An approach to substituted dihydroisoquinolin-1(2H)-ones from Baylis-Hillman adducts

Article abstract of DOI:10.1016/S0040-4039(03)01307-8

In this communication we describe an easy and straightforward alternative method for the preparation of 3,4-substituted isoquinolin-1(2H)-ones, using Baylis-Hillman adducts as starting material.

Full text of DOI:10.1016/S0040-4039(03)01307-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5731–5735
An approach to substituted dihydroisoquinolin-1(2H)-ones from
Baylis–Hillman adducts
Fernando Coelho,* Demetrius Veronese, Elizandra C. S. Lopes and Rodrigo C. Rossi
DQO, IQ/Unicamp, PO Box 6154, 13084-971 Campinas, Sa˜o Paulo, Brazil
Received 14 February 2003; revised 23 May 2003; accepted 26 May 2003
Abstract—In this communication we describe an easy and straightforward alternative method for the preparation of 3,4-substi-
tuted isoquinolin-1(2H)-ones, using Baylis–Hillman adducts as starting material.
© 2003 Elsevier Ltd. All rights reserved.
Isoquinolinones are important compounds from both
the synthetic and applied points of view. Their struc-
tures are incorporated in several alkaloids1 and other
pharmacologically important compounds.2 Isoquinoli-
nones have already been employed as useful intermedi-
ates in the synthesis of indenoisoquinolines,3
protoberberines,4,5 and dibenzoquinolizines5 and are
also of interest in medicinal chemistry.6
materials for the synthesis of different classes of natural
and non-natural products12 we envisaged developing an
alternative strategy to prepare substituted isoquino-
linones.
The widespread occurrence of the isoquinolinone unit
in several classes of alkaloids, associated with the
medicinal interest in this class of compounds, easily
justifies the need for new approaches for the synthesis
of isoquinolinones. In this comunication, we describe
an alternative, easy and direct method for the prepara-
tion of 3,4-disubstituted isoquinolinones from Baylis–
Hillman adducts.
Due to their biological and pharmacological impor-
tances, several methods have been reported for the
synthesis of isoquinolinones.1d Most of these methods
involve the use of either a preformed isoquinoline or
homophthalic acid, which is in turn obtained by a
several step sequence.7 Isoquinolines are converted into
isoquinolinones by a further two-step sequence either
through isoquinolium salts and their oxidation with
different reagents,8 or by photolysis of isoquinoline
N-oxide.9 Homophthalic acids are transformed into
isoquinolinones via isocoumarins or isoquinolone-4-
carboxylic acid,7 or via homophthalimide.7f,10
The reaction sequence to achieve our target is outlined
in Scheme 1. 3,4-Disubstituted dihydroisoquinolinones
such as 1 could be easily prepared via an intramolecular
acylation with isocyanate 2, which in turn could be
readily produced from a Baylis–Hillman adduct in a 6
steps sequence.
The Baylis–Hillman reaction13 of piperonal (3), 6-bromo-
piperonal (4) and 2-bromobenzaldehyde (5) with
methyl acrylate, in the presence of ultrasound14 pro-
vides the adducts 6, 7 and 8, with good chemical yields
(Scheme 2 and Table 1). In the next step of our
Lithiated phthalides undergo cyclocondensation reac-
tions with benzaldimines to give isoquinolinones with
good chemical yields. This strategy has been used to
prepare a mixture of cis/trans 3,4-disubstituted dihy-
droisoquinolinones.11 Intermolecular Diels–Alder reac-
tions were also used as the key step for the preparation
of substituted isoquinolinones.11c,d
In an ongoing research program directed to the utilisa-
tion of Baylis–Hillman adducts as versatile starting
Keywords: Baylis–Hillman; dihydroisoquinolinone; heterocycles.
* Corresponding author. Tel.: 55 19 3788-3085; fax: 55 19 37883023;
e-mail: coelho@iqm.unicamp.br
Scheme 1. Retrosynthetic analysis towards the dihydroiso-
quinolinone core.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01307-8

