Iridium-catalyzed [2 + 2 + 2] cycloaddition of α,ω-diynes with nitriles

Article abstract of DOI:10.1021/ja3028394

[Ir(cod)Cl]₂/DPPF or BINAP efficiently catalyzed the cycloaddition of α,ω-diynes with nitriles to give pyridines. The reaction can accommodate a very wide range of nitriles. Both aliphatic and aromatic nitriles smoothly reacted with α,ω-diynes to give pyridines. Ten equivalents of unactivated aliphatic nitrile were enough to give the product in high yield. Aliphatic nitriles bearing an acetal or amino moiety could be used for the reaction. The highly regioselective cycloaddition of unsymmetrical diyne bearing two different internal alkyne moieties was achieved. The observed regioselectivity could be reasonably explained by considering the different reactivities of the α-position in iridacyclopentadiene. Regioselective cycloaddition was successfully applied to the synthesis of terpyridine and quinquepyridine. This chemistry was extended to a new and efficient synthesis of oligoheteroarenes. Five aromatic or heteroaromatic rings were connected in a single operation. [Ir(cod)Cl]₂/chiral diphosphine catalyst can be applied to enantioselective synthesis. Kinetic resolution of the racemic secondary benzyl nitrile catalyzed by [Ir(cod)Cl] ₂/SEGPHOS gave a central carbon chiral pyridine in 80% ee. The mechanism was analyzed on the basis of the B3LYP level of density functional calculations.

Full text of DOI:10.1021/ja3028394

Article
pubs.acs.org/JACS
Iridium-Catalyzed [2 + 2 + 2] Cycloaddition of α,ω-Diynes with
Nitriles
Gen Onodera,†,‡ Yoshihisa Shimizu,‡ Jun-na Kimura,‡ Junya Kobayashi,‡ Yukiko Ebihara,‡ Kei Kondo,‡
Ken Sakata,§ and Ryo Takeuchi*,‡
‡Department of Chemistry and Biological Science, Aoyama Gakuin University, 5-10-1 Fuchinobe, Chuo, Sagamihara,
Kanagawa 252-5258, Japan
§Faculty of Pharmaceutical Sciences, Hoshi University, Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
S
* Supporting Information
ABSTRACT: [Ir(cod)Cl]2/DPPF or BINAP efficiently cata-
lyzed the cycloaddition of α,ω-diynes with nitriles to give
pyridines. The reaction can accommodate a very wide range of
nitriles. Both aliphatic and aromatic nitriles smoothly reacted
with α,ω-diynes to give pyridines. Ten equivalents of unacti-
vated aliphatic nitrile were enough to give the product in high
yield. Aliphatic nitriles bearing an acetal or amino moiety could
be used for the reaction. The highly regioselective cycloaddi-
tion of unsymmetrical diyne bearing two different internal
alkyne moieties was achieved. The observed regioselectivity
could be reasonably explained by considering the different reactivities of the α-position in iridacyclopentadiene. Regioselective
cycloaddition was successfully applied to the synthesis of terpyridine and quinquepyridine. This chemistry was extended to a new
and efficient synthesis of oligoheteroarenes. Five aromatic or heteroaromatic rings were connected in a single operation.
[Ir(cod)Cl]2/chiral diphosphine catalyst can be applied to enantioselective synthesis. Kinetic resolution of the racemic secondary
benzyl nitrile catalyzed by [Ir(cod)Cl]2/SEGPHOS gave a central carbon chiral pyridine in 80% ee. The mechanism was analyzed
on the basis of the B3LYP level of density functional calculations.
on the development of transition metal catalysts other than
Co. Yamamoto and co-workers reported the RuCp*(cod)Cl-
catalyzed cycloaddition of α,ω-diynes with activated nitriles
such as electron-deficient nitriles and α-halonitriles.8 Although
the reaction conditions are mild, a major drawback of the
RuCp*(cod)Cl-catalyzed reaction is the limited scope of nitriles.
Simple nitriles such as acetonitrile and benzonitrile could not be
INTRODUCTION
■
Heteroaromatic compounds play an important role in chem-
istry.1 Moreover, heteroaromatic compounds are indispensable
in recent far-reaching developments in material and biological
science because they can be used as a substructure in functional
materials, agrochemicals, and pharmaceuticals.2 Traditionally,
the synthesis of heteroaromatic compounds has been based
on a condensation reaction that gives a byproduct as waste
under strong acidic or basic conditions. A more environ-
mentally benign synthesis of heteroaromatic compounds that
does not give a waste byproduct under neutral conditions is
needed. Transition metal catalysis continues to be a fruitful
source of new methods for the synthesis of heteroaromatic
compounds,3 since transition metal catalysts can directly con-
struct complex structures from easily accessible starting materials
under neutral and mild reaction conditions. Among transition
metal-catalyzed reactions, the cycloaddition of unsaturated mole-
cules is one of the most straightforward and atom-economical
reactions for constructing a substituted heteroaromatic ring.4
Since Yamazaki and Wakatsuki pioneered the CpCo(PPh3)2-
catalyzed reaction of alkynes with nitriles to give substituted
pyridines,5 much attention has been focused on the development
of a Co-catalyzed cycloaddition to give pyridine.6 Vollhardt
developed CpCo(CO)2-catalyzed partially intramolecular
modes of the reaction using α,ω-diynes or cyanoalkynes as
one component.7 Recently, there have been extensive studies
́
used for the RuCp*(cod)Cl-catalyzed reaction. Saa and co-
workers performed a mechanistic study in the same area.9 With
Cp or Cp* metal complexes, it can be difficult to control the
reaction by tuning the steric and electronic effects of the Cp
ligand, since the introduction of substituents to the Cp ligand
requires considerable synthetic operations. A wide variety of
electronically and sterically different phosphines are now com-
mercially available. We can alter the catalytic activity both
electronically and sterically by choosing a suitable phosphine
ligand, which can lead to changes in product-, chemo-, regio-,
and enantioselectivity. A metal phosphine complex-catalyzed
pyridine synthesis is desired, since the reaction can be easily
controlled by choosing the appropriate phosphine ligand.
Rhodium catalyst has been reported to be a less-selective
catalyst for pyridine synthesis due to the formation of an arene
product by the cyclotrimerization of alkynes.10 Tanaka reported
Received: March 23, 2012
Published: May 18, 2012
© 2012 American Chemical Society
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a
that [Rh(cod)2]BF4/BINAP was a more selective catalyst for
pyridine synthesis.11 In addition to these examples, the Ni(cod)2-
NHC catalyst has been reported by Louie.12 These Rh and Ni
catalysts require preactivation before diynes can be reacted with
nitriles. In the case of Ni, air-sensitive Ni(cod)2 and free NHC
in dichloroethane must be stirred for at least 8 h before the
reaction. In the case of Rh, COD ligand must be removed from
the Rh center by hydrogenation before the reaction. Con-
centration of the solution after [Rh(cod)2]BF4 and phosphine
ligand are stirred in CH2Cl2 under a hydrogen atmosphere
gives catalytically active solution for use in pyridine synthesis.
