Synthesis of some N-methyl-1,2,3,4-tetrahydroisoquinolines by Friedel-Crafts cyclisation using benzotriazole auxiliary

Article abstract of DOI:10.1039/a807543c

1-Hydroxymethylbenzotriazole reacts with phenylethylamines to give the respective N,N-bis(benzotriazol-1-ylmethyl)phenylethylamines, which are then subject to an intramolecular Friedel-Crafts cyclisation at room temperature to yield N-benzotriazol-1-ylmet

Full text of DOI:10.1039/a807543c

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Synthesis of some N-methyl-1,2,3,4-tetrahydroisoquinolines
by Friedel–Crafts cyclisation using benzotriazole auxiliary
Cornelia Locher and Naseem Peerzada
Faculty of Science, Northern Territory University, Darwin N.T. 0909, Australia
Received (in Cambridge) 28th September 1998, Accepted 18th November 1998
1-Hydroxymethylbenzotriazole reacts with phenylethylamines to give the respective N,N-bis(benzotriazol-1-
ylmethyl)phenylethylamines, which are then subject to an intramolecular Friedel–Crafts cyclisation at room
temperature to yield N-benzotriazol-1-ylmethyl-1,2,3,4-tetrahydroisoquinolines. These crystalline UV- and oxygen-
stable products can be reduced at room temperature to the corresponding N-methyl-1,2,3,4-tetrahydroisoquinolines
using NaBH4. The method offers an elegant approach to a wide range of N-methylated 1,2,3,4-tetrahydroisoquin-
olines since it can be applied not only for the synthesis of 1,2,3,4-tetrahydroisoquinolines with electron-donating
substituents on the aromatic moiety, but also for deactivated derivatives. All steps involved work under very mild
conditions in high to excellent yields.
ing group,21–23 to establish a new synthesis routine for a wide
Introduction
range of N-substituted 1,2,3,4-tetrahydroisoquinolines. The
Isoquinoline alkaloids represent one of the largest groups of
method can be applied to the preparation of derivatives with
alkaloids and have attracted a great deal of interest over the
electron-donating groups but also to the synthesis of deacti-
decades due to their potent biological activities.1–3 In recent
vated 1,2,3,4-tetrahydroisoquinolines producing high to excel-
years, research has often focused on the role of endogenously
lent yields under very mild synthesis conditions. Furthermore,
derived tetrahydroisoquinolines in peripheral and central
the crystalline intermediate products of the reaction are very
mechanisms and their possible therapeutic applications.4–6 In
this context various structures are discussed including the
1,2,3,4-tetrahydroisoquinolines of general type 1 as inhibitors
stable derivatives which can easily be transformed on a need
basis into various, often UV- and oxygen-sensitive, N-sub-
stituted 1,2,3,4-tetrahydroisoquinolines, hence providing ideal
storage intermediates.
The synthesis (Scheme 1) first involves the reaction of
R5
R4
R6
R7
R3
R2
R3
R3
N
R2
R2
R1
N
N
EtOH
60 °C
R8
R1
+
N
NH2
N
Bt
1
R1
R1, R3, R4 = H or C1–C2 alkyl group
CH2OH
Bt
R
2 = H or CH3 group
2
3
4
R5–R8 = H or electron-withdrawing groups
N
N
N
AlCl3
25 °C
of the enzyme phenylethanolamine N-methyltransferase.7,8 The
Bischler–Napieralski,9–11 Pictet–Spengler12,13 and Pomeranz–
Fritsch14,15 reactions as well as the Bobbitt variation14 of the
latter are well-known, generally suitable methods for the syn-
thesis of 1,2,3,4-tetrahydroisoquinolines in vitro. These
methods are, however, often restricted to tetrahydroisoquin-
olines with electron-donating substituents on the aromatic
part of the structure or produce poor yields when applied to the
synthesis of isoquinolines with electron-withdrawing
groups.16–19 An interesting approach, suitable for the synthesis
of deactivated 1,2,3,4-tetrahydroisoquinolines, was introduced
by Deady and co-workers20 but imposed difficulties, as claimed
by Mendelson et al.,7 in regard to its reproducibility. A more
recent method by Stokker17 is exclusively applicable to 1,2,3,4-
tetrahydroisoquinolines with electron-withdrawing substitu-
ents, but it produces only moderate yields for unsubstituted
1,2,3,4-tetrahydroisoquinoline and fails completely for acti-
vated derivatives. There continues to be a lack of general
methods for the synthesis of a wide range of 1,2,3,4-tetra-
hydroisoquinolines independent from the nature of their sub-
stituents on the aromatic moiety of the structure.
