Rhodium-catalyzed oxidative coupling of benzylamines with alkynes through dehydrogenation and dehydrogenative cyclization

Article abstract of DOI:10.1246/cl.2011.600

Oxidative coupling of benzylamines with internal alkynes accompanied by dehydrogenation and dehydrogenative cyclization proceeds efficiently under rhodium catalysis to selectively give the corresponding 3,4-substituted isoquinoline derivatives. The proced

Full text of DOI:10.1246/cl.2011.600

doi:10.1246/cl.2011.600
600
Published on the web May 11, 2011
Rhodium-catalyzed Oxidative Coupling of Benzylamines with Alkynes
through Dehydrogenation and Dehydrogenative Cyclization
Keisuke Morimoto, Koji Hirano, Tetsuya Satoh,* and Masahiro Miura*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871
(Received March 24, 2011; CL-110249; E-mail: satoh@chem.eng.osaka-u.ac.jp, miura@chem.eng.osaka-u.ac.jp)
Oxidative coupling of benzylamines with internal alkynes
accompanied by dehydrogenation and dehydrogenative cycliza-
tion proceeds efficiently under rhodium catalysis to selectively
give the corresponding 3,4-substituted isoquinoline derivatives.
The procedure is also applicable to the reactions of (1-naph-
thylmethyl)amine with diaryl- and dialkylacetylenes to construct
benzo[h]isoquinoline and benzo[e]isoindole frameworks, re-
spectively.
Scheme 1.
Scheme 2.
Nitrogen-containing fused heteroaromatic frameworks can
be seen in a wide range of fine chemicals including medicines
and organic functional materials.1 Among them, isoquinoline
derivatives are well-known to be utilized as anesthetic, anti-
spasmodic, and antimicrobial reagents.2 Therefore, the synthesis
of isoquinolines from simple, readily available building blocks
has attracted much attention.
Table 1. Reaction of (1-naphthylmethyl)amine (1a) with
diphenylacetylene (2a)a
Among practical methods for constructing fused hetero-
cyclic compounds is the transition-metal-catalyzed coupling
of aromatic substrates with internal alkynes. Larock and co-
workers developed an isoquinoline synthesis through the
palladium-catalyzed coupling of ortho-halogenated benzaldi-
mines with alkynes (Scheme 1, X º H, Y º H).3 From the
atom- and step-economical points of view, prefuctionalization of
the aromatic substrates should be minimized. Recently, several
groups have reported that halogen-free, N-substituted benzaldi-
mines couple with alkynes under rhodium catalysis (X = H,
Y º H).4,5 As an example using more simple, N-unsubstituted
imines (X = Y = H), we disclosed the rhodium-catalyzed
oxidative coupling of benzophenone imine with alkynes to
produce 3,4-substituted 1-phenylisoquinolines in good yields.6
However, the substrate has so far been limited to only
benzophenone imine. One of the reasons is that N-unsubstituted
aldimines are labile under the oxidative coupling conditions.7
In the context of our further study of the rhodium-catalyzed
oxidative coupling,8 we have undertaken the coupling using
readily available benzylamines and (1-naphthylmethyl)amine as
stable building blocks in place of imines with alkynes. As a
result, the catalytic coupling with arylalkynes has been found
to proceed smoothly accompanied by dehydrogenation and
dehydrogenative cyclization by employing a copper oxidant to
produce isoquinoline and benzo[h]isoquinoline derivatives
(Scheme 2). The new findings are described herein.
Entry
Additive Temp/°C Time/h Yield of 3ab/%
1
2
3
®
120
120
120
120
120
120
120
120
100
130
140
10
10
6
6
10
6
6
6
6
10
6
60
68
35
31
55
16
0
DABCO
Na2CO3
DBU
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
4
5c
6d
7e
8f
9
0
9
10
11
72 (72)
65
aReaction conditions: 1a (1 mmol), 2a (0.5 mmol),
[Cp*RhCl2]2 (0.01 mmol), Cu(OAc)2¢H2O (2 mmol), additive
(1 mmol), o-xylene (5 mL) under N2. GC yield based on the
amount of 2a used. Value in parentheses indicates yield after
isolation. c1a (0.5 mmol) was used. dIn DMF (2.5 mL).
e[RhCl(cod)]2 (0.01 mmol) was used in place of [Cp*RhCl2]2.
f[Cp*IrCl2]2 (0.01 mmol) was used in place of [Cp*RhCl2]2.
b
cyclo[2.2.2]octane) improved the yield of 3a up to 68%
8b,8d
(Entry 2).8a Other additives, Na2CO3
and DBU, decreased
In an initial attempt, (1-naphthylmethyl)amine (1a)
(1 mmol) was treated with diphenylacetylene (2a) (0.5 mmol)
in the presence of [Cp*RhCl2]2 (0.01 mmol, Cp*: pentamethyl-
cyclopentadienyl) and Cu(OAc)2¢H2O (2 mmol) as catalyst and
oxidant, respectively, in o-xylene at 120 °C for 10 h under N2.
As a result, an oxidative coupling product, 3,4-diphenylbenzo-
[h]isoquinoline (3a), was obtained in 60% yield (Entry 1 in
Table 1). Addition of DABCO (1 mmol, DABCO: 1,4-diazabi-