To expand the scope and selectivity, new catalysts that are suit-
able for a wide range of alkynes and nitriles including unacti-
vated aliphatic nitriles are needed. Furthermore, a more con-
venient catalyst that does not require preactivation is desired. In
the course of our study on the iridium-catalyzed carbon−carbon
bond-forming reaction,13 we first found that [Ir(cod)Cl]2/DPPE
is an efficient catalyst for the cycloaddition of alkynes to give
arenes.13d−f,i−k Recently, we found that [Ir(cod)Cl]2/BINAP
is an efficient catalyst for the reaction of α,ω-diynes with
isocyanates to give 2-pyridone.13o We have shown that
Ir/diphosphine catalyst is a powerful tool in cycloaddition
chemistry. To date, Ir-catalyzed pyridine synthesis has not yet
been reported. In this paper, we report the full details of the
iridium complex-catalyzed cycloaddition of α,ω-diynes with nitriles.
We extend this chemistry to the synthesis of oligoheteroarenes.
One of the advantages of the Ir catalyst described here is that
even the reaction with unactivated aliphatic nitriles gives the
corresponding pyridine in good to high yield. Another advantage is
that the experimental procedure is more convenient than in the
case of Rh or Ni. In particular, preactivation of the catalyst is not
needed.
Table 1. Reaction of 1,6-Diyne (1a) with Benzonitrile 2a
time
(h)
yield
b
entry catalyst (mol %) ligand (mol %) temperature
(%)
1
2
3
4
5
6
[Ir(cod)Cl]2 (2) none
reflux
reflux
reflux
reflux
reflux
reflux
24
24
2
0
0
[Ir(cod)Cl]2 (2) PPh3 (8)
[Ir(cod)Cl]2 (2) DPPE (4)
[Ir(cod)Cl]2 (2) DPPP (4)
[Ir(cod)Cl]2 (2) DPPB (4)
6
3
66
73
0
3
[Ir(cod)Cl]2 (2) DPPPentane
(4)
24
7
[Ir(cod)Cl]2 (2) DPPBenzene
(4)
reflux
3
2
c
8
9
[Ir(cod)Cl]2 (2) FDPPE (4)
reflux
reflux
reflux
reflux
reflux
reflux
24
3
78
91
84
75
0
[Ir(cod)Cl]2 (2) DPPF (4)
10 [Ir(cod)Cl]2 (2) (R)-BINAP (4)
11 [Ir(cod)Cl]2 (2) BIPHEP (4)
12 [Ir(cod)Cl]2 (2) Xantphos (4)
2
2
24
24
13 [Ir(cod)2]SbF6
(4)
DPPF (4)
0
14 [Ir(cod)Cl]2 (2) DPPF (4)
15 [Ir(cod)Cl]2 (2) DPPF (4)
16 [Ir(cod)Cl]2 (1) DPPF (2)
50 °C
rt
2
24
3
89
12
91
89
reflux
reflux
17 [Ir(cod)Cl]2
DPPF (1)
3
(0.5)
d
18
[Ir(cod)Cl]2
(0.25)
DPPF (0.5)
DPPF (0.2)
reflux
reflux
3
90
70
e
19
[Ir(cod)Cl]2
(0.1)
24
a
A mixture of 1a (1 mmol), 2a (3 mmol), [Ir(cod)Cl]2 (2 mol %),
ligand (4 mol %), and benzene (5 mL) was stirred under Ar. Isolated
yield. FDPPE is (C6F5)2PCH2CH2P(C6F5)2. A mixture of 1a (1.5
mmol), 2a (4.5 mmol), [Ir(cod)Cl]2 (0.25 mol %), DPPF (0.5 mol %),
and benzene (7.5 mL) was stirred under Ar. A mixture of 1a (2 mmol),
b
SCREENING OF THE CATALYST
c
d
■
2,7-Nonadiyne 1a reacted with 3 equiv of benzonitrile (2a) to
give a pentasubstituted pyridine derivative 3aa in the presence
of 2 mol % of [Ir(cod)Cl]2 and 4 mol % of diphosphine ligand
(P/Ir = 2). The catalytic activity depended on the ligand used.
The results are summarized in Table 1. DPPF was found to be
the most efficient ligand (entry 9). The reaction was completed
in 3 h under refluxing benzene to give 3aa in 91% yield. The
catalyst loading could be reduced to 0.25 mol % without
reducing the yield at 2 mol % (entry 18). Even a catalyst
loading as low as 0.1 mol % gave 3aa in 70% yield (entry 19).
For most cyclotrimerization catalysts, more than 3 mol % of
catalyst is needed for pyridine synthesis. These results show
that the iridium complex has greater catalytic activity than any
other transition metal complexes reported so far. [Ir(cod)Cl]2
without any ligand did not give 3aa (entry 1). PPh3 was not
effective (entry 2). We previously reported that DPPE was an
efficient ligand for the cycloaddition of 1,6-diynes with
monoynes to give indane derivatives. However, DPPE was far
less efficient than DPPF for pyridine synthesis (entry 3). DPPE,
DPPP, and DPPB were all inferior to DPPF (entries 3−5).
DPPPentane was not effective at all (entry 6). DPPBenzene
(1,2-bis(diphenylphosphino)benzene), which has a more rigid
carbon framework than DPPE, gave the product in 2% yield
(entry 7). The reaction with FDPPE as a ligand gave 3aa
in lower yield than in the reaction with DPPF (entry 8).
(R)-BINAP was the second-best ligand. The reaction gave
3aa in 84% yield (entry 10). BIPHEP was less effective than
(R)-BINAP (entry 11). The use of Xantphos (9,9-dimethyl-
4,5-bis(diphenylphosphino)xanthene) as a ligand inhibited the
e
2a (6 mmol), [Ir(cod)Cl]2 (0.1 mol %), DPPF (0.2 mol %), and
benzene (10 mL) was stirred under Ar.
reaction (entry 12). The optimal reaction temperature was 50−
80 °C. The reaction at 50 °C gave 3aa in 89% yield (entry 14).
The reaction at room temperature gave 3aa in 12% yield and
a substantial amount of the starting material was recovered
(entry 15).
REACTION OF 1a WITH VARIOUS AROMATIC
NITRILES 2
■
Diyne 1a reacted with various aromatic nitriles 2b−n to give
pyridine derivatives 3ab−an under the reaction conditions
optimized above. The results are summarized in Table 2. Diyne
1a reacted with p-bromobenzonitrile (2d) and p-nitrobenzoni-
trile (2e) to give 3ad and 3ae in excellent yields, while the
reactions with o-methylbenzonitrile (2b) and p-formylbenzoni-
trile (2c) gave 3ab and 3ac in moderate to good yields (entries
1−4). The reactions with p- and m-acetylbenzonitrile (2f and
2g) gave pyridine derivatives 3af and 3ag in respective yields of
94% and 95%, but the reaction with o-acetylbenzonitrile (2h)
gave no product (entries 5−7). p-(p-Tolyl)benzonitrile (2i)
and 1-naphthonitrile (2j) reacted smoothly with 1a to give the
products 3ai and 3aj in good yields (entries 8 and 9). The
reaction with 2-thiophenecarbonitrile (2k) gave 3ak in 34%
yield (entry 10). We next studied the cycloaddition of diyne 1a
with phenyl dicyanides 2l−n to give 1:1 products and 2:1 products.