Bt
=
CHCl3
R3
R3
R2
R1
R2
R1
NaBH4
MeOH
25 °C
N
Bt
N
CH3
5
6
R1
R2
R3
a
H
Cl
H
Cl
H
H
H
H
H
H
H
Cl
Cl
H
b
c
d
e
f
OCH3
OCH3 OCH3
H
Scheme 1
1-hydroxymethylbenzotriazole 2 with a phenylethylamine 3 to
give the respective N,N-bis(benzotriazol-1-ylmethyl)phenyl-
ethylamine 4. The crystalline product is the precursor for the
subsequent Friedel–Crafts ring closure to the corresponding
N-benzotriazol-1-ylmethyl-1,2,3,4-tetrahydroisoquinoline 5 by
removal of one benzotriazolyl moiety using a Lewis acid
This paper reports the use of benzotriazole, a very versatile
synthetic auxiliary in heterocyclic chemistry and excellent leav-
J. Chem. Soc., Perkin Trans. 1, 1999, 179–184
179

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Table 1 N,N-Bis(benzotriazol-1-ylmethyl)phenylethylamines 4
Found (Required) (%)
Compound
(Formula)
Mp/ЊC
(EtOH)
R1
R2
R3
Yield (%)
C
H
N
δ (Bt-CH2-N)
4aa (C22H21N7)
4b (C22H20N7Cl)
4c (C22H20N7Cl)
4d (C22H19N7Cl2)
4e (C23H23N7O)
4f (C24H25N7O2)
H
Cl
H
Cl
OCH3
OCH3
H
H
H
H
H
OCH3
H
H
Cl
Cl
H
H
92
92
80
88
95
76
123–124
149–150
116–118
125–126
97–99
68.8 (68.9)
63.0 (63.2)
63.2 (63.2)
58.7 (58.4)
67.2 (66.8)
64.2 (65.0)
5.6 (5.5)
4.9 (4.8)
4.9 (4.8)
4.5 (4.2)
5.9 (5.6)
5.7 (5.7)
25.5 (25.6)
23.4 (23.5)
23.1 (23.5)
21.9 (21.7)
23.9 (23.7)
22.1 (22.1)
5.62 (s, 4H)
5.62 (s, 4H)
5.68 (s, 4H)
5.68 (s, 4H)
5.62 (s, 4H)
5.64 (s, 4H)
91–93
a Lit.,25 mp 122–124 ЊC, δ (N-CH2-N) 5.71 (s).
Table 2 N-Benzotriazol-1-ylmethyl-1,2,3,4-tetrahydroisoquinolines 5 by intramolecular cyclisation with AlCl3
Found (Required) (%)
Compound
(Formula)
Yield
(%)
Mp/ЊC
(EtOH)
R1
R2
R3
t/h
C
H
N
δ [Bt-CH2-N]
δ [Ar-CH2-N]
5a (C16H16N4)
H
Cl
H
Cl
H
H
H
H
H
H
H
Cl
Cl
H
H
4
87
88
155–157
146–148
144–145a
72.6 (72.7)
64.2 (64.3)
64.1 (64.3)
6.2 (6.1) 21.2 (21.2)
5.1 (5.1) 18.4 (18.8)
5.1 (5.1) 18.6 (18.8)
5.64 (s, 2H)
5.62 (s, 2H)
5.61 (s, 2H)
3.86 (s, 2H)
3.80 (s, 2H)
3.81 (s, 2H)
5b (C16H15N4Cl)
5c (C16H15N4Cl)
5d (C16H14N4Cl2)
5e (C17H18N4O)
5f (C18H20N4O2)
8
68
140
4
14
NRb
83
OCH3
OCH3 OCH3
128–130
137–140
69.2 (69.4)
66.6 (66.7)
6.1 (6.2) 18.9 (19.0)
6.3 (6.2) 16.9 (17.3)
5.62 (s, 2H)
5.63 (s, 2H)
3.82 (s, 2H)
3.77–3.84
(m, 8H)c
4
94
a Repeated recrystallisation from EtOH and EtOAc. b No reaction. c Signal overlaps with those from OCH3.
nium ion (Scheme 2) reacted intramolecularly with the aro-
matic ring, with the rate of this electrophilic cyclisation being
influenced by the number and nature of the substituents on the
benzene ring. The intramolecular ring-closure, however, not
only produced very high yields with activated (4e,f) or unsubsti-
tuted (4a) structures, but was also applicable to phenylethyl-
amines with electron-withdrawing substituents (4b,c) on the
aromatic ring (Table 2).
R3
R3
AlCl3
–Bt–
R2
R1
R2
R1
25 °C
+
N
Bt
N
Bt
Bt
4
R3
The only reaction showing somewhat different behaviour was
the ring closure of N,N-bis(benzotriazol-1-ylmethyl)-2-chloro-
phenylethylamine 4c. When reacted for 4–8 h at room temper-
ature, the characteristic peak at δ 3.81 for Ar-CH2-N, indicating
a successful ring closure, could be detected in the crude product
R2
R1
N
Bt
5
1
by H NMR analysis; the reaction, however, was found to be
Scheme 2
incomplete and required a substantially longer reaction time.
After work-up the synthesis yielded a viscous yellow oil which
crystallised slowly. It afforded only low quantities of 5c after
repeated recrystallisation with EtOH–EtOAc.
A more successful approach to the cyclisation of 4c appears
to be the use of conc. H2SO4, a method already employed for
the synthesis of 1-aryl-1,4-dihydroisoquinolin-3(2H)-ones.26
Compound 4c was added to conc. H2SO4 at 0 ЊC with stirring.
The mixture was slowly brought to room temperature, basified
and extracted with CH2Cl2. The solution yielded an oily residue
which slowly crystallised (yield 71%) to 5c.
whereby the reaction proceeds via an iminium ion (Scheme 2).
Replacement of the second benzotriazolyl group leads to a wide
range of N-substituted 1,2,3,4-tetrahydroisoquinolines, in this
case N-methyl-1,2,3,4-tetrahydroisoquinolines 6.
