Ring-opening reactions of N-aryl-1,2,3,4-tetrahydroisoquinolines: Synthesis of novel isoquino[2,1-a][3,1]benzoxazine derivatives

Article abstract of DOI:10.1016/S0040-4020(99)01015-7

The aldehydes 7e and 7h were prepared by treatment of the 1,2,3,4- tetrahydroisoquinolines 5e and 5h, respectively, with N-bromosuccinimide (NBS). Basic hydrolysis of compounds 7e and 7h gave the 4bH,6H-isoquino[2,1- a][3,1]benzoxazine derivatives 9 (R=H, OMe). Heterocycle 10 was obtained from the reaction of compound 5c with NBS and isolated as the ethyl derivative 11. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(99)01015-7

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 461–464
Ring-Opening Reactions of
N-Aryl-1,2,3,4-tetrahydroisoquinolines:
Synthesis of Novel Isoquino[2,1-a][3,1]benzoxazine Derivatives
Stephen P. Stanforth
School of Applied and Molecular Sciences, University of Northumbria at Newcastle, Newcastle upon Tyne, NE1 8ST, UK
Received 27 September 1999; revised 19 October 1999; accepted 11 November 1999
Abstract—The aldehydes 7e and 7h were prepared by treatment of the 1,2,3,4-tetrahydroisoquinolines 5e and 5h,, respectively, with
N-bromosuccinimide (NBS). Basic hydrolysis of compounds 7e and 7h gave the 4bH,6H-isoquino[2,1-a][3,1]benzoxazine derivatives 9
(RˆH, OMe). Heterocycle 10 was obtained from the reaction of compound 5c with NBS and isolated as the ethyl derivative 11. ᭧ 2000
Elsevier Science Ltd. All rights reserved.
Introduction
intermediate 6b, only the aldehyde 7b.1 The preference
for formation of this aldehyde 7b was attributed to
unfavourable steric interactions between the methyl group
and the hydroxy group in the aminal structure 8b. When
electron-deficient groups are located at the ortho position
of the N-4-nitroaryl ring, for example, in compounds 5
We have recently been interested in the N-bromosuccini-
mide (NBS) mediated oxidation of N-aryl-1,2,3,4-tetra-
hydroisoquinoline derivatives 1 in which the aryl group
was electron-deficient (nitroaryl, nitropyridyl, fluorinated
aryl, fluorinated pyridyl).1–4 After hydrolysis of the inter-
mediate iminium salts 2 the aldehydes 3 rather than their
tautomeric hemi-aminals 4 were normally isolated (Scheme
1). The preference for the formation of the aldehyde struc-
tures 3 was rationalised in terms of electronic, steric and
hydrogen bonding effects.
(RˆH, XˆNO2 and RˆH, XˆF4), the corresponding
1
aldehyde structures 7 are produced. In these cases, the
amine nitrogen atoms in structures 7 are not sufficiently
nucleophilic to allow cyclisation to the hemi-aminals to
occur. Additionally, in the former compound intramolecular
hydrogen bonding between the ortho nitro group and the
amine NH group favours the aldehyde structure.
The iminium salt 6a (Scheme 2) has been prepared5–7 on
several occasions from the reaction of 2-(2-bromoethyl)-
benzaldehyde and 2-nitroaniline. Hydrolysis of this
iminium salt 6a was reported to give only the hemi-aminal
8a.7 In view of this result we anticipated that hydrolysis of
iminium salt 6b would also give the hemi-aminal 8b
because the inductive effect of the methyl group would
render the amine nitrogen atom in aldehyde 7b more nucleo-
philic than in compound 7a. However, oxidation of
compound 5b with NBS gave, after hydroylsis of the
It is reasonable to assume that an equilibrium exists between
the tautomers 7 and 8 even though only one of the tautomers
may be evident by 1H NMR spectroscopy. In this paper we
report our studies on trapping some hemi-aminal tautomers
8 from the NBS mediated oxidation reactions of some N-4-
nitroaryl-tetrahydroisoquinolines 5 which would normally
be expected to yield aldehyde structures 7. These studies
have also enabled the synthesis of some novel 4bH,6H-
isoquino[2,1-a][3,1]benzoxazine derivatives (Scheme 2).