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yield (entries 12 and 14). When an excess amount of diyne to
dicyanide was used, both of the cyano groups participated in
cycloaddition to give a product with two pyridine rings.
Aromatic nitrile 2n was an exceptional case. The reaction of 2n
with 4 equiv of 1a gave 1:1 product 3an in 92% yield (entry 16).
Only one of the two cyano groups participated in the
cycloaddition even in the presence of an excess amount of 1a.
The steric hindrance by the cyano group at the ortho-position
of 2n would inhibit the second cycloaddition.
Table 2. Reaction of 1,6-Diyne (1a) with Various Aromatic
Nitriles 2
a
REACTION OF 1a WITH VARIOUS ALIPHATIC
NITRILES 5
■
Several examples of pyridine synthesis with aliphatic nitriles
have been reported. With the Cp*Ru(cod)Cl-catalyzed cyclo-
addition of diynes with nitriles, a major drawback is that
applicable nitriles are limited to activated nitriles in which a
cyano group or halogen is connected to a carbon−nitrogen
triple bond by one or two methylene units.8 The presence of
another cyano group or halogen atom is essential for the Ru-
catalyzed reaction, since they act as a coordinating group to the
Ru center to induce cycloaddition.8a,9 With [Rh(cod)2]BF4/
BINAP-catalyzed cycloaddition, acetonitrile, the most common
aliphatic nitrile, has been reported to participate in cyclo-
addition to give the product in 63% yield.11b However,
acetonitrile was used as a solvent in the Rh-catalyzed reaction.
To enhance the synthetic value of the reaction, the scope of
suitable unactivated aliphatic nitriles has to be explored. In
addition, the amount of unactivated nitrile required to give the
product in high yield should be reduced. Encouraged by the
good results with aromatic nitriles, we next examined the
reaction with aliphatic nitriles. A wide range of unactivated
aliphatic nitriles could be used for our cycloaddition. Ten
equivalents of nitrile was enough to give the product in good
yield. The results are summarized in Table 3. The reaction with
10 equiv of acetonitrile (5a) gave 6aa in 75% yield (entry 2).
Similarly, diyne 1a smoothly reacted with n-butyronitrile (5b)
to give 6ab in 68% yield (entry 4). Especially noteworthy is that
the reaction with 3 equiv of acetonitrile (5a) for 2 h gave the
product in 64% yield (entry 1). Longer alkyl nitriles such as
n-hexanenitrile (5c) and n-heptanenitrile (5d) underwent
cycloaddition to give 6ac and 6ad in 67% and 71% yields,
respectively (entries 5 and 6). The reactions with 10 equiv of
benzyl cyanide (5e) and 3-phenylpropionitrile (5f) gave
products 6ae and 6af in 90% and 84% yields, respectively
(entries 8 and 10). Comparison of the product yields suggested
that 5e and 5f were more reactive toward cycloaddition than
5a−d. The reaction with 5g bearing an acetal moiety gave 6ag
in 79% yield (entry 11). The acetal group remained intact
during cycloaddition. While the use of aminonitrile in
cycloaddition for pyridine synthesis has not been reported,
our catalytic reaction can use aminonitrile. α-Aminonitrile (5h),
β-aminonitrile (5i−k) and γ-aminonitrile (5l) underwent
cycloaddition to give products 6ah−al in 77−90% yields
(entries 12−16). A pyrrolidine moiety, piperidine moiety,
and morpholine moiety could be introduced at the side chain
of the pyridine ring. When diyne 1a was reacted with 3 equiv
of aliphatic dicyanide (5m), only one of the two cyano
groups participated in cycloaddition to give product 6am
bearing a single intact cyano group in 92% yield (entry 17).
Secondary nitriles reacted with diyne 1a. The reaction
with isobutyronitrile (5n) gave product 6an in 60% yield
(entry 19). The reaction with cyclohexanecarbonitrile (5o)
gave a product in a yield comparable to that in the reaction with
a
A mixture of 1a (1 mmol), 2 (3 mmol), [Ir(cod)Cl]2 (0.01 mmol),
DPPF (0.02 mmol), and benzene (5 mL) was stirred under Ar.
b
c
Isolated yield. A mixture of 1 (2 mmol), 2 (0.5 mmol), [Ir(cod)Cl]2
(0.01 mmol), DPPF (0.02 mmol), and benzene (5 mL) was stirred
under Ar.
The molar ratio of 1a to 2 controlled the selectivity of 1:1
addition and 2:1 addition. The reactions of 1 mmol of 1a
with 3 mmol of p-, m-, and o-dicyanobenzene (2l−n) gave 1:1
products 3al, 3am, and 3an in 80−99% yields (entries 11, 13,
and 15). When an excess amount of dicyanide to diyne 1a was
used, only one of the two cyano groups participated in
cyclization to give a product substituted with an intact cyano
group. On the other hand, the reactions of 2 mmol of 1a with
0.5 mmol of 2l and 2m gave only the 2:1 products in excellent
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Table 3. Reaction of 1,6-Diyne (1a) with Various Aliphatic
Nitriles 5
REACTIONS OF VARIOUS DIYNES 1 WITH NITRILES
2 AND 5
■
a
Various diynes (1b−l) were subjected to cycloaddition with
nitriles. Three equivlents of benzonitrile (2a) or 10 equiv of
acetonitrile (5a) was used as a nitrile component. The results
are summarized in Table 4. Et-substituted diyne 1b reacted
Table 4. Reaction of Various 1,6-Diynes (1) with Nitriles 2
a
or 5
a
A mixture of 1a (1 mmol), 5, [Ir(cod)Cl]2 (0.01 mmol), DPPF (0.02
b
mmol), and benzene (5 mL) was stirred under Ar. Isolated yield.
isobutyronitrile (5n) (entry 20). The reaction with 3-cyclo-
hexene-1-carbonitrile (5p) gave a product in higher yield than
that with cyclohexanecarbonitrile (5o) (entry 21). The
reaction with cyclopropanecarbonitrile (5q) gave cyclo-
propyl-substituted pyridine 6aq in 88% yield (entry 22).
Cleavage of the cyclopropyl ring did not occur during
the reaction. The reaction with pivalonitrile (5r) gave no
product due to steric hindrance (entry 23). Activated
aliphatic nitrile was also a good substrate for the reaction.
