenylation – amination – Michael addition furnish-
ing 4-methylene-tetrahydroisoquinolines and 4-methylene-
tetrahydronaphthalenes (31), which utilized 5 as key sub-
strates. We therefore initially selected 8a–8d (Fig. 2) as the
prototypical dual aryl iodide – Michael acceptors, but using
carbon monoxide, instead of allene, to evaluate the novel
Scheme 1 three-component cascade. Subsequently, the in-
native catalytic approaches to isoindolinones involving inter-
or intramolecular carbopalladation of imines have been re-
ported by Cho et al. in a series of papers (25–30).
Results and discussion
Recently, we reported palladium catalysed three-component
© 2005 NRC Canada

992
Can. J. Chem. Vol. 83, 2005
Fig. 2. Prototypical dual aryl iodide – Michael acceptors.
e EWG = CO
f EWG = CO
N
N
O
O
EWG
g EWG = CO
N
a EWG = CO2Me (E:Z = 5:1)
b EWG = CN (Z only)
c EWG = COMe (E only)
d EWG = COPh (E only)
h EWG = CO
i EWG = CO
j EWG = CO
N
N
N
Me
X
N
N
8
N
N
NH
N
vestigation was extended to the particular biologically im-
portant heterocyclic amides 8e–8j (Fig. 2) as the electron-
withdrawing group in the Michael acceptor. Compounds of
type 8a–8j could react with carbon monoxide (1 atm, 1 atm =
101.325 kPa) and a primary amine in the presence of palla-
dium(0) to afford N-substituted isoindolinones via either
path a or path b (Scheme 1). In path a, carbon monoxide in-
sertion is followed by amination to give the amide 6, which
subsequently undergoes intramolecular Michael addition to
afford N-substituted isoindolinones 7. In path b, the order of
events, beginning with an intermolecular Michael addition,
is reversed.
haps entry 3, that the reactive nucleophiles are not the
neutral species (vide infra).
Note that for all isoindolones where the electron-
withdrawing group (EWG) is CN or CO2Me naming and
(or) numbering is as shown by 9a and 9b (Table 1). When
EWG is a ketone, amide, or 2-pyridyl, the numbering is as
shown by 13e (Table 1).
Aliphatic amine nucleophiles
The cascade successfully incorporated primary aliphatic
amines furnishing 16–21 (Table 2, entries 1–6). We briefly
studied the diastereoselectivity of the Michael addition reac-
tion with (R)-(+)-α-methylbenzylamine (Table 2, entries 7
and 8), which afforded a 1:1.75 and a 2:3 diastereomeric
mixture of 22a and 22b, respectively. S-Alanine methyl ester
similarly afforded 23a as an 1:1 diastereomer mixture. In a
case of 23a, 2 mol equiv. of amine and increasing the reac-
tion time to 48 h were required for complete conversion,
probably owing to competitive self-condensation of the
amino acid ester (diketopiperazine formation). Thus, under
our standard conditions there is little inherent diastereo-
selectivity.
Arylamine nucleophiles
Compounds 8a and 8b reacted with carbon monoxide, a
primary aromatic or heteroaromatic amine, Pd(OAc)2 (10 mol%)
and PPh3 (20 mol%) and Cs2CO3 in toluene at 90 °C over
24 h to afford isoindolinones 9–12 in good yield (Table 1,
entries 1–4). The reactivity of aniline nucleophiles (Table 1,
entries 1–3) with different para substituents showed that the
more nucleophilic p-anisidine (Table 1, entry 2) afforded
10a in 90% yield, whereas p-(trifluoromethyl)aniline (Ta-
ble 1, entry 3), a weaker nucleophile, gave 11a in 68% yield
under the same reaction conditions. However, 2-aminothi-
azole required 48 h under the same reaction conditions for
complete conversion to 12a (73%) (Table 1, entry 4). In the
cases of the use of 2- and 4-aminopyridines (Table 1, entries
5 and 6), a catalyst system comprising Pd2dba3 (2.5 mol%)
and tris(2-furyl)phosphine (10 mol%) was utilized to provide
the corresponding isoindolinones 13 and 14 in excellent
yield, whilst bicyclic heteroaromatic amines in the presence
of a modified catalyst system consisting of Pd(PPh3)2Cl2 (2
mol%) and TFP (12 mol%) afforded isoindolinone 15e
(86%) (Table 1, entry 7). The pKas of the nucleophiles (Ta-
ble 1) fall into two groups. Those (Table 1, entries 1–3) in-
volving protonation at the NH2 group and those (Table 1,
entries 4–8) involving protonation on sp2 N centres in the
heterocyclic rings. It is likely that in all cases, except per-
Unexpectedly, Michael acceptor 8, where EWG = NO2,
failed to furnish the cascade product with benzylamine using
the same catalyst system possibly owing to its instability un-
der the reaction conditions.
Amide and sulfonamide nucleophiles
Amides and sulfonamides were also successfully used as
nucleophiles in the above cascades (Table 3). When
trifluoroacetamide was utilized as a nucleophile, hydrolysis
occurred furnishing NH amide 25e in good yield (Table 3,
entry 2). This opens up a significant number of further syn-
thetic opportunities.
2-Vinylpyridine as a Michael acceptor
It is well-known that 2-vinylpyridines can function as Mi-
chael acceptors (32) and this prompted the evaluation of 8k
© 2005 NRC Canada

Grigg et al.
993
Table 1. Three-component carbonylation – amination – Michael addition cascades employing primary
aromatic amines.a–c
Nucleophile
(pKa)d
Aryl
iodide
Yield (%)e
Product
Entry
1
EWG
NH2
1
75
65
8a
8b
9a
9b
2
N
3
4
(4.61)
O
EWG
NH2
90
79
8a
8b
10a
10b
2
3
4
N
OMe
MeO
(5.21)
O
CO2Me
NH2
68
8a
8a
11a
12a
N
CF3
F3C
(2.77)
O
CO2Me
N
N
S
NH2
S
N
73 f
(5.42)
O
N
NH2
O
N
5
6
86
8e
13e
4
3
1
2
(6.67)
N
N
O
92
99
89
88
58
8e
8f
8g
8i
14e
14f
14g
14i
14j
EWG
NH2
N
N
N
(9.26)
O
8j
O
CF3
N
3
4
CF3
7
86
8e
15e
N
5
H2N
N
N
CF3
2
N
1
6
N
O
7
(2.35)
8
CF3
Note: EWG = electron-withdrawing group.
aEntries 1–4: primary amine (1.2 mol equiv.), Pd(OAc)2 (10 mol%), PPh3 (20 mol%), Cs2CO3 (2 mol equiv.),
toluene, 90 °C, 24 h.
bEntries 5–6: primary amine (1.2 mol equiv.), Pd2dba3 (2.5 mol%), TFP (10 mol%), Cs2CO3 (2 mol equiv.), toluene,
90 °C, 18 h.
cEntry 7: primary amine (1.2 mol equiv.), Pd(PPh3)2Cl2 (2 mol%), TFP (12 mol%), Cs2CO3 (2 mol equiv.), toluene,
110 °C, 18 h.
dCalculated using ACD/I-Lab version 8.0 software.
eIsolated yield.
fReaction time 48 h.
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994
Can. J. Chem. Vol. 83, 2005
Table 2. Three-component carbonylation – amination – Michael addition cascades employing achiral
and chiral primary aliphatic amines.a–c
Aryl
iodide
Yield (%)d
Entry
1
Nucleophile
Product
8a
16a
91
69
61
70
EWG
8b
8c
8d
16b
16c
16d
NH2
N
O
EWG
95
88
8a
8b
17a
17b
NH2
N
2
3
N
O
N
87
77
55
55
8a
8b
8c
8d
18a
18b
18c
18d
EWG
N
NH2
S
O
S
EWG
79
52
8a
8b
19a
19b
NH2
4
5
N
O
CO2Me
NH2
69
8a
20a
N
N
H
NH
O
EWG
MeO
MeO
NH2
85
96
8e
21e
21h
N
6
OMe
OMe
8h
O
EWG
74
77
8a
8b
22a
22b
H2N
7
8
N
Me
Me
Me
O
MeO2C
H2N
Me
CO2Me
63
8a
23a
N
CO2Me
O
Note: EWG = electron-withdrawing group.
aEntries 1–5, 7, and 8: primary amine (1.2 mol equiv.), Pd(OAc)2 (10 mol%), PPh3 (20 mol%), Cs2CO3 (2 mol equiv.),
toluene, 90 °C, 24 h.
bEntry 6: primary amine (1.2 mol equiv.), Pd(PPh3)2Cl2 (2 mol%), TFP (12 mol%), Cs2CO3 (2 mol equiv.), toluene, 110 °C, 18 h.
cEntries 7 and 8: amine (2 mol equiv.), reaction time 48 h.
dIsolated yield.
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Grigg et al.
995
Table 3. Three-component carbonylation – amination – Michael addition cascades employing amide and
sulphonamide nucleophiles.a
Aryl
iodide
Entry
Nucleophile
Product
Yield (%)b
EWG
62
52
8e
O
24e
24f
O
1
N
O
H2N
Me
8f
Me
O
N
O
2
3
60
56
8e
8e
25e
26e
H2N
CF3
NH
O
O
N
O
S
H2N
Ph
NSO2Ph
O
O
Note: EWG = electron-withdrawing group.
aPrimary amine (1.2 mol equiv.), Pd(PPh3)2Cl2 (2 mol%), TFP (12 mol%), Cs2CO3 (2 mol equiv.), toluene, 110 °C, 18 h.
bIsolated yield.
in our three-component cascade using alkyl-, aryl-, and
heteroarylamines (Table 4). For these cascades, we used our
cyclopalladated catalyst 27 (5 mol%), which is known to
form Pd nanoparticles rapidly in the presence of carbon
monoxide (33a). The corresponding isoinolinones 28–33
were obtained in good yield in all cases.
Overall, the cascade results in the formation of one C—C
and two C—N bonds, one ring and one stereocentre.
Experimental
Melting points were determined on a Reichert hot-stage
apparatus and are uncorrected. IR spectra were recorded on
a Nicolet Magna FT-IR 560 spectrometer (to prepare sam-
ples for IR, a small amount of sample was dissolved in di-
chloromethane, transferred onto a germanium plate, and left
to evaporate to provide a film). NMR spectra were recorded
at 250 MHz on a Bruker AC 250 spectrometer, at 300 MHz
on a Bruker DPX 300 spectrometer, and at 500 MHz on a
Bruker DRX 500 spectrometer. Unless otherwise specified,
deuteriochloroform was used as the solvent with tetra-
methylsilane (TMS) as the internal standard. Chemical shifts
are given in parts per million (ppm, δ) downfield from TMS
and the coupling constants are given in Hertz (Hz). The
splitting patterns are designed as singlet (s), doublet (d),
triplet (t), quartet (q), multiplet (m), and double doublet
(dd). The mass spectral mode of ionization is EI unless oth-
erwise stated. EI and FAB were obtained using a VG-
Autospec operating at 70 eV. ES were obtained on a LCT
Micromass (TOF). Accurate molecular weights were deter-
mined using perfluorotributylamine or polyethylenimine as
an internal standard at Leeds University or from the EPSRC
Swansea Mass Spectroscopy Service. Microanalyses were
obtained using a Carlo Erba MOD 11016 elemental analyser.