Scheme 1.
Keywords: tetrahydroisoquinolines; isoquino[2,1-a][3,1]benzoxazines; ring-opening.
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(99)01015-7

462
S. P. Stanforth / Tetrahedron 56 (2000) 461–464
Scheme 2. (a) RˆH, XˆH; (b) RˆH, XˆCH3; (c) RˆH, XˆCHO; (d) RˆH, XˆCH2OH; (e) RˆH, XˆCH2OAc; (f) RˆOMe, XˆCHO; (g) RˆOMe,
XˆCH2OH; (h) RˆOMe, XˆCH2OAc.
Oxidation Reactions
the O–CH–N proton, the diastereotopic methylene group
was observed as an AB system and the –CH2CH2– group
was seen as an ABCD system.
Compound 5c (95% yield) was prepared from 1,2,3,4-tetra-
hydroisoquinoline and 2-chloro-5-nitrobenzaldehyde. Reduc-
tion of compound 5c with NaBH4 yielded the hydroxy-
methyl derivative 5d which was readily acylated with
acetic anhydride in the presence of triethylamine giving
compound 5e (73%). Similarly, compound 5f (52%)
was prepared from 6,7-dimethoxy-1,2,3,4-tetrahydro-
isoquinoline hydrochloride and 2-chloro-5-nitrobenzal-
dehyde. Reduction of compound 5f with NaBH4 gave
compound 5g which was acylated as described above
affording compound 5h (81%).
In an analogous series of reactions, compound 5h and
NBS gave the aldehyde 7h in excellent yield as expected.
Treatment of this aldehyde 7h with ethanolic potassium
hydroxide solution gave the 4bH,6H-isoquino[2,1-a]-
[3,1]benzoxazine derivative 9 (RˆOMe) in 71% yield via
1
the intermediates 7g and 8g. The H NMR spectrum of
compound 9 (RˆOMe) was similar to that of compound 9
(RˆH) exhibiting a singlet (d 5.65) for the O–CH–N
proton, an AB system for the methylene group and an
ABCD system for the –CH2CH2– group.
We anticipated that the reaction between compound 5e and
NBS would yield the aldehyde 7e by comparison with the
results described above for oxidation of methyl-substituted
compound 5b. When compound 5e was treated with NBS
the aldehyde 7e (77%) was obtained in accordance with
expectations. Deacylation of this compound by boiling
with ethanolic potassium hydroxide solution afforded the
novel 4bH,6H-isoquino[2,1-a][3,1]benzoxazine derivative
9 (RˆH) directly in excellent yield. The formation of
heterocycle 9 (RˆH) occurs via the aldehyde 7d and
hemi-aminal 8d intermediates, neither of which could be
isolated. The hydroxy group of the hemi-aminal inter-
mediate 7d is rapidly displaced by the ortho hydroxymethyl
We have also investigated the oxidation of compound 5c
using NBS. As noted above, the oxidation of systems 5 in
which the X group is electron deficient gave aldehyde struc-
tures and it was therefore of interest to establish whether the
dialdehyde 7c could be prepared. Treatment of heterocycle
5c with NBS did not give the dialdehyde 7c but instead the
4bH,6H-isoquino[2,1-a][3,1]benzoxazine derivative 11 was
obtained in good yield (71%) essentially as one diastereo-
isomer after crystallisation from ethanol. The relative
stereochemistry of the asymmetric centres has not been
established. Evidently, the hydroxy group of the hemi-
aminal tautomer 8c reacts as a nucleophile at the ortho
aldehyde group giving the intermediate 10 which is subse-
quently converted to the ethoxy derivative 11 when treated
1
group giving the product 9 (RˆH). The H NMR spectrum
of compound 9 (RˆH) was consistent with its proposed
structure, in particular a singlet (d 5.65) was attributed to
1
with ethanol in the crystallisation process. The H NMR

S. P. Stanforth / Tetrahedron 56 (2000) 461–464
463
spectrum of compound 11 showed two singlets (d 5.82 and
5.68) which were attributed to the O–CH–O and O–CH–N
protons as well as the familiar ABCD system for the
–CH2CH2– moiety.
