A new approach to synthesis of 3,3-dialkyl-3,4-dihydroisoquinoline derivatives

Article abstract of DOI:10.1002/hc.20049

The synthesis of 3,3-dialkyl-3,4-dihydroisoquinolines via heterocyclization in three-component reaction of an activated arene with isobutyraldehyde and nitriles is described.

Full text of DOI:10.1002/hc.20049

Heteroatom Chemistry
Volume 15, Number 7, 2004
A New Approach to Synthesis of
3,3-Dialkyl-3,4-dihydroisoquinoline Derivatives
Yu. V. Shklyaev,1 M. A. Yeltsov,1 Yu. S. Rozhkova,1 A. G. Tolstikov,1
and V. M. Dembitsky2
1Institute of Technical Chemistry, Ural Branch of the Russian Academy of Sciences, 13 Lenin
Street, 614900 Perm, Russian Federation
2Department of Organic Chemistry, P.O. Box 39231, Hebrew University of Jerusalem, Jerusalem
91391, Israel
Received 5 August 2004
1-substituted 3,4-dihydroisoquinolines with diverse
ABSTRACT: The synthesis of 3,3-dialkyl-3,4-dihy-
substituents in the aromatic moiety of the molecule
[3]. Due to recently developed methods, this type of
synthesis is feasible even if electron-seeking groups
droisoquinolines via heterocyclization in three-
component reaction of an activated arene with isobu-
ꢀ
C
tyraldehyde and nitriles is described.
2004 Wiley
such as halogens and a nitrogroup are present in the
aromatic ring [4]. Compounds such as 1-substituted
3,4-dihydroisoquinolines with alkyl substituents at
3ꢁ are rather poorly studied [5]. Methods for their
synthesis have been developed and mostly published
in Russian chemical journals by V. S. Shklyaev [6].
However, a few publications have lately appeared
suggesting new approaches to the traditional iso-
quinoline synthesis, such as the synthesis of 3,3-
dimethyl-3,4-dihydroisoquinoline-N-oxide, a potent
preparation against septic and traumatic stresses
[7]. Noteworthy, the author needed to use the N-
activated modification of the Pickte–Spengler reac-
tion as 2-methyl-3-phenyl-2-aminopropanes, being
in a free form, gave isoquinolines in relatively low
yields both in the Pickte–Spengler and in the Bishler–
Napieralski reactions.
Periodicals, Inc. Heteroatom Chem 15:486–493, 2004;
Published online in Wiley InterScience (www.interscience.
wiley.com). DOI 10.1002/hc.20049
INTRODUCTION
Recent interest in the medicinal chemistry of par-
tially hydrogenated isoquinoline alkaloids and their
derivatives is first conditioned by high-biological ac-
tivity of this class of heterocycles and their ubiquity
in nature [1].
The Bishler–Napieralski reaction is of great im-
portance in synthesizing 3,4-dihydroisoquinolines
[2]. Numerous modifications of this reaction afford
However, to obtain 3,4-dihydroisoquinoline
derivatives by oxidation of tetrahydro-isoquinoline
derivatives is nonpractical, and the Graaf–Ritter
reaction seems to be the method of choice in
this case. One of the first attempts to synthesize
1,3,3-trimethyl-3,4-dihydroisoquinoline [8] allowed
the target product in low yield. V. S. Shklyaev and
co-workers’ contribution to the synthesis of 1-sub-
stituted 3,3-dialkyl-3,4-dihydroisoquinoline made
Correspondence to: V. M. Dembitsky; e-mail: dvalery@cc.huji.
ac.il.
Contract grant sponsor: Russian Federation President’s Grant
for supporting Leading Organic Synthesis Schools.
Contract grant number: NS-2020.2003.3.
Contract grant sponsor: Presidium of the Russian Academy of
Sciences.
Contract grant sponsor: Russian Federation Foundation for
Basic Research.
Contract grant number: 04-03-95045, Urals.
