Tetrahydroisoquinolines by friedel-crafts cyclizations promoted by Iron(III) chloride hexahydrate

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Tetrahydroisoquinolines by Friedel-
Crafts Cyclizations Promoted by Iron(III)
Chloride Hexahydrate
Richard A. Bunce a , Nicholas R. Cain a & John G. Cooper a
a Department of Chemistry, Oklahoma State University Stillwater,
Oklahoma, USA
Version of record first published: 30 Mar 2012.
To cite this article: Richard A. Bunce, Nicholas R. Cain & John G. Cooper (2012):
Tetrahydroisoquinolines by Friedel-Crafts Cyclizations Promoted by Iron(III) Chloride Hexahydrate,
Organic Preparations and Procedures International: The New Journal for Organic Synthesis, 44:2,
131-145
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Organic Preparations and Procedures International, 44:131–145, 2012
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2012.643201
Tetrahydroisoquinolines by Friedel-Crafts
Cyclizations Promoted by Iron(III)
Chloride Hexahydrate
Richard A. Bunce, Nicholas R. Cain, and John G. Cooper
Department of Chemistry, Oklahoma State University Stillwater,
Oklahoma, USA
An ongoing synthetic project required access to substituted 4,4-dimethyl-1,2,3,4-
tetrahydroisoquinolines as the core ring structure for a potential drug analog. We recently
ꢀR
reported an approach to tetrahydronaphthalenes1 via Amberlyst 15 -promoted cyclization
of 5-aryl-2-methyl-2-pentanol derivatives and hoped to extend our method2 to the prepara-
tion of this heterocyclic system. Beyond our interest in these structures, the 4,4-dimethyl-
1,2,3,4-tetrahydroisoquinoline scaffold has been a key structural element in agents to treat
cancer,3–5 hepatitis C,6 CNS disorders7 and psychosis.8
Based on our earlier work,1 the synthesis of these compounds would require derivatives
of 1-(benzylamino)-2-methyl-2-propanol. Substrates incorporating this framework were
synthesized in three steps from benzylamines 1a-i by (1) treatment with pyridine and
p-toluenesulfonyl chloride to generate sulfonamides 2a-i, (2) alkylation at nitrogen using
sodium hydride and methyl bromoacetate in N,N-dimethylformamide (DMF) to provide
sulfonamide esters 3a-i and (3) addition of methylmagnesium iodide to the ester function
to give tertiary alcohols 4a-i (Scheme 1). The sulfonamide group was chosen due to its
stability and the acidity of the amide proton, which served to facilitate the alkylation step.
This group can be difficult to remove, however, and might require modification in our final
synthesis of these derivatives.
ꢀR
Attempts to cyclize tertiary alcohols 4a-i using Amberlyst 15 in benzene at 80◦C
and at 23◦C did not proceed as planned, but gave predominantly loss of the alcohol-bearing
side-chain and isolation of sulfonamides 2a-i (at 80◦C) and alkene products (at 23◦C).
Similar results were obtained when aluminum chloride and ethylaluminum dichloride were
employed. Following these disappointing results, it was decided to try the cyclization
using a milder Lewis acid. Recent work by others has demonstrated that iron(III) chlo-
ride hexahydrate (FeCl3·6H2O) is an effective catalyst for Friedel-Crafts cyclizations of
sensitive compounds.9,10 We found that treatment of 4a-i with 2.5 eq of FeCl3·6H2O in
dichloromethane in a sealed tube at 55–60◦C or in refluxing chloroform gave good to
Received August 19, 2011; in final form October 26, 2011.
Nick Cain and John Cooper were undergraduate research participants, 2010–2011.
Address correspondence to Richard A. Bunce, Department of Chemistry, 107 Physical Sciences,
Oklahoma State University, Stillwater, OK 74078-3071, USA. E-mail: rab@okstate.edu
131

132
Bunce et al.
Scheme 1
Synthesis of the cyclization substrates
excellent yields of the cyclized products (Table 1). Substrates with ortho and para aro-
matic substitution proceeded to give a single cyclized product (X at C8 from the ortho
and at C6 from the para) while meta-substituted substrates yielded the expected C7- and
C5-substituted products with the less sterically congested C7-substituted isomer favored
by ≥2:1. Work-up and purification were accomplished by standard methods.
In the current study, loss of the alcohol-bearing chain from the nitrogen to give 2 did not
occur to a significant extent, except in 4g and 4h where the aromatic ring was deactivated
Table 1
Cyclization Results
Ratio
Yield (%) of
X
Time (h)
Cyclization
5-X
6-X
7-X
8-X
a
b
c
d
e
f
g
h
i
H
4
4
4
4
2
2
6
6
4
91
82
91
90
82
0 [a]
82 [b]
54 [b]
84
2-CH3
3-CH3
4-CH3
3-OCH3
4-OCH3
3-C1
—
31
—
24
—
22
—
—
—
90
—
—
—
54
—
60
—
58
—
60
—
82
—
—
—
—
—
—
4-C1
2,3-Benzo
[a] 1-Tosylamino-2-methyl-2-propanol (7) was isolated in 87% yield. [b] Compounds 2g (14%)
and 2h (40%) were also isolated from 4g and 4h, respectively.

Tetrahydroisoquinolines by Friedel-Crafts Cyclizations
133
Scheme 2
Fragmentation of the 4-methoxyphenyl substrate (4f)
by Cl. This could possibly occur by displacement of the sulfonamide nitrogen, as the anion
or as an iron-coordinated species, by the neighboring oxygen.11 A different fragmentation
pathway was noted from the 4-methoxyphenyl substrate 4f, which yielded a polymeric
residue along with 1-tosylamino-2-methyl-2-propanol (7) (Scheme 2). In this reaction, the
observed products could arise by dealkylation of the methyl ether and displacement of
the sulfonamide anion by delocalization of the phenoxide electrons through the aromatic
system. Again, iron coordination to nitrogen could potentially facilitate this process.
In conclusion, a synthetic approach to tetrahydroisoquinolines from N-tosyl-1-
(benzylamino)-2-methyl-2-propanol derivatives using an FeCl3·6H2O-promoted Friedel-
Crafts-type cyclization has been developed. This strategy produced tetrahydroisoquinolines
in good to excellent yields. The use of this mild Lewis acid reduced fragmentation processes
encountered using more stringent reaction conditions.
Experimental Section
Unless otherwise indicated, all reactions were carried out under dry nitrogen in oven-dried
glassware. All reagents and solvents were used as received from various vendors. Reactions
were monitored by thin layer chromatography (TLC) on silica gel GF plates (Analtech No.
21521). Larger-scale separations were performed by preparative thin layer chromatography
(PTLC) on 20-cm × 20-cm silica gel GF plates (Analtech No. 02015). Band elution for
both methods was monitored using a hand-held UV lamp. Melting points are uncorrected.
FT-IR spectra were measured as thin films on NaCl disks. 1H- and 13C-NMR spectra were
obtained in CDCl3 at 300 MHz and 75 MHz, respectively, using tetramethylsilane as the
internal standard. Elemental analyses are satisfactory, and the data are shown.
Representative Procedure for Tosylation of Benzylamines:
N-Benzyl-4-methylbenzenesulfonamide (2a)
A 250-mL, three-necked, round-bottomed flask, equipped with an addition funnel, a con-
denser and a magnetic stirrer, was charged with 2.00 g (18.7 mmol) of benzylamine (1a),
20 mL of pyridine and 10 mL of benzene. To the stirred solution was added 4.28 g
(22.4 mmol) of p-toluenesulfonyl chloride (p-TsCl) portionwise over 5 min. The mixture
was stirred at room temperature for 12 h and then poured into 200 mL of 1 M HCl and ex-
tracted with ether (3 × 50 mL). The combined organic extracts were washed with 1 M HCl (4
× 50 mL), once with water (50 mL), once with 5% aqueous NaHCO3 (50 mL) and once with
saturated aqueous NaCl (50 mL), then dried (MgSO4) and concentrated under vacuum to

