Synthesis of substituted isoquinolines via nickel-catalyzed [2+2+2] cycloaddition of alkynes and 3,4-pyridynes

Article abstract of DOI:10.3987/COM-09-S(S)126

A novel methodology for the synthesis of substituted isoquinolines via a nickel(0)-catalyzed [2+2+2] cycloaddition of 3,4-pyridynes with two molecules of alkyne has been established. In this reaction, it was found that 2-butyn-1,4-diol derivatives and 1,3-diynes are suitable as substrates and that a propargylic oxygen functionality in alkynes is essential for the reactivity and the selectivity of the products.

Full text of DOI:10.3987/COM-09-S(S)126

HETEROCYCLES, Vol. 80, No. 2, 2010
917
HETEROCYCLES, Vol. 80, No. 2, 2010, pp. 917 - 924. © The Japan Institute of Heterocyclic Chemistry
Received, 4th September, 2009, Accepted, 13th October, 2009, Published online, 14th October, 2009
DOI: 10.3987/COM-09-S(S)126
SYNTHESIS OF SUBSTITUTED ISOQUINOLINES VIA
NICKEL-CATALYZED [2+2+2] CYCLOADDITION OF ALKYNES AND
3,4-PYRIDYNES
Toshihiko Iwayama and Yoshihiro Sato*
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812,
Japan
E-mail: biyo@pharm.hokudai.ac.jp
Abstract – A novel methodology for the synthesis of substituted isoquinolines
via a nickel(0)-catalyzed [2+2+2] cycloaddition of 3,4-pyridynes with two
molecules of alkyne has been established. In this reaction, it was found that
2-butyn-1,4-diol derivatives and 1,3-diynes are suitable as substrates and that a
propargylic oxygen functionality in alkynes is essential for the reactivity and the
selectivity of the products.
A transition metal-catalyzed [2+2+2] cycloaddition of three components of alkynes is a useful and highly
atom-economic way for constructing various aromatic compounds.ꢀ Recently, we have succeeded in
developing the first transition metal-catalyzed [2+2+2] cycloaddition of pyridynes with diynes by virtue
of a nickel(0) catalyst (Scheme 1).2,3
R
Et3Si
R
N
+
X
X
N
TfO
or
1
2
4
Ni(0) catalyst
CsF
or
R
R
N
Et3Si
X
X
N
TfO
X
5
3
X
Scheme 1. Previous study on Ni(0)-catalyzed [2+2+2] cycloaddition of 3,4-pyridynes
This paper is dedicated to Prof. Akira Suzuki in celebration of his 80th birthday.

