Synthesis of 1,2-dihydroisoquinolines via rhenium-catalyzed tandem cyclization and nucleophilic addition of 2-(1-alkynyl)arylaldimines

Article abstract of DOI:10.1246/cl.180200

A synthetic method for 1,2-dihydroisoquinolines via the 6-endo-dig cyclization of 2-alkynylaldimines and nucleophilic addition has been developed. When the 2-alkynylaldimines were reacted with various nucleophiles such as nitromethane, dimethyl malonate,

Full text of DOI:10.1246/cl.180200

Advance Publication Cover Page
Synthesis of 1,2-Dihydroisoquinolines via Rhenium-Catalyzed Tandem Cyclization and
Nucleophilic Addition of 2-(1-Alkynyl)arylaldimines
Rui Umeda, Tetsuya Ishida, Yota Nakagawa, Mitsuru Inoue, Tatsuo Yajima, and Yutaka Nishiyama*
Advance Publication on the web April 7, 2018
doi:10.1246/cl.180200
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2018 The Chemical Society of Japan
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1
Synthesis of 1,2-Dihydroisoquinolines via Rhenium-Catalyzed Tandem Cyclization and
Nucleophilic Addition of 2-(1-Alkynyl)arylaldimines
Rui Umeda, Tetsuya Ishida, Yota Nakagawa, Mitsuru Inoue, Tatsuo Yajima and Yutaka Nishiyama*
Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan
E-mail: nishiya@kansai-u.ac.jp
1
2
3
4
5
6
7
8
9
The synthetic method of 1,2-dihydroisoquinolines via
4
4
5
8
9
0
ketene silyl acetal, and the three-component coupling
reaction of 2-(phenylethynyl)benzaldehyde, aniline and
the 6-endo-dig cyclization of 2-alkynylaldimines and the
nucleophilic addition has been developed. When the 2-
alkynylaldimines were reacted with various nucleophiles
such as nitromethane, dimethyl malonate, phenylacetylene,
hydrosilane, allylstannane, and ketene silyl acetal in the
presence of a rhenium catalyst, the corresponding 1,2-
dihydroisoquinolines were obtained in moderate to good
yields.
5
pronucleophiles (Scheme 2).
H
H
Nu
R1
R1
R2
R1
ReBr(CO)
5
NuH
N
N
N
R2
R2
Re
H
H
NuH
Nu
PhNH
2
Ph
Ph
ReBr(CO)5
Ph
Ph
O
N
1
1
0
1
Keywords:
Dihydroisoquinolines
Rhenium,
2-Alkynylaldimines,
1,2-
N
Ph
5
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
The 1,2-dihydroisoquinoline ring system is well known
52
Scheme 2.
and used as the core nucleus in a wide variety of
5
5
5
5
5
5
5
6
6
6
6
6
6
6
6
6
6
7
7
7
7
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
When
N-[2-(phenylethynyl)benzylidene]-4-
1
biologically active pharmacophores.
A
number of
methoxybenzenamine (1a) was treated with one equivalent
amount of nitromethane (2a) in the presence of the
approaches to the synthesis of 1,2-dihydroisoquinilines has
2
been
reported.
Among
the
various
methods,
ReBr(CO)
80 °C
5
(10 mol%) catalyst in dichloroethane solvent at
for 15 h, 1-nitromethyl-3-phenyl-2-(4-
functionalization of the isoquinolines core, which was
generated by the 6-endo-dig ring closure reaction of 2-(1-
alkynyl)arylaldimines, with carbon pronucleophiles was
recently discovered as a powerful synthetic tool of the 1,2-
dihydroisoquinolines; however, there are some drawbacks
on these methods; (i) limitation of the substrates and (ii)
methpxyphenyl)-1,2-dihydroisoquinoline (3a) was obtained
in 20% yield without the formation of 5-exo-dig cyclized
product (Entry 1 in Table 1). The yield of the 3a was
improved by increasing the amount of nitromethane,
extending the reaction time and increasing the reaction
temperature to 100 °C (Entries 1-5). ReCl(CO)
almost the same catalytic ability as ReBr(CO) , 3a was
obtained in 40% yield (Entries 3 and 6). In the case of other
rhenium complexes, such as Re (CO)10 and CH ReO , the
yield of 3a slightly decreased (Entries 7 and 8). When
toluene was used as the solvent, the reaction smoothly
proceeded to give 3a in 87% yield (Entry 9). Even when
acetonitrile and THF were used as the solvent, the reaction
occurred to give 3a in 21 and 58% yields, respectively, but
in the case of hexane, 3a was not obtained at all (Entries 10-
12).
3
instability under a moist or air conditions.
5
showed
Recently, we have found that the rhenium complex
show a novel catalytic ability for the benzannnulation
reaction of 2-(phenylethynyl)benzaldehyde and alkynes in
the presence of trichloroacetic acid giving the corresponding
5
2
3
3
4
2,3-disubstituted naphthalenes (Scheme 1). For the reaction,
it was proposed the reaction path including the
intermolecular nucleophilic attack of the oxygen of the
formyl function on the carbon-carbon triple bond of the 2-
(1-alkynyl)benzaldehydes.
H
H
R
R
ReBr(CO)
5
R
R
O
O
CCl
3
COOH
74
Table 1. Various Reaction Conditions
O O
Ph
Ph
Re
- PhCOCCCl
3
O
3
3
4
5
NO
2
O
Scheme 1.
N
cat. (10 mol%)
solvent (4 mL)
3
3
3
3
4
4
4
4
4
4
4
4
6
7
8
9
0
1
2
3
4
5
6
7
+
3 2
CH NO
N
We have become interested in the application of the
rhenium catalytic system for the efficient construction of the
1,2-dihydroisoquinolines core by the intermolecular
nucleophilic attack of the nitrogen of the imino group on the
carbon-carbon triple bond of the 2-(1-alkynyl)arylaldimines.
Now, the synthesis of 1,2-dihydroisoquinolines by the
rhenium-catalyzed reaction of 2-(1-alkynyl)arylaldimines
and pronucleophiles was examined. We describe the results
of the reaction of the 2-(1-alkynyl)arylaldimines and
pronucleophiles, such as nitroalkanes, active methylene
compounds, terminal alkyne, hydrosilane, allylstannane, and
Ph
a (0.2 mmol)
Ph
1
2a
3a
7
5
Entry Catalyst
Solvent
2a
(eq.)
1
2
4
4
4
4
4
Temp.,
Time, Yield,
a
°C
80
80
80
80
100
80
80
h
%
1
2
3
4
5
6
7
ReBr(CO)5 (CH Cl)2
ReBr(CO)5 (CH Cl)2
2
15
15
15
48
15
15
15
20
39
41
75
90(82)
40
24
2
ReBr(CO)
ReBr(CO)
ReBr(CO)
ReCl(CO)
Re
5
5
5
(CH
(CH
(CH
(CH
2
2
2
2
2
Cl)
Cl)
Cl)
Cl)
Cl)
2
2
2
2
2
5
2
(CO)10 (CH