2004 Wiley Periodicals, Inc.
c
ꢀ
486

A New Approach to Synthesis of 3,3-Dialkyl-3,4-dihydroisoquinoline Derivatives 487
SCHEME 1
it rather a routine procedure [9–12]. This method
appeared to be suitable for synthesizing 1-alkyl-
substituted 3,3-dialkyl-3,4-dihydroisoquinoline
derivatives themselves as well as benzo[f]- and
benzo[h]-3,4-dihydroisoquinolines and hexahydro-
phenanthridines [13–15].
The only disadvantage of the method is prob-
ably that organomagnesium synthesis is needed to
obtain initial carbinol. This was overcome in a three-
component “one-pot” synthesis from 1,2- or 1,4-
dimethoxybenzenes, isobutylene oxide, and nitriles
added in a 1:1:1 combination to concentrated H2SO4
[16]; however, isobutylene oxide is rather an expen-
sive and toxic reagent.
nitrile, acetonitrile, methylrhodane, cyanoacetic es-
ter, cyanoacetamide, and chloroacetamide. This was
not, however, true for benzyl cyanide or substituted
benzyl cyanides, where the syntheses were more dif-
ficult.
Veratrole, isobutyraldehyde, and benzyl cyanide
used in this reaction gave the reaction product,
1H NMR spectrum of which lacked a proton sig-
nal of CH2 benzene ring at C1, whereas its IR
spectrum showed a 1600 cm−1 band characteristic
of ketone carbonyl. MS-spectrum showed the peak
of the molecular ion corresponding to 1-benzoyl-
3,3,-dimethyl-3,4-dihydroisoquinoline 9 (Scheme 4).
Three-component condensation using 3,4-
dimethoxybenzyl cyanide as the major reaction
component led to the adduct of two molecules of the
above nitrile and isobutyraldehyde (10), the Bayer
reaction product (11), and ∼15% isoquinoline (12),
the latter containing a keto-group at C1 (Scheme 5).
We continue our studies of 3,3-dialkyl-3,4-
dihydroisoquinolines [17], and here we report the
synthesis of some novel derivatives.
RESULTS AND DISCUSSION
Basically, when isobutylene oxide is treated with
sulfuric acid, isobutyraldehyde should be formed.
Indeed, 3,3-dimethyl-3,4-dihydroisoquinoline
derivatives could be readily synthesized by three-
component condensation of activated arenes,
isobutyraldehyde, and nitriles (Scheme 1).
As for indan and tetralin, the reactions occurred
in a similar way and resulted in products 3 and 4
(Scheme 2). No change in the reaction course was
observed when benzdioxane was used as arene (1H
NMR, mp, formulas weight, and yields for all syn-
thesized compounds, see Tables 1 and 2).
The effects of the aldehyde component were ex-
amined, and ꢀ-alkyl-substituted aldehyde was found
to give readily 3,4-dihydroisoquinoline derivatives
6 and 7, whereas propionic aldehyde led to 9,10-
diethylanthracene 8 (Scheme 3).
The effects of the nitrile group were examined,
and, as was determined, three-component synthesis
occurred readily for benzyl nitrile and p-nitrobenzyl
SCHEME 2

