A microwave-assisted alternative synthesis of 8-amino-2-methyl-3,4- dihydroisoquinolin-1-one

Article abstract of DOI:10.1055/s-2007-965978

A shorter, alternative synthesis of 8-amino-2-methyl-3,4- dihydroisoquinolin-1-one is described in 32% overall yield, over three steps starting from commercially available 2-methyl-6-nitrobenzonitrile. The synthesis includes two 'one-pot' procedures in wh

Full text of DOI:10.1055/s-2007-965978

SHORT PAPER
981
A Microwave-Assisted Alternative Synthesis of 8-Amino-2-methyl-3,4-
dihydroisoquinolin-1-one
Synthesis of
8
t
-Amino
e
-2-methyl-
v
3, 4-dihydroi
e
AstraZeneca Plc., Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
Fax +44(1625)586707; E-mail: steve.glossop@astrazeneca.com
Received 29 November 2006; revised 20 January 2007
compound from commercially available 2-methyl-6-ni-
trobenzonitrile. The two literature routes based on patents
are briefly summarized in Schemes 1 and 2.
Abstract: A shorter, alternative synthesis of 8-amino-2-methyl-
3,4-dihydroisoquinolin-1-one is described in 32% overall yield,
over three steps starting from commercially available 2-methyl-6-
nitrobenzonitrile. The synthesis includes two ‘one-pot’ procedures
in which the key process involves the microwave-assisted hydroly-
sis of a nitrile group followed by lactamization under elevated tem-
peratures.
The use of toxic reagents such as allyltributyltin, CrO3/
H2SO4 and (PhO)2P(O)N3, along with the particularly
low-yielding permanganate oxidation step3 (a) and an
overall yield of 12% made the first route (Scheme 1) un-
attractive.
Key words: lactam, microwaves, cyclization, Bredereck’s reagent,
isoquinolinone
In the second sequence (Scheme 2), synthesis of com-
pound 1 begins with the Raney-Nickel reduction of meth-
yl 2-(cyanomethyl)-6-nitrobenzoate (12). This interme-
diate is not commercially available but can be prepared in
three steps from 2-methyl-6-nitrobenzoic acid (9).4,5 Un-
fortunately, the yields for the individual reactions are not
quoted and due to the number of synthetic steps, as well
as the use of cyanide, this is also an unattractive route.
In the course of our research, access to 8-amino-2-methyl-
3,4-dihydroisoquinolin-1-one (1) was required. Although
the structure of 1 is quite simple, the known syntheses are
quite lengthy. Two recent reports1,2 describe syntheses of
compound 1; however, both procedures involve seven
synthetic steps from commercially available starting ma-
terials and utilize a number of toxic reagents. Herein is re-
ported a shorter, alternative synthesis of the title
We observed that subjecting compound 16 (Scheme 3) to
elevated temperatures led to an unexpected side reaction.
NO2
NO2
O
NO2
O
a
b
OH
O
Br
Br
Br
2
3
4
NO2
O
NO2
O
d
e
c
O
O
OH
5
6
NO2
O
NH2
O
NO2
O
g
f
O
O
N
O
OH
O
N
H
O
8
1
7
Scheme 1 WO 2006/021454 – Reagents and conditions: (a) KMnO4, Na2CO3, H2O, 100 °C, 18 h, 40%; (b) Cs2CO3, MeOH, r.t., then MeI,
DMF, 0 °C to r.t., 14 h, ca. 100%; (c) allyltributyltin, Pd(Ph3P)4, toluene, 110 °C, 20 h then CsF, H2O, ca. 100%; (d) BH3·SMe2, THF, 0 °C, 4
h, then H2O2, NaOH, r.t., 1 h, 90%; (e) CrO3, H2SO4, 0 °C to r.t., 4 h, 80%; (f) (PhO)2P(O)N3, Et3N, toluene, 80 °C, 2 h then CuCl2, MeOH,
80 °C, 2 h, 68%; (g) NaH, THF, MeI, 0 °C to r.t., then Fe (powder), 1 N HCl, EtOH, 59%.