2
9g
8
9
1
1
1
CH
3
ReO
3
(CH
toluene
hexane
2
Cl)
2
4
4
4
4
4
80
80
80
80
80
15
15
15
15
15
25
87
0
21
58
4-CH
3
OC
6
H
4
Ph 1a
Ph
3i, (86)
ReBr(CO)
ReBr(CO)
ReBr(CO)
ReBr(CO)
5
5
5
5
a
3
8
Reaction conditions: 1 (0.2 mmol), NuH (0.8 mmol) ReBr(CO)
5
(10
0
1
2
39 mol%), CH ClCH Cl (4 mL) at 80 °C for 15 h.
2
2
b 1
CH
3
CN
40
H-NMR yield. The number in parenthesis shows the isolated yield.
c
d
e
THF
41 At 100 ºC. For 96 h. Benzoic acid (0.2 mmol) was added.
42 Reaction conditions: ReBr(CO) (5 mol%) at 100 °C for 24 h.
5
a 1
f
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
H-NMR yield. The number in parenthesis shows the isolated yield.
g
43
44
4
At 100 ºC for 48 h.
To determine the applications of the reaction, we first
5
We examined the tandem reaction of (2-
46 phenylethynyl)benzylidene]benzeneamine 1a with
47 hydrosilane, allylstannane or ketene silyl acetal (Scheme 3).
When 1a was treated with triethylhydrosilane in the
49 presence of ReBr(CO) catalyst, the corresponding 2,3-
50 disubstituted 1,2-dihydroisoquinoline 3j was formed in 39%
yield. The yield of product 3j was improved by the addition
52 of proton source, such as di-tert-butyl-p-cresol, and 3j was
53 formed in 93% yield. In the case of allylsilane,
dihydroisoquinoline was not obtained at all. In contrast to
55 allylsilane, when allylstannane was used as allylation agent,
56 the corresponding 1,2,3-trisubstituted 1,2-
dihydroisoquinoline 3k was formed in 99% yield. The
examined the reaction of various 2-(1-alkynyl)arylaldimines
and nitromethane (2a) (Table 2). For the reaction of N-[2-
(2-phenylethynyl)benzylidene]benzeneamine 1b and N-[2-
4
8
(2-phenylethynyl)benzylidene]-4-methylbenzenamine
1c,
the corresponding 1,2-dihydroisoquinolines, 3b and 3c,
were formed in 75 and 78% yields, with the formation of
small amount of complicated by-products (Entries 2 and 3).
In the case of the N-benzyl aldimine, the yield of 1,2-
dihydroisoquinoline 3d decreased due to the formation of
various complicated by-products (Entry 4). The 3-alkyl
substituted 1,2-dihydroisoquinoline 3e was also synthesized
by the rhenium catalytic system (Entry 5) In contrast to
aldimines, in the case of ketimine, the corresponding 1,2-
dihydroisoquinoline was not obtained at all. When 1a was
treated with nitroethane under the same reaction conditions
as that of entry 3 in Table 1, the yield of the product 3f was
low; however, the yield of 3f was improved by the addition
of benzoic acid and the corresponding 1,2-
dihydroisoquinoline was obtained in 73% yield with a
mixture of diastereoisomers (Entry 6). The use of active
5
5
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
5
4
5
7
58 reaction of ketene silyl acetal proceeded smoothly in the
59 presence of 2,6-di-tert-butyl-p-cresol to give the
0 corresponding 1,2,3-trisubstituted dihydroisoquinoline 3l in
6
61 88% yield.
O
BHT (0.4 mmol)
ReBr(CO) (10 mol%)
O
5
N
3
Et SiH
ClCH
1
2
CH
2
Cl (4 mL)
N
00 °C, 24 h
methylene compounds instead of nitromethane as
a
Ph
Ph
1
a (0.2 mmol)
(0.8 mmol)
3j, 93 (85)%
pronucleophile was next investigated. When 1b was treated
with dimethyl malonate, the 6-endo-dig cyclization of 1b
and the tandem nucleophilic addition efficiently proceeded
to give the corresponding 1,2,3-trisubstituted 1,2-
dihydroisoquinoline 3g in 84% yield (Entry 7). For the
reaction of malonitrile, the desired product 3h was not
obtained (Entry 8). The terminal alkyne, such as
phenylacetylene, proved to be a prenucleophile for this
tandem cyclization (Entry 9).
O
PhCOOH (0.4 mmol)
O
ReBr(CO)
5
(10 mol%)
N
SnBu
3
ClCH CH
2
2
Cl (4 mL)
N
100 °C, 48 h
Ph
Ph
1
a (0.2 mmol)
(0.6 mmol)
3k, 99 (90)%
O
O
BHT (0.2 mmol)
O
ReBr(CO)
5
(10 mol%)
MeO
N
OTMS
OMe
(0.8 mmol)
ClCH
2
CH
2
Cl (4 mL)
N
100 °C, 48 h
Ph
Ph
3l, 88 (71)%
1a (0.2 mmol)
The number in parenthesis shows the isolated yield.
a
62
3
5
Table 2. Synthesis of Various 1,2-Dihydroisoquinolines
6
3
Scheme 3.
Nu
R1
R1
64
65 pot
We were next interested in the rhenium-catalyzed one-
synthesis of 1,2,3-trisubstituted 1,2-
N
ReBr(CO)
5
(10 mol%)
N
+
NuH
2
CH ClCH
2
Cl (4 mL)
R2
66 dihydroisoquinolines by the three-component coupling of 2-
R2
6
6
7
8
alkynylbenzaldehyde, amine and pronucleophile (Scheme 4).
When 2-(phenylethynyl)benzaldehyde was treated with
1
(0.2 mmol)
(0.8 mmol)
3
3
3
6
7
1
2
b
69 aniline and nitromethane in the presence of a catalytic
Entry
R
R
NuH
Yield, %
7
7
0
1
amount of ReBr(CO)
component coupling reaction efficiently proceeded to give
corresponding 1,2,3-trisubstituted 1,2-
73 dihydroisoquinoline 3b in 86% yield. Even when dimethyl
5
at 100 °C for 48h, the three-
1c
4-CH
3
3
OC
6
H
4
Ph 1a
Ph 1b
Ph 1c
Ph 1d
CH
CH
CH
CH
CH
3
3
3
3
3
NO
NO
NO
NO
NO
2
2
2
2
2
3a, 90 (82)
3b, 75 (66)
3c, 78 (76)
3d, 47 (40)
3e, 73 (48)
d
2
3
Ph
72 the
d
4-CH
C
6
H
4
4
5
6
PhCH
2
7
7
7
4
5
6
malonate instead of nitromethane was used as the
pronucleophile, the desired product 3g was obtained in 85%
yield.
Ph
4 9
C H 1e
e
Ph
Ph 1b
C
H
2 5
NO
2
3f, 73 (44)
d.r. = 5 : 1
3g, 84 (68)
f
7
Ph
Ph
Ph 1b
Ph 1b
CH
2
(COOCH
3 2
)
f
8
CH
(CN)
3h, 0
2
2

