Synthesis of macrocycles via cobalt-mediated [2 + 2 + 2] cycloadditions

Article abstract of DOI:10.1021/ja045001w

We investigated the formation of macrocycles from α,ω-diynes in cobalt-mediated co-cyclotrimerization reactions. Long-chain α,ω-diynes underwent metal-mediated [2 + 2 + 2] cycloadditions with nitriles, cyanamides, or isocyanates in the presence of CpCo(CO

Full text of DOI:10.1021/ja045001w

Published on Web 02/18/2005
Synthesis of Macrocycles via Cobalt-Mediated [2 + 2 + 2]
Cycloadditions
Llorente V. R. Bon˜aga, Han-Cheng Zhang, Alessandro F. Moretto, Hong Ye,
Diane A. Gauthier, Jian Li, Gregory C. Leo, and Bruce E. Maryanoff*
Contribution from Drug DiscoVery, Johnson & Johnson Pharmaceutical,
Research & DeVelopment, Spring House, PennsylVania 19477-0776
Received August 18, 2004; E-mail: bmaryano@prdus.jnj.com
Abstract: We investigated the formation of macrocycles from R,ω-diynes in cobalt-mediated co-cyclotri-
merization reactions. Long-chain R,ω-diynes underwent metal-mediated [2 + 2 + 2] cycloadditions with
nitriles, cyanamides, or isocyanates in the presence of CpCo(CO)2 (Cp ) cyclopentadienide) to yield pyridine-
containing macrocycles, i.e., meta- and para-pyridinophanes, such as 5m/5p, 35m/35p, and 41m/41p.
The regioselectivity of these reactions was affected by the length and type of linker unit between the alkyne
groups, as well as by certain stereoelectronic factors. An analogous R,ω-cyano-alkyne, 28, combined with
an alkyne to yield two isomeric meta-pyridinophanes, such as 5m and 29m, and an ortho cycloadduct
(benzannulation product), such as 29o. We developed a reaction protocol for these cobalt-based [2 + 2 +
2] cycloadditions that involves markedly improved conditions such that this process offers a convenient,
flexible synthetic approach to macrocyclic pyridine-containing compounds. For example, diyne 6 reacted
with p-tolunitrile in 1,4-dioxane to give 7p and 7m (7:1 ratio) in 87% yield at a moderate temperature of ca.
100 °C in 24 h without photoirradiation or syringe-pump addition. Isocyanates were also effective reactants,
as exemplified by the formation of 44p almost exclusively (44p:44m > 50:1) in 64% yield from diyne 8 and
2-phenylethylisocyanate. By using this improved protocol we were able to co-cyclotrimerize long-chain
R,ω-diynes with alkynes in certain cases to demonstrate a successful macrocyclic variant of the Vollhardt
reaction. For instance, diyne 6 reacted with dipropylacetylene to give paracyclophane 57p and benzannulene
57o (2:1 ratio) in 29% yield.
Introduction
via a new carbon-carbon or carbon-heteroatom bond, with
the desired functionalities already intact.5,6 A more challenging
Macrocyclic compounds are important synthetic targets due
to their broad applications in host-guest and supramolecular
chemistry.1 Biologically active macrocycles are also of high
interest on account of their therapeutic applications, as exempli-
fied by macrolide antibiotics,2 macrocyclic protease inhibitors,3
and Taxol analogues.4 To achieve effective macrocyclizations
it is often necessary to employ special reaction conditions, such
as high dilution, template control, and/or conformational
control.5 Since the synthesis of large rings can be problematic,
most approaches involve the formation of a single ring, often
process is the simultaneous generation of a large ring and a
smaller ring to provide considerable molecular complexity in
one step.
Transition-metal-based reactions are appealing for macrocy-
clization because the metal center can preorganize the reactive
groups and lower the activation free energy of the entropically
disfavored end-to-end cyclization of long-chain R,ω-bifunc-
tionalized substrates. In addition, numerous transition-metal-
mediated carbocyclizations for forming small- and medium-
size rings are available.7 Macrocyclizations have been effected
with impressively high yields for ruthenium- and molybdenum-
catalyzed ring-closing metathesis (RCM) reactions of bis-alkenes
and bis-alkynes.8,9 Relative to the mode of assembly of interest
to us, some cyclizations that simultaneously generate a mac-
rocycle and another small ring (e.g., arene or heterocycle) have
(1) (a) Dietrich, B.; Viout, P.; Lehn, J.-M. Macrocyclic Chemistry: Aspects
of Organic and Inorganic Supramolecular Chemistry; VCH: New York,
1993 and references therein. (b) Ru¨diger, V.; Schneider, H.-J. Chem.-Eur.