918
HETEROCYCLES, Vol. 80, No. 2, 2010
The reaction of ꢀ,ꢁ-diynes 1 and 3,4-pyridyne precursors 2 or diynes 3 having a 3,4-pyridyne precursor
moiety in the chain with a zerovalent nickel catalyst in the presence of CsF gave the corresponding
tricyclic isoquinolines 4 or tetracyclic isoquinolines 5, respectively, in good yields. In the context, we
planned to develop the synthesis of substituted isoquinolines via a [2+2+2] cycloaddition of 3,4-pyridynes
with two molecules of alkynes, as shown in Scheme 2. If a [2+2+2] cycloaddition of two molecules of
alkyne 6 and 3,4-pyridyne 2’ derived from the precursor 2 in the presence of a fluoride anion proceeds in
a similar to that in the previous study shown in Scheme 1, substituted isoquinoline derivative 7 should be
produced. By using alkynes as a substrate instead of diynes in the [2+2+2] cycloaddition, it would be
more difficult to control the stereochemistry of the product 7 and to prevent the formation of trimers 8
and polymers of alkynes. Thus, this would be a more challenging subject than previously reported
cases.
R
R
R3
R3
N
[2+2+2]
cycloaddition
R
R
R
R
R
R
R1
R2
+
+
polymers of alkynes
+
N
6
2'
R
R
F-
R3
7: R=R1 or R2
8: R=R1 or R2
(trimers of 6)
Et3Si
TfO
N
2
Scheme 2. Plan for synthesis of substituted isoquinolines from two molecules of alkyne and pyridynes.
First, a [2+2+2] cycloaddition of 3,4-pyridyne and two molecules of acetylene (6a) was examined (Table
1, run 1). Treatment of 2a with 20 mol% Ni(cod)2 and 40 mol% PPh3 in the presence of CsF (3
equivalents to 2a) under an atmosphere of acetylene (6a, 1 atm) in CH3CN at room temperature gave
isoquinoline (7aa) in 40% yield accompanied by the formation of unidentified polymers. Various
symmetrical di-substituted alkynes were screened as a coupling partner instead of acetylene under
conditions similar to those previously reported, and it was found that 2-butyn-1,4-diol derivative 6b could
be applied to the nickel-catalyzed [2+2+2] cycloaddition of 3,4-pyridyne precursor 2a. Thus, the
reaction of 6b and 2a (ratio of 6b/2a=1/4) with 20 mol% Ni(cod)2 and 40 mol% PPh3 in the presence of
CsF (3 equivalents to 2a) in CH3CN at room temperature gave the corresponding isoquinoline derivative
7ba in 60% yield (run 2). When the ratio of the substrates 6b and 2a was changed from 1/4 to 4/1, the
yield of 7ba was improved to 72% (run 3). It was found that loading of the nickel catalyst could be
reduced to 10 mol% without lowering of the yield under the conditions, producing 7ba in 73% yield (run
4). On the other hand, the yield of 7ba was decreased to 51% when the catalyst loading was reduced to
5 mol % (run 5). When non-protected 2-butyn-1,4-diol (6c) was used as an alkyne substrate, no desired

HETEROCYCLES, Vol. 80, No. 2, 2010
919
product 7ca was obtained (run 6). On the other hand, the reaction of 6d, having two THP groups as
protecting groups, and 2a under the same conditions gave isoquinoline 7da in 70% yield (run 7). The
existence of a carbonyl group in the protecting groups also retarded the reaction, and the reaction of 6e or
6f under the same conditions gave the corresponding product 7ea or 7fa, respectively, in a low yield (runs
8 and 9).
Table 1. [2+2+2] Cycloaddition of alkynes 6 and 2aa
R
20 mol% Ni(cod)2
40 mol% PPh3
Et3Si
TfO
R
R
+
R
R
N
CsF (3 eq. to 2a)
N
MeCN, rt
6
2a
7
R
product (7)
yield (%)
run
alkyne (6)
ratio of 6/2a
40c
60d
1b
N
—
7aa
6a
6b
MOMO
MOMO
MOMO
MOMO
2
1/4
N
OMOM
7ba
MOMO
3
6b
6b
6b
4/1
4/1
4/1
7ba
7ba
7ba
72c
73c
51c
4e
5f
R
R
R
R
R'O
N
OR'
6
6c: R'=H
4/1
4/1
4/1
4/1
7ca: R=CH2OH
—
7e
8e
9e
6d: R'=THP
7da: R=CH2OTHP
70c
12c
14c
6e: R'=CONEt2
6f: R'=Ac
7ea: R=CH2OCONEt2
7fa: R=CH2OAc
a All reactions except for run 1 were carried out as follows: a solution of 6 was added
over a period of 3 h to a mixture of 2a, Ni(cod)2, PPh3, and CsF, and the resultant
mixture was stirred for an additional 2 h. b The reaction was carried out under an
atmosphere of acetylene (1 atm). c Based on 2a. d Based on 6. e 10 mol% Ni(cod)2
and 20 mol% PPh3 were used. f 5 mol% Ni(cod)2 and 10 mol% PPh3 were used.
Next, unsymmetrical alkynes having a propargylic oxygen functionality such as 6g-6i (Figure 1) were
screened in the [2+2+2] cycloaddition with 2a under the similar conditions, producing none or a trace
amount of desired isoquinolines as a mixture of isomers. After various attempts, it was found that
1,3-diyne 6j showed a good reactivity and selectivity.4 Thus, the reaction of 6j and 2a under the
optimized conditions gave the corresponding isoquinoline derivative 7ja as a single isomer in 60% yield
along with a mixture of unidentified polymers (Table 2, run 1). The stereochemistry of 7ja was
1
unambiguously determined by NOE experiments after assignment of the related protons using H NMR,
13C NMR, and HMBC spectra (Figure 2). The reactions of 1,3-diynes 6k-6n under the same conditions

