Preparation of 1,7-disubstituted-1,2,3,4-Tetrahydroisoquinolines

Article abstract of DOI:10.1081/SCC-120005939

A simple procedure for the preparation of 1,7-disubstituted- 1,2,3,4-tetrahydroisoquinolines from 3,4-dihydroisoquinoline (2) is presented. This strategy overcomes the limitation of cyclisation approaches which generally require electron rich ring systems

Full text of DOI:10.1081/SCC-120005939

This article was downloaded by: [University of Edinburgh]
On: 15 October 2014, At: 05:49
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
PREPARATION OF 1,7-DISUBSTITUTED-1,2,3,4-
TETRAHYDROISOQUINOLINES
Jag P. Heer a , John D. Harling a & Mervyn Thompson a
a Medicinal Chemistry , GlaxoSmithKline , New Frontiers Science Park, Third Avenue, Harlow,
Essex, CM19 5AW, UK
Published online: 16 Aug 2006.
To cite this article: Jag P. Heer , John D. Harling & Mervyn Thompson (2002) PREPARATION OF 1,7-DISUBSTITUTED-1,2,3,4-
TETRAHYDROISOQUINOLINES, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 32:16, 2555-2563, DOI: 10.1081/SCC-120005939
To link to this article: http://dx.doi.org/10.1081/SCC-120005939
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
SYNTHETIC COMMUNICATIONS
Vol. 32, No. 16, pp. 2555–2563, 2002
PREPARATION OF 1,7-DISUBSTITUTED-
1,2,3,4-TETRAHYDROISOQUINOLINES
*
Jag P. Heer, John D. Harling, and Mervyn Thompson
Medicinal Chemistry, GlaxoSmithKline, New Frontiers
Science Park, Third Avenue, Harlow,
Essex CM19 5AW, UK
ABSTRACT
A simple procedure for the preparation of 1,7-disubstituted-
1,2,3,4-tetrahydroisoquinolines from 3,4-dihydroisoquinoline
(2) is presented. This strategy overcomes the limitation of
cyclisation approaches which generally require electron rich
ring systems. A variety of 1-substituents has been incorpo-
rated using the appropriate organometallic or activated
methylene nucleophile to prepare both electron rich (7a–f)
and electron deficient 1,7-disubstituted-1,2,3,4-tetrahydroiso-
quinolines (16, 17).
We were interested in the preparation of 1-substituted-2-methyl-7-
amino-1,2,3,4-tetrahydroisoquinolines (7a–f) en route to anticonvulsant
agents and preliminary details have been reported.[1] However, there are
limited generic routes to 1-alkyl or 1-aryl 7-amino-1,2,3,4-tetrahydroiso-
quinolines. The 7-amino substituent is usually derived from a nitro group
*Corresponding author. E-mail: jag.p.heer@gsk.com
2555
DOI: 10.1081/SCC-120005939
Copyright & 2002 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2556
HEER, HARLING, AND THOMPSON
and classical synthetic approaches to isoquinolines (Pomerantz–Fritsch),[2]
3,4-dihydroisoquinolines (Bischler–Napieralski)[3] and 1,2,3,4-tetrahydro-
isoquinolines (Pictet–Spengler)[4] rely on cyclisation by intramolecular
electrophilic substitution of an aromatic ring. Preparation of 1-substituted-7-
nitro-1,2,3,4-tetrahydroisoquinolines by cyclisation (Scheme 1, A bond
formation) is problematic as both the electrophile (nitrilium/iminium
species) and the aromatic ring are deactivated.
Modification of an unsubstituted 1,2,3,4-tetrahydroisoquinoline is
an alternative strategy. There is a wealth of literature detailing preparation
of 1-substituted-1,2,3,4-tetrahydroisoquinolines by generation of a benzylic
anion followed by reaction with an electrophile. Regiocontrol and stabilisa-
tion of a 1-benzylic anion is achieved by attachment of a suitable functional
group to the nitrogen of tetrahydroisoquinoline. Directing/stabilising
groups include amides,[5] carbamates[6] and amidines.[7] Borane adducts
of tertiary amines have also been used to prepare 1,2-disubstituted tetrahy-
droisoquinolines.[8] A number of these strategies was examined but we
found that they all failed with systems bearing substituents in the aromatic
ring. This failure was presumably due to competing ortho-lithiation of
sp2 carbon atoms adjacent to a variety of nitrogen substituents present in
the aromatic ring of our substrates.