3
2
O N
3
3
2
3
M. A.; Raja, R.; Banerjea, A. C. Verma, A. K.; Kukreti, S.;
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CHO
ReBr(CO)
5
(5 mol%)
Ph
Ph
N
+
PhNH
2
+ CH NO
34
35
3
2
CH ClCH
2
2
Cl (4 mL)
Ph
100 °C, 48 h
3
3
3
3
6
7
8
9
3b, 86%
0
.2 mmol
0.2 mmol
0.8 mmol
CH
3
OOC
COOCH
3
CHO
ReBr(CO)
5
(5 mol%)
Ph
N
+
PhNH
2
+ CH (COOCH )
40
41
2
3
2
toluene (4 mL)
80 °C, 48 h
Ph
Ph
.2 mmol
4
2
0
0.2 mmol
0.8 mmol
3g, 85%
1
2
43
Scheme 4.
4
4
4
5
3
4
5
6
7
8
9
0
1
2
3
4
5
46
47
A plausible reaction pathway for the rhenium-
catalyzed reaction is shown in Scheme 5. First, the
decarbonylation of ReBr(CO) to form ReBr(CO) , which is
5 4
the coordinative unsaturated 16-electron complex, is the
first step of the catalytic reaction. The intermolecular
nucleophilic attack of the nitrogen of the imino group on the
carbon-carbon triple bond, which is activated by the
coordination with the rhenium complex, formed the
corresponding I. The nucleophilic addition of nitroalkanes,
active methylene compounds and the terminal alkyne to I,
followed by the protonation gave the corresponding 1,2-
4
4
5
5
8
9
0
1
2
3
7
52
53
5
5
5
5
4
5
6
7
1
1
1
1
1
1
58
59
60
8
,9
dihydroisoquinolines.
6
1
ReBr(CO)
+ CO - CO
ReBr(CO)
5
Nu
62
63
R1
N
∆
R1
6
4
N
R2
4
65
66
67
H
R2
6
6
7
7
7
7
7
8
9
0
1
2
3
4
Nu
R1
R1
N
N
H
4
5
(a) Umeda, R.; Tabata, H.; Tobe, Y.; Nishiyama, Y. Chem. Lett.
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Umeda, R.; Kaiba, K.; Morishita, S.; Nishiyama, Y.
ChemCatChem 2011, 3, 1743-1746.
R2
ReBr(CO)
4
R2
ReBr(CO)
75
76
4
7
7
7
8
Synthesis of 1,2-dihydroisoquinolines by the three component
coupling reaction:(a) Basavaish, D.; Thamihoraci, P. Eur. J.Org.
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R1
R2
N
79
Nu
H
8
8
8
0
1
2
ReBr(CO)
4
I
1
1
6
7
83
84
85
86
Scheme 5.
1
1
2
2
2
2
2
2
2
2
2
8
9
0
1
2
3
4
5
6
7
8
In summary, we showed that the rhenium complex acts
as the catalyst for the reaction of 2-(1-alkynyl)arylaldimines
and pronucleophiles, such as nitroalkanes, active methylene
compounds, terminal alkyne, hydrosilane, allylstannane, and
ketene silyl acetal, and the three-component coupling
reaction of 2-(phenylethynyl)benzaldehyde, aniline and
8
8
8
9
91
92
7
8
9
0
9
9
9
9
3
4
5
6
pronucleophiles
giving
the
corresponding
1,2-
dihydroisoquinolines. The application of the reaction and
determining the reaction pathway are now in progress.
97
9
8
2
3
3
9 References and Notes
99
00
1
0
1
1
For selected examples, see: (a) Tandon, V.; Urvashi; Yadav, P.;
Sur, S.; Abbat, C.; Tiwari, V.; Hewer, R.; Papathonasopoulos,