Flash column chromatography was performed using silica
gel 60 (Merck 9385, 230–400 mesh).
Mechanism
We have only very briefly probed the mechanism of the
reaction. A control experiment in which carbon monoxide
was omitted as the reagent and benzylamine used as the
nucleophile was carried out, but no Michael adduct resulting
from the reaction of 8a with benzylamine was detected un-
der the standard reaction conditions. Intermediates were de-
tected in a study of a related reaction by our group (33b). It
is inherently unlikely that with such a disparate collection of
N-nucleophiles that the mechanism is identical in every case.
Rather, one would expect that the reactive nucleophiles in
the case of the aryl and heteroarylamines and the amides and
sulfonamides are the N-deprotonated species, whilst in the
case of the aliphatic amines the neutral species are involved.
Our control experiment is supportive of path a rather than
path b (Scheme 1), but clearly a more detailed study is indi-
cated before drawing any firm conclusions.
Summary
N-Substituted isoindolinones have been successfully syn-
thesized via a novel palladium catalysed three-component
carbonylation – amination – intramolecular Michael addition
cascade process. The reaction tolerates a wide variety of N-
nucleophiles and delivers a diverse range of isoindolinones.
Commercially available reagents and solvents were used
without further purification. The term ether refers to diethyl
© 2005 NRC Canada

996
Can. J. Chem. Vol. 83, 2005
Table 4. Three-component carbonylation – amination – Michael addition cascades of the 2-vinyl pyridine Michael
acceptor 8k.a
4
N
3
N
Pd(0)
NR
2
+
CO + RNH2
I
1
O
8k
F
O
N
catalyst =
Pd
27
AcO
2
Entry
Nucleophile
Product
Yield (%)b
N
NH2
1
2
64
70
28
29
N
O
N
NH2
N
N
O
N
N
3
4
74
64
30
31
NH2
N
S
O
S
NH2
N
N
O
N
N
O
O
N
NH2
5
67
32
MeO
N
OMe
O
N
N
6
72
33
N
NH2
S
N
S
O
Note: R = alkyl, aryl, heteroaryl.
aPrimary amine (1.2 mol equiv.), catalyst 27 (5 mol%), Cs2CO3 (2 mol equiv.), toluene, 95 °C, 48 h.
bIsolated yield.
© 2005 NRC Canada

Grigg et al.
997
ether and petroleum ether refers to the fraction with a boil-
ing point of 40–60 °C.
petroleum ether afforded the product (0.16 g, 65%) as
colourless needles, mp 183 to 184 °C. IR (cm–1): 1683,
1496, 1391, 1214. H NMR (CDCl3, 250 MHz) δ: 2.69 (dd,
1
1H, J = 16.8, 7.2 Hz, CHHCN), 3.02 (dd, 1H, J = 16.8,
3.3 Hz, CHHCN), 5.35 (dd, 1H, J = 6.9, 3.3 Hz, NCH), 7.2–
7.35 (m, 1H, ArH), 7.45–7.75 (m, 6H, ArH), 7.98 (dd, 1H,
J = 7.2, 1.0 Hz, Ar 4-H). 13C NMR (CDCl3, 62.5 MHz) δ:
22.3, 55.9, 115.4, 115.8, 122.8, 124.4, 125.1, 127.1, 130.1,
130.3, 132.4, 133.3, 136.0, 142.1, 167.0. MS m/z (%): 248
([M+], 22), 208 (100), 77 (37). Anal. calcd. for C16H12N2O:
C 77.25, H 5.05, N 11.10; found: C 77.40, H 4.85, N 11.25.
General procedure A
Michael acceptor 8 (1 mmol), N-nucleophile (1.2 mmol),
Pd(OAc)2 (0.022 g, 0.1 mmol), PPh3 (0.052, 0.2 mmol), and
Cs2CO3 (0.650 g, 2 mmol) were mixed in dry toluene
(10 mL). Carbon monoxide was then introduced through a
balloon and the mixture heated with stirring at 90 °C for
24 h, cooled to room temperature, filtered to remove inor-
ganic materials, and concentrated in vacuo. The crude prod-
uct was purified by flash column chromatography.
Methyl [2-(4-methoxyphenyl)-3-oxo-2,3-dihydro-1H-
isoindol-1-yl]acetate (10a)
General procedure B
Michael acceptor 8 (0.5 mmol), N-nucleophile (0.6 mmol),
Pd(OAc)2 (0.011 g, 0.05 mmol), PPh3 (0.026, 0.1 mmol),
and Cs2CO3 (0.325 g, 1 mmol) were mixed in dry toluene
(6 mL). Carbon monoxide was then introduced through a
balloon and the mixture heated with stirring at 95 °C for
48 h. Work-up was as for general procedure A.
Prepared according to general procedure A employing 8a
(0.288 g, 1 mmol) and p-anisidine (0.147 g, 1.2 mmol).
Column chromatography of the crude product eluting with
2:3 v/v ethyl acetate – petroleum ether afforded the product
(0.279 g, 90%) as colourless needles, mp 97–99 °C. IR (cm–1):
1
2952, 1735, 1694, 1613, 1512, 1467, 1438, 1386. H NMR
(CDCl3, 250 MHz) δ: 2.50 (dd, 1H, J = 16.0, 8.5 Hz,
CHHCO), 2.90 (dd, 1H, J = 16.0, 4.5 Hz, CHHCO), 3.62 (s,
3H, OMe), 3.83 (s, 3H, OMe), 5.50 (dd, 1H, J = 8.5, 4.5 Hz,
NCH), 6.98 (d, 2H, J = 6.8 Hz, ArH), 7.43 (d, 2H, J =
6.8 Hz, ArH), 7.52–7.60 (m, 3H, ArH), 7.92 (d, 1H, J =
7.5 Hz, Ar 4-H). 13C NMR (CDCl3, 62.5 MHz) δ: 38.1,
52.4, 55.9, 58.5, 115.0, 122.9, 124.6, 126.5, 129.3, 129.5,
132.3, 132.6, 144.6, 158.3, 167.3, 171.3. ES-MS m/z (%):
334 ([MNa+], 100). Anal. calcd. for C18H17NO3: C 69.45, H
5.55, N 4.50; found: C 69.55, H 5.80, N 4.35.
General procedure C
As for general procedure A, but with Pd2dba3 (0.024 g,
0.025 mmol) and TFP (0.025 g, 0.1 mmol) as the catalyst
precursors and heating at 90 °C for 18 h.
General procedure D
As for general procedure A, but with Pd(PPh)3Cl2
(0.014 g, 0.02 mmol) and TFP (0.029 g, 0.12 mmol) as the
catalyst precursors, dry dioxane as the solvent, and heating
under reflux for 18 h.
[2-(Methoxyphenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-
yl)acetonitrile (10b)
General procedure E
As for general procedure A, but with precatalyst 27
(0.02 g, 0.025 mmol).
Prepared according to general procedure B employing 8b
(0.13 g, 0.5 mmol) and p-anisidine (0.074 g, 0.6 mmol).
Column chromatography of the crude product eluting with
2:3 v/v ethyl acetate – petroleum ether afforded the product
(0.11 g, 79%) as colourless needles, mp 197–199 °C. IR
(cm–1): 1695, 1513, 1387, 1248. 1H NMR (CDCl3,
250 MHz) δ: 2.67 (dd, 1H, J = 16.8, 7.2 Hz, CHHCN), 3.0
(dd, 1H, J = 16.8, 3.4 Hz, CHHCN), 3.84 (s, 3H, OMe),
5.25 (dd, 1H, J = 7.2, 3.3 Hz, NCH), 7.0, 7.39 (2 × d, 2 ×
2H, J = 9.0 Hz, ArH), 7.3–7.5 (m, 3H, ArH), 7.97 (dd, 1H,
J = 7.1, 1.3 Hz, Ar 4-H). 13C NMR (CDCl3, 62.5 MHz) δ:
22.4, 55.9, 57.6, 115.4, 115.9, 122.8, 125.0, 126.6, 128.6,
130.2, 132.4, 133.1, 142.2, 158.8, 167.0. ES-MS m/z (%):
301 ([MNa+], 100). Anal. calcd. for C17H14N2O2: C 73.30, H
5.00, N 10.05; found: C 73.10, H 5.10, N 10.15.
Methyl (3-oxo-2-phenyl-2,3-dihydro-1H-isoindol-1-
yl)acetate (9a)
Prepared according to general procedure A employing 8a
(0.288 g, 1 mmol) and aniline (0.111 g, 1.2 mmol). Column
chromatography of the crude product eluting with 3:7 v/v
ethyl acetate – petroleum ether afforded the product
(0.208 g, 75%) as colourless needles, mp 121 to 122 °C. IR
(cm–1): 2951, 1736, 1697, 1649, 1597, 1498, 1456, 1379. H
1
NMR (CDCl3, 250 MHz) δ: 2.50 (dd, 1H, J = 16.3, 8.5 Hz,
CHHCO), 2.95 (dd, 1H, J = 16.3, 4.5 Hz, CHHCO), 3.64 (s,
3H, OMe), 5.60 (dd, 1H, J = 8.5, 4.5 Hz, NCH), 7.26 (m,
1H, ArH), 7.60–7.43 (m, 7H, ArH), 7.90 (d, 1H, J = 7.5 Hz,
Ar 4-H). 13C NMR (CDCl3, 62.5 MHz) δ: 37.8, 52.4, 57.9,
123.0, 124.2, 124.6, 126.3, 129.3, 129.7, 132.2, 132.8,
136.8, 144.6, 167.2, 171.2. ES-MS m/z (%): 304 ([MNa+],
100). Anal. calcd. for C17H15NO3: C 72.60, H 5.40, N 5.00;
found: C 72.55, H 5.40, N 4.85.
Methyl {3-oxo-2-[4-(trifluoromethyl)phenyl]-2,3-dihydro-
1H-isoindol-1-yl}acetate (11a)
Prepared according to general procedure A employing 8a
(0.288 g, 1 mmol) and p-(trifluoromethyl)aniline (0.193 g,
1.2 mmol). Column chromatography of the crude product
eluting with 3:7 v/v ethyl acetate – pentane afforded the
product (0.237 g, 68%) as colourless needles, mp 156–
158 °C. IR (cm–1): 2955, 1736, 1705, 1612, 1520, 1469,
3-Oxo-2-phenyl-2,3-dihydro-1H-isoindol-1-yl)acetonitrile
(9b)
Prepared according to general procedure B employing 8b
(0.255 g, 1 mmol) and aniline (0.111 g, 1.2 mmol), catalyst
27 (0.040 g, 0.05 mmol), and cesium carbonate (0.65 g,
2 mmol) in dry toluene (12 mL). Column chromatography
of the crude product eluting with 2:3 v/v ethyl acetate –
1
1438, 1375. H NMR (CDCl3, 250 MHz) δ: 2.50 (dd, 1H,
J = 16.3, 8.8 Hz, CHHCO), 2.98 (dd, 1H, J = 16.3, 3.8 Hz,
CHHCO), 3.67 (s, 3H, OMe), 5.67 (dd, 1H, J = 8.8, 3.8 Hz,
NCH), 7.52–7.80 (m, 7H, ArH), 7.93 (dd, 1H, J = 8.3,
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Can. J. Chem. Vol. 83, 2005
7.5 Hz, Ar 4-H). 13C NMR (CDCl3, 62.5 MHz) δ: 38.1,
52.6, 57.4, 123.0, 123.1, 124.9, 126.7, 126.8, 126.9, 129.6,
129.7, 131.7, 133.3, 140.1, 144.4, 167.4, 171.0. FAB-MS
m/z (%): 350 ([MH+], 100). Anal. calcd. for C18H14F3NO3: C
61.85, H 4.05, N 4.00; found: C 61.65, H 4.00, N 4.05.