SYNTHESIS 2007, No. 7, pp 0981–0983
x
x
.
x
x
.2
0
0
7
Advanced online publication: 12.03.2007
DOI: 10.1055/s-2007-965978; Art ID: P14106SS
© Georg Thieme Verlag Stuttgart · New York

982
S. C. Glossop
SHORT PAPER
O
NO2
O
NO2
O
NO2
a
b
O
O
OH
Br
11
10
9
NO2
O
NH2
O
c
d
e
O
NH
CN
13
12
Ph
Ph
Ph
Ph
NH2
O
N
O
O
N
f
g
N
N
NH
1
15
14
Scheme 2 WO 2006/021544 – Reagents and conditions: (a) (MeO)2SO2, DIPEA, acetone; (b) NBS, CCl4, (PhCO)2O2, hn; (c) NaCN, solvent;
(d) Raney-Nickel, H2, MeOH, r.t., 16 h; (e) BnBr (3.5 equiv), K2CO3, DMF, 50 °C, 16 h; (f) NaH, DMF, MeI, 30 h; (g) Pd(OH)2, H2, MeOH, 48 h.
Cl
Cl
for one hour. The methyl group of 18 is sufficiently acti-
vated by the presence of both the nitrile and nitro groups
that the reaction proceeds quickly, generating the enamine
intermediate 19. Attempts to synthesize 19 using dimeth-
ylformamide dimethylacetal7 (DMFDMA), with or with-
out the presence of a Lewis acid, were unsuccessful. The
crude enamine compound was reduced under mild condi-
tions with NaBH(OAc)3 in the presence of acetic acid to
give 2-(2-dimethylaminoethyl)-6-nitrobenzonitrile 20 in
81% yield, over two stages.
Cl
O
CN
CO2H
NMe2
⋅HCl
6 N HCl
∆
N
NMe2
100 °C
48 h
16
17
Scheme 3 Decomposition of 2-chloro-6-(dimethylaminometh-
yl)benzoic acid hydrochloride with heat
During the purification process for compound 16, it was
noted that when the crude hydrochloride salt was heated
to >120 °C a ‘clean’ decomposition reaction occurred,
leading to the lactam compound 17. Due to the similarities
between the title compound 1 and the thermal degradation
product 17, it seemed feasible that this route might be
applicable to the synthesis of compound 1 following the
retrosynthetic strategy outlined in Scheme 4.
NO2
O
NO2
NO2
CN
CN
a
b
N
i, ii
i, ii
N
18
20
22
NO2
O
NH2
O
NO2
NH2
O
NO2
O
NH2
CO2H
c
N
N
N
N
N
1
23
1
22
21
Scheme 5 Alternative synthesis of compound 1. Reagents and con-
ditions: (a) i. t-BuOCH(NMe2)2 (Bredereck’s reagent), neat, 100 °C,
1 h, ii. NaBH(OAc)3, DME, AcOH, r.t., 18 h, 81%; (b) i. 6 N HCl,
microwave, 160 °C, 15 h, ii. sulfolane, 200 °C, 2 h, 48%; (c) 10%
Pt/C, H2, EtOAc, EtOH, 24 h, 83%.
NO2
NO2
NO2
CN
CN
CN
N
N
Quite harsh conditions, involving microwave irradiation
at 160 °C for 15 hours, were required to hydrolyze the cy-
ano compound 20 to the acid 21. The 15 hours heating
time was necessary as shorter reaction times led to com-
plex mixtures of starting material 20, required product 21
and the amide 23. The crude hydrochloride salt of com-
pound 21 was then heated in an open vessel to effect the
cyclization, via the effective loss of methanol, to give 2-
18
20
19
Scheme 4 Alternative retrosynthesis towards 8-amino-2-methyl-
3,4-dihydroisoquinolin-1-one
The alternative synthesis (Scheme 5) begins with the reac-
tion between commercially available 2-methyl-6-nitro-
benzonitrile (18) and neat Bredereck’s reagent,6 at 100 °C
Synthesis 2007, No. 7, 981–983 © Thieme Stuttgart · New York

SHORT PAPER
Synthesis of 8-Amino-2-methyl-3,4-dihydroisoquinolin-1-one
983
residue and the mixture was heated in an open vessel at 200 °C for
2 h. The mixture was cooled to r.t. and then the residue was dis-
solved in CH2Cl2 (200 mL) with stirring for 10 min. The mixture
was filtered and the resulting filtrate was evaporated to afford a vis-
cous oily product, which was transferred to a Kugelrohr apparatus.
