Possible neighbouring group participation of a nitro-group in the conversion of 3-hydroxymethyl-2-(2-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline into its 3-chloromethyl derivative

Article abstract of DOI:10.1002/jhet.5570420629

The alcohol 12 reacted with 4-toluenesulfonyl chloride in boiling dichloromethane solution to give the chlorinated product 13 rather than the expected tosylate 3 by a mechanism that could involve neighbouring group participation of the nitro-substituent.

Full text of DOI:10.1002/jhet.5570420629

Sep-Oct 2005
1215
Possible Neighbouring Group Participation of a Nitro-group in the
Conversion of 3-Hydroxymethyl-2-(2-nitrophenyl)-1,2,3,4-
tetrahydroisoquinoline into its 3-Chloromethyl derivative.
Michael J. Donaghy and Stephen P. Stanforth*
School of Applied Sciences, University of Northumbria, Newcastle upon Tyne, NE1 8ST, UK.
Received February 10, 2005
The alcohol 12 reacted with 4-toluenesulfonyl chloride in boiling dichloromethane solution to give the
chlorinated product 13 rather than the expected tosylate 3 by a mechanism that could involve neighbouring
group participation of the nitro-substituent. In contrast, the isomeric alcohol 15 reacted normally with 4-
toluenesulfonyl chloride giving the tosylate 16 under similar conditions.
J. Heterocyclic Chem., 42, 1215 (2005).
We have recently reported the preparation of a series of
obtained by base-induced elimination. Tautomerisation of
this enamine might be then expected to yield the 6-methyl
derivative 8 of compound 7 (Scheme 1). This note
describes an unexpected reaction of the 4-toluenesulfonate
derivative 3.
5,6-dihydrobenzimidazo[2,1-a]isoquinoline derivatives 6
[1] and their corresponding N-oxide derivatives 5 [1,2] as
part of a study of analogues of the anti-cancer agent
Ellipticine (1) and its 9-oxygenated derivatives (Scheme 1)
[1]. N-Oxides 5 were readily prepared by cyclodehydration
of 2-(2-nitroaryl)-1,2,3,4-tetrahydroisoquinolines 2 in
boiling propionic acid (the t-amino effect) [3] and deoxy-
genation of these compounds with phosphorus trichloride
yielded derivatives of heterocyle 6 [1]. We were also inter-
ested in the preparation of the fully conjugated benzimi-
dazo[2,1-a]isoquinolines 7 but the attempted oxidation of
derivatives of heterocycles 6 were unsuccessful. Literature
precedence suggested that this transformation might not be
readily achieved because 2,3,9,10-tetramethoxybenzimi-
dazo[2,1-a]isoquinoline had only been obtained in 10 %
yield by palladium on carbon mediated dehydrogenation
of the corresponding 5,6-dihydroderivative [4]. An alter-
native approach to these fully conjugated heterocycles was
therefore sought.
The synthetic route to the 4-toluenesulfonate derivative
3 is shown in Scheme 2. 1,2,3,4-Tetrahydroisoquinoline-3-
carboxylic acid (9) was reacted with 2-fluoronitrobenzene
(10) and the resulting carboxylic acid was esterified
directly by treatment with dimethyl sulfate under basic
conditions giving the ester 11. Reduction of ester 11 was
achieved by treatment with lithium borohydride in the
presence of trimethoxyborane yielding the alcohol 12 [5].
When the alcohol 12 was treated with 4-toluenesulfonyl
chloride in pyridine, unexpectedly, the chloride 13 was
obtained. The formation of the chloride 13 has been ratio-
nalised as shown in Scheme 2 in which neighbouring
group participation by the nitro-group results in a
favourable 7-endo-tet intramolecular reaction [6] giving a
putative cyclic intermediate that is then attacked by chlo-
ride yielding the product 13. Compound 13 could also be
prepared by an alternative route by the reaction of alcohol
The strategy we envisaged was to prepare the 4-toluene-
sulfonate derivative 3 from which the enamine 4a might be