134
Bunce et al.
give a light tan solid. Trituration with 4:1 hexane:ether gave 4.54 g (93%) of sulfon-
amide 2a as an off-white solid, mp. 109–111◦C (lit.12 mp. 111–112◦C). IR: 3269, 1323,
1
1166 cm−1; H-NMR: δ 7.75 (d, J = 8.2 Hz, 2 H), 7.29 (d, J = 8.2 Hz, 2 H), 7.32–7.22
(m, 3 H), 7.19 (m, 2 H), 4.89 (t, J = 6.0 Hz, 1 H), 4.10 (d, J = 6.0 Hz, 2 H), 2.43 (s, 3 H);
13C-NMR: δ 143.5, 136.8, 136.3, 129.7, 128.6, 127.8, 127.1, 47.2, 21.5 (one aromatic C
was unresolved).
N-(2-Methylbenzyl)-4-methylbenzenesulfonamide (2b)
This compound was prepared from 2.26 g (18.7 mmol) of 2-methylbenzylamine (1b) using
20 mL of pyridine, 10 mL of benzene and 4.28 g (22.4 mmol) of p-TsCl. Work-up and
trituration as above gave 4.47 g (87%) of sulfonamide 2b as a white solid, mp. 118–119◦C
(lit.13 mp. 118.7–119.2◦C). IR: 3279, 1325, 1168 cm−1; 1H-NMR: δ 7.75 (d, J = 8.2 Hz,
2 H), 7.30 (d, J = 8.2 Hz, 2 H), 7.11 (m, 4 H), 4.70 (br t, J = 6.0 Hz, 1 H), 4.07 (d, J =
6.0 Hz, 2 H), 2.43 (s, 3 H), 2.23 (s, 3 H); 13C-NMR: δ 143.4, 136.6, 136.5, 133.9, 130.5,
129.7, 128.8, 128.1, 127.1, 126.1, 45.3, 21.5, 18.7.
N-(3-Methylbenzyl)-4-methylbenzenesulfonamide (2c)
This compound was prepared from 2.26 g (18.7 mmol) of 3-methylbenzylamine (1c) using
20 mL of pyridine, 10 mL of benzene and 4.28 g (22.4 mmol) of p-TsCl. Work-up and
trituration as above gave 4.57 g (89%) of sulfonamide 2c as an off-white solid, mp. 55–56◦C.
1
IR: 3283, 1325, 1157 cm−1; H-NMR: δ 7.75 (d, J = 8.2 Hz, 2 H), 7.29 (d, J = 8.2 Hz,
2 H), 7.15 (t, J = 7.7 Hz, 1 H), 7.04 (d, J = 7.1 Hz, 1 H), 6.97 (br s, 2 H), 4.81 (br s,
1 H), 4.07 (d, J = 6.0 Hz, 2 H), 2.43 (s, 3 H), 2.27 (s, 3 H); 13C-NMR: δ 143.4, 138.3,
136.8, 136.1, 129,7, 128.55, 128.53, 128.51, 127.1, 124.8, 47.2, 21.5, 21.2. 1H-NMR data
has been reported, but contains an error;14 no melting point was given.
Anal. Calcd for C14H15NO2S: C, 64.37; H, 5.75; N, 5.36. Found: C, 64.48; H, 5.79; N,
5.22.
N-(4-Methylbenzyl)-4-methylbenzenesulfonamide (2d)
This compound was prepared from 2.26 g (18.7 mmol) of 4-methylbenzylamine (1d) using
20 mL of pyridine, 10 mL of benzene and 4.28 g (22.4 mmol) of p-TsCl. Work-up and
trituration as above gave 4.78 g (93%) of sulfonamide 2d as an off-white solid, mp. 93–95◦C
1
(lit.13 mp. 94.7–95.5◦C). IR: 3277, 1322, 1157 cm−1; H-NMR: δ 7.75 (d, J = 8.2 Hz, 2
H), 7.29 (d, J = 8.2 Hz, 2 H), 7.07 (apparent s, 4 H), 4.81 (m 1 H), 4.05 (d, J = 6.0 Hz,
2 H), 2.43 (s, 3 H), 2.30 (s, 3 H); 13C-NMR: δ 143.4, 137.6, 136.8, 133.2, 129.7, 129.3,
127.8, 127.1, 47.0, 21.5, 21.0.
N-(3-Methoxybenzyl)-4-methylbenzenesulfonamide (2e)
This compound was prepared from 2.56 g (18.7 mmol) of 3-methoxybenzylamine (1e)
using 20 mL of pyridine, 10 mL of benzene and 4.28 g (22.4 mmol) of p-TsCl. Work-
up and trituration as above gave 4.73 g (87%) of sulfonamide 2e as an off-white solid,
1
mp. 79–81◦C (lit.15 mp. 81.3◦C). IR: 3283, 2841, 1329, 1161cm−1; H-NMR: δ 7.74 (d,