488 Shklyaev et al.
TABLE 1 Physical and Chemical Characteristics and Data Analysis for Synthesized Compounds
Found, Calculated (%)
Molecular Formula
C
H
N
mp ( ◦C)
Yield (%)
1a
1b
1c
1d
2a
2b
2c
2d
3a
3b
3c
3d
4a
4b
4c
4d
5a
5b
5c
5d
6c
7a
7b
8
C14H19NO2
C14H19NO2S
72.00, 72.10
63.49, 63.40
66.70, 66.89
65.10, 65.22
74.20, 74.34
72.22, 72.10
74.61, 74.73
73.89, 73.77
75.11, 75.19
73.51, 73.42
75.70, 75.76
75.02, 74.97
75.77, 75.62
74.30, 74.13
76.41, 76.25
75.71, 75.56
72.66, 72.70
63.80, 63.85
67.17, 67.31
65.71, 65.68
70.09, 69.95
74.73, 74.70
67.19, 67.25
74.45, 74.55
74.37, 74.28
69.01, 68.91
81.43, 81.31
82.33, 82.44
86.73, 86.70
75.23, 75.19
86.53, 86.59
77.73, 77.64
82.10, 82.10
66.43, 66.36
79.41, 79.30
8.30, 8.15
7.30, 7.17
7.69, 7.54
7.40, 7.35
7.45, 7.37
8.27, 8.15
8.54, 8.42
8.11, 8.20
7.20, 7.17
7.87, 7.80
8.10, 8.12
7.80, 7.68
7.31, 7.40
8.00, 8.11
8.26, 8.36
8.03, 8.15
7.53, 7.41
6.70, 6.51
7.00, 6.98
6.59, 6.61
7.46, 7.34
9.34, 9.40
8.53, 8.47
7.31, 7.39
6.60, 6.55
6.44, 6.57
8.48, 8.53
7.34, 7.26
7.80, 7.68
7.10, 7.17
8.44, 8.36
7.60, 7.49
6.51, 6.51
7.40, 7.28
7.88, 8.04
6.17, 6.01
5.00, 5.28
4.50, 4.59
10.01, 10.14
4.25, 4.13
5.88, 6.01
5.00, 5.13
11.53, 11.48
4.03, 3.99
5.63, 5.71
5.00, 4.92
10.84, 10.93
4.01, 3.84
5.55, 5.41
4.51, 4.68
10.49, 10.37
5.98, 6.06
5.45, 5.32
4.50, 4.62
10.37, 10.21
4.00, 4.08
4.89, 4.84
4.30, 4.36
—
4.30, 4.33
3.80, 3.65
4.80, 4.74
4.96, 4.81
5.72, 5.62
4.07, 3.99
5.12, 5.05
4.59, 4.53
5.32, 5.32
5.82, 5.95
3.72, 3.85
148–150/12 mmHg
64–65 Hexane
104–105 Hexane
154–155 Ethylacetate
150–151 Ethylacetate
50–51 Hexane
86–87 Methanol
181–182 Ethylacetate
155–157 Ethanol
50,5–51,5 Hexane
78–79 Hexane
172–173 Ether–hexane
150–151 Ethanol
62
51
60
69
33
43
54
57
32
50
26
25
43
59
67
64
44
35
72
28
58
39
60
98
40 73
15 74
15
13 75
51
52
55
56
75
25
44
C17H23NO4
C15H20N2O3
21H25NO3 Salicylate
C14H19NS
C
C
C
H
NO2
17 23
15H20N2O
C
22H25NO3 Salicylate
15H19NS
C18 23NO2
16H20N2O
C23H27NO3 Salicylate
16H21NS
C19 25NO2
17H22N2O
14H17NO2
C
H
C
C
75–76 Hexane
119–120 Hexane
H
C
C
208–209 Ethylacetate
97–98 Hexane-CH2Cl2
82–83 Methanol
123–124 Ethylacetate
212–214 Methanol
126–128.5 Ethylacetate
180–183 3 MM
C
C
14H17NO2S
17H21NO4
C
15H18N2O3
C
20H25NO4
18H27NO2
18H27NO2S
C
C
198–205 3 mmHg
204–205 Hexane
133–135 Ethanol
174–176 Ethanol
107–109 Hexane
C22H26O4
9
C20H21NO3
C22H25NO5
12
13
14
17
18
19
20
21
23
24
C
C
20H25NO
20H21NO
124–126 Heptane
205–209a Ethylacetate
149–151 hexane
C
C
C
C
18H19
22H25NO3
20H23
20H23NO2
N
N
210–211a Ethylacetate
209–211a Ethylacetate
160–163a Ethylacetate
232–234 Benzene
130–133a Ethylacetate
C
18H17NO
13H17NO3
24H29NO2
C
C
amp hydrochloride.
Similar results were obtained for ortho-xylol,
with some of the product 13 being formed in the
reaction (Scheme 6).
Formally, the formation of 13 can be explained
by the reaction of benzyl carbon cation 15 with
a benzyl cyanide molecule; however, the reaction
of xylol with isobutyraldehyde adduct and one
molecule of benzyle cyanide 16 seems more likely
(Scheme 7).