Synthesis of 1-alkyl-1,2,3,4-tetrahydroisoquinolines can be achieved
by nucleophilic addition of organometallic reagents to compounds derived
from 3,4-dihydroisoquinoline (2) which can be prepared in high yield[9]
from commercially available 1,2,3,4-tetrahydroisoquinoline. Unlike carbo-
nyl chemistry, the reaction of imines with organometallic nucleophiles rarely
proceeds efficiently without activation.[10] However, Lewis acid activation
of 3,4-dihydroisoquinoline (2) yielded the 1-methyl derivative (3) in good
yield (Scheme 1).
3,4-Dihydroisoquinoline activation by quaternisation of an imine
intermediate with iodomethane is extremely useful for the preparation of
1-substituted-2-methyl-7-amino-1,2,3,4-tetrahydroisoquinolines (Scheme 2).
The imine double bond serves not only to introduce the 1-substituent
54
i.
ii.
NH
N
NH
8
1
A
Me
2
1
3
i. NBS, NaOH, CH2Cl2 (>95%), ii. BF3.OEt2, MeMgCl, CH2Cl2 (70%)
Scheme 1.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
1,7-DISUBSTITUTED-1,2,3,4-TETRAHYDROISOQUINOLINES
2557
i. KNO3, H2SO4 (76%), ii. SnCl2, EtOH, HCl (88%), iii. Mel, acetone (0>95%), iv.
RMgBr, thf, ꢀ78ꢁC
Scheme 2.
Table 1.
Compound
R
Yield (%)
(7a)
(7b)
(7c)
(7d)
(7e)
(7f)
Methyl
i-Propenyl
Phenyl
Benzyl
i-Butyl
Allyl
67
95
75
70
53
54
but also to control the regiochemistry of nitration, to give exclusively
7-nitro-3,4-dihydroisoquinoline (4).[9] A number of different Grignard
reagents was used to prepare several 1-substituted compounds (7a–f) in
good to excellent yield (Table 1).
This methodology can also be used to prepare tetrahydroisoquinolines
bearing quaternary benzylic C-1 carbon atoms (12) (Scheme 3). Nitration of
commercially available 1-methyl-3,4-dihydroisoquinoline (8) yielded exclu-
sively 1-methyl-7-nitro-3,4-dihydroisoquinoline (9). Reduction followed by
quaternisation with iodomethane gave the activated substrate (11) for the
final alkylation reaction. However, when the iminium salt (11) was treated
with an excess of methyl magnesium chloride only low to moderate yields of
the target compound were obtained. Presumably, this is due to proton
abstraction from the methyl substituent resulting in imine-enamine tauto-

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2558
HEER, HARLING, AND THOMPSON
Scheme 3.
Scheme 4.
merism. Less basic, more nucleophilic reagents such as organocerium
and alkylcopper reagents may overcome this limitation.[10]
As discussed earlier, synthesis of electron deficient tetrahydroisoqui-
nolines by cyclisation strategies is difficult. One approach has been to use
a modified Pictet–Spengler reaction involving reaction between a Lewis acid
activated ethyl glyoxylate synthon and an N-phenylsulfonylated 4-nitro-
phenethylamine (13) (Scheme 4).[11] This approach is limited to a small
range of 1-substituents that can be incorporated and removal of the
phenylsulfonyl group can be troublesome. More recently electron deficient
tetrahydroisoquinolines have been prepared from tri-substituted aromatic
rings employing an N2–C3 cyclisation strategy.[12] However, the limitation
of this strategy is that several synthetic transformations are required to
prepare the cyclisation precursor.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
1,7-DISUBSTITUTED-1,2,3,4-TETRAHYDROISOQUINOLINES
2559
Scheme 5.
Scheme 6.
Our 3,4-dihydroisoquinoline strategy was used to prepare electron
deficient ring systems (e.g., 16) (Scheme 5). Organo-zinc reagents were
found to be more reliable than Grignard reagents in reactions with
substrates bearing aromatic nitro groups. For example, dimethyl zinc
was successfully employed in the preparation of 1,2,4,4-tetramethyl-7-
nitro-1,2,3,4-tetrahydroisoquinoline (16), in excellent yield.