Tetrahydroisoquinolines by Friedel-Crafts Cyclizations
135
J = 8.2 Hz, 2 H), 7.28 (d, J = 8.2 Hz, 2 H), 7.16 (t, J = 7.7 Hz, 1 H), 6.74 (m, 3 H), 5.02
(br t, J = 6.0 Hz, 1 H), 4.07 (d, J = 6.0 Hz, 2 H), 3.72 (s, 3 H), 2.42 (s, 3 H); 13C-NMR: δ
159.7, 143.4, 137.8, 136.8, 129.7, 129.6, 127.1, 120.0, 113.6, 113.0, 55.1, 47.1, 21.5.
N-(4-Methoxybenzyl)-4-methylbenzenesulfonamide (2f)
This compound was prepared from 2.56 g (18.7 mmol) of 4-methoxybenzylamine (1f)
using 20 mL of pyridine, 10 mL of benzene and 4.28 g (22.4 mmol) of p-TsCl. Work-up
and trituration as above gave 4.90 g (90%) of sulfonamide 2f as an off-white solid, mp.
122–123◦C (lit.16 mp. 122–124◦C). IR: 3257, 2838, 1324, 1161 cm−1; 1H-NMR: δ 7.75 (d,
J = 8.2 Hz, 2 H), 7.31 (d, J = 8.2 Hz, 2 H), 7.11 (d, J = 8.8 Hz, 2 H), 6.80 (d, J = 8.8 Hz,
2 H), 4.67 (br t, J = 6.0 Hz, 1 H), 4.05 (d, J = 6.0 Hz, 2 H), 3.77 (s, 3 H), 2.44 (s, 3 H);
13C-NMR: δ 159.3, 143.4, 136.9, 129.7, 129.2, 128.2, 127.2, 114.0, 55.3, 46.8, 21.5.
N-(3-Chlorobenzyl)-4-methylbenzenesulfonamide (2g)
This compound was prepared from 2.66 g (18.7 mmol) of 3-chlorobenzylamine (1g) using
20 mL of pyridine, 10 mL of benzene and 4.28 g (22.4 mmol) of p-TsCl. Work-up and
trituration as above gave 5.14 g (93%) of sulfonamide 2g as an off-white solid, mp. 83–84◦C
(lit.15 mp. 84.6◦C). IR: 3269, 1317, 1158 cm−1; 1H-NMR: δ 7.71 (d, J = 8.2 Hz, 2 H), 7.29
(d, J = 8.2 Hz, 2 H), 7.19 (m, 2 H), 7.12 (s, 1 H), 7.11 (m, 1 H), 5.04 (br s, 1 H), 4.09
(d, J = 6.0 Hz, 2 H), 2.43 (s, 3 H); 13C-NMR: δ 143.7, 138.3, 136.7, 134.4, 129.9, 129.7,
127.90, 127.88, 127.1, 125.9, 46.6, 21.5.
N-(4-Chlorobenzyl)-4-methylbenzenesulfonamide (2h)
This compound was prepared from 2.66 g (18.7 mmol) of 4-chlorobenzylamine (1h) using
20 mL of pyridine, 10 mL of benzene and 4.28 g (22.4 mmol) of p-TsCl. Work-up and
trituration as above gave 5.02 g (91%) of sulfonamide 2h as an off-white solid, mp.
104–105◦C (lit.15 mp. 106.1◦C). IR: 3235, 1317, 1157 cm−1; 1H-NMR: δ 7.73 (d, J = 8.2 Hz,
2 H), 7.30 (d, J = 8.2 Hz, 2 H), 7.23 (d, J = 8.2 Hz, 2 H), 7.13 (d, 2 H, J = 8.2), 4.88 (t, J
= 6.0 Hz, 1 H), 4.09 (d, J = 6.0 Hz, 2 H), 2.44 (s, 3 H); 13C-NMR: δ 143.7, 136.7, 134.8,
133.7, 129.8, 129.2, 128.8, 127.1, 46.5, 21.5.
N-(1-Naphthylmethyl)-4-methylbenzenesulfonamide (2i)
This compound was prepared from 2.93 g (18.7 mmol) of 1-naphthylmethylamine (1i)
using 20 mL of pyridine, 10 mL of benzene and 4.28 g (22.4 mmol) of p-TsCl. Work-up
and trituration as above gave 5.08 g (87%) of sulfonamide 2i as an off-white solid, mp.
152–154◦C (lit.17 mp. 153–154◦C). IR: 3280, 1325, 1158 cm−1; 1H-NMR: δ 7.88 (m, 1 H),
7.82 (m, 1 H), 7.76 (d, J = 8.2 Hz, 2 H), 7.48 (m, 2 H), 7.30 (superimposed d, J = 8.2 Hz,
2 H and m, 3 H), 4.72 (t, J = 6.0 Hz, 1 H), 4.52 (d, J = 6.0 Hz, 2 H), 2.44 (s, 3 H);
13C-NMR: δ 143.5, 136.5, 133.7, 131.3, 131.1, 129.7, 129.0, 128.7, 127.2, 126.9, 126.7,
126.0, 125.2, 123.2, 45.4, 21.5.

136
Bunce et al.
Representative Procedure for Alkylation of the N-Benzyl-p-toluenesulfonamides:
Methyl N-Tosyl-2-(benzylamino)acetate (3a)
In a 250-mL, three-necked, round-bottomed flask, equipped with an addition funnel, a
condenser and a magnetic stirrer, 0.44 g of 60% sodium hydride in mineral oil (11.0 mmol)
was washed with hexanes (3 × 5 mL) to remove the mineral oil and 10 mL of anhydrous
DMF was added. Stirring was begun and a solution of 2.61 g (10.0 mmol) of 2a in 15 mL of
anhydrous DMF was added dropwise over 20 min. Stirring was continued for an additional
20 min at which time a solution of 1.68 g (1.04 mL, 11.0 mmol) of methyl bromoacetate
in 10 mL of dry DMF was added and the mixture was stirred for 6 h. The crude reaction
was added to 100 mL of saturated aqueous NaCl and the mixture was extracted with ether
(3 × 100 mL). The combined organic extracts were washed once with saturated NaCl
(50 mL), dried (MgSO4) and concentrated under vacuum to give a viscous light yellow oil
that solidified on standing. Trituration of the solid with 5–10% ether in petroleum ether
gave 2.73 g (82%) of ester 3a as a white solid, mp. 53–55◦C. IR: 1751, 1346, 1160 cm−1
;
1H-NMR: δ 7.78 (d, J = 8.2 Hz, 2 H), 7.37–7.28 (m, 5 H), 7.24 (m, 2 H), 4.48 (s, 2 H),
3.92 (s, 2 H), 3.54 (s, 3 H), 2.45 (s, 3 H); 13C-NMR: δ 169.2, 143.5, 136.8, 134.9, 129.5,
128.7, 128.5, 128.1, 127.4, 51.9, 51.3, 46.5, 21.6.
Anal. Calcd for C17H19NO4S: C, 61.26; H, 5.71; N, 4.20. Found: C, 61.39; H, 5.74; N,
4.14.
Methyl N-Tosyl-2-(2-methylbenzylamino)acetate (3b)
This compound was prepared from 2.75 g (10.0 mmol) of 2b, 0.26 g (11.0 mmol) of oil-free
NaH and 1.68 g (1.04 mL, 11.0 mmol) of methyl bromoacetate. Work-up and trituration
as above gave 2.82 g (81%) of ester 3b as a white solid, mp. 65–66◦C. IR: 1748, 1340,
1161 cm−1; 1H-NMR: δ 7.76 (d, J = 8.2 Hz, 2 H), 7.34 (d, J = 8.2 Hz, 2 H), 7.17 (m, 2
H), 7.12 (m, 2 H), 4.51 (s, 2 H), 3.84 (s, 2 H), 3.48 (s, 3 H), 2.45 (s, 3 H), 2.32 (s, 3 H);
13C-NMR: δ 169.1, 143.5, 137.9, 136.2, 132.3, 130.7, 129.6, 129.5, 128.3, 127.4, 126.1,
51.8, 49.5, 46.5, 21.5, 19.0.
Anal. Calcd for C18H21NO4S: C, 62.25; H, 6.05; N, 4.03. Found: C, 62.34; H, 6.06; N,
3.95.
Methyl N-Tosyl-2-(3-methylbenzylamino)acetate (3c)
This compound was prepared from 2.75 g (10.0 mmol) of 2c, 0.26 g (11.0 mmol) of
oil-free NaH and 1.68 g (1.04 mL, 11.0 mmol) of methyl bromoacetate. Work-up as
above gave 2.81 g (81%) of ester 3c as a yellow oil that did not crystallize. This material
was spectroscopically pure and was used without further purification. IR: 1748, 1340,
1161 cm−1; 1H-NMR: δ 7.77 (d, J = 8.2 Hz, 2 H), 7.33 (d, J = 8.2 Hz, 2 H), 7.19 (t, J =
7.7 Hz, 1 H), 7.09 (d, J = 7.7 Hz, 1 H), 7.02 (superimposed s, 1 H and d, 1 H), 4.45 (s,
2 H), 3.91 (s, 2 H), 3.54 (s, 3 H), 2.44 (s, 3 H), 2.30 (s, 3 H); 13C-NMR: δ 169.1, 143.4,
138.4, 136.8, 134.7, 129.5, 129.2, 128.8, 128.5, 127.3, 125.6, 51.9, 51.1, 46.4, 21.5, 21.2.
Anal. Calcd for C18H21NO4S: C, 62.25; H, 6.05; N, 4.03. Found: C, 62.40; H, 6.09; N,
3.97.

