Cobalt-catalyzed intramolecular [2 + 2 + 2] cocyclotrimerization of nitrilediynes: An efficient route to tetra- And pentacyclic pyridine derivatives

Article abstract of DOI:10.1021/ol062988t

In this paper, we wish to report the intramolecular [2 + 2 + 2] cocyclotrimerization of nitrilediynes catalyzed by the Col²(dppe)/Zn system at 80°C in CH₃CN. Under these reaction conditions, various highly substituted nitrilediynes h

Full text of DOI:10.1021/ol062988t

ORGANIC
LETTERS
2007
Vol. 9, No. 3
505-508
Cobalt-Catalyzed Intramolecular
[2 2] Cocyclotrimerization of
+
2 +
Nitrilediynes: An Efficient Route to
Tetra- and Pentacyclic Pyridine
Derivatives
Hong-Tai Chang, Masilamani Jeganmohan, and Chien-Hong Cheng*
Department of Chemistry, National Tsing Hua UniVersity, Hsinchu 30013, Taiwan
chcheng@mx.nthu.edu.tw
Received December 11, 2006
ABSTRACT
In this paper, we wish to report the intramolecular [2
+
2
+
2] cocyclotrimerization of nitrilediynes catalyzed by the CoI2(dppe)/Zn system at
and positions
2] cocylotrimerization to afford tetra- and
80 C in CH3CN. Under these reaction conditions, various highly substituted nitrilediynes having steric conjunction at the
°
r
â
to a nitrile group and a bulkier substitution at the terminal carbon of alkyne undergo [2
pentacyclic pyridine derivatives in good to excellent yields.
+ 2 +
The preparation of complex polycyclic pyridine derivatives
is an important synthetic goal because of the utility of these
molecules as potential pharmaceuticals.1 In addition, these
derivatives are versatile building bocks in the synthesis of
natural products2a-c and useful ligands in phosphorescent
emitters for organic light-emitting diodes.2d-g Transition-
metal-catalyzed [2 + 2 + 2] cocyclotrimerization of two
alkynes with a nitrile is an exceedingly attractive method
for the construction of pyridine derivatives in highly atom-
economical manner.3-9 Wakatsuki and Yamazaki reported4a
the first example of intermolecular cobalt-catalyzed cocy-
(3) (a) Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1984, 23, 539.
(b) Bonnemann, H.; Brijoux, W. AdV. Heterocycl. Chem. 1990, 48, 177.
(c) Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49. (d) Shore,
N. E. Chem. ReV. 1988, 88, 1081. (d) Saito, S.; Yamamoto, Y. Chem. ReV.
2000, 100, 2901. (e) Kotha, S.; Brahmachary, E.; Lahiri, K. Eur. J. Org.
Chem. 2005, 4741. (f) Gandon, V.; Aubert, C.; Malacria, M. Chem.
Commun. 2006, 2209.
(4) (a) Wakatsuki, Y.; Yamazaki, H. Tetrahedron Lett. 1973, 36, 3383.
(b) Naiman, A.; Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1977,
16, 708.
(1) (a) Gilchrist, T. L. Heterocyclic Chemistry; Longman: Essex, 1998.
(b) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles; Wiley-
VCH: New York, 2003. (c) ComprehensiVe Heterocyclic Chemistry II; Bird,
C. W., Ed.; Pergamon: Oxford, 1996. (d) Joule, J. A.; Mills, K. Heterocyclic
Chemistry, 4th ed.; Blackwell: Oxford, 2000. (e) Jones, G. Pyridines and
their benzoderivatives: synthesis. In ComprehensiVe Heterocyclic Chemistry
II; Katritzky, A., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford,
1996; Vol. 5, pp 167-243.
(2) (a) Wang, Y.; Dong, X.; Larock, R. C. J. Org. Chem. 2003, 68, 3090.
(b) Moody, C. J.; Hughes, R. A.; Thompson, S. P.; Alcaraz, L. Chem.
