β-phenylethylamines, indolines and isoquinolones via hydroamination of styrenes by microwave irradiation

Article abstract of DOI:10.1055/s-2001-14585

Microwave irradiation promotes hydroamination of styrenes. This method can be used as a direct way of producing different kinds of bioactive compounds: open chain compounds like β-phenylethylamines or cyclized products like indolines or isoquinolones.

Full text of DOI:10.1055/s-2001-14585

LETTER
875
-Phenylethylamines, Indolines and Isoquinolones via Hydroamination of
Styrenes by Microwave Irradiation
Julio A. Seijas,* M. Pilar Vázquez-Tato,* M. Montserrat Martínez
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Santiago de Compostela, Aptdo. 280, 27080-Lugo, Spain
Fax +34 982 224904; E-mail: qoseijas@lugo.usc.es or pilarvt@lugo.usc.es
Received 12 February 2001
The scope of application of this microwave enhancement
of hydroamination of styrene with base catalysis was de-
termined by checking the influence of substitution either
on the aniline or in the styrene. Thus, 2-methylaniline re-
acts with styrene affording N-(2-methylphenyl)-2-phenyl-
ethylamine in a 56% yield (Table, entry 2), despite the
steric hindrance from the substituent in the ortho position.
This product posseses the carbon skeleton of enfenamic
acid, an antiinflamatory agent. However, when we heated
anthranilic acid and styrene in the presence of potassium
tert-butoxide, no addition product was isolated; only
aniline from decarboxylated anthranilic acid was recov-
ered. This enhancing of the decarboxylation of aromatic
acids by microwaves was recently reported,6 but only in
the presence of quinoline/Cu(II) or N-ethylmorpholine.
As a masking group to avoid decarboxylation we used ni-
trile. Thus, anthranilonitrile was irradiated with micro-
waves together with styrene and potassium tert-butoxide,
but no addition product was obtained, only 4-amino-2-(2-
aminophenyl)quinazoline from self condensation was
formed. One reason to explain the lack of addition be-
tween styrene and anthranilonitrile can be found in their
frontier orbitals.7
Abstract: Microwave irradiation promotes hydroamination of sty-
renes. This method can be used as a direct way of producing differ-
ent kinds of bioactive compounds: open chain compounds like
ß-phenylethylamines or cyclized products like indolines or isoqui-
nolones.
Key words: amination, domino reaction, indoline, isoquinolone,
microwave heating, nucleophilic addition, phenethylamine
Synthesis of -phenylethylamines has been always an ob-
ject of interest due to their pharmacological properties,
these compounds cover a wide range of different activi-
ties: antihistaminic, adrenergic, sympathomimethic, anor-
exic, etc.1 Besides, the -phenylethylamine fragment is a
useful building block for many syntheses of more elabo-
rated skeletons. Many natural products contain -phenyl-
ethylamine in their skeleton either as an ethylamino
branch or forming part of the polycyclic topologies -as is
in the case of isoquinolinic and indole alkaloids.2
Our group has been focusing its interest on the reactivity
of styrene derivatives with nucleophiles.3 We have found
that primary and secondary lithium amides added to sty-
rene give -phenylethylamines at 0 °C.3c From these stud-
ies we found out that when styrene was treated with
lithium salt of aniline, under the same conditions for 24 h,
no reaction was observed. Previously it had been
reported4 that when hydroamination of styrenes was car-
ried out in a sealed tube at high temperatures, the addition
reaction took place although in a wide range of yields.
This, combined to our last report5 on the synthesis of 4-
aminoquinazolines by microwave irradiation of potassi-
um salt of anthranilonitrile and different nitriles under mi-
crowave irradiation, led us to believe that microwaves
could be used to promote the addition of aniline to sty-
rene, avoiding the use of heating in sealed tubes and the
need for solvent.
Scheme 1 Hydroamination of styrenes to -phenylethylamines.
We also explored the influence of the presence of a second
nitrogen atom in the nucleophilic center; thus, phenylhy-
drazine gave a 85% yield of 1-(2-phenylethyl)-1-phenyl-
hydrazine (Table, entry 3).
So, an equimolecular ratio of styrene and aniline were ir-
radiated with a 10% potassium tert-butoxide yielding a
59% of N-phenyl-2-phenylethylamine. We optimized the
reaction by checking the reagents ratio and we found that
better yields were obtained for 1:10:1 ratio of styrene,
aniline and potassium tert-butoxide respectively, which
afforded N-phenyl-2-phenylethylamine in a yield of 81%
(Scheme 1 and Table, entry 1). We affirmed the necessity
of having an excess of aniline with respect to styrene and
it is also important to keep the ratio of the base at 10% re-
garding aniline.
