One-pot multistep synthesis of 3,4-fused isoquinolin-1(2H)-one analogs

Article abstract of DOI:10.1016/j.tetlet.2011.01.089

We have developed a robust approach for the synthesis of 3,4-fused isoquinolin-1(2H)-one analogs. A benzonitrile or a nicotinonitrile bearing an ortho-substituent, such as -OH, -SH, or -NHR (R = alkyl or aryl) can be deprotonated by KOtBu and then reacted with methyl 2-(bromomethyl)benzoate (8) to form its corresponding O-, S-, or N-alkylation product. The product thus formed is then treated with KOtBu again to initiate a cascade process that will lead to the formation of its corresponding 3,4-fused isoquinolin-1(2H)-one. This multistep synthesis as well as the final product purification is achieved in a one-pot manner.

Full text of DOI:10.1016/j.tetlet.2011.01.089

Tetrahedron Letters 52 (2011) 1574–1577
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot multistep synthesis of 3,4-fused isoquinolin-1(2H)-one analogs
⇑
Lianhai Li , Waepril Kimberly S. Chua
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Hwy., Kirkland, Québec, Canada H9H 3L1
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed a robust approach for the synthesis of 3,4-fused isoquinolin-1(2H)-one analogs. A
benzonitrile or a nicotinonitrile bearing an ortho-substituent, such as –OH, –SH, or –NHR (R = alkyl or
aryl) can be deprotonated by KOtBu and then reacted with methyl 2-(bromomethyl)benzoate (8) to form
its corresponding O-, S-, or N-alkylation product. The product thus formed is then treated with KOtBu
again to initiate a cascade process that will lead to the formation of its corresponding 3,4-fused isoquin-
olin-1(2H)-one. This multistep synthesis as well as the final product purification is achieved in a one-pot
manner.
Received 25 October 2010
Revised 8 January 2011
Accepted 18 January 2011
Available online 1 February 2011
Keywords:
One-pot
Multistep
Ó 2011 Elsevier Ltd. All rights reserved.
Synthesis
3,4-Fused isoquinolin-1(2H)-one
Improving efficiency is one of the main goals of modern organic
synthesis.1,2 This is further reinforced by our increasing awareness
of various environmental concerns and the issue of sustainability
in the past decades. To date, the design, development, and utiliza-
tion of efficient and environmentally benign synthetic processes
have become a conscientious choice of synthetic chemists.3,4 One
attractive strategy is to design and develop novel one-pot, multi-
step syntheses that will help simplify reaction handling and prod-
uct purification, improve synthetic efficiency, and reduce solvent
consumption and disposal. This, in turn, will reduce the consump-
tion of natural resources, minimize the potential harmful impact of
various chemicals on the environment, and ultimately, improve
sustainability.5
In a recent medicinal chemistry program, we identified that
substituted 11-alkyl-6,11-dihydro-5H-indolo[3,2-c]isoquinolin-5-
one 1 (Fig. 1), after further transformations, served as a novel scaf-
fold for the inhibition of an anti-viral target. To facilitate our SAR
exploration, we needed an efficient and general approach to syn-
thesize intermediate 1 where R and R’ represent two key points
for structural diversification. Indeed, compounds bearing a 6,11-
dihydro-5H-indolo[3,2-c]isoquinolin-5-one core have previously
been found to possess interesting biological activities6,7 and their
synthesis has been a subject of two prior publications.8,9 After eval-
uating these two methods , the one in which compound 2a was ac-
cessed via a simple and efficient one-pot process from 3a and 4, as
outlined in Scheme 1, drew our attention.8 Based on this report, we
first explored the possibility of whether 3a can be replaced by
2-methylaminobenzonitrile (6a) in the above-mentioned reac-
O
HN
R'
N
R
X
1
Figure 1. Target structure.
O
N
O
N
MeO
O
Br
OMe
N
-
N
O
OMe
O
O
O
O
O
OEt
4
OEt
7a
7b
O
NH
N
OEt
2a
O
CN
HN
ref. 8
4
NH
O
ref. 8
OEt
3a
N
H
5
O
Scheme 1.
tion. Unfortunately, we failed to obtain the desired product 1
(Scheme 2). This prompted us to test a few other substrates, such
as 6b, 3b, and 3c in the same reaction. Once again, in spite of the
fact that the synthesis of compound 2a from 3a under the reported
conditions proceeded similarly well in our hands, all three
⇑
Corresponding author at present address: 4201 Hugo, Pierrefonds, Quebec,
Canada H9H 2V6. Tel.: +1 514 3576713.
E-mail addresses: Lianhai_li@merck.com, Lianhai.li@gmail.com (L. Li).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.089

