Synthesis of substituted 2,2′-bipyridines and 2,2′:6′, 2″-terpyridines by cobalt-catalyzed cycloaddition reactions of nitriles and α,ω-diynes with exclusive regioselectivity

Article abstract of DOI:10.1002/adsc.200700380

A variety of substituted 2,2′-bipyridines were synthesized by a 1,2-bis(diphenylphosphino)-ethane (dppe)/cobalt chloride hexahydrate (CoCl ₂·6H₂O)/zinc-catalyzed [2 + 2+2] cycloaddition reaction of diynes and nitriles, with all reactions exhibiting exclusive regioselectivity. Thus, symmetrical and unsymmetrical 1,6-diynes and 2-cyanopyridine reacted in the presence of 5 mol % of dppe, 5 mol % of CoCl ₂·6H₂O and 10 mol% of zinc powder to provide the corresponding 2,2′-bipyridines. Under identical reaction conditions, 1-(2-pyridyl)-1,6-diynes and nitriles reacted smoothly with exclusive regioselectivity to produce 2,2′-bipyridines in good yield. 2,2′-Bipyridines were also obtained by the double [2 + 2 + 2] cycloaddition reaction of 1,6,8,13-tetraynes with nitriles. Similarly, 2,2′:6′,2″-terpyridines were synthesized from 1-(2-pyridyl)-1,6-diyne and 2-cyanopyridine. The regiochemistry observed can be explained by considering the electronic nature of cobaltacyclopentadiene intermediates and nitriles. A survey of the exclusive regiochemical trend gives reasonable credence to the synthetic potential of the present method.

Full text of DOI:10.1002/adsc.200700380

FULL PAPERS
DOI: 10.1002/adsc.200700380
Synthesis of Substituted 2,2’-Bipyridines and 2,2’:6’,2’’-Terpyri-
dines by Cobalt-Catalyzed Cycloaddition Reactions of Nitriles
and a,w-Diynes with Exclusive Regioselectivity
Avijit Goswami,a Kazuhiko Ohtaki,a Kouki Kase,a Taichi Ito,a
and Sentaro Okamotoa,*
a
Department of Material& Life Chemistry, Kanagawa University, 3-27-1 Rokkakubashi, Kanagawa-ku, Yokohama
221-8686, Japan
Fax : (+81)-45-413-9770; e-mail: okamos10@kanagawa-u.ac.jp
Received: July 31, 2007; Published online: December 14, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A variety of substituted 2,2’-bipyridines pyridines were also obtained by the double [2+2+
were synthesized by a 1,2-bis(diphenylphosphino)- 2]cycloaddition reaction of 1,6,8,13-tetraynes with ni-
ethane
(dppe)/cobalt
chloride
hexahydrate triles. Similarly, 2,2’:6’,2’’-terpyridines were synthe-
(CoCl2·6H2O)/zinc-catalyzed [2+2+2]cycloaddition sized from 1-(2-pyridyl)-1,6-diyne and 2-cyanopyri-
reaction of diynes and nitriles, with all reactions ex- dine. The regiochemistry observed can be explained
hibiting exclusive regioselectivity. Thus, symmetrical by considering the electronic nature of cobaltacyclo-
and unsymmetrical1,6-diynes and 2-cyanopyridine
reacted in the presence of 5 mol% of dppe, 5 mol%
of CoCl2·6H2O and 10 mol% of zinc powder to pro-
pentadiene intermediates and nitriles. A survey of
the exclusive regiochemical trend gives reasonable
credence to the synthetic potentialof the present
vide the corresponding 2,2’-bipyridines. Under iden- method.
