Solid-phase synthesis of isoquinolinones using Bischler-Napieralski cyclization

Article abstract of DOI:10.1016/j.tetlet.2004.09.059

A traceless solid-phase synthetic approach to isoquinolinones is described here. This approach allows introducing both electron-donating as well as electron-withdrawing moieties on the benzene nuclei of isoquinolinones with high yields and purities. Isoquinolinone is a structural unit found in many natural products having various important biological activities. A traceless solid-phase synthetic approach has been developed to prepare isoquinolinone derivatives. This approach enables one to synthesize isoquinolinones having various moieties on benzene nuclei and also can produce derivatives with a proton on the amide nitrogen.

Full text of DOI:10.1016/j.tetlet.2004.09.059

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8323–8326
Solid-phase synthesis of isoquinolinones
using Bischler–Napieralski cyclization
Meei-Shiou Chern and Wen-Ren Li*
Department of Chemistry, National Central University, Chung-Li 32054, Taiwan
Received 24 July 2004; revised 7 September 2004; accepted 9 September 2004
Available online 25 September 2004
Abstract—Isoquinolinone is a structural unit found in many natural products having various important biological activities. A
traceless solid-phase synthetic approach has been developed to prepare isoquinolinone derivatives. This approach enables one to
synthesize isoquinolinones having various moieties on benzene nuclei and also can produce derivatives with a proton on the amide
nitrogen.
ꢀ 2004 Elsevier Ltd. All rights reserved.
R1
Combinatorial solid-phase synthesis has been recog-
nized as one of the powerful tools for drug discovery
R6
R2
R3
in pharmaceutical industries. This technique facilitates
the speedy availability of closely related analogues for
activity evaluation.1,2 Among the broad range of tem-
plates, heterocyclic scaffolds represent the most promis-
ing molecules as lead structures for the discovery of
potential pharmacophores. In particular, isoquinolin-
ones3–8 are present in a large number of natural
products that possess a broad spectrum of biological
activities. Thalifoline, doryphorine,9 ruprechstyril,10
narciclasine,11 pancratistatin and lycoricidine12 are some
of the important examples from this family. Many
interesting syntheses involving either a construction
or reactions of isoquinolinones are reported.4,7,13–18
Considering the therapeutic value of such motifs in var-
ious bioactive molecules,19 solid-phase syntheses of
compounds containing similar moieties have attracted
researchers.6,20–25
N
R8
I
O
II
Figure 1.
and even the starting material is not readily available.
However, the disconnection-II provides a wide choice
for starting materials and various amino acids such as
phenylethylamine, tyrosine and phenylalanine can be
selected as precursors. Also, these starting materials
are commercially available and inexpensive. Hence, it
was preferred to follow the disconnection-II and use
Bischler–Napieralski reaction for cyclization and co-
comintant cleavage.
Bischler–Napieralski cyclization26 is commonly used in
solution synthesis of various biologically important com-
pounds;27–33 but has not been used on solid supports to
synthesize isoquinolinones. In this reaction, the presence
of an electron-donating group on aromatic ring in phen-
ethylamides and carbamates is an essential precondition
for cyclization using various reagents such as POCl3,
SnCl4, BF3 etherate, a mixture of SnCl4 and POCl3,
PPA, Tf2O, etc. Reported reagent viz. P2O5 in refluxing
POCl334 can cyclize substrates lacking electron-donating
groups but can produce only N-alkylated isoquinol-
inones in good yields and not isoquinolinones having a
proton on the amide nitrogen. Here we report the first
The retrosynthetic analysis of isoquinolinone template
(Fig. 1) revealed two possibilities of disconnections.
Either the bond between a carbonyl carbon and a nitro-
gen that is amide linkage (disconnection-I) or the bond
between a carbonyl carbon and a benzene ring (discon-
nection-II) can be disconnected. The disconnection-I
leaves a little flexibility to choose a starting material
Keywords: Solid-phase synthesis; Isoquinolinones; Bischler–Napieral-
ski cyclization.
*
Corresponding author. Tel.: +886 3 422 7704; fax: +886 3 427
7972; e-mail: ch01@ncu.edu.tw
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.059

