A convenient synthesis of 1-substituted 1,4-dihydroisoquinolin-3-ones

Article abstract of DOI:10.1081/SCC-120004056

A number of isoquinolin-3-ones have been obtained in fair to good yields by reaction of phenylacetonitrile with carbonyl compounds in PPA.

Full text of DOI:10.1081/SCC-120004056

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A CONVENIENT SYNTHESIS OF 1-SUBSTITUTED 1,4-
DIHYDROISOQUINOLIN-3-ONES
Didier Barbry a , Guillaume Sokolowski a & Philippe Champagne b
a Laboratoire d'Ingénierie Moléculaire , UPRES EA 2699 , Université des Sciences et
Technologies de Lille , Villeneuve d'Ascq, F-59655, France
b Laboratoire des Matériaux Avancés Céramiques , EA 2443, ISTV UVHC , Le Mont Houy,
Valenciennes, 59313 Valenciennes Cedex 9
Published online: 17 Oct 2011.
To cite this article: Didier Barbry , Guillaume Sokolowski & Philippe Champagne (2002) A CONVENIENT SYNTHESIS
OF 1-SUBSTITUTED 1,4-DIHYDROISOQUINOLIN-3-ONES, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 32:12, 1787-1790, DOI: 10.1081/SCC-120004056
To link to this article: http://dx.doi.org/10.1081/SCC-120004056
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SYNTHETIC COMMUNICATIONS, 32(12), 1787–1790 (2002)
A CONVENIENT SYNTHESIS OF
1-SUBSTITUTED
1,4-DIHYDROISOQUINOLIN-3-ONES
Didier Barbry,1, Guillaume Sokolowski,1
*
and Philippe Champagne2
1Laboratoire d’Ingenierie Moleculaire, UPRES EA
2699, Universite desScienceset Technologiesde Lille,
F-59655 Villeneuve d’Ascq, France
2Laboratoire desMate riaux AvancesCe ramiques,
EA 2443, ISTV UVHC,
Le Mont Houy 59313 ValenciennesCedex 9
ABSTRACT
A number of isoquinolin-3-ones have been obtained in fair to
good yieldsby reaction of phenylacetonitrile with carbonyl
compoundsin PPA.
Key Words: Isoquinolinones; Phenylacetonitrile; PPA
The isoquinoline moiety occurs in a large number of alkaloids.
Because of their application in chemotherapy, this heterocyclic system has
generated much interest from synthetic chemists and biochemists. Very few
methodshave been developed to prepare isoquinolin-3-ones. They are gen-
erally obtained by condensation of amides with aromatic aldehydes with or
without the assistance of the benzotriazole group[1,2] but cyclisations of
chloroamides or diazoacetamides have also been described.[3,4] We here
*Corresponding author. E-mail: didier.barbry@univ-lille1.fr
1787
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1788
BARBRY, SOKOLOWSKI, AND CHAMPAGNE
Table 1. Synthesis of 1,4-Dihydroisoquinolin-3-ones
R2
Yield (%)
R1
Compound
C6H5
Me
C6H5
Me
Et
H
H
2a
90
68a
40
50
45
51b
35
40
20
2b
2c
2d
2e
2f
2g
2h
2i
Me
Me
Me
Me
Me
(CH3)2CHCH2CH2
C6H5CH2
Cyclo hexyl
Cyclo pentyl
aWith five equivalentsof aldehyde.
bWith one equivalentsof ketone.
report (Table 1) an easily access to these compounds by reaction of phenyl-
acetonitrile with all king of carbonyl compoundsin polyphopshoric acid
(PPA). Deak et al.[5] reported only the synthesis of 1-arylisoquinolin-3-
onesin good yieldsfrom benzaldehydesand phenylacetonitrile.
ꢀ
The reaction isperformed at 140 C in PPA in which the nitrile (10%
w/w) isintroduced and then an excessof carbonyl compound isadded
dropwise. A part of enolisable carbonyl compounds is consumed in aldol
type condensations which lower the yield of isoquinolinone. The formation
of the latter involvesthe initial attack of the nitrogen atom on the proto-
nated carbonyl before aromatic electrophilic substitution. It is known
that electrophilic attackson phenylacetonitrile afford only 25% of ortho-
substitution.[6] So the inverse order of the two steps would lead to smaller
amounts of isoquinolones.
EXPERIMENTAL
Hundred gram of PPA were heated to 140ꢀC. Ten gram (0.085 mol) of
phenylacetonitrile were then added. After stirring for 5 min, the carbonyl