J. 2000, 6, 3771-3776. (c) Beer, P. D.; Gale, P. A. Angew. Chem., Int.
Ed. 2001, 40, 486-516. (d) Pease, A. R.; Jeppesen, J. O.; Stoddart, J. F.;
Luo, Y.; Collier, C. P.; Heath, J. R. Acc. Chem. Res. 2001, 34, 433-444.
(e) Andrievsky, A.; Ahuis, F.; Sessler, J. L.; Vo¨gtle, F.; Gudat, D.; Moini,
M. J. Am. Chem. Soc. 1998, 120, 9712-9713.
(2) (a) Phan, L. T.; Clark, R. F.; Rupp, M.; Or, Y. S.; Chu, D. T. W.; Ma, Z.
Org. Lett. 2000, 2, 2951-2954 and references therein. (b) Resek, J. E.;
Wang, X. C.; Bhatia, A. V. Curr. Opin. Drug DiscoV. DeV. 2000, 3, 807-
817.
(3) Bartlett, P. A.; Yusuff, N.; Pyun, H.-J.; Rico, A. C.; Meyer, J. H.; Smith,
W. W.; Burger, M. T. Medicinal Chemistry into the Millennium; Royal
Society of Chemistry: London, 2001; Vol. 264, pp 3-15.
(4) (a) Ojima, I.; Geng, X.; Lin, S.; Pera, P.; Bernacki, R. J. Bioorg. Med.
Chem. Lett. 2002, 12, 349-352. (b) Ojima, I.; Lin, S.; Inoue, T.; Miller,
M. L.; Borella, C. P.; Geng, X.; Walsh, J. J. J. Am. Chem. Soc. 2000, 122,
5343-5353.
(5) (a) Parker, D. Macrocycle Synthesis: A Practical Approach; Oxford
University Press: Oxford, 1996. (b) Formanovskii, A. A.; Mikhura, I. V.
In Macrocyclic Compounds in Analytical Chemistry; Zolotov, Y. A., Ed.;
Chemical Analysis Series 143; Wiley: New York, 1997; Chapter 5, pp
5-39. (c) Storm, O.; Lu¨ning, U. Chem. Eur. J. 2002, 8, 793-798. (d)
Kim, B. H.; Jeong, E. J.; Hwang, G. T.; Venkatesan, N. Synthesis 2001,
14, 2191-2202. (e) For a review on the synthesis of large rings, see:
Roxburgh, C. J. Tetrahedron 1995, 51, 9767-9822.
(6) For examples, see: (a) Smith, B. B.; Hill, D. E.; Cropp, T. A.; Walsh, R.
D.; Cartrette, D.; Hipps, S.; Shachter, A. M.; Pennington, W. T.; Kwochka,
W. R. J. Org. Chem. 2002, 67, 5333-5337. (b) Pigge, F. C.; Ghasedi, F.;
Rath, N. P. J. Org. Chem. 2002, 67, 4547-4552.
9
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J. AM. CHEM. SOC. 2005, 127, 3473-3485
3473

A R T I C L E S
Bon˜aga et al.