ticalreaction conditions, 1-(2-pyridy)l-1,6-diynes and
nitriles reacted smoothly with exclusive regioselectiv- Keywords:
2,2’-bipyridine;
cobalt
catalyst;
ity to produce 2,2’-bipyridines in good yield. 2,2’-Bi-
ACHTRE[UGN 2+2+2]cycloaddition; terpyridine
Introduction
tion reaction of alkynes and nitriles has attracted
much interest as a straightforward, atom-economical
2,2’-Bipyridines are of great importance as the sub- route to substituted pyridines[4] and the methods have
structure of biologically active compounds and partic- been extensively applied to bipyridine synthesis. Al-
ularly as a ligand capable of attachment to various though several fully intra- and intermolecular reac-
metalatoms. Their metalcompelxes exhibit unique
tions with alkynes and nitriles to bipyridines have
characteristics allowing them to fulfill a variety of been reported,[5] from a synthetic viewpoint they
synthetically useful roles such as a catalyst and its pre- suffer from lack of selectivity control, i.e., regio- and
cursor, the substructure of polymer and self-assem- chemoselectivity for intermolecular reactions, or sub-
bling molecules, photosensitizer, and optical device strate availability and generality of the product struc-
materials.[1] Therefore, many synthetic methods con- ture for intramolecular reactions. In contrast to these
sisting of non-catalyzed heterocycle syntheses[2] and reactions, the partially intramolecular reactions shown
metal-catalyzed reactions have been developed. In as Eq. (1) to Eq. (5) in Scheme 1 can be performed
modern organic synthesis, the bipyridines have been with readily available substrates and will have a rea-
prepared by transition metal-catalyzed homo-coupling sonable generality with respect to product structure
(Ullmann-type reactions) of 2-halopyridine or cross- and, therefore, further development of this synthetic
coupling between 2-halo- and 2-metalated pyridines.[3] method is likely. In contrast to many results of bipyri-
However, these processes are not necessarily general dine synthesis by the reactions of cyanoalkynes and
and are limited by the availability and reactivity of alkynes shown in Eqs. (1) and (2), the regioselectivity
the halo- and/or metalated pyridine substrates. Re- of which was not necessarily high,[6] the reactions of
cently, the metal-catalyzed [2+2+2]-type cycloaddi- diynes and nitriles depicted in Eqs. (3) to (5) have
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cently, 2,2’-bipyridine synthesis by the reaction of 4
and 2 [Eq. (4)] has been reported: tetrahydro-1,1’-bi-
sisoquinoline derivatives were synthesized by the mi-
crowave-assisted CpCo(CO)2-catalyzed reaction of ni-
triles with isoquinoline-attached 1,7-diyne, where a
high regioselectivity to produce the 2,2’-bipyridine
structure was attained.[7] Regarding the tandem reac-
tion of Eq. (5), it has been reported that the Ru-cata-
lyzed reaction of a tetrayne of the type 6 with malo-
nonitrile or chloroacetonitrile gave the corresponding
7 selectively,[8] however, there is no report of the reac-
tion with usual unactivated alkyl and aryl nitriles.
We have recently developed a facile synthesis for
substituted pyridines by [2+2+2]cycloaddition reac-
tion of a,w-diynes and nitriles by using a 1,4-diphos-
phine/CoCl2·6H2O/Zn catalyst, where unactivated ni-
triles such as acetonitrile and benzonitrile reacted
smoothly under mild reaction conditions.[9] Based on
these results, we planned the preparation of 2,2’-bipyr-
idines by the cycloadditions of the types in Eqs. (3) to
(5). Thus, the cycloaddition of 1,6-diynes 1 with 2-cya-
nopyridine (2a) will give 2,2’-bipyridines 3 and their
regioisomers 3’ [Eq. (3)], whereas the reaction of 1-
(2-pyridyl)-1,6-diynes 4 with nitriles 2 may afford 2,2’-
bipyridines 5 and their 2,3’-isomers 5’ [Eq. (4)]. In ad-
dition, 2,2’-bipyridines 7 and their isomers 7’ and 7’’
may be obtained by tandem cycloaddition of tet-
raynes 6 and nitriles 2 [Eq. (5)]. In these reactions, it
is desired that the individual regioselectivity could be
controlled to produce 2,2’-isomers. Herein we disclose
the successfulresutls of these syntheses.
Results and Discussion
Reactions of 1,6-Diynes 1 with 2-Cyanopyridine (2a)
A preliminary investigation revealed that the reac-
tions of Eq. (1) were not effectively catalyzed by the
present reagent, a dppe/CoCl2·6H2O/Zn, but the reac-
tions of diynes and nitriles [Eqs. (3) to (5)] proceeded
smoothly.