The advantage of this approach is that a variety of 1-alkyl-7-nitro-
1,2,3,4-tetrahydroisoquinolines can be prepared with relative ease compared
to existing procedures. For example, an activated methylene compound,
monomethyl malonate, has also been used in place of an organo-zinc
reagent to prepare an electron deficient tetrahydroisoquinoline (17)
(Scheme 6).
In conclusion, 3,4-dihydroisoquinoline is a versatile precursor for
the preparation of a number of novel 1,7-disubstituted-1,2,3,4-tetrahydro-
isoquinolines. This approach is superior to cyclisation strategies and toler-
ates aromatic ring substituents that limit approaches based on benzylic
anion generation. Electron deficient 1,2,3,4-tetrahydroisoquinolines are
accessible in a few steps and the attachment and removal of auxiliary
activating groups is not required.
EXPERIMENTAL
Chromatography refers to flash chromatography through Merck
Silica Gel 60 (less than 0.063 mm) and the eluent is stated. Infra red spectra

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2560
HEER, HARLING, AND THOMPSON
were recorded for dichloromethane solutions on a Perkin-Elmer 1600 FTIR.
1HNMR spectra were obtained using a Brucker AC250 and the solvent
is stated. Accurate mass measurements were recorded by Analytical
Sciences, SB, on a Jeol JMS DX303/DA 5000 at 70 eV. All solutions were
dried over anhydrous magnesium sulfate unless stated otherwise. Solvents
were removed under reduced pressure using a Buchi Rotavapor unless
stated otherwise.
7-Amino-3,4-dihydroisoquinoline (5): 7-Nitro-3,4-dihydroisoquinoline[9]
(0.6 g, 3.4 mmol) was dissolved in ethanol (100 mL) and heated to 60ꢁC.
This hot solution was treated with a solution of tin (II) chloride dihydrate
(3.08 g, 13.7 mmol) in concentrated hydrochloric acid (10 mL) and heated at
60ꢁC for 1 h. After cooling to room temperature, the resultant mixture was
poured into ice-water (100 mL) and basified (pH9) with potassium hydro-
xide pellets, liberating an oily residue. The residue was extracted into
dichloromethane and dried. Chromatographic purification using a dichlor-
omethane solution of ammonia in methanol (0.5%c. ammonia : 4.5%
methanol : 95% dichloromethane) yielded 7-amino-3,4-dihydroisoquinoline
(5) as a dark yellow oil (0.436 g, 88%); ꢀmax/cmꢀ1 (CH2Cl2) 3685, 3383 and
1619; ꢁH [250 MHz, CDCl3] 2.63 (2H, t, J ¼ 7Hz), 3.67 (2H, br.s), 3.73 (2H,
dt, J ¼ 7 and 2 Hz), 6.62 (1H, d, J ¼ 2 Hz), 6.70 (1H, dd, J ¼ 8 and 2 Hz),
6.95 (1H, d, J ¼ 8 Hz), 8.24 (1H, s); Found: 146.0844. C9H10N2 requires:
146.0844.
7-Amino-1,2-dimethyl-1,2,3,4-tetrahydroisoquinoline (7a): 7-Amino-
3,4-dihydroisoquinoline (5) (0.4 g, 2.74 mmol) was dissolved in acetone
(125 mL) and treated with iodomethane (0.5 mL, 8.03 mmol). The reaction
mixture was left stirring at room temperature for 18 h. The resultant yellow
precipitate (6) was collected by filtration and dried in vacuo at
ambient temperature (0.726 g, 92%); m/z (API) 161(Mþ, 100%). 7-Amino-
2-methyl-3,4-dihydroisoquinolinium iodide (6) (0.5 g, 1.7 mmol) was
suspended in anhydrous tetrahydrofuran (50 mL) and cooled to –78ꢁC
under an argon atmosphere. The cooled solution was treated with
methyl magnesium chloride (2.14 mL of a 3 M solution in tetrahydrofuran,
6.96 mmol), added as a single portion. The reaction was stirred at ambient
temperature for 18 h before pouring into water (50 mL). The organic
solvent was removed and the organic product extracted into dichloro-
methane and dried. Evaporation under reduced pressure furnished
7-amino-1,2-dimethyl-1,2,3,4-tetrahydroisoquinoline (7a) as a pale yellow oil
(0.3 g, 98%). For ease of handling, the product was converted into the mono
hydrochloride by the addition of 1 molar equivalent of ethereal hydrogen
chloride followed by solvent evaporation under reduced pressure; ꢀmax/cmꢀ1
(CH2Cl2) 3621 and 3421; ꢁH [250 MHz, CDCl3 hydrochloride salt] 1.37
(3H, d, J ¼ 7 Hz), 2.46 (3H, s), 2.54–2.83 (3H, m), 2.96–3.06 (1H, m),

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
1,7-DISUBSTITUTED-1,2,3,4-TETRAHYDROISOQUINOLINES
2561
3.45–3.55 (3H, m), 6.45 (1H, d, J ¼ 2 Hz), 6.51 (1H, dd, J ¼ 8 and 2 Hz), 6.88
(1H, d, J ¼ 8 Hz); Found: 176.1314. C11H16N2 requires: 176.1314.