Tetrahydroisoquinolines by Friedel-Crafts Cyclizations
Methyl N-Tosyl-2-(4-methylbenzylamino)acetate (3d)
137
This compound was prepared from 2.75 g (10.0 mmol) of 2d, 0.26 g (11.0 mmol) of oil-free
NaH and 1.68 g (1.04 mL, 11.0 mmol) of methyl bromoacetate. Work-up and trituration
as above gave 2.88 g (83%) of ester 3d as a white solid, mp. 64–66◦C. IR: 1752, 1343,
1161 cm−1; 1H-NMR: δ 7.77 (d, J = 8.2 Hz, 2 H), 7.32 (d, J = 8.2 Hz, 2 H), 7.12 (apparent
s, 4 H), 4.44 (s, 2 H), 3.90 (s, 2 H), 3.54 (s, 3 H), 2.44 (s, 3 H), 2.32 (s, 3 H); 13C-NMR: δ
169.2, 143.4, 137.9, 136.8, 131.7, 129.5, 129.3, 128.6, 127.4, 51.9, 50.9, 46.3, 21.5, 21.1.
Anal. Calcd for C18H21NO4S: C, 62.25; H, 6.05; N, 4.03. Found: C, 62.31; H, 6.08; N,
4.01.
Methyl N-Tosyl-2-(3-methoxybenzylamino)acetate (3e)
This compound was prepared from 2.91 g (10.0 mmol) of 2e, 0.26 g (11.0 mmol) of oil-
free NaH and 1.68 g (1.04 mL, 11.0 mmol) of methyl bromoacetate. Work-up as above
gave 2.90 g (80%) of ester 3e as a yellow oil that did not crystallize. This material was
spectroscopically pure and was used without further purification. IR: 2841, 1749, 1343,
1161 cm−1; 1H-NMR: δ 7.78 (d, J = 8.2 Hz, 2 H), 7.33 (d, J = 8.2 Hz, 2 H), 7.21 (t, J =
7.7 Hz, 1 H), 6.81 (m, 3 H), 4.46 (s, 2 H), 3.92 (s, 2 H), 3.75 (s, 3 H), 3.55 (s, 3 H), 2.44
(s, 3 H); 13C-NMR: δ 169.1, 159.8, 143.7, 136.7, 136.4, 129.6, 129.5, 127.4, 120.7, 113.9,
113.6, 55.1, 51.9, 51.2, 46.4, 21.5.
Anal. Calcd for C18H21NO5S: C, 59.50; H, 5.79; N, 3.86. Found: C, 59.71; H, 5.84; N,
3.83.
Methyl N-Tosyl-2-(4-methoxybenzylamino)acetate (3f)
This compound was prepared from 2.91 g (10.0 mmol) of 2f, 0.26 g (11.0 mmol) of oil-free
NaH and 1.68 g (1.04 mL, 11.0 mmol) of methyl bromoacetate. Work-up and trituration as
above gave 2.98 g (82%) of ester 3f as a white solid, mp. 78–80◦C. IR: 2840, 1748, 1339,
1
1159 cm−1; H-NMR: δ 7.77 (d, J = 8.2 Hz, 2 H), 7.33 (d, J = 8.2 Hz, 2 H), 7.15 (d,
J = 8.2 Hz, 2 H), 6.83 (d, J = 8.2 Hz, 2 H), 4.41 (s, 2 H), 3.89 (s, 2 H), 3.79 (s, 3 H), 3.54
(s, 3 H), 2.44 (s, 3 H); 13C-NMR: δ 169.2, 159.5, 143.4, 136.8, 130.1, 129.5, 127.4, 126.7,
114.0, 55.2, 51.9, 50.7, 46.2, 21.5.
Anal. Calcd for C18H21NO5S: C, 59.50; H, 5.79; N, 3.86. Found: C, 59.62; H, 5.80; N,
3.79.
Methyl N-Tosyl-2-(3-chlorobenzylamino)acetate (3g)
This compound was prepared from 2.96 g (10.0 mmol) of 2g, 0.26 g (11.0 mmol) of
oil-free NaH and 1.68 g (1.04 mL, 11.0 mmol) of methyl bromoacetate. Work-up as
above gave 3.31 g (90%) of ester 3g as a yellow oil that did not crystallize. This material
was spectroscopically pure and was used without further purification. IR: 1748, 1343,
1
1160 cm−1; H-NMR: δ 7.76 (d, J = 8.2 Hz, 2 H), 7.33 (d, J = 8.2 Hz, 2 H), 7.25 (m,
2 H), 7.19 (s, 1 H), 7.16 (m, 1 H), 4.46 (s, 2 H), 3.93 (s, 2 H), 3.56 (s, 3 H), 2.45 (s, 3 H);
13C-NMR: δ 169.0, 143.7, 137.2, 136.6, 134.6, 130.0, 129.6, 128.5, 128.3, 127.4, 126.6,
52.0, 50.8, 46.7, 21.6.

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Bunce et al.
Anal. Calcd for C17H18ClNO4S: C, 55.51; H, 4.90; N, 3.81. Found: C, 55.73; H, 4.97;
N, 3.69.
Methyl N-Tosyl-2-(4-chlorobenzylamino)acetate (3h)
This compound was prepared from 2.96 g (10.0 mmol) of 2h, 0.26 g (11.0 mmol) of oil-free
NaH and 1.68 g (1.04 mL, 11.0 mmol) of methyl bromoacetate. Work-up and trituration as
above gave 3.41 g (93%) of ester 3h as a white solid, mp. 66–68◦C. IR: 1748, 1342, 1160
cm−1; 1H-NMR: δ 7.75 (d, J = 8.2 Hz, 2 H), 7.33 (d, J = 8.2 Hz, 2 H), 7.29 (d, J = 8.2
Hz, 2 H), 7.20 (d, J = 8.2 Hz, 2 H), 4.44 (s, 2 H), 3.91 (s, 2 H), 3.55 (s, 3 H), 2.44 (s, 3
H); 13C-NMR: δ 169.0, 143.7, 136.6, 134.0, 133.5, 129.9, 129.6, 128.8, 127.4, 52.0, 50.7,
46.6, 21.5.
Anal. Calcd for C17H18ClNO4S: C, 55.51; H, 4.90; N, 3.81. Found: C, 55.57; H, 4.87;
N, 3.78.
Methyl N-Tosyl-2-(1-naphthylmethylamino)acetate (3i)
This compound was prepared from 3.11 g (10.0 mmol) of 2i, 0.26 g (11.0 mmol) of oil-free
NaH and 1.68 g (1.04 mL, 11.0 mmol) of methyl bromoacetate. Work-up and trituration
as above gave 2.98 g (78%) of ester 3i as a white solid, mp. 83–84◦C. IR: 1748, 1340,
1
1161 cm−1; H-NMR: δ 8.23 (d, J = 8.8 Hz, 1 H), 7.84 (obscured signal, 2 H), 7.81 (d,
J = 8.2 Hz, 2 H), 7.52 (m, 2 H), 7.36 (d, J = 8.2 Hz, 2 H), 7.36 (obscured signal, 1 H), 7.29
(d, J = 7.0 Hz, 1 H), 4.96 (s, 2 H), 3.80 (s, 2 H), 3.39 (s, 3 H), 2.46 (s, 3 H); 13C-NMR: δ
169.1, 143.6, 136.1, 133.7, 131.9, 129.8, 129.6, 129.4, 128.5, 128.1, 127.5, 126.7, 126.1,
125.0, 123.8, 51.7, 49.4, 46.5, 21.6.
Anal. Calcd for C21H21NO4S: C, 65.80; H, 5.48; N, 3.66. Found: C, 65.76; H, 5.51; N,
3.74.
Representative Procedure for Grignard Addition to the Sulfonamide Esters:
N-Tosyl-1-(benzylamino)-2-methyl-2-propanol (4a)
A 250-mL three-necked, round-bottomed flask, equipped with an addition funnel, a con-
denser and a magnetic stirrer, was charged with 1.00 g (41.7 mmol) of magnesium metal
and 5 mL of ether. To this mixture was added a small portion of a solution of 2.13 g
(0.93 mL, 15.0 mmol) of methyl iodide in 25 mL of ether. Several of the magnesium
turnings were carefully crushed with a glass rod until the reaction was initiated and the
remainder of the methyl iodide solution was slowly added dropwise to maintain a gentle
reflux. When the addition was complete, the reaction was gently heated for 10 min to assure
complete formation of the Grignard reagent. The heat source was removed and a solution of
1.67 g (5.00 mmol) of 3a in 10 mL of ether was added dropwise over 15 min. The reaction
mixture was heated for 15 min, then cooled and 25 mL of saturated aqueous NH4Cl was
added dropwise. The mixture was filtered through a cotton pad (removes remaining mag-
nesium turnings) into a separatory funnel containing 75 mL of saturated aqueous NH4Cl
and the mixture was extracted with ether (3 × 50 mL). The combined organic extracts were
washed once with water (50 mL) and once with saturated aqueous NaCl (50 mL), then dried
(MgSO4) and concentrated under vacuum to give a viscous light yellow oil. Purification by

