Synthesis of (1H)-isochromen-1-imines by nickel-catalyzed reaction of 2-iodobenzamides with alkynes

Article abstract of DOI:10.1246/cl.2012.798

2-Iodobenzamides reacted with alkynes in the presence of a nickel(0)/P(4-ClC₆H₄)₃ catalyst to produce substituted (1H)-isochromen-1-imines. The reaction proceeded through the formation of an oxanickelacycle, alkyne insertion, and reductive elimination.

Full text of DOI:10.1246/cl.2012.798

doi:10.1246/cl.2012.798
798
Published on the web July 28, 2012
Synthesis of (1H)-Isochromen-1-imines by Nickel-catalyzed Reaction
of 2-Iodobenzamides with Alkynes
Tomoya Miura,* Kentaro Hiraga, Takeharu Toyoshima, Motoshi Yamauchi, and Masahiro Murakami*
Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Katsura, Kyoto 615-8510
(Received June 15, 2012; CL-120651; E-mail: tmiura@sbchem.kyoto-u.ac.jp, murakami@sbchem.kyoto-u.ac.jp)
2-Iodobenzamides reacted with alkynes in the presence of a
nickel(0)/P(4-ClC6H4)3 catalyst to produce substituted (1H)-
isochromen-1-imines. The reaction proceeded through the
formation of an oxanickelacycle, alkyne insertion, and reductive
elimination.
[
]
[
]
Transition-metal-catalyzed annulation reactions have ex-
panded the repertoire of synthetic methods of heterocyclic
compounds.1 2-Halobenzamides comprising a carbon-halogen
bond and two nucleophilic sites at nitrogen and oxygen atoms in
the molecule present a versatile platform for such reactions.2 For
example, 2-halobenzamides react with terminal alkynes in the
presence of a copper catalyst to give 3-methyleneisoindolin-
1-ones through the Sonogashira reaction and the following
cyclization in a 5-exo mode at the nitrogen atom.2d The use of
benzylamine in place of terminal alkynes leads to the formation
of quinazolin-4(3H)-ones through cyclization in a 6-endo
mode.2i Recently, Cheng and co-workers have reported that a
nickel-catalyzed reaction of 2-halobenzamides with alkynes
builds a six-membered ring by cyclization at the nitrogen atom
to give 1(2H)-isoquinolones (Figure 1, top).2f Herein, we report
that cyclization at the oxygen atom3-5 becomes possible for the
same substrate combination depending on the ligand used for
nickel (Figure 1, bottom). The use of monodentate ligands such
as P(4-ClC6H4)3 directs the site of ring-closure to the oxygen
atom of the amide group producing (1H)-isochromen-1-
imines,3,6 which are important structural motif for pharmaco-
phores7 as well as synthetic intermediates.8
Initially, a variety of phosphine ligands were examined
using [Ni(cod)2] as the catalyst precursor in a reaction of 2-iodo-
N-(4-tolyl)benzamide (1a) with diphenylethyne (2a) (Table 1).
A mixture of 1a (1.0 equiv) and 2a (1.5 equiv) in toluene was
heated at 80 °C for 17 h in the presence of [Ni(cod)2] (10 mol %),
a phosphine ligand (Ni:P = 1:2), and K2CO3 (1.5 equiv). When
dppe [1,2-bis(diphenylphosphino)ethane] was employed, N-cy-
clization product 3aa (74%) was obtained in preference to O-
cyclization product 4aa (18%) in accordance with results
reported by Cheng et al. (Entry 1).2f Other bidentate bisphos-
phine ligands such as dppm and dppp gave a considerable
mixture of N-cyclization product 3aa and O-cyclization product
4aa (Entries 2 and 3). Much to our surprise, the use of
monodentate triarylphosphine ligands switched the product
selectivity in favor of the O-cyclization (Entries 4-6).9 In
particular, 4aa was obtained in 77% isolated yield when P(4-
ClC6H4)3 was employed. Thus, it became possible to obtain
either N-cyclization or O-cyclization by an appropriate choice of
the ligand for nickel.
Figure 1. Two annulation pathways for the reaction of N-
substituted 2-iodobenzamides with alkynes.
Table 1. Ni(0)-catalyzed annulation reaction: screening of
phosphine ligandsa
[
]
X
Yield/%b
3aa 4aa
Entry
Ligand (L)
X
1
2
3
4
5
6
dppe
dppm
dppp
PPh3
10
10
10
20
20
20
73 (74)
18
9
26
0
17
49
82
P(4-MeOC6H4)3
P(4-ClC6H4)3
0
53
0
95 (77)
aAll reactions were carried out on a 0.2 mmol scale. bNMR
yield using mesitylene as an internal standard. Isolated yield in
parenthesis.
possessing aryl and alkyl groups on the nitrogen atom reacted
with 2a to exclusively afford the corresponding O-cyclization
products 4ba-4da in isolated yields ranging from 59% to 76%
(Entries 1-3).10 On the other hand, the reaction failed to occur
with N-unprotected 2-iodobenzamide, which remained intact
after heating even at 120 °C. In addition to diphenylethyne (2a),
aliphatic internal alkynes such as oct-4-yne (2b) and 1,4-
dibenzyloxybut-2-yne (2c) successfully participated in the
annulation reaction (Entries 4 and 5). The regioselectivities
observed with unsymmetrical internal alkynes varied with
significant similarities to those observed in the case of N-
cyclization reaction.2f Whereas 1-arylprop-1-ynes 2d-2f showed
moderate to good regioselectivities (83:17-95:5, Entries 6-8),
little selectivity was observed with 4-methylpent-2-yne (2g) and
1-(trimethylsilyl)prop-1-yne (2h) (Entries 9 and 10). In contrast,
the electron-deficient alkyne 2i gave the single regioisomer 4ai
The results obtained with various combinations of 2-iodo-
benzamides 1a-1d and alkynes 2a-2k using a nickel(0)/P(4-
ClC6H4)3 catalyst are listed in Table 2. 2-Iodobenzamides 1b-1d
Chem. Lett. 2012, 41, 798-800
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