Recrystallisation from ethanol gave yellow needles, mp
95–96ЊC. [Found: C, 66.05; H, 5.3; N, 8.35. C18H18N2O4
requires C, 66.2; H, 5.6; N, 8.6%], nmax 1736, 1519, 1341,
1243 and 1224 cmϪ1, d 8.30 (1H, d, Jˆ3 Hz, ArH), 8.15
(1H, dd, Jˆ9 and 3 Hz, ArH), 7.30–7.00 (5H, m, ArH), 5.22
(2H, s, ϾCH2), 4.29 (2H, s, ϾCH2), 3.38 (2H, t, Jˆ6 Hz,
–CH2CH2–), 3.05 (2H, t, Jˆ6 Hz, –CH2CH2–) and 2.18
(3H, s, –CH3).
These studies have successfully produced the novel
4bH,6H-isoquino[2,1-a][3,1]benzoxazine derivatives
9
(RˆH, OMe) and 11 by intramolecular trapping of
hemi-aminal intermediates. The hemi-aminal hydroxy
group can behave either as a leaving group giving hetero-
cycles 9 (RˆH, OMe) or as a nucleophile giving compound
11.
2-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl)-5-
nitrobenzaldehyde 5f. In a similar manner to that described
above for compound 5c, 6,7-dimethoxy-1,2,3,4-tetrahydro-
isoquinoline hydrochloride (2.45 g, 10.7 mmol), 2-chloro-
5-nitrobenzaldehyde (2.1 g, 11.3 mmol) and K2CO3 (3.5 g,
25.4 mmol) in DMSO (15 mL) gave compound 5f (1.9 g,
52%) as a yellow solid after trituration with ethanol.
Recrystallisation from methanol/DCM gave fluffy yellow
needles, mp 178ЊC. [Found: C, 63.4; H, 5.2; N, 8.15.
C18H18N2O5 requires C, 63.1; H, 5.3; N, 8.2%], nmax 1675,
1601, 1520, 1324 and 1262 cmϪ1, d 10.09 (1H, s, –CHO),
8.69 (1H, d, Jˆ3 Hz, ArH), 8.28 (1H, dd, Jˆ9 and 3 Hz,
ArH), 7.13 (1H, d, Jˆ9 Hz, ArH), 6.68 (1H, s, ArH), 6.60
(1H, s, ArH), 4.46 (2H, s, ϾCH2), 3.88 (3H, s, –OCH3), 3.87
(3H, s, –OCH3), 3.69 (2H, t, Jˆ6 Hz, –CH2CH2–) and 3.02
(2H, t, Jˆ6 Hz, –CH2CH2–).
Experimental
1H NMR spectra were recorded at either 90 or 270 MHz in
CDCl3 solution. Infra red spectra were determined as KBr
discs.