Tetrahydroisoquinolines by Friedel-Crafts Cyclizations
139
crystallization from ether-petroleum ether afforded 1.37 g (82%) of alcohol 4a as a white
1
solid, mp. 78–80◦C. IR: 3521, 1332, 1155 cm−1; H-NMR: δ 7.72 (d, J = 8.2 Hz, 2 H),
7.34 (d, J = 8.2 Hz, 2 H), 7.33 (m, 5 H), 4.41 (s, 2 H), 3.15 (s, 2 H), 2.43 (s, 3 H), 2.40 (br
s, 1H), 1.09 (s, 6 H); 13C-NMR: δ 143.6, 136.2, 129.7, 128.7, 128.5, 128.2, 127.8, 127.4,
71.0, 59.4, 54.8, 27.6, 21.4.
Anal. Calcd for C18H23NO3S: C, 64.86; H, 6.91; N, 4.20. Found: C, 64.97; H, 6.96; N,
4.14.
N-Tosyl-1-(2-methylbenzylamino)-2-methyl-2-propanol (4b)
This compound was prepared by reaction of 1.74 g (5.00 mmol) of 3b with 3.0 eq of
methylmagnesium iodide in ether. Work-up as above gave 1.39 g (80%) of alcohol 4b
as a yellow oil. This material was spectroscopically pure and was used without further
1
purification. IR: 3517, 1336, 1158 cm−1; H-NMR: δ 7.74 (d, J = 8.2 Hz, 2 H), 7.34 (d,
J = 8.2 Hz, 2 H), 7.15 (m, 2 H), 7.10 (m, 2 H), 4.31 (s, 2 H), 3.07 (s, 2 H), 2.45 (coincident
s, 3 H and 1 H), 2.37 (s, 3 H), 0.95 (s, 6 H); 13C-NMR: δ 143.8, 137.5, 134.4, 133.5, 130.7,
129.7, 129.5, 128.1, 127.7, 125.9, 70.4, 59.5, 53.7, 27.3, 21.5, 19.2.
Anal. Calcd for C19H25NO3S: C, 65.71; H, 7.20; N, 4.03. Found: C, 65.89; H, 7.27; N,
3.89.
N-Tosyl-1-(3-methylbenzylamino)-2-methyl-2-propanol (4c)
This compound was prepared by reaction of 1.74 g (5.00 mmol) of 3c with 3.0 eq of
methylmagnesium iodide in ether. Work-up as above and purification by crystallization
from ether-petroleum ether gave 1.35 g (78%) of alcohol 4c as a white solid, mp. 57–59◦C.
1
IR: 3523, 1332, 1158 cm−1; H-NMR: δ 7.72 (d, J = 8.2 Hz, 2 H), 7.32 (d, J = 8.2 Hz,
2 H), 7.17 (t, J = 7.7 Hz, 1 H), 7.06 (d, J = 7.7 Hz, 1 H), 7.00 (d, J = 7.2 Hz, 1 H), 6.89
(s, 1 H), 4.39 (s, 2 H), 3.16 (s, 2 H), 2.44 (coincident s, 3 H and 1 H), 2.25 (s, 3 H), 1.12 (s,
6 H); 13C-NMR: δ 143.5, 138.3, 136.2, 136.0, 129.7, 129.2, 128.6, 128.5, 127.5, 125.7,
71.1, 59.3, 54.7, 27.6, 21.5, 21.2.
Anal. Calcd for C19H25NO3S: C, 65.71; H, 7.20; N, 4.03. Found: C, 65.79; H, 7.18; N,
3.97.
N-Tosyl-1-(4-methylbenzylamino)-2-methyl-2-propanol (4d)
This compound was prepared by reaction of 1.74 g (5.00 mmol) of 3d with 3.0 eq of
methylmagnesium iodide in ether. Work-up as above and purification by crystallization
from ether-petroleum ether gave 1.49 g (86%) of alcohol 4d as a white solid, mp. 80–81◦C.
IR 3524, 1332, 1154 cm−1; 1H-NMR: δ 7.73 (d, J = 8.2 Hz, 2 H), 7.32 (d, J = 8.2 Hz, 2
H), 7.09 (apparent s, 4 H), 4.36 (s, 2 H), 3.14 (s, 2 H), 2.44 (coincident s, 3 H and 1 H),
2.32 (s, 3 H), 1.09 (s, 6 H); 13C-NMR: δ 143.6, 137.7, 136.0, 133.0, 129.7, 129.3, 128.7,
127.5, 71.0, 59.4, 54.7, 27.6, 21.5, 21.1.
Anal. Calcd for C19H25NO3S: C, 65.71; H, 7.20; N, 4.03. Found: C, 65.75; H, 7.21; N,
4.00.

