Synthesis of isoindolinones: Intramolecular [4+2] cycloaddition/retro [4+2] of pyridone propiolamides

Article abstract of DOI:10.1016/j.tetlet.2019.151105

A new synthesis of isoindolinones was discovered during a screening campaign aimed at the development of novel methods for the synthesis of pyridone-EZH2 inhibitor analogues. The reaction proceeds via an intramolecular [4+2] cycloaddition of a pyridone with a tethered propiolamide moiety followed by extrusion of isocyanic acid. The discovery, optimization, and scope of the methodology are described.

Full text of DOI:10.1016/j.tetlet.2019.151105

Tetrahedron Letters 60 (2019) 151105
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of isoindolinones: Intramolecular [4+2] cycloaddition/retro
[4+2] of pyridone propiolamides
⇑
Jonathan E. Wilson , Joshua Garvey, Kennedy M. Taveras
Constellation Pharmaceuticals, 215 First Street, Suite 200, Cambridge, MA 02142, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 July 2019
Accepted 1 September 2019
Available online 4 September 2019
A new synthesis of isoindolinones was discovered during a screening campaign aimed at the develop-
ment of novel methods for the synthesis of pyridone-EZH2 inhibitor analogues. The reaction proceeds
via an intramolecular [4+2] cycloaddition of a pyridone with a tethered propiolamide moiety followed
by extrusion of isocyanic acid. The discovery, optimization, and scope of the methodology are described.
Ó 2019 Elsevier Ltd. All rights reserved.
Keywords:
Isoindolinone
Pyridone
Cycloaddition
Extrusion
Isoindolinones are a heterocycle found in a variety of bioactive
compounds with an array of activities including calcium channel
antagonism (Falipamil) [1], potassium channel opening (Celikalim)
[2], PARP-inhibition (NMS-P118) [3], metabotropic glutamate
receptor potentiation (AZD8529) [4], anti-inflammation (Indopro-
fen) [5], immunomodulation (Lenalidomide and CC-220) [6,7],
and GABAA-agonism (Pagoclone) [8]. Additionally, the isoin-
dolinone scaffold is present in some natural products such as
hericerin and porritoxin [9,10].
In the course of a synthetic effort aimed at the synthesis of
pyridone EZH2 inhibitor analogues related to CPI-1205, we
inadvertently discovered a novel reaction that produces highly
substituted isoindolinones from substituted N-((2-oxo-1,2-dihy-
by an amide coupling with butynoic acid. We then surveyed a wide
range of conditions to induce a heteroconjugate addition reaction
of N-cyclohexylaniline or 2-halo-N-cyclohexylanilines to 4.
Although in certain instances we observed trace amounts of the
heteroconjugate addition intermediate
5
and the desired
3-indole-amide product 6, in instances where metal catalysts were
used, we consistently generated side-product with a mass 43 amu
less than the mass of the starting material 4. This change in mass
corresponds to loss of isocyanic acid. Based on this observation,
we hypothesized that isoindolinone 8 was formed by extrusion
of isocyanic acid from an azabicyclo[2.2.2]octadienone intermedi-
ate 7 which was generated from an intramolecular [4+2] cycload-
dition reaction of the butynamide moiety and the diene
embedded in the pyridone ring system of 4 (Scheme 2).
Our initial hypothesis was supported by 1H and 13C NMR of 8
that were consistent with a product derived from the reaction
mechanism outlined in Scheme 2. Additionally, the product was
substantially less polar than the starting material 4 which is in
agreement with the conversion of the polar amide moiety of the
pyridone starting material to the nonpolar benzene moiety of the
isoindolinone product.
We further confirmed our mechanistic hypothesis through
independent preparation of 2-benzyl-7-phenylisoindolin-1-one
via the intramolecular [4+2] cycloaddition/isocyanic acid extrusion
reaction and via a two-step sequence, consisting of alkylation of 7-
bromoisoindolin-1-one (CAS no.: 200049-46-3) with benzylbro-
mide and subsequent Suzuki coupling with phenylboronic acid.
The products derived from these two sequences yielded products
with identical LCMS retention times and 1H NMR spectra
(Scheme 3).
dropyridin-3-yl)methyl)propiolamides.
Pyridone-propiolamide
intermediates such as 1, were designed to enable the development
of novel methods for the synthesis of a subclass of EZH2 inhibitors
containing highly substituted 3-indole carboxylic acid side-chains
(see Fig. 1).
The process that we had set out to develop was a domino reac-
tion consisting of a heteroconjugate addition reaction of an aniline
to 1 followed by an intramolecular palladium catalyzed-coupling
of intermediate 2 to form the indole C-3-arene bond of 3. Processes
of this nature would provide access to a wide variety of EZH2 inhi-
bitors from readily accessible substituted anilines (Scheme 1).
We began our studies by preparing 4 via a two-step protocol
consisting of a reductive amination of para-methoxybenzaldehyde
with 3-(aminomethyl)-4,6-dimethyl-pyridin-2(1H)-one followed
⇑
Corresponding author.
E-mail address: jonathan.wilson@constellationpharma.com (J.E. Wilson).
https://doi.org/10.1016/j.tetlet.2019.151105
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.