First, Table 1 summarizes the results of the reaction
of Eq. (3) in Scheme 1. In the reaction of diynes in-
volving a terminal alkyne group(s), a large excess
amount (20 equivs.) of 2a was employed to minimize
self-cycloaddition of the diynes to a dimer. The reac-
tions of symmetrical1,6-diynes 1a and 1b with 2-cya-
Scheme 1. Synthesis of bipyridines by [2+2+2]cycloaddi-
tion reactions.
been less explored and thus lack information to evalu- nopyridine (2a) provided the corresponding 2,2’-bipyr-
ate their synthetic potential. To our knowledge, there idines in good isolated yields (entries 1 and 2). Un-
is one example of the reaction of Eq. (3) where 1 con- symmetricaldiynes 1c–h also reacted smoothly with
sisting of two terminalaklynes (R 1, R2 =H) and 2,6- 2a and it is noteworthy that the reactions provided
dicyanopyridine instead of 2a were used and their the corresponding bipyridine with complete regiose-
Ru-catalyzed reaction yielded 2-(2-pyridyl)-6-cyano- lectivity (entries 3–8). In the reactions of mono-substi-
pyridine.[4h] The reactions of unsymmetricaldiynes
1
tuted diynes 1c–e (R2 =H), the substituent R1 is locat-
(R1 ¼R2) and their regioselectivity have not been in- ed at the 3-position of the generated pyridine ring
vestigated at all. During our investigation, quite re- (entries 3–5). Meanwhile, the reaction of 1f exclusive-
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Table 1. 2,2’-Bipyridine synthesis by the reaction of 1 and 2a [Eq. (3) of Scheme 1].
Entry
1
1
2a (equivs.)
Time [h]
3
Product
Yield[a] (3:3’)[b]
65% (ꢀ)
1a: R1 =H, R2 =H
(20)
3aa
3ba
2
3
4
5
6
7
1b: R1 =Me, R2 =Me
1c: R1 =Me, R2 =H
1d: R1 =n-Bu, R2 =H
1e: R1 =SiMe3, R2 =H
1f: R1 =H, R2 =Ph
1g: R1 =Me, R2 =Ph
(2)
12
12
3
58% (ꢀ)
(20)
(20)
(20)
(20)
(2)
3ca
3da
3ea
3fa
3ga
3ha
78% (>99:1)
67% (>99:1)
76% (>99:1)
78% (>99:1)
47% (>99:1)
91% (>99:1)
12
12
12
24
8
1h: R1 =SiMe3, R2 =n-Bu
(2)
[a]
Isolated yield.
Determined by H NMR analysis of the crude mixture.
[b]
1
ly gave the product 2,2’-bipyridine 3fa with a phenyl gest that the regioselectivity was controlled not steri-
group at the 2-position of the resulting pyridine cally but electronically. It can be considered that, in
(entry 6). In addition, unsymmetricaldiynes with two
all cases, the more electron-rich alkyne of the two
internalaklynes 1g and 1h also reacted with 2a in a present in diynes 1 is attached to the carbon of cyano
completely regioselective fashion. These results sug- group of 2a (vide infra).
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The resulting silyl-substituted pyridines such as 3ha Reactions of 1-(2-Pyridyl)-1,6-diynes 4 with Nitriles 2
are synthetically useful: Protiodesilylation and saponi-
fication/decarboxylation of 3ha, by treatment with n- Next, we investigated the reaction of nitriles 2 with
Bu4NF in wet DMSO, provided 4,5,6-trisubstituted unsymmetricaldiynes of type 4 having a 2-pyridyl
2,2’-bipyridine 8 as a single regioisomer (Scheme 2), moiety as a terminus [Eq. (4) in Scheme 1] and con-
1
the H NMR spectra of which were compared with firmed the regioselectivity between 2,2’-isomer 5 and
those of the carboxylic acid derived from 3da by sapo- 2,3’-isomer 5’. Severalrepresentative restusl are
nification/decarboxylation.