2-(1,2,3,4-Tetrahydroisoquinol-2-yl)-5-nitrobenzalde-
hyde 5c. To a stirred mixture of 1,2,3,4-tetrahydroisoquino-
line (1.3 g, 9.8 mmol) and K2CO3 (2.0 g, 14.5 mmol) in
dimethylsulfoxide (DMSO) (10 mL) at room temperature
was added 2-chloro-5-nitrobenzaldehyde (1.7 g, 9.2 mmol)
in portions over 1 min. The mixture became dark in colour
and was then heated at 70–75ЊC (oil-bath temperature) for
2 h. The reaction mixture was allowed to cool to room
temperature, poured into water, and extracted with dichloro-
methane (DCM). The combined organic extracts were
washed with water, dried (MgSO4) and evaporated giving
compound 5c (2.62 g, 95%) as a yellow oil which solidified
upon standing. Compound 5c was recrystallised from DCM/
ethanol giving yellow crystals, mp 115–117ЊC. [Found: C,
68.0; H, 4.85; N, 10.15. C16H14N2O3 requires C, 68.1; H,
5.0; N, 9.9%], nmax1686, 1598 and 1318 cmϪ1, d 10.10 (1H,
s, –CHO), 8.63 (1H, d, Jˆ3 Hz, ArH), 8.30 (1H, dd, Jˆ9
and 3 Hz, ArH), 7.30–7.00 (5H, m, ArH), 4.55 (2H, s,
ϾCH2), 3.72 (2H, t, Jˆ6 Hz, –CH2CH2–) and 3.15 (2H, t,
Jˆ6 Hz, –CH2CH2–).
2-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl)-5-
nitrobenzyl acetate 5h. In a similar manner to that
described above for the preparation of compound 5e,
compound 5f (0.70 g, 2.1 mmol) and NaBH4 (0.1 g,
2.6 mmol) gave 2-(6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinol-2-yl)-5-nitrobenzyl alcohol 5g (0.68 g) as a yellow
foam, d 8.30 (1H, d, Jˆ3 Hz, ArH), 8.10 (1H, dd, Jˆ9 and
3 Hz, ArH), 7.20 (1H, d, Jˆ9 Hz, ArH), 6.65 (1H, s, ArH),
6.60 (1H, s, ArH), 5.30 (2H, s, ϾCH2), 4.80 (1H, s, –OH),
4.20 (2H, s, ϾCH2), 3.85 (6H, s, 2× –OCH3), 3.40 (2H, t,
Jˆ6 Hz, –CH2CH2–) and 3.00 (2H, t, Jˆ6 Hz, –CH2CH2–).
Compound 5g (0.62 g), acetic anhydride (0.30 mL) and
triethylamine (0.20 mL) in DCM (5 mL) then gave
compound 5h (0.64 g, 81%) as a yellow solid, mp 162–
163ЊC (from ethanol). [Found: C, 62.25; H, 5.45; N, 7.2.
C20H22N2O6 requires C, 62.2; H, 5.75; N, 7.25%], nmax
1736, 1617, 1522, and 1240 cmϪ1, d 8.30 (1H, d, Jˆ3 Hz,
ArH), 8.15 (1H, dd, Jˆ9 and 3 Hz, ArH), 7.15 (1H, d,
Jˆ9 Hz, ArH), 6.66 (1H, s, ArH), 6.59 (1H, s, ArH), 5.24
(2H, s, ϾCH2), 4.23 (2H, s, ϾCH2), 3.88 (6H, s, 2×
–OCH3), 3.36 (2H, t, Jˆ6 Hz, –CH2CH2–), 2.92 (2H, t,
Jˆ6 Hz, –CH2CH2–) and 2.18 (3H, s, –CH3).
