Three complementary methods offering access to 5-substituted 1,2,3,4- tetrahydroisoquinolines

Article abstract of DOI:10.1016/S0040-4020(98)00541-9

The scope and limitations of three independent, though related routes leading to 5-substituted tetrahydroisoquinolines are explored : the Pictet- Spengler type cyclization of ortho-substituted 2-phenylethylamines, the Pomeranz-Fritsch type cyclization of meta-substituted benzylamines and the electrophilic trapping of 5-lithiated 4-lithiooxytetrahydroquinolines. The introduction of the substituent relies in all three cases on a neighboring group assisted, site selective metalation step.

Full text of DOI:10.1016/S0040-4020(98)00541-9

TETRAHEDRON
Tetrahedron 54
9023-9032
Three Complementary Methods
Offering Access to 5-Substituted
Schlosser Gyula Simig and
de Chimie organique de
de Chimie
CH- 1015
Switzerland
Received 31 March 1998; accepted 2 June 1998
Abstract
:
The scope and limitations of three independent, though related routes leading to
substituted tetrahydroisoquinolines are explored : the Pictet-Spengler type cyclization of
substituted
benzylamines and the
the
trapping of
cyclization of
The
introduction of the substituent relies in all three cases on a neighboring group assisted, site selective
step. 1998 Elsevier Science Ltd. All rights reserved.
Pomeranz-Fritsch type cyclization of
convenient entry to
and
benzylamine derivatives opens the most
and 6-position, respectively
carrying substituents at the
The outcome is less unequivocal when mefa-substituted benzylamines are used as the starting materials
since now mixtures are formed, in which the 7-isomer is generally the predominant component if it is not even
formed exclusively
tuted isoquinolines.
In other words, the S-isomers are the least accessible among the aromatically substi-
X
We present in the following three complementary
methods that selectively lead to
isoquinolines. All of them involve at some stage a neighboring group assisted, site specific hydrogen/lithium
exchange (“metalation”) at the aromatic ring.
The
possibility is to opt for a Pictet-Spengler or a Bischler-Napieralski rather than a
This means, as the principal building block this time a
Fritsch type cyclization
is required.
(Fax
39 65)
1998 Elsevier Science Ltd. All rights reserved.

et al. /Tetrahedron 54 (1998) 9023-9032
9024
a substituent is located at an ortho-position of the aryl ring, it will inevitably have to occupy the
in
To
resulting
this approach we have prepared
1 with butyllithium and
2. Aldehyde 3 was converted into the
3 by consecutive reaction of
disulfide followed by acid hydrolysis of the
5 via the 4 obtained by
condensation with nitromethane under basic conditions and subsequent catalytic hydrogenation. Compound 5,
when treated with formaldehyde under acidic conditions, eventually
the tetrahydroisoquinoli 6.
Li
I
(a)
(c)
aq.
later
(d)
(e)
aq.
later
later
aq.
finally
and
are less readily available than arylmethylamines
of access to the isoquinoline 6 by starting with
7 was submitted to a halogen/metal exchange performed
it was tempting to explore the
The corresponding
with butyllithium in
and next allowed to react with
aldehyde 9 which was condensed with
The
8 thus
under
obtained
hydrolyzed to set

M. Schlosser et al. /Tetrahedron 54 (1998) 9023-9032
9025
reductive conditions before being
to give the
10, the hydroxy group of which
could be easily removed by hydrogenolysis.
Th e aminoacetal 1 1 , derived
(9) by reductive amination, has two empty
ortho-positions in which the side chain could “bite” thus giving rise to the actually formed isoquinoline 1 0 or
its elusive regioisomer 12. The high selectivity found in favor of product 10 is another manifestation of the
pronounced
aromatic substitution reactions. The N-methyl aminoacetal 13, obtained by reductive amination of aldehyde 9
with shows the same kind of extreme regioselectivity,
effect
of alkoxy groups (here as part of a dioxolane ring) in electrophilic
isoquinoline 14 (42%) as the sole isolated product.
11:
13:
R
H
1 2
10:
14:
H
OR’ OCH,,
R
R
CH,
In the same way,
was converted via the aminoacetals 15 and 17 into the
quinolines 16 (51%) and 18 (49%). Evidently, neither alkylthio groups nor a bromine atom strongly bias the
of electrophilic aromatic substitution so that the alkoxy unit incorporated in the
dioxonate ring can dictate the regiochemical course of the cyclization step.