method is complementary to the exclusive formation amount of nitrile proceeded smoothly to give the cor-
of 3,4,5- or 4,5,6-trisubstituted 2,2’-bipyridines. responding bipyridines in good yields and, to our de-
Regiochemically,
the shown in Table 2. The reaction with an appropriate
The formation of 8 and subsequent comparison of light, 2,2’-bipyridines 5 were produced exclusively in
the aromatic peaks of its NMR spectra with those of all cases. Malononitrile (2c)[8,9] and perfluoroalkylni-
the isomer derived from 3da confirmed the regioche- trile 2e[10] were highly reactive so that the reaction
mistries of 3da and 3ha. Likewise, the structure was with 1.5 equivs. of them proceeded smoothly to pro-
suggested for 3ea and 3fa as depicted in Table 1. The vide the corresponding 5 in good yield (entries 2 and
COLOC (correlation spectroscopy via long-range 5). The resulting cyanomethyl-substituted 2,2’-bipyri-
coupling spectrum) experiment of 3ca and 3ga con- dines such as 5bc and 5ac or their derivatives after
firmed their regiochemistry: In each case the fact that manipulation of the cyano moiety might be expected
the ring methylprotons had correaltions with three
aromatic carbons indicated that the methylgroup is
present at the 3-position of the pyridine.
as a tridentate ligand to metal. In addition, perfluoro-
alkylated bipyridines such as 5ce might be interesting
from the viewpoint of fluorous chemistry.[11]
To confirm the regiochemistry of the products, the
COLOC measurement was carried out. In the case of
5ab and 5cb, protons of one methylgroup had two
correlations with aromatic carbons, while another
methylshowed three correaltions. Methylprotons of
5ac, 5ad and 5ce, respectively, had three correlations
with aromatic carbons. In addition, the methylene
protons of the nitrile a in 5bc and 5ac had two corre-
lations with pyridine carbons, respectively. These facts
establish that their regiochemistry is as depicted.
Crystallography of 5ab and 5ac fully confirmed their
2,2’-bipyridine structure (Figure 1).
Reactions of 1,6,8,13-Tetraynes 6 with Nitriles 2
Table 3 shows the results of the tandem reaction of
Scheme 2. Protiodesilylation of silylated pyridine 3ha.
tetraynes 6 with nitriles 2 to bis-annulated bipyridines.
Figure 1. X-ray structures of compounds 5ab (left) and 5ac (right).
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Synthesis of Substituted 2,2’-Bipyridines and 2,2’:6’,2’’-Terpyridines
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Table 2. Bipyridine synthesis by the reaction of 2 and 4 [Eq. (4) of Scheme 1)].
Entry
1
4
2 (equivs.)
Time [h]
12
Product
Yield[a] (5:5’)[b]
81% (>99:1)
4a: R1 =Me, Z=C
N
2b: R3 =Me (20)
5ab
5bc
5ac
2
3
4b: R1 =H, Z=C
(CO2Et)2
2c: R3 =CH2CN (1.5)
2c: R3 =CH2CN (1.5)
6
6
71% (>99:1)
86% (>99:1)
4a
4
5
4a
2d: R3 =Ph (5)
12
12
6
5ad
5cb
5ce
54% (>99:1)
89% (>99:1)
64% (>99:1)
4c: R1 =Me, Z=O
2b (20)
6
4c
2e: R3 =C7F15 (1.5)
[a]
Isolated yield.
Determined by H NMR analysis of the crude mixture.
[b]
1
As revealed from the table, all reactions performed measurement confirmed the regiochemistry as depict-
gave the corresponding bipyridine in moderate to ex- ed for 7ab, 7bb and 7cb. In addition, the structures of
cellent yield and, among three possible regioisomers, 7bb and 7cd were corroborated by X-ray crystallogra-
the 2,2’-bipyridine 7 was obtained exclusively.
phy (Figure 2).
Similar to the assignment of 5, the correlations of
aromatic carbons to methylprotons on the COLOC
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Table 3. Bipyridine synthesis by the tandem reaction of 2 and 6 [Eq. (5) of Scheme 1].
Entry
6
2 (equivs.)