ArH), 7.60–7.69 (m, 2H, ArH), 7.77 (d, 2H, J = 4.8 Hz,
pyridyl 3- and 5-H), 7.94 (dd, 1H, J = 7.5, 1.0 Hz, Ar 7-H),
8.64 (d, 2H, J = 4.8 Hz, pyridyl 2- and 6-H). 13C NMR
(CDCl3, 75 MHz) δ: 24.7, 26.0, 26.8, 36.8, 43.5, 47.0, 57.1,
115.2, 123.9, 124.8, 129.4, 131.2, 133.7, 144.6, 145.9,
151.3, 167.7, 168.0. ES-MS m/z (%): 358 ([MNa+], 100).
Anal. calcd. for C20H21N3O2: C 71.6, H 6.3, N 12.5; found:
C 71.3, H 6.35, N 12.75.
Methyl [3-oxo-2-(1,3-thiazol-2-yl)-2,3-dihydro-1H-
isoindol-1-yl]acetate (12a)
Prepared according to general procedure A employing 8a
(0.288 g, 1 mmol) and 2-aminothiazole (0.120 g, 1.2 mmol).
Column chromatography of the crude product eluting with
2:3 v/v ethyl acetate – pentane afforded the product (209 mg,
73%) as pale yellow needles, mp 150 to 151 °C. IR (cm–1):
2951, 1733, 1706, 1616, 1595, 1505, 1466, 1437, 1411,
1369. 1H NMR (CDCl3, 250 MHz) δ: 2.85 (dd, 1H, J = 16.3,
8.8 Hz, CHHCO), 3.69 (s, 3H, OMe), 3.78 (dd, 1H, J =
16.3, 3.5 Hz, CHHCO), 5.78 (dd, 1H, J = 8.8, 3.5 Hz,
NCH), 7.06 (d, 1H, J = 3.5 Hz, thiazolyl 5-H), 7.54 (d, 1H,
J = 3.5 Hz, thiazolyl 4-H), 7.63–7.66 (m, 3H, ArH), 7.95
(dd, 1H, J = 7.5, 1.0 Hz, Ar 4-H). 13C NMR (CDCl3,
62.5 MHz) δ: 37.4, 52.4, 58.6, 114.2, 123.5, 124.9, 129.6,
130.4, 134.0, 138.3, 144.5, 157.4, 166.5, 171.1. ES-MS m/z
(%): 311 ([MNa+], 100). Anal. calcd. for C14H12N2O3S: C
58.30, H 4.20, N 9.70, S 11.10; found: C 58.35, H 4.35, N
9.80, S 10.95.
3-[2-(1,4-Dioxa-8-azaspiro[4,5]dec-8-yl)-2-oxoethyl]-2-
pyridin-4-ylisoindolin-1-one (14f)
Prepared according to general procedure D employing 8f
(0.399 g, 1 mmol) and 4-aminopyridine (0.113 g, 1.2 mmol).
Column chromatography of the crude product eluting with
4:1 v/v ethyl acetate – hexane afforded the product (0.390 g,
99%) as a pale yellow gum. IR (cm–1): 1701, 1656, 1504,
1
1454, 1380. H NMR (CDCl3, 300 MHz) δ: 1.55 (m, 2H,
NCH2CH2), 1.73 (m, 2H, NCH2CH2), 2.50 (dd, 1H, J =
16.2, 9.8 Hz, CHHCO), 3.05 (dd, 1H, J = 16.2, 2.6 Hz,
CHHCO), 3.27–3.40 (m, 2H, NCH2CH2), 3.69–3.77 (m, 2H,
NCH2CH2), 3.94–4.01 (m, 4H, OCH2CH2O), 5.94 (dd, 1H,
J = 9.8, 2.6 Hz, NCH), 7.52–7.60 (m, 1H, ArH), 7.62–7.66
(m, 2H, ArH), 7.76 (d, 2H, J = 6.2 Hz, pyridyl 3- and 5-H),
7.94 (d, 1H, J = 7.5 Hz, Ar 7-H), 8.65 (d, 2H, J = 6.2 Hz,
pyridyl 2- and 6-H). 13C NMR (CDCl3, 75 MHz) δ: 32.2,
35.9, 36.8, 40.6, 43.9, 57.0, 64.9, 106.9, 115.2, 123.8, 124.8,
129.5, 131.2, 133.8, 144.5, 145.8, 151.4, 167.9, 168.0. MS
m/z (%): 394 ([MNa+], 100), 225 (23), 211 (32), 186 (44),
144 (82), 95 (69), 80 (51). Anal. calcd. for C22H23N3O4: C
67.20, H 5.90, N 10.70; found: C 67.00, H 5.90, N 10.80.
3-(2-Oxo-2-piperidin-1-ylethyl)-2-pyridin-2-ylisoindolin-
1-one (13e)
Prepared according to general procedure D employing 8e
(0.341 g, 1.0 mmol) and 2-aminopyridine (0.113 g, 1.2 mmol).
Column chromatography of the crude product eluting with
4:1 v/v ethyl acetate – hexane afforded the product (0.288 g,
86%) as a pale yellow gum. IR (cm–1): 2250, 1693, 1468,
3-(2-Azepan-1-yl-2-oxoethyl)-2-pyridin-4-ylisoindolin-1-
one (14g)
1
Prepared according to general procedure D employing 8g
(0.355 g, 1 mmol) and 4-aminopyridine (0.113 g, 1.2 mmol).
Column chromatography of the crude product eluting with
4:1 v/v ethyl acetate – hexane afforded the product (0.310 g,
89%) as a pale yellow gum. IR (cm–1): 1701, 1656, 1504,
1403, 1210, 1107, 1030, 960. H NMR (CDCl3, 300 MHz)
δ: 1.42–1.61 (m, 6H, CH2CH2CH2CH2CH2), 2.38 (dd, 1H,
J = 15.2, 9.9 Hz, CHHCO), 3.34 (m, 2H, NCH2), 3.55 (dd,
1H, J = 15.2, 3.0 Hz, CHHCO), 3.64 (m, 2H, NCH2), 6.14
(dd, 1H, J = 9.9, 3.0 Hz, NCH), 7.07 (m, 1H, ArH), 7.50 (t,
1H, J = 7.3 Hz, ArH), 7.59 (t, 1H, J = 7.4 Hz, ArH), 7.77
(m, 2H, pyridyl H), 7.92 (d, 1H, J = 7.3 Hz, Ar 7-H), 8.43
(dd, 1H, J = 4.1, 0.8 Hz, pyridyl 4-H), 8.60 (d, 1H, J =
8.4 Hz, pyridyl 6-H). 13C NMR (CDCl3, 75 MHz) δ: 24.9,
26.0, 26.9, 37.9, 43.3, 47.0, 57.7, 115.9, 119.8, 124.4, 128.9,
131.9, 133.3, 138.3, 146.4, 148.2, 151.4, 168.2, 168.7. MS
m/z (%): 336 ([MH+], 100), 251 (68), 223 (20), 209 (71).
Anal. calcd. for C20H21N3O2: C 71.60, H 6.30, N 12.50;
found: C 71.80, H 6.30, N 12.45.
1
1454, 1380. H NMR (CDCl3, 300 MHz) δ: 1.21–1.50 (m,
6H, azepyl H), 1.71–1.83 (m, 2H, azepyl H), 2.47 (dd, 1H,
J = 16.1, 9.6 Hz, CHHCO), 3.05 (dd, 1H, J = 16.1, 3.0 Hz,
CHHCO), 3.14–3.32 (m, 2H, NCH2), 3.50–3.58 and 3.67–
3.76 (2 × m, 2 × 1H, NCH2), 5.97 (dd, 1H, J = 9.6, 3.0 Hz,
NCH), 7.51–7.67 (m, 3H, ArH), 7.78 (d, 2H, J = 4.8 Hz,
pyridyl 3- and 5-H), 7.95 (d, 1H, J = 7.5 Hz, Ar 7-H), 8.64
(d, J = 4.8 Hz, pyridyl 2- and 6-H). 13C NMR (CDCl3,
75 MHz) δ: 27.2, 27.3, 27.9, 29.2, 37.2, 46.7, 48.2, 57.2,
115.2, 123.8, 124.8, 129.4, 131.2, 133.7, 144.6, 146.0,
151.3, 168.0, 169.2. MS m/z (%): 50 ([MH+], 100), 273 (11),
159 (18), 142 (67), 120 (22), 95 (100), 80 (73). Anal. calcd.
for C21H23N3O2: C 72.20, H 6.80, N 12.10; found: C 72.20,
H 6.60, N 12.00.
3-(2-Oxo-2-piperidin-1-ylethyl)-2-pyridin-4-ylisoindolin-
1-one (14e)
Prepared according to general procedure D employing 8e
(0.341 g, 1.0 mmol) and 4-aminopyridine (0.113 g, 1.2 mmol).
Column chromatography of the crude product eluting with
4:1 v/v ethyl acetate – hexane afforded the product (0.308 g,
92%) as a colourless viscous oil. IR (cm–1): 1701, 1656,
3-[2-Oxo-2-(4-pyrimidin-2-ylpiperazin-1-yl)ethyl]-2-
pyridin-4-ylisoindolin-1-one (14i)
1
Prepared according to general procedure D employing 8i
(0.420 g, 1 mmol) and 4-aminopyridine (0.113 g, 1.2 mmol).
Column chromatography of the crude product eluting with
4:1 v/v ethyl acetate – hexane afforded the product (0.363 g,
88%) as a pale brown gum. IR (cm–1): 1701, 1656, 1504,
1504, 1454, 1380, 1210. H NMR (CDCl3, 300 MHz) δ:
1.42 (m, 2H, CH2CH2CH2CH2CH2), 1.61 (m, 4H,
CH2CH2CH2CH2CH2), 2.49 (dd, 1H, J = 16.2, 9.7 Hz,
CHHCO), 3.01 (dd, 1H, J = 16.2, 2.8 Hz, CHHCO), 3.14–
3.28 (m, 2H, NCH2), 3.58–3.75 (m, 2H, NCH2), 5.96 (dd,
1H, J = 9.7, 2.7 Hz, NCH), 7.54 (dt, 1H, J = 7.2, 1.4 Hz,
1
1454, 1380, 1210. H NMR (CDCl3, 300 MHz) δ: 2.55 (dd,
© 2005 NRC Canada

Grigg et al.
999
1H, J = 16.2, 9.0 Hz, CHHCO), 3.09 (dd, 1H, J = 16.2,
2.8 Hz, CHHCO), 3.70–3.93 (m, 6H, piperazyl H), 5.98 (dd,
1H, J = 9.0, 2.8 Hz, NCH), 6.56 (m, 2H, piperazyl H), 7.28–
7.69 (m, 3H, ArH), 7.77 (d, 2H, J = 6.0 Hz, pyridyl 3- and
5-H), 7.96 (d, 1H, J = 7.4 Hz, Ar 7-H), 8.33 (m, 3H,
pyrimidyl H), 8.65 (d, 2H, J = 6.0 Hz, pyridyl 2- and 6-H).