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F. Coelho et al. / Tetrahedron Letters 44 (2003) 5731–5735
Subsequent hydroboration reaction of the double bond
of these silyl ethers with 9-BBN gave alcohols 16a/b,
17a/b and 18a/b (Scheme 3 and Table 1), as a mixture
of diastereoisomers, in which the syn is always the
major one.12c After separation,15 the alcohols (16a, 17a
and 18a) were treated with TPAP in the presence of
NMO16 to furnish the corresponding aldehydes 19–21,
which were treated with sodium chlorite to provide the
acids 22–24 in a very good overall chemical yields (see
Scheme 2. Preparation of the Baylis–Hillman adducts.
Reagents and conditions: (a) methyl acrylate, ultrasound, rt,
24–72 h; (b) TIPSOTf, Et3N, CH2Cl2 or 2,6-lutidine, rt, 2 h;
(c) DIBAL-H, CH2Cl2, −78°C, 2 h; (d) TBDPSCl, DMF,
imidazole, rt, 14 h.
sequence, the methyl ester group of Baylis–Hillman
adducts were chemoselectively reduced. Attempts to
run this reduction with DIBAL-H without protection
of the secondary hydroxyl groups furnished the desired
diol 9, however with only a 50% chemical yield (Scheme
2). This problem was easily solved by protecting the
secondary hydroxyl group as a silyl ether (triisopropyl-
silyl). Subsequent reduction with DIBAL-H provided
the allyl alcohols 10, 11 and 12, with very good overall
chemical yields (Table 1).
Scheme 3. Synthesis of dihydroisoquinolinones. Reagents and
conditions: a. (i) 9-BBN, THF, 0°C“rt, 16–18 h; (ii) NaOH 3
mol/L, 30% H2O2, 0°C“rt, 1.5 h; b. TPAP, NMO, CH2Cl2,
The preparation of the lactam ring exhibited in the
isoquinolinone structures could be readily secured by
an intramolecular acylation reaction using a carbamate
or an isocyanate as acylating agent.8a Then, the allyl
alcohols 10–12 were treated with t-butyldiphenylsilyl
chloride in the presence of DMF to give the silyl ethers
13, 14 and 15 (Scheme 2 and Table 1 for yields).
,
MS 4 A, rt, 1 h; c. NaClO2, NaH2PO4, t-BuOH, 2-methyl-
but-2-ene, 0°C“rt, 4 h; d. (i) ethyl chloroformate, acetone,
Et3N, 0°C, 45 min; (ii) NaN3, rt, 2 h; (iii) refluxing toluene, 2
h; e. refluxing methanol, 12 h; f. t-BuLi, THF, −78°C, 30 min;
g. TBAF, THF, rt, 2 h.
Table 1. Chemical yields for the preparation of the dihydroisoquinolinones.
R1–R3
R1=R2=CH2OCH2;
R3=H
R1=R2=CH2OCH2;
R3=Br
R1=R2=H; R3=Br
Baylis–Hillman reaction
DIBAL-H reduction
TBDPS protection
Hydroboration reaction
Product
6
73
7
80
8
78
Yield (%)a
Product
10
86
11
83
12
88
Yield (%)a,b
Product
13
90
14
91
15
94
Yield (%)a
Product
16a/b
syn:anti
89
17a/b
syn:anti
77
18a/b
syn:anti
77
Yield (%)a
Oxidation reactions
Product
22
86
23
81
24
88
Yield (%)a,c
Carbamate/isoquinolinone formation
Product
27
28
29
Yield (%)a
60d
40e
40e
a All yields are for isolated and purified products.
b Yield for two steps (TIPS protection and reduction).
c Yields for two oxidation steps.
d Preparation of carbamate, overall yield for 4 steps.
e Overall yield for the preparation of the dihydroisoquinolinones, 4 steps.