Substituted styrenes in the double bond like -methylsty-
rene and -methylstyrene, in the same conditions yielded
N-phenyl-1-methyl-2-phenylethylamine and N-phenyl-2-
methyl-2-phenylethylamine respectively, but in moderate
yields (Table, entries 4 and 5).
We also studied the behavior of 2-chlorostyrene, since as
shown by Beller et al.,4b this compound presents the pos-
sibility of suffering a domino reaction giving an indoline
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876
J. A. Seijas et al.
LETTER
Table Hydroamination of styrenes to -phenylethylamines
ing -phenylethylamine 3 (Table, entry 7) in a quantita-
tive yield. This excellent yield confirmed our previous
studies on the behavior of these compounds towards 1,6-
conjugated additions of nucleophiles.3 Afterwards this
compound, without any further purification, was irradiat-
ed under microwaves for 30 seconds, with oxalic acid
yielding 5 in 90%, and provided a good one-pot cycliza-
tion procedure for this ring system (Scheme 3). To our
knowledge this is the first time microwave mediated hy-
drolisis of oxazoline group is reported.
aThese reactions were carried out with a reagents ratio of styrene:ani-
line:t-BuOK, 1:10:1.
Scheme 3 One pot hydroamination-cyclization of o-vinylphenylo-
xazolines to afford N-phenyl-3,4-dihydroisoquinolin-1-ones.
structure. This fragment is present in a large number of
products with biological and pharmacological interest for
instance analgesics.8 We have found that the structure of
the final product could be controlled by the reaction con-
ditions, if we use a ratio of styrene:aniline:t-BuOK 1:10:1.
N-Phenyl-2-(2-chlorophenyl)ethylamine was the reaction
product in a 67% yield after 3 minutes of irradiation, orig-
inating from the addition of aniline to the styrenic double
bond (Table, entry 6), with no cyclization product. How-
ever, if the ratio of reagents was 1:1:2 the addition-cy-
clization product 4 was achieved in a very good yield
(96%), after 5 min of irradiation (Scheme 2). This micro-
wave enhanced cyclization to indoline gave a yield almost
twice as high, and four hundred times faster, than the
yields previously reported with conventional heating,
without the appearance of the oxidation subproduct previ-
ously described for this reaction.
In summary, here we present a method based on the hy-
droamination of styrenes by irradiation in a domestic mi-
crowave oven in the presence of potassium tert-butoxide.
It proved to be an efficient method in the preparation of
three different skeletons of great importance in the chem-
istry of biologically active products.10 By choosing ade-
quate precursors lineal compounds ( -phenyl-
ethylamines), five-membered cyclization products (indo-
lines) or six-membered cyclization products (isoquinolo-
nes) can be obtained, all in one pot reaction. The good to
excellent yields, together with the green chemistry aspect
of microwave heating without a solvent, and the easiness
of preparation (avoiding the use of pressure vessels),
make this procedure a useful tool for organic synthesis.
Acknowledgement
The authors thank DGES for financial support (PB96-0932).
References and Notes
(1) a) The Merck Index, 12th ed.; Budavari, S., Ed.; Merck& Co.,
Inc.: Whitehouse Station, NJ 1996. b) Shulgin, A.; Shulgin, A.
PiHKAL: A Chemical Love Story; 2nd half. Transform Press.
Berkeley.
Scheme 2 Domino hydroamination-cyclization of styrene to give
N-phenylindoline.
(2) Comprehensive Natural Products Chemistry, Barton, D.;
Nakanishi, K., Eds.; Elsevier: Amsterdam, 1999.
(3) a) Seijas, J. A.; Vázquez-Tato, M. P.; Castedo, L.; Estévez, R.
J.; Ruíz, M. J. Org. Chem. 1992, 57, 5283-5284. b) Martínez,
M. M.; Ónega, M. G.; Tellado, M. F.; Seijas, J. A.; Vázquez-
Tato, M. P. Tetrahedron 1997, 41, 14127-14130. c) Seijas, J.
A.; Vázquez-Tato, M. P.; Entenza, C.; Martínez, M. M.;
Ónega, M. G.; Veiga, S. Tetrahedron Lett. 1998, 39, 5073-
5076.
(4) a) Wegler, R.; Pieper, G. Chem. Ber. 1950, 83, 1. b) Beller,
M.; Briendl, C.; Riermeier, T. H.; Eichberger, M.;
Trauthwein, H. Angew. Chem., Int. Ed. 1998, 37, 3389.
c) Müller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675-703.
