Nickel(0)-catalyzed [2 + 2 + 2] cycloaddition of diynes and 3,4-pyridynes: Novel synthesis of isoquinoline derivatives

Article abstract of DOI:10.1039/b912022j

A transition metal-catalyzed [2 + 2 + 2] cycloaddition between α,ω-diynes and 3,4-pyridynes has been realized for the first time, producing isoquinolines in good yields by using a nickel(0) catalyst.

Full text of DOI:10.1039/b912022j

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Nickel(0)-catalyzed [2 + 2 + 2] cycloaddition of diynes and
3,4-pyridynes: novel synthesis of isoquinoline derivativesw
Toshihiko Iwayama and Yoshihiro Sato*
Received (in College Park, MD, USA) 18th June 2009, Accepted 17th July 2009
First published as an Advance Article on the web 3rd August 2009
DOI: 10.1039/b912022j
A transition metal-catalyzed [2 + 2 + 2] cycloaddition between
a,x-diynes and 3,4-pyridynes has been realized for the first time,
producing isoquinolines in good yields by using a nickel(0)
catalyst.
arynes.5 However, the desired product, 3aa, was not obtained
and 1a was recovered in 95% yield. After various attempts to
find a good catalyst for this reaction, it was found that nickel is
suitable as a catalyst in the [2 + 2 + 2] cycloaddition of
3,4-pyridynes. That is, to a mixture of Ni(cod)2 (10 mol%),
PPh3 (40 mol%) and CsF (3 equiv. with respect to 2a) in
CH3CN, was added a solution of diyne 1a (2 equiv. with
respect to 2a) and 3,4-pyridyne precursor 2a in CH3CN via a
canula at room temperature, and the mixture was stirred for 3 h.
After the usual work-up, isoquinoline derivative 3aa was
obtained in 43% yield along with dimer 4a in 28% yield
(Table 1, run 1). Increasing both the ratio of 2a to 1a and
the amount of the catalyst loading from 10% to 20% slightly
improved the yield of 3aa to 50% (run 2). To suppress the
formation of the dimer 4a, we investigated the protocol for
addition of substrates. When a solution of diyne 1a was added
to a mixture of precursor 2a, nickel catalyst and CsF using a
syringe pump over a period of 3 h, the yield of 3aa was
improved to 58% and the formation of the dimer 4a was also
reduced (run 3). Furthermore, when 4 equiv. of 2a with respect
to 1a were used, the yield of the product reached 62% (run 4).
According to this optimal protocol, the loading of the catalyst
could be reduced to 10 mol%, giving 3aa in 63% yield (run 5).
Next, the scope of both diynes and 3,4-pyridynes in
the [2 + 2 + 2] cycloaddition was investigated under the
The transition metal-catalyzed [2 + 2 + 2] cycloaddition of
alkynes is a useful and highly atom-economic way to construct
various aromatic rings.1 In recent years, arynes have been
utilized as substrates in [2 + 2 + 2] cycloadditions.2–5
Pyridynes are the analogues of arynes containing a nitrogen
in the ring, and can be classified into 2,3-pyridyne and 3,4-
pyridyne by the position of the nitrogen in the ring (Fig. 1).
Their reactivities have been investigated in Diels–Alder and
nucleophilic substitution reactions.6 Compared with the
extensive studies on the utilization of arynes in [2 + 2 + 2]
cycloadditions, the reactivity of pyridynes towards [2 + 2 + 2]
cycloadditions has not been studied at all. Herein, we report
the first example for a transition metal-catalyzed [2 + 2 + 2]
cycloaddition of diynes 1 and 3,4-pyridynes 20, generated
in situ from silyl triflate precursor 2,7 providing isoquinoline
derivative 3 (Scheme 1).
Initially, the [2 + 2 + 2] cycloaddition of diyne 1a with
precursor 2a was investigated using a palladium catalyst
according to the optimized conditions of the above-mentioned
Table 1 [2 + 2 + 2] Cycloaddition of 1a and 2aa
Fig. 1 Arynes and pyridynes.
Run
Catalyst (mol%)
Time/h
3aa (%)
4a (%)b
1cd
2e
Ni(cod)2 (10), PPh3 (40)
Ni(cod)2 (20), PPh3 (80)
Ni(cod)2 (20), PPh3 (80)
Ni(cod)2 (20), PPh3 (80)
Ni(cod)2 (10), PPh3 (40)
3
3
—
—
—
43
50
58
62
63
28
13
8
6
7
g
3ef
4fh
5fh
g
Scheme 1 Plan for the [2 + 2 + 2] cycloaddition of diynes and
g
3,4-pyridynes.
a
b
3 equiv. of CsF with respect to the precursor 2a was used. Based on
c
d
1a. The ratio of 1a : 2a was 2 : 1. Diyne 1a was recovered in
Faculty of Pharmaceutical Sciences, Hokkaido University,
Sapporo 060-0812, Japan. E-mail: biyo@pharm.hokudai.ac.jp;
Fax: +81 11 706 4982; Tel: +81 11 706 4982
w Electronic supplementary information (ESI) available: Typical
procedures for [2 + 2 + 2] cycloaddition, spectral data, and 1H and
13C NMR spectra of all new compounds. See DOI: 10.1039/b912022j
e
20%. The ratio of 1a : 2a was 1 : 2. A solution of 1a was added over
f
g
a period of 3 h to a mixture of 2a, Ni catalyst and CsF. The reaction
h
was quenched just after finishing addition of a solution of 1a. The
ratio of 1a : 2a was 1 : 4.
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Table 2 Scope of diynes and pyridynes in the [2 + 2 + 2] cycloadditiona
Table 3 Intramolecular [2 + 2 + 2] cycloaddition of various
substratesab
Pyridyne
precursor
Yield
(%)
Run Diyne
1
Product
Run
Substrate
Product
Yield (%)
65
50
38
1
75
2
3
2a
2a
2
3
69
62
4
61
60
5
1a
4
5
59
41
43
6
18
1a
a
A solution of diyne 1 was added via a syringe pump over a period of
3 h to a mixture of precursor 2 (4 equiv.), Ni(cod)2 (10 mol%), PPh3
(40 mol%), and CsF (3 equiv. with respect to 2) in CH3CN at room
temperature.
6