Scheme 1. General Concept of the Macrocyclization Method
Scheme 2. Cobaltacyclobutadiene Complexes from R,ω-Diynes
and BTMSA
been reported, such as for the intramolecular addition of rhodium
carbenes,10 the palladium-catalyzed coupling of enynes with
alkynes,11 and the cycloaddition of Fischer chromium carbenes
with alkynes.12 Macrocyclizations via the Heck reaction are also
noteworthy.13 Although these various methods deliver macro-
cycles in a single step, with a significant increase in molecular
complexity, they all are unimolecular in nature, which inherently
limits the available product diversity. Additionally, this in-
tramolecularity enhances the degree of success. We wondered:
Could a bimolecular macrocyclization process14 that is condu-
cive to a wider range of product diversity also be viable? For
this purpose we envisioned the use of transition-metal-mediated
[2 + 2 + 2] cycloadditions of long-chain R,ω-diynes and
monoalkynes (Scheme 1), such as in the well-known “Vollhardt
reaction”.15,16 However, it is important to keep in mind that such
a bimolecular reaction poses a significant barrier to the efficient
formation of macrocycles in that the high-dilution conditions
(e.g., 0.005 M) required to optimize the macrocyclization relative
to oligomerization can also serve to impede the necessary
bimolecular process.17 To achieve success, these competing
factors would have to be adequately balanced.
We describe herein our studies on the cobalt-catalyzed [2 +
2 + 2] cycloaddition of R,ω-diynes with a third reactive group,
including nitriles, cyanamides, isocyanates, and alkynes. The
scope and limitations of these reactions, in terms of substrates,
conditions, regiochemistry, and mechanism, have been explored.
In several cases this chemistry has provided effective syntheses
of macrocycles containing pyridine, 2-aminopyridine, or 2-oxo-
pyridine units, as meta- and para-pyridinophanes, in isolated
yields greater than 50%. Additionally, we were able to co-
cyclotrimerize alkynes in an intermolecular, macrocyclic variant
of the “Vollhardt reaction”.
(7) (a) In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer-Verlag: Berlin, 1999; Vols. 1 and 2. (b) In
Transition Metals in Organic Synthesis; Beller, M., Bolm, C., Eds.; Wiley-
VCH: Weinhem, 1998; Vols. 1 and 2. (c) Aubert, C.; Buisine, O.; Malacria,
M. Chem. ReV. 2002, 102, 813-834. (d) Brummond, K. M.; Kent, J. L.
Tetrahedron 2000, 56, 3263-3283. (e) Fru¨hauf, H.-W. Chem. ReV. 1997,
97, 523-596. (f) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J.
Chem. ReV. 1996, 96, 635-662. (g) For leading references on the synthesis
of medium-sized rings (seven-nine members) by the use of transition
metals, see: Yet, L. Chem. ReV. 2000, 100, 2963-3007. Mori, M.;
Kitamura, T.; Sato, Y. Synthesis 2001, 654-664.
Results and Discussion
Preliminary Studies. We initially investigated the synthesis
of macrocycles by co-cyclotrimerization of R,ω-diynes and an
external alkyne with virtually no success. For instance, in the
reactions of bis-alkynes 1 or 3 with bis(trimethylsilyl)acetylene
(BTMSA),15a-c which does not suffer self-trimerization, the
hoped-for benzannulene or cyclophane products were not formed
at all. Instead, we isolated the corresponding bis-η4-cyclobuta-
diene-cobalt complexes 2 or 4 along with unreacted diynes
(Scheme 2; Cp ) cyclopentadienide). Use of a stoichiometric
amount of BTMSA (relative to the diyne) rather than a large
excess resulted only in intractable, presumably polymeric
material. In this regard, cyclobutadiene-cobalt complexes have
already been identified in reactions of BTMSA with 1,n-diynes
(n ) 6, 7)15 and long-chain bis-alkynes.18 It is noteworthy that
significant amounts of macrocyclic [2 + 2 + 2] adducts were
not produced in the study by Brisbois et al.18 Reported examples
of macrocycle formation via metal-mediated alkyne cyclotri-
merization are uncommon, and the successful cases have been
intramolecular reactions in which all three alkyne groups are
tethered to the same molecular backbone.16
(8) (a) Blechert, S.; Connon, S. J. Angew. Chem., Int. Ed. 2003, 42, 1900-
1923. (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29.
(c) Tae, J.; Yang, Y.-K. Org. Lett. 2003, 5, 741-744.
(9) (a) Grela, K.; Ignatowska, J. Org. Lett. 2002, 4, 3747-3749 and references
therein. (b) Fu¨rstner, A. Chem.-Eur. J. 2001, 7, 5299-5317. (c) Fu¨rstner,
A. Angew. Chem., Int. Ed. 2000, 39, 3013-3043.
(10) (a) Doyle, M. P.; Hu, W. Synlett 2001, 1364-1370. (b) Doyle, M. P.; Hu,
W.; Chapman, B.; Marnett, A. B.; Peterson, C. S.; Vitale, J. P.; Stanley, S.
