New chiral isoquinolinium salt derivatives from chiral primary amines via zincke reaction

Full text of DOI:10.1021/jo961539b

9596
J . Org. Chem. 1996, 61, 9596-9598
Sch em e 1
New Ch ir a l Isoqu in olin iu m Sa lt
Der iva tives fr om Ch ir a l P r im a r y Am in es
via Zin ck e Rea ction
Denis Barbier, Christian Marazano,*
Bhupesh C. Das,* and Pierre Potier
Institut de Chimie des Substances Naturelles, C.N.R.S.,
91198 Gif-sur-Yvette Cedex, France
Received August 7, 1996
Recent publications from our laboratory have shown
that the Zincke reaction with chiral primary amines
provides a very practical entry to new pyridinium salt
derivatives of interest in asymmetric synthesis.1 Selec-
tive reduction of these salts to 1,2- or 1,4-dihydropy-
ridines, which could be equilibrated to dihydropyridinium
salt equivalents, afforded versatile intermediates for the
enantioselective synthesis of alkaloids containing sub-
stituted six-membered nitrogen heterocycles.2 We now
describe the extension of this methodology to the syn-
theses of chiral isoquinolinium salt derivatives of practi-
cal interest for the asymmetric synthesis of substituted
tetrahydroisoquinolines.
Sch em e 2
Reaction of salt 1 (Scheme 1), easily obtained from
isoquinoline and 1-chloro-2,4-dinitrobenzene, with anilines
to give N-phenylisoquinolinium salts was reported by
Zincke and Weisspfenning.3 This reaction proceeded in
the same way as that for the corresponding pyridinium
salts. It was thus not surprising to observe that the
treatment of salt 1 with 1.2 equiv of (R)-(+)-1-phenyl-
ethylamine (2) in refluxing 1-butanol, according to the
conditions found appropriate in the pyridine series,1 gave,
presumably via intermediates such as 3,4 the desired
chiral isoquinolinium salt 4, which was recovered in 77%
yield after a simple extraction procedure.
Sch em e 3
By contrast, the Zincke reaction of salt 1 with (R)-
(-)-phenylglycinol (5) (Scheme 2) in refluxing 1-butanol
did not proceed at all, the only products obtained, along
with the unreacted amine 5, being isoquinoline and
1-chloro-2,4-dinitrobenzene resulting from decomposition
of salt 1. A simple explanation for this failure was that
the chloride anion was nucleophilic enough to compete
favorably with the chiral amine. A straightforward alter-
native was to make use of a less nucleophilic counteran-
ion. We therefore selected a lipophilic dodecyl sulfate
group which, in addition to being less nucleophilic, should
provide salts better soluble in organic solvents.2b Salt 6
was thus easily obtained by treatment of 1 with sodium
dodecyl sulfate. As anticipated, this new salt gave a good
yield of the desired chiral derivative 7 in refluxing
1-butanol. Formation of a precipitate of adduct 8, char-
acterized as a crystalline solid, was observed at ambient
temperature. Such an adduct was not obtained in the
pyridine series. The butyl sufate salt 9 was obtained in
place of the expected dodecyl sulfate salt when salt 6
was refluxed with (R)-(+)-1-phenylethylamine (2) in
1-butanol.
Extension of this approach to methoxy-substituted
isoquinoline derivatives was also investigated, and the
results are summarized in Scheme 3. The Bischler-
Napieralski reaction of (dimethoxyphenyl)ethylamine5
gave the dihydroisoquinoline derivative 10, whose aro-
(1) Ge´nisson, Y.; Marazano, C.; Mehmandoust, M.; Gnecco, D.; Das,
B. C. Synlett 1992, 431.
(2) (a) Gnecco, D.; Marazano, C.; Das, B. C. J . Chem. Soc., Chem.
Commun. 1991, 625. (b) Ge´nisson, Y.; Marazano, C.; Das, B. C. J . Org.
Chem. 1993, 58, 2052. (c) Wong, Y.-S.; Marazano, C.; Gnecco, D.; Das,
B. C. Tetrahedron Lett. 1994, 35, 707. (d) Ge´nisson, Y.; Mehmandoust,
M.; Marazano, C.; Das, B. C. Heterocycles 1994, 39, 811.
(3) Zincke, T. H.; Weisspfenning, G. J ustus Liebigs Ann. Chem. 1913,
396, 103. For an extension of this reaction to hydrazine derivatives,
see: Agai, B.; Lempert, K. Tetrahedron 1972, 28, 2069.