13C NMR (CDCl3, 75 MHz) δ: 37.0, 42.2, 43.8, 43.9, 45.6,
57.0, 111.1, 115.2, 123.8, 124.9, 129.5, 131.2, 133.8, 144.5,
145.7, 151.4, 161.7, 161.8, 167.9, 168.4. MS m/z (%): 415
([MH+], 98), 207 (50), 165 (100), 134 (18), 95 (78), 80 (51).
Anal. calcd. for C23H22N6O2: C 66.65, H 5.35, N 20.30;
found: C 66.70, H 5.45, N 20.60.
91%) as colourless prisms, mp 92–94 °C. IR (cm–1): 2951,
1736, 1690, 1617, 1495, 1469, 1435, 1408, 1360. H NMR
1
(CDCl3, 250 MHz) δ: 2.85 (dd, 1H, J = 16.3, 7.3 Hz,
CHHCO), 2.86 (dd, 1H, J = 16.3, 5.5 Hz, CHHCO), 3.63 (s,
3H, OMe), 4.43 (d, 1H, J = 15.5 Hz, NCHHPh), 4.83 (dd,
1H, J = 7.3, 5.5 Hz, NCH), 5.20 (d, 1H, J = 15.5 Hz,
NCHHPh), 7.25–7.31 (m, 5H, ArH), 7.40–7.54 (m, 3H,
ArH), 7.95 (d, 1H, J = 7.5 Hz, Ar 4-H). 13C NMR (CDCl3,
62.5 MHz) δ: 37.8, 44.7, 52.4, 56.5, 122.8, 124.3, 128.0,
128.3, 129.0, 129.2, 132.1, 133.3, 137.4, 145.2, 168.8,
171.1. FAB-MS m/z (%): 296 ([MH+], 100). Anal. calcd. for
C18H17NO3: C 73.20, H 5.80, N 4.75; found: C 73.00, H
5.85, N 4.60.
3-[2-Oxo-(2-aminopyrimidin-2-yl)ethyl]-2-pyridin-4-
ylisoindolin-1-one (14j)
(2-Benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetonitrile
(16b)
Prepared according to general procedure D employing 8j
(0.351 g, 1 mmol) and 4-aminopyridine (0.113 g, 1.2 mmol).
Column chromatography of the crude product eluting with
4:1 v/v ethyl acetate – hexane afforded the product (0.199 g,
58%) as a pale yellow gum. IR (cm–1): 1699, 1651, 1500,
Prepared according to general procedure B employing 8b
(0.13 g, 0.5 mmol) and benzylamine (0.064 g, 0.6 mmol).
Column chromatography of the crude product eluting with
2:3 v/v ethyl acetate – petroleum ether afforded the product
(0.09 g, 69%) as colourless needles, mp 104–106 °C. IR
(cm–1): 2248, 1689, 1469, 1405. 1H NMR (CDCl3,
250 MHz) δ: 2.72 (dd, 1H, J = 16.9, 6.6 Hz, CHHCO), 2.93
(dd, 1H, J = 16.9, 4.4 Hz, CHHCO), 4.42 (d, 1H, J =
15.4 Hz, NCHHPh), 4.56 (dd, 1H, J = 6.5, 4.4 Hz, NCH),
5.29 (d, 1H, J = 15.4 Hz, NCHHPh), 7.29–7.35 (m, 5H,
ArH), 7.56–7.61 (m, 3H, ArH), 7.95 (dd, 1H, J = 8.0,
1.5 Hz, Ar 4-H). 13C NMR (CDCl3, 62.5 MHz) δ: 22.1,
44.7, 55.3, 116.1, 122.7, 124.8, 128.4, 128.5, 129.5, 129.9,
132.1, 132.8, 136.6, 142.9, 168.6. MS m/z (%): 262 ([MH+],
100), 222 (51), 91 (100). Anal. calcd. for C17H14N2O: C
77.85, H 5.30, N 10.70; found: C 77.60, H 5.45, N 10.80.
1
1455, 1379. H NMR (CDCl3, 300 MHz) δ: 2.46 (dd, 1H,
J = 15.6, 9.5 Hz, CHHCO), 3.29 (dd, 1H, J = 15.6, 3.1 Hz,
CHHCO), 5.87 (dd, 1H, J = 9.5, 3.1 Hz, NCH), 7.08 (d, 2H,
J = 6.3 Hz, pyridyl 3- and 6-H), 7.52–7.64 (m, 3H, ArH),
7.75 (m, 3H, pyrimidyl H), 8.17 (d, 1H, J = 8.4 Hz, Ar 7-H),
8.45 (bs, 1H, NH), 8.63 (d, 2H, J = 6.3 Hz, pyridyl 2- and 6-
H). 13C NMR (CDCl3, 75 MHz) δ: 0.9, 56.5, 114.6, 115.3,
120.8, 123.3, 125.1, 129.7, 132.2, 133.9, 139.1, 144.3,
145.0, 148.3, 151.1, 151.4, 167.6, 168.6. MS m/z (%): 345
([MH+], 6), 207 (22), 165 (17), 144 (23), 137 (48), 94 (78),
80 (38). Anal. calcd. for C20H16N4O2: C 69.80, H 4.70, N
16.30; found: C 69.50, H 4.75, N 16.10.
2-[5,7-Bis(trifluoromethyl)-1,8-naphthyridin-2-yl]-3-(2-
oxo-2-piperidin-1-ylethyl)isoindolin-1-one (15e)
2-Benzyl-3-(2-oxopropyl)isoindolin-1-one (16c)
Prepared according to general procedure B employing 8c
(0.15 g, 0.5 mmol) and benzylamine (0.064 g, 0.6 mmol).
Column chromatography of the crude product eluting with
2:3 v/v ethyl acetate – petroleum ether afforded the product
(0.085 g, 61%) as colourless prisms, mp 87–89 °C. IR (cm–1):
1717, 1687, 1469, 1408, 1362, 1160. 1H NMR (CDCl3,
250 MHz) δ: 2.50 (s, 3H, Me), 2.68 (dd, 1H, J = 17.8,
6.3 Hz, CHHCO), 2.89 (dd, 1H, J = 17.8, 5.9 Hz, CHHCO),
4.62, 4.89 (2 × d, 2 × 1H, J = 15.4 Hz, NCH2Ph), 5.03 (dd,
1H, J = 6.3, 5.9 Hz, NCH), 7.25–7.30 (m, 5H, ArH), 7.35
(dd, 1H, J = 7.3, 0.7 Hz, ArH), 7.50 (m, 2H, ArH), 7.90 (dd,
1H, J = 7.5, 1.2 Hz, Ar 7-H). 13C NMR (CDCl3, 62.5 MHz)
δ: 30.8, 45.2, 47.1, 55.9, 122.8, 124.3, 127.9, 128.3, 128.9,
129.1, 132.1, 132.3, 137.6, 145.9, 168.9, 206. ES-MS m/z
(%): 280 ([MH+], 100). Anal. calcd. for C18H17NO2: C
77.40, H 6.10, N 5.00; found: C 77.30, H 6.15, N 4.95.
Prepared according to general procedure D employing 8e
(0.341 g, 1.0 mmol) and 7-amino-2,4-bis(trifluromethyl)-
1,8-napthyridine (0.232 g, 1.2 mmol). Column chromatogra-
phy of the crude product eluting with 4:1 v/v ethyl acetate –
hexane afforded the product (0.449 g, 86%) as a colourless,
viscous oil. IR (cm–1): 1710, 1650, 1505, 1445, 1382. H
1
NMR (CDCl3, 300 MHz) δ: 1.49–1.69 (m, 6H, piperidyl H),
2.67 (dd, 1H, J = 14.5, 9.3 Hz, CHHCO), 3.57–3.71 (m, 4H,
piperidyl H), 3.82 (dd, 1H, J = 14.5, 3.2 Hz, CHHCO), 6.15
(dd, 1H, J = 9.3, 3.2 Hz, NCH), 7.55 (t, 1H, J = 7.4 Hz,
ArH), 7.68 (m, 1H, ArH), 7.74 (d, 1H, J = 7.6 Hz, ArH),
7.97 (d, 1H, J = 7.6 Hz, Ar 7-H), 8.00 (s, 1H, napthyridyl 6-
H), 8.60 (d, 1H, J = 9.4 Hz, napthyridyl 3-H), 9.26 (d, 1H,
J = 9.4 Hz, napthyridyl 4-H). 13C NMR (CDCl3, 75 MHz) δ:
24.9, 26.1, 26.9, 37.6, 43.4, 47.6, 58.2, 113.7, 119.7, 124.5,
125.0, 129.3, 130.9, 134.4, 135.4, 146.2, 155.3, 168.0,
169.1. ES-MS m/z (%): 421 ([MH+], 100). Anal. calcd. for
C23H21ClN4O2: C 65.65, H 5.05, Cl 8.40, N 13.30; found: C
65.60, H 5.20, Cl 8.25, N 13.05.
2-Benzyl-3-(2-oxo-2-phenylethyl)isoindolin-1-one (16d)
Prepared according to general procedure B employing 8d
(0.167 g, 0.5 mmol) and benzylamine (0.064 g, 0.6 mmol).
Column chromatography of the crude product eluting with
2:3 v/v ethyl acetate – petroleum ether afforded the product
(0.12 g, 70%) as colourless prisms, mp 97 to 98 °C. IR (cm–1):
1683, 1596, 1448, 1408, 1211, 988. 1H NMR (CDCl3,
250 MHz) δ: 3.14 (dd, 1H, J = 17.6, 7.2 Hz, CHHCO), 3.47
(dd, 1H, J = 17.6, 5.3 Hz, CHHCO), 4.53, 5.06 (2 × d, 2 ×
1H, J = 15.3 Hz, NCH2Ph), 5.24 (dd, 1H, J = 7.2, 5.3 Hz,
Methyl (2-benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-
yl)acetate (16a)
Prepared according to general procedure A employing 8a
(0.288 g, 1 mmol) and benzylamine (0.128 g, 1.2 mmol).
Column chromatography of the crude product eluting with
2:3 v/v ethyl acetate – pentane afforded the product (0.268 g,
© 2005 NRC Canada

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Can. J. Chem. Vol. 83, 2005
NCH), 7.15–7.25 (m, 5H, ArH), 7.35–7.50 (m, 6H, ArH),
7.56 (t, 1H, J = 7.0 Hz, ArH), 7.79 (dd, 2H, J = 8.1, 0.9 Hz,
ArH), 7.91 (d, 1H, J = 8.5 Hz, Ar 7-H). 13C NMR (CDCl3,
62.5 MHz) δ: 42.5, 45.0, 56.3, 123.3, 124.3, 127.9, 128.4,
128.5, 128.8, 129.1, 132.1, 132.3, 134.0, 136.6, 137.5,
146.3, 168.9, 196.0. ES-MS m/z (%): 364 ([MNa+], 100).
Anal. calcd. for C23H19NO2: C 80.90, H 5.55, N 4.10; found:
C 80.70, H 5.60, N 4.10.