Diyne 1a reacted smoothly with ethyl cyanoformate (5s)
to give 6as in quantitative yield (entry 24). The reaction
with acrylonitrile (5t) gave 6at in 11% yield (entry 25).
When chloroacetonitrile (5u) and malononitrile (5v) were
used, no corresponding product was obtained (entries 26
and 27).
a
A mixture of 1 (1 mmol), 2a (3 mmol), [Ir(cod)Cl]2 (0.01 mmol),
DPPF (0.02 mmol), and benzene (5 mL) was stirred under Ar.
b
c
d
Isolated yield. 10 mmol of 5a was used instead of 2a. 2 mol % of
e
[Ir(cod)Cl]2 and 4 mol % of DPPF were used. (R)-BINAP was used
instead of DPPF. Product 3ea was obtained in 7% ee. Enantiomeric
excess was determined by HPLC.
with benzonitrile (2a) and acetonitrile (5a) to give the
corresponding products 3ba and 6ba in respective yields of
71% and 21% (entries 1 and 2). The reaction of terminal diyne
1c with 2a gave dimers and trimers of 1c instead of pyridine
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3ca (entry 3). Cycloaddition with a terminal alkyne moiety was
preferred over cycloaddition with nitrile 2a. The substituent at
the 5-position in 2,7-nonadiyne affected the reaction, indicating
that a Thorpe−Ingold effect was important for the cycliza-
tion.14 Diketone 1d reacted with 2a and 5a to give 3da and 6da
in respective yields of 82% and 63% (entries 4 and 5). The
reaction of 1a gave higher product yields than those with 1d.
Diyne substituted with a phenyl group at the 5-position of 2,7-
nonadiyne reacted with 2a and 5a to give 3ea and 6ea in
respective yields of 85% and 79% (entries 6 and 8). These
yields were comparable to those with 1a. When (R)-BINAP
was used as a ligand, 3ea was obtained in 86% yield with 7% ee
(entry 7). A substituent other than a carbonyl group was also
effective for the cycloaddition. Methoxymethyl-substituted
diyne (1f) reacted with 2a and 5a to give 3fa and 6fa in
respective yields of 83% and 77% (entries 9 and 10). Similarly,
acetoxymethyl-substituted diyne 1g smoothly underwent cyclo-
addition (entries 11 and 12). Diyne 1h bearing a methone
moiety reacted with 2a and 5a to give 3ha and 6ha in respective
yields of 77% and 75% (entries 13 and 14). Diyne 1i bearing
Meldrum’s acid was a less efficient substrate than 1h (entries 15
and 16). As mentioned above, the [Ir(cod)Cl]2/DPPF catalyst
system is efficient for the formation of bicyclic pyridines with a
five-membered ring from both 2,7-nonadiyne derivatives (1a
and 1d−i) and 3,8-undecadiyne 1b. We next examined the
possibility of the formation of a six-membered ring from 2,8-
decadiyne 1j. The reaction of 1j with 2a and 5a gave 5,6,7,8-
tetrahydroisoquinoline derivatives 3ja and 6ja in respective
yields of 95% and 70% (entries 17 and 18). Thus, the
[Ir(cod)Cl]2/DPPF catalyst system is effective for the
formation of both five- and six-membered bicyclic pyridines.
The reaction of 2,8-decadiyne (1k) with 2a gave no product
(entry 19). Tosylamide-tethered diyne 1l reacted with 2a to
give 3la in 11% yield (entry 20).
reaction of 1n with 2a was the same as that of the reaction of
1m with 5a and 5e. The reactions of Me3Si-substituted diyne
1o with 5a and 5e gave the product in moderate yields, while
the reaction with 5s gave the product in 93% yield (entries 5, 6,
and 7). The reactions were completely regioselective and gave a
product in which the trimethylsilyl group was substituted at the
β-position. The regioselectivity of the reaction of 1o was
opposite those of 1m and 1n. The reaction of 1p bearing
terminal alkyne moiety and iternal alkyne moiety with 2a gave
no corresponding product (entry 8). We next examined the
reaction of ester tethered-diyne 1q in which an ester group is
conjugated with one of the two internal alkyne moieties. In
contrast to the reaction of 1m−o, the slow addition of 1q to a
reaction mixture containing a catalyst and nitrile over 2 h was
needed to give the product in high yield. Self-dimerization and
-trimerization of 1q competed with pyridine ring formation.
The reactions of ester tethered-diyne 1q with 2a, 5a, and 5e
gave 3qa, 6qa, and 6qe in 74−62% yields as a single product in
which a carbonyl group was substituted at the β-position
(entries 9−11). The reaction of 1q with 5s gave 6qs in 56%
yield without the slow addition of 1q (entry 12). Ester
tethered-diyne 1r in which a phenyl group and carbonyl group
are conjugated with the same alkyne moieties was also a good
substrate for regioselective pyridine synthesis. Ester tethered-
diyne 1r reacted with 2a, 5a, 5e, and 5s to give the respective
products in 72−91% yields (entries 13−16). The regioselec-
tivity of the reaction of 1r was the same as that of 1q. Slow
addition of ester diyne 1r to the reaction mixture was needed
for the reactions with 2a, 5a, and 5e. Ester tethered-diyne 1s
bearing one alkyne moiety conjugated with a carbonyl group
and another alkyne moiety conjugated with a Ph group.
Although the reaction of ester tethered-diyne 1s gave the
product in low yields, the reaction was regioselective and gave a
single product favoring a pyridine substituted with a carbonyl
group at the β-position (entries 17−20). Our iridium catalyst
system is the most regioselective of any other transition metal
catalyst for cycloaddition to give pyridine.
REGIOSELECTIVE CYCLOADDITION OF
■
UNSYMMETRICAL DIYNE WITH NITRILES
The reaction of unsymmetrical diyne with nitrile can give two
regioisomeric pyridines. With an unsymmetrical diyne possess-
ing a terminal alkyne moiety and internal alkyne moiety, the
regioselectivity of the Ru-catalyzed reaction was studied in
detail.8 The reaction of malonate-derived diyne possessing a
terminal alkyne moiety and methyl-substituted internal alkyne
moiety with cyanoformate 5s has been reported to give 2,3,4,6-
and 2,3,4,5-substituted pyridines in a ratio of 88:12.8b
Unsymmetrical diyne bearing two internal alkyne moieties is
a more challenging substrate for regioselective pyridine
synthesis. The reaction of such unsymmetrical diynes was
limited.8b,11b We examined two types of unsymmetrical diyne:
diyne with a sterically different substituent and diyne with an
electronically different substituent. The results are summarized
in Table 5. The structure of the products was determined on
the basis of 2D-NMR analysis (see the Supporting Information,
S115−S126 and S203−S266). We first examined the reaction
of malonate-derived diynes possessing two different internal
alkyne moieties. Ph-substituted diyne 1m underwent cyclo-
addition with 5a and 5e to give 6ma and 6me in 94% yield as a
single product in which the phenyl group was substituted at the
α-position (entries 1 and 2). The reaction of 1m with 5s gave
an 88:12 mixture of 6ms and 6′ms in 95% yield, favoring
pyridine substituted with a Ph group at the α-position (entry 3).