(4) For a description of the mechanism, see ref 1 and two reviews:
(a) Kost, A. N.; Gromov, S. P.; Sagitullin, R. S. Tetrahedron 1981, 37,
3423. (b) Becher, J . Synthesis 1980, 589.
(5) Polniaszek, R. P.; Kaufman, C. R. J . Am. Chem. Soc 1989, 111,
4859.
S0022-3263(96)01539-3 CCC: $12.00 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 26, 1996 9597
matization6 afforded the required dimethoxyisoquinoline
11.7 Condensation of 11 with 1-chloro-2,4-dinitrobenzene
met with no difficulty. In contrast to Zincke salt 1, the
reaction of salt 12 with chiral amines to give products
resulting from opening of the isoquinolinium ring (see
intermediate 3) failed completely, the primary amine
attacking the 2,4-dinitrobenzene ring and thus regener-
ating dimethoxyisoquinoline 11. Such failures were
already reported in the case of the treatment of salt 12
with other primary amines such as anilines,8 and no
alternative conditions were found. This behavior could
obviously be attributed to a decreased electrophilicity of
the isoquinolinium ring due to the donor effects of the
methoxy groups. We therefore applied conditions previ-
ously selected by us to overcome similar drawbacks in
the pyridine series.1,2b As expected, attack of the iso-
quinolinium ring with an excess of 2 was thus effected
by using dichloromethane as solvent to give the desired
open form intermediates (see 3). The electrocyclization
of these intermediates now seemed to be assisted by the
donor effect of the methoxy groups: simply refluxing the
dichloromethane solution leads to salt 13 in good yield.
Finally, treatment of dodecyl sulfate salt 14 with an
excess of 5 in refluxing 3-methyl-3-pentanol gave the
desired salt 15, these last conditions being also identical
to those found appropriate in the substituted pyridine
series.1
8.45 (d, J ) 6.9 Hz, 1 H), 8.54 (dd, J ) 1.3, 8.3 Hz, 1 H), 8.67
(dd, J ) 1.6, 6.9 Hz, 1 H), 10.12 (d, J ) 1.6 Hz, 1 H); 13C NMR
(75.47 MHz, CD3OD) δ 20.7, 71.8, 127.8, 128.4, 128.6, 129.1,
130.5, 130.8, 131.9, 132.6, 134.3, 138.5, 138.9, 139.03, 149.7; MS
(FAB) m/ z (relative intensity) 234 (M+, 78), 130, 105.
2-(2,4-Din it r op h en yl)isoq u in olin iu m Dod ecyl Su lfa t e
(6). A solution of Zincke salt 1 (60.1 g, 181.3 mmol) and sodium
dodecyl sulfate (57.5 g, 200 mmol) in CH2Cl2 (1 L) was refluxed
for 3 h. After filtration over Celite and removal of solvent,
orange crystals of salt 6 were obtained from AcOEt in
a
quantitative yield: mp 75-82 °C; 1H NMR (300 MHz, CDCl3) δ
0.87 (t, J ) 6.4 Hz, 3 H), 1.16-1.43 (m, 18 H), 1.38 (m, 2 H),
3.61 (t, J ) 6.9 Hz, 2 H), 7.98 (ddd, J ) 4, 4, 8 Hz, 1 H), 8.19 (d,
J ) 8.7 Hz, 1 H), 8.23 (d, J ) 4 Hz, 1 H), 8.25 (d, J ) 4 Hz, 1 H),
8.45 (d, J ) 6.8 Hz, 1 H), 8.59 (dd, J ) 2.5, 8.7 Hz, 1 H), 8.61 (d,
J ) 8 Hz, 1 H), 8.82 (dd, J ) 1.5, 6.8 Hz, 1 H), 8.99 (d, J ) 2.5
Hz, 1 H), 10.46 (d, J ) 1.5 Hz, 1 H); 13C NMR (62.89 MHz,
CDCl3) δ 13.8, 22.3-31.6 (10 C), 67.0, 121.9, 125.7, 127.1, 127.3,
129.6, 131.5, 131.8, 131.9, 135.2, 138.1, 138.7, 138.8, 142.8, 148.8,
151.6; MS (FAB) m/ z (relative intensity) 296 (M+, 100), 130 (6).
Anal. Calcd for C27H35O8N3S‚0.9H2O: C, 56.12; H, 6.42: N, 7.27;
O, 24.64; S, 5.55. Found: C, 56.18; H, 6.42; N, 7.06; O, 24.55;
S, 5.41.
