A practical one-pot procedure for the synthesis of N-H isoquinolones

Article abstract of DOI:10.1016/j.tetlet.2013.02.003

A practical one-pot procedure for the preparation of N-H isoquinolones has been developed. This 2-step process via C-H activation of N-alkoxyl benzamides and NaH-mediated dealkoxylation reaction has been demonstrated to be a high yielding alternative meth

Full text of DOI:10.1016/j.tetlet.2013.02.003

Tetrahedron Letters 54 (2013) 2001–2005
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Tetrahedron Letters
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A practical one-pot procedure for the synthesis of N–H isoquinolones
⇑
Shaonan Lu , Yingfu Lin , Hongban Zhong, Kang Zhao, Jianhui Huang
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District,
Tianjin, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical one-pot procedure for the preparation of N–H isoquinolones has been developed. This 2-step
process via C–H activation of N-alkoxyl benzamides and NaH-mediated dealkoxylation reaction has been
demonstrated to be a high yielding alternative methodology for the efficient synthesis of a wide range of
representative N–H isoquiolones. In addition, the experimental precedent supported mechanism of the
dealkoxylation reaction was also proposed.
Received 9 December 2012
Revised 23 January 2013
Accepted 1 February 2013
Available online 9 February 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
C–H activation
Isoquinolone
N–O bond cleavage
Organometallics
Pd-catalysis
1. Introduction
O
H
O
OR1
H
R2
R3
N
H
N
There have been a considerable number of syntheses of isoqui-
nolones using modern directing group associated direct C–H func-
tionalization reactions in the last 3 years.1,2 Among these amide
directed and associated isoquinolone syntheses, when alkoxyl
benzamide was utilized as the substrate, both C–H bond activation
(Scheme 1, Eq. A, marked in red) and N–O bond cleavage
(Scheme 1, Eq. A, marked in blue) were observed for Rh3a,b- and
Ru4b,d-catalysed N–H isoquiolone syntheses.2,3
More recently we have reported new approaches using relatively
cheap Pd-catalysts for the tailoring of these isoquinolones.5a,b Inter-
estingly, we have found that under our Pd-catalysed conditions,
when alkoxyl benzamides reacted with alkynes, the alkoxyl groups
were retained without N–O bond cleavage detected and N–OR1 iso-
quinolones were achieved instead of N–H isoquiolones. (Scheme 1,
Eq. B)
eq A
R3
Rh cat. or Ru cat.
R2
R
1 = Me or Piv
Fagnou (Rh cat.):
Wang and Ackermann (Ru cat.):
O
O
OR1
OR1
R2
R3
N
H
N
eq B
R3
Pd cat.
H
R2
Our group (Pd cat.):
R1 = Me or iPr
Scheme 1. Rh-, Ru- and Pd-catalysed isoquinolone syntheses.
As an alternative methodology to Rh3- and Ru4-catalysed N–H
isoquiolone syntheses, our research interests have moved to the
developement of a Pd-catalysed approach for the access of these
versatile intermediates. Herein we report our latest discovery to-
wards the practical synthesis of N–H isoquinolones via a two-step
one-pot procedure from N-alkoxybenzamides. After Pd-catalysed
isoquinolone ring formation, the reaction mixture was treated with
NaH for deprotection to give N-unsubstituted isoquinolone. In
addition, a plausible N–O bond cleavage reaction mechanism was
also proposed at the end of the article.
2. Results and discussion
2.1. Base screening for the demethoxylation reaction
Initial attempts on the direct one step synthesis of N–H isoqui-
nolone by the introduction of inorganic bases were not successful.
Only less than 10% of demethoxylated product was obtained in
most of the cases when cheap readily available inorganic bases
KOH, Na2CO3, NaOAc, K3PO4 and NaH were employed.
⇑
Corresponding author. Tel.: +86 22 2740 5316; fax: +86 22 2740 4031.
E-mail address: jhuang@tju.edu.cn (J. Huang).
These two authors contributed equally to this work.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.003