Results and discussion
Reaction of 1-hydroxymethylbenzotriazole with phenylethyl-
amines
1-Hydroxymethylbenzotriazole 2 was produced following its
established literature synthesis by reaction of benzotriazole
and formaldehyde which was shown to yield the 1-substituted
isomer.24 Various phenylethylamines 3a–f were reacted with
1-hydroxymethylbenzotriazole 2 with the ratio of starting
material being 1:2,25 yielding good to excellent quantities
of N,N-bis(benzotriazol-1-ylmethyl)phenylethylamines 4a–f
(Table 1).
The ring closure of N,N-bis(benzotriazol-1-ylmethyl)-2,4-
dichlorophenylethylamine 4d, however, failed with both
methods and starting material was recovered even if the reac-
tion times were substantially increased. Deactivation of the
aromatic ring by the electron-withdrawing chloro substituents
reduced the electron availability on it for the required electro-
philic cyclisation to occur.
N-Methylation of N-benzotriazol-1-ylmethyl-1,2,3,4-tetrahydro-
isoquinolines
Cyclisation of N,N-bis(benzotriazol-1-ylmethyl)phenylethyl-
amines
The crystalline, UV- and oxygen-stable products 5 can easily
be converted into a wide range of N-substituted-1,2,3,4-tetra-
hydroisoquinolines by replacing the remaining benzotriazolyl
moiety with a variety of nucleophiles. Benzotriazole has been
demonstrated to be easily replaced by different alkyl substitu-
ents, using Grignard reagents or organozinc compounds,27–29
which leads to various N-alkylated compounds. Employing
When the intermediate precursors N,N-bis(benzotriazol-1-
ylmethyl)phenylethylamines 4a–f were treated with excess of
anhydrous AlCl3 in a molar ratio of 1:4 in CHCl3 at room
temperature, one benzotriazolyl moiety was eliminated from
the molecule, yielding N-benzotriazol-1-ylmethyl-1,2,3,4-tetra-
hydroisoquinolines 5a–f. During the reaction the resultant imi-
180
J. Chem. Soc., Perkin Trans. 1, 1999, 179–184

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Table 3 N-Methyl-1,2,3,4-tetrahydroisoquinolines 6
Compound
(Formula)
Yield
(%)
Mp/ЊC
(EtOH)
Mp (picrate)/
ЊC (EtOH)
R1
R2
R3
δ [N-CH3]
6a (C10H13N)
H
Cl
H
OCH3
OCH3
H
H
H
H
H
H
Cl
H
H
70
60
55
95
67
liquid
liquid
liquid
liquid
74–75c
150–153a
167–169
176–178
140–142b
154–156d
2.44 (s, 3H)
2.44 (s, 3H)
2.43 (s, 3H)
2.42 (s, 3H)
2.43 (s, 3H)
6b (C10H12NCl)
6c (C10H12NCl)
6e (C11H15NO)
6f (C12H17NO2)
OCH3
a Lit.,36 148–150 ЊC. b Lit.,37 142–143 ЊC. c Lit.,33 69–70 and 82 ЊC (hemihydrate). d Lit.,33 160 ЊC.
alcohols or thiols yields the respective N-alkoxymethyl deriv-
atives and their thio analogues under very mild conditions.30
The benzotriazolyl moiety can also easily be reduced with
NaBH4,29,31 in this case yielding the respective N-methylated
derivatives.
presented in this paper offers a new approach to a wide range of
N-alkylated 1,2,3,4-tetrahydroisoquinolines. Under very mild
synthesis conditions it is possible to produce not only activated
or unsubstituted 1,2,3,4-tetrahydroisoquinolines which are also
easily accessible by more traditional routines, but 1,2,3,4-
tetrahydroisoquinolines with electronegative substituents on
the aromatic moiety for which only a limited number of syn-
theses have been reported. As demonstrated, the intermediates
of the reaction are ideal storage forms for various N-methylated
tetrahydroisoquinolines, but the very nature of benzotri-
azole as auxiliary undoubtedly also allows the transformation
of these intermediates into a wide range of other N-substituted
1,2,3,4-tetrahydroisoquinolines.