920
HETEROCYCLES, Vol. 80, No. 2, 2010
also produced isoquinolines 7ka-7na as single isomers (Table 2, runs 2-5), and those stereochemistries
were determined in a manner similar to that in the case of 7ja by NOE experiments.
Figure 1.
Figure 2.
R'O
NOE
Hb
R
R
H
OMOM
OMOM
5
4
6g: Me
6h: Ph
6
N
7
Me
8
1
Me
R
H
R'O
MOMO
Ha
NOE
6i
Table 2. [2+2+2] Cycloaddition of 1,3-diynes and 2aa
run
alkyne (6)
product (7)b
yield (%)
60
MeO
MeO
MeO
MeO
1
N
OMe
6j
7ja
MeO
MOMO
MOMO
MOMO
2
3
4
5
68
46
61
57
N
OMOM
OMOM
MOMO
Ph
6k
6l
7ka
MOMO
MOMO
Ph
N
Ph
7la
MOMO
MOMO
nBu
nBu
N
OMOM
6m
6n
nBu
7ma
MOMO
MOMO
AcO
AcO
N
OMOM
AcO
MOMO
7na
a All reactions were carried out as follows: a solution of alkyne 6 (4 eq. to
2a) was added via a syringe pump over a period of 3 h to a mixture of 2a,
Ni(cod)2 (10 mol%), PPh3 (20 mol%), and CsF (3 equiv. to 2a) in MeCN at
room temperature, and the resulting mixture was stirred for an additional 2
h. b The stereochemistries of products 7ja-7na were determined by NOE
experiments between H1 and Ha, and H4 and Hb, respectively (see, Figure
2).
It is noteworthy that all products in these cases were always obtained as a single isomer, with unreacted
alkyne parts of the starting 1,3-diynes 6j-6n located at C6- and C7-positions and protected
hydroxymethyl moieties located at C5- and C8-positions in the isoquinoline rings of the products
7ja-7na.

HETEROCYCLES, Vol. 80, No. 2, 2010
921
We next turned our attention to the scope of 3,4-pyridynes in the [2+2+2] cycloaddition. The results of
reactions of 6b with various 3,4-pyridyne precursors 2 are summarized in Table 3.
Table 3. Scope of 3,4-pyridyne precursors in the [2+2+2] cycloaddition with 6b
OMOM
R
R"
N
10 mol% Ni(cod)2
20 mol% PPh3
R"
N
R
R
Et3Si
TfO
+
CsF, MeCN
rt
MOMO
R
7 (R=CH2OMOM)
6b
run
2
pyridyne precursor (2)
product (7)
yield (%)
R
Et3Si
R
R
N
1
2
3
4
80
81
80
10
TfO
N
7bb
7bc
2b
2c
2d
2e
OPiv
R
OPiv
R
Et3Si
TfO
R
R
N
N
OMe
R
R
OMe
Et3Si
OMe
R
R
OMe
N
N
TfO
7bd
R
R
Et3Si
TfO
R
R
N
N
7be
CONEt2
R
CONEt2
The reaction of 6b and 2b, which has a pivaloyloxymethyl group at the C2 position of the pyridine ring,
under the above-described optimal conditions gave the corresponding isoquinoline 7bb in 80% yield
(Table 3, run 1). Electron-donating groups such as a methoxy group on the pyridyne precursor are
tolerated in the [2+2+2] cycloaddition, and the reaction of 2c or 2d with 6b produced the corresponding
isoquinoline 7bc or 7bd in 81% or 80% yield, respectively. On the other hand, in the case of 2e having
an electron-withdrawing group, the yield of the product 7be was lowered to 10%.
The scope of 3,4-pyridynes in the [2+2+2] cycloaddition of 1,3-diynes was also investigated, and the
results of the reaction with 6k and 6m are summarized in Table 4. The reaction of 1,3-diyne 6k and the
precursor 2b, 2c, or 2d under the optimized conditions produced the corresponding isoquinoline 7kb, 7kc,
or 7kd as a single isomer in 72%, 70%, or 74% yield, respectively (runs 1-3). In the case of the reaction