OR’
Br
OR’
Br
OH
0
0
N
N
N
Br
Br
1 6 :
1 6 :
H
15:
R
C H ,
1 7 :
OR’ OCH,,
The 4-hydroxy group is a structural motif which is invariably associated with the Pomeranz-Fritsch
method when performed according to the protocol It may or may not be subsequently removed
by elimination or reduction. However, as long as present, it may be deprotonated and then exploited as a
neighboring group directing the hydrogen/metal exchanging attack of an organolithium reagent to the nearby
The thirdpossibility of introducing a substituent into the
of isoquinolines is based on
and applications in the
are known.
this concept. Numerous precedents
of lithium benzylalcoholate
of lithium
carbocyclic series (e.g., the
The lithiation of
(19) did occur although it proceeded
only sluggishly. An excess of tert-butyllithium in diethyl ether and prolonged reaction times (6 h at 25 “C)
were required to achieve acceptable yields of the trapping products 20 22
45% and 5
respectively).
El OH
OH
1 9
2 0 :
21: El
22: El
I

Schlosser et al. /Tetrahedron 54 (1998) 9023-9032
Against our expectation, the metalation was not much accelerated when we turned to the
(23) as the substrate. After treatment with excess
lithium in
(again for 6 h at 25 “C) followed by interception with various electrophileq the
substituted derivatives 24 26 were isolated in satisfactory yields
60% and
respectively).
OH
OH
N ,
N ,
N
2 3
2 4 :
25:
I
26:
Since the
18 is so readily available, it was an obvious idea to submit it to consecutive
0-lithiation and halogen/metal interconversion, thus generating the intermediate 27 instantaneously. Strange
enough, only small amounts (0 20%) of S-substituted derivatives where identified
variety of electrophiles (deuterium oxide, methyl iodide, formaldehyde,
trapping with a
and carbon
dioxide). The situation improved to some extent when the same reaction sequence was applied to the
methoxyisoquinoline 28. Intermediate 29 was efficiently intercepted with heavy water
of deuterium
incorporation), whereas the treatment with methyl iodide gave only about 15% of the expected product.
Moreover, at least one third of the isoquinoline 28 was invariably lost by transformation into insoluble
materials, presumably by concomitant base-promoted 1
of the resulting
of methanol and subsequent dimerization
OR
OR
2 7 : O R
29: OR
18: OR
28: OR
O H
3 0
O C H,
O C H,
Several factors which can compromise the outcome of the reactions appear to coincide. The flatness of the
ring structures and aggregation make the intermediates 27 and 29 virtually insoluble and thus protect them
against the action of electrophiles. At the same time, the oxygen functions in the vicinity of the organometallic
bond may trigger a single electron
radicals (OR Li or OCH3) which will seek and
the latter to the electrophilic reagent, thus generating
stabilization by hydrogen atom abstraction from the
solvent. No such complication is encountered with flexible precursors. For example, the
substituted
aminoacetal 17 undergoes the halogen/metal exchange with butyllithium and the subsequent electrophilic
trapping
quantitatively (e.g., with
83% of 14).
EXPERIMENTAL PART
(CH-9470
were purchased
or Aldrich (D-89552 Steinheim), unless
literature sources or details of the preparation are given. Solutions of butyllithium
in hexane
(1.5 M and 11.5 M”, i.e. containing the organometallic reagent to the extent of 90%) were supplied by

M.
et al. /Tetrahedron 54 (I 998) 9023-9032
(D-60271
reagents were used without
potassium
purification.
by Callery (Pittsburgh, PA 15230). All commercial
Air
were stored in Schlenk tubes or Schlenk burettes. They were
protected by and handled under an atmosphere of 99.995% pure nitrogen (glassware
D-9871 1 Frauenwald).
Pfeifer,
or aromatic hydrocarbons (e.g., hexane, benzene and toluene) were obtained
by
careful szeotropic distillation.
the characteristic blue color of in
and
were dried by distillation
sodium wire
generated sodium diphenyl ketyl had been found to persist.
were dried with sodium sulfate. Before distillation of compounds prone to radical
polymerization or sensitive to acids a spatula tip of or, respectively, potassium carbonate was
added.