Naphthyl-substituted diyne 1n reacted smoothly with 2a to
give 3na in 96% yield (entry 4). The regioselectivity of the
REGIOCHEMICAL AND MECHANISTIC
CONSIDERATIONS
■
The regioselectivity observed here should be explained based
on mechanistic considerations. A plausible mechanism is as
follows (Scheme 1). Diyne oxidatively adds to the iridium
active species to give iridacyclopentadiene.15 Nitrile reacts with
iridacyclopentadiene to give pyridine. The regioselectivity
observed here can be explained by considering the different
reactivities of the α-carbon in iridacyclopentadiene formed by
the oxidative cyclization of diyne. Two different substituents on
terminal alkyne carbons lead to the different reactivities of the
α-carbons in iridacyclopentadiene. When the steric effect is
predominant, the less-hindered α-carbon preferentially reacts
with a nitrile carbon atom. When the electronic effect is
predominant, the more electron-rich α-carbon preferentially
reacts with a nitrile carbon atom. These two effects determine
the regioselectivity (Scheme 2). A methyl group is electron-
donating, while phenyl and naphthyl groups are electron-
withdrawing.16 When diyne 1m and 1n were used, the methyl-
substituted α-carbon in intermediates 7m and 7n is more
electron-rich than the phenyl- or naphthyl-substituted α-carbon
to react preferentially with a nitrile carbon to give 6ma, 6me,
6ms, and 3na. Phenyl and 1-naphthyl groups are more bulky
than a methyl group. The less-hindered α-position in
iridacyclopentadiene 7m and 7n preferentially reacts with the
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a
Table 5. Reaction of Unsymmetrical Diynes (1) with Nitriles 2 or 5
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Table 5. continued
a
A mixture of 1 (1 mmol), 2a (3 mmol) or 5 (10 mmol), [Ir(cod)Cl]2 (0.01 mmol), ligand (0.02 mmol), and benzene (5 mL) was stirred under Ar.
b
c
The structure of product except for 3na was determined by 2D NMR (see Supporting Information S115−S126 and S203−S266). Addition time of
d
e
f
g
1
diyne 1 in the case of using a syringe pump. Isolated yield. Determined by H NMR. 3 mmol of 5s was used. The structure of 3na was
determined by X-ray analysis (Figure 1). 2 mol % of [Ir(cod)Cl]2 and 4 mol % of ligand were used. 2 mmol of 5s was used.
h
i
nitrile carbon. The regioselectivity given by an electronic effect
is the same as that given by a steric effect in the case of 1m and
1n. A trimethylsilyl group is more electron-donating than a
methyl group.16 With diyne 1o, the trimethylsilyl-substituted
α-carbon in intermediate 7o is more electron-rich than the
methyl-substituted α-carbon to react preferentially with the
nitrile carbon atom to give 6′oa, 6′oe, and 6′os. A trimethylsilyl
group is more bulky than a methyl group. If steric effect is
predominant, the methyl-substituted α-carbon in intermediate
7o should react with the nitrile carbon to give 6oa, 6oe, and 6os.
The regioselectivity given by the electronic effect is opposite
to that given by the steric effect. The results in the reaction
of 1o showed that the electronic effect was predominant
over the steric effect to determine the regioselectivity. Ester-
tethered diyne 1q is a good substrate for evaluating the
electronic effect of an internal carbonyl group on regioselec-
tivity, since, with regard to steric considerations, diyne 1q
possesses the same alkyne terminus. The steric hindrance at
each α-carbon in iridacyclopentadiene 7q is the same in this
Figure 1. ORTEP drawing of 3na. Hydrogen atoms are omitted for
clarity. Thermal ellipsoids are drawn at 50% probability.
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electronic effect is opposite to that given by the steric effect.
The methyl-substituted α-carbon should react with the nitrile
carbon atom when the steric effect is predominant over the
electronic effect. Since an ester group is more electron-
withdrawing than a phenyl group, the phenyl-substituted α-
carbon should react with the nitrile carbon atom when the
electronic effect is predominant over the steric effect. The
results of the reaction of 1s showed that the electronic effect was
predominant over the steric effect, and an internal ester group
played a decisive role in determining the regioselectivity. In all
cases, the regioselectivity was directed by the electronic effect.
Scheme 1
THE REACTION OF DIYNE WITH
HETEROAROMATIC NITRILES
■
On the basis of these results, we studied the reactions of diynes
with heteroaromatic nitriles. The reaction with cyanopyridine is
expected to give bipyridines.17 The bipyridine framework is
important for the synthesis of biologically active compounds
such as pharmaceuticals and agrochemicals.18 In particular, 2,2′-
bipyridine compounds are of great importance as ligands that
can attach to various metal atoms.19 An atom-economical
synthesis of bipyridines is needed. Cyanopyridines were good
substrates for the cycloaddition. The results are summarized in
Table 6. Cyanopyridines 2o−q reacted with 1a to give
bipyridines 3ao−3aq in yields of 88−99% (entries 1−3).
Cyanopyridine 2r, which is more hindered than 2o, gave 3ar in
94% yield (entry 4). A more electron-deficient heteroaromatic
ring than pyridine decreased the yield. The reaction with
2-cyanopyrazine (2s) gave product 3as in 60% yield (entry 5).
2-Cyanoquinoline (2t) gave 3at in 98% yield (entry 6). As with
diyne 1a, Et-substituted diyne 1b reacted with 2o to give 3bo in
70% yield (entry 7). Regioselective cycloaddition to give
terpyridine was possible. Diyne 1t bearing a 2-pyridyl terminus
reacted with 2-cyanopyridine (2o) to give 2,2′:6′,2″-terpyridine
3to as a single product in 93% yield (entry 9). The structure of
3to was determined by X-ray analysis (Figure 2). (R)-BINAP
was more efficient than DPPF for the reaction of 1t with 2o
(entries 8 and 9). We developed another version of terpyridine
synthesis. The reaction of dicyanobenzene with an excess
amount of diyne 1a gave benzene substituted with two pyridine
rings (Table 2, entries 12 and 14). These results prompted us
to study the reaction of 2,5-dicyanopyridine (2u) with an excess
amount of diyne. The reaction of 4 equiv of 1a with 2u gave
2,2′:6′,2″-terpyridine 8au in 85% yield (entry 10). Similarly,
diynes 1b and 1d reacted with 2u to give the corresponding
terpyridines 8bu and 8du in nearly quantitative yields (entries
11 and 12). Six-membered ring formation was possible in
terpyridine synthesis. The reaction of 2,8-decadiyne 1j with
2u gave terpyridine 8ju with two six-membered rings in
quantitative yield (entry 13). Our iridium catalyst could be
successfully applied to the synthesis of bipyridines and
terpyridines.