922
HETEROCYCLES, Vol. 80, No. 2, 2010
of 2b, 2c, and 2d with 6m under the same conditions, the isoquinolines 7mb, 7mc, and 7md were again
produced as a single isomer in good yields, respectively (runs 4-6).
Table 4. Scope of 3,4-pyridyne precursors in the [2+2+2] cycloaddition of 1,3-diynes
R
R'
R"
N
10 mol% Ni(cod)2
20 mol% PPh3
R"
N
Et3Si
TfO
MOMO
+
R
CsF, MeCN
rt
R
R'
6
2
7 (R'=CH2OMOM)
yield (%) run alkyne (6) precursor (2)
nBu
run
1
alkyne (6)
OMOM
precursor (2)
product (7)
product (7)
yield (%)
nBu
R'
R'
Et3Si
MOMO
N
72
70
74
4
5
6
2b
2c
2d
79
TfO
N
N
7kb
2b
2c
2d
7mb
MOMO
MOMO
OPiv
R'
R'
nBu
nBu
R'
R'
OPiv
OPiv
6k
6m
MOMO
Et3Si
TfO
MOMO
N
N
6m
2
6k
77
N
7kc
OMe
MOMO
MOMO
7mc
nBu
nBu
R'
R'
OMe
N
R'
R'
OMe
N
OMe
OMe
Et3Si
TfO
OMe
3
6k
6m
82
N
MOMO
nBu
R'
7kd
7md
R'
The stereochemistries of 7kb, 7kd, 7mb, and 7md were determined in a similar manner by NOE
experiments (Figure 3). On the other hand, 7kc and 7mc were successfully converted to 7ka and 7ma
via conversion of the C1-methoxy group to a chloride5 (Scheme 3), the spectral data of which were
identical to those obtained by the experiments described in Table 2. Notably, in these cases, the same
tendency as that in the above-mentioned reactions in Table 2 was observed for the stereochemistry
concerned the alkyne moieties and the protected hydroxymethyl moieties in the products.
Figure 3
Scheme 3
NOE
NOE
OMe
Hb
Hb
MOMO
R
MOMO
MOMO
R
MOMO
MOMO
1) POCl3, DMF
2) MOMCl, iPr2NEt
3) Zn, AcOH
H
R
R
H
R
R
5
4
5
4
6
6
N
N
N
N
7
7
8
1
8
1
R
H
R
OMe
MOMO
OPiv
NOE
MOMO
MOMO
Ha
Hc
Ha
7kc (R=CH2OMOM)
7mc (R=nBu)
7ka: 38% (3 steps from 7kc)
7ma: 42% (3 steps from 7mc)
NOE
7kb or 7mb
7kd or 7md
A possible mechanism of the [2+2+2] cycloaddition of 3,4-pyridyne and two molecules of alkynes is
shown in Scheme 4. On the basis of the results described above, it is obvious that the existence of a
propargylic oxygen functionality in alkynes 6 is crucial to enhance the reactivity and to control the