(-)-2-[(1R )-2-H yd r oxy-1-p h e n yle t h yl]isoq u in olin iu m
Dod ecyl Su lfa t e (7). Zincke salt 6 (28.9 g, 51.51 mmol)
dissolved in 1-butanol (300 mL) was added dropwise to a solution
of (-)-(R)-phenylglycinol (5, 7.8 g, 64.37 mmol) in 1-butanol
(200 mL) with stirring. A precipitate of orange crystals was
formed. An analytical sample of these crystals was filtered and
identified as 1-(butyloxy)-2-(2,4-dinitrophenyl)-1,2-dihydroiso-
quinoline (8): mp 124-130 °C; 1H NMR (300 MHz, CDCl3) δ
0.78 (t, J ) 7.3 Hz, 3 H), 1.15-1.31 (m, 2 H), 1.35-1.48 (m, 2
H), 3.08 (ddd, J ) 6.3, 6.3, 8.9 Hz, 1 H), 3.25 (ddd, J ) 6.3, 6.3,
8.9 Hz, 1 H), 6.05 (dd, J ) 1.2, 7.5 Hz, 1 H), 6.12 (d, J ) 7.5 Hz,
1 H), 6.27 (d, J ) 1.2 Hz, 1 H), 7.22-7.45 (m, 4 H), 8.08 (d, J )
9.2 Hz, 1 H), 8.61 (dd, J ) 2.7, 9.2 Hz, 1 H), 8.72 (d, J ) 2.7 Hz,
1 H); 13C NMR (62.89 MHz, CDCl3) δ 13.7, 19.4, 31.8, 62.8, 85.9,
108.4, 122.5, 124.1, 125.0, 126.7, 127.0, 127.9, 128.2, 129.5, 130.9,
141.3, 141.8, 144.0; MS (EI) m/ z (rel. intensity) 369 (M•+, 10),
236 (100), 204 (2). Anal. Calcd for C19H19N3O5: C, 61.78; H,
5.18; N, 11.38; O, 21.38. Found: C, 61.58; H, 5.21; N, 11.38; O,
21.66. The heterogeneous solution obtained above was then
refluxed overnight. After removal of solvent, the residue was
chromatographed over silica gel (800 g) using a gradient of CH2-
Cl2-MeOH (100:0 to 85:15) to give salt 7 (20.2 g, 39.22 mmol,
75%) as a pale brown gum: [R]D -37 (c 3.4, EtOH); 1H NMR
(300 MHz, CD3OD) δ 0.87 (t, J ) 6.6 Hz, 3 H), 1.12-1.43 (m, 18
H), 1.60 (2 H), 4.0 (t, J ) 6.6 Hz, 2 H), 4.42 (dd, J ) 4.1, 12.5
Hz, 1 H), 4.64 (dd, J ) 9.2, 12.5 Hz, 1 H), 6.19 (dd, J ) 4.1, 9.2
Hz, 1 H), 7.43-7.50 (m, 3 H), 7.56-7.62 (m, 2 H), 8.03 (ddd, J
) 1.7, 6.5, 8.3 Hz, 1 H), 8.20 (ddd, J ) 1.1, 6.5, 8.3 Hz, 1 H),
8.26 (dd, J ) 1.7, 8.3 Hz, 1 H), 8.44 (d, J ) 6.9 Hz, 1 H), 8.54
(dd, J ) 1.1, 8.3 Hz, 1 H), 8.66 (dd, J ) 1.6, 6.9 Hz, 1 H), 10.09
(d, J ) 1.6 Hz, 1 H); 13C NMR (62.89 MHz, CD3OD) δ 14.4, 23.6-
32.9 (10 C), 63.1, 69.0, 77.3, 127.6, 128.3, 128.8, 129.3, 130.5,
131.0, 131.9, 132.4, 134.5, 135.3, 138.4, 139.0; MS (FAB) m/ z
(relative intensity) 250 (M+, 100), 130 (88), 121 (19).
Use of these new chiral isoquinolinium salt derivatives
for the enantioselective syntheses of 1- and/or 3-substi-
tuted tetrahydroisoquinolines will be reported shortly.