The latter conversion has been used to synthesise various
N-methyl-1,2,3,4-tetrahydroisoquinolines 6. The respective
N-benzotriazol-1-ylmethyl-1,2,3,4-tetrahydroisoquinolines 5a–
f were reduced with NaBH4 at room temperature. After work-
up the corresponding N-methyl-1,2,3,4-tetrahydroisoquinolines
6a–f were obtained in generally good yields (Table 3). The pur-
ity of the products was analysed by GC/MS and in all cases a
single peak was observed. The yield of the conversion of com-
pound 5e into 7-methoxy-N-methyl-1,2,3,4-tetrahydroisoquin-
oline 6e, although not optimised, is comparable with the trad-
itional synthesis by Mirza from 7-methoxy-1,2,3,4-tetra-
hydroisoquinoline methiodide.32 The procedure has been
applied to the synthesis of the natural occurring 6,7-dimethoxy-
N-methyl-1,2,3,4-tetrahydroisoquinoline (N-methylheliamine)
6f, found in Pachycereus weberi, Thalictrum dioicum, T. polyg-
amum, Backebergia militaris, Nelumbo nucifera, Pilosocereus
guerreronis and Papaver bracteatum.33 Theoretically two iso-
mers, the 6,7-dimethoxy- 5f as well as the 7,8-dimethoxy-
substitued isomer 5fЈ, could be expected from the cyclisation of
N,N-bis(benzotriazol-1-ylmethyl)-3,4-dimethoxyphenylethyl-
amine 4f. The preferred isomer was isolated in high yield and,
Experimental
General
All reagents used were AR grade. Melting points were deter-
mined on a Gallenkamp Melting Point Apparatus and are
uncorrected. FTIR spectra were taken on a Mattson Polaris
FTIR-Spectrophotometer in Nujol and UV/VIS data on a
Varian DMS 200 UV Visible Spectrophotometer, using ethanol
as solvent. 1H and 13C NMR spectra were recorded with a
Varian Gemini 200 (200 MHz) in deuteriochloroform (CDCl3)
1
with tetramethylsilane (TMS) as internal reference. H NMR
chemical shifts (δ) are reported in parts per million (ppm,
δTMS = 0.00) and 13C NMR results (in ppm) are referenced to
CDCl3 (δ 77.0 for centerline). Coupling patterns are indicated
as s (singlet), d (doublet), q (quartet) and m (multiplet). GC/MS
spectra were obtained on a Varian Star 3400 CX spectrometer
with a SGE 30QC2.5/BPX1.0 column. Elemental analyses were
performed in the Research School of Chemistry, Australian
National University, Canberra, Australia.
1
after reduction with NaBH4, H NMR analysis presented two
singlets at δ 6.59 and 6.50 for the aromatic protons, confirming
6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline 6f as
the product. After reduction of the crude cyclised intermediate,
GC/MS analysis of the crude product detected two compounds,
6f and 6fЈ, with the same molecular weight (m/z 207) in a ratio
of approximately 8:1 (Scheme 3). This demonstrated the high
H3CO
1. AlCl3
2. NaBH4
H3CO
General procedure for compounds 4a–f: N,N-bis(benzotriazol-1-
ylmethyl)phenylethylamine 4a
89%
N
Bt
N
H3CO
H3CO
CH3
4f
6f
Phenylethylamine 3a (3.45 g, 28.5 mmol) was added to 1-
hydroxymethylbenzotriazole 2 (8.50 g, 57.0 mmol) while stir-
ring. The mixture was heated and ethanol added dropwise until
everything dissolved. The material was refluxed for 30 min
and then kept at Ϫ5 ЊC to promote crystallisation. The white
crystals 4a (10.05 g, 92%) were recrystallised from EtOH. Mp
123–124 ЊC (EtOH); λmax(EtOH)/nm (ε/dm3 molϪ1 cmϪ1) 207
(31821), 259 (10245) and 276 (7756); νmax(Nujol)/cmϪ1 1205,
1160, 1145, 1075, 990, 745; δH(200 MHz; CDCl3; Me4Si) 8.09
(2H, d, J 5), 7.53–7.38 (6H, m), 7.17 (3H, d, J 3), 7.03 (2H, t,
J 3), 5.62 (4H, s, NCH2N), 3.17 (2H, t, J 5, NCH2CH2), 2.83
(2H, t, J 5, NCH2CH2); δC(50 MHz; CDCl3) 33.9 (ArCH2), 52.1
(NCH2CH2), 64.3 (NCH2N), 109.9, 120.1, 124.3, 126.5, 128.0,
128.6, 133.3, 138.8, 146.2.
Bt
1. AlCl3
2. NaBH4
11%
N
H3CO
CH3
OCH3
6f′
Scheme 3
regioselectivity of the intramolecular ring closure, which can be
explained by steric hindrance of the electrophilic attack at the
position ortho to the methoxy substituent on the aromatic
structure, manifesting the para-directing effect of alkoxy
groups.34 This phenomenon is also well-documented for m-
methoxy-substituted β-arylamines which cyclise to the 6-
methoxy regioisomer as the major, often even exclusive,
product.35
N,N-Bis(benzotriazol-1-ylmethyl)-4-chlorophenylethylamine
4b. 1-Hydroxymethylbenzotriazole 2 (7.51 g, 50.4 mmol) was
reacted with 4-chlorophenylethylamine 3b (3.93 g, 25.4 mmol)
for one hour. Crystallisation started almost immediately to
yield compound 4b (9.68 g, 92%) as a fine, white powder. Mp
149–150 ЊC (EtOH); λmax(EtOH)/nm (ε/dm3 molϪ1 cmϪ1) 208
Conclusion
Using benzotriazole as auxiliary, the Friedel–Crafts cyclisation
J. Chem. Soc., Perkin Trans. 1, 1999, 179–184
181

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(34641), 259 (12838) and 274 (10127); νmax(Nujol)/cmϪ1 1200,
1145, 980, 960, 750, 725, 670, 630, 575, 525; δH(200 MHz;
CDCl3; Me4Si) 8.10 (2H, d, J 5), 7.51–7.39 (6H, m), 7.06 (2H, d,
J 5), 6.88 (2H, d, J 5), 5.62 (4H, s, NCH2N), 3.12 (2H, t, J 6,
NCH2CH2), 2.78 (2H, t, J 6, NCH2CH2); δC(50 MHz; CDCl3)
33.0 (ArCH2), 51.6 (NCH2CH2), 64.4 (NCH2N), 109.7, 120.2,
124.4, 128.1, 128.6, 129.9, 132.2, 133.2, 137.2, 146.2.