Commun. 2002, 1760. (c) Bach, T.; Heuser, S. Synlett 2002, 2089. (d) Xie,
H. Z.; Liu, M. W.; Wang, O. Y.; Zhang, X. H.; Lee, C. S.; Hung, L. S.;
Lee, S. T.; Teng, P. F.; Kwong, H. L.; Zheng, H.; Che, C. M. AdV. Mater.
2001, 13, 1245. (e) Andrade, B. W. D.; Thompson, M. E.; Forrest, S. R.
AdV. Mater. 2002, 14, 147. (f) Paulose, B. M. J. S.; Rayabarbu, D. K.;
Cheng, C.-H. AdV. Mater. 2004, 16, 2003. (g) Wong, W.-Y.; Zhou, G.-J.;
Yu, X.-M.; Kwok, H.-S.; Tang, B.-Z. AdV. Funct. Mater. 2006, 16, 838.
(5) For cobalt-catalyzed reactions: (a) Brien, D. J.; Naiman, A.;
Vollhardt, K. P. C. J. Chem. Soc., Chem. Commun. 1982, 133. (b) Varela,
J. A.; Castedo, L.; Saa, C. J. Org. Chem. 1997, 62, 4189. (c) Moretto, A.
F.; Zhang, H.-C.; Maryanoff, B. E. J. Am. Chem. Soc. 2001, 123, 3157;
2002, 124, 6792. (d) Banaga, L. V. R.; Zhang, H.-C.; Maryanoff, B. E.
Chem. Commun. 2004, 2394. (e) Gutnov, A.; Heller, B.; Fischer, C.; Drexler,
H.-J.; Spannenberg, A.; Sundermann, B.; Sundermann, C. Angew. Chem.,
Int. Ed. 2004, 43, 3795. (f) Senaiar, R, S.; Young, D. D.; Deiters, A. Chem.
Commun. 2006, 1313.
10.1021/ol062988t CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/12/2007

clotrimerization of two alkynes with a nitrile affording
pyridine derivatives, while Naiman and Vollhardt observed4b
the first cobalt-catalyzed partially intermolecular cocyclo-
trimerization of diynes with a nitrile providing bicyclic
pyridines. There are now numerous examples of [2 + 2 +
2] cocyclotrimerization of alkynes or diynes with a nitrile
using various metal complexes such as Co,4-5 Ru,6 Ni,7 and
Rh8a as catalysts.9 However, to the best of our knowledge,
only one report of the intramolecular version appeared very
recently.6e This report discussed only three examples of
cyanodiynes, which having less hindered substituents (H or
Me) at the terminal carbon underwent the intramolecular
cocyclotrimerization via slow-addition technique in order to
aviod the bimolecular side reactions.
smoothly in the presence of CoI2(dppe) (5 mol %) and Zn
(2.75 mmol) in CH3CN at 80 °C for 16 h yielding tetracyclic
pyridine derivative 2a in 85% yield (Scheme 1). The other
Scheme 1. Cobalt-Catalyzed Intramolecular [2 + 2 + 2]
Cocyclotrimerization of Symmetrical Nitrilediynes
Our continuous interest in metal-catalyzed cocyclotrim-
erization reactions10 prompted us to explore the possibility
of using cobalt phosphine complexes as catalysts for the [2
+ 2 + 2] cocyclotrimerization of nitrilediynes. In this paper,
we wish to report the intramolecular [2 + 2 + 2] cocyclo-
trimerization of nitrilediynes catalyzed by a cobalt phosphine
complex under relatively mild conditions. The cobalt com-
plex shows excellent catalytic activity toward nitrilediynes
having steric conjunction at R and â positions to a nitrile
group and a bulkier substitution at the terminal carbon of
alkyne. Although many synthetic routes to pyridines exist,
most methods are scarcely used due to the lack of generality
or selectivity and the requirement of harsh reaction condi-
tions.11 The present catalytic reaction provides an efficient
method for the synthesis of tetra- and pentacyclic pyridine
derivatives in excellent yields under mild conditions in one
pot.
competitive cycloaddition products were not observed in the
1H NMR of the crude reaction mixture. Product 2a was
1
thoroughly characterized by its H and 13C NMR and mass
spectral data. Control experiments revealed that in the
absence of the cobalt catalyst or Zn powder, no 2a was
obtained.