The temperature of dry ice methanol baths is consistently indicated -75
and “room temperature” (22
unless stated otherwise
26 “C) as 25 “C.
(mp) are reproducible after
and are corrected by using a calibration curve which was established with authentic standards. If no melting
points are given, it means that all attempts to crystallii the liquid product have failed even at temperatures as
low as -75
Silica gel (Merck
The solid support was suspended in hexane and, when all air bubbles had escaped, was
sluiced into the column. When the level of the liquid was still some 3 cm above the silica layer, the dry
60) of 70 230 mesh (0.06 0.20 mm) particle size was used for
powder, obtained by adsorption of the crude product mixture on 15 20 g silica gel and subsequent
evaporation of the solvent, was poured on top of the column.
Nuclear magnetic resonance spectra of hydrogen-l and carbon-13 nuclei in deuterochloroform solution
(unless stated otherwise) were recorded at 400 MHz, chemical shifts referring to the signal of
silane. Coupling constants
are measured in Hz. Coupling patterns are abbreviated as (singlet), d (doublet),
(triplet), q (quartet), dd (doublet of doublets) and m (multiplet).
were obtained at 70
ratios given for bromine-containing molecules or fragments thereof refer to the
ionization potential maintaining a source temperature of 200
The
isotopomers.
Elementary
were executed by the laboratory of I.
D-96301
The expected
numbers are calculated on the basis of atomic weights according to the 1986
recommendations.
(2) At -75
14 0.15 mol) were added to a solution of
(1; 23 g, 0.10 mol) in tetrahydrofiuan (0.20 L). The mixture was kept 2 h at 25
The organic layer was washed with brine (25 dried and
evaporated. Recrystallization of the residue from methanol gave product 2 as a colorless solid; mp 102 103
butyllithium (0.11 mol) in hexane (75
and, 20 min later,
(13
N-cyclohexylimine
before it was poured into water (50
H, symm. m), 2.42 (3 H, s), 1.5 (10 m). -MS 277
262
180 (100%). Analysis
for (277.38) C 64.95, H 6.90; found C 64.72, H 6.82%.
(3)
After addition of 10% hydrochloric acid, the mixture was vigorously stirred for 48 h. The organic layer was
decanted, washed with a saturated aqueous solution (2 x 50 of sodium carbonate and water (2 x 50
dried and evaporated. The residue was triturated with hexanes (50 and crystalhi methanol to
product 3 as a colorless solid; mp 79 81 12.9 g (91%). 1665 cm-‘,
10.39 (1 H, s), 7.55 (1 6.83 (1 d, 6.14 (2 s), 2.52 (3 s). -MS 196
2 (20.0 g, 72 mmol) was dissolved in dichloromethane (0.20 L).

9 0 2 8
M. Schlosser et al. Tetrahedron 54 (1998) 9023-9032
181
167 (14%). 162
149 (19%). Analysis
for
(196.22) C 55.09, H 4.11;
found C 55.07, H 4.19%.
(4) A mixture of aldehyde 3 (3.9
6.1 100 mmol), ammonium acetate (3.1 40 mmol) and acetic acid (10
before being kept 15 h in a The precipitate was collected by filtration
20 mmol),
nitromethane (5.4
heated for 2 h under
was
under suction, washed with 50% aqueous ethanol and diethyl ether and recrystallized from ethanol to give the
colorless solid 4; mp 119 120 2.8 (56%). ‘H-NMR 8.64 (1 I-I, 7.57 (1
6.14 (2 s), 2.47 (3 H, s). MS : 239 193
(239.24) C 50.20, H 3.79; found C 50.54, H 3.81%.
J
J
7.21 (1 I-I, d,
J
6.84 (1 d,
J
178
(100%). Analysis
for
(6) A solution of the nitro
compound 4 (2.4 9.5 mmol) in tetrahydrofuran (20
hydride (1.4 g, 38 mmol) in tetrahydrofuran (20
was added
to a suspension of lithium
After 5 h of stirring at 25
poured into a saturated aqueous solution of sodium sulfate and extracted with diethyl ether (2 x 25
the mixture was
The
precipitate was removed by filtration and thoroughly extracted with diethyl ether (3 x 25 The
organic layers were washed with brine (2 x 25
amine 5, was treated with an 18% aqueous solution (6
and evaporated. The oily residue, presumed to contain
of formaldehyde (40 mmol) for 15 h at 25
Then 20% hydrochloric acid (25 mmol) was added under stirring and the homogeneous mixture evaporated to
dryness. Recrystallization
255 256 (dec.); 0.71 (29%). ‘H-NMR
3.15 t, 2.40 (3 -MS 223
(259.75) C 50.86, H 5.43; found C 51.00, H 5.34%.