1216
M. J. Donaghy and S. P. Stanforth
Vol. 42
12 with carbon tetrachloride and triphenylphosphine thus
confirming the structure of the chloride 13.
sulfonyl chloride with ice-cooling) these workers iso-
lated the mesylate 18.
In support of this mechanism involving neighbouring
group participation by the nitro-group, the isomeric alco-
hol 15 was also prepared. In an analogous method to the
preparation of ester 11, treatment of compound 9 with 4-
fluoronitrobenzene and subsequent esterification of the
resulting acid gave the ester 14 which was then reduced
with lithium borohydride affording the alcohol 15.
Reaction of this alcohol 15 with 4-toluenesulfonyl chlo-
ride, under identical conditions as those used for the trans-
formation of compound 12 into compound 13, gave the 4-
toluenesulfonyl derivative 16 as expected.
Simig and co-workers have described the formation
of the chloride 19 directly from the alcohol 17 in 53 %
yield [7]. Their reaction conditions were harsh com-
pared with ours and involved treating the alcohol 17
with methanesulfonyl chloride in boiling pyridine solu-
tion. Under milder conditions (pyridine and methane-
EXPERIMENTAL
Infra-red spectra were recorded as potassium bromide discs
using a Perkin Elmer Paragon 1000 spectrophotometer. Proton
NMR spectra were determined at 270 MHz in deuteriochloro-
form solution using a Jeol GX270 instrument. Elemental analyses
were performed by the Department of Chemistry, University of
Newcastle upon Tyne, UK. High resolution mass spectra were
either performed at the EPSRC national mass spectrometry ser-
vice centre, Swansea, UK (electrospray) or at the University of
Newcastle upon Tyne, UK (electron impact).
Methyl 2-(2-Nitrophenyl)-1,2,3,4-tetrahydroisoquinoline-3-car-
boxylate (11).
To a stirred mixture of racemic 1,2,3,4-tetrahydroisoquinoline-
3-carboxylic acid (9) (4.0 g, 22.7 mmol) and potassium carbonate
(5.6 g, 40.7 mmol) in dimethylsulfoxide (20 mL) at room temper-
ature was added 2-fluoronitrobenzene (10) (3.36 g, 23.8 mmol) in
portions. The mixture was then heated at 100 °C (4 hours) with
stirring, allowed to cool to room temperature and poured into
water. The mixture was acidified with dilute hydrochloric acid to
pH 1 at room temperature and then extracted with
dichloromethane (3 x 50 mL). The organic fractions were washed
several times with water, dried (magnesium sulfate) and evapo-
rated giving the crude 2-(2-nitrophenyl)-1,2,3,4-tetrahydroiso-
quinoline-3-carboxylic acid (5.89 g, 87 %) as an orange solid, mp
141-143 °C (from ethanol). This compound had ir: 1699, 1602,
-1
1
1508, 1334 and 1235 cm ; H nmr: δ 7.82 (dd, 1H, J = 6 and 1
Hz, Ar-H), 7.55-7.00 (m, 7H, ArH), 4.80 ( d, 1H, J = 9 Hz, 1-H),
4.35 ( dd, 1H, J = 4 and 1 Hz, 3-H), 4.10 (d, 1H, J = 9 Hz, 1-H),
3.49 ( dd, 1H, J = 9 and 4 Hz, 4-H) and 3.35 (dd, 1H, J = 9 and 1