Syntheses of products by condensation of
isobutyraldehyde and benzyl cyanide could be at-
tributed to the enhanced (compared to acetonitrile,
cyanoacetic ester, or methylrhodane) nucleophilic
nature of the nitrile group of benzyl cyanide, and
hence, isobutyraldehyde, in the protonated form, re-
acts rather with a nitrile group, but not with arene.
In the case of homoveratric acid nitrile, the nitrile
group is the main target for attack despite verat-
role present and due to sufficiently increased nu-
cleophilic reactivity of the nitrile group. To confirm
this hypothesis, three-component condensation of
dimethyl-(3,4-dimethyl)-benzyl carbinol with benzyl
cyanide in the presence of phenylacetoacetonitrile
was performed (Scheme 8).
In the reaction of benzyl cyanide with dimethyl-
benzyl carbinol for 15 min corresponding 1-benzyl-
3,4-dihydroisoquinolines 17, 19, 20 were always
formed and oxidized by the atmospheric O2 in ben-
zene to 1-benzoyl derivatives 12, 14, and 21 (∼75%
yield, Scheme 9).
As phenylacetoacetonitrile synthesized readily
3,4-dihydroisoquinoline derivatives, we introduced
nitriles of 2-phenylvalerianic acid (21) and 1-phenyl-
cyclopentancarboxylic acid (22) in the reaction.
With nitrile 21, 3,3-dimethyl-6,7-dimethoxy-3,4-
dihydro-isocarbostyryl 23 was found to be the

A New Approach to Synthesis of 3,3-Dialkyl-3,4-dihydroisoquinoline Derivatives 489
TABLE 2 1H NMR Data for Synthesized Compounds 1–24
1a 1.13 (6H, s, gem-CH3); 2.28 (3H, s, 1-CH3); 2.55 (2H, s, 4-CH2); 3.84 (6H, s, OCH3); 6.58 (1H, s,5-Harene); 6.93 (1H, s,
8-Harene
)
1b Data see Ref. 18
1c 1.21 (6H, s, gem-CH3); 1.24 (3H, t, OCH2CH3 J = 9 Hz); 2.69 (2H, s, 4-CH2); 3.83 (6H, s, 6,7-OCH3); 4.10 (2H, q, OCH2
J = 10ꢀµ); 4.98 (1H, s, Hvinyl); 6.55 (1H, s, 5-Harene); 7.06 (1H, s, 8-Harene);
1d 1.23 (6H, s, 3-(Me)2); 2.69 (2H, s, 4-CH2); 3.65 (3H, s, 6-OMe); 3.84 (3H, s, 7-OMe); 5.03 (1H, s, CH-vinyl); 5.19 (2H,
ddd C, NH2); 6.61 (1H, s, 5-H); 7.04 (1H, s, 8-H); 9.74 (1H, br s, C, NHisoquin).
2a 1.18 (6H, s, 3-(Me)2); 2.24 (6H, s, 6,7-Me); 2.34 (3H, s, 1-Me); 2.68 (2H, s, 4-CH2); 7.00–7.74 (6H, l.m, H-arene); 12.00
(1H, br s, OHphenol).
2b 1.14 (6H, s, 3-(Me)2); 2.24 (6H, s, 6,7-Me); 2.35 (3H, s, 1-SMe); 2.64 (2H, s, 4-CH2); 7.00 (1H, s, 5-H); 7.32 (1H, s, 8-H).
2c 1.19 (3H, t, CH3 ester.); 1.23 (6H, s, 3-(Me)2); 2.24 (6H, s, 6,7-Me); 2.74 (2H, s, 4-CH2); 4.05 (2H, q, OCH2); 5.03 (1H, s,
CH-vinyl); 6.97 (1H, s, 5-H); 7.43 (1H, s, 8-H); 8.84 (1H, s, NHisoquin).