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1-SUBSTITUTED 1,4-DIHYDROISOQUINOLIN-3-ONES
1789
compound (0.17 mol, 2 equivalents) was added dropwise to the mixture
which wasstirred for one hour at 140 ꢀC and then poured into iced water.
After extraction thrice with methylene chloride (200 ml), the combined
organic layerswere dried (MgSO ) and the solvent removed. Diethyl ether
4
(50 ml) wasadded. The precipitate wasfiltered and extracted (soxhlet) with
petroleum ether. After removal of the solvent, the compound was dried
under reduce pressure.
1,4-Dihydro-1-phenylisoquinolin-3-one[7] 2a: F ¼ 138ꢀC; H NMR: 3.65
1
(dd, 2H, J ¼ 18.8), 5.2 (s, 1H), 7.0–7.5 (m, 9H), 7.8 (s, 1H); 13C NMR: 36.5,
59.9, 126.7, 126.8, 127.2, 127.6, 127.9, 128.0, 128.9, 131.3, 134.7, 141.6,
171.6.
1,4-Dihydro-1-methylisoquinolin-3-one[8] 2b: F ¼ 97ꢀC; 1H NMR: 1.5
(d, 3H, J ¼ 6.8), 3.6 (dd, 2H, J ¼ 18.1), 4.65 (q, 1H), 7.1–7.3 (m, 4H), 8.1
(s, 1H); 13C NMR: 23.6, 36.1, 51.3, 124.8, 126.8, 127.3, 127.8, 131.0, 136.2,
171.9. MS (EI): 118, 146 (100%), 161.
1,4-Dihydro-1-methy-1-phenylisoquinolin-3-one[9]
2c:
F ¼ 167ꢀC;
1H NMR: 1.95 (s, 3H), 3.55 (dd, 2H, J ¼ 10.1), 7.1–7.3 (m, 9H), 8.3
(s, 1H); 13C NMR: 26.9, 37.4, 61.4, 124.9, 125.8, 126.8, 127.2, 127.7,
127.9, 128.5, 131.9, 139.9, 145.4, 171.9. MS (EI): 77, 105, 222 (100%), 237.
1,4-Dihydro-1,1-dimethylisoquinolin-3-one 2d: F ¼ 110ꢀC; 1H NMR:
1.5 (s, 6H), 3.55 (s, 2H), 7.0–7.2 (m, 4H), 8.3 (s, 1H); 13C NMR: 30.8,
35.8, 56.0, 123.5, 127.0, 127.2, 127.8, 130.2, 140.0, 171.3. MS (EI): 160
(100%), 175. Anal. calcd for C11H13NO: C, 75.40; H, 7.48; N, 7.99;
O, 9.13; found C, 75.28; H, 7.51; N, 7.87.
1,4-Dihydro-1-ethyl-1-methylisoquinolin-3-one
2e:
F ¼ 159ꢀC;
1H NMR: 0.7 (t, 3H), 1.55 (s, 3H), 1.8 (m, 2H), 3.6 (dd, 2H, J ¼ 18.7),
7.1–7.25 (m, 4H), 8.2 (s, 1H); 13C NMR: 8.4, 29.7, 35.7, 36.9, 59.6, 124.3,
126.8, 127.0, 127.9, 130.9, 137.7, 171.3. MS (EI): 160 (100%), 189. Anal.
calcd for C12H15NO: C, 76.16; H, 7.99; N, 7.40; O, 8.45; found C, 76.01; H,
8.08; N, 7.46.
1,4-Dihydro-1-ethyl-1-(3-methyl)butylisoquinolin-3-one 2f: F ¼ 109ꢀC;
1H NMR: 0.7 (2d, 6H, J ¼ 6.6), 0.9 (m, 1H), 1.1 (m, 1H), 1.4 (m, 1H),
1.65 (s, 3H), 1.7 (td, 1H, J ¼ 12.4/4.4), 1.85 (td, 1H), 3.6 (dd, 2H,
J ¼ 19.4), 7.05–7.25 (m, 4H), 8.1 (s, 1H); 13C NMR: 22.4, 22.5, 28.0, 30.4,
32.8, 35.5, 41.9, 59.3, 124.2, 126.8, 127.0, 127.9, 130.7, 138.2, 171.0. MS (EI):
160 (100%), 231. Anal. calcd for C15H21NO: C, 77.88; H, 9.15; N, 6.05; O,
6.92; found C, 77.90; H, 9.22; N, 6.11.
1-Benzyl-1,4-dihydro-1-methylisoquinolin-3-one
2g:
F ¼ 165ꢀC;
1H NMR: 1.7 (s, 3H), 2.3 (d, 1H, J ¼ 20.6), 3.05 (dd, 2H, J ¼ 13.1), 3.2 (d,
1H), 6.7 (d, 2H, J ¼ 7.8), 6.85 (d, 1H, J ¼ 7.4), 7.2–7.25 (m, 6H), 7.3 (s, 1H);
13C NMR: 29.4, 34.9, 51.9, 60.1, 124.4, 126.7, 126.8, 127.4, 127.8, 128.9,
130.7, 131.8, 135.8, 137.1, 171.9. MS (EI): 160 (100%), 251. Anal. calcd

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1790
BARBRY, SOKOLOWSKI, AND CHAMPAGNE
for C17H17NO: C, 81.24; H, 6.82; N, 5.57; O, 6.37; found C, 80.81; H, 6.84;
N, 5.56.
10,40-Dihydrospiro(cyclohexane-1,10-isoquinolin-3-one)[1] 2h: F ¼ 174ꢀC;
1H NMR: 1.15 (m, 10H), 3.6 (s, 2H), 6.9 (s, 1H), 7.1–7.3 (m, 4H); 13C NMR:
21.5, 24.9, 36.4, 37.5, 57.6, 123.4, 126.9, 127.2, 128.0, 131.2, 140.4, 170.7. MS
(EI): 130, 144, 172 (100%), 215.
10,40-Dihydrospiro(cyclopentane-1,10-isoquinolin-3-one) 2i: F ¼ 94ꢀC;
1H NMR: 1.7–2.1 (m, 8H), 3.6 (s, 2H), 7.1–7.3 (m, 4H), 8.0 (s, 1H);
13C NMR: 24.0, 36.7, 41.2, 66.4, 123.3, 126.9, 127.1, 127.8, 131.2, 139.4,
171.9. MS (EI): 172 (100%), 201. Anal. calcd for C13H15NO: C, 77.58;
H, 7.51; N, 6.96; O, 7.95; found C, 76.81; H, 7.64; N, 6.65.
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Received in the UK March 5, 2001