A. J. Am. Chem. Soc. 2000, 122, 5718-5728.
(11) For a review, see: (a) Saito, S.; Yamamoto, Y. Chem. ReV. 2000, 100,
2901-2915. See also: (b) Gevorgyan, V.; Tando, K.; Uchiyama, N.;
Yamamoto, Y. J. Org. Chem. 1998, 63, 7022-7025. (c) Saito, S.; Salter,
M. M.; Gevorgyan, V.; Tsuboya, N.; Tando, K.; Yamamoto, Y. J. Am.
Chem. Soc. 1996, 118, 3970-3971.
(12) (a) Wang, H.; Wulff, W. D.; Rheingold, A. L. J. Am. Chem. Soc. 2003,
125, 8980-8981. (b) Wang, H.; Wulff, W. D.; Rheingold, A. L. J. Am.
Chem. Soc. 2000, 122, 9862-9863. (c) Wang, H.; Wulff, W. D. J. Am.
Chem. Soc. 1998, 120, 10573-10574. (d) Do¨tz, K. H.; Gerhardt, A. J.
Organomet. Chem. 1999, 578, 223-228.
(13) (a) Dyker, G.; Kadzimirsz, D.; Henkel, G. Tetrahedron Lett. 2003, 44,
7905-7907 and references therein. (b) Geng, X.; Miller, M. L.; Lin, S.;
Ojima, I. Org. Lett. 2003, 5, 3733-3736.
(14) For some rare examples, see: (a) Schafer, L. L.; Nitschke, J. R.; Mao, S.
S. H.; Liu, F.-Q.; Harder, G.; Haufe, M.; Tilley, T. D. Chem.-Eur. J. 2002,
8, 74-83. (b) Mao, S. S. H.; Liu, F.-Q.; Tilley, T. D. J. Am. Chem. Soc.
1998, 120, 1193-1206.
(15) (a) Hillard, R. L., III; Vollhardt, K. P. C. J. Am. Chem. Soc. 1977, 99,
4058-4069. (b) Vollhardt, K. P. C. Acc. Chem. Res. 1977, 10, 1-8. (c)
Funk, R. L.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1980, 102, 5253-
5261. (d) For reviews on [2 + 2 + 2] cycloadditions, see: Grotjahn, D. B.
In ComprehensiVe Organometallic Chemistry II; Abel, E. W., Stone, F. G.
A., Wilkinson, G., Eds.; Pergamon: Oxford, 1995; Vol. 12, pp 741-770.
Schore, N. E. Chem. ReV. 1988, 88, 1081-1119.
(16) Intramolecular alkyne trimerizations, with the three alkyne groups in the
substrate molecule, have afforded macrocyclic products with reasonable
yields. (a) Lofthagen, M.; Chadha, R.; Siegel, J. S. J. Am. Chem. Soc. 1991,
113, 8785-8790. (b) Kinoshita, H.; Shinokubo, H.; Oshima, K. J. Am.
Chem. Soc. 2003, 125, 7784-7785. (c) For related examples, see: Granier,
T.; Cardenas, D. J.; Echavarren, A. M. Tetrahedron Lett. 2000, 41, 6775-
6779. Hansen, J.; Blake, A. J.; Li, W.-S.; Mascal, M. J. Chem. Soc., Perkin
Trans. 1 1998, 3371-3376. Damrauer, R.; Hankin, J. A.; Haltiwanger, R.
C. Organometallics 1991, 10, 3962-3964. Mascal, M.; Hansen, J.; Blake,
A. J.; Li, W.-S. Chem. Commun. 1998, 355-356. Hubert, A. J.; Hubert,
M. Tetrahedron Lett. 1966, 5779-5782. Hubert, A. J. J. Chem. Soc. (C)
1967, 6-14, 1984-1985.