5.5 Hz, CHHCO), 3.66 (s, 3H, OMe), 4.58 (d, 1H, J =
16.0 Hz, NCHHAr), 4.92 (dd, 1H, J = 6.8, 5.5 Hz, NCH),
5.32 (d, 1H, J = 16.0 Hz, NCHHAr), 6.91 (dd, 1H, J = 5.3,
3.5 Hz, thienyl 4-H), 7.01 (dd, 1H, J = 3.5, 1.3 Hz, thienyl
3-H), 7.18 (dd, 1H, J = 5.3, 1.3 Hz, thienyl 5-H), 7.41–7.51
(m, 3H, ArH), 7.83 (dd, 1H, J = 7.5, 1.0 Hz, Ar 4-H). 13C
NMR (CDCl3, 62.5 MHz) δ: 37.7, 39.3, 52.5, 56.2, 122.9,
124.2, 126.0, 127.0, 127.3, 129.0, 131.9, 132.4, 139.9,
145.2, 168.4, 171.1. MS m/z (%): 301 ([M+], 44), 228 (47),
97 (100). Anal. calcd. for C16H15NO3S: C 63.75, H 5.00, N
4.65, S 10.65; found: C 63.50, H 4.90, N 4.80, S 10.60.
Methyl [3-oxo-2-(pyridin-4-ylmethyl)-2,3-dihydro-1H-
isoindol-1-yl]acetate (17a)
Prepared according to general procedure A employing 8a
(0.288 g, 1 mmol) and p-(aminomethyl)pyridine (0.129 g,
1.2 mmol). Column chromatography of the crude product
eluting with 4:1 v/v ethyl acetate – petroleum ether afforded
the product (0.275 g, 93%) as pale yellow needles, mp 148
to 149 °C. IR (cm–1): 2952, 1734, 1689, 1601, 1563, 1494,
[3-Oxo-2-(thien-2-ylmethyl)-2,3-dihydro-1H-isoindol-1-
yl]acetonitrile (18b)
Prepared according to general procedure A employing 8b
(0.255 g, 1 mmol) and 2-aminomethylthiophene (0.135 g,
1.2 mmol) and heating at 95 °C for 48 h. Column chroma-
tography of the crude product eluting with 2:3 v/v ethyl ace-
tate – petroleum ether afforded the product (0.22 g, 82%) as
colourless needles, mp 129–131 °C. IR (cm–1): 2251, 1690,
1
1469, 1435, 1409, 1364. H NMR (CDCl3, 250 MHz) δ:
2.73 (dd, 2H, J = 6.3, 4.3 Hz, CH2CO), 3.61 (s, 3H, OMe),
4.55 (d, 1H, J = 16.3 Hz, NCHHAr), 4.91 (t, 1H, J = 6.3 Hz,
NCH), 5.08 (d, 1H, J = 16.3 Hz, NCHHAr), 7.18 (d, 2H, J =
4.5 Hz, pyridyl 3- and 5-H), 7.28–7.59 (m, 3H, ArH), 7.90
(dd, 1H, J = 7.5, 1.0 Hz, Ar 4-H), 8.55 (d, 2H, J = 4.5 Hz,
pyridyl 2- and 6-H). 13C NMR (CDCl3, 62.5 MHz) δ: 38.2,
44.1, 52.6, 57.0, 122.8, 122.9, 124.5, 129.3, 131.5, 132.7,
145.0, 146.4, 150.6, 169.1, 171.0. ES-MS m/z (%): 319
([MNa+], 100). Anal. calcd. for C17H16N2O3: C 68.90, H
5.45, N 9.45; found: C 68.75, H 5.40, N 9.45.
1
1469, 1405. H NMR (CDCl3, 250 MHz) δ: 2.82 (dd, 1H,
J = 16.5, 6.5 Hz, CHHCN), 2.99 (dd, 1H, J = 16.9, 4.5 Hz,
CHHCN), 4.55 (d, 1H, J = 15.8 Hz, NCHHAr), 4.67 (dd,
1H, J = 6.5, 4.5 Hz, NCH), 5.43 (d, 1H, J = 15.8 Hz,
NCHHAr), 6.96 (dd, 1H, J = 5.1, 3.5 Hz, thienyl 4-H), 7.07
(d, 1H, J = 3.5 Hz, thienyl 3-H), 7.25 (dd, 1H, J = 5.1,
1.2 Hz, thienyl 5-H), 7.55–7.65 (m, 3H, ArH), 7.91 (dd, 1H,
J = 7.9, 1.3 Hz, Ar 4-H). 13C NMR (CDCl3, 62.5 MHz) δ:
22.2, 39.3, 55.1, 116.2, 122.8, 124.8, 126.6, 127.6, 129.9,
131.8, 132.9, 138.9, 142.9, 168.2. MS m/z (%): 268 ([M+],
44), 228 (24), 97 (100). Anal. calcd. for C15H12N2OS: C
67.10, H 4.50, N 10.50, S 11.90; found: C 66.90, H 4.50, N
10.60, S 11.90.
[3-Oxo-2-(pyridin-4-ylmethyl)-2,3-dihydro-1H-isoindol-1-
yl]acetonitrile (17b)
Prepared according to general procedure A employing 8b
(0.255 g, 1 mmol) and 4-aminomethylpyridine (0.13 g,
1.2 mmol) and heating at 95 °C for 48 h. Column chroma-
tography of the crude product eluting with 4:1 v/v ethyl ace-
tate – petroleum ether afforded the product (0.23 g, 88%) as
colourless prisms, mp 147 to 148 °C. IR (cm–1): 2251, 1690,
3-(2-Oxopropyl)-2-(thien-2-ylmethyl)isoindolin-1-one (18c)
Prepared according to general procedure A employing 8c
(0.272 g, 1 mmol) and 2-aminomethylthiophene (0.135 g,
1.2 mmol) and heating at 95 °C for 48 h. Column chroma-
tography of the crude product eluting with 2:3 v/v ethyl
acetate – petroleum ether afforded the product (0.095 g,
55%) as colourless prisms, mp 74–77 °C. IR (cm–1): 1716,
1
1602, 1469, 1406. H NMR (CDCl3, 250 MHz) δ: 2.80 (dd,
1H, J = 16.9, 5.9 Hz, CHHCN), 2.92 (dd, 1H, J = 16.9,
4.9 Hz, CHHCN), 4.52 (d, 1H, J = 16.2 Hz, NCHHAr), 4.64
(dd, 1H, J = 5.4, 4.9 Hz, NCH), 5.23 (d, 1H, J = 16.2 Hz,
NCHHAr), 7.23 (d, 2H, J = 5.0 Hz, pyridyl 3- and 5-H),
7.55–7.68 (m, 3H, ArH), 7.93 (dd, 1H, J = 8.2, 1.3 Hz, Ar 4-
H), 8.57 (d, 2H, J = 5.0 Hz, pyridyl 2- and 6-H). 13C NMR
(CDCl3, 62.5 MHz) δ: 22.4, 43.8, 55.8, 115.9, 122.8, 122.9,
124.9, 130.2, 131.5, 133.2, 142.8, 145.7, 150.8, 168.8. MS
m/z (%): 263 ([M+], 41), 223 (100), 92 (87). Anal. calcd. for
C16H13N3O: C 73.00, H 4.90, N 16.00; found: C 72.70, H
5.05, N 16.15.
1
1686, 1407, 1365. H NMR (CDCl3, 250 MHz) δ: 2.48 (s,
3H, Me), 2.76 (dd, 1H, J = 17.9, 6.4 Hz, CHHCO), 2.99 (dd,
1H, J = 17.9, 5.8 Hz, CHHCO), 5.03, 5.13 (2 × d, 2 × 1H,
J = 15.6 Hz, NCH2Ar), 5.11 (dd, 1H, J = 6.4, 5.8 Hz, NCH),
6.92 (dd, 1H, J = 5.0, 3.5 Hz, thienyl 4-H), 6.94 (dd, 1H, J =
3.5, 1.3 Hz, thienyl 5-H), 7.21 (dd, 1H, J = 5.0, 1.3 Hz,
thienyl 3-H), 7.37 (dd, 1H, J = 7.1, 0.8 Hz, ArH), 7.46 (td,
1H, J = 6.9, 1.1 Hz, ArH), 7.53 (td, 1H, J = 7.5, 1.6 Hz,
ArH), 7.86 (dd, 1H, J = 7.8, 1.2 Hz, Ar 7-H). 13C NMR
(CDCl3, 62.5 MHz) δ: 30.9, 39.9, 47.2, 55.7, 122.9, 124.3,
126.0, 127.0, 127.2, 128.9, 121.9, 132.4, 140.2, 145.9,
168.6, 207.0. MS m/z (%): 285 ([M+], 14), 227 (66), 146
(39), 131 (37), 97 (100), 43 (67). Anal. calcd. for
C16H15NO2S·0.25H2O: C 66.30, H 5.35, N 4.85; found: C
66.60, H 5.20, N 5.00.
Methyl [3-oxo-2-(thien-2-ylmethyl)-2,3-dihydro-1H-
isoindol-1-yl]acetate (18a)
Prepared according to general procedure A employing 8a
(0.288 g, 1 mmol) and 2-(aminomethyl)thiophene (0.135 g,
1.2 mmol). Column chromatography of the crude product
eluting with 3:7 v/v ethyl acetate – pentane afforded the
product (0.261 g, 87%) as pale yellow needles, mp 148 to
149 °C. IR (cm–1): 2950, 1734, 1690, 1617, 1500, 1469,
3-(2-Oxo-2-phenylethyl)-2-(thien-2-ylmethyl)isoindolin-1-
one (18d)
Prepared according to general procedure B employing 8d
1
1436, 1406, 1366. H NMR (CDCl3, 250 MHz) δ: 2.69 (dd,
1H, J = 16.0, 6.8 Hz, CHHCO), 2.92 (dd, 1H, J = 16.0,
© 2005 NRC Canada

Grigg et al.
1001
(0.167 g, 0.5 mmol) and 2-aminomethylthiophene (0.068 g,
0.6 mmol). Column chromatography of the crude product
eluting with 2:3 v/v ethyl acetate – petroleum ether afforded
the product (0.095 g, 55%) as colourless prisms, mp 99 to
100 °C. IR (cm–1): 1684, 1406, 1211, 987. 1H NMR (CDCl3,
250 MHz) δ: 3.24 (dd, 1H, J = 17.7, 6.8 Hz, CHHCO), 3.55
(dd, 1H, J = 17.7, 5.5 Hz, CHHCO), 4.68, 5.21 (2 × d, 2 ×
1H, J = 15.6 Hz, NCH2Ar), 5.33 (dd, 1H, J = 6.8, 5.5 Hz,
NCH), 6.82 (dd, 1H, J = 5.1, 3.4 Hz, thienyl 4-H), 6.96 (d,
1H, J = 3.4 Hz, thienyl 5-H), 7.13 (d, 1H, J = 5.1 Hz,
thienyl 3-H), 7.38–7.49 (m, 5H, ArH), 7.58 (t, 1H, J =
7.0 Hz, ArH), 7.85–7.89 (m, 3H, ArH). 13C NMR (CDCl3,
62.5 MHz) δ: 39.8, 42.7, 56.0, 123.3, 124.3, 126.0, 127.2,
127.2, 128.5, 128.9, 129.2, 132.0, 132.4, 134.2, 136.6,
140.0, 146.3, 168.6, 198.0. ES-MS m/z (%): 370 ([MNa+],
100). Anal. calcd. for C21H17NO2S: C 72.60, H 4.90, N 4.00,
S 9.20; found: C 72.40, H 4.90, N 4.00, S 9.00.