2002
S. Lu et al. / Tetrahedron Letters 54 (2013) 2001–2005
O
Our attention was then moved to the demethoxylation of isoqu-
inolone 3a and we were attempting to develop a 2-step sequence
instead of direct synthesis of N–H isoquinolone 4a. Different from
Cheng’s photolysis for the demethoxylation of NN–OMe phenanth-
ridinone for the synthesis of crinasiadine,6 we serendipitously ob-
served that the N–O bond cleavage occurred when isoquinolone 3a
was treated with inorganic bases. A base screening was then car-
ried out and a number of readily available bases were examined.
We were pleased to find that all the bases examined have shown
positive results for the bond cleavage although some of the bases
have resulted in slow conversion which gave rise to the desired
product in low yields. As depicted in Scheme 2, inorganic bases
such as NaOAc, NaOH, K3PO4 and KOH provided the N–H isoquin-
olinone 4a in nearly 20% yield while Na2CO3 led to the product in
O
Base (3.0 equiv.)
DMF, 120 oC, 24 h
OMe
Ph
NH
Ph
N
Ph
Ph
3a
Base
NaOAc
Na2CO3
NaOH
K3PO4
KOH
4a
16 %
7%
16%
20%
17%
14%
99%
Et3N
NaH
0.5 h
Scheme 2. Base screening for the demethoxylation of isoquinoline.
Table 1
One-pot synthesis of N–H isoquinolone 4
1. Pd(OAc)2 (10 mol%),
O
NaI.2H2O (1.0 equiv.)
NaOAc, DMF, 120 oC
O
H
H
OR1
N
Ar
N
H
Ar
2. NaH (3.0 equiv.)
R2
R3
4
1
R2
R3
2
(
, 3.0 equiv.)
Entry
1
Benzamide 1
Alkyne 2
Isoquinolone 4
Yield %
96
O
Ph
Ph
Ph
Ph
Ph
O
OMe
O
N
H
Ph
NH
2a
Ph
1a
Ph
4a
O
OMe
N
H
Ph
NH
Ph
2a
2
3
4
5
99
57
70
26
Me O
Me O
1b
Ph
4b
O
O
OMe
N
Ph
NH
Ph
H
2a
AcHN
AcHN
Ph
1c
4c
O
O
OMe
N
H
Ph
NH
2a
Cl
Cl
Ph
1d
Ph
4d
O
O
OMe
OMe
N
Ph
NH
H
2a
O2N
O2N
Ph
1e
Ph
O
4e
Ph
O
Me O
Me O
Ph
N
NH
Ph
2a
H
6
7
87
1f
Ph
4f
O
Ph
O
Cl
OMe
Cl
N
Ph
NH
Ph
H
2a
44a
1g
Ph
4g

S. Lu et al. / Tetrahedron Letters 54 (2013) 2001–2005
2003
Table 1 (continued)
Entry
Benzamide 1
Alkyne 2
Isoquinolone 4
Yield %
O
Ph
O
OMe
N
H
Ph
NH
2a
8
9
80
90
81
Ph
1h
Ph
4h
4i
O
Ph
O
OMe
OMe
O
S
O
S
N
H
NH
Ph
Ph
2a
1i
1j
Ph
O
O
Ph
N
H
Ph
NH
Ph
2a
10
Ph
O
4j
O
Pr
OMe
OMe
N
Pr
NH
Pr
2b
H
11
12
13
76
1a
Pr
O
4k
4l
O
Ph
N
H
Et
NH
Ph
2c
94 (85)b
1a
Et
O
O
Ph
O
O
N
H
Ph
NH
2a
81
Ph
Ph
1h
4a
Ph
O
O
N
Ph
NH
Ph
H
2a
14
15
16
83
57
Me O
Me O
Ph
1i
4b
O
Ph
O
O
N
H
Ph
NH
Ph
2a
Cl
Cl
Ph
1j
4d
O
Ph
O
O
N
Et
NH
Ph
2c
H
62 (56)b
Et
O
1k
4l
O
Ph
O
N
H
Ph
Ph
NH
Ph
2a
17
89
Ph
1l
4a
a
N–H isoquinolone 4a was also isolated in 22% yield.
The overall yield of 2 regioisomers and the yields in the parentheses are the yields for the major regioisomers.
b
less than 10%. Organic base, Et3N also facilitated the desired prod-
uct in 14% yield. NaH surprisingly, however, delivered the corre-
sponding isoquinolone in an excellent 99% yield with much
shorter reaction time.
2.2. One-pot procedure for the synthesis of N–H isoquinolones
On the basis of previous discovery of amide directed C–H acti-
vation synthesis of isoquinolones, modified reaction conditions