One can appreciate these negative results in the synthesis of
macrocycles by examining the mechanism of the cobalt-
mediated alkyne cyclotrimerization (Scheme 3, X ) CR′).19 The
formation of arene adducts could be achieved via two main
pathways, a and b, depending on which alkyne moieties undergo
(17) (a) Under high-dilution conditions the unfavorable statistics of intramo-
lecular cyclization relative to an intermolecular oligomerization can be
overcome.5 (b) A discussion of these two competing reaction pathways,
with their disparate requirements, appeared as early as 1935 (Spangel, E.
W.; Carothers, W. H. J. Am. Chem. Soc. 1935, 57, 929-934).
(18) Brisbois, R. G.; Fogel, L. E.; Nicaise, O. J.-C.; DeWeerd, P. J. J. Org.
Chem. 1997, 62, 6708-6709.
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Synthesis of Macrocycles
A R T I C L E S
Table 1. Pyridinophanes from R,ω-Diynes and p-Tolunitrile
Scheme 3. Generalized Mechanism for “CpCo”-Mediated
Cyclotrimerization of R,ω-Diynes with Alkynes (X ) CR′) or Nitriles
(X ) N)
oxidative addition to generate the cobaltacyclopentadiene
intermediates. Incorporation of the alkyne via a cycloaddition
process,19b with subsequent decomplexation, generates the arene.
Unfortunately, there are several adverse processes, including
oligomerization, polymerization, isomerization, decomposition,
self-trimerization, and cyclobutadienecobalt complex formation,
which militate against the desired outcome. The isolation of
bis-η4-cyclobutadiene-cobalt complexes in our experiments
indicates that when insertion of another alkyne molecule is slow
or less favored, a formal [2 + 2] cycloaddition occurs
preferentially (via pathway a). Consequently, the catalytically
active cobalt species would be sequestered as inert η4-cyclo-
butadiene-cobalt complexes.15,18,20 To overcome this problem,
we sought a different triply bonded species, one with X * CR′,
which is unlikely to coordinate with a reactive Co(I) species.
A nitrile reactant (X ) N) seemed like a promising candidate21
as it is suitably reactive and can only insert into a Co(III)
intermediate. In this way, we would obviate pathway a to
generate macrocyclic pyridine derivatives via pathway b.22
Cyclotrimerization with Nitriles.23 We were gratified to find
that reaction of bis-alkyne 3 with p-tolunitrile (1 mol equiv)
provided a 57% yield of two pyridine-containing macrocycles,
5m and 5p, in a 1:1 ratio (eq 1).24 Pyridinophanes 5m and
5p differ in their substitution pattern for the pyridine units,
i.e., 2,4,6- (meta-) and 2,3,6- (para-) trisubstituted pyridines,
a Conditions: molar ratio of nitrile:diyne ) 1:1; 15 mol % CpCo(CO)2,
o-xylene (0.01 M), 140 °C, syringe-pump addition, 100 h, Ar atmosphere,
hν. b Entries 1-6, R ) H; entry 7, R ) R2 ) CO2Me. c Ratios determined
from isolated isomeric products.
respectively. Since the regiochemistry obtained here is
fairly similar to that observed in the analogous acyclic reaction
(2,4,6:2,3,6 ) ca. 2:1),21f there are probably no special forces
influencing the overall chemical pathway. Formation of a
pyridine group as part of a new macrocycle in this way supplies
substantial molecular complexity in a single step with excellent
atom economy.25
(19) (a) Varela, J. A.; Saa, C. Chem. ReV. 2003, 103, 3787-3801. (b) Hardesty,
J. H.; Koerner, J. B.; Albright, T. A.; Lee, G.-Y. J. Am. Chem. Soc. 1999,
121, 6055-6067. (c) DFT calculations showed that the alternative pathway
via insertion and reductive elimination steps is energetically improbable
since the latter step is symmetry forbidden.19a,b
(20) Gleiter, R.; Kratz, D. Angew. Chem., Int. Ed. Engl. 1990, 29, 276-279.
(21) (a) Naiman, A.; Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1977,
16, 708-709. (b) Brien, D. J.; Naiman, A.; Vollhardt, K. P. C. J. Chem.