F. Coelho et al. / Tetrahedron Letters 44 (2003) 5731–5735
5733
Table 1 and Scheme 3).12c,17 Attempts to perform the
oxidation directly to the corresponding carboxylic acids
failed.12c
ever we were unable to detect the formation of com-
pound 28. Due to the lability of the silyl group in the
Bischler–Napieralski protocols, we decided to change
the secondary hydroxyl protective group. Instead of a
silyl ether, the secondary hydroxyl of the Baylis–Hill-
man adduct 6 was protected as a PMB–ether (33).
Using the same reaction sequence described above,
PMB-ether (33) was transformed into the carbamate 34.
Attempts to perform the Bischler–Napieralski reaction
with 34 gave as the only product the isoquinolol 35, in
a chemical yield of 42% (Scheme 4, Part B).
The acids 22–24 were then submitted to a Curtius
rearrangement18,19 in order to incorporate the nitrogen
atom exhibited by the isoquinolinone unit. Thus, treat-
ment of acids 22–24 successively with ethyl chlorofor-
mate and sodium azide gave the acylazide
intermediates, which were rearranged to the corre-
sponding isocyanates (not isolated) by refluxing in
toluene.
These results clearly demonstrate that it is possible to
prepare disubstituted dihydroisoquinolin-1(2H)-ones
from the Baylis–Hillman adducts 7 and 8. The sequence
is very simple, however it shows a poor to reasonable
diastereoselectivity. The preliminary results obtained in
our laboratory also demonstrate that this sequence can
be easily scaled up. On an experimental scale, reactions
with 3–10 g can be conveniently carried out. The 3,4-
disubstituted dihydroisoquinolin-1(2H)-ones 30 and 31
were prepared in 9 steps using a multistep sequence in
an overall yield of 14%.
After evaporation of the toluene, isocyanates 25 and 26
were treated in situ with t-butyl lithium in ethyl ether at
−78°C to furnish the products 28 and 29, with overall
yields of 40% from the acids 23/24 (4 steps, Table 1).
Removal of the protective groups with TBAF in THF
at room temperature gave the 3,4-disubstituted dihy-
droisoquinolin-1(2H)-ones 30 and 31 in 76% yields
(Scheme 3).20
Alternatively, the isocyanate generated from acid 22
was treated in refluxing methanol to give the carbamate
27 with an overall yield of 60% from the corresponding
acid (4 steps). To promote the internal acylation, carba-
mate 27 was then treated with triflic anhydride in the
presence of DMAP.21f The only product detected in this
reaction was the disubstituted oxazolin-2-one (32)
(Scheme 4, Part A).
As far as we know this is also the first report relating to
the preparation of 3,4-disubstituted dihydroisoquinolin-
1(2H)-ones from a Baylis–Hillman adduct.22 An addi-
tional reductive step on the carbonyl group of 30 and
31 could also permit access to dihydroisoquinolines
using the same sequence. Efforts to optimize some steps
of this sequence are ongoing in our laboratory. Appli-
cations toward specific natural products and the further
development of an asymmetric version of this strategy
are currently underway and will be reported in due
course.
To drive this reaction in the direction of the protected
dihydroisoquinolin-1(2H)-one (28) we tried several dif-
ferent Bischler–Napieralski12c experimental protocols
(e.g. POCl3/py, POCl3/toluene; P2O5/POCl3, etc), how-
Acknowledgements
The authors thank FAPESP for grants to ECSL (c
00/07938-4) and RCR (98/13779-9) and for financial
support (98/14640-0 and 02/00461-3). The authors also
thank CNPq for grants to FC (31369/87-9) and to DV
(140568/2000-0). We thank Professor C. H. Collins for
the revision of this text.
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1
(film, wmax) 3423, 3196, 1669, 1611 cm−1; H NMR (300
MHz, DMSO-d6) l 7.28 (s, 1H), 6.99 (s, 1H), 6.1 (s, 2H,
CH2OCH2), 4.61 (d, J=4.76 Hz, 1H), 3.63 (br s, 2H),
3.34–3.7 (m, 1H); 13C NMR (75.4 MHz, DMSO-d6) l
163.6, 150.9, 147.6, 137.2, 122.8, 107.9, 107.0, 102.3, 65.6,
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