2004
S. Lu et al. / Tetrahedron Letters 54 (2013) 2001–2005
were utilized. In the presence of catalytic amount of Pd(OAc)2, ha-
lide salt as well as NaOAc, under air conditions, the ring construc-
tion went fluently. After the reaction was completed, 3.0 equiv of
NaH was added and the reaction underwent N–O bond cleavage
to give our desired N–H isoquinolinones in good to excellent yields
as illustrated in Table 1.
H
H
-
Na
O
O
O
H
H
H
N
Path A
H
Path A
Ph
Ph
O
The reaction scope is wide enough which covered various benz-
amides, alkynes as well as N-substituents. Electron rich benzamide
1b has shown excellent reactivity to give isoquinolone 4b in 99%
yield and the electron rich benzamide 1c bearing another directing
group also provided our desired product 4c in a good 57% yield
(Table 1, entries 2 and 3). Electron-deficient para-chloro benzam-
ide 1d is also tolerant for this type of transformation; the
corresponding isoquinolone was obtained in 70% yield. Even benz-
amide with a strong electron-withdrawing nitro group para to the
benzamide, the product was also formed albeit with a low yield
(Table 1, entry 5). When benzamide with a meta-substituted halo-
gen atom was subjected into the reaction system, we do find that
during the cyclization and demethoxylation, dechlorination reac-
tion occurred and the corresponding dechlorinated isoquinolone
4a was isolated in 22% yield as well as 44% of our desired product
4g (Table 1, entry 7). The introduction of ortho-substituent did not
affect the reactivity; isoquinolone 4h was successfully prepared in
80% yield. Different from Wang’s Ru-catalysed reaction of
thiophenyl amide reaction (a low 35% yield of desired product
was isolated),3d under our conditions, heterocyclic amides are also
demonstrated to be good substrates where the corresponding iso-
quinolones were accessed fluently with good 90% and 81% yields
(entries 9 and 10). Symmetrical aliphatic alkyne behaved similarly
as diphenyl acetylene to facilitate the dialkyl substituted isoquino-
lone 4k in 76% yield. It is worth noting that when unsymmetrial al-
kyne 2c was utilized, a mixture of 10:1 mixture of 4l and 4l0 was
observed and the major isomer 4l was isolated in 85% yield (entry
12). The regioselectivity outcome has been rationalized in our
previous Letter during the ring formation studies.4a Different
N-substituents are also compared, hindered secondary alkyl
substituted benzamides have demonstrated similar reactivity as
well as regioselectivity as they gave the corresponding N–H isoqu-
inolones in comparable good yields with good regioselectivity
compared to N–OMe benzamides (Table 1, entries 13–16 versus
entries 1, 2, 4 and 12). In addition, we were pleased to find that
the reaction of N–OPh 1l also facilitated our desired isoquinolone
4a in a good 89% yield (Table 1, entry 17).
O
3a-A
OMe
NH
Ph
N
Ph
H
Ph
Ph
Na
O
O
3a
4a
Path B
N
Me
Path B
Ph
Ph
3a-B
-
MeOH
Scheme 3. Proposed reaction pathways.
O
O
OH
NaH (3.0 equiv.)
DMF, 120 oC, 1h
N
NH
Ph
Ph
Ph
Ph
4a
3m
O
(83%)
O
NH2
Ph
NaH (3.0 equiv.)
DMF, 120 oC, 1h
N
NH
Ph
Ph
Ph
4a
3n
(74%)
Scheme 4. The control reactions on the N–O bond cleavage
Ph
O
O
O
NaH (3.0 equiv.)
DMF, 120 oC, 1h
N
NH
Ph
OH
Ph
Ph
Ph
4a
3o
obseved by HPLC
Scheme 5. HPLC analysis.
analysis of the crude reaction mixture, where we have successfully
observed the formation of benzyl alcohol during the cleavage of N–
OBn bond of isoquinolone 3o (Scheme 5).
2.3. Mechanistic investigation of N–O bond cleavage process
With respect to the reaction mechanism, we have proposed 2
possible reaction pathways. As illustrated in Scheme 3, take N–
OMe isoquinolone 3a for example, under pathway A, the N–O bond
cleavage undergoes amide directed hydride deprotonation via
intermediate 3a-A, to give N–H isoquinolone 4a with the loss of
formaldehyde. Alternatively, the direct attack of hydride to the
oxygen atom gives desired free N–H product with the elimination
of MeOH.
3. Conclusions
In summary, we have developed a practical one-pot procedure
for the synthesis of a wide range of N–H isoquinolones in good
to excellent yields. In addition, a plausible reaction pathway was
proposed with experimental precedents. These would allow the
synthesis of isoquinolones in an alternative high yielding protocol.
Elucidating the appropriate reaction mechanism over the 2 pos-
sible pathways can be viable by choosing an isoquinolone without
Acknowledgment
the
a-proton (the proton marked green in colour) as shown in
Scheme 3a-A. The treatment of isoquinolones 3m and 3n7,8 with
3.0 equiv of NaH, gave our desired isoquinolone 4a in good 83%
and 74% yields respectively, after the reaction mixture was heated
at 120 °C in DMF for 1 h (Scheme 4).
The project was supported by the Cultivation Foundation for the
New Faculties from the Tianjin University (No. 60302010).
Supplementary data
Theses experimental results as well as the results from the reac-
tion of N–OPh (Table 1, entry 17) suggests that path B is likely to be
the appropriate reaction pathway for the dealkoxylation reaction
which is different from what Nikitin9 had proposed in his earlier
communication. This has also been further proved by the HPLC
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.02.
003.

S. Lu et al. / Tetrahedron Letters 54 (2013) 2001–2005
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