7-Amino-1-isopropenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline
(7b):
Prepared according to the procedure for 7a using isopropenyl magnesium
bromide (0.5 M solution in tetrahydrofuran). The title compound (7b) was
isolated in 95% yield; ꢀmax/cmꢀ1 (CH2Cl2) 3655 and 3466; ꢁH [250 MHz,
CDCl3] 1.52 (3H, s), 2.31 (3H, s), 2.36–2.63 (2H, m), 2.78–3.14 (2H, m), 3.48
(2H, br.s), 3.58 (1H, br.s), 5.06 (2H, d, J ¼ 1 Hz), 6.49–6.53 (2H, m),
6.87–6.90 (1H, m); Found: 202.1470. C13H18N2 requires: 202.1470.
7-Amino-2-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline (7c): Prepared
according to the procedure for 7a using phenyl magnesium bromide (3 M
solution in tetrahydrofuran). The title compound (7c) was isolated in 75%
yield; ꢀmax/cmꢀ1 (CH2Cl2) 3662, 3453 and 3390; ꢁH [250 MHz, CDCl3] 2.21
(3H, s), 2.54–2.76 (2H, m), 3.06–3.20 (2H, m), 3.41 (2H, br.s), 4.18 (1H, s),
5.95 (1H, d, J ¼ 2 Hz), 6.49 (1H, dd, J ¼ 8 and 2 Hz), 6.67 (1H, dd, J ¼ 8 and
1 Hz), 6.92 (1H, d, J ¼ 8 Hz), 7.18–7.33 (4H, m); Found: 238.1474. C16H18N2
requires: 238.1470.
7-Amino-1-benzyl-2-methyl-1,2,3,4-tetrahydroisoquinoline (7d): Prepared
according to the procedure for 7a using benzyl magnesium chloride (1 M
solution in tetrahydrofuran). The title compound (7d) was isolated in 70%
yield; ꢀmax/cmꢀ1 (CH2Cl2) 3660 and 3430; ꢁH [250 M Hz, CDCl3] 2.51 (3H,
s), 2.54–2.61 (1H, m), 2.69–2.90 (3H, m), 3.10–3.26 (2H, m), 3.41 (2H, br.s),
3.70 (1H, t, J ¼ 6 Hz), 6.03 (1H, d, J ¼ 2 Hz), 6.47 (1H, dd, J ¼ 8 and 2 Hz),
6.86 (1H, d, J ¼ 8 Hz), 7.12–7.54 (5H, m); Found: 252.1626. C17H20N2
requires: 252.1627.
7-Amino-1-isobutyl-2-methyl-1,2,3,4-tetrahydroisoquinoline (7e): Prepared
according to the procedure for 7a using isobutyl magnesium chloride
(2 M solution). The title compound (7e) was isolated in 53% yield;
ꢀ
max/cmꢀ1 (CH2Cl2) 3615 and 3403; ꢁH [250 M Hz, CDCl3] 0.97 (6H,
overlap.t, J ¼ 7 Hz), 1.32–1.52 (1H, m), 1.71–1.98 (2H, m), 2.50 (3H, s),
2.42–2.64 (1H, m), 2.77–2.96 (2H, m), 3.20–3.38 (1H, m), 3.53 (1H, br. t,
J ¼ 7 Hz), 3.56 (2H, br s), 6.38 (1H, d, J ¼ 2 Hz), 6.53 (1H, dd, J ¼ 8
and 2 Hz), 6.88 (1H, d, J ¼ 8 Hz); Found: 218.1784. C14H22N2 requires:
218.1783.