8324
M.-S. Chern, W.-R. Li / Tetrahedron Letters 45 (2004) 8323–8326
1. 4-nitrophenyl chloroformate,
R1
DIPEA, CH2Cl2
H
R2
R3
OH
O
N
R1
R4
R2
R3
O
Hydroxymethyl Resin
R4
4
2
2.
, DIPEA, DMF
NH2
3
route C (R3 = OH, R4
CO2Me; entries 12-13)
=
route B
route A
(R4 = H; entries 1-9)
(R3 = H, R4 = CO2Me;
entries 10-11)
1. n-PrBr, Cs2CO3, DMF
2. LiBH4, THF
3. MsCl, DIPEA, CH2Cl2
1. LiBH4, THF
2. MsCl, DIPEA, CH2Cl2
R1
H
O
N
R2
R3
R1
R5
H
SH , NaH
6
R6
O
N
R2
O
O
7 R6 = H or
R3
H2CS
R5
DMF
OMs
5
route E
hexamethyldisiloxane,
P2O5, POCl3
route D
NaH, R7X
DMF
R1
R6
R8
R2
R3
R7
R1
P2O5
R2
R3
N
O
N
POCl3
R6
8
O
O
1 (R8 = H or R7)
Scheme 1.
solid-phase synthesis of isoquinolinone derivatives hav-
ing a proton on the amide nitrogen and electron-donat-
ing or -withdrawing groups on benzene nuclei.
yield.37,38 The mesylate 5 was not stable to long time
storage and had to be used immediately for the next
step. In the third route, that is route C (entries 12 and
13), the hydroxyl group present at R3 in resin 4 was der-
ivatized to a n-propyl ether and then the methyl ester,
similar to route B, was reduced to the corresponding
alcohol. The resulting alcohol was mesylated to yield
resin 5. To obtain a n-propyl ether, a weak base
In the present synthetic strategy (Scheme 1), hydroxy-
methyl resin (2) was used as a solid support because it
can form carbamates, which are stable under acidic con-
ditions required in Bischler–Napieralski cleavage. To
begin, the resin 2 was activated by reacting with 4-nitro-
phenyl chloroformate35,36 in the presence of diisopropyl-
ethylamine (DIPEA) and the activated resin was
condensed with amines 3 to obtain carbamate resins 4.
Three different routes (route A, B, and C) were adopted
to introduce threefold diversity on the core structure
of isoquinolinones. In route A (entries 1–9), R4 was
retained as H (R4 = R6 = H in compound 7). In route
B, R4 was a methyl ester moiety, which was reduced (en-
tries 10 and 11) to the corresponding alcohol. When the
reduction using NaBH4 did not go to the completion,
another two combinations of reducing agents that is
NaBH4/LiCl and NaBH4/LAH were tried. Both combi-
nations were too strong to reduce the methyl ester selec-
tively because the carbamate was affected. Finally,
LiBH4 in THF was the reagent of choice to give the cor-
responding alcohol by reducing the methyl ester selec-
tively. The alcohol obtained was reacted with
thiophenol to afford thioether through Mitsonobu cou-
pling. But this attempt was not successful on solid sup-
ports. Hence, it was decided to transform the hydroxyl
group to a better leaving group such as OMs or OTs.
The yield of tosylate was low but the alcohol was deriva-
tized to afford mesylate 5 using DIPEA with better
39
K2CO3 in various solvents was used but it could not
complete the conversion even when the reaction was
40
repeated. After trying several bases, Cs2CO3 in DMF
was found to be an effective choice. Further, mesylates
5, obtained from both routes (route B and C) were reacted
with thiol 6 using NaH in DMF to obtain thioethers 7.18
Carbamate resins 7 obtained from the above three
routes were, either after alkylation (route D) or directly
(route E), subjected to cyclization and subsequent cleav-
age. In the route D, resin 7 was alkylated with various
alkyl halides using NaH in DMF. This alkylation was
found to be critically temperature dependent. Reaction
at room temperature for 24h did not afford complete
alkylation and even after repetition. However, when a
slightly elevated temperature (40ꢁC) was used, the
reaction was completed after 24h to yield the alkylated
carbamate resin 8. A Brucker AVANCE-500MHz
gel-phase NMR was used to check the completion of
alkylation. Bischler–Napieralski cyclization26 reaction
was utilized to obtain the isoquinolinone ring and to
simultaneously cleave products from solid supports.
To affect cyclization through the route D, 5equiv of
P2O5 was used in 0.1M of distilled POCl3 at 80ꢁC.34