HETEROCYCLES, Vol. 80, No. 2, 2010
923
selectivity of the products in this nickel(0)-catalyzed [2+2+2] cycloaddition with 3,4-pyridiynes.6 Thus,
the oxygen at a propargylic position of 6 would initially coordinate to a nickel complex and form the
nickel complex I. Then oxidative addition would proceed to produce nickelacyclopentadiene
intermediate II in a stereoselective manner. Insertion of 3,4-pyridyne 2’, generated in situ from the
precursor 2 and CsF, into the nickel-carbon bond of II would afford seven-membered nickelacycle
intermediate IIIa or IIIb, from which reductive elimination would proceed to stereoselectively produce
substituted isoquinoline 7.
Scheme 4. ꢀꢁchanism for [2+2+2] cycloaddition of 3,4-pyridynes and two molecules of alkyne
R2O
R"
R1
R1
OR2
x 2
Ni
N
R1
6
7
R2O
R2
O
O
R1
R1
Ni
R2O
R1
R2O
R"
N
R1
R2
N
R"
or
I
R1
Ni
R1
Ni
R2
R2
O
O
R2
IIIa
IIIb
O
O
R1
R1
Ni
R"
N
R"
Et3Si
TfO
CsF
R2
N
II
2
2'
In summary, we succeeded in developing a novel methodology for the synthesis of substituted
isoquinolines via a nickel(0)-catalyzed [2+2+2] cycloaddition of 3,4-pyridynes with two molecules of
alkyne. Through screening of various alkynes, 2-butyn-1,4-diol derivatives and 1,3-diynes were found
to be suitable as substrates for this [2+2+2] cycloaddition. It was also found that a propargylic oxygen
functionality in these alkynes is essential for the reactivity and the selectivity of the products in the
reaction. Further studies along this line are in progress.
ACKNOWLEDGEMENTS
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 Takeda Science Foundation, the Uehara Memorial
Foundation, and the Akiyama Foundation, which are gratefully acknowledged.

924
HETEROCYCLES, Vol. 80, No. 2, 2010
REFERENCES AND NOTES
1. For recent reviews, see: (a) J. A. Varela and C. Saá, Chem. Rev., 2003, 103, 3787; (b) S. Kotha, E.
Brahmachary, and K. Lahiri, Eur. J. Org. Chem., 2005, 4741; (c) Y. Yamamoto, Curr. Org. Chem.,
2005, 9, 503; (d) P. R. Chopade and J. Louie, Adv. Synth. Catal., 2006, 348, 2307; (e) V. Gandon, C.
Aubert, and M. Malacria, Chem. Commun., 2006, 2209; (f) K. Tanaka, Synlett, 2007, 1977; (g) D.
Peña, D. Pérez, and E. Guitián, Chem. Rec., 2007, 7, 326; (h) T. Shibata and K. Tsuchikawa, Org.
Biomol. Chem., 2008, 1317; (i) R. B. Galan and T. Rovis, Angew. Chem. Int. Ed., 2009, 48, 2830.
2. T. Iwayama and Y. Sato, Chem. Commun., 2009, 5245.
3. For recent examples ofꢀnickel(0)-catalyzed [2+2+2] cycloadditions involving arynes as a substrate,
see: (a) J.-C. Hsieh, D. K. Rayabarapu, and C.-H. Cheng, Chem. Commun., 2004, 532; (b) J.-C.
Hsieh and C.-H. Cheng, Chem. Commun., 2005, 2459; (c) N. Saito, K. Shiotani, A. Kinbara, and Y.
Sato, Chem. Commun., 2009, 4284; (d) Z. Qiu and Z. Xie, Angew. Chem. Int. Ed., 2009, 48, 5729.
4. For a nickel(0)-catalyzed [2+2+2] cycloaddition of 1,3-diynes and diynes, see: (a) Y. Sato, K.
Ohashi, and M. Mori, Tetrahedron Lett., 1999, 40, 5231; (b) A. Jeevanandam, R. P. Korivi, I-w.
Huang, and C.-H. Cheng, Org. Lett., 2002, 4, 807. For a [2+2+2] cycloaddition of 1,3-diynes with
a nickel-benzyne complex, see: (c) K. R. Deaton and M. S. Gin, Org. Lett., 2003, 5, 2477; (d) K. R.
Deaton, C. S. Strouse, and M. S. Gin, Synthesis, 2004, 3084.
5. T. R. Kasturi, H. R. Y. Jois, and L. Mathew, Synthesis, 1984, 743.
6. The effect of a propargylic oxygen functionality in enhancing the reactivity in the nickel-mediated
[2+2+2] cycloaddition has already been reported by Smith, see: P. Bhatarah and E. H. Smith, J.
Chem. Soc., Perkin Trans. 1, 1990, 2603.