2d 1.20 (6H, s, 3-(Me)2); 2.23 (6H, s, 6,7-Me); 2.69 (2H, s, 4-CH2); 5.08 (1H, s, CH-vinyl); 6.05 (2H, br s, NH2); 6.92 (1H, s,
5-H); 7.33 (1H, s, 8-H); 9.38 (1H, br s, NHisoquin).
3a* 1.26 (6H, s, 3-(Me)2); 1.77 (4H, br s.,7-CH2+8CH2); 2.60 (3H,s, 1-Me); 2.77 (4H, br s, 6-CH2+9CH2); 2.77 (s, 2H,
4-CH2); 6.75–7.75 (5,10H + 4H Sal)
3b 1.24 (6H, s, 3-(Me)2); 1.76 (4H, br s,7-CH2+8CH2); 2.55 (3H,s,1-SMe); 2.75 (4H, br s., 6-CH2+9CH2); 2.75 (s, 2H,
4-CH2); 6.90 (1H,s,5-H); 7.77 (1H,s,10-H)
3c 1.21 (6H, s, 3-(Me)2); 1.19 (3H, t,CH3-CH2O); 1.77 (4H, br s.,7-CH2+8CH2); 2.73 (4H, br s, 6-CH2+9CH2); 2.73 (s, 2H,
4-CH2); 4.06 (2H, q,OCH2); 5.03 (1H, s, CHvinyl); 6.90 (1H,s, 5-H); 7.83 (1H,s,10-H); 8.88 (1H, s, NH)
3d 1.19 (6H, s, 3-(Me)2); 1.77 (4H, br s, 7-CH2+8CH2); 2.72 (4H, br s.,6-CH2+ 9CH2); 2.69 (s, 2H, 4-CH2); 5.08 (1H,s,
CHvinyl); 6.13 (2H, br s, NH2); 6.86 (1H, s, 5-H); 7.57 (1H,s,10-H); 9.40 (1H,s, NHisoquin
)
4a 1.16 (6H, s, 3-(Me)2); 2.06 (2H,m,7-CH2); 2.32 (3H,s,1-Me); 2.61 (s, 2H, 4-CH2); 2.86 (4H, qq., 6-CH2 + 8-CH2); 6.95
(1H,s,5-H);7.31 (1H,s,9-H)
4b 1.28 (6H, s, 3-(Me)2); 2.13 (2H, m, 7-CH2); 2.49 (3H, s, SCH3); 2.72 (s, 2H, 4-CH2); 2.96 (4H, q, 6-CH2 + 8-CH2); 7.05
(1H,s,5-H); 7.60 (1H,s,9-H)
4c 1.27 (6H, s, 3-(Me)2); 1.30 (3H, t, OCH2CH3); 2.11 (2H, m, 7-CH2); 2.78 (s, 2H, 4-CH2); 2.87 (4H, q, 6-CH2 + 8-CH2);
4.19 (2H, q, OCH2); 5.14 (1H,s, Hvinyl); 7.00 (1H, s,5-H); 7.61 (1H,s,9-H); 8.99 (1H, br s, NH)
4d 1.23 (6H, s, 3-(Me)2); 2.09 (2H, m, 7-CH2); 2.76 (s, 2H, 4-CH2); 2.89 (4H, t, 6-CH2 + 8-CH2); 5.00 (1H, s, Hvinyl); 5.07
(2H, br s, NH2); 6.99 (1H,s,5-H); 7.46 (1H, s, 9-H); 9.51 (1H, br s, NHisoquin
)
5a 1.08 (6H, s, 3-(Me)2); 2.19 (3H, s, Me); 2.47 (s, 2H, 4-CH2); 4.25 (OCH2CH2O, 4H, m); 6.55 (1H, s,5-H); 6.90 (1H, s, 8-H)
5b 1.10 (6H, s, 3-(Me)2); 2.32 (1 H, s, SMe); 2.49 (s, 2H, 4-CH2); 4.17 (OCH2CH2O, 4H, m); 6.54 (1H,s,5-H); 7.11 (1H, s,
8-H)
5c 1.19 (3H, t, J = 7.6, Me); 1.20 (6H, s, 3-(Me)2); 2.70 (s, 2H, 4-CH2); 4.03 (2H, q, J = 7.6, OCH2); 4.26 (OCH2CH2O, 4H,
m); 4.94 (1H, s, CH); 6.75 (1H,s,5-H); 7.19 (1H, s, 8-H); 8.90 (1H, s, NH)
5d 1.18 (6H, s, 3-(Me)2); 2.60 (s, 2H, 4-CH2); 4.20 (OCH2CH2O,4H, m); 4.82 (1 H, s, CH ) 4.85 (2 H, br s, NH2); 6.55
(1H,s,5-H); 7.06 (1H, s, 8-H); 9.45 (1 H, s, NH)
6c 1.23 (3H, t, J = 7.6, Me); 1.35–1.58 (10H, m, Hcyclohexyl); 2.64 (s, 2H, 4-CH2); 4.09 (2H, q, J = 7.6, OCH2); 4.18