1-Allyl-7-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (7f): Prepared
according to the procedure for preparation of 7a using allyl magnesium
chloride (2 M solution in tetrahydrofuran). The title compound (7f) was
isolated in 54% yield; ꢀmax/cmꢀ1 (CH2Cl2) 3630 and 3397; ꢁH [250 MHz,
CDCl3] 2.48 (3H, s), 2.52–2.83 (5H, m), 3.09–3.21 (1H, m), 3.54 (1H, br.t,
J ¼ 6 Hz), 3.87 (2H, br.s), 5.01–5.11 (2H, m), 5.72–5.88 (1H, m), 6.44 (1H, d,
J ¼ 2 Hz), 6.50 (1H, d, J ¼ 2 Hz), 6.88 (1H, d, J ¼ 8 Hz); Found: 202.1472.
C13H18N2 requires: 202.1470.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2562
HEER, HARLING, AND THOMPSON
1-Methyl-7-nitro-3,4-dihydroisoquinoline (9): A solution of 1-methyl-
3,4-dihydroisoquinoline (2.57 g, 17.7 mmol) in concentrated sulfuric acid
(10 mL) was added dropwise to a stirred mixture of potassium nitrate
(1.93 g, 19.1 mmol) in concentrated sulfuric acid (10 mL) at –5ꢁC. The mix-
ture was allowed to warm to room temperature over 2 h before heating at
60ꢁC for 4 h. Then the reaction mixture was poured into ice-water (100 mL)
and basified (pH9) with potassium hydroxide pellets. Extraction into
dichloromethane, dried and solvent removal under reduced pressure yielded
the crude product. Chromatographic purification using a dichloromethane
solution of ammonia in methanol (0.5% c. ammonia : 4.5% methanol : 95%
dichloromethane) yielded 1-methyl-7-nitro-3,4-dihydroisoquinoline (9) as a
dark brown oil (1.92 g, 57%); ꢀmax/cmꢀ1 (CH2Cl2) 1633, 1528, 1345 and
1266; ꢁH [250 MHz, CDCl3] 2.48 (3H, s), 2.82 (2H, t, J ¼ 8 Hz), 3.75 (2H,
dt, J ¼ 8 and 2 Hz), 7.38 (1H, d, J ¼ 8 Hz), 8.24 (1H, dd, J ¼ 8 and 2 Hz),
8.33 (1H, d, J ¼ 2 Hz); Found: 190.0740. C10H10N2O2 requires: 190.0742.
7-Amino-1-methyl-3,4-dihydroisoquinoline (10): Prepared according to
the procedure for 5 using 1-methyl-7-nitro-3,4-dihydroisoquinoline (9) (2 g,
10.5 mmol). 1-Methyl-7-amino-3,4-dihydroisoquinoline (10) was isolated as
a dark brown oil in 55% yield; ꢀmax/cmꢀ1 (CH2Cl2) 3684, 3466, 3383, and
1618; ꢁH [250 MHz, CDCl3] 2.35 (3H, s), 2.59 (2H, t, J ¼ 7 Hz), 3.62 (2H, t,
J ¼ 7 Hz), 3.40-3.75 (2H, br.s), 6.71 (1H, dd, J ¼ 8 and 2 Hz), 6.83 (1H, d,
J ¼ 2 Hz), 6.98 (1H, d, J ¼ 8 Hz); Found: 160.1002. C10H12N2 requires:
160.1001.
7-Amino-1,1,2-trimethyl-1,2,3,4-tetrahydroisoquinoline (12): 7-Amino-
1,2-dimethyl-3,4-dihydroisoquinolinium iodide (11) was prepared according
to the procedure for preparation of 6 using 7-amino-1-methyl-3,4-dihydro-
isoquinoline (10) (0.9 g, 5.6 mmol). The iminium salt (11) was isolated as an
orange powder (1.44 g, 85%); m/z (API) 175 (Mþ, 100%). 7-Amino-1,2-
dimethyl-3,4-dihydroisoquinolinium iodide (11) (1.44 g, 4.8 mmol) was sus-
pended in tetrahydrofuran (200 mL) and cooled to ꢀ78ꢁC under an argon
atmosphere. The cooled solution was treated with methyl magnesium chlo-
ride (10 mL of a 3 M solution in tetrahydrofuran), added as a single portion.