Sep-Oct 2005
Possible Neighbouring Group Participation of a Nitro-group
1217
Hz, 4-H). A mixture of this carboxylic acid (5.89 g, 19.8 mmol),
potassium carbonate (4.0 g, 28.9 mmol) and dimethylsulfate (2.0
mL, 21.2 mmol) in acetone (20 mL) was heated at reflux (2
hours), allowed to cool to room temperature and then poured into
water. The mixture was extracted with dichloromethane (3 x 50
mL), the organic extracts were washed with water, dried (magne-
sium sulfate) and evaporated giving the ester 11 (3.08 g, 52 %) as
a yellow solid, mp 111-112 °C. Compound 11 had: ir: 1727, 1606,
ous layer was extracted with dichloromethane (10 mL). The com-
bined organic fractions were washed with water, dried (magne-
sium sulfate) and evaporated giving an orange oil (0.21 g) which
was purified by column chromatography over silica gel (eluent:
petroleum ether bp 60-80 °C: ethyl acetate, 20:1) yielding com-
pound 13 (0.07 g, 27 %), identical with an authentic sample.
Methyl 2-(4-Nitrophenyl)-1,2,3,4-tetrahydroisoquinoline-3-car-
boxylate (14).
-1 1
1524, 1342, 1203 and 1164 cm , H nmr: δ 7.84 (d, 1H, J = 8 Hz,
Ar-H), 7.57-7.44 (m, 2H, Ar-H), 7.19-7.06 (m, 5H, Ar-H), 4.92
(d, 1H, J = 15 Hz, 1-H), 4.31 (dd, 1H, J = 4 and 1 Hz, 3-H), 4.16
Compound 14 was prepared using a similar procedure to that
described above for the preparation of compound 11. 2-(4-
Nitrophenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
was prepared as an orange solid, mp 193-195 °C (ethanol) in 53 %
(d, 1H, J = 15 Hz, 1-H), 3.57 (s, 3H, -CH ), 3.58 (dd, 1H, J = 16
3
and 4 Hz, 4-H) and 3.25 (dd, 1H, J = 16 and 1 Hz, 4-H); ms: m/z
-1 1
yield and had: ir: 1715, 1597, 1484, 1317 and 1112 cm ; H-nmr:
(electrospray positive) calcd. for C H N O (M+H): 313.1184.
17 17
2 4
δ 8.20 (d, 2H, J = 6 Hz, Ar-H), 7.30-7.15 (m, 4H, Ar-H), 6.82 (d,
2H, J = 6 Hz, Ar-H), 4.90 (dd, 1H, J 4 and 1 Hz, 3-H), 4.70 (d, 1H,
J = 12 Hz, 1-H), 4.58 (d, 1H, J = 12 Hz, 1-H), 3.42 (dd, 1H, J = 10
and 1 Hz, 4-H), 3.35 (dd, 1H, J = 10 and 3 Hz, 4-H). Esterification
of this acid gave compound 14 as a yellow solid, mp 149 °C
(methanol) in 87 % yield. Compound 14 had: ir: 1743, 1601,
1488, 1347, 1200 and 1179 cm ; H-nmr: δ 8.18 (d, 2H, J = 7 Hz,
Ar-H), 7.30-7.15 (m, 4H, Ar-H), 6.80 (d, 2H, J = 7 Hz, Ar-H),
4.91 (dd, 1H, J = 4 and 1 Hz, 3-H), 4.73 (d, 1H, J = 12 Hz, 1-H),
Found: 313.1189.
Anal. Calcd. for C H N O : C, 65.4; H, 5.1; N, 9.0. Found:
C, 65.4; H, 4.6; N, 8.9.
17 16
2 4
3-Hydroxymethyl-2-(2-nitrophenyl)-1,2,3,4-tetrahydroisoquino-
line (12) and 3-Chloromethyl-2-(2-nitrophenyl)-1,2,3,4-tetrahy-
droisoquinoline (13).
-1 1
To a stirred mixture of ester 11 (0.50 g, 1.6 mmol) and
trimethoxyborane (0.02 mL, 0.16 mmol) in anhydrous ether (20
mL) at room temperature was added lithium borohydride (0.04 g,
1.8 mmol). The mixture was heated at reflux (4 hours) under an
atmosphere of nitrogen, allowed to cool to room temperature and
poured carefully into water and extracted with ether. The organic
layer was washed with water, dried (magnesium sulfate) and
evaporated giving compound 12 (0.30 g, 66 %) as an orange oil.
Compound 12 had ir: 3500-3200 (broad), 1603, 1512, 1345, and
4.60 (d, 1H, J = 12 Hz, 1-H), 3.59 (s, 3H, -CH ), 3.40 (dd, 1H, J =
3
12 and 1 Hz, 4-H) and 3.32 (dd, 1H, J = 10 and 3 Hz, 4-H).
Anal. Calcd. for C H N O : C, 65.4; H, 5.1; N, 9.0. Found:
17 16
2 4
C, 65.5; H, 5.0; N, 8.9.
3-Hydroxymethyl-2-(4-nitrophenyl)-1,2,3,4-tetrahydroisoquino-
line (15) and 3-(4-Methylbenzenesulfonyloxymethyl)-2-(4-nitro-
phenyl)-1,2,3,4-tetrahydroisoquinoline (16).
-1 1