This methodology can be used to prepare another interest-
ing ring system: the isoquinolinic one, which is present in
a great number of natural products of biological signifi-
cance.2 We envisaged 2-(2-carboxyphenyl)ethylamines as
precursors to N-phenyl-3,4-dihydroisoquinolin-1-ones;
thus we heated 2-carboxystyrene with aniline and base,
but only decomposition products were obtained, even
with very short irradiation times. We turned our attention
to oxazoline ring as protection for the acid group; so we
reacted
2-(3-methoxy-2-vinylphenyl)-4,4-dimethyl-2-
oxazoline9 with aniline and we obtained the correspond-
Synlett 2001, No. 6, 875–877 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
-Phenylethylamines, Indolines and Isoquinolones
877
(5) Seijas, J. A.; Vázquez-Tato, M. P.; Martínez, M. M.
Tetrahedron Lett. 2000, 41, 2215-2217.
(6) Frederiksen; L. B.; Grobosch, T. H.; Jones; J. R.; Lu, S.-Y.;
Ahao, C.-C. J. Chem. Res., Synop. 2000, 42-43.
(d, 2H, J = 7.6 Hz), 3.87 (br s, 1H), 3.48 (t, 2H, J = 7.0 Hz),
3.0 (t, 2H, J = 7.0 Hz). IR (KBr, film): 3415 (NH) cm-1.
N-Phenyl-2,3-dihydroindole (4): The procedure was similar as
for 3, reacting o-chlorostyrene (100 mg, 0.721 mmol), aniline
(67 mg, 0.721 mmol) and potassium tert-butoxide (162 mg,
1.442 mmol) during 5 min., yielding N-phenyl-2,3-
dihydroindole (4)4b (135 mg, 96%).
5-Methoxy-N-phenyl-3,4-dihydroisoquinolin-1-one (5): A
mixture of 2-(3-methoxy-2-vinylphenyl)-4,4-dimethyl-2-
oxazoline (122 mg, 0.528 mmol), aniline (492 mg, 5.28
mmol) and tert-butoxide potassium (59 mg, 0.528 mmol) was
heated as the procedure stated above during 5 min. To the
crude mixture was added oxalic acid (600 mg, 6.67 mmol) and
irradiated during 30 seconds. Reaction mixture was dissolved
in CH2Cl2 and washed with aq. NaOH 10%, aq. HCl 10% and
water. The organic layer was dried (Na2SO4), and evaporated
to give chomatographically pure 5-methoxy-N-phenyl-3,4-
dihydroisoquinolin-1-one (5) (120 mg, 90%). 1H NMR (300
MHz, CDCl3) : 7.79 (d, 1H, J = 8.0 Hz), 7.42-7.20 (m, 6H),
7.03 (d, 1H, J = 8.5 Hz), 3.97 (t, 2H, J = 6.5 Hz), 3.90 (s, 3H),
3.12 (t, 2H, J = 6.5 Hz). IR (KBr): 1670 (CON) cm-1. M. p.
246-248 (Cl2CH2).
(7) The energy gap between the HOMO of the potassium salt of
anthranilonitrile and the LUMO of styrene is wider than the
gap between the HOMO of the salt of anthranilonitrile and the
LUMO of anthranilonitrile. Meanwhile benzonitrile has a
lower lying LUMO than anthranilonitrile, and in this case the
4-aminequinazoline from anthranilonitrile and benzonitrile is
obtained instead of the 4-aminoquinazoline from self-
condensation of anthranilonitrile.5 PCGAMESS and
MacMolPlt, with 3-21G** basis for ab initio calculations in
the gas phase were used.
(8) a) Glamkowski, E. J.; Fortunato, J. M. U.S. Patent 4 448 784,
1984; Chem. Abstr. 1985, 101, 151748e.
(9) Meyers, A. I.; Gabel, R.; Mielich, E. D. J. Org. Chem. 1978,
43, 1372-1379.
(10) General Procedure. N-Phenyl-2-phenylethylamine (3): A
mixture of styrene (100 mg, 0.962 mmol), aniline (895 mg,
9.62 mmol) and potassium tert-butoxide (107 mg, 0.962
mmol) in a open test tube was heated in a domestic microwave
(1000 W, 70% of total power) until no starting styrene was
observed by TLC (10 min.). The crude reaction was purified
by chromatography column on silicagel to afford N-phenyl-2-
phenylethylamine (154 mg, 81%). 1H NMR (300 MHz,
CDCl3) : 7.43-7.26 (m, 7H), 6.82 (t, 1H, J = 7.2 Hz), 6. 72
Article Identifier:
1437-2096,E;2001,0,06,0875,0877,ftx,en;D03701ST.pdf
Synlett 2001, No. 6, 875–877 ISSN 0936-5214 © Thieme Stuttgart · New York