The sulfolane solvent was distilled off (200 °C/8 mmHg) and the
residue was then allowed to cool and aq 2 N HCl (20 mL) was added
with vigorous stirring and sonication to form a light brown precipi-
tate. The solid was filtered and dried in a dessicator to give 22 as a
buff-colored product (0.68 g, 48%); mp 177–179 °C (MeCN);
Rf = 0.58 (EtOAc).
methyl-8-nitro-3,4-dihydroisoquinolin-1-one (22) in 48%
yield. Compound 22 was hydrogenated in the presence of
Pt/C catalyst to afford the title compound 1 in 83% yield.
In summary, this chemistry represents a shorter alterna-
tive synthesis of 8-amino-2-methyl-3,4-dihydroisoquino-
lin-1-one (1) which can be carried out quickly and easily,
yielding excellent quality material in 32% total yield from
2-methyl-6-nitrobenzonitrile (18), over three stages.
IR (KBr): 3043, 2922, 1658, 1536 cm–1.
All chemicals used were of reagent grade and used as supplied.
Evaporation of solvent was carried out using a rotary evaporator un-
der reduced pressure (2–400mbar) with a bath temperature of up to
60 °C. Microwave chemistry was carried out on the Emrys-Opti-
mizer microwave synthesizer apparatus. Chromatography was car-
ried out on silica gel; TLC carried out on silica plates (Merck, Art.
5554). In general, the course of reactions was followed by TLC and/
or LC-MS. NMR spectra were obtained on a Bruker DPX-300 spec-
trometer at 300 MHz using CDCl3 or DMSO-d6 as solvent. Chemi-
cal shifts are expressed in ppm downfield from TMS, which was
used as an internal standard. Melting points of small samples were
obtained after recrystallization; solvents given in parentheses. LC-
MS data was recorded utilizing the electrospray (ES+) technique.
Values for m/z are given; the mass ion quoted is [MH]+ which refers
to the protonated mass ion.
1H NMR (300 MHz, CDCl3): d = 3.05 (t, J = 6.4 Hz, 2 H, ArCH2),
3.15 (s, 3 H, CH3), 3.62 (t, J = 6.4 Hz, 2 H, NCH2), 7.32–7.38 (m, 2
H, H-5,7), 7.49 (t, J = 7.7 Hz, 1 H, H-6).
13C NMR (300 MHz, DMSO-d6): d = 27.4, 34.3, 46.8, 120.9, 121.3,
130.2, 132.2, 141.6, 150.0, 159.3.
MS (ES+): m/z = 207.58.
8-Amino-2-methyl-3,4-dihydroisoquinolin-1-one (1)
2-Methyl-8-nitro-3,4-dihydroisoquinolin-1-one (22; 2.01 g, 9.73
mmol) was dissolved in warm EtOAc (100 mL) and EtOH (10 mL)
and to this was added 10% Pt/C (500 mg). The mixture was stirred
under an atmosphere of H2 for 24 h. The catalyst was removed by
filtration and washed with cold EtOAc (50 mL). The filtrate was
evaporated and the crude residue was chromatographed on silica
gel, eluting with 0–10% MeOH in EtOAc to give 1 as a light brown
solid (1.41 g, 82%); mp 124–126 °C (MeCN); Rf = 0.79 (EtOAc).
2-(2-Dimethylaminoethyl)-6-nitrobenzonitrile (20)
2-Methyl-6-nitrobenzonitrile (18; 3.24 g, 20 mmol) was taken up in
Bredereck’s reagent (10 mL) and heated to 100 °C for 1 h. The thick
resulting mixture was allowed to cool and the excess Bredereck’s
reagent was removed in vacuo. The crude residue was taken up in
DME (60 mL), AcOH (5.2 mL) was added and then the mixture was
treated with NaBH(OAc)3 (6.46 g, 30.4 mmol) with stirring at r.t.
for 18 h under N2. The mixture was concentrated in vacuo and then
poured into EtOAc (300 mL) and washed with aq 2 N NaOH solu-
tion (200 mL). The mixture was extracted with EtOAc (2 × 300
mL), washed with aq 2 N NaOH solution (200 mL), H2O (2 × 200
mL) and then brine (200 mL). The organic layer was dried (MgSO4)
and evaporated to afford a crude oily mixture. Chromatography on
silica gel, eluting with a gradient of CH2Cl2 to CH2Cl2–MeOH–aq
NH3(7 N)–MeOH (90:9:1) gave 20 as a brown solid product (3.53
g, 81%); mp 71–73 °C (hexanes–EtOAc, 5:1); Rf = 0.39 (EtOAc–
MeOH, 9:1).