aqueous ethanol
the colorless hydrochloride of isoquinoline 6; mp
6.73 (1 H, s), 6.04 (2 I-I, s), 4.30 (2 I-I, s), 3.54 (2
t,
206
193
176
161
(38%). Analysis
:
for
Product 6 was also obtained by treatment of the hydroxyisoquinoline 10 (0.72
3.0 mmol), described
below, with sodium borohydride (0.23
6.0 mmol) in a mixture of trifluoroacetic acid (2.0
and
dichloromethane (4.0
triturated with a 5% aqueous solution (10
for 16 h at 25 “C. The residue left behind upon evaporation to dryness was
of sodium hydroxide and then collected by filtration. It was
dissolved in ethanol (5
gave the hydrochloride of 6 as colorless needles; mp 255 256
and precipitated in diethyl ether (10
Recrystallization
(dec.); 0.62 (79%).
aqueous ethanol
(7) A solution of
0.15 mol;
18 0.18 mol) in
prepared
and cyclohexylamine (21
toluene (0.25
was heated under
for 2
the water formed was continuously removed by
means of a Dean-Stark separator. After evaporation of the solvent, the residue was crystallized
mp 97.5 98.5 41 (87%). ‘H-NMR 8.12 (1 s), 7.28 (1
6.07 (2 I-I, s), 3.16 (1 H, symm. m), 1.5 (10 I-I, m). -MS 311
45 (100%). Analysis for
methanol;
J 7.23
d,
282
(1 I-I, d,
230
H 5.09%.
J
280
(310.19) C 54.21, H 5.20; found C 54.44,
(8)
(13
-75 “C, a solution (75
14 0.15 mol) were added to bromoimine
(0.20 L). The homogeneous mixture was kept 3 h at -75 before it was
of butyllithium
(0.11 mol) in hexanes and, 20 min later,
7 (3 1 0.10 mol) in
allowed to reach 25
The residue obtained
washing with water (3 x 50
heptanes; mp 63 64
drying and evaporation
16 (57%). ‘H-NMR
was triturated with hexanes (0.10 L) and crystallized
I-I, s), s,
MS 177
(277.38) C 64.95, H 6.90; found C 65.01, H 6.82%.
s), 3.15 (1 I-I, symm. m), 2.51 (3 I-I, s), 1.5
(10 I-I,
196
195
181
45 (100%).
for
(9) : The
into aldehyde 3 (see above); mp 80 81
9.83 (1 I-I, s), 7.36 (1 I-I, d,
195 151 (11%). Analysis
8 was hydrolyzed as described for the conversion of
(from methanol); 8.6 (82%). IR 1670
7.19 (1 H, d, 6.14 (2 I-I, s), 2.55 (3 I-I, MS 196
for (196.22) C 5.09, H 4.11; found C 55.08, H
2
‘H-NMR
:
J
J
4.25%.

et al. /Tetrahedron 54 (1998) 9023-9032
(10) A suspension of
2.3 22 mmol) in methanol (20
stirred until a homogeneous solution had formed. The latter was cooled to
10 was dissolved in it. After 2 h at 25 “C, the solvent was evaporated and the residue taken up in
Under cooling, a 40% aqueous solution
9
was
(3.9 20
and aminoacetaldehyde
acetal(2.4
0
and sodium borohydride (0.38
hydrochloric acid (0.10 L). The mixture was kept 16 h at 25
of sodium hydroxide was added. Product 10 was extracted with dichloromethane (3 x 75
(60
combined organic layers were dried and evaporated.
The
Recrystalhzation of the residue
‘H-NMR
4.76 (1 s, broad), 4.55 (1 s, broad), 3.75 (1 H, d,
s, broad), 3.03 (1 d, 2.73 (1 dd, 13.3, 2.38 (3
210 204 45 (100%). Analysis for
isopropanol gave a
colorless powder; mp 159 161
2.2 g (47%).