2
J.E. Wilson et al. / Tetrahedron Letters 60 (2019) 151105
Scheme 3. Synthesis of 2-benzyl-7-phenylisoindolin-1-one via the [4+2] cycload-
dition/isocyanic acid extrusion reaction and from 7-bromoisoindolin-1-one.
A range of solvents, temperatures, and concentrations were sur-
veyed to optimize the efficiency and yield of the model reaction
where 4 is transformed into 8 (Table 1). A range of solvents were
suitable for the reaction. While reactions in toluene generated
multiple unidentified decomposition products, those performed
in t-amylalcohol and dioxane were generally very clean by LCMS.
Dimethylacetamide was also a good solvent for the process but
an unidentified byproduct with a LCMS retention time close to that
of 8 was formed, complicating purification of the product. While
reactions in dioxane were very similar to those in t-amylalcohol,
we selected t-amylalcohol for further studies as it solubilized the
starting materials more effectively than dioxane. Decreasing the
concentration of the reaction from 0.1 M to 0.03 M had little effect
on the outcome but increasing the concentration to 0.3 M led to
the formation of unidentified side products. The reaction proceeds
slowly or not at all at temperatures below 100 °C. Although
extended reaction times were required to drive the reaction of 4
to 8 to completion, we found later that the rate of the reaction is
affected by the substitution pattern of the starting material. Simple
heating of a 0.1 M solution of 4 in t-amylalcohol in a sealed tube at
120 °C for 96 h proved to be the optimal set of conditions to induce
the desired [4+2] cycloaddition/isocyanic acid extrusion reaction
that yields 8 (Table 1).
Fig. 1. Structures of isoindolinone drug candidates and natural products.
Scheme 1. Proposal for a domino reaction to access 3-indolecarboxamide-pyridone
EZH2 inhibitors.
With a set of effective reaction conditions in hand, we set out to
explore the substrate scope of the methodology. A broad range of
substituents at R3 are tolerated including hydrogen, methyl, 1°-
alkyl, 2°-alkyl, and aromatic (Table 2, entries 1–5). Disubstituted
or unsubstituted pyridone moieties were also viable substrates in
the reaction. As noted above, the rate of the reaction is affected
by the substitution pattern of the substrate. With respect to the
propiolamide substituent R3, the rate of the reaction appears to
increase in the following order: 2°-alkyl < 1°-alkyl < methyl < aro-
matic. In general, substituted pyridones are more reactive than
unsubstituted pyridones.
The scope of the amide N-substituent was also examined. A
wide variety of groups were tolerated including 1°-alkyl, 2°-alkyl,
aromatic and hydrogen. In general, amides substituted with 2°-
alkyl groups are more reactive than 1°-alkyl-substituted amides
and N–H amides. The reactivity trends with respect to the R4 sub-
stituent and the pyridone moiety were consistent with those out-
lined for the examples in Table 1. Additionally, several different
functional groups were well tolerated, including an ester, a pro-
tected amine, and an acetal (Table 3).
We have also demonstrated that the reaction can be run
directly on a crude material from the amide coupling reaction mix-
ture used for the substrate synthesis to directly provide the desired
isoindolinone product from an amine precursor. While we have
only attempted this two-step, one-pot procedure for the single
example shown in Eq. (1), we expect that this variation of the reac-
Scheme 2. Mechanism for the formation of isoindolinone byproduct.
The process outlined above is akin to the more well-known 2-
pyrone [4+2] cycloaddition/CO2 extrusion reaction [11–15]. While
intermolecular variants of the pyridone-alkyne [4+2]/isocyanate
extrusion process outlined in scheme 2 have been documented
and reviewed in the literature, the intramolecular variant resulting
in the formation of isoindolinones has not been described [16–43].
The optimization and scope of this process is detailed herein.