Scheme 2
case. Consequently, the electronic effect plays a decisive role in
determining the regioselectivity. With iridacyclopentadiene 7q,
an α-carbon conjugated with an internal carbonyl group is more
electron-deficient than an α-carbon that is not conjugated with
a carbonyl group. The nitrile nitrogen atom reacts at the more
electron-deficient α-carbon to give 3qa, 6qa, 6qe, and 6qs.
With ester diyne 1r, an ester group and phenyl group were
substituted on the same alkyne. The electron-withdrawing
properties of these groups influence the same α-carbon. Phenyl-
substituted α-carbon conjugated with an internal carbonyl
group in intermediate 7r preferentially reacts with a nitrile
nitrogen atom to give 3ra, 6ra, 6re, and 6rs. With regard to the
steric effect, the less-hindered methyl-substituted α-carbon
reacted with the nitrile carbon atom to give the same product
directed by the electronic effect. In the case of 1r, the
regioselectivity given by the electronic effect is the same as that
given by the steric effect. On the other hand, in the case of
ester-tethered diyne 1s, the regioselectivity given by the
SYNTHESIS OF OLIGOHETEROARENES
■
Oligoarenes and oligoheteroarenes are useful molecules in
various research areas that involve functional molecules, self-
assembling molecules, and biologically active compounds.20
One of the most reliable methods for the construction of these
structures is the transition metal-catalyzed cross-coupling
reaction.21 Suginome reported a masking strategy in the
Suzuki−Miyaura coupling as a new route to oligoarenes with
a defined structure.22a However, a cross-coupling methodology
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a
Table 6. Reaction of Diynes (1) with Heteroaromatic Nitriles 2
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Table 6. continued
a
b
A mixture of 1 (1 mmol), 2 (3 mmol), [Ir(cod)Cl]2 (0.01 mmol), DPPF (0.02 mmol), and benzene (5 mL) was stirred under Ar. Isolated yield.
c
d
e
f
2 mol % of [Ir(cod)Cl]2 and 4 mol % of DPPF were used. With complete regioselectivity. (R)-BINAP was used as a ligand. A mixture of
1 (2 mmol), 2 (0.5 mmol), [Ir(cod)Cl]2 (0.01 mmol), DPPF (0.02 mmol), and benzene (5 mL) was stirred under Ar.
regioselective cycloaddition. In the synthesis of the starting
diynes, various aromatic or heteroaromatic rings can be
introduced to the diyne terminus by Sonogashira coupling.
Diynes 1n and 1t−v were prepared in high yields. As described
in Table 2, the use of 4 equiv of diyne was needed to cyclize
both of the cyano groups. The results are summarized in
Scheme 3. Unsymmetrical diyne 1n bearing a naphthyl
terminus reacted with 2u to give terpyridine 8nu bearing two
naphthyl rings in 96% yield with the use of (R)-BINAP as a
ligand. The reaction was completely regioselective and gave a
single product. This result prompted us to attempt the
synthesis of 2,2′:6′,2″:6″,2‴:6‴,2″″-quinquepyridine. As ex-
pected, the reaction of diyne 1t bearing a 2-pyridyl terminus
with 2u gave quinquepyridine 8tu in 86% yield with complete
regioselectivity. We introduced a 2-quinolyl group and 2-thienyl
group to the diyne terminus to extend the scope of this
methodology. Diyne 1u bearing a 2-quinolyl terminus reacted
with 2m and 2u to give 8um and 8uu in respective yields of
86% and 84%. Similarly, diyne 1v bearing a 2-thienyl terminus
reacted with 2m and 2u to give 8vm and 8vu in respective
yields of 79% and 62%. The structure of 8nu·CH2Cl2, 8tu, and
8vm was determined by X-ray analysis (Figures 3, 4, and 5,
respectively). The structure of 8um, 8uu, and 8vu was
determined on the basis of 2D-NMR analysis (see the
Supporting Information, S281−S288 and S291−S294). Nota-
bly, a terpyridine with two heteroaromatic termini was
obtained. The cycloaddition strategy is more efficient than a
sequential cross-coupling strategy, since this method can
connect five heteroaromatic rings in a single operation. As
described above, symmetrical oligoheteroarenes were obtained
in high yields. If this method can be successfully applied to the
synthesis of unsymmetrical oligoheteroarene, it should be quite
valuable for organic synthesis. Unsymmetrical oligoheteroarene
could be obtained by stepwise cyclization using two different
diynes (Scheme 4). When an excess amount of 2m to 1t was
used, only one of the two cyano groups participated in
Figure 2. ORTEP drawing of 3to. Hydrogen atoms are omitted for
clarity. Thermal ellipsoids are drawn at 50% probability.
for the synthesis of oligoarenes and oligoheteroarenes is a
tedious multistep synthesis. Moreover, the installation of a
metal group into heteroaromatic compounds is often difficult
because of problems with the stability of the resulting
heteroaromatic metal reagent.23 For example, 2-pyridyl boronic
acid and its esters are easily decomposed by proton.23 In
addition to the stability problem, the transmetalation of an
electron-deficient heteroaromatic boron reagent to palladium is
relatively slow.24 There are still problems to overcome in the
cross coupling of heteroaromatic compounds. A more efficient
and convenient route to oligoarenes and oligoheteroarenes with
a defined structure is needed. We extended the regioselective
cycloaddition of unsymmetrical diyne bearing a heteroaromatic
terminus with 2,5-dicyanopyridine or 1,3-dicyanobenzene to
give a new synthetic route to oligoheteroarenes. An advantage
of this methodology is that construction and connection of the
ring can be performed in a single operation. We attempted to
construct oligoheteroarenes in one step by our Ir-catalyzed
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Scheme 3
Figure 5. ORTEP drawing of 8vm. Hydrogen atoms and minor parts of
disorder are omitted for clarity. Thermal ellipsoids are drawn at 50% probability.
established as an important class of chiral building blocks
not only in natural products25 but also in asymmetric
synthesis.19a,26 A limited number of examples of enantiose-
lective cycloaddition to give chiral pyridine have been reported.
Axially chiral pyridine and central carbon chiral pyridine have
been reported. Axially chiral pyridine given by the chiral
Cp-cobalt complex-catalyzed cycloaddition of a sterically
demanding diyne has been reported.6e,g Pyridine bearing a
chiral quaternary stereocenter was synthesized in 64% ee by the
Rh-catalyzed enantioselective desymmetrization of substituted
malononitrile with diyne.11b The synthesis of chiral spirobipyr-
idine by the Rh-catalyzed double cycloaddition of bisalkyneni-
trile has been reported.11a Co-catalyzed cycloaddition with
chiral nitrile to give a central carbon chiral pyridine has been
reported.27 However, cycloaddition to give a chiral pyridine by
the kinetic resolution of racemic nitriles has not been reported.