2-(1,2,3,4-Tetrahydroisoquinol-2-yl)-5-nitrobenzyl acetate
5e. To a suspension of compound 5c (0.56 g, 2.0 mmol) in
methanol (10 mL) at room temperature was added NaBH4
(0.10 g, 2.6 mmol). The mixture was heated at reflux for 1 h,
allowed to cool to room temperature, evaporated and water
was added to the residue. The mixture was extracted with
DCM, the combined organic extracts were washed with
water, dried (MgSO4) and evaporated giving 2-(1,2,3,4-
tetrahydroisoquino-2-yl)-5-nitrobenzyl alcohol 5d (0.54 g)
as a yellow oil, d 8.31 (1H, d, Jˆ3 Hz, ArH), 8.12 (1H, dd,
Jˆ9 and 3 Hz, ArH), 7.30–7.00 (5H, m, ArH), 5.30 (1H, s,
–OH), 4.81 (2H, s, ϾCH2), 4.28 (2H, s, ϾCH2), 3.40 (2H,
t, Jˆ6 Hz, –CH2CH2–) and 3.05 (2H, t, Jˆ6 Hz,
–CH2CH2–). Compound 5d was dissolved in DCM
(5 mL) and triethylamine (0.2 mL) and then acetic anhy-
dride (0.2 mL) was added. The reaction mixture was
allowed to stand (1.5 h) and then a further portion
(0.05 mL) of acetic anhydride was added. After standing
(1.5 h), the mixture was washed with dilute hydrochloric
acid, water and dried (MgSO4). The solvent was evaporated
giving compound 5e (0.47 g, 73%) as a yellow oil which
was triturated with ethanol affording a bright yellow solid.
2-[2-(2-Formylphenyl)ethylamino)]-5-nitrobenzyl acetate
7e. To a solution of compound 5e (1.60 g, 4.9 mmol) in
DCM (20 mL) at room temperature was added NBS
(0.9 g, 5.1 mmol) portionwise over 2 min with swirling.
The mixture was heated at reflux (10 min), allowed to
cool to room temperature, washed with dilute sodium
hydroxide solution and then water and dried (MgSO4).
The solvent was evaporated giving a yellow oil (1.66 g)
which was triturated with ethanol giving compound 7e
(1.30 g, 77%) as a bright yellow solid, mp 103ЊC (from
ethanol). [Found: C, 62.8; H, 5.4; N, 8.15. C18H18N2O5
requires C, 63.1; H, 5.3; N, 8.2%], nmax 3425, 1743, 1695,
1592 and 1299 cmϪ1, d 10.11 (1H, s, –CHO), 8.20–7.20
(6H, m, ArH), 6.68 (1H, d, Jˆ10 Hz, ArH), 5.64 (1H, broad

464
S. P. Stanforth / Tetrahedron 56 (2000) 461–464
s, ϾNH), 5.00 (2H, s, ϾCH2), 3.50 (4H, m, –CH2CH2–) and
2.09 (3H, s, –CH3).
1091 cmϪ1, d 8.14 (1H, dd, Jˆ9 and 3 Hz, ArH), 7.88
(1H, d, Jˆ2 Hz, ArH), 7.02 (1H, s, ArH), 6.90 (1H, d,
Jˆ9 Hz, ArH), 6.68 (1H, s, ArH), 5.65 (1H, s, ϾCH–),
5.08 (AB system, dA 5.19 dB 4.98, JABˆ14 Hz, ϾCH2),
3.90 (3H, s, –OCH3), 3.88 (3H, s, –OCH3), 3.84–3.50
[2H, m (AB part of ABCD system), –CH2CH2–] and
2-[2-(4,5-Dimethoxy-2-formylphenyl)ethylamino)]-5-
nitrobenzyl acetate 7h. In a similar manner to that
described above for compound 7e, compound 5h (0.19 g,
0.049 mmol) and NBS (0.09 g, 0.051 mmol) gave
compound 7h (0.20 g, 100%) as feathery yellow needles,
mp 191ЊC (from ethanol). [Found: C, 59.9; H, 5.35; N,
6.9. C20H22N2O7 requires, C, 59.7, H, 5.5, N, 7.0%], nmax
3317, 1736, 1676, 1590, 1516, 1331, 1304, 1272, 1237 and
1107 cmϪ1, d 10.05 (1H, s, –CHO), 8.15 (2H, m, ArH), 7.31
(1H, s, ArH), 6.78 (1H, s, ArH), 7.65 (1H, d, Jˆ9 Hz, ArH),
5.70 (1H, broad t, Jˆ5 Hz, ϾNH), 5.00 (2H, s, ϾCH2), 3.95
(6H, s, 2×–OCH3), 3.56 (2H, m, –CH2CH2–), 3.38 (2H, t,
Jˆ6 Hz, –CH2CH2–) and 2.03 (3H, s, –OCOCH3).