J.E. Wilson et al. / Tetrahedron Letters 60 (2019) 151105
3
Table 1
Optimization of pyridone-propiolamide [4+2]/isocyanic acid-extrusion reaction.
Entrya
Solvent
Temp
(°C)
Time
(h)
Ratiob
(SM/IS)
Ratioc
(P/IS)
1
2
3
4
toluene
t-amylOH
dioxane
120
120
120
120
120
120
100
80
24
24
24
24
24
24
24
24
24
48
96
0.94
1.23
1.28
0.75
1.35
0.66
1.57
2.07
2.10
1.14
0.55
0.57
0.62
0.85
1.74
0.56
1.01
0.12
0.01
0.00
1.00
1.65
DMA
5d
6e
7
t-amylOH
t-amylOH
t-amylOH
t-amylOH
t-amylOH
t-amylOH
t-amylOH
8
9
10
11
60
120
120
a
b
c
All reactions were run on a 0.5 mmol scale at a concentration of 0.1 M unless otherwise noted.
Ratio of LCMS area at 254 nm of N-((2-oxo-1,2-dihydropyridin-3-yl)methyl)propiolamide to an internal standard of
Ratio of LCMS area of 254 nM of 2-(4-methoxybenzyl)-4,6,7-trimethylisoindolin-1-one to an internal standard of -tetralone. See the experimental section for additional
a-tetralone.
a
information.
d
The reaction concentration was 0.03 M.
The reaction concentration was 0.3 M.
e
Table 2
Propiolamide and pyridone scope in the pyridone-propiolamide [4+2]/isocyanic acid extrusion reaction.
Entrya
R1
R2
R3
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
OMe
OMe
SMe
SMe
H
Me
CH2OH
CH2OTBS
C6H11
Ph
Ph
Ph
n-C3H7
Me
n-C3H7
24
72
48
24
168
140
72
24
48
72
72
39
60
57
60
80
71
30
77
22
97
54
9
10
11
a
All reactions were run at a concentration of 0.1 M in t-amylalcohol at 120 °C for the time indicated in the table.
Isolated yield of purified isoindolinone. See the experimental section for further details.
b
Table 3
Amide N-substituent and pyridone scope in the pyridone-propiolamide [4+2]/isocyanic acid extrusion reaction.
Entrya
R1
R2
R3
R4
Time (h)
Yield (%)b
1
2
3
Me
Me
Me
Me
Me
Me
(CH2)3Ph
(CH2)3Ph
Me
Ph
Ph
60
24
24
94
88
91
4
5
Me
Me
Me
Me
CH2CO2Et
Ph
Ph
72
16
83
92
6
7
8
9
Me
H
Me
H
Me
H
Cl
H
H
Ph
Ph
Ph
Ph
96
96
24
72
34
44
81
24
4-Et-Ph
C6H11
Bn
a
All reactions were run at a concentration of 0.1 M in t-amylalcohol at 120 °C for the time indicated in the table.
Isolated yield of purified isoindolinone.
b

4
J.E. Wilson et al. / Tetrahedron Letters 60 (2019) 151105
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