1045 cm ; H-nmr: δ 7.82 (d, 1H, J = 7 Hz, Ar-H), 7.40 (t, 1H, J
Using a similar method to that described above, reduction of
= 7 Hz, Ar-H), 7.22-6.95 (m, 6H, Ar-H), 4.58 (d, 1H, J = 16 Hz,
1-H), 4.12 (1H, m), 3.85-3.55 (m, 3H), 3.28 (dd, 1H, J = 12 and 6
Hz) and 2.78 (dd, 1H, J = 16 and 2 Hz). To a cooled (0 °C),
stirred, mixture of compound 12 (0.50 g, 1.8 mmol) and triethy-
lamine (0.62 mL, 4.4 mmol) in dichloromethane (25 mL) was
added 4-toluenesulfonyl chloride (0.42 g, 2.2 mmol). The mix-
ture was then heated at reflux (2 hours), allowed to cool to room
temperature and poured into an excess of dilute hydrochloric
acid. The organic layer was separated and the aqueous layer was
extracted with dichloromethane (20 mL). The combined organic
fractions were washed with water, dried (magnesium sulfate) and
evaporated giving a brown oil (0.67 g). The oil was purified by
column chromatography over silica gel (eluent: petroleum ether
bp 60-80 °C: ethyl acetate, 20:1) giving the chloride 13 (0.18 g,
34 %) as a yellow solid, mp 100-103 °C. Compound 13 had ir:
ester 14 gave compound 15 (74 %) as a yellow oil. Compound 15
-1
1
had ir: 3500-3200 (broad), 1596, 1486, 1314 and 1112 cm ; H-
nmr: δ 8.18 (d, 2H, J = 9 Hz, Ar-H), 7.29-7.20 (m, 4H, Ar-H),
6.92 (d, 2H, J = 9 Hz, Ar-H), 4.58 (d, 1H, J = 16 Hz, 1-H), 4.43
(d, 1H, J = 16 Hz, 1-H), 4.42 (m, 1H), 3.60 (m, 1H), 3.40 (m, 1H)
and 3.12 (m, 2H). Compound 15 was reacted with 4-toluenesul-
fonyl chloride in an analogous manner to compound 12 giving
the tosylate 16 (42 %) as an orange solid, mp 160-162 °C after
column chromatography over silica gel (eluent: petroleum ether
bp 60-80 °C: ethyl acetate, 20:1). Compound 16 had ir: 1596,
-1 1
1502, 1324, 1173, 1096 and 975 cm ; H-nmr: δ 8.13 (d, 2H, J =
9 Hz, Ar-H), 7.65 (d, 2H, J = 9 Hz, Ar-H), 7.30-7.12 (m, 6H, Ar-
H), 6.79 (d, 2H, J = 9 Hz, Ar-H), 4.53 (m, 1H), 4.48 (d, 1H, J = 16
Hz, 1-H), 4.29 (d, 1H, J = 16 Hz, 1-H), 3.90 (m, 1H), 3.61 (m,
1H), 3.11 (m, 2H) and 2.42 (s, 3H, -CH ).
-1
1
3
1604, 1518, 1342, 1236, 1162 and 751 cm ; H-nmr: δ 7.81 (d,
1H, J = 9 Hz, Ar-H), 7.47 (t, 1H, J = 8 Hz, Ar-H), 7.25-7.00 (m,
6H, Ar-H), 4.58 (d, 1H, J = 16 Hz, 1-H), 4.10 (d, 1H, J = 16 Hz,
Anal. Calcd. for C
H N O S: C, 63.0; H, 5.0; N, 6.4.
23 22 2 5
Found: C, 63.1; H, 5.2; N, 6.4.
1-H), 3.92, (m, 1H, 3-H), 3.67 (m, 1H, -CH Cl), 3.46 (dd, 1H, J =
2
Acknowledgements.
6 and 2 Hz, -CH Cl), 3.44 (dd, 1H, J = 16 and 5 Hz, 4-H) and
2
We thank the EPSRC national mass spectrometry service cen-
tre, Swansea, UK for high resolution mass spectra.
2.90 (dd, 1H, J = 16 and 2 Hz, 4-H); ms: m/z (electron impact)
+
calcd. for C H N O Cl: 302.0822. Found: 302.0826 (M ).
16 15
2 2
Anal. Calcd. for C
H N O Cl: C, 63.5; H, 5.0; N, 9.3.
16 15 2 2
Found: C, 63.6; H, 4.7; N, 9.1.
REFERENCES AND NOTES
Compound 13 was also prepared as follows. A mixture of alco-
hol 12 (0.25g, 0.9 mmol, triphenylphosphine (0.30 g, 0.9 mmol)
and carbon tetrachloride (0.27 g, 1.7 mmol) in anhydrous
dichloromethane (10 mL) was heated under reflux (4 hours) with
stirring. The mixture was allowed to cool to room temperature and
poured into water. The organic layer was separated and the aque-
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[2] K. A. Hedley and S. P. Stanforth, J. Heterocyclic Chem., 32,
529 (1995).
[3] O. Meth-Cohn, Adv. Heterocyclic Chem., 65, 1 (1996).

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M. J. Donaghy and S. P. Stanforth
Vol. 42
[4] T. Kametani, Y. Fujimoto and M. Mizushima, J. Heterocyclic
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