We examined the reaction of diyne 1a with racemic secondary
nitrile 5w in the presence of a catalytic amount of [Ir(cod)Cl]2/
(R)-SEGPHOS. (Optimization of the reaction conditions for
the kinetic resolution of a racemic nitrile: see the Supporting
Information, S2-S3). We chose secondary nitrile 5w as a nitrile
component because a benzyl nitrile is more reactive than an
aliphatic nitrile. The corresponding product 6aw was obtained
in 75% with 80% ee (Scheme 5). Recrystallization of 6aw
with 67% ee from isopropyl alcohol gave 6aw with 99% ee.
The absolute configuration was determined to be R by the
anomalous dispersion method (Figure 7). Since the absolute
configuration of the product was (R), it is clear that (R)-5w
reacts with diyne 1a faster than (S)-5w.
Figure 3. ORTEP drawing of 8nu·CH2Cl2. Hydrogen atoms and
CH2Cl2 are omitted for clarity. Thermal ellipsoids are drawn at 50%
probability.
Figure 4. ORTEP drawing of 8tu. Hydrogen atoms are omitted for
clarity. Thermal ellipsoids are drawn at 50% probability.
cyclization. Diyne 1t reacted with 3 equiv of 2m to give 3tm
bearing an intact cyano group in 92% yield. An excess amount
of diyne 1v to 3tm was used to complete the second
cyclization. Two equivalents of 1v reacted with 3tm to give
unsymmetrical oligoheteroarene 9 bearing a pyridine terminus
and thiophen terminus in 84% yield. The structure of 9 was
determined by X-ray analysis (Figure 6).
ENANTIOSELECTIVE [2 + 2 + 2] CYCLOADDITION
TO GIVE PYRIDINE BY THE KINETIC RESOLUTION
OF A RACEMIC NITRILE
■
THEORETICAL CALCULATIONS FOR THE
REACTION MECHANISMS
There have already been several theoretical studies on
■
Much attention has been paid to enantioselective [2 + 2 + 2]
cycloaddition to give pyridine, since chiral pyridines have been
transition metal-catalyzed [2 + 2 + 2] cyclotrimerizations.28
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Scheme 4
Figure 7. ORTEP drawing of 6aw. Hydrogen atoms are omitted for
clarity. Thermal ellipsoids are drawn at 50% probability.
Figure 6. ORTEP drawing of 9. Hydrogen atoms and minor parts of
disorder are omitted for clarity. Thermal ellipsoids are drawn at 50%
probability.
Scheme 6
Scheme 5
to IV is −40.8 kcal/mol. Thus, this step provides a large
degree of stabilization. As shown in Figure 8, the lengths of
the C2−C3, C3−C4, and C4−C5 bonds in IV are 1.347, 1.464, and
1.349 Å, respectively. The lengths of the C2−C3 and C4−C5
bonds show a double bond character. Complex IV is con-
sidered to be a metallacyclopentadiene rather than a metal-
lacyclopentatriene. The end-on coordination of acetonitrile
to the iridium atom in IV gives complex V. The complexa-
tion energy is calculated to be 18.2 kcal/mol and complex V
is more stable than complexes V′ (complexation energy:
1.2 kcal/mol) and V″ (complexation energy: 12.3 kcal/mol).
On the other hand, no side-on complex was found in the
present study.33
However, the detailed mechanisms of these reactions have not
been fully clarified. To the best of our knowledge, there has
been no theoretical study on the reaction mechanism of
iridium-catalyzed cycloaddition with nitrile. To shed light on
the reaction mechanism of the cycloaddition between 1,6-diyne
and acetonitrile, density functional theory (DFT) calculations
using the B3LYP hybrid functional29 with the Gaussian09
program30 (LANL2DZ31 for Ir atom and 6-31G*32 for other
atoms) were carried out for the model reaction of 1,6-diyne (I)
with acetonitrile catalyzed by the iridium complex (II) (Scheme 6).
Since the DPPP ligand is more efficient than DPPE (Table 1),
the DPPP model ligand in which the phenyl group at DPPP
is replaced by a hydrogen atom was used for the iridium
complex II.
The optimized structures and energy diagrams are shown
in Figures 8 and 9, respectively. The reaction pathways are
shown in Scheme 7. The initial complex III generated by the
complexation of I with II is transformed into complex IV
through transition state TSI. The activation energy from III
to TSI is 4.6 kcal/mol and the reaction energy from III
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Figure 8. Optimized structures of stationary points for the model reaction between I and acetonitrile catalyzed by iridium complex II. Bond lengths
are in angstroms.
Figure 9. Relative energy diagram (kcal/mol) for the model reaction. Values in parentheses are relative Gibbs free energies at 298.15 K in the gas
phase.
Three pathways (i, ii, and iii) from V to the final state (IX + II)
are possible (Scheme 7). In pathway i, the first bond for-
mation occurs between the nitrile carbon and the C5 atom
to give complex VI via TSII. The Ir−C2 and C3−C4 bonds
become shorter, from 2.083 and 1.468 Å to 1.970 and 1.388 Å,
respectively, as a result of transformation from V to VI. In
contrast, the Ir−C5 bond lengthens from 2.110 Å to 2.164 Å.
The length of the Ir−C2 bond of 1.970 Å in VI shows a double
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Scheme 7
bond character. Complex VI has an azairidabicyclo[3.2.0]-
heptatriene structure. Related iridabicyclo[3.2.0]heptatriene
was recently isolated by Paneque.34 A process similar to that
for the formation of azaruthenabicyclo[3.2.0]heptatriene is pro-
posed based on the DFT calculation for the CpRuCl-mediated
cyclotrimerization of acetylene with CF3CN.8b Subsequent
bond formation occurs between the nitrile nitrogen and
C2 via TSIII to give VII, in which the Ir−C2 (2.141 Å), Ir−
N(nitrile) (2.214 Å), Ir−C(nitrile) (2.227 Å), and Ir−C5
(2.268 Å) bonds are almost the same length. Complex VII
can be considered to be a η4-pyridine Ir (+1) complex. A
similar η4-benzene Rh (+1) complex has been proposed in
a theoretical study on the cyclotrimerization of acetylene
catalyzed by Wilkinson’s catalyst.28t η4-Benzene Ir (+1) com-
plex has been isolated.35 The η4-complex VII is transformed
into the η2-complex VIII via TSIV, and VIII readily dis-
sociates into IX and II. Overall, the reaction system is highly
exothermic.
In pathway ii, the first bond formation occurs between nitrile
nitrogen and C2 atom to give X via TSV. Subsequent bond
formation occurs between nitrile carbon and C5 atom to give
VII via TSVI. Since transition states TSV and TSVI are at
higher energies than TSII and TSIII, as shown in Figure 9,
pathway ii is unfavorable compared to pathway i.