To understand the nature of the present catalytic reaction,
various cobalt phosphine complexes were tested for the
activities using 1a as the substrate. Monodentate phosphine
complexes CoCl2(PPh3)2 and CoI2(PPh3)2 were active but
gave 2a in only 15 and 20% yields, respectively. Bidentate
phosphine complexes are much more active. CoI2(dppm) and
CoI2(dppp) afforded 2a in 55 and 49% yields, respectively,
while CoI2(dppe) provided the highest 85% yield of 2a. For
comparison, CpCo(CO)2, which is the most widely used
catalyst for the [2 + 2 + 2] cycloaddition of alkynes with a
nitrile,4-5,9 did not show any catalytic activity for the
cocyclotrimerization of 1a in CH3CN at 80 °C for 16 h. It
should be noted that most of the CpCo(CO)2-catalyzed
reactions require higher temperature or photoactivation. The
present CoI2(dppe)/Zn catalyst system requires only 80 °C
without photoinduction. Of the solvents tested, CH3CN was
most effective, affording the highest yield of 2a. The other
solvents, THF, toluene, and NMP, were totally ineffec-
tive.
The intramolecular [2 + 2 + 2] cocyclotrimerization of
1,7-bis(2-cyanomethylbenzene)hepta-1,6-diyne 1a proceeded
(6) For Ru-catalyzed reactions: (a) Yamomoto, Y.; Okuda, S.; Itoh, K.
Chem. Commun. 2001, 1102. (b) Yamomoto, Y.; Ogawa, R.; Itoh, K. J.
Am. Chem. Soc. 2001, 123, 6189. (c) Varela, J. A.; Castedo, L.; Saa, C. J.
Org. Chem. 2003, 68, 8595. (d) Yamomoto, Y.; Kinpara, K.; Saigoku, T.;
Takagishi, H.; Okuda, S.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc. 2005,
127, 605 and references therein. (e) Yamomoto, Y.; Kinpara, K.; Ogawa,
R.; Nishiyama, H.; Itoh, K. Chem. Eur. J. 2006, 12, 5618.
(7) For Ni-catalyzed and Zr-mediated reactions: (a) Eisch, J. J.; Ma,
X.; Han, K. I.; Gitua, J. N.; Kruger, C. Eur. J. Inorg. Chem. 2001, 77. (b)
Takahashi, T.; Tsai, F.-Y.; Kotora, M. J. Am. Chem. Soc. 2000, 122, 4994.
(c) Takahashi, T.; Tsai, F.-Y.; Li, Y.; Wang, H.; Kondo, Y.; Yamanaka,
M.; Nakajima, K.; Kotora, M. J. Am. Chem. Soc. 2002, 124, 5059. (d)
McCormick, M. M.; Duong, H. A.; Zuo, G.; Louie, J. J. Am. Chem. Soc.
2005, 127, 5030. (e) Tekavec, T. N.; Zuo, G.; Simon, K.; Louie, J. J. Org.
Chem. 2006, 71, 5834.
The scope of the present [2 + 2 + 2] cocyclotrimerization
using substituted nitrilediynes was investigated under the
optimized reaction conditions (Scheme 1 and Table 1).
Similar to 1a, symmetrical nitrilediynes 1b,c having an
oxygen or nitrogen at the central position afforded polycyclic
pyridine derivatives 2b and 2c in 74 and 61% yields,
respectively (Scheme 1). The cocyclotrimerization of unsym-
metrical nitrilediynes 1d and 1e having a phenyl group at
one of the terminal position and 2-cyanomethylbenzene at
the other terminal position proceeded smoothly to give
tetracyclic pyridine derivatives 2d and 2e in excellent yields
(Table 1, entries 1 and 2). Similarly, thienyl-, silyl-, and
methyl-substituted nitrilediynes 1f-i gave the desired pyri-
dine derivative 2f-i in 74, 79, 84, and 58% yields,
respectively (entries 4-6).