(OCH2CH2O,4H, m); 4.94 (1H, s, CH); 6.56 (1H,s,5-H); 7.12 (1H, s, 8-H); 9.23 (1H, s, NH)
7a 0.79 (3H, t, CH3 alkyl); 0.80 (3H, t, CH3 alkyl); 1.17–1.53 (8H, lm, Halkyl); 2.29 (3H, s, 1-CH3); 2.53 (2H, s, 4-CH2); 3.84 (6H,
s, 6,7-MeO); 6.57 (1H, s, 5-Harene); 6.92 (1H, s, 8-Harene); 6.55 (1H, s, 5-Harene); 7.08 (1H, s, 8-Harene
)
7b 0.80 (6H, t, CH3 alkyl); 1.17–1.48 (8H, lm, Halkyl); 2.36–2.29 (3H, s, 1-SCH3); 2.53 (2H, s, 4-CH2); 3.83 (6H, s, 6,7-MeO);
8
9
1.33 (6H, t, 2Me); 3.45 (4H, q, 2CH2); 3.95 (12H, s, 2,3,6,7-OMe); 7.40 (4H, s, H-arene).
1.28 (3H, s, gem-Me); 2.74 (2H, s, 4-CH2); 3.69 (3H, s, 6-OMe); 3.87 (3H, s,7-OMe); 6.65 (1H, s,5-Harene); 6.77 (1H,
s,8-Harene); 7.41–7.99 (5H, m, Hphenyl).
12 1.25 (s,6H, gem-Me); 2.76 (s,2H, 4CH2); 3.62–3.90 (m,12H, MeO); 6.73 (s,1H, 5H); 6.79 (s,1H, 8H); 7.05 (d,1H, 5ꢁH);
7.51 (d,1H, 6ꢁH), 7.54 (s, 1H, 2ꢁ-H)
13 0.69 (d, 6H, gem-Me); 1.78 (m, 1H, Me CH); 2.12 (s, 3H, Mearene); 2.19 (s, 3H, Mearene); 3.51 (s, 2H, CH2Ph); 4.60 (t,
0.5H, CH-NH); 4.99 (t, 0.5H, CH-NH)2; 5.95 (m, 1H, NH); 6.68–7.31 (m, 8H, Harene
)
14 1.27 (s, 6H, gem-Me); 2.09 (s, 3H, 6-Mearene); 2.20 (s, 3H, 7-Mearene); 2.73 (s, 2H, 4-CH2); 6.93 (d, 1H, 5-Harene);
7.37–7.53 (m, 5H, Hphenyl); 7.97 (d, 1H, 8-Harene
)
17 1.59 (s,6H, gem-Me); 2.14 (s,3H,6Me); 2.29 (s,3H,7Me); 2.86 (s,2H, 4CH2); 4.70 (s,2H, CH2 benzyl); 7.00 (s,1H, 5H);
7.17–7.39 (m, 5H, Hphenyl); 7.56 (s,1H, 8H)
18 1.29 (s,6H, gem-Me); 1.94 (s,3H,MeAc); 2.75 (s,2H, 4CH2); 3.12 (s,3H,6MeO); 3.85 (s,3H,7MeO); 6.28 (s,1H, 5H); 6.56
(s,1H, 8H); 7.18–7.31 (m,5H,Hphenyl); 13.01 (s,1H, NH)
19 1.62 (s,6H, gem-Me); 2.96 (s,2H,4CH2); 4.76 (s,2H, CH2 benzene); 7.15–7.39 (m, 7H, 5H 6H+Hphenyl); 7.58 (t,1H, 7H);
7.86 (d,1H, 8H)
20 1.60 (s,6H, gem-Me); 2.91 (c,2H, 4CH2); 3.73 (s,3H, 6MeO); 3.90 (s,3H, 7MeO); 4.71 (s,2H, CH2 benzyl); 6.65 (s,1H, 5H);
6.77 (s,1H, 8H); 7.17–7.37 (m, 5H, Hphenyl); 14.83 (s,1H, HCl)
23 1.27 (s,6H, gem-Me); 2.80 (s, 2H, 4CH2); 3.87 (s,6H, 6MeO 7MeO); 6.05 (br s.,1H, NH); 6.59 (s,1H, 5-H); 7.49 (s,1H, 8-H)
24 1.74–1.77 (m,10H, gem-Me + 2CH2m.); 2.27 (m, 2H, CH2m.); 2.76 (m, 2H,CH2m); 2.89 (s, 2H, 4CH2); 3.42 (s, 3H,
6MeO); 3.88 (s, 3H,7MeO); 6.66 (s,1H, 5H); 6.86 (s,1H, 8H); 7.21–7.52 (m, 5H,Hphenyl
)

490 Shklyaev et al.
SCHEME 3
only reaction product, whereas nitrile 22 gave