L. Li, Waepril Kimberly S. Chua / Tetrahedron Letters 52 (2011) 1574–1577
1575
CN
substrate. We found that by heating a mixture of 11a (1.1 equiv)
and compound 8 (1.0 equiv) with 4 equiv of K2CO3 in DMF at
80 °C for 3 h (Condition A, Table 1, entry 1), only the alkylation
product 12a was formed. No trace of the desired cyclization prod-
uct 13a was observed by LCMS. Apparently, the basicity of K2CO3
was not sufficient to affect a benzylic deprotonation of compound
12a which was thought to be critical for the initiation of the fol-
lowing cascade process toward 13a. However, the formation of
12a in high yield was encouraging and all that remained was to
find a base that can affect the requisite benzylic deprotonation.
We found that compound 11a (1.1 equiv), after being treated with
1.1 equiv of NaH in DMF at 0 °C (until the bubbling stopped), re-
acted smoothly with compound 8 (1.0 equiv) to furnish the desired
alkylation product 12a cleanly after 1.5 h at rt. At this point, we
added another 1.1 equiv of NaH to the resulting reaction mixture
and found that compound 12a was completely consumed after
1 h at 80 °C to afford the desired product 13a, based on LCMS anal-
ysis (Condition B, Table 1, entry 2). Following an acidic work-up,
this was also confirmed by 1H NMR analysis of the crude reaction
mixture thus obtained (75% estimated yield). Unfortunately, vari-
ous attempts to purify 13a failed due to the presence of an insep-
arable by-product, the corresponding carboxylic acid of ester
12a.13 On the other hand, when the reaction was carried out with
KOtBu in THF and a slightly modified work-up (i.e., 4 equiv, of HCl
was added dropwise to the reaction mixture at 80 °C and the de-
sired product crystallized out of the reaction mixture upon cooling
to room temperature), the desired cyclized product 13a was ob-
tained in 97% isolated yield (Condition C, Table 1, entry 3).15
With the newly optimized reaction conditions in hand, we then
proceeded to explore its reactant scope. As shown in Table 2 and 2-
hydroxybenzonitrile with a bromine substituent at various posi-
tions (i.e., 11b–d), all furnished the desired cyclization product
(i.e., 13b–d) in good to excellent yield. As expected di-ortho substi-
tuted phenol 11b, as a consequence of its greater steric demand,
was found to be more recalcitrant toward cyclization. Interestingly,
when simple 2-mercaptobenzonitrile 11e was the substrate used,
the desired product 13e was obtained in a yield comparable to that
of 13a.
X
NH
Me
1
X
ref. 8
6a: X = CH
6b: X = N
O
CN
NH
R'
HN
N
4
X
R'
X
X
EtO
O
ref. 8
OEt
2
O
3b: R',X = H,N
3c: R',X = Br,CH
Scheme 2.
substrates failed to afford the desired product 1 (Scheme 2). These
failures, especially with substrates 3b and 3c, suggested a narrow
reactant scope of the original report and thus prevented us from
developing an efficient, general synthesis of 1 from 2 (Scheme 2).
In order to determine what the root cause of this narrow reac-
tion scope was, we analyzed the reaction mechanism postulated
in the previous Letter8 and hypothesized that the methoxycarbonyl
group attached to the benzylic carbon in compound 4 was
detrimental to the reaction. Firstly, the methyl ester activates its
a
-proton toward an initial, unproductive deprotonation versus
the desired alkylation via bromide displacement. The carbanion
thus formed is not stable and the reaction will then suffer from
various decomposition pathways. Secondly, even for the material
that underwent the desired SN2 alkylation to furnish the cyclized
intermediate 7a, formation of
2 still required a subsequent
decarboxylation step. Finally, the cumulative impact of the ste-
ric hindrance imparted by this ester group on all the reaction steps
is negative. Consequently, we envisioned that if 1-[2-(bromo-
methyl)phenyl]-2-methoxyethanone (8) was used instead of
compound 4, the reported transformation should proceed much
more readily (Scheme 3). This was supported by numerous litera-
ture examples where methyl 2-(bromomethyl)benzoate was used
as an efficient alkylation reagent.10–12
Unfortunately, when 2-alkylaminobenzonitrile 6a was sub-
jected to Condition C as described above, we only detected the par-
tial formation of the desired N-alkylation product by LCMS.
Besides, a coupling product between compound 8 and potassium
tert-butoxide (i.e., methyl 2-(tert-butoxymethyl)benzoate) was
For our initial proof-of-concept as well as subsequent reaction
optimizations, we chose 2-hydroxybenzonitrile 11a as our model
MeO
O
MeO
O
Br
Br
?
OMe
Table 1
Exploration of reaction conditions using 2-hydroxybenzonitrile as substrate
O
4
8
O
CN
HN
O
OH
11a
Conditions
8
+
CN
HN
N
R'
O
13a
X
NH
Me
R'
X
1
R
Entry
1
Conditionsd
Product
Yield%
100a
6
O
EtO
CN
8
A
?
O
EtO
CN
O
12a
R'
EtO
CN
N
O
2
3
B
13a
13a
75b
97c
?
X
N
R
R'
C (Ref. 15)
X
a
b
c
10
R
Based on LCMS.
Based on 1H NMR.
Isolated yield.
9
d
See text for detailed description.
Scheme 3.