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Bunce et al.
N-Tosyl-1-(3-methoxybenzylamino)-2-methyl-2-propanol (4e)
This compound was prepared by reaction of 1.82 g (5.00 mmol) of 3e with 3.0 eq of
methylmagnesium iodide in ether. Work-up as above gave 1.45 g (80%) of alcohol 4e
as a yellow oil. This material was spectroscopically pure and was used without further
purification. IR 3524, 2838, 1332, 1161 cm−1; 1H-NMR: δ 7.73 (d, J = 8.2 Hz, 2 H), 7.32
(d, J = 8.2 Hz, 2 H), 7.19 (t, J = 7.7 Hz, 1 H), 6.79 (m, 2 H), 6.72 (s, 1 H), 4.40 (s, 2 H),
3.72 (s, 3 H), 3.16 (s, 2 H), 2.43 (2 s, 3 H and 1 H), 1.12 (s, 6 H); 13C-NMR: δ 159.7, 143.6,
137.7, 136.1, 129.7, 129.6, 127.4, 120.8, 113.68, 113.65, 71.1, 59.3, 55.1, 54.7, 27.6, 21.4.
Anal. Calcd for C19H25NO4S: C, 62.81; H, 6.89; N, 3.86. Found: C, 63.01; H, 6.95; N,
3.75.
N-Tosyl-1-(4-methoxybenzylamino)-2-methyl-2-propanol (4f)
This compound was prepared by reaction of 1.82 g (5.00 mmol) of 3f with 3.0 eq of
methylmagnesium iodide in ether. Work-up as above and purification by crystallization
from ether-petroleum ether gave 1.51 g (83%) of alcohol 4f as a white solid, mp. 82–84◦C.
IR 3521, 2837, 1329, 1157 cm−1; 1H-NMR: δ 7.73 (d, J = 8.2 Hz, 2 H), 7.32 (d, J = 8.2 Hz,
2 H), 7.14 (d, J = 8.2 Hz, 2 H), 6.82 (d, J = 8.2 Hz, 2 H), 4.33 (s, 2 H), 3.79 (s, 3 H),
3.13 (s, 2 H), 2.49 (br s, 1 H), 2.45 (s, 3 H), 1.09 (s, 6 H); 13C-NMR: δ 159.3, 143.6, 136.0,
130.2, 129.7, 128.0, 127.5, 114.0, 71.0, 59.3, 55.2, 54.4, 27.6, 21.5.
Anal. Calcd for C19H25NO4S: C, 62.81; H, 6.89; N, 3.86. Found: C, 62.89; H, 6.91; N,
3.80.
N-Tosyl-1-(3-chlorobenzylamino)-2-methyl-2-propanol (4g)
This compound was prepared by reaction of 1.84 g (5.00 mmol) of 3g with 3.0 eq of
methylmagnesium iodide in ether. Work-up as above and purification by crystallization
from ether-petroleum ether gave 1.47 g (80%) of alcohol 4g as a white solid, mp. 70–72◦C.
IR: 3521, 1332, 1157 cm−1; 1H-NMR: δ 7.70 (d, J = 8.2 Hz, 2 H), 7.32 (d, J = 8.2 Hz, 2
H), 7.20 (m, 2 H), 7.12 (m, 1 H), 7.00 (s, 1 H), 4.45 (s, 2 H), 3.17 (s, 2 H), 2.44 (s, 3 H),
2.29 (br s, 1 H), 1.16 (s, 6 H); 13C-NMR: δ 143.8, 138.3, 136.3, 134.4, 129.8, 129.7, 128.5,
127.8, 127.3, 126.8, 71.4, 58.9, 53.8, 27.8, 21.5.
Anal. Calcd for C18H22NO3S: C, 58.78; H, 5.99; N, 3.81. Found: C, 58.87; H, 6.02; N,
3.74.
N-Tosyl-1-(4-chlorobenzylamino)-2-methyl-2-propanol (4h)
This compound was prepared by reaction of 1.84 g (5.00 mmol) of 3h with 3.0 eq of
methylmagnesium iodide in ether. Work-up as above and purification by crystallization
from ether-petroleum ether gave 1.51 g (82%) of alcohol 4h as a white solid, mp. 95–96◦C.
IR: 3522, 1333, 1154 cm−1; 1H-NMR; δ 7.70 (d, J = 8.2 Hz, 2 H), 7.32 (d, J = 8.2 Hz, 2
H), 7.25 (d, J = 8.2 Hz, 2 H), 7.15 (d, J = 8.2 Hz, 2 H), 4.40 (s, 2 H), 3.15 (s, 2 H), 2.43 (s,
3 H), 2.23 (br s, 1 H), 1.12 (s, 6 H); 13C-NMR: δ 143.7, 136.1, 134.9, 133.7, 130.0, 129.8,
128.7, 127.4, 71.3, 59.2, 54.0, 27.7, 21.5.

Tetrahydroisoquinolines by Friedel-Crafts Cyclizations
141
Anal. Calcd for C18H22ClNO3S: C, 58.78; H, 5.99; N, 3.81. Found: C, 58.82; H, 6.01;
N, 3.77.
N-Tosyl-1-(1-naphthylmethylamino)-2-methyl-2-propanol (4i)
This compound was prepared by reaction of 1.92 g (5.00 mmol) of 3i with 3.0 eq of
methylmagnesium iodide in ether. Work-up as above gave 1.46 g (76%) of alcohol 4i
as a yellow oil. This material was spectroscopically pure and was used without fur-
1
ther purification. IR: 3514, 1331, 1161 cm−1; H-NMR: δ 8.34 (d, J = 8.8 Hz, 1 H),
7.81 (obscured signal, 2 H), 7.79 (d, J = 8.2 Hz, 2 H), 7.52 (m, 2 H), 7.34 (d, J = 8.2 Hz,
2 H), 7.32 (obscured signal, 1 H), 7.23 (d, J = 7.1 Hz, 1 H), 4.72 (s, 2 H), 3.09 (s, 2 H),
2.45 (coincident s, 3 H and 1 H), 0.73 (s, 6 H); 13C-NMR: δ 143.9, 133.9, 133.7, 132.0,
130.9, 129.8, 129.2, 128.5, 127.8, 126.7, 126.1, 124.8, 123.9, 70.2, 59.3, 54.2, 27.2, 21.5
(one aromatic C was unresolved).
Anal. Calcd for C22H25NO3S: C, 68.93; H, 6.53; N, 3.66. Found: C, 69.11; H, 6.60; N,
3.49.
Representative Procedure for Ring Closure of the Tetrahydroisoquinolines:
N-Tosyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline (5a)
A 15-mL Pyrex pressure vessel (Chemglass CG-1880–01 with O-ring CG-309–210),
equipped with a magnetic stirrer, was charged with a solution of 100 mg (0.30 mmol) of
4a in 5 mL of dichloromethane, 203 mg (0.75 mmol) of powdered iron(III) chloride hexa-
hydrate (FeCl3·6H2O) was added and the vessel was sealed under dry argon. The mixture
was heated at 55–60◦C for 4 h, then cooled and added to 25 mL of saturated aqueous NaCl.
The layers were separated, the aqueous phase was washed with ether (2 × 25 mL), and the
combined organic extracts were washed once with water (50 mL) and once with saturated
aqueous NaCl (50 mL), then dried (MgSO4) and concentrated under vacuum. The crude
product was purified on a 20 cm × 20 cm PTLC plate eluted with 20% ethyl acetate in
hexanes to afford one major band containing 86 mg (91%) of tetrahydroisoquinoline 5a as
a white solid, mp. 145–146◦C. IR: 1349, 1164 cm−1; 1H-NMR: δ 7.74 (d, J = 8.2 Hz, 2 H),
7.35 (d, J = 8.2 Hz, 2 H), 7.30 (d, J = 7.7 Hz, 1 H), 7.19 (t, J = 7.1 Hz, 1 H), 7.12 (td, J =
7.1, 1.1 Hz, 1 H), 6.99 (d, J = 7.7 Hz, 1 H), 4.20 (s, 2 H), 3.01 (s, 2 H), 2.44 (s, 3 H), 1.34
(s, 6 H); 13C-NMR: δ 143.6, 142.7, 142.6, 130.4, 129.7, 127.8, 127.1, 126.2, 126.1, 125.8,
56.0, 48.5, 35.4, 28.4, 21.5.
Anal. Calcd for C18H21NO2S: C, 68.57; H, 6.67; N, 4.44. Found: C, 68.52; H, 6.64; N,
4.47.
Note: The reactions to prepare 5a, 5d and 5h were also carried out in a 50-mL round-
bottomed flask on the same scale in 5 mL of refluxing chloroform under argon for the times
indicated in Table 1. The yields were as follows: 5a, 90%; 5d, 89%; and 5h, 58% (with
36% fragmentation).
N-Tosyl-4,4,8-trimethyl-1,2,3,4-tetrahydroisoquinoline (5b)
This compound was prepared from 100 mg (0.29 mmol) of 4b and 196 mg (0.73 mmol)
of FeCl3·6H2O in dichloromethane heated at 55–60◦C for 4 h under argon. Work-up and