the yield (Entries 3 and 4, DBU: 1,8-diazabicyclo[5.4.0]undec-
7-ene). With a reduced amount of 1a (0.5 mmol), the product
yield somewhat decreased (Entry 5). The reaction was sluggish
in DMF (Entry 6). Using [RhCl(cod)]2 or [Cp*IrCl2]2 as a
catalyst in place of [Cp*RhCl2]2, the reaction did not proceed at
all (Entries 7 and 8). The reaction efficiency was found to be
sensitive toward reaction temperature (Entries 9-11). At 130 °C,
the highest yield was obtained (Entry 10).
Chem. Lett. 2011, 40, 600-602
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601
Table 2. Reaction of (arylmethyl)amines 1 with alkynes 2a
Entry
1
2
Product(s), Yieldb/%
1a
1
2
3
2b: X = Me
2c: X = OMe
2d: X = Cl
3b: X = H, 64
3c: X = OMe, 73
3d: X = Cl, 53
Scheme 3.
Scheme 4.
4
5
1a
2e: R = Me
2f: R = n-Bu
3e: R = Me, 35
3f: R = n-Bu
3 e
: R = Me, 6
′
3 f: R = n-Bu
, 3
, 44
′
6c
7c
8c
2a
3g: Y = H, 60
3h: Y = Me, 58
3i: Y = OMe, 50
3j: Y = Cl, 18
1b: Y = H
1c
: Y = Me
1d: Y = OMe
9c 1e: Y = Cl
Scheme 5.
10c
1f
2a
3k, 74
aReaction conditions: 1 (1 mmol), 2 (0.5 mmol), [Cp*RhCl2]2
(0.01 mmol), Cu(OAc)2¢H2O (2 mmol), DABCO (1 mmol), in
Scheme 6.
b
o-xylene (5 mL) at 130 °C for 10 h under N2. Isolated yield
First, the dehydrogenation of 1 occurs to form the corresponding
imine A.9 Actually, treatment of 1a with the [Cp*RhCl2]2/
Cu(OAc)2¢H2O/DABCO system in the absence of 2 afforded
(1-naphthyl)methanimine A, which immediately underwent
condensation with another molecule of 1a to produce 4
(Scheme 4).7a,10 It was confirmed that the dehydrogenation did
not proceed at all in the absence of the rhodium catalyst. In the
absence of DABCO, on the other hand, the reaction took place,
but the yield of 4 decreased to 45%. Therefore, DABCO seems
to promote the dehydrogenation step in the oxidative coupling
of 1 with 2 and enhance the yield of 3 (Entry 2 versus 1 in
Table 1). The imine A may undergo oxidative coupling with 2
in a similar mechanism to that proposed for the reaction of
benzophenone imine with 26 through cyclorhodation, alkyne
insertion, and reductive elimination to produce 3.
c
based on the amount of 2 used. 1 (1.5 mmol) was used.
Under the conditions employed for Entry 10 in Table 1, the
couplings of 1a with 4-methyl- (2b), 4-methoxy- (2c), and 4-
chloro- (2d) substituted diphenylacetylenes provided the corre-
sponding 3,4-diarylbenzo[h]isoquinoline 3b-3d (Entries 1-3 in
Table 2). 1-Phenylpropyne (2e) reacted with 1a to give 4-
methyl-3-phenylbenzo[h]isoquinoline (3e) predominantly, along
with a minor amount of a separable regioisomer 3¤e (Entry 4).
Similarly, from the reaction of 1-phenyl-1-hexyne (2f), 4-butyl-
3-phenylbenzo[h]isoquinoline (3f) was obtained along with its
regioisomer 3¤f (Entry 5). The reaction of benzylamine (1b)
(1.5 mmol) with 2a took place in a similar manner to give 3,4-
diphenylisoquinoline (3g) selectively (Entry 6). A series of 4-
substituted benzylamines 1c-1e underwent coupling to form 3h-
3j (Entries 7-9). A sterically hindered amine, 2-methylbenzyl-
amine (1f), also reacted with 2a efficiently to afford 8-methyl-
3,4-diphenylisoquinoline (3k) (Entry 10).
In addition, the reactions of 1a with dialkylacetylenes 2g
and 2h were found to give 3H-benzo[e]isoindole derivatives 5a
and 5b, respectively (Scheme 5). No benzo[h]isoquinoline type
product could be detected.
A plausible mechanism for the oxidative coupling of 1 with
2 through dehydrogenation and dehydrogenative cyclization is
illustrated in Scheme 3, in which neutral ligands are omitted.
In these reactions, the seven-membered intermediate B¤
is generated in a similar manner to that to B in Scheme 3
(Scheme 6). Since B¤ has a ¢-hydrogen, its elimination appears
Chem. Lett. 2011, 40, 600-602
© 2011 The Chemical Society of Japan
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602
to take place in preference to reductive elimination to form C.8d
Then, C undergoes intramolecular allene insertion into the Rh-H
bond and reductive elimination to produce 5.
In summary, we have demonstrated that benzylamines and
(1-naphthylmethyl)amine undergo oxidative coupling with
alkynes under rhodium catalysis accompanied by dehydrogen-
ation and dehydrogenative cyclization to afford isoquinoline and
benzo[h]isoquinoline derivatives, respectively.11
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10 However, it would be possible that other Rh-catalyzed
reactions are involved for the formation of 4.
11 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
Chem. Lett. 2011, 40, 600-602
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/