799
Table 2. Ni(0)-catalyzed annulation reaction of N-substituted
2-iodobenzamides 1a-1d with alkynes 2a-2ka
[
]
Entry 1 (R)
2 (R1, R2)
4
Yield/%b,c
1
2
3
4
5
6
7
8
9
1b (4-CF3C6H4) 2a (Ph, Ph)
1c (4-MeOC6H4) 2a (Ph, Ph)
4ba 59
4ca 76
4da 66
4ab 84
1d (Bn)
1a (Tol)
1a (Tol)
1a (Tol)
1a (Tol)
1a (Tol)
1a (Tol)
2a (Ph, Ph)
2b (Pr, Pr)
2c (CH2OBn, CH2OBn) 4ac 84
2d (Me, Ph)
2e (Me, 4-CF3C6H4)
2f (Me, 4-MeOC6H4) 4af 83 (95:5)d
2g (Me, i-Pr)
2h (SiMe3, Me)
2i (CO2Et, Pr)
2j (Bpin, Ph)
2k (H, Ph)
4ad 73 (84:16)d
4ae 69 (83:17)d
Scheme 1. Proposed mechanism for the formation of 4 from 1
and 2.
4ag 81 (52:48)
4ah 68 (68:32)d
4ai 76 (>95:5)
4aj 81 (>95:5)
4ak 38 (>95:5)e
10 1a (Tol)
11 1a (Tol)
12 1a (Tol)
13 1a (Tol)
Table 3. Sequential reaction for the synthesis of (1H)-isochro-
men-1-onesa
aConditions: 1 (0.2 mmol), 2 (0.3 mmol), [Ni(cod)2] (10
mol %), P(4-ClC6H4)3 (20 mol %), and K2CO3 (0.3 mmol) in
toluene (2 mL) at 80 °C for 17 h. bIsolated yield unless
c
otherwise noted. Combined yield of regioisomers. Numbers
in parenthesis describe the regioselectivity. dUsing
(0.6 mmol). Using 2k (1.0 mmol).
2
e
(Entry 11). High regioselectivity was observed also with boryl-
substituted alkyne 2j (Entry 12). The reaction of 1a with
phenylethyne (2k) gave the product 4ak in only 38% yield
because of self-oligomerization of 2k (Entry 13).
(1H)-Isochromen-1-imines 4ea and 4fa having electron-
donating and -withdrawing substituents on the benzene ring
were synthesized in 85% and 78% yields, respectively (eqs 1
and 2).
5a 77%b
5b 79%b
5d 60% (85:15)c,d
5c 83%b
aConditions: 1d (0.2 mmol), 2 (0.3 mmol), [Ni(cod)2] (10
mol %), P(4-ClC6H4)3 (20 mol %), and K2CO3 (0.3 mmol) in
toluene (2 mL) at 80 °C for 17 h, and then (CO2H)2 (0.2 mmol)
and H2O (3.4 mmol) in THF (5 mL) was stirred at 60 °C
for 10 h. bIsolated yield. cCombined yield of regioisomers.
d
Numbers in parenthesis describe the regioselectivity. Using
2d (0.6 mmol).
ð1Þ
ð2Þ
proposed by Cheng et al. Initially, oxidative addition of the
carbon-iodine bond of 1 onto nickel(0) affords the aryl-nickel
species A. Subsequent deprotonation of the amide hydrogen by
K2CO3 forms the five-membered ring azanickelacycle B.5c
Allylic isomerization of B generates the five-membered ring
oxanickelacycle C. We presume that the less coordinating
character of P(4-ClC6H4)3 compared with bidentate bisphos-
phine ligands offers a vacant site more facilely to promote the
allylic isomerization. Then, insertion of alkynes 2 affords the
seven-membered ring oxanickelacyclic intermediate D or E,
depending on the nature of alkynes, as Cheng et al. explained for
their N-cyclization reaction.2f,11 Finally, reductive elimination
follows to give O-cyclization products 4, regenerating the
nickel(0) complex for the next catalytic cycles.
In addition, (2H)-pyran-2-imine derivative 4gb was pro-
duced in 70% yield from 3-iodoacrylamide derivative 1g and
oct-4-yne (2b) (eq 3).
ð3Þ
When a crude mixture of 4 with an N-benzyl group was
subjected to aqueous acidic conditions [oxalic acid (1.0 equiv) in
THF/H2O],12 hydrolysis of the imine moiety readily took place
to form the corresponding (1H)-isochromen-1-ones 5a-5d in
good yield (Table 3).
We assume the mechanism depicted in Scheme 1 for the
production of 4 from 1 and 2, which is closely related to that
Chem. Lett. 2012, 41, 798-800
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

800
In conclusion, an efficient synthetic route of (1H)-isochro-
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men-1-imines starting from 2-iodobenzamides and alkynes has
been established.13 Of note is that, unlike the case with the
analogous reaction using dppe, O-cyclization products are
exclusively formed when P(4-ClC6H4)3 is employed as the
ligand, presenting a complementary cyclization mode.
5
This work was supported in part by MEXT (Grant-in-Aid
for Scientific Research on Innovative Areas Nos. 22105005 and
22106520, Young Scientists (A) No. 23685019), Takeda Sci-
ence Foundation, and Asahi Glass Foundation.
6
7
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© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/