(3.58 g, 26.9 mmol) was slowly added with stirring. The mixture
was stirred at 25 ЊC for 4 h with a drying tube (anhydrous
CaCl2) attached. The product was then poured onto crushed ice
(approx. 25 g) and NaOH (2 , 75 ml) was added to pH 14. The
organic and aqueous layer were separated and the aqueous
material was extracted with CHCl3 (3 × 30 ml). The combined
organic extracts were rewashed with NaOH (2 , 90 ml), dried
with anhydrous MgSO4, filtered and evaporated under reduced
pressure to yield compound 5a as a slightly yellow, oily product
(1.54 g, 87%) which crystallised rapidly and was recrystallised
from EtOH. Mp 155–157 ЊC (EtOH); λmax(EtOH)/nm (ε/dm3
N,N-Bis(benzotriazol-1-ylmethyl)-2-chlorophenylethylamine
4c. 1-Hydroxymethylbenzotriazole 2 (2.80 g, 18.8 mmol) and
2-chlorophenylethylamine 3c (1.46 g, 9.4 mmol) were reacted
for one hour. Crystallisation occurred very quickly to give
product 4c (3.13 g, 80%) as a fine, white powder. Mp 116–
118 ЊC (EtOH); λmax(EtOH)/nm (ε/dm3 molϪ1 cmϪ1) 216 (7619),
257 (9287) and 273 (8657); νmax(Nujol)/cmϪ1 1220, 1190, 1160,
1120, 1050, 970, 740; δH(200 MHz; CDCl3; Me4Si) 8.10 (2H, d,
J 5), 7.62–7.37 (6H, m), 7.21 (1H, s), 7.05–6.97 (3H, m), 5.68
(4H, s, NCH2N), 3.19 (2H, t, J 7, NCH2CH2), 2.96 (2H, t,
J 7, NCH2CH2); δC(50 MHz; CDCl3) 31.8 (ArCH2), 50.4
(NCH2CH2), 64.4 (NCH2N), 109.8, 118.4, 120.1, 124.3, 127.0,
128.0, 129.5, 130.9, 133.3, 133.9, 136.3, 146.2.
molϪ1 cmϪ1
) 206 (27060), 253 (6970) and 273 (5808);
νmax(Nujol)/cmϪ1 1260, 1210, 1150, 1090, 1050, 955, 940, 740;
δH(200 MHz; CDCl3; Me4Si) 8.08 (1H, d, J 4), 7.68 (1H, d, J 4),
7.52 (1H, t, J 7), 7.38 (1H, t, J 7), 7.10–6.90 (4H, m), 5.64
(2H, s, NCH2N), 3.86 (2H, s, ArCH2N), 2.96–2.91 (4H, m,
ArCH2CH2N); δC(50 MHz; CDCl3) 29.0 (ArCH2CH2N), 48.4
(ArCH2N), 52.3 (ArCH2CH2N), 69.1 (NCH2N), 110.1, 118.4,
120.1, 124.1, 125.9, 126.4, 126.6, 127.7, 128.9, 133.6, 134.0,
146.1.
N-Benzotriazol-1-ylmethyl-7-chloro-1,2,3,4-tetrahydroiso-
quinoline 5b. N,N-Bis(benzotriazol-1-ylmethyl)-4-chlorophenyl-
ethylamine 4b (2.51 g, 6.0 mmol) was reacted with AlCl3 (3.58 g,
26.9 mmol) for 8 h. Product 5b was obtained as white crystals
(1.58 g, 88%). Mp 146–148 ЊC (EtOH); λmax(EtOH)/nm (ε/dm3
molϪ1 cmϪ1) 207 (40498), 254 (11264) and 273 (9923);
νmax(Nujol)/cmϪ1 1205, 1150, 1055, 960, 780, 770, 750; δH(200
MHz; CDCl3; Me4Si) 8.07 (1H, d, J 4), 7.67 (1H, d, J 4), 7.51
(1H, t, J 7), 7.37 (1H, t, J 7), 7.04–6.98 (3H, m), 5.62 (2H, s,
NCH2N), 3.80 (2H, s, ArCH2N), 2.93 (2H, d, J 2, ArCH2-
CH2N), 2.86 (2H, d, J 2, ArCH2CH2N); δC(50 MHz; CDCl3)
28.5 (ArCH2CH2N), 48.2 (ArCH2N), 51.9 (ArCH2CH2N), 68.8
(NCH2N), 109.9, 120.2, 124.1, 126.5, 126.6, 127.8, 130.2, 131.5,
132.1, 134.0, 135.5, 146.1.