M.-S. Chern, W.-R. Li / Tetrahedron Letters 45 (2004) 8323–8326
8325
In conclusion, the present solid-phase synthesis is a
traceless approach to 1,2,3,4-tetrahydroisoquinolinones.
As per our knowledge, this is the first methodology,
which introduces electron-donating and electron-
withdrawing substituents at R1 and R3 positions on
solid supports and also allows modifications at R3 posi-
tion as demonstrated by entries 12 and 13. Moreover,
most of the presently reported methods produce
isoquinolinones having an alkyl substituted nitrogen.
This methodology facilitates solid-phase preparation of
isoquinolinones having a hydrogen at R8 position
(on the nitrogen). Such proton may enhance interaction
of a substrate with a receptor and thus this approach
should find broad application in producing pharmaceu-
tically important derivatives.
hexamethyl
disiloxane
O
O
O
O
HN
OEt
NH
P2O5, POCl3
O
O
1i
Scheme 2.
Unsubstituted carbamate resins 7 were cyclized and
cleaved from solid supports through route E. As the
above method did not give the desired product in good
yield, route E was optimized in solution (Scheme 2). The
cyclization in the solution using P2O5 and POCl3 gave
only 20% yield and also the use of either triflic anhy-
dride/4-(N,N-dimethylamino)pyridine41 or oxalyl chlo-
42
ride/FeCl3
furnished very low yields.
A
new
approach to temporarily protect the carbamate nitrogen
with hexamethyldisiloxane in situ was adopted. Phos-
phorus oxychloride and hexamethyldisiloxane were used
as a co-solvent system (1:1) with 5equiv of P2O5. As
shown in Scheme 2, this approach yielded the desired
product 1i in 81% yield. Further, this methodology
was applied to cyclize and cleave isoquinolinones on
solid supports in excellent yields (route E).43 Represent-
ative products were prepared on solid supports in
excellent yields and purities by the protocol described
above and these results are summarized in Table 1. Each
compound was fully characterized by 1H, 13C NMR
and mass spectrometric techniques. There was a
notable observation for entry 8. Along with the expected
product, isomer 9 was also produced in 13% yield.
Acknowledgements
The authors are grateful to the National Science Coun-
cil, Taiwan, for the financial support (92-2113-M-008-
014) of this work.
References and notes
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Entry
1
1
R1
R2
R3
H
R6
H
R8
Overall yieldsa (%)
74
1a
H
H
CH3
2
1b
H
H
H
H
72
H C
2
3
4
1c
1d
H
H
OCH3
OCH3
OCH3
OCH3
H
H
CH3
64
61
H C
2
5
6
7
1e
1f
H
F
H
H
H
Br
H
H
H
74
67
68
H C
2
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CH2CH3
1g
H
OCH3
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1h
H
OCH3
H
H
H
52b
H C
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9
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1i
1j
H
H
OCH3
H
OCH3
H
H
CH2CH3
82
74
H CS
2
Cl
11
12
13
1k
1l
H
H
H
H
H
H
H
CH2CH3
H
63
63
53
H CS
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O(CH2)2CH3
O(CH2)2CH3
H CS
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Cl
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a Reported yields are isolated yields after flash chromatography on silica gel. The overall yields are based on the initial loading of the hydroxymethyl
resin.
b Total yield: 65% (1h: 52% and itÕs isomer 9: 13%).
.
N
O
O
9

8326
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1
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CDCl3 (d, ppm): 2.90 (t, 2H, J = 6.7Hz), 3.53–3.61 (m,
2H), 3.90 (s, 6H), 6.40 (br s, 1H), 6.65 (s, 1H), 7.54 (s, 1H);
13C NMR in CDCl3 (d, ppm): 28.01, 40.48, 56.06, 56.12,
109.58, 110.15, 121.39, 132.65, 148.04, 152.17, 166.55;
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