Product
Yield[a] (7:7’+7’’)[b]
68% (>99:1)
1
6a: R1 =Ph, Z=O
2b: R3 =Me (80)[c]
7ab
2
3
4
6a
2d: R3 =Ph (10)
7ad
7bb
7cb
41% (>99:1)
87% (>99:1)
90% (>99:1)
6b: R1 =H, Z=C
(CO2Et)2
2b (80)[c]
6c: R1 =Ph, Z=C
(CO2Et)2
2b (40)
5
6c
2d (10)
7cd
86% (>99:1)
[a]
Isolated yield.
Determined by H NMR analysis of the crude mixture.
Acetonitrile was used as a solvent. When 40 equivs. of acetonitrile in NMP were used, a similar yield of the correspond-
ing bipyridine was obtained.
[b]
[c]
1
Study for the Preparation of Terpyridines and
Quarterpyridines
dines and quarterpyridines by the present method.[12]
These polypyridines are of interest as a ligand for
metalcompel xes and substructure of other functiona-l
With the aforementioned results in hand, we next ized molecules. Thus, based on the results of the reac-
concentrated our efforts to the preparation of terpyri- tions of Eqs. (3) and (4), a mixture of 1-(2-pyridyl)-
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Synthesis of Substituted 2,2’-Bipyridines and 2,2’:6’,2’’-Terpyridines
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Figure 2. X-ray structures of compounds 7bb (left) and 7cd (right).
1,6-diyne 4c and 2-cyanopyridine (2a) was subjected presence of a dppe/CoCl2·6H2O/Zn catalyst produced
to the catalysis and the reaction provided 2,2’:6’,2’’- 2,2’:6’,2’’:6’’,2’’’-quarterpyridine 7da with complete re-
terpyridine 5ca as a sole product in 69% isolated gioselectivity but the yield was low (5%), due to
yield (Scheme 3).
steric hinderance. Instead, the reaction mainly pro-
It was expected that a combination of tetraynes 6 duced mono-cyclized product 9da in 42% isolated
and 2-cyanopyridine (2a) would provide quarterpyri- yield with >99:1 regioselectivity. Although further
dines by the reaction of type Eq. (5). As illustrated in improvement is required to successfully form quarter-
Scheme 4, the reaction of 6d and 2a (2 equivs.) in the pyridine, the resulting dipyridyl-diyne 9 was a good
substrate for preparing terpyridines of type 10
Scheme 3. Synthesis of 2,2’:6’,2’’-terpyridine 5ca and its crys-
tallographic structure.
Scheme 4. Terpyridine and quarterpyridine from tetrayne 6.
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(Scheme 4). Thus, treatment of isolated 9da with a ficiency of the 2-pyridylmoiety. This characteristic
dppe/CoCl2·6H2O/Zn catalyst in acetonitrile (2b) may be responsible for the regioselectivity of the re-
yielded terpyridine 10dab as a single isomer in 46% action, independent of the nitriles utilized.
isolated yield. Crystallographic results of the resulting
7da and 10dab are shown in Figure 3.
The reactions of 6 with 2 to 7 may seem to be of
the tandem type but actually they proceeded in a
domino fashion[13] and involved two different types of
regioselection as illustrated in Scheme 6. Thus, for
2,2’-bipyridine formation, it is essentialthat the for-
mation of the first pyridine provides an intermediate
Consideration of Regioselectivity and Its Prospects
The reactions of Eqs. (3) to (5) in Scheme 1 by a 9 selectively. The following cycloaddition of 9 with 2
dppe/CoCl2·6H2O/Zn catalyst gave 2,2’-bipyridines providing 2,2’-isomer 7 might also proceed selectively,
with high regioselectivity. Regarding the reaction of 1 similarly to the reaction of 4 and 2 to 5.
and 2-cyanopyridine (2a), the selectivity may be con-
We postulate that the dppe/CoCl2·6H2O/Zn-cata-
trolled electronically: The inductive effect of the two lyzed pyridine formation may proceed through a
substituents R1 and R2 of 1 affects the reactivity of (dppe)Co(I)Clcompel x generated by the reduction of
the proposed cobaltacyclopentadiene intermediates in (dppe)CoCl2 with zinc, which might react with diynes
directing the regioisomeric pathway of the addition to provide cobaltacyclopentadiene intermediates 11
reaction with the cycano group of 2a. It is noteworthy (Scheme 7). The exclusive regioselectivity observed
that the regioselectivity observed here in the reaction throughout the three different types of reactions in
of 2-cyanopyridine (2a) is much better than that in
the reaction with usualnitreils such as PhCN and
MeCN as we reported (Scheme 5).[9] This may be at-
tributed to the more electron deficient nature of the
2-pyridylmoiety of 2a compared to the substituent of
usualnitriel s.