N,N-Bis(benzotriazol-1-ylmethyl)-2,4-dichlorophenylethyl-
amine 4d. The reaction between 1-hydroxymethylbenzotriazole
2 (2.02 g, 13.6 mmol) and 2,4-dichlorophenylethylamine 3d
(1.29 g, 6.8 mmol) for one hour yielded compound 4d (2.70 g,
88%) as fine white crystals. Mp 125–126 ЊC (EtOH);
λmax(EtOH)/nm (ε/dm3 molϪ1 cmϪ1) 207 (43597), 259 (13417)
and 277 (9809); νmax(Nujol)/cmϪ1 1275, 1200, 1150, 990,
890, 845, 795, 740; δH(200 MHz; CDCl3; Me4Si) 8.10 (2H, d,
J 4), 7.53–7.41 (6H, m), 7.14 (1H, s), 6.84 (2H, q, J 12), 5.68
(4H, s, NCH2N), 3.11 (2H, t, J 8, NCH2CH2), 2.89 (2H, t,
J 8, NCH2CH2); δC(50 MHz; CDCl3) 30.9 (ArCH2), 49.7
(NCH2CH2), 64.5 (NCH2N), 109.6, 120.2, 124.4, 127.2, 128.1,
129.2, 131.5, 133.0, 133.2, 134.4, 134.9, 146.2.
N-Benzotriazol-1-ylmethyl-5-chloro-1,2,3,4-tetrahydroiso-
quinoline 5c. Method A. N,N-Bis(benzotriazol-1-ylmethyl)-2-
chlorophenylethylamine 4c (1.01 g, 2.4 mmol) and AlCl3 (1.29
g, 9.7 mmol) were reacted for 68 h to give an orange oil which
crystallised slowly (0.69 g, 96% yield of crude product).
Repeated recrystallisation from EtOH–EtOAc yielded com-
pound 5c as slightly beige crystals (0.10 g, 14%). Mp 144–
N,N-Bis(benzotriazol-1-ylmethyl)-4-methoxyphenylethyl-
amine 4e. 1-Hydroxymethylbenzotriazole 2 (2.16 g, 14.5 mmol)
was reacted with 4-methoxyphenylethylamine 3e (1.09 g, 7.2
mmol) for one hour to yield fine needles of product 4e (2.83 g,
95%). Mp 97–99 ЊC (EtOH); λmax(EtOH)/nm (ε/dm3 molϪ1
cmϪ1) 208 (35963), 225 (16361), 260 (13597) and 273 (11850);
νmax(Nujol)/cmϪ1 1255, 1195, 1150, 1040, 830, 745; δH(200
MHz; CDCl3; Me4Si) 8.10 (2H, d, J 5), 7.52–7.39 (6H, m),
6.92 (2H, d, J 5), 6.70 (2H, d, J 5), 5.62 (4H, s, NCH2N),
3.75 (3H, s, OCH3), 3.13 (2H, t, J 8, NCH2CH2), 2.77 (2H, t,
J 8, NCH2CH2); δC(50 MHz; CDCl3) 33.0 (ArCH2), 52.3
(NCH2CH2), 55.1 (OCH3), 64.4 (NCH2N), 109.9, 113.9, 120.1,
124.3, 128.0, 129.6, 130.8, 133.3, 146.3, 158.3.
145 ЊC (EtOH–EtOAc); λmax(EtOH)/nm (ε/dm3 molϪ1 cmϪ1
)
206 (35164), 253 (8761) and 275 (7092); νmax(Nujol)/cmϪ1 1205,
1150, 1050, 955, 750; δH(200 MHz; CDCl3; Me4Si) 8.07 (1H, d,
J 4), 7.67 (1H, d, J 4), 7.51 (1H, t, J 7), 7.37 (1H, t, J 7), 7.16
(1H, d, J 4), 7.03 (1H, t, J 8), 6.90 (1H, d, J 4), 5.61 (2H, s,
NCH2N), 3.81 (2H, s, ArCH2N), 2.95 (2H, d, J 2, ArCH2-
CH2N), 2.89 (2H, d, J 2, ArCH2CH2N); δC(50 MHz; CDCl3)
27.3 (ArCH2CH2N), 48.2 (ArCH2N), 52.3 (ArCH2CH2N), 68.8
(NCH2N), 110.0, 120.1, 124.1, 125.1, 126.9, 127.2, 127.8, 131.9,
133.9, 134.4, 136.0, 146.1.
N,N-Bis(benzotriazol-1-ylmethyl)-3,4-dimethoxyphenylethyl-
amine 4f. Product 4f (2.42 g, 76%) was obtained as white crys-
tals from the reaction of 1-hydroxymethylbenzotriazole 2 (2.12
g, 14.2 mmol) and 3,4-dimethoxyphenylethylamine 3f (1.30 g,
7.2 mmol). Mp 91–93 ЊC (EtOH); λmax(EtOH)/nm (ε/dm3 molϪ1
cmϪ1) 210 (33945), 231 (14038), 264 (16640) and 280 (15200);
νmax(Nujol)/cmϪ1 1140, 1075, 1025, 820, 745; δH(200 MHz;
CDCl3; Me4Si) 8.10 (2H, d, J 5), 7.53–7.38 (6H, m), 6.64 (1H, d,
J 5), 6.56 (1H, d, J 5), 6.45 (1H, s), 5.64 (4H, s, NCH2N), 3.82
(3H, s, OCH3), 3.71 (3H, s, OCH3), 3.15 (2H, t, J 7, NCH2CH2),
2.76 (2H, t, J 7, NCH2CH2); δC(50 MHz; CDCl3) 33.6 (ArCH2),
52.3 (NCH2CH2), 55.6 (OCH3), 64.5 (NCH2N), 109.8, 111.1,
111.6, 120.1, 120.5, 124.4, 128.0, 131.3, 133.2, 146.2, 147.7,
149.0.