Pathway iii starts with complex VI. Transformation of VI
to azairidacycloheptatriene XI via TSVII proceeds with
cleavage of the Ir−C5 bond of complex VI. A process similar
to that for the formation of azaruthenacycloheptatriene is
proposed in CpRuCl-mediated cyclotrimerization.8b TSVII is
at a slightly higher energy than TSIII in pathway i, as shown
in Figure 9. Reductive elimination from XI via TSVIII gives
complex XII, in which the pyridine nitrogen atom
coordinates to iridium (+1). According to the energy
diagram shown in Figure 9, the transition states in path-
way i, TSII, TSIII, and TSIV, are at lower energies than those
in the other pathways. On the basis of these results, path-
way i is preferred to the other pathways. The reaction pro-
ceeds via asynchronous addition of a carbon−nitrogen triple
bond to iridacyclopentadiene to give azairidabicyclo[3.2.0]-
heptatriene.
CONCLUSION
■
We have developed a new and efficient catalyst for the
cycloaddition of alkynes with nitriles to give pyridines. Our
catalyst system offers considerable advantages compared to
previously reported catalyst systems: (1) The experimental
procedure is more convenient than any previously reported.
Pretreatment of the catalyst system is not necessary. The
procedure simply requires mixing of [Ir(cod)Cl]2 and an
appropriate diphosphine ligand in solvent before the addi-
tion of substrates. (2) The catalytic activity can be altered at
will through the use of various commercially available
phosphines. (3) Aliphatic nitriles as well as aromatic nitriles
can be used. The product was obtained in good to high yield.
(4) Unsymmetrical diyne undergoes highly regioselective
cycloaddition with nitrile to give a single product in high
yield. (5) Oligoheteroarenes, including bipyridines and
terpyridines, can be obtained by regioselective cycloaddition.
Construction and connection of the heteroaromatic rings are
performed in a single step. (6) Enantioselective [2 + 2 + 2]
cycloaddition by the kinetic resolution of a racemic nitrile
gives a centro chiral pyridine with high enantiomeric excess.
(7) The reaction proceeds via asynchronous addition of a
carbon−nitrogen triple bond to iridacyclopentadiene to give
azairidabicyclo[3.2.0]heptatriene, which gives a η4-pyridine
Ir (+1) complex.
EXPERIMENTAL SECTION
■
Representative Procedure for the [2 + 2 + 2] Cycloaddition
of Diyne (1) with Nitrile (2) (1:1 Reaction). A flask was charged
with [Ir(cod)Cl]2 (7.2 mg, 0.01 mmol) and DPPF (11.3 mg, 0.02
mmol). The flask was evacuated and filled with argon. To the flask
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were added benzene (5 mL) and benzonitrile (2a) (325 mg, 3.2
mmol). Diyne 1a (235 mg, 1.0 mmol) was added to the reaction
mixture. The mixture was stirred under reflux for 3 h. The progress
of the reaction was monitored by GLC. After the reaction was
complete, the solvent was evaporated in vacuo. Column chro-
matography of the residue gave 3aa (n-hexane/AcOEt = 70/30, 305
mg, 0.9 mmol, 91% yield).
Representative Procedure for the [2 + 2 + 2] Cycloaddition
of Diyne (1) with Dinitrile (2) (2:1 Reaction). A flask was charged
with [Ir(cod)Cl]2 (7.0 mg, 0.01 mmol), DPPF (11.8 mg, 0.02 mmol),
and 1,4-dicyanobenzene (2l) (65 mg, 0.5 mmol). The flask was
evacuated and filled with argon. To the flask was added benzene
(5 mL) and diyne 1a (473 mg, 2.0 mmol) was added to the reaction
mixture. The mixture was stirred under reflux for 3 h. The progress of
the reaction was monitored by GLC. After the reaction was complete,
the solvent was evaporated in vacuo. Column chromatography of the
residue gave 4al (n-hexane/AcOEt = 30/70, 290 mg, 0.48 mmol, 95%
yield).
Representative Procedure for the Synthesis of Oligoheter-
oarene. A flask was charged with [Ir(cod)Cl]2 (7.7 mg, 0.01 mmol),
(R)-BINAP (12.6 mg, 0.02 mmol), and 2,6-dicyanopyridine (2u) (65
mg, 0.5 mmol). The flask was evacuated and filled with argon. To the
flask was added benzene (5 mL) and diyne 1n (741 mg, 2.1 mmol)
was added to the reaction mixture. The mixture was stirred under
reflux for 24 h. The solvent was evaporated in vacuo. Column
chromatography of the residue gave 8nu (n-hexane/AcOEt = 60/40,
397 mg, 0.48 mmol, 96% yield).
Procedure for the Enantioselective Cycloaddition of 1a with
5w. A flask was charged with [Ir(cod)Cl]2 (6.7 mg, 0.01 mmol) and
(R)-SEGPHOS (13.0 mg, 0.02 mmol). The flask was evacuated and
filled with argon. To the flask were added benzene (5 mL) and
nitrile (5w) (2658 mg, 20 mmol). Diyne 1a (236 mg, 1.0 mmol)
was added to the reaction mixture. The mixture was stirred under
reflux for 1 h. The progress of the reaction was monitored by GLC.
After the reaction was complete, the solvent was evaporated in
vacuo. Column chromatography of the residue gave 6aw (n-hexane/
AcOEt = 70/30, 275 mg, 0.75 mmol, 75% yield, 80% ee). The ee
value was determined by HPLC analysis with a Chiralcel OZ-H
column (eluent: n-hexane/2-propanol = 99.65/0.35; flow rate: 1.0
mL/min; column temperature: 35 °C; retention time: 27.9 min (R)
and 34.3 min (S)).
ACKNOWLEDGMENTS
■
This research was supported by Grant-in-Aid for Scientific
Research (C) (21550107) from the Japan Society for the
Promotion of Science and the Ministry of Education, Culture,
Sports, Science, and Technology of Japan. We thank Rigaku
Corporation for the single-crystal X-ray analysis of 6aw. We
thank Prof. Nishibayashi and Dr. Miyake for measuring HRMS
spectra.
REFERENCES
■
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(2) Pozharskii, A. F.; Soldatenkov, A. T.; Katritzky, A. R. Heterocycles
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(99% ee (R)).
ASSOCIATED CONTENT
■
S
* Supporting Information
NMR spectroscopic data and high-resolution mass spectra data
of 3, 4, 6, 8, and 9, single-crystal X-ray diffraction data of
compounds 3na, 3to, 8nu·CH2Cl2, 8tu, 8vm, 9, and 6aw,
computational details, total energy and free energy at 298 K,
and Cartesian coordinates of stationary points. This material is
available free of charge via the Internet at http://pubs.acs.org.
́
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Lett. 2000, 2, 3131.
AUTHOR INFORMATION
■
Corresponding Author
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* takeuchi@chem.aoyama.ac.jp
Present Address
†Division of Chemistry and Materials Science, Graduate School
of Engineering, Nagasaki University, 1−14 Bunkyo, Nagasaki
852−8521, Japan.
Notes
The authors declare no competing financial interest.
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