(8) For Rh-catalyzed and Ti-mediated recactions: (a) Diversi, P.; Ermini,
L.; Ingrosso, G.; Lucherini, A. J. Organomet. Chem. 1993, 447, 291. (b)
Suzuki, D.; Tanaka, R.; Urabe, H.; Sato. F. J. Am. Chem. Soc. 2002, 124,
3518. (c) Tanaka, R.; Yuza, A.; Watai, Y.; Suzuki, D.; Takayama, Y.; Sato,
F.; Urabe, H. J. Am. Chem. Soc. 2005, 127, 7774.
(9) Varela, J. A.; Saa, C. Chem. ReV. 2003, 103, 3787 and references
therein.
(10) (a) Hsiao, T.-Y.; Santhosh, K. C.; Liou, K.-F.; Cheng, C.-H. J. Am.
Chem. Soc. 1998, 120, 12232. (b) Sambaiah, T.; Li, L.-P.; Huang, D.-J.;
Lin, C.-H.; Rayabarapu, D. K.; Cheng, C.-H. J. Org. Chem. 1999, 64, 3663.
(c) Shanmugasundaram, M.; Wu, M.-S.; Cheng, C.-H. Org. Lett. 2001, 3,
4233. (d) Shanmugasundaram, M.; Wu, M.-S.; Jeganmohan, M.; Huang,
C.-H.; Cheng, C.-H. J. Org. Chem. 2002, 67, 7724. (e) Jeevanandam, A.;
Korivi, R. P.; Huang, W.-I.; Cheng, C.-H. Org. Lett. 2002, 4, 807. (f) Wu,
M.-S.; Shanmugasundaram, M.; Cheng, C.-H. Chem. Commun. 2003, 718.
(g) Jayanth, T. T.; Jeganmohan, M.; Cheng, C.-H. J. Org. Chem. 2004, 69,
8445.
(11) (a) Couture, A.; Bochu, C.; Grandclaudon, P. Tetrahedron Lett. 1989,
30, 6865. (b) Abbiati, G.; Arcadi, A.; Bianchi, G.; Giuseppe, S.; Marinelli,
F.; Rossi, E. J. Org. Chem. 2003, 68, 6959 and references therein.
506
Org. Lett., Vol. 9, No. 3, 2007

expected cycloaddition to give pentacyclic pyridines 2k and
2l in 87 and 65% yields (entries 8 and 9). Nitrilediynes 1m-
o, having an oxygen or an amide group at the internal atom
X and a cyclohexane substitution at the R carbon to the nitrile
group, give the corresponding substituted pentacyclic py-
ridines 2m-o in 92, 71, and 83% yields (entries 10-12).
Likewise, nitrilediyne 1p with dimethyl substitution at the
R carbon also gave a highly functionalized pyridine 2p in
81% yield (entry 13). In a similar manner, nitrilediynes 1q
and 1r having a keto group at the â position afford tetracyclic
pyridine derivatives 2q and 2r in 87 and 77% yields (entries
14 and 15). Compared to 1q and 1r, nitrilediyne 1s is less
reactive requiring 60 h at 80 °C to produce 2s in only 46%
yield (entry 16). The construction of a 6-membered ring from
the 1,7-octadiyne group in 1s appears less facile than the
formation of the corresponding 5-membered rings from 1q
and 1r. These above results clearly revealed that nitrilediynes
having steric conjunction at the R and â position to the nitrile
group and bulkier substitutions at the terminal carbon works
smoothly to give the corresponding cocyclotrimerization
products in good to excellent yields (entries 8-16).
Table 1. Cobalt-Catalyzed Intramolecular [2 + 2 + 2]
Cocyclotrimerization of Unsymmetrical Nitrilediynesa
The catalytic reaction is likely initiated by the reduction
of Co(II) species to Co(I) species by zinc powder.13
Coordination of the diyne groups of nitrilediyne to the cobalt
center followed by cyclometalation produces cobaltacyclo-
pentadiene intermediate A. Intramolecular coordination of
the nitrile group and subsequent insertion into a Co(III)-
carbon bond gives cobaltacycloheptadiene intermediate B.