Method B. Compound 4c (0.53 g, 1.3 mmol) was added to
conc. H2SO4 (3 ml) at 0 ЊC while stirring. The mixture was
brought to room temperature and stirred at 25 ЊC for a further
2 h, poured onto crushed ice (approx. 5 g) and basified with
NaOH (10 , 15 ml) to pH 14. CH2Cl2 (15 ml) was added and
the layers separated. The aqueous material was extracted with
CH2Cl2 (5 × 5 ml) and the combined organic extracts were
rewashed with NaOH (2 , 25 ml), dried with anhydrous
MgSO4 and evaporated under reduced pressure. The solution
yielded an oily residue which slowly crystallised to give product
5c (0.27 g, 71%).
N-Benzotriazol-1-ylmethyl-7-methoxy-1,2,3,4-tetrahydroiso-
quinoline 5e. The reaction of N,N-bis(benzotriazol-1-ylmethyl)-
4-methoxyphenylethylamine 4e (1.23 g, 3.0 mmol) and AlCl3
(1.59 g, 11.9 mmol) for 4 h gave compound 5e as white crystals
(0.77 g, 83%). Mp 128–130 ЊC (EtOH); λmax(EtOH)/nm (ε/dm3
General procedure for compounds 5a–f: N-benzotriazol-1-yl-
methyl-1,2,3,4-tetrahydroisoquinoline 5a
N,N-Bis(benzotriazol-1-ylmethyl)phenylethylamine 4a (2.57 g,
6.7 mmol) was dissolved in CHCl3 (25 ml). Anhydrous AlCl3
182
J. Chem. Soc., Perkin Trans. 1, 1999, 179–184

View Article Online
molϪ1 cmϪ1) 206 (34251), 224 (12818), 259 (7997) and 278
(8585); νmax(Nujol)/cmϪ1 1610, 1505, 1325, 1225, 1150, 1040,
975, 845, 775, 745; δH(200 MHz; CDCl3; Me4Si) 8.08 (1H, d,
J 4), 7.70 (1H, d, J 4), 7.51 (1H, t, J 7), 7.38 (1H, t, J 7), 6.98
(1H, d, J 4), 6.71 (1H, d, J 4), 6.53 (1H, s), 5.62 (2H, s,
NCH2N), 3.82 (2H, s, ArCH2N), 3.73 (3H, s, OCH3), 2.94 (2H,
d, J 2, ArCH2CH2N), 2.85 (2H, d, J 2, ArCH2CH2N); δC(50
MHz; CDCl3) 28.2 (ArCH2CH2N), 48.7 (ArCH2N), 52.4
(ArCH2CH2N), 55.1 (OCH3), 69.0 (NCH2N), 110.1, 111.1,
113.0, 120.0, 124.1, 125.6, 127.7, 129.8, 134.0, 134.7, 146.1,
157.9.
mmol) and gave product 6c (0.06 g, 55%) as a colourless oil.
δH(200 MHz; CDCl3; Me4Si) 7.18 (1H, d, J 4, ArH), 7.05 (1H, t,
J 7, ArH), 6.91 (1H, d, J 4, ArH), 3.54 (2H, s, ArCH2N), 2.88
(2H, t, J 6, ArCH2CH2N), 2.69 (2H, t, J 6, ArCH2CH2N), 2.43
(3H, s, CH3N); δC(50 MHz; CDCl3) 27.3 (ArCH2CH2N), 45.7
(NCH3), 52.5 (ArCH2CH2N), 57.8 (ArCH2N), 124.9, 126.6,
126.9, 132.2, 134.4, 137.1; m/z 184 (19%), 183 (12), 182 (91), 181
(Mϩ, 18), 180 (100), 178 (5), 146 (15), 145 (6), 144 (8), 103 (29),
102 (7). Picrate: mp 176–178 ЊC (EtOH). Anal. calc. for
C16H15N4O7Cl: C, 46.8; H, 3.7; N, 13.6; Found: C, 46.8; H, 3.6;
N, 13.6%.
N-Benzotriazol-1-ylmethyl-6,7-dimethoxy-1,2,3,4-tetrahydro-
isoquinoline 5f. N,N-Bis(benzotriazol-1-ylmethyl)-3,4-dimeth-
oxyphenylethylamine 4f (1.02 g, 2.3 mmol) was reacted with
AlCl3 (1.23 g, 9.2 mmol) for 4 h. Product 5f (0.70 g, 94%) was
obtained as a yellow oil which rapidly crystallised. Mp 137–
140 ЊC (EtOH); λmax(EtOH)/nm (ε/dm3 molϪ1 cmϪ1) 207
(44096), 220 (12798) and 281 (10433); νmax(Nujol)/cmϪ1 1605,
1515, 1375, 1225, 1140, 1110, 1020, 995, 855, 830, 740; δH(200
MHz; CDCl3; Me4Si) 8.08 (1H, d, J 4), 7.70 (1H, d, J 4), 7.52
(1H, t, J 7), 7.38 (1H, t, J 7), 6.55 (1H, s), 6.48 (1H, s), 5.62 (2H,
s, NCH2N), 3.84–3.77 (8H, m, ArCH2N ϩ OCH3), 2.94 (2H, d,
J 2, ArCH2CH2N), 2.85 (2H, d, J 2, ArCH2CH2N); δC(50 MHz;
CDCl3) 28.4 (ArCH2CH2N), 48.4 (ArCH2N), 51.8 (ArCH2-
CH2N), 55.7 (OCH3), 69.0 (NCH2N), 109.2, 110.0, 111.3,
120.0, 124.0, 125.4, 126.5, 127.6, 133.9, 146.0, 147.4, 147.7.