4
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
6
7
8
Takemoto et al. have disclosed that proton source was essential
for the Lewis acid-catalyzed reaction of 2-(1-
alkynyl)arylaldimines with organometallic compounds. See:
Ref. 3g.
(a) Zingales, F.; Sartorelli, U.; Canziani, F.; Raveglia, M. Inorg.
Chem. 1967, 6, 154-157; (b) Jolly, P. W.; Stone, F. G. A. J.
Chem. Soc. 1965, 5259-5261; (c) Abel, E. W.; Hargreaves, G.
B.; Wilkinson, G. J. Chem. Soc. 1958, 3149-3152.
Nucleophilic addition to quinolinium salts is a well known
method of functionalization on the quinoline ring. See: (a)
Hewavitharanage, P.; Danilov, E. O.; Neckers, D. C. J. Org.
Chem. 2005, 70, 10653-10659. (b) Diaba, F.; Lewia, I.;
Grignon-Dubois, M.; Navarre, S. J. Org. Chem. 1996, 61,
4830-4832 and references cited therein.
1
1
1
1
1
1
1
1
1
9
When 1a was treated with ketene silyl acetal in the presence of
D
2
O, the deuterium atom was introduced at the 4-position of
1,2,3-trisubstituted 1,2-dihydroisoquinoline 3l.
1
2
9
0