Regarding the reaction of 4 and 2 [the type of Eq.
(4)], the electronic nature of the two alkyne groups of
the diyne 4 utilized here is very different compared to
that of usualdiynes such as 1a–h, due to electron-de-
Scheme 5. Reaction of 1f and 2b.[9]
Scheme 6. Reaction pathway from 6 and 2 to 7, 7’ or 7’’.
Figure 3. X-ray structures of compounds 7da (left) and 10dab (right). Hydrogen atoms have been excluded for clarity.
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FULL PAPERS
studies, a survey of the exclusive regiochemical trends
observed here gives reasonable credence to the syn-
thetic potentialof the present method.
Conclusions
We have demonstrated that a dppe/cobalt-catalyzed
cycloaddition reaction of diynes and nitriles is an effi-
cient means for preparation of substituted 2,2’-bipyri-
dines and 2,2’:6’,2’’-terpyridines with exclusive regio-
selectivity. A survey of the results provides reasonable
credence to the synthetic potentialto the method.
Moreover, the reaction is practicalsince the cataylsis
uses commercially available inexpensive starting ma-
terials, and the reaction procedure is operationally
simple. Because of the broad application of 2,2’-bipyr-
idines in medicinal, synthetic, and material chemistry
fields, a practical and atom-economical method for
their synthesis should generate great interest.
Experimental Section
General Procedure for the Cycloaddition of Diynes 1,
4 or6 and Nitriles 2 to 2,2 ’-Bipyridine Derivatives
Catalyzed by a Dppe/CoCl2·6H2O/Zn Reagent
To a stirred mixture of zinc powder (3.5 mg, 0.05 mmol),
diyne 1, 4 or tetrayne 6 (0.5 mmol) and nitrile 2 (1.5–
80 equivs.) in NMP (1 mL) was added
a solution of
CoCl2·6H2O (6 mg, 0.025 mmol) and dppe (12 mg,
0.03 mmol) in NMP (1 mL) at room temperature. The mix-
ture was then stirred at room temperature or at 508C. The
reaction progress was monitored by TLC analysis. After
completion of the reaction, a small portion of EtOAc or
ether was added and the mixture was passed through a pad
of Celite with EtOAc or ether. The filtrate was concentrated
to dryness and the residue was chromatographed on silica
gelusing hexane/AcOEt to give the corresponding bipyri-
dine derivative.
Scheme 7. Summary of regioselectivity with electronic
nature of the substrates.
the present work, i.e., the reactions of Eq. (3), Eq. (4)
and the transformation of 6 to 9 in the reaction of Eq.
(5), can be systematically rationalized by considering
the differences of the electronic natures between the
two alkynes in the diynes (Scheme 7): Thus, a rela-
tively electron-rich alkyne moiety in diynes 1, 4 and 6
was attached to the electron-poor position (carbon
atom) of the cyano group in 2 in all cases. Probably,
an intermediate cobaltacycle of the type 11 derived
from the corresponding 1, 4 or 6 might have a similar
electronic nature influenced by the substituents R and
R’ and the reaction may proceed through [4+2]cyclo-
addition (A) or insertion (B) pathways.[4e,14] Although
confirmation of the reaction mechanism from metalla-
cycle intermediates 11 to pyridines, i.e., A or B, is dif-
ficult at this time and must await the results of further
Acknowledgements
This study was partially supported by the Scientific Frontier
Research Project from the Ministry of Education, Culture,
Sports, Science and Technology, Japan. We also thank the
Japan Society for the Promotion of Science (JSPS) for a
grant to A.G. We thank Mr. Takeshi Hagiwara, Kanagawa
University for his measurement of the X-ray crystal structure.
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