Soc., Chem. Commun. 1982, 133-134. (c) Reference 19a. (d) Bo¨nnemann,
H.; Brijoux, W. AdV. Heterocycl. Chem. 1990, 48, 177-222. (e) Bo¨nne-
mann, H.; Bogdanovic, B.; Brijoux, W.; Brinkmann, R.; Kajitani, M.;
Mynott, R.; Natarajan, G. S.; Samson, M. G. Y. Transition Metal-Catalyzed
Synthesis of Heterocyclic Compounds. In Catalysis of Organic Reactions;
Kosak, J. R., Ed.; Marcel Dekker: New York, 1984; Chapter 2, pp 31-
62. (f) Bo¨nnemann, H. Angew. Chem., Int. Ed. Engl. 1978, 17, 505-515.
(g) Bo¨nnemann, H. Angew. Chem., Int. Ed. Engl. 1985, 24, 248-262. (h)
Chelucci, G. Tetrahedron: Asymmetry 1995, 6, 811-826.
(22) Macrocycles containing pyridine units can be used as ligands for transition
metals and as supramolecular building blocks (Nitschke, J. R.; Zu¨rcher,
S.; Tilley, T. D. J. Am. Chem. Soc. 2000, 122, 10345-10352).
We explored the scope and limitations of this novel macro-
cyclization strategy, such as variation of the R,ω-diyne substrates
with respect to length and substitution of the tether, and the
electronic nature of the alkyne groups. As shown in Table 1,
moderate to good yields of meta- and para-pyridinophanes with
ring sizes ranging from 15 to 23 were obtained from the
(23) For a preliminary communication, see: Moretto, A. F.; Zhang, H.-C.;
Maryanoff, B. E. J. Am. Chem. Soc. 2001, 123, 3157-3158 [Additions
and corrections: Moretto, A. F.; Zhang, H.-C.; Maryanoff, B. E. J. Am.
Chem. Soc. 2002, 124, 6792].
(24) In the intermolecular cycloaddition of two molecules of a terminal alkyne
and one molecule of a nitrile the 2,4,6-trisubstituted and 2,3,6-trisubstituted
pyridines are obtained in a ratio of 2:1 to 3:1.21f
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A R T I C L E S
Bon˜aga et al.
Table 2. Pyridinophanes from R,ω-Diyne 3 and Various Nitriles
cyclotrimerizations of various R,ω-bis-alkynes with p-tolunitrile.
1,15-Bis-alkynes appended to the ortho positions of a benzene
ring with ether (entry 1), bis-ether (entry 3),26 or ester (entry 4)
linkages provided 15-membered meta- and 16-membered para-
pyridinophanes, with the latter predominating. An acyclic 1,15-
diyne 1 devoid of substitution on the tether and thus lacking
any Thorpe-Ingold assistance in the cyclization gave a 1:1 ratio
of 15- and 16-membered pyridinophanes (entry 5). Cyclization
of a 1,22-diyne 13 bearing a geminal disubstitution in the tether
chain resulted in the formation of 22- and 23-membered
macrocycles (entry 6).
The potential for one-step formation of a highly substituted
pyridine unit led us to investigate the substitution pattern in
the alkyne moieties. Macrocycles bearing tetrasubstituted py-
ridine units were formed from p-tolunitrile and diyne 15, which
bears an ester substituent (entry 7). Silyl-substituted pyridines
would be attractive targets;15d,27 however, monosilylated bis-
alkyne 17 was unreactive to cycloaddition with p-tolunitrile
(entry 8). Alkynes substituted on both termini with TMS or ester
groups, as in 18 and 19, also did not react (entries 9 and 10).
Various nitrile partners with different types of substituents
were surveyed to assess reactivity as well. In general, nitriles
conjugated to an arene, heteroarene, or alkene group underwent
macrocyclization with diyne 3 with reasonable efficiency (Table
2). Nitriles with phenyl (entries 1-4), furyl (entry 5), and pyridyl
(entry 6) substituents gave moderate to good yields of pyridi-
nophanes. The electronic nature of substituents on the phenyl
ring showed a minor influence on yield, although an electron-
withdrawing substituent favored the formation of the meta
isomer (entry 4 vs entries 1-3). Nitriles conjugated to the
cyclohexenyl (entry 7) and styrene units (entry 8) furnished
pyridinophanes in moderate yields with the former preferentially
generating the meta isomer. Nitriles linked to cyclic and acyclic
alkyl groups furnished