3.20–2.00 [2H,
m
(CD part of ABCD system),
–CH2CH2–].
6-Ethoxy-8-nitro-12H,13H-dihydro-4bH,6H-isoquino-
[2,1-a][3,1]benzoxazine 11. To a solution of compound 5c
(1.4 g, 4.97 mmol) in DCM at room temperature was added
NBS (1.0 g, 5.62 mmol) portionwise over a few minutes
with swirling. The mixture became warm and an orange
colour developed. The mixture was heated at reflux for
1.25 h, allowed to cool to room temperature, washed with
dilute sodium hydroxide solution and then water, and dried
(MgSO4). The solvent was evaporated giving a yellow foam
(1.5 g) to which ethanol was added. After standing over the
weekend, compound 11 (1.15 g, 71%), a yellow solid, was
collected. A small sample was recrystallised from ethanol
giving yellow needles, mp 182ЊC. [Found: C, 66.3; H, 5.5;
N, 8.6. C18H18N2O4 requires: C, 66.2; H, 5.7; N, 8.6%], nmax
1586, 1609, 1496, 1405, 1319 and 1096 cmϪ1, d 8.17 (2H,
m, ArH), 7.50 (1H, m, ArH), 7.36 (2H, m, ArH), 7.24 (1H,
m, ArH), 6.97 (1H, d, Jˆ9 Hz, ArH), 5.82 (1H, s, ϾCH–),
5.68 (1H, s, ϾCH–), 4.20 (1H, m, –CH2CH3), 3.85 (1H, m,
–OCH2CH3), 3.82–3.60 [2H, m (AB part of ABCD system),
–CH2CH2–], 3.08 [2H, m, (CD part of ABCD system),
–CH2CH2–] and 1.42 (3H, t, Jˆ7 Hz, –CH3).
8-Nitro-12H,13H-dihydro-4bH,6H-isoquino[2,1-a][3,1]-
benzoxazine 9 (RˆH). A mixture of compound 7e (0.15 g,
0.44 mmol), potassium hydroxide (0.05 g, 0.89 mmol) and
ethanol (3 mL) was heated at reflux for 0.5 h. The mixture
was then allowed to cool to room temperature and the
solvent was evaporated. Dilute hydrochloric acid and
DCM was added to the residue and the organic layer was
separated, washed with water, dried (MgSO4) and evapo-
rated giving compound 9 (RˆH) (0.15 g, 100%) as small
yellow needles, mp 179–180ЊC (from ethanol). [Found: C,
67.9; H, 4.7; N, 9.85. C16H14N2O3 requires C, 68.1, H, 5.0,
N, 9.9%], nmax 1608, 1511, 1488, 1311, 1265, 1202 and
1092 cmϪ1, d 8.13 (1H, dd, Jˆ9 and 3 Hz, ArH), 7.89
(1H, d, Jˆ2 Hz, ArH), 7.56 (1H, m, ArH), 7.35–7.20 (3H,
m, ArH), 6.86 (1H, d, Jˆ9 Hz, ArH), (5.75 1H, s, ϾCH–),
5.10 (AB system, dA 5.18 dB 5.02, JABˆ14 Hz, ϾCH2),
References
3.82–3.56 [2H,
m
(AB part of ABCD system),
–CH2CH2–] and 3.18–2.90 [2H, m (CD part of ABCD
system), –CH2CH2–].
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compound 7h (0.10 g, 0.25 mmol), potassium hydroxide
(0.10 g, 1.79 mmol) and ethanol (10 mL) gave compound
9 (RˆOMe) (0.06 g, 71%) as yellow/orange needles, mp
195–197ЊC. [Found: C, 63.0; H, 5.05; N, 8.15.
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