Final reductive elimination affords product 2 and regenerates
the Co(I) catalyst.
a All reactions were carried out using substituted nitrilediynes 1d-s (1.00
mmol), CoI2(dppe) (5 mol %), and Zn (2.75 mmol) in CH3CN (3.0 mL) at
80 °C for 16 h. b Isolated yields. c The reaction time was 60 h.
It is important to point out that in most of the reported [2
+ 2 + 2] cocyclotrimerization reactions of diynes with a
nitrile and with other carbon-carbon multiple bonds, the
reactions proceeded only with diynes having less hindered
substituents (H, Me, or Et) at the terminal carbon(s).3-9 For
diynes having bulkier substituents (Ph or naphthyl), the
reaction gave only minor amount of the corresponding
cocyclotrimerization product.3-9 In contrast, in our present
system, the [2 + 2 + 2] cocyclotrimerization of nitrilediynes
requires a bulkier substituent such as Ph, thienyl, SiMe3, or
naphthyl at the terminal carbon to obtain high product yields
(Table 1, entries 1-16). This observation is crucial to the
success of the present catalytic reaction. While the exact
reason is not yet clear, a bulkier group at the terminal alkyne
carbon likely prevents intermolecular [2 + 2 + 2] cocyclo-
To our surprise, nitrilediynes having structures similar to
1d-i but with a terminal alkyne group (R3 ) H) do not
undergo the expected [2 + 2 + 2] cocyclotrimerization under
the standard reaction conditions. Among the nitrilediynes
with a terminal alkyne group tested, only 1j having a
quaternary carbon center afforded the expected product in
52% yield (entry 7). This is probably due to the stronger
Thorpe-Ingold effect12 of 1j relative to the other nitrilediynes
1d-i (R3 ) H) leading to easier formation of the cobaltacycle
intermediate.
The current method can be successfully extended to
various nitrilediynes 1k-s in which substituents are present
at the R and â carbon of the nitrile group. Thus, nitrilediynes
1k and 1l possessing a cyclopropane group underwent the
(13) (a) Wang, C.-C.; Lin, P.-S.; Cheng, C.-H. J. Am. Chem. Soc. 2002,
124, 9696. (b) Chang. H.-T.; Jeganmohan, M.; Cheng, C.-H. Chem.
Commun. 2005, 4955. (c) Hilt, G.; Hess, W.; Vogler, T.; Hengst, C. J.
Organomet. Chem. 2005, 690, 5170 and references therein.
(12) (a) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc. 1915,
107, 1080. (b) Yamamoto, Y.; Kitahara, H.; Ogawa, R.; Itoh, K. J. Org.
Chem. 1998, 63, 9610.
Org. Lett., Vol. 9, No. 3, 2007
507

trimerization among the alkynyl groups due to the steric
hindrance imparted by the substituents (R3) but allows the
less reactive and yet less bulkier CN group to have a greater
chance to undergo intramolecular [2 + 2 + 2] cocyclotri-
merization with the two alkyne groups.
In conclusion, we have demonstrated the first intramo-
lecular [2 + 2 + 2] cocyclotrimerization of nitrilediynes
catalyzed by the Co(dppe)I2/Zn system to afford polycyclic
pyridine derivatives at relatively low temperature in a highly
atom-economical manner. The presence of a bulkier substitu-
tion at the terminal alkyne carbon of the nitrilediynes is
essential for this catalytic intramolecular [2 + 2 + 2]
cocyclotrimerization to proceed smoothly. The cobalt system
appears to be an alternative to the widely used CoCp(CO)2
as the catalyst for [2 + 2 + 2] cycloaddition.
Acknowledgment. We thank the National Science Coun-
cil of the Republic of China (NSC-95-2113-M-007-005) for
support of this research.
Supporting Information Available: Starting material
1
preparations, spectral data, and copies of H and 13C NMR
spectra of all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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Org. Lett., Vol. 9, No. 3, 2007