The reaction was stirred at room temperature for 18 h and then poured into
water (200 mL). The organic solvent was removed and the resultant oily
residue was extracted into dichloromethane. Evaporation under reduced
pressure and chromatography, eluting with a dichloromethane solution of
ammonia in methanol (0.5% c. ammonia : 4.5% methanol : 95% dichloro-
methane) yielded 7-amino-1,1,2-trimethyl-1,2,3,4-tetrahydroisoquinoline
(12) as a light yellow oil (0.07 g, 8%). For ease of handling, the product
was converted into the mono hydrochloride by the addition of 1 molar
equivalent of ethereal hydrogen chloride followed by solvent evaporation
under reduced pressure; ꢀ max/cmꢀ1 (CH2Cl2) 3634, and 3410; ꢁH [250 MHz,

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
1,7-DISUBSTITUTED-1,2,3,4-TETRAHYDROISOQUINOLINES
2563
CDCl3, hydrochloride salt] 1.45 (6H, s), 2.48 (3H, s), 2.80 (2H, t, J ¼ 6 Hz),
2.96 (2H, t, J ¼ 6 Hz), 6.51 (1H, dd, J ¼ 8 and 2 Hz), 6.57 (1H, d, J ¼ 2 Hz),
6.86 (1H, d, J ¼ 8 Hz); Found: 190.1472. C12H18N2 requires: 190.1470.
7-Nitro-1,2,4,4-tetramethyl-1,2,3,4-tetrahydroisoquinoline (16): 7-Nitro-
2,4,4-trimethyl-3,4-dihydroisoquinolinium iodide (15) (1.5 g, 4.3 mmol)
was suspended in tetrahydrofuran (50 mL) under an argon atmosphere at
0ꢁC. To this suspension was added dimethyl zinc (3.3 mL of a 2 M solution
in toluene) with rapid stirring. The reaction was allowed to warm to room
temperature over 1 h and saturated ammonium chloride solution (10 mL)
was added. The organic solvent was removed and the resultant residue
partitioned between dichloromethane (100 mL) and water (100 mL). The
dichloromethane layer was separated, dried and evaporation under reduced
pressure gave the title compound (16) (0.91 g, 90%); ꢀmax/cmꢀ1 (CH2Cl2)
1508, 1451, 1425 and 1271; ꢁH [250 MHz, CDCl3] 1.30 (3H, s), 1.35 (3H, s),
1.40 (3H, d, J ¼ 6 Hz), 2.37 (1H, d, J ¼ 12 Hz), 2.47 (3H, s), 2.66 (1H, d,
J ¼ 12 Hz), 3.63 (1H, q, J ¼ 6 Hz), 7.41–7.46 (1H, m), 7.97–8.03 (2H, m);
Found: 234.1368. C13H18N2O2 requires: 234.1368.
REFERENCES
1. Harling, J.D.; Heer, J.P.; Thompson, M. PCT Int. Appl. 2000, 87pp.,
WO 0009486.
2. Gensler, W.J. Org. Reac. 1951, 6, 191–206.
3. Whaley, W.M.; Govindachari, T.R. Org. Reac. 1951, 6, 74–150.
4. Whaley, W.M.; Govindachari, T.R. Org. Reac. 1951, 6, 151–1190.
Chen, H.G.; Goel, O.P. Synth. Commun., 1995, 25, 49–56.
5. Seebach, D.; Lohmann, J.; Syfrig, M.A.; Yoshifuji, M. Tetrahedron,
1983, 39, 1963–1974.
6. Coppola, G.M. J. Heterocyclic Chem. 1991, 28, 1769–1772.
7. Meyers, A.I.; Boes, M.; Dickman, D.A. Org. Synth. 1989, 67, 60–68.
8. Kessar, S.V.; Singh, P.; Vohra, R.; Kaur, N.P.; Singh, K.N. J. Chem.
Soc. Chem. Commun. 1991, 568–570. Ebden, M.R.; Simpkins, N.S.
Tetrahedron Lett. 1995, 36, 8697–8700.
9. Pelletier, J.C.; Cava, M.P. J. Org Chem. 1987, 52, 616–622. Venkov,
A.P. Synth. Commun. 1996, 26, 127–134.
10. Bloch, R. Chem. Rev. 1998, 98, 1407–1438.
11. Kohno, H.; Sekine, Y. Heterocycles 1996, 42, 141–144.
12. Quallich, G.J.;Makowski, T.W.;Sanders, A.F.;Urban,F.J.;Vazquez, E.
J. Org. Chem. 1998, 63, 4116–4119.
Received in the UK July 19, 2001

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.