Column chromatography of the crude product eluting with
1:1 v/v ethyl acetate – pentane afforded the product (0.241 g,
69%) as a yellow oil. IR (cm–1): 3293, 2950, 1733, 1676,
1619, 1513, 1469, 1455, 1436, 1415, 1364. 1H NMR
(CDCl3, 250 MHz) δ: 2.57 (dd, 1H, J = 16.3, 7.0 Hz,
CHHCO), 2.80 (dd, 1H, J = 16.3, 5.5 Hz, CHHCO), 3.12
(m, 2H, NCH2CH2Ar), 3.64 (s, 3H, OMe), 4.29, 4.45
(2 × m, 2 × 1H, NCH2CH2Ar), 4.87 (dd, 1H, J = 7.0, 5.5 Hz,
NCH), 6.98 (d, 1H, J = 2.3 Hz, ArH), 7.11–7.14 (m, 2H,
ArH), 7.30–7.49 (m, 3H, ArH), 7.67 (m, 1H, ArH), 7.82 (d,
1H, J = 1.3 Hz, Ar 4-H), 8.78 (bs, 1H, NH). 13C NMR
(CDCl3, 62.5 MHz) δ: 24.8, 37.7, 41.4, 52.6, 56.9, 111.9,
112.7, 119.0, 119.7, 122.3, 122.7, 122.8, 124.0, 127.7,
129.0, 132.2, 132.4, 136.8, 145.2, 168.8, 171.4. ES-MS m/z
(%): 349 ([MH+], 100). Anal. calcd. for C21H20N2O3: C
72.40, H 5.80, N 8.05; found: C 72.10, H 5.90, N 7.85.
2-[2-(3,4-Dimethoxyphenyl)ethyl]-3-(2-oxo-2-piperidin-1-
ylethyl)isoindolin-1-one (21e)
Methyl (2-cyclopropyl-3-oxo-2,3-dihydro-1H-isoindol-1-
yl)acetate (19a)
Prepared according to general procedure D employing 8e
(0.341 g, 1 mmol) and 2-(3,4-dimethoxyphenyl)ethylamine
(0.217 g, 1.2 mmol). Column chromatography of the crude
product eluting with 4:1 v/v ethyl acetate – hexane afforded
the product (0.358 g, 85%) as a brown gum. IR (cm–1):
1699, 1650, 1510, 1450, 1382, 1210. 1H NMR (CDCl3,
300 MHz) δ: 1.28–1.89 (m, 6H, piperidyl H), 2.44 (dd, 1H,
J = 16.1, 7.1 Hz, CHHCO), 2.68 (dd, 1H, J = 16.1, 5.7 Hz,
CHHCO), 2.94 (m, 2H), 3.23 (t, 2H, J = 5.5 Hz,
NCH2CH2Ar), 3.40 (m, 1H, piperidyl H), 3.65 (t, 2H, J =
5.5 Hz, NCH2CH2Ar), 3.82, 3.84 (2 × s, 2 × 3H, 2 × OMe),
4.11 (m, 3H, piperidyl H), 5.19 (dd, 1H, J = 7.1, 5.7 Hz,
NCH), 6.77–6.83 (m, 3H, ArH), 7.43–7.52 (m, 3H, ArH),
7.85 (d, 1H, J = 7.1 Hz, Ar 7-H). 13C NMR (CDCl3,
75 MHz) δ: 24.8, 26.0, 26.8, 34.4, 37.3, 43.3, 47.0, 56.2,
57.4, 111.5, 112.5, 121.3, 123.4, 123.7, 131.9, 132.4, 146.4,
147.9, 149.2, 168.2, 168.8. MS m/z (%): 423 ([MH+], 100),
271 (5), 164 (40), 146 (6). HR-MS calcd. for C25H30N2O4+H+:
423.2284; found: 423.2281.
Prepared according to general procedure A employing 8a
(0.288 g, 1 mmol) and cyclopropylamine (0.206 mL,
3 mmol). Column chromatography of the crude product
eluting with 1:1 v/v ethyl acetate – pentane afforded the
product (0.181 g, 74%) as a pale yellow oil. IR (cm–1):
1
2952, 1735, 1694, 1614, 1468, 1436, 1404, 1370. H NMR
(CDCl3, 250 MHz) δ: 0.80–1.10 (m, 4H, 2 × cyclopropyl
CH2), 2.66 (m, 1H, cyclopropyl CH), 2.67 (dd, 1H, J = 15.6,
8.0 Hz, CHHCO), 3.11 (dd, 1H, J = 15.6, 5.0 Hz, CHHCO),
3.74 (s, 3H, OMe), 4.83 (dd, 1H, J = 8.0, 5.0 Hz, NCH),
7.43–7.53 (m, 3H, ArH), 7.8 (dd, 1H, J = 7.5, 6.8 Hz, Ar 4-
H). 13C NMR (CDCl3, 62.5 MHz) δ: 5.3, 8.2, 23.3, 39.3,
52.5, 58.2, 122.8, 124.0, 129.0, 132.2, 132.6, 144.7, 169.3,
171.4. FAB-MS m/z (%): 246 ([MH+], 100). Anal. calcd. for
C14H15NO3: C 68.55, H 6.15, N 5.70; found: C 68.30, H
6.40, N 5.50.
2-(Cyclopropyl)-3-oxo-2,3-dihydro-1H-isoindol-1-
yl)acetonitrile (19b)
Prepared according to general procedure B employing 8b
(0.255 g, 1 mmol) and cyclopropylamine (0.206 mL, 3 mmol)
and heating at 95 °C for 48 h. Column chromatography of
the crude product eluting with 2:3 v/v ethyl acetate – petroleum
ether afforded the product (0.11 g, 52%) as a pale yellow oil.
IR (cm–1): 2250, 1693, 1468, 1403, 1210, 1107, 1030, 960.
1H NMR (CDCl3, 250 MHz) δ: 0.81–1.18 (m, 4H, 2 ×
cyclopropyl CH2), 2.70 (m, 1H, cyclopropyl CH), 2.89 (dd,
1H, J = 16.8, 7.2 Hz, CHHCN), 3.10 (dd, 1H, J = 16.8,
4.4 Hz, CHHCN), 4.63 (dd, 1H, J = 7.2, 4.4 Hz, NCH),
7.32–7.75 (m, 3H, ArH), 7.85 (dd, 1H, J = 7.3, 1.1 Hz, Ar 4-
H). 13C NMR (CDCl3, 62.5 MHz) δ: 5.3, 8.3, 22.6, 23.3,
57.3, 116.3, 122.7, 124.5, 129.9, 132.6, 132.7, 142.5, 169.1.
MS m/z (%): 212 ([M+], 32), 172 (100), 128 (31), 102 (30),
89 (37), 77 (43), 41 (53). Anal. calcd. for C13H12N2O·H2O:
C 71.90, H 5.75, N 12.90; found: C 71.60, H 6.05, N 13.20.
2-[2-(3,4-Dimethoxyphenyl)ethyl]-3-[2-(4-
methylpiperazin-1-yl)-2-oxoethyl]isoindolin-1-one (21h)
Prepared according to general procedure D employing 8h
(0.356 g, 1 mmol) and 2-(3,4-dimethoxyphenyl)ethylamine
(0.217 g, 1.2 mmol). Column chromatography of the crude
product eluting with 4:1 v/v ethyl acetate – hexane afforded
the product (0.419 g, 96%) as a brown gum. IR (cm–1):
1708, 1656, 1500, 1444, 1382, 1200. 1H NMR (CDCl3,
300 MHz) δ: 2.29 (s, 3H, NMe), 2.30–2.40 (m, 6H,
piperidyl H), 2.43 (dd, 1H, J = 16.2, 7.4 Hz, CHHCO), 2.69
(dd, 1H, J = 16.2, 5.5 Hz, CHHCO), 2.69 (m, 2H, NCH2CH2Ar),
3.28 (m, 2H, piperidyl H), 3.42 (m, 1H, piperidyl H), 3.67–
3.88 (m, 2H, NCH2CH2Ar), 3.81, 3.84 (2 × s, 2 × 3H, 2 ×
OMe), 4.09 (m, 1H, piperidyl H), 5.15 (dd, 1H, J = 7.2,
5.5 Hz, NCH), 6.73–6.79 (m, 3H, ArH), 7.43–7.52 (m, 3H,
ArH), 7.85 (d, 1H, J = 6.7 Hz, Ar 7-H). 13C NMR (CDCl3,
75 MHz) δ: 34.4, 37.1, 42.2, 43.4, 45.7, 46.3, 55.0, 55.3,
56.2, 56.3, 57.4, 111.6, 112.5, 121.3, 123.4, 123.9, 128.8,
131.9, 132.0, 132.4, 146.2, 147.9, 149.2, 168.5, 168.8. MS
m/z (%): 438 ([MH+], 100), 286 (3), 164 (32), 99(7). HR-
MS calcd. for C25H31N3O4+H+: 438.2393; found: 438.2393.
Methyl {2-[(2-1H-indazol-3-yl)ethyl]-3-oxo-2,3-dihydro-
1H-isoindol-1-yl}acetate (20a)
Prepared according to general procedure A employing 8a
(0.288 g, 1 mmol) and tryptamine (0.192 g, 1.2 mmol).
© 2005 NRC Canada

1002
Can. J. Chem. Vol. 83, 2005
(42), 132 (57), 105 (100), 77 (64). Anal. calcd. for
C18H16N2O: C 78.20, H 5.80, N 10.15; found: C 78.00, H
6.10, N 10.10.
Methyl {3-oxo-2-[(1R)-1-phenylethyl]-2,3-dihydro-1H-
isoindol-1-yl}acetate (22a)
Prepared according to general procedure A employing 8a
(0.288 g, 1 mmol) and (R)-(+)-α-methylbenzylamine (0.145 g,
1.2 mmol). Column chromatography of the crude product
eluting with 2:3 v/v ethyl acetate – pentane afforded a 1:1.75
inseparable diastereomeric product mixture (0.217 g, 74%
combined yield) as a pale yellow oil. IR (cm–1): 2951, 1735,
Methyl (2S)-2-[(2-methoxy-2-oxoethyl)-3-oxo-1,3-
dihydro-2H-isoindol-1-yl]propanoate (23a)
Prepared according to general procedure A employing 8a
(0.288 g, 1 mmol) and S-alanine methyl ester hydrochloride
(0.279 g, 2 mmol) and heating at 90 °C for 48 h. Column
chromatography of the crude product eluting with 3:2 v/v
ethyl acetate – pentane afforded a 1:1 inseparable diastereo-
meric mixture of the product (0.185 g, 63%) as a yellow oil.
IR (cm–1): 2952, 1738, 1693, 1617, 1469, 1436, 1416, 1353.