above-mentioned optimal conditions. The results are summar-
ized in Table 2.
The reaction of 1,6-heptadiyne (1b), which has no geminal
substituents, with 2a proceeded smoothly, giving isoquinoline
derivative 3ba in 65% yield (run 1). Diynes 1c or 1d, containing
a tosyl amide or an oxygen atom in the tether, were also
tolerated in the [2 + 2 + 2] cycloaddition with 2a to produce
the corresponding isoquinoline derivatives 3ca or 3da,
respectively, although the yields were modest (runs 2 and 3).
The reaction of 1a and the precursor 2b or 2c, having a
methoxy group at the C6 or C2 position, also gave isoquino-
line derivative 3ab or 3ac, respectively, in good yields
(runs 4 and 5). On the other hand, the existence of an
electron-withdrawing substituent on the aromatic ring in the
precursor clearly retarded the reaction, resulting in a decrease
of the yield of product 3ad in the reaction between 1a and 2d
(run 6).
a
A solution of substrate 5 was added via a syringe pump over a period
of 8 h to a mixture of Ni(cod)2 (10 mol%), PPh3 (20 mol%), and CsF
b
(3 equiv.) in CH3CN at 0 1C. E = CO2Me.
hand, the reactions of the substrates 5e and 5f, with an oxygen
in the tether, under the above-mentioned optimized conditions
gave the corresponding products 6e and 6f, respectively, in
41% and 43% yields. It was speculated that coordination of an
oxygen atom to the nickel catalyst retarded the reaction,
resulting in a lower yield (runs 5 and 6).
A possible mechanism of the [2 + 2 + 2] cycloaddition of
diyne and 3,4-pyridyne is shown in Scheme 2. Oxidative
addition of diyne 1 to nickel(0) complex would proceed to
afford nickelacyclopentadiene intermediate I. Then, insertion
of pyridyne 20, generated in situ from precursor 2 and CsF,
into the nickel–carbon bond of I would afford seven-
membered nickelacycle intermediate IIa or IIb. Reductive
elimination of nickel(0) complex from IIa or IIb would
proceed to give isoquinoline 3. An alternative pathway that
involves the formation of nickelacycle IIIa or IIIb by oxidative
cycloaddition of one alkyne part of diyne 1 and pyridyne 20
would not be excluded. In this pathway, insertion of the
residual alkyne part into the nickel-carbon bond of IIIa
or IIIb also gave the intermediate IIa or IIb, respectively,
producing isoquinoline 3.
We next turned our attention to an intramolecular
[2 + 2 + 2] cycloaddition of diyne and pyridyne in the tether.
In the intramolecular reaction, synchronous coordination of
the diyne part and the pyridyne part to the nickel complex
would be important. Thus, the reaction protocol was again
modified. It was found that the reaction proceeded even
at 0 1C and that the ratio of catalyst to ligand could be
reduced from 1 : 4 to 1 : 2. When the period of addition of
the substrate was prolonged from 3 h to 8 h, the yield of the
product reached 75% (Table 3, run 1). The existence of a
protected nitrogen such as a tosyl amide in the tether did not
affect the reaction, producing the polycyclic isoquinoline
derivatives 6b–6d in good yields (runs 2–4). On the other
In summary, we succeeded in utilizing 3,4-pyridynes in a
transition metal-catalyzed [2 + 2 + 2] cycloaddition for the
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3 Selected references for [2 + 2 + 2] cycloaddition of a stoichiometric
amount of Ni(0)–aryne complex and alkynes, see: (a) M. A. Bennett
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4 For Pd(0)-catalyzed [2 + 2 + 2] cycloaddition of three molecules of
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´ ´
´
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´ ´
L. Castedo, J. Am. Chem. Soc., 1999, 121, 5827–5828;
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D. Perez and E. Guitian, J. Org. Chem., 2008, 73, 7996–8000. For
´ ´
Ni(0)-catalyzed [2 + 2 + 2] cycloaddition of arynes and diynes, see:
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´ ´
Scheme 2 Possible mechanism for the [2 + 2 + 2] cycloaddition.
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5 We have recently reported the synthesis of arylnaphthalene ligands
via Pd(0)-catalyzed [2 + 2 + 2] cycloaddition of arynes and allenes,
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first time and we obtained various isoquinolines, including a
polycyclic skeleton containing an isoquinoline subunit.
Although the yields are still modest in some cases, the present
results should pave the way for the development of a novel
method for the synthesis of isoquinolines, which are an
important class of compounds found in a variety of natural
products and biologically active substances. Further studies
along this line are in progress.
Part of this work was supported by Grant-in-Aid for
Scientific Research (B) (No. 19390001) from JSPS, Grant-in-
Aid for Science Research on Priority Areas (No. 19028001 and
20037002, ‘‘Chemistry of Concerto Catalysis’’) from MEXT,
Japan and by The Novartis Foundation (Japan) for the
Promotion of Science, The Uehara Memorial Foundation,
and the Akiyama Foundation, which are gratefully
acknowledged.
Notes and references
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2 For reviews on a transition metal-catalyzed [2 + 2 + 2] cyclo-
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Chem. Commun., 2009, 5245–5247 | 5247