Exp er im en ta l Section
2-(2,4-Din itr oph en yl)isoqu in olin iu m Ch lor ide (1). Finely
powdered 1-chloro-2,4-dinitrobenzene (34.5 g, 170.5 mmol) was
added to isoquinoline (22 g, 170.5 mmol), and the resulting
mixture was heated at 60 °C with vigorous stirring for 2 h [after
0.25 h, acetone (10 mL) was added in order to avoid formation
of a glassy solid]. Salt 1 was then precipitated with acetone and
filtered. Orange crystals (49.2 g, 148.4 mmol, 87%) were
collected from MeOH-EtOAc: mp 199-200 °C; 1H NMR (250
MHz, CD3OD) δ 8.22 (ddd, J ) 1.4, 7, 8.3 Hz, 1 H), 8.37 (d, J )
8.7 Hz, 1 H), 8.44 (ddd, J ) 1.2, 7, 7.5 Hz, 1 H), 8.50 (d, J ) 7.5
Hz, 1 H), 8.60 (d, J ) 8.3 Hz, 1 H), 8.74 (d, J ) 6.8 Hz, 1 H),
8.91 (dd, J ) 1.5, 6.8 Hz, 1 H), 8.96 (dd, J ) 2.5, 8.7 Hz, 1 H),
9.31 (d, J ) 2.5 Hz, 1 H), 10.29 (d, J ) 1.5 Hz, 1 H); 13C NMR
(62.89 MHz, CD3OD) δ 123.3, 127.2, 128.6, 128.9, 131.3, 132.8,
133.2, 133.4, 136.4, 139.9, 140.4, 144.6, 150.8, 152.7; MS (FAB)
m/ z (relative intensity) 296 (M+, 100), 204 (23), 130 (5). Anal.
Calcd for C15H10O4N3Cl‚0.1H2O: C, 54.02; H, 3.08; N, 12.6; O,
19.67; Cl, 10.63. Found: C, 54.02; H, 3.28; N, 12.34; O, 19.77;
Cl, 10.91.
2-(2,4-Din itr oph en yl)-6,7-dim eth oxyisoqu in olin iu m Ch lo-
r id e (12). Finely powdered 1-chloro-2,4-dinitrobenzene (11.73
g, 57.9 mmol) was added to 6,7-dimethoxyisoquinoline (11, 7.3
g, 38.6 mmol) in acetone (200 mL), and the resulting mixture
was refluxed for 4 h. Salt 12 precipitated during the reaction.
This precipitate was filtered and dissolved in a minimum of hot
AcOEt; this, on cooling, gave 12, which was collected as an
orange powder (12.1 g, 30.9 mmol, 80%): mp 162-167 °C; 1H
NMR (300 MHz, CD3OD) δ 4.10 (s, 3 H), 4.21 (s, 3 H), 7.83 (s, 1
H), 8.32 (d, J ) 8.6 Hz, 1 H), 8.41 (d, J ) 6.8 Hz, 1 H), 8.63 (dd,
J ) 1.4, 6.8 Hz, 1 H), 8.90 (dd, J ) 2.5, 8.6 Hz, 1 H), 9.25 (d, J
) 2.5 Hz, 1 H), 9.76 (d, J ) 1.4 Hz, 1 H); 13C NMR (75.47 MHz,
CD3OD) δ 57.4, 58.0, 107.1, 108.8, 123.2, 124.4, 125.5, 131.0,
133.0, 134.7, 138.8, 140.7, 145.1, 147.0, 150.8, 155.4, 161.9; MS
(FAB) m/ z (relative intensity) 356 (M+, 100), 190 (46).
(+)-2-[(1R)-1-P h en yleth yl]isoqu in olin iu m Ch lor id e (4).
To a solution of Zincke salt 1 (2.5 g, 7.5 mmol) in n-BuOH (50
mL) was added (+)-(1R)-1-phenylethylamine (2, 1.1 mL, 9.1
mmol), and this mixture was boiled under reflux for 15 h.
Removal of solvent under reduced pressure left a gum which
was dissolved in water and filtered. The aqueous phase was
collected, basified with a few drops of concentrated ammonia,
and washed twice with AcOEt in order to remove the remaining
2,4-dinitrophenylamine and the excess of 2. Evaporation of
water gave salt 4 (1.57 g, 5.8 mmol, 77%) as a pale brown gum:
1
[R]D +46 (c 3.3, EtOH); H NMR (300 MHz, CD3OD) δ 2.21 (d,
J ) 7 Hz, 3 H), 6.30 (q, J ) 7 Hz, 1 H), 7.42-7.50 (m, 3 H),
7.55-7.59 (m, 2 H), 8.08 (ddd, J ) 1.7, 6.5, 8.3 Hz, 1 H), 8.25
(ddd, J ) 1.3, 6.5, 8.3 Hz, 1 H), 8.30 (dd, J ) 1.7, 8.3 Hz, 1 H),
(+)-2-[(1R)-1-P h en ylet h yl]-6,7-d im et h oxyisoq u in olin i-
u m Ch lor id e (13). A solution of Zincke salt 12 (2 g, 5.5 mmol)
in MeOH (10 mL) was diluted with CH2Cl2 (150 mL). 2 (2 mL,
15.5 mmol) in CH2Cl2 (50 mL) was added dropwise to this
solution with stirring, and the resulting mixture was refluxed
overnight. Isoquinolinium salt 13 was isolated as a pale brown
(6) Zhao, B.; Snieckus, V. Tetrahedron Lett. 1991, 32, 5277.