1H NMR spectra of both isomers were assigned from the
1
1686, 1615, 1494, 1468, 1436, 1398. H NMR spectra of
both isomers were assigned from the mixture of
1
diastereomers. Diastereomer 1 (minor): H NMR (CDCl3,
250 MHz) δ: 1.80 (d, 3H, J = 7.3 Hz, Me), 2.15 (dd, 1H, J =
16.8, 8.3 Hz, CHHCO), 2.55 (dd, 1H, J = 16.8, 4.3 Hz,
CHHCO), 3.56 (s, 3H, OMe), 5.10 (dd, 1H, J = 8.3, 4.3 Hz,
NCHCH2), 5.73 (q, 1H, J = 7.3 Hz, NCHMe), 7.27–7.36 (m,
5H, ArH), 7.42–7.52 (m, 3H, ArH), 7.87 (dd, 1H, J = 8.0,
1
mixture of diastereomers. Diastereomer 1: H NMR (CDCl3,
250 MHz) δ: 1.62 (d, J = 7.5 Hz, 3H, Me), 2.62 (m, 1H,
CHHCO), 2.99 (m, 1H, CHHCO), 3.71 (s, 3H, OMe), 3.75
(s, 3H, OMe), 4.64 (m, 1H, NCHCH2), 5.10 (m, 1H, NCH),
7.41–7.59 (m, 3H, ArH), 7.83 (m, 1H, Ar 4-H).
1
7.0 Hz, Ar 4-H). Diastereomer 2 (major): H NMR (CDCl3,
250 MHz) δ: 1.80 (d, 3H, J = 7.3 Hz, Me), 2.55 (dd, 1H, J =
16.3, 12.3 Hz, CHHCO), 2.97 (dd, 1H, J = 16.3, 4.0 Hz,
CHHCO), 3.59 (s, 3H, OMe), 4.68 (dd, 1H, J = 12.3,
4.0 Hz, NCHCH2), 5.54 (q, 1H, J = 7.3 Hz, NCHMe), 7.27–
7.36 (m, 5H, ArH), 7.42–7.52 (m, 3H, ArH), 7.87 (dd, 1H,
J = 8.0, 7.0 Hz, Ar 4-H). ES-MS (isomer mixture) m/z (%):
332 ([MNa+], 100). Anal. calcd. for C19H19NO3: C 73.75, H
6.20, N 4.55; found (isomer mixture): C 73.70, H 6.30, N
4.35.
1
Diastereomer 2: H NMR (CDCl3, 250 MHz) δ: 1.67 (d, J =
7.5 Hz, 3H, Me), 2.79 (m, 1H, CHHCO), 3.02 (m, 1H,
CHHCO), 3.75 (s, 6H, 2 × OMe), 4.91 (m, 1H, NCHCH2),
5.10 (m, 1H, NCH), 7.41–7.59 (m, 3H, ArH), 7.83 (m, 1H,
Ar 4-H). ES-MS (isomer mixture) m/z (%): 314 ([MNa+],
100). Anal. calcd. for C15H17NO5: C 61.85, H 5.90, N 4.80;
found (isomer mixture): C 62.15, H 6.05, N 4.70.
2-Acetyl-3-(2-oxo-2-piperidin-1-ylethyl)isoindolin-1-one
(24e)
{3-Oxo-2-[(1R)-1-phenylethyl]-2,3-dihydro-1H-isoindol-1-
yl}acetonitrile (22b)
Prepared according to general procedure D employing 8e
(0.341 g, 1.0 mmol) and acetamide (0.072 g, 1.2 mmol).
Column chromatography of the crude product eluting with
4:1 v/v ethyl acetate – hexane afforded the product (0.186 g,
62%) as colourless prisms, mp 107–109 °C. IR (cm–1):
2995, 1700, 1648, 1500, 1450, 1382. 1H NMR (CDCl3,
300 MHz) δ: 1.48–1.67 (m, 6H, piperidyl H), 2.44 (dd, 1H,
J = 15.5, 9.7 Hz, CHHCO), 2.68 (s, 3H, Me), 3.31–3.38 (m,
2H, piperidyl H), 3.51 (dd, 1H, J = 15.5, 2.7 Hz, CHHCO),
3.53–3.67 (m, 2H, piperidyl H), 5.68 (dd, 1H, J = 9.7,
2.7 Hz, NCH), 7.50 (t, 1H, J = 7.4 Hz, ArH), 7.63 (dt, 1H,
J = 7.7, 1.1 Hz, ArH), 7.74 (d, 1H, J = 7.7 Hz, ArH), 7.80
(d, 1H, J = 7.6 Hz, Ar 7-H). 13C NMR (CDCl3, 75 MHz) δ:
24.8, 26.0, 26.1, 37.6, 43.2, 46.9, 57.0, 124.9, 125.3, 129.3,
130.3, 134.8, 146.8, 167.9, 168.3, 171.6. ES-MS m/z (%):
301 ([MH+], 100). Anal. calcd. for C17H20N2O3: C 68.00, H
6.70, N 9.35; found: C 68.30, H 6.55, N 9.40.
Prepared according to general procedure A employing 8b
(0.255 g,
1 mmol) and (R)-(+)-α-methylbenzylamine
(0.145 g, 1.2 mmol) and heating at 95 °C for 48 h. Column
chromatography of the crude product eluting with 2:3 v/v
ethyl acetate – petroleum ether afforded a 2:3 separable
diastereomeric mixture the product (0.212 g, 77% combined
yield). Diastereomer 1 (major): colourless prisms, mp 89–
94 °C. [α]D +145.6 (0.71, CHCl3). IR (cm–1) ν: 1685, 1468,
1
1395, 1218. H NMR (CDCl3, 250 MHz) δ: 1.75 (d, 3H, J =
7.2 Hz, Me), 1.99 (dd, 1H, J = 16.8, 7.5 Hz, CHHCN), 2.51
(dd, 1H, J = 16.8, 3.5 Hz, CHHCN), 4.81 (dd, 1H, J = 7.5,
3.5 Hz, NCHCH2), 5.83 (q, 1H, J = 7.2 Hz, NCHMe), 7.36–
7.44 (m, 3H, ArH), 7.51 (m, 2H, ArH), 7.61 (m, 3H, ArH),
7.94 (d, 1H, J = 6.7 Hz, Ar 4-H). 13C NMR (CDCl3,
62.5 MHz) δ: 17.1, 23.4, 49.5, 54.3, 116.2, 122.6, 124.7,
127.7, 128.6, 129.4, 129.9, 132.1, 132.8, 140.7, 143.4,
168.9. MS m/z (%): 276 ([M+], 49), 261 (27), 158 (48), 132
(53), 105 (100), 77 (72), 51 (32). HR-MS calcd. for
C18H16N2O: 277.1341; found: 277.1338. Anal. calcd. for
C18H16N2O: C 78.20, H 5.80, N 10.15; found: C 77.80, H
5.90, N 10.25. Diastereomer 2 (minor): colourless prisms,
mp 123–127 °C. [α]D +70 (0.86, CHCl3). IR (cm–1): 1685,
2-Acetyl-3-[2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2-
oxoethyl]isoindolin-1-one (24f)
Prepared according to general procedure D employing 8f
(0.399 g, 1 mmol) and acetamide (0.072 g, 1.2 mmol). Col-
umn chromatography of the crude product eluting with 4:1
v/v ethyl acetate – hexane afforded the product (0.186 g,
52%) as colourless needles, mp 145–147 °C. IR (cm–1):
2990, 1690, 1648, 1500, 1456, 1382. 1H NMR (CDCl3,
300 MHz) δ: 1.61–1.73 (m, 4H, 2 × NCH2CH2), 2.48 (dd,
1H, J = 15.6, 9.7 Hz, CHHCO), 2.68 (s, 3H), 3.47–3.51 (m,
4H, 2 × NCH2CH2), 3.54 (dd, 1H, J = 15.6, 2.7 Hz,
CHHCO), 3.72–3.77 (m, 4H, 2 × OCH2), 5.68 (dd, 1H, J =
9.7, 2.7 Hz,), 7.51 (dt, 1H, J = 7.4, 0.7 Hz, ArH), 7.64 (dt,
1
1468, 1395, 1218. H NMR (CDCl3, 250 MHz) δ: 1.82 (d,
3H, J = 7.2 Hz, Me), 2.76 (dd, 1H, J = 16.8, 6.5 Hz,
CHHCN), 2.94 (dd, 1H, J = 16.8, 3.4 Hz, CHHCN), 4.36
(dd, 1H, J = 6.5, 3.4 Hz, NCHCH2), 5.74 (q, 1H, J = 7.2 Hz,
NCHMe), 7.34–7.40 (m, 5H, ArH), 7.48 (m, 1H, ArH), 7.56
(m, 1H, ArH), 7.91 (d, 1H, J = 6.6 Hz, Ar 4-H). 13C NMR
(CDCl3, 62.5 MHz) δ: 18.8, 23.9, 51.2, 55.2, 115.9, 122.4,
124.6, 127.9, 128.6, 129.5, 129.9, 132.3, 132.7, 139.4,
143.0, 168.8. MS m/z (%): 276 ([M+], 58), 261 (38), 158
© 2005 NRC Canada

Grigg et al.
1003
1H, J = 7.4, 1.2 Hz, ArH), 7.72 (d, 1H, J = 7.4 Hz, ArH),
7.90 (d, 1H, J = 7.6 Hz, Ar 7-H). 13C NMR (CDCl3,
75 MHz) δ: 35.2, 35.9, 37.5, 40.3, 43.9, 57.0, 64.9, 107.1,
124.8, 125.4, 129.4, 130.4, 134.8, 146.7, 168.0, 168.3,
171.6. ES-MS m/z (%): 359 ([MH+], 100). Anal. calcd. for
C19H22N2O5: C 63.70, H 6.20, N 7.80; found: C 63.50, H
6.25, N 7.65.
Ar 7-H), 8.53 (m, 1H, pyridyl 4-H). 13C NMR (CDCl3,
62.5 MHz) δ: 44.4, 44.8, 59.2, 122.4, 123.1, 124.2, 124.5,
127.8, 128.3, 128.6, 129.1, 131.7, 132.4, 136.7, 137.7,
145.6, 149.8, 157.0, 168.9. ES-MS m/z (%): 315 ([MH+],
100). Anal. calcd. for C21H18N2O: C 80.20, H 5.75, N 8.90;
found: C 80.00, H 5.85, N 8.90.
2-Pyridin-4-ylmethyl-3-pyridin-2-ylmethylisoindolin-1-
one (29)
3-(2-Oxo-2-piperidin-1-ylethyl)isoindolin-1-one (25e)
Prepared according to general procedure D employing 8e
(0.341 g, 1.0 mmol) and 1,1,1-trifluoroacetamide (0.136 g,
1.2 mmol). Column chromatography of the crude product
eluting with 4:1 v/v ethyl acetate – hexane afforded the prod-
uct (0.155 g, 60%) as a pale yellow gum. IR (cm–1): 2991,
Prepared according to general procedure E employing 8k
(0.15 g, 0.5 mmol) and 4-aminomethylpyridine (0.065 g,
0.6 mmol). Column chromatography of the crude product
eluting with ethyl acetate afforded the product (0.11 g, 70%)
as a colourless oil. IR (cm–1): 1689, 1600, 1470, 1436, 1412.