142
Bunce et al.
purification by PTLC using 20% ethyl acetate in hexanes gave 78 mg (82%) of 5b as
1
a white solid, mp. 140–142◦C. IR: 1340, 1168 cm−1; H-NMR: δ 7.76 (d, J = 8.2 Hz,
2 H), 7.36 (d, J = 8.2 Hz, 2 H), 7.17 (d, J = 7.1 Hz, 1 H), 7.11 (t, J = 7.1 Hz, 1 H), 6.97
(d, J = 7.1 Hz, 1 H), 4.09 (s, 2 H), 3.00 (s, 2 H), 2.43 (s, 3 H), 2.17 (s, 3 H), 1.34 (s, 6
H); 13C-NMR: δ 143.6, 142.5, 134.2, 133.0, 129.7, 128.9, 127.7, 127.6, 126.7, 123.4, 55.3,
46.5, 35.3, 28.5, 21.5, 18.9.
Anal. Calcd for C19H23NO2S: C, 69.30; H, 6.99; N, 4.26. Found: C, 69.27; H, 6.97; N,
4.15.
N-Tosyl-4,4,7-trimethyl-1,2,3,4-tetrahydroisoquinoline (5c-A)
and N-Tosyl-4,4,5-trimethyl-1,2,3,4-tetrahydroisoquinoline (5c-B)18
These compounds were prepared from 100 mg (0.29 mmol) of 4c and 196 mg (0.73 mmol)
of FeCl3·6H2O in dichloromethane heated at 55–60◦C for 4 h under argon. Work-up and
purification by PTLC using 10% ethyl acetate in hexanes gave two bands: Band 1, 57 mg
(60%) of 5c-A as a white solid, mp. 175–177◦C; Band 2, 29 mg (31%) of 5c-B as a white
solid, mp. 123–124◦C.
The spectral data for 5c-A were: IR: 1339, 1168 cm−1; 1H-NMR: δ 7.73 (d, J = 8.2 Hz,
2 H), 7.35 (d, J = 8.2 Hz, 2 H), 7.18 (d, J = 8.2 Hz, 1 H), 7.00 (d, J = 8.2 Hz, 1 H), 6.81
(s, 1 H), 4.16 (s, 2 H), 2.99 (s, 2 H), 2.43 (s, 3 H), 2.26 (s, 3 H), 1.32 (s, 6 H); 13C-NMR: δ
143.6, 139.6, 135.7, 133.1, 130.2, 129.7, 128.0, 127.7, 126.6, 125.6, 56.1, 48.4, 35.0, 28.4,
21.5, 20.8.
Anal. Calcd for C19H23NO2S: C, 69.30; H, 6.99; N, 4.26. Found: C, 69.33; H, 7.01; N,
4.21.
The spectral data for 5c-B were: IR: 1343, 1165 cm−1; 1H-NMR: δ 7.74 (d, J = 8.2 Hz,
2 H), 7.36 (d, J = 8.2 Hz, 2 H), 7.00 (m, 2 H), 6.83 (d, J = 7.1 Hz, 1 H), 4.15 (s, 2 H), 2.92
(s, 2 H), 2.46 (s, 3 H), 2.44 (s, 3 H), 1.43 (s, 6 H); 13C-NMR: δ 144.1, 140.8, 137.2, 133.2,
131.9, 131.7, 130.1, 128.3, 126.4, 125.1, 59.1, 49.9, 36.6, 26.7, 23.4, 22.0.
Anal. Calcd for C19H23NO2S: C, 69.30; H, 6.99; N, 4.26. Found: C, 69.43; H, 7.04; N,
4.13.
N-Tosyl-4,4,6-trimethyl-1,2,3,4-tetrahydroisoquinoline (5d)
This compound was prepared from 100 mg (0.29 mmol) of 4d and 196 mg (0.73 mmol)
of FeCl3·6H2O in dichloromethane heated at 55–60◦C for 4 h under argon. Work-up and
purification by PTLC using 20% ethyl acetate in hexanes gave 88 mg (93%) of 5d as a
white solid, mp. 109–111◦C. IR: 1351, 1165 cm−1; 1H-NMR: δ 7.73 (d, J = 8.2 Hz, 2 H),
7.35 (d, J = 8.2 Hz, 2 H), 7.09 (s, 1 H), 6.94 (d, J = 8.2 Hz, 1 H), 6.88 (d, J = 8.2 Hz,
1 H), 4.16 (s, 2 H), 2.99 (s, 2 H), 2.43 (s, 3 H), 2.30 (s, 3 H), 1.32 (s, 6 H); 13C-NMR: δ
143.5, 142.3, 136.5, 133.1, 129.7, 127.7, 127.3, 127.0, 126.2, 126.0, 56.0, 48.3, 35.2, 28.4,
21.5, 21.2.
Anal. Calcd for C19H23NO2S: C, 69.30; H, 6.99; N, 4.26. Found: C, 69.49; H, 7.03; N,
4.07.

Tetrahydroisoquinolines by Friedel-Crafts Cyclizations
143
N-Tosyl-7-methoxy-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline (5e-A)
and N-Tosyl-5-methoxy-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline (5e-B)18
These compounds were prepared from 100 mg (0.28 mmol) of 4e and 189 mg (0.70 mmol)
of FeCl3·6H2O in dichloromethane heated at 55–60◦C for 2 h under argon. Work-up and
purification by PTLC using 10–15% ethyl acetate in hexanes gave two bands: Band 1,
27 mg (28%) of 5e-B as a white solid, mp. 108–109◦C; Band 2, 62 mg (65%) of 5e-A as a
white solid, mp. 176–178◦C.
The spectral data for 5e-B were: IR: 2939, 1343, 1165 cm−1; 1H-NMR: δ 7.73 (d, J =
8.2 Hz, 2 H), 7.35 (d, J = 8.2 Hz, 2 H), 7.10 (t, J = 7.9 Hz, 1 H), 6.72 (d, J = 7.9 Hz,
1 H), 6.61 (d, J = 7.9 Hz, 1 H), 4.11 (s, 2 H), 3.80 (s, 3 H), 2.91 (s, 2 H), 2.43 (s, 3 H), 1.40
(s, 6 H); 13C-NMR: δ 158.5, 143.6, 132.8, 132.6, 130.5, 129.7, 127.8, 126.8, 118.7, 109.6,
58.3, 55.0, 49.2, 35.3, 25.6, 21.5.
Anal. Calcd for C19H23NO3S: C, 66.09; H, 6.67; N, 4.06. Found: C, 66.14; H, 6.71; N,
3.97.
The spectral data for 5e-A were: IR: 2841, 1340, 1165 cm−1; 1H-NMR: δ 7.74 (d, J =
8.2 Hz, 2 H), 7.35 (d, J = 8.2 Hz, 2 H), 7.20 (d, J = 8.8 Hz, 1 H), 6.76 (dd, J = 8.8, 2.7 Hz,
1 H), 6.51 (d, J = 2.7 Hz, 1 H), 4.16 (s, 2 H), 3.74 (s, 3 H), 2.99 (s, 2 H), 2.43 (s, 3 H), 1.31
(s, 6 H); 13C-NMR: δ 157.6, 143.6, 134.7, 133.0, 131.5, 129.7, 127.7, 126.8, 113.5, 110.5,
56.1, 55.2, 48.6, 35.8, 28.5, 21.5.
Anal. Calcd for C19H23NO3S: C, 66.09; H, 6.67; N, 4.06. Found: C, 66.10; H, 6.69; N,
4.03.
1-Tosylamino-2-methyl-2-propanol (7)
This compound was isolated from the attempted cyclization of 100 mg (0.28 mmol) of
4f using 189 mg (0.70 mmol) of FeCl3·6H2O in dichloromethane heated at 55–60◦C for
2 h under argon. As the reaction proceeded, an intractable dark solid was formed on the
inside of the reaction vessel. This was separated from the crude reaction mixture and the
liquid phase was worked up as described above to give a light brown residue. PTLC of this
material using 40% ether in hexanes afforded 58 mg (87%) of alcohol 7 as a yellow oil. IR:
3498, 3277, 1325, 1158 cm−1; 1H-NMR (major rotamer): δ 7.75 (d, J = 8.2 Hz, 2 H), 7.32
(d, J = 8.2 Hz, 2 H), 4.86 (br t, J = 6.6 Hz, 1 H), 3.79 (br s, 1 H), 2.87 (d, J = 6.6 Hz,
2 H), 2.43 (s, 3 H), 1.23 (s, 6 H); 13C-NMR (major rotamer): δ 143.4, 136.7, 129.7, 127.0,
70.1, 53.4, 27.1, 21.5.
Anal. Calcd for C11H17NO3S: C, 54.32; H, 7.00; N, 5.76. Found: C, 54.47; H, 7.06; N,
5.55.
N-Tosyl-7-chloro-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline (5g-A)
and N-Tosyl-5-chloro-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline (5g-B)18
These compounds were prepared from 100 mg (0.27 mmol) of 4g and 184 mg (0.68 mmol)
of FeCl3·6H2O heated at 55–60◦C for 6 h under argon. Work-up as above and PTLC using
10–15% ethyl acetate in hexanes gave three bands: Band 1, 58 mg (60%) of 5g-A as a white