6.54 (1 s), 6.01 (1 d,
3.60 (1 d,
s). MS 239
(239.29)
5.98 (1 H,
3.23 (1
219
195
C 55.21, H 5.48; found C 55.46, H 5.13%.
(14) A suspension of
and a 40% aqueous solution (3.5 of
(3.9 g, 20 mmol) in methanol (20
methylamine (40 mmol) was stirred until a homogeneous solution had formed. Sodium borohydride (0.38 10
mmol) was dissolved in this mixture. After 16 h at 25 “C, the solution was evaporated to dryness and water
was added. The extract with dichloromethane (3 x 50
was dried and evaporated. The residue was
dissolved in ethanol (40
ether (20
and precipitated by addition of concentrated hydrochloric acid (2 and diethyl
The crude hydrochloride was dissolved in a 20% aqueous solution (15
of sodium
After drying and evaporation of the combined organic layers,
5.1 g, 25 mmol) and sodium hydrogen carbonate (5.0 g, 60 mmol)
hydroxide and extracted with ether (3 x 10
bromoacetaldehyde diethyl
(4.0
were added and the residue was heated for 6 h to 125 “C. The semisolid mixture was extracted with diethyl
ether (3 x 10 Evaporation of the filtrate a yellowish oil. This crude material (intermediate 13
according to nmr) was dissolved in 20% hydrochloric acid (0.10 16 h at 25 “C, the mixture was
stirred with charcoal, filtered and made alkaline by addition of 40% aqueous sodium hydroxide (60
Product 14 was extracted with dichloromethane (3 x 50 dried and collected after evaporation of the
solvent. Recrystalhzation toluene gave a colorless solid; mp 115 116 “C; 2.2 g (42%). ‘H-NMR
6.37 (1 s), 6.01 (1 d,
broad), 3.44 (1 dd, 14.8, 2.95 (1
(3 H, s), 2.29 (1 dd, J 11.8, 2.8). MS 253
5.96 (1 H, d,
2.90 (1
4.72 (1
symm. m), 3.95 (1
s,
d,
ddd, 11.8, 2.0,
J
2.39 (3
s), 2.30
for
210
45 (100%). Analysis
(253.31) C 56.90, H 5.97; found C 57.10, H 5.84%.
14 was independently prepared
the
compound 10 (0.24
of formaldehyde (1.3
sodium borohydride (50 mg, 2.3 mmol) and, 15 min
1 .O mmol) to which 1% hydrochloric acid (3
mmol) were added. 5 min of heating under
later, a 40% aqueous solution (1 of sodium hydroxide were added at 25
and recrystallized
and a 36% aqueous solution (0.10
The precipitate was collected
0.17 g (67%).
a 1 1 (v/v) mixture of ethyl acetate and hexanes; mp 115 116
The 1-bromoisoquinolinols 16 and 18 (see below) were prepared as described above for the
10 and 14. However, some of the reactions were carried out on a considerably increased
scale and some of the intermediate products (such as 17) were isolated and characterized.
described above (see prepara-
was
2.3 g, 22 mmol) in methanol (20
tion of
(4.6 20
prepared
consecutively treated with sminoacetaldehyde
sodium borohydride (0.38
179
4.68 (1 H, s, broad), 3.86 (2
MS 273
found C 44.37, H 3.78%.
(2.4
10 mmol) and 20% hydrochloric acid (0.10 L) to
product 16; mp 178
6.00 (1 d,
2.39 (2 broad).
(272.10) C 44.14, H 3.70;
(from isopropanol); 2.8 g (51%). ‘H-NMR 6.45 (1
s), 6.01 (1 H, d,
J
J
symm.
45 (100%). Analysis
3.37 ( 1 H, d,
J
2.90 (1 H, d,
for
J
244
(18)
described above
11 5 50 mmol; prepared
(
(see preparation of

M. Schlosser et al. Tetrahedron 54 (1998) 9023-9032
aldehyde was consecutively treated with methylamine (100 mmol) in 85% aqueous methanol (85
and
sodium borohydride (1.9
mmol).
hydrochloride precipitated from
the acidified solution in ethanol upon addition of diethyl
mp 226 227
ethanol); 10.1 (72%).