1576
L. Li, Waepril Kimberly S. Chua / Tetrahedron Letters 52 (2011) 1574–1577
Table 2
Table 4
Exploration of reaction scope
Exploration of reaction scope with various substituents on the phenyl ring
O
O
Cl
HN
1. KOtBu(1.1 equiv)
2. 8
CN
CN
H
N
HN
X
Cl
R = Me, 81% yield
R = Bn, 61% yield
X
H
3. KOtBu (1.1 equiv)
R
+
8
R
N
R
Conditions C (ref. 15)
R
6h: R = Me
6i: R = Bn
1h: R = Me
1i: R = Bn
Entry
Benzonitrile
Product
Yield%a
O
CN
O
HN
CN
H
OH
HN
Cl
11b
R = Me, 84% yield
R = Bn, 81% yield
N
R
Br
13b
13c
1
2
88
80
N
R
Br
Cl
O
CN
OH
O
6j: R = Me
6k: R = Bn
1j: R = Me
1k: R = Bn
HN
11c
11d
O
HN
CN
H
O
Br
R = Me, 84% yield
R = Bn, 63% yield
Br
N
R
CN
OH
O
N
R
HN
O
Cl
Cl
6l: R = Me
6m: R = Bn
1l: R = Me
3
4
73
95
13d
13e
Br
1m: R = Bn
Br
CN
SH
O
HN
S
11e
1. KOtBu(1.1 equiv)
2. 8
O
CN
H
HN
3. KOtBu (1.1 equiv)
N
O
a
Isolated yield.
OEt
N
H
one-pot
5
3a
Table 3
Exploration of reaction scope with various X and R moieties
63% yield
Scheme 4.
O
CN
1. KOtBu(1.1 equiv)
2. 8
H
N
HN
has an N-isopropyl moiety, gave product 1g in 25% yield but in high
purity. The low yield is likely due to the steric hindrance of the
isopropyl group (Table 3).
R
3. KOtBu (1.1equiv)
X
Conditions D (ref. 15)
N
R
X
To evaluate the effect of substituents on the phenyl ring,
substrates 6h–m were then investigated. Gratifyingly, the transfor-
mation proceeded in good yield in all cases (Table 4). Finally, we
decided to investigate if this transformation could be used to
synthesize the biologically active compound 5, an intermediate
previously used for the synthesis of poly(ADP-ribose)polymerase-
1 (PARP-1) inhibitors.14 Starting from substrate 3a and using
Conditions D, we were able to obtain compound 5 in one pot in
63% yield (Scheme 4).
Entry
X, R
Nitrile
Product
Yield%
1
2
3
4
5
6
7
CH, Me
N, Me
CH, Bn
N, Bn
6a
6b
6c
6d
6e
6f
1a
1b
1c
1d
1e
1f
71
84
85
77
70
70
25
CH, isobutyl
CH, Ph
CH, iPr
6g
1g
In summary, we have developed a robust approach for the syn-
thesis of several 3,4-fused isoquinolin-1(2H)-one derivatives. Both
benzonitrile and nicotinonitrile bearing a substituent, such as –OH,
–SH, or –NHR (R = alkyl or aryl) at the 2-position can be reacted
with methyl 2-(bromomethyl)benzoate (8) in the presence of KOt-
Bu to afford the corresponding 3,4-fused isoquinolin-1(2H)-one.15
This multistep synthesis as well as the final product purification
is achieved in an efficient one-pot manner.
observed, suggesting that the initial reaction time between aniline
6a and the base was not sufficient. On the other hand, by allowing
the reaction between 6a and KOtBu to proceed for 1 h at 0 °C prior
to the addition of compound 8, the desired N-alkylation product
was obtained without the formation of methyl 2-(tert-butoxym-
ethyl)benzoate. After the addition of another 1.1 equiv of KOtBu,
the mixture was stirred for 1 h at 80 °C and the final cyclized
product 1a was detected by LCMS. After the in situ crystallization
work-up conditions as described previously, spectroscopically pure
compound 1a was obtained in 71% yield. The pyridine-containing
substrate 6b afforded the cyclized product 1b in 84% yield under
these new conditions (assigned as Conditions D).15 In order to eval-
uate how a substituent on the aniline nitrogen affected the reac-
tion, substrates 6c–g were subjected to the reaction sequence
using Conditions D. To summarize, all these substrates, except
6g, afforded the desired products in good yield. Substrate 6g, which
References and notes
1. Trost, B. M. Science 1991, 254, 1471.
2. Trost, B. M. Science 1983, 219, 245.
3. Song, J. J.; Reeves, J. T.; Fandrick, D. R.; Tan, Z.; Yee, N. K.; Senanayake, C. H.
Green Chem. Lett. Rev. 2008, 1, 141.
4. Anastas, P. T.; Beach, E. S. Green Chem. Lett. Rev. 2007, 1, 9.
5. Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6, 3321.
6. Jagtap, P.; Roy, A.; Williams, W. U.S. Patent US 7393955, 2008.
7. Saundane, A. R.; Rudresh, K.; Satyanarayan, N. D.; Hiremath, S. P. Indian J.
Pharm. Sci. 1998, 60, 379.