(7) For an alternative synthesis of isoquinoline 11, see: Birch, A.
J .; J ackson, A. H.; Shannon, V. R. J . Chem. Soc., Perkin Trans. 1 1974,
2185.
(8) Kabachnik, M. I., Zitser, A. I. Zh. Obshch. Khim. 1937, 7, 162;
Chem. Abstr. 1937, 31, 4320.

9598 J . Org. Chem., Vol. 61, No. 26, 1996
Notes
gum (1.4 g, 4.3 mmol, 85%) using the workup procedure used
for the preparation of salt 4: [R]D +23 (c 2, EtOH); 1H NMR
(250 MHz, CDCl3) δ 2.17 (d, J ) 7 Hz, 3 H), 4.03 (s, 3 H), 4.06
(s, 3H), 6.25 (q, J ) 7 Hz, 1 H), 7.47-7.6 (m, 5 H), 7.61 (s, 1 H),
7.71 (s, 1 H), 8.2 (d, J ) 6.9 Hz, 1 H), 8.5 (dd, J ) 1.6, 6.9 Hz,
1 H), 9.78 (d, J ) 1.6 Hz, 1 H); 13C NMR (62.89 MHz, CDCl3) δ
20.7, 57.23, 57.7, 70.7, 106.6, 108.4, 125.1, 125.8, 128.4-130.6
(5 C), 132.9, 137.4, 139.4, 144.6, 154.6, 159.8; MS (FAB) m/ z
(relative intensity) 294 (M+, 100), 190 (40), 105 (64).
(-)-2-[(1R)-2-Hyd r oxy-1-p h en yleth yl]-6,7-d im eth oxyiso-
qu in olin iu m Dod ecyl Su lfa te (15). Dodecyl sulfate salt 14
(4 g, 6.44 mmol), obtained from the corresponding chloride 12
according to the procedure used for the preparation of salt 6,
was dissolved in 3-methyl-3-pentanol (100 mL). A solution of 5
(2.2 g, 16.06 mmol) in 3-methyl-3-pentanol (25 mL) was added
dropwise with stirring. After 2 h at ambient temperature, the
resulting mixture was refluxed for 1 h. Removal of solvent under
vacuum gave a residue, which was chromatographed over silica
gel (100 g) using acetone as eluent to give isoquinolinium salt
15 (2.35 g, 4.08 mmol, 64%) as a pale brown gum: [R]D -18
(c 2.6, EtOH); 1H NMR (300 MHz, CDCl3) δ 0.87 (t, J ) 6.2 Hz,
3 H), 1.21-1.37 (m, 18 H), 1.65 (m, 2 H), 4.06 (s, 6 H), 4.08 (t,
J ) 6.9 Hz, 2 H), 4.33 (dd, J ) 4.1, 12.9 Hz, 1 H), 4.67 (dd, J )
10.5, 12.9 Hz, 1 H), 6.16 (dd, J ) 4.1, 10.5 Hz, 1 H), 7.17 (s, 1
H), 7.26-7.41 (m, 5 H), 7.83 (s, 1 H), 7.89 (d, J ) 6.9 Hz, 1 H),
8.17 (dd, J ) 1.4, 6.9 Hz, 1 H), 9.84 (d, J ) 1.4 Hz, 1 H); 13C
NMR (75.47 MHz, CDCl3) δ 14.1, 22.7-31.9 (10 C), 56.9, 57.1,
63.0, 68.3, 75.2, 105.1, 108.1, 123.7, 124.4, 127.8-129.9 (5 C),
132.2, 134.5, 135.7, 144.5, 153.0, 158.2; MS (FAB) m/ z (relative
intensity) 310 (M+, 68), 190 (100), 121 (23).
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of compounds 1, 4, 6-9, and 12-15 with attribution
of signals (20 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O961539B