IR (KBr): 3428, 3309, 2948, 2869, 1615, 1554 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.89 (t, J = 6.6 Hz, 2 H, ArCH2),
3.10 (s, 3 H, CH3), 3.48 (t, J = 6.6 Hz, 2 H, NCH2), 6.19 (br s, 2 H,
NH2), 6.38 (d, J = 7.2 Hz, 1 H, H-5), 6.51 (d, J = 8.2 Hz, 1 H, H-7),
7.08 (t, J = 7.7 Hz, 1 H, H-6).
13C NMR (300 MHz, DMSO-d6): d = 28.3, 34.3, 47.3, 109.4, 113.5,
114.6, 131.8, 139.8, 150.5, 166.7.
MS (ES+): m/z = 177.50.
References
(1) Imbach, P.; Kawahara, E.; Konishi, K.; Matsuura, N.;
Miyake, T.; Ohmori, O.; Roesel, J.; Teno, N.; Umemura, I.
PCT Int. Appl. WO 2006021454, 2006; Chem. Abstr. 2006,
144, 274291.
IR (KBr): 2972, 2782, 2387, 2295, 2226, 1541, 1521, 1462, 1342
cm–1.
(2) Stadtmueller, H.; Engelhardt, H.; Steegmaier, M.; Baum, A.;
Guertler, U.; Schoop, A.; Quant, J.; Solca, F.; Hauptmann,
R.; Reiser, U.; Zahn, S. K.; Herfurth, L. PCT Int. Appl., WO
2006021544, 2006; Chem. Abstr. 2006, 144, 292768.
(3) Hewson, A. T.; Hughes, K.; Richardson, S. K.; Sharpe, D.
A.; Wadsworth, A. H. J. Chem. Soc., Perkin Trans. 1 1991,
1565.
1H NMR (300 MHz, DMSO-d6): d = 2.21 (s, 6 H, CH3), 2.57 (t,
J = 7.3 Hz, 2 H, ArCH2), 3.07 (t, J = 7.3 Hz, 2 H, NCH2), 7.89 (t,
J = 8.0 Hz, 1 H, H-4), 7.97 (dd, J = 7.8, 1.2 Hz, 1 H, H-3), 8.22 (dd,
J = 8.1, 1.3 Hz, 1 H, H-5).
13C NMR (300 MHz, DMSO-d6): d = 31.7, 44.8, 59.0, 106.4, 114.0,
123.5, 133.5, 135.9, 147.9, 149.0.
(4) Bondinell, W. E.; Pendleton, R. G. Eur. Pat. Appl.
EP0002624, 1979; Chem. Abstr. 1979, 92, 22401.
(5) Ozaki, F.; Ishibashi, K.; Ikuta, H.; Ishihara, H.; Souda, S.
PCT W09518097, 1995; Chem. Abstr. 1995, 123, 256357.
(6) Haefliger, W.; Knecht, H. Tetrahedron Lett. 1984, 25, 285.
(7) Siu, J.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem.
2004, 2, 160.
MS (ES+): m/z = 220.54.
2-Methyl-8-nitro-3,4-dihydroisoquinolin-1-one (22)
2-(2-Dimethylaminoethyl)-6-nitrobenzonitrile (20; 1.5 g, 6.85
mmol) was taken up in aq 6 N HCl (15 mL), sealed in a closed mi-
crowave vessel and subjected to microwave irradiation at 160 °C
for 15 h. The reaction was allowed to cool and the solvent was care-
fully removed in vacuo. Sulfolane (10 mL) was added to the crude
Synthesis 2007, No. 7, 981–983 © Thieme Stuttgart · New York