245 244 1), 215 (100%). Analysis
for
(280.55) C 38.53, H
3.95; found C 38.68, H 4.04%. Reaction of the free amine, set
the hydrochloride (5.6 20 mmol)
with a 40% aqueous solution of sodium hydroxide, with bromoacetaldehyde diethyl
mmol) in the presence of sodium hydrogen carbonate (5.0 60 mmol) at 125 afforded the aminoacetall7
5.1 25
which was purified by
bp 130 135
ntl.5255; 4.7 (65%).
:
6.95 (1
d. J
6.82 (1 d,
J
6.03 ( 2 s), 4.63 (1 H, t,
3.65 (2 H, dq, J9.7,
3.53 (2 dq,
J
9.2
3.45 (2 H, s), 2.57 (2 H, d,
J
for
2.29 (3 H, s), 1.22 (6 H, t, J 7.0). MS 361 (1%, 215
(lOO%), 103 (60%). Analysis
Crude aminoacetal 17 [prepared
(360.25) C 50.01, H 6.16; found C 50.08, H 6.09%.
was isolated as described above
0.10 mol of
(see preparation of 14). Product 18 was obtained as a colorless solid, mp 134 135
13.9 (49% over-all
6.33 (1 s), 6.05 (1
J
6.01 ( 1 H, d,
3.02 (1 d,
J
J
[with respect to
4.67 (1
broad), 4.00 (1 s, broad), 3.48 (1 d,
11.8, 2.5). MS 287
J
14.8). 3.08 (1 H,
244
J
2.40 (3 s), 2.34 (1 dd,
(286.12)
J
45 (100%). Analysis
The same product was formed when the l-bromoisoquinolinol 16 (0.27
1
mmol) was simultaneously
treated with formaldehyde and sodium borohydride in acidic aqueous medium (see above the alternative
preparation of 14, at the end of the paragraph dealing with this compound); mp 134 135 “C; 0.20 (70%).
( 2 0 )
(19; 4.1 25 mmol)
(0.15 L) and pentane (50
methylsilane (9.5
added to a solution of
being stored 6 h at 25 “C, the mixture was treated with
it was with 5% sulfuric acid (approx.
organic layers were
bp 108 109
(75 mmol) in diethyl ether
8.2 75 mmol) at -25 “C. At 25
0.10 L) and the aqueous phase extracted with diethyl ether (3 x 0.10 L). The
dried and evaporated. The residue was purified by distillation; mp -49 to -47
1.5090; 3.7 (63%). The slightly orange colored oil was triturated with hydrogen chloride in ethanol. The
initially amorphous solid
7.60 (1 H, d, 7.37 (1 t,
(1 d, 3.58 (2 s), 3.07 (3 s), 0.38 (9 H, s).
methanol; mp 22 224 “C; 4.3 (63%).
7.22 (1 d, 5.15 (1 t, 4.55 (1 d,
141.3 (1 C, s), 140.6 (1 s), 134.1
127.5 (1 C, d, 65.9 (1 C, d, 60.5
45.9 (1 C, 119.4). MS 235
177 (100%). Analysis (271.86) C 57.43, H
J
4.34
J
(1 C, s), 133.4 (1 C,
J
J
126.7 (1 C, d,
J
J
(1 C, t,
234
J
58.2 (1 C, t,
J
J
0.8 (3 C, q,
J
216
202
for
8.16; found C 57.45, H 8.22%.
(21) Using iodine (19 75 mmol) instead of
chlorotrimethylsilane, the hydrochloride of 21 was obtained; mp 199 201 ethanol); 4.8 (59%).
5.07 (1 H, t, 4.54
12.7, 3.10 (3 H, s).
(325.57) C 36.89, H 4.02;
:
7.93 (1 d,
4.33 (1 d,
270 (lOO%), 245 (45%). Analysis
found C 36.66, H 4.10%.
7.28 (1 d,
7.14 (1 H, t,
3.53 (1
for
(1 d,
J
J
3.71 (1 dt, 12.7,
J
J
MS 188
Applying the same protocol as described
for the preparation of product 20, but replacing chlorotrimethylsilane by
50 mmol), the aldehyde 22 was formed, which was extracted
(3.8,
3.7
the ethereal solution with sodium
and,
decomposition of the
with an aqueous solution of sodium hydroxide, collected as a
slightly ocherous colored amorphous solid; mp 106 108 (dec.) 2.45 (51%).