1H NMR (CDCl3, 250 MHz) δ: 3.50 (dd, 1H, J = 14.2,
6.6 Hz, NCHCHHAr), 3.31 (dd, 1H, J = 14.2, 6.0 Hz,
NCHCHHAr), 4.45, 5.10 (2 × d, 2 × 1H, J = 16.0 Hz,
NCH2Ar), 5.14 (dd, 1H, J = 6.6, 6.0 Hz, NCH), 6.83 (m,
1H, pyridyl 3-H), 7.04 (m, 1H, pyridyl 5-H), 7.05 (d, 2H,
J = 5.5 Hz, pyridyl 3′- and 5′-H), 7.18 (m, 1H, pyridyl 4-H),
7.44–7.45 (m, 3H, ArH), 7.88 (m, 1H, Ar 7-H), 8.48 (d, 2H,
J = 5.5 Hz, pyridyl 2′- and 6′-H), 8.54 (m, 1H, pyridyl 4-H).
13C NMR (CDCl3, 62.5 MHz) δ: 41.7, 44.2, 59.7, 122.6,
122.9, 123.1, 124.3, 124.5, 128.8, 131.7, 132.1, 136.9,
145.7, 146.8, 149.9, 150.3, 156.7, 169.2. MS m/z (%): 316
([MH+], 100), 200 (48), 151 (91). HR-MS calcd. for
C20H18N3O+H+: 316.1444; found: 316.1446.
1
1700, 1648, 1498, 1445, 1382. H NMR (CDCl3, 300 MHz)
δ: 1.43–1.66 (m, 6H, piperidyl H), 2.38 (dd, 1H, J = 16.5,
10.8 Hz, CHHCO), 3.06 (dd, 1H, J = 16.5, 2.9 Hz,
CHHCO), 3.33 (m, 2H, piperidyl H), 3.44–3.69 (m, 2H,
piperidyl H), 5.03 (dd, 1H, J = 10.8, 2.9 Hz, NCH), 7.02 (bs,
1H, NH), 7.42–7.52 (m, 2H, ArH), 7.57 (t, 1H, J = 7.2 Hz,
ArH), 7.87 (d, 1H, J = 7.4 Hz, Ar 7-H). 13C NMR (CDCl3,
75 MHz) δ: 24.8, 25.9, 26.7, 37.4, 43.2, 46.8, 53.8, 122.7,
124.5, 128.8, 132.1, 132.4, 146.8, 168.6, 170.1. ES-MS m/z
(%): 259 ([MH+], 100). Anal. calcd. for C15H18N2O2: C
69.75, H 7.00, N 10.85; found: C 69.90, H 7.20, N 10.65.
3-(2-Oxo-2-piperidin-1ylethyl)-2-(phenylsulfonyl)iso-
indolin-1-one (26e)
3-Pyridin-2-ylmethyl-2-thiophen-2-ylmethylisoindolin-1-
one (30)
Prepared according to general procedure D employing 8e
(0.341 g, 1 mmol) and benzenesulfonamide (0.188 g, 1.2 mmol).
Column chromatography of the crude product eluting with
4:1 v/v ethyl acetate – hexane afforded the product (0.223 g,
56%) as colourless needles, mp 190–192 °C. IR (cm–1):
2995, 1710, 1667, 1498, 1450, 1380. 1H NMR (CDCl3,
300 MHz) δ: 1.52–1.70 (m, 6H, piperidyl H), 2.69 (dd, 1H,
J = 16.0, 9.9 Hz, CHHCO), 3.30–3.42 (m, 2H, piperidyl H),
3.57–3.72 (m, 2H, piperidyl H), 3.80 (dd, 1H, J = 16.0,
2.6 Hz, CHHCO), 5.81 (dd, 1H, J = 9.9, 2.6 Hz, NCH), 7.44
(t, 1H, J = 7.5 Hz, ArH), 7.50–7.65 (m, 5H, ArH), 7.70 (d,
1H, J = 7.8 Hz, ArH), 7.77 (d, 1H, J = 7.7 Hz, ArH), 8.12
(dd, 1H, J = 8.5, 1.3 Hz, Ar 7-H). 13C NMR (CDCl3, 75 MHz)
δ: 24.8, 26.0, 26.8, 39.8, 43.3, 47.0, 60.2, 124.9, 125.2,
128.6, 129.4, 129.5, 134.5, 134.8, 138.8, 147.1, 167.1,
167.7. ES-MS m/z (%): 399 ([MH+], 100). Anal. calcd. for
C21H22N2O4: C 63.30, H 5.60, N 6.90; found: C 63.25, H
5.60, N 6.90.
Prepared according to general procedure E employing 8k
(0.15 g, 0.5 mmol) and 2-aminomethylthiophene (0.068 g,
0.6 mmol). Column chromatography of the crude product
eluting with 1:2 v/v ethyl acetate – petroleum ether afforded
the product (0.12 g, 74%) as colourless prisms, mp 124 to
1
125 °C. IR (cm–1): 1688, 1591, 1469, 1436, 1408. H NMR
(CDCl3, 250 MHz) δ: 3.21 (dd, 1H, J = 14.0, 6.9 Hz,
NCHCHHAr), 3.45 (dd, 1H, J = 14.0, 5.4 Hz, NCHCHHAr),
4.54, 5.38 (d, 1H, J = 15.7 Hz, NCHHAr), 5.10 (dd, 1H, J =
6.9, 5.4 Hz, NCH), 5.38 (d, 1H, J = 15.7 Hz, NCHHAr),
6.86 (d, 1H, J = 7.7 Hz, thienyl 4-H), 6.89–6.95 (m, 2H,
ArH), 7.00–7.05 (m, 1H, thienyl 3-H), 7.15–7.20 (m, 2H,
ArH), 7.35–7.45 (m, 2H, ArH), 7.51 (dt, 1H, J = 7.7, 1.8 Hz,
thienyl 5-H), 7.77–7.83 (m, 1H, Ar 7-H), 8.57 (d, 1H, J =
4.5 Hz, pyridyl 4-H). 13C NMR (CDCl3, 62.5 MHz) δ: 39.5,
41.4, 59.1, 122.5, 123.1, 124.2, 124.5, 125.8, 126.9, 127.2,
128.6, 131.8, 132.3, 136.8, 140.1, 145.6, 149.9, 157.0,
168.5. ES-MS m/z (%): 321 ([MH+], 100). Anal. calcd. for
C19H16N2OS: C 71.20, H 5.05, N 8.75, S 10.00; found: C
71.10, H 5.15, N 8.65, S 9.80.
2-Benzyl-3-pyridin-2-ylmethylisoindolin-1-one (28)
Prepared according to general procedure E employing 8k
(0.15 g, 0.5 mmol) and benzylamine (0.064 g, 0.6 mmol).
Column chromatography of the crude product eluting with
1:2 v/v ethyl acetate – petroleum ether afforded the product
(0.10 g, 64%) as colourless prisms, mp 118 to 119 °C. IR
2-(2-Morpholin-4-ylethyl)-3-pyridin-2-ylmethyliso-
indolin-1-one (31)
1
(cm–1): 1685, 1590, 1469, 1436. H NMR (CDCl3, 250 MHz)
Prepared according to general procedure E employing 8k
(0.15 g, 0.5 mmol) and 2-morpholin-4-ylethylamine (0.079 g,
0.6 mmol). Column chromatography of the crude product
eluting with ethyl acetate afforded the product (0.11 g, 64%)
as a colourless oil. IR (cm–1): 1684, 1652, 1470, 1434, 1310,
δ: 3.10 (dd, 1H, J = 14.0, 7.1 Hz, NCHCHHAr), 3.41 (dd,
1H, J = 14.0, 5.3 Hz, NCHCHHAr), 4.37 (d, 1H, J =
15.3 Hz, NCHHPh), 5.00 (dd, 1H, J = 7.1, 5.3 Hz, NCH),
5.27 (d, 1H, J = 15.3 Hz, NCHHPh), 6.81 (m, 1H, pyridyl 3-
H), 6.97 (m, 1H, pyridyl 5-H), 7.15–7.30 (m, 6H, ArH),
7.40–7.50 (m, 3H, pyridyl 6-H and 2 × ArH), 7.85 (m, 1H,
1
1116, 861, 775. H NMR (CDCl3, 250 MHz) δ: 2.47 (t, 4H,
J = 4.1 Hz, NCH2CH2N(CH2)2), 2.59 (t, 4H, J = 4.1 Hz,
© 2005 NRC Canada

1004
Can. J. Chem. Vol. 83, 2005
NCH2CH2N(CH2)2), 3.05 (dd, 1H, J = 13.9, 7.5 Hz,
ject, and the Thailand Postgraduate Education and Research
in Chemistry (PERCH) Fund for support.
NCHCHHAr), 3.29 (dt, 2H,
J
=
14.3, 6.3 Hz,
NCH2CH2N(CH2)2), 3.47 (dd, 1H, J = 13.9, 5.2 Hz,
NCHCHHAr), 3.66 (t, 4H, J = 4.5 Hz, CH2OCH2), 4.17 (dt,
2H, J = 14.3, 6.7 Hz, NCH2CH2N(CH2)2), 5.32 (dd, 1H, J =
7.5, 5.2 Hz, NCH), 6.93–6.97 (m, 2H, ArH), 7.19 (dd, 1H,
J = 7.1, 5.0 Hz, ArH), 7.38–7.45 (m, 2H, ArH), 7.57 (dt, 1H,
J = 7.6, 1.9 Hz, ArH), 7.76–7.82 (m, 1H, Ar 7-H), 8.59 (d,
1H, J = 4.1 Hz, pyridyl 4-H). 13C NMR (CDCl3, 62.5 MHz)
δ: 37.6, 41.5, 54.1, 57.2, 59.9, 67.4, 122.5, 122.9, 123.9,
124.6, 128.5, 131.5, 132.6, 136.8, 145.9, 149.9, 157.3,
168.7. ES-MS m/z (%): 338 ([MH+], 100). HR-MS calcd. for
C20H24N3O2+H+: 338.1863; found: 338.1859.
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(0.11 g, 67%) as colourless prisms, mp 127–129 °C. IR (cm–1):
1685, 1512, 1472, 1457, 1387, 1247. 1H NMR (CDCl3,
250 MHz) δ: 2.83 (dd, 1H, J = 13.9, 8.6 Hz, CHHAr), 3.46
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76.10, H 5.40, N 8.30.
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and the reaction heated at 95 °C for 96 h. Column chroma-
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1591, 1505, 1465, 1435, 1368, 1276, 1212, 1134. H NMR
(CDCl3, 250 MHz) δ: 2.31 (dd, 1H, J = 13.5, 8.5 Hz,
CHHAr), 3.20 (dd, 1H, J = 13.5, 3.4 Hz, CHHAr), 5.01 (dd,
1H, J = 8.5, 3.4 Hz, NCH), 6.93 (d, 1H, J = 7.7 Hz,
thiazolyl 5-H), 7.02 (d, 1H, J = 7.0 Hz, thiazolyl 4-H), 7.03–
7.10 (m, 2H, ArH), 7.44–7.52 (m, 3H, ArH), 7.62 (d, 1H,
J = 3.6 Hz, ArH), 7.85 (m, 1H, Ar 7-H), 8.50 (m, 1H,
pyridyl 4-H). 13C NMR (CDCl3, 62.5 MHz) δ: 40.7, 61.9,
114.0, 122.3, 123.8, 124.6, 129.0, 130.4, 132.3, 136.6,
138.5, 145.7, 149.8, 156.9, 157.6, 166.7. ES-MS m/z (%):
308 ([MH+], 100). Anal. calcd. for C17H13N3OS: C 66.40, H
4.25, N 13.65, S 10.40; found: C 66.20, H 4.15, N 13.75, S
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© 2005 NRC Canada