144
Bunce et al.
solid, mp. 177–178◦C; Band 2, 21 mg (22%) of 5g-B as a white solid, mp. 115–116◦C;
Band 3, 11 mg (14%) of 2g as a white solid, mp. 83–84◦C (mixture mp undepressed).
1
The spectral data for 5g-A were: IR: 1342, 1165 cm−1; H-NMR: δ 7.73 (d, J =
8.2 Hz, 2 H), 7.36 (d, J = 8.2 Hz, 2 H), 7.25 (d, J = 7.1 Hz, 1 H), 7.15 (dd, J = 7.1, 2.2 Hz,
1 H), 6.99 (d, J = 2.2 Hz, 1 H), 4.15 (s, 2 H), 2.99 (s, 2 H), 2.43 (s, 3 H), 1.32 (s, 6 H);
13C-NMR: δ 143.8, 141.2, 132.9, 132.2, 131.7, 129.8, 127.7, 127.36, 127.33, 126.0, 55.8,
48.2, 35.2, 28.4, 21.5.
Anal. Calcd for C18H20ClNO2S: C, 61.80; H, 5.72; N, 4.01. Found: C, 61.86; H, 5.72;
N, 3.98.
The spectral data for 5g-B were: IR: 1343, 1165 cm−1; 1H-NMR: δ 7.74 (d, J = 8.2
Hz, 2 H), 7.37 (d, J = 8.2 Hz, 2 H), 7.21 (d, J = 7.7 Hz, 1 H), 7.05 (t, J = 7.7 Hz, 1 H), 6.91
(d, J = 7.2 Hz, 1 H), 4.14 (s, 2 H), 2.93 (s, 2 H), 2.45 (s, 3 H), 1.53 (s, 6 H); 13C-NMR: δ
143.9, 139.2, 134.1, 133.9, 132.6, 130.5, 129.8, 127.9, 127.0, 125.5, 58.6, 49.7, 36.7, 25.3,
21.5.
Anal. Calcd for C18H20ClNO2S: C, 61.80; H, 5.72; N, 4.01. Found: C, 61.96; H, 5.78;
N, 3.78.
N-Tosyl-6-chloro-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline (5h)
This compound was prepared from 100 mg (0.27 mmol) of 4h and 184 mg (0.68 mmol)
of FeCl3·6H2O heated at 55–60◦C for 6 h under argon. Work-up as above and PTLC using
20% ethyl acetate in hexanes gave two bands: Band 1, 51 mg (54%) of 5h, mp. 108–109◦C;
Band 2, 32 mg (40%) of 2h, mp. 104–105◦C (mixture mp undepressed). The spectral data
for 5h were: IR: 1338, 1162 cm−1; 1H-NMR: δ 7.73 (d, J = 8.2 Hz, 2 H), 7.36 (d, J = 8.2 Hz,
2 H), 7.26 (d, J = 1.6 Hz, 1 H), 7.10 (dd, J = 8.2, 1.6 Hz, 1 H), 6.93 (d, J = 8.2 Hz, 1 H),
4.15 (s, 2 H), 2.99 (s, 2 H), 2.44 (s, 3 H), 1.32 (s, 6 H); 13C-NMR: δ 144.6, 142.8, 132.9,
132.7, 129.8, 128.8, 127.7, 127.6, 126.3, 126.0, 55.6, 48.0, 35.6, 28.3, 21.5.
Anal. Calcd for C18H20ClNO2S: C, 61.80; H, 5.72; N, 4.01. Found: C, 61.75; H, 5.74;
N, 3.93.
N-Tosyl-4,4-dimethyl-1,2,3,4-tetrahydrobenzo[h]isoquinoline (5i)
This compound was prepared from 100 mg (0.26 mmol) of 4i and 176 mg (0.65 mmol) of
FeCl3·6H2O heated at 55–60◦C for 4 h under argon. Work-up and purification by PTLC
eluted with 20% ethyl acetate in hexanes gave 80 mg (84%) of 5i as a white solid, mp.
149–151◦C. IR: 1343, 1165 cm−1; 1H-NMR: δ 7.83 (d, J = 8.2 Hz, 2 H), 7.79 (m, 1 H),
7.73 (t, J = 9.3 Hz, 2 H), 7.52 (m, 2 H), 7.44 (d, J = 8.2 Hz, 1 H), 7.38 (d, J = 8.2 Hz,
2 H), 4.62 (s, 2 H), 3.11 (s, 2 H), 2.44 (s, 3 H), 1.41 (s, 6 H); 13C-NMR: δ 143.7, 139.9,
138.1, 133.1, 131.6, 129.8, 128.5, 127.8, 127.5, 126.6, 125.5, 124.9, 123.7, 121.9, 55.6,
46.2, 35.7, 28.1, 21.5.
Anal. Calcd for C22H23NO2S: C, 72.33; H, 6.30; N, 3.84. Found: C, 72.25; H, 6.26; N,
3.88.
Acknowledgments
J. G. C. wishes to thank Oklahoma State University for a 2010–2011 Wentz Project Schol-
arship. Funding for the 300 MHz NMR spectrometer of the Oklahoma Statewide Shared

Tetrahydroisoquinolines by Friedel-Crafts Cyclizations
145
NMR Facility was provided by NSF (BIR-9512269), the Oklahoma State Regents for
Higher Education, the W. M. Keck Foundation, and Conoco, Inc. The authors also wish to
thank the OSU College of Arts and Sciences for funds to upgrade our departmental FT-IR
instruments.
References and Notes
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and the C5-substituted product is designated as B.