10.20 (1 H,
s), 7.76 (1 H, d,
7.43 (1 H, t,
3.07 (1 ddd,
190
7.32 (1 d,
12.1, 3.1, 2.62 (1 H, d,
174 119 (100%).
5.16 (1 H, s, broad), 3.82 (1 H, d,
J
3.35 (1 H, d,
+
J
J
J
12.1,
2.48 (3
-MS 192
191

M. Schlosser et al. /Tetrahedron 54 (1998) 9023-9032
(24)
(23; 5.2
25
was added to a
of
(75
in tetrahydrofuran (0.10 L) and hexanes (50
6 h at 25
the mixture was
treated with chlorobimethylsilane (9.5
(approx. 0.10 L). Product 24 was isolated by
evaporation and bp 126 128
hydrogen chloride in ethanol and
222 “C; 5.7 g (72%). ‘H-NMR
8.2 75
and, h later, neutralized with 5% acid
of the aqueous
5.0 g (72%).
with diethyl ether (3 x 0.10 L),
of the oil with a solution of
from methanol gave a colorless amorphous solid; mp 220
6.68 (1 I-I, s), 5.94 (2
s), 5.04 (1
s, broad), 4.41 (1 I-I, d, J
4.23 (1
d, J
3.56 (1 H, d, J
154.8 (1 C,
101.9 (1 C, t,
1.0 (3 C, q,
3.49 (1 d, J
3.04 (3 I-I, s), 0.41 (9
s).
120.9 (1 C,
56.4 (1
148.2 (1 C, s), 131.7 (1 C, s), 123.2 (1 C,
107.6 (1 C, d,
J
J
64.2 (1 C, dd,
J
146.6,
59.9 (1 C, t,
262
J
C, t,
J
44.1 (1 C,
J
J
119.9). MS : 279
(315.87) C 53.24, H 7.02; found C 52.71, H 7.11%.
221 (100%).
Analysis
for
(25) Using iodine (19 75
mmol) instead of chlorotrirnethylsilane, product 25 was obtained; mp 123 128 (dec.); 5.5 g (60%).
‘H-NMR 6.70 (1 s), 6.07 (2 I-I, s), 5.0 (1 m), 4.43 (1 I-I, d, 4.22 (1 I-I, d,
I-I, d, 3.48 (1 I-I, d, s). -MS: 333
J
J
Applying the same protocol
as
for the preparation of product 24, but replacing
by methyl iodide (3.1
7.1 50 mmol), derivative 26 was formed. It was isolated by extraction with diethyl ether and distillation, An
orange-red colored oil (3.7 g) was collected and converted into the hydrochloride as described; mp 23 1 235
(dec.;
broad), 4.39 (1 I-I, J
2.29 (3 H, s). MS 221
ethanol); 4.3 g (66%).
6.55 (1 I-I, s), 5.97 (2
3.63 (1 d, J 3.45 (1 I-I, d, J
178 162
d,
5.02 (1
3.05 (3 I-I, s),
4.19 (1 I-I, d, J
202
86 (100%). Analysis
for
(257.72) C 55.93, H 6.26; found C 56.08, H 5.98%.
(28) A solution
containing a small quantity (2 of
concentrated hydrochloric acid was heated for 20 h under reflux. The hydrochloride of product 28 was
precipitated by addition of diethyl ether (50 collected by filtration and dissolved in water. A
volume (approx. 1 of a 40% aqueous solution of sodium hydroxide was added to make the solution
slightly Product 28 was extracted with diethyl ether (3 x 20 The combined organic layers were
dried and evaporated. The residue was triturated with hexanes and crystallized from heptanes; mp 103 104
of the bromoisoquinol 18 (2.9 g, 10
in methanol (20
1.6 g (53%).
3.80 (1 I-I, d,
J 12.3, 2.2). MS 301
48.02, H 4.70; found C 48.05, H 4.68%.
‘H-NMR
3.54 (3 I-I, s), 3.26 (1 I-I,
271
6.47 (1 I-I, s), 6.01 (1 H, d,
J
6.00 (1 I-I, d,
3.13 (1 I-I, d,
258 (100%). Analysis
J
4.25 (1
m),
s), 2.27 (1 H, dd,
(300.15) C
J
J
J
2.48 (3
for
This work was
(grants
supported by the
Nationalfonds zur
lichen
and
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Chem.
Trans. I
2261.
(prepared from
according to a general
of