L. Li, Waepril Kimberly S. Chua / Tetrahedron Letters 52 (2011) 1574–1577
1577
8. Jagtap, P. G.; Baloglu, E.; Southan, G.; Williams, W.; Roy, A.; Nivorozhkin, A.;
Landrau, N.; Desisto, K.; Salzman, A. L.; Szabo, C. Org. Lett. 2005, 7, 1753. The
reaction was done by first reacting NaH with a 2-aminonitrile derivative (3a–c
or 6a–b) in toluene and then refluxing with compound 4 for certain period of
time (4–10 h). An acidic work-up was then employed.
9. Hiremath, S. P.; Saundane, A. R.; Mruthyunjayaswamy, B. H. M. J. Heterocycl.
Chem. 1993, 30, 603.
10. For an example of N-alkylation of a N-substituted aniline, see: Hanna, P. E.;
Grund, V. R.; Anders, M. W. J. Med. Chem. 1974, 17, 1020.
11. For an example of S-alkylation of a thiophenol, see: Fink, B. E.; Gavai, A. V.;
Tokarski, J. S.; Goyal, B.; Misra, R.; Xiao, H.-Y.; Kimball, S. D.; Han, W.-C.; Norris,
D.; Spires, T. E.; You, D.; Gottardis, M. M.; Lorenzi, M. V.; Vite, G. D. Bioorg. Med.
Chem. Lett. 2006, 16, 1532.
12. For an example of O-alkylation of a phenol, see: Dvornikovs, V.; Smithrud, D. B.
J. Org. Chem. 2002, 67, 2160.
solubility of 13a in various organic solvents including DMSO prevented
purification via silica gel flash chromatography.
14. Jagtap, P.; Roy, A.; Williams, W. US Patent, US 7393955, 2008.
15. Method: To a DMF (2 mL) solution of benzonitrile or nicotinonitrile (1.1 mmol)
was added dropwise at 0 °C a THF solution of potassium tert-butoxide (1.1 mL,
1.1 mmol). Immediately following this addition (Conditions C) or after an
additional hour at 0 °C (Conditions D), methyl 2-(bromomethyl)benzoate (8,
0.229 g, 1.0 mmol) was added in one portion. The resulting mixture was stirred
at room temperature for 1.5 h. To the mixture thus obtained was then added
dropwise to a solution of potassium tert-butoxide in THF (1.1 mL, 1.1 mmol).
The resulting mixture was heated at 80 °C for 1 h. The reaction was then
quenched with the dropwise addition of 20 mL of HCl solution (0.2 M) at 80 °C.
Upon cooling to room temperature, the desired product crystallized directly
from the reaction media. The product was then collected via filtration and
washed with distilled water and ether to afford a 3,4-fused isoquinolin-1(2H)-
one in high purity.
13. Our attempts to purify 13a by trituration with various organic solvents such as
ether or THF failed to remove the acid contaminant completely. The low