7-Methoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline 6e. N-
Benzotriazol-1-ylmethyl-7-methoxy-1,2,3,4-tetrahydroisoquin-
oline 5e (0.35 g, 1.2 mmol) was reduced with NaBH4 (0.12 g, 3.2
mmol). Product 6e was obtained as a colourless oil (0.20 g,
95%); δH(200 MHz; CDCl3; Me4Si) 7.00 (1H, d, J 5, ArH), 6.69
(1H, d, J 5, ArH), 6.55 (1H, s, ArH), 3.75 (3H, s, CH3O), 3.53
(2H, s, ArCH2N), 2.83 (2H, t, J 7, ArCH2CH2N), 2.65 (2H, t,
J 7, ArCH2CH2N), 2.42 (3H, s, CH3N); δC(50 MHz; CDCl3)
28.1 (ArCH2CH2N), 45.9 (NCH3), 53.0 (ArCH2CH2N), 55.1
(CH3O), 58.0 (ArCH2N), 111.1, 112.5, 126.0, 129.6, 135.8,
157.7; m/z 178 (11%), 177 (Mϩ, 38), 176 (100), 161 (6), 146 (7),
135 (11), 134 (100), 133 (10), 132 (12), 131 (7), 119 (9), 118 (5),
117 (7), 105 (13), 104 (26), 103 (14), 91 (35), 79 (5), 78 (25), 77
(11), 65 (11). Picrate: mp 140–142 ЊC (EtOH) (lit.,37 142–
143 ЊC).
General procedure for compounds 6a–f: N-methyl-1,2,3,4-tetra-
hydroisoquinoline 6a
6,7-Dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline 6f.
N-Benzotriazol-1-ylmethyl-6,7-dimethoxy-1,2,3,4-tetrahydro-
isoquinoline 5f (0.21 g, 0.6 mmol) was reduced with NaBH4
(0.07 g, 1.9 mmol) to yield product 6f (0.09 g, 67%) as a white
residue. Mp 74–75 ЊC (EtOH); δH(200 MHz; CDCl3; Me4Si)
6.59 (1H, s), 6.50 (1H, s), 3.82 (6H, s, CH3O), 3.49 (2H, s,
ArCH2N), 2.83 (2H, t, J 5, ArCH2CH2N), 2.65 (2H, t, J 5,
ArCH2CH2N), 2.43 (3H, s, CH3N); δC(50 MHz; CDCl3) 28.5
(ArCH2CH2N), 45.9 (NCH3), 52.8 (ArCH2CH2N), 55.7
(CH3O), 57.4 (ArCH2N), 109.2, 111.3, 125.7, 126.6, 147.2,
147.5; m/z 208 (23%), 207 (Mϩ, 29), 206 (100), 192 (9), 191 (7),
190 (16), 165 (8), 164 (68), 162 (7), 149 (25), 148 (5), 121 (25),
103 (10), 93 (8), 91 (16), 77 (16). Picrate: mp 154–156 ЊC
(EtOH) (lit.,33 160 ЊC).
NaBH4 (0.31 g, 8.2 mmol) was dissolved in MeOH (25 ml) and
N-benzotriazol-1-ylmethyl-1,2,3,4-tetrahydroisoquinoline 5a
(0.87 g, 3.3 mmol) was added in small amounts with stirring.
The solution was stirred at 25 ЊC for 7 h with a drying tube
(anhydrous CaCl2) attached. The solvent was then removed
under reduced pressure to yield a slightly yellow, oily residue.
CH2Cl2 (10 ml) as well as NaOH (2 , 10 ml) were added and
the layers separated. The aqueous phase was extracted with
CH2Cl2 (3 × 10 ml) and the combined organic extracts
rewashed with NaOH (2 , 30 ml). The organic solution was
dried with anhydrous MgSO4, filtered and evaporated under
reduced pressure to yield product 6a (0.34 g, 70%) as a pale
yellow oil with a strong ammoniacal odour. δH(200 MHz;
CDCl3; Me4Si) 7.11–6.98 (4H, m, ArH), 3.57 (2H, s, ArCH2N),
2.91 (2H, t, J 6, ArCH2CH2N), 2.67 (2H, t, J 6, ArCH2CH2N),
2.44 (3H, s, CH3N); δC(50 MHz; CDCl3) 28.9 (ArCH2CH2N),
45.9 (NCH3), 52.7 (ArCH2CH2N), 57.7 (ArCH2N), 125.7,
126.2, 126.5, 128.7, 133.8, 134.6; m/z 148 (17%), 147 (Mϩ, 22),
146 (100), 144 (8), 131 (7), 130 (4), 118 (4), 117 (4), 115 (5), 104
(20), 103 (14), 78 (11), 77 (6). Picrate: mp 150–153 ЊC (EtOH)
(lit.,36 148–150 ЊC).
Acknowledgments
C. L. is grateful for the receipt of a NTU Postgraduate
Research Scholarship and N. P. would like to thank A. R.
Katritzky for a short training in Benzotriazole chemistry.
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