the “normal” derivative 24. Obviously, for nitrile
21, the reaction proceeded via 1-(1ꢁ-butyl)-benzyl-
3,3-dimthyl-6,7-dimethoxy-3,4-dihydroisoquinoline
25, which was oxidized under the reaction condi-
tions. Product 24 suggested significant influence
of the possible imine–enamic tautomerism on
C1 Cꢁ bond oxidation and, particularly, described
by authors [12] conclusion on 1-butyl-substituted
derivatives of 3,4-dihydroisoquinolne to be present
solely in the imine form (Scheme 10).
not virtually depend on the number of radicals at
both position 3 and nitrile group.
EXPERIMENTAL
Chemicals (reagent grade) and solvents were pur-
chased from Aldrich or Merck and used as re-
ceived. Melting temperatures were determined on
PTP instrument and not corrected. IR spectra were
recorded on UR-20 spectrophotometer in vaseline
1
oil. H NMR spectra were measured on a Bruker
DRX-500 instrument (500.13 MHz) using TMS as
internal standard. Mass-spectra were measured on
a Finnigan MAT instrument under standard condi-
tions (EI, 70 eV). The reaction course and the purity
of the compounds were monitored by TLC on Silufol
UV-254 plates in a chloroform–acetone (9:1) mixture
using a 0.5% solution of chloronile in toluene for UV-
visualization.
CONCLUSIONS
Results obtained in this study show that three-
component synthesis of 1-benzyl-substituted-3,3-
dimethyl-3,4-dihydoisoquinoline depends signifi-
cantly on the substituents at nitrile group, but does
General Procedure for Synthesis of 1-Substituted
3,3-dimethyl-3,4-dihydroisoquinolines by
Three-Component Condensation
A mixture of activated arene (0.1 mol), isobutyralde-
hyde (0.1 mol), and nitrile (0.1 mol) was added drop-
wise with stirring to concentrated H2SO4 (50 mL)
for 15–20 min at 0–5◦C. The mixture was stirred for
30 min, poured into water (300 mL) and extracted
SCHEME 4

A New Approach to Synthesis of 3,3-Dialkyl-3,4-dihydroisoquinoline Derivatives 491
SCHEME 5
with toluene (50 mL). An organic layer containing
the Bayer reaction product was separated, and a
water layer was basified by ammonium carbonate
to pH 8–9. The precipitate was separated, washed
with water, dried, and re-crystallized. In the case of
oily substances, hydrochlorides were obtained. Com-
pounds were dissolved in dry ester, and the precipi-
tate was separated and re-crystallized from ethyl ac-
etate.
Synthesis of 1-Benzyl-3,3-dimethyl-3,
4-dihydroisoquinolines (General Procedure)
A mixture of a corresponding dimethylbenzyl car-
bonyl (0.1 mol) and benzyl cyanide (11.7 g, 0.1 mol)
was added dropwise with stirring and cooling with
water and ice to concentrated H2SO4(50 mL). The
mixture was stirred for 15 min, poured into water
SCHEME 6
SCHEME 7

492 Shklyaev et al.
SCHEME 8
SCHEME 9
SCHEME 10

A New Approach to Synthesis of 3,3-Dialkyl-3,4-dihydroisoquinoline Derivatives 493
1998; 2nd supplements Vol. IV (F/G), p. 507–561; (d)
Bentley, K. W. In Rodd’s Chemistry of Carbon Com-
pounds, 2nd ed: Sainsbury, M., (ed); Elsevier: Amster-
dam, 1998: 2nd Supplements Vol. IV (G/H), p. 113–
134.
(300 mL), and extracted with toluene (50 mL), and a
water layer was basified by ammonium carbonate to
pH 8. The precipitated oil was separated with methyl-
tertbutyl ether (2 × 150 mL), dried over Na2SO4, and
the solvent was removed on a rotary evaporator. The
residue was dissolved in ester (150 mL) and exposed
to dry HCL flow until the solution was completely
transparent. The precipitate was re-crystallized from
ethyl acetate.
[4] Kohno, H.; Yamada, K. Heterocycles 1999, 1, 103–
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[5] Budnikova, M. V.; Rubinov, D. B.; Mikhal’chuk, A. L.
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[6] (a) Mikhalchuk, A. L.; Gulyakevich, O. V.; Shklyaev,
Y. V.; Shklyaev, V. S., Akhrem, A. A. Khim Geterotsikl
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Soedin 1998, 2, 236–240; (c) Mikhailovsky, A. G.;
Shklyaev, V. S. Khim Geterotsikl Soedin; 1995, 12,
1697–1698; (d) Feshin, V. P.; Shklyaev, V. S.; Misyura,
I. L.; Konshin, M. Y.; Vakhrin, M. I.; Sapozhnikov,
Y. B.; Aleksandrov, B. B. Zh Obshch Khim 1996, 66,
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[7] Watson, T. J. N. J Org Chem 1998, 2, 406–407.
[8] Engel, E.; Seeger, E.; Teufel, H. Chem Ber 1971,
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Legotkina, G. I. USSR Patent 771093, Bull Izobr 1980,
38, 136–145.
[10] Shklyaev, V. S.; Aleksandrov, B. B.; Mikhailovskii,
A. G.; Vakhrin, M. I. Khim Geterotsikl Soedin 1989,
9, 1239–1242.
[11] Shklyaev, V. S.; Aleksandrov, B. B.; Legotkina, G. I.
Khim Geterotsikl Soedin 1983, 9, 1560–1565.
[12] Aleksandrov, B. B.; Gavrilov, M. S.; Vakhrin, M. I.;
Shklyaev, V. S. Khim Geterotsikl Soedin 1983, 6, 794–
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[13] Aleksandrov, B. B.; Shklyaev, V. S.; Shklyaev, Yu. V.
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General Procedure of Oxidation of 1-Benzyl-3,3-
dimethyl-3,4-dihydroisoquinoline Derivatives
1-benzyl-3,3-dimethyl-3,4-dihydroisoquinoline (1 g)
was dissolved in benzene (40 mL), and with heat-
ing and exposed to the air (flow) for 2 h. Major por-
tion of isoquinoline was oxidized within approxi-
mately 40 min; the initial spot, however, disappeared
completely from the TCL plate after ∼2 h. Benzene
was removed on a rotary evaporator, and the residue
was re-crystallized from hexane. 1-benzoyl deriva-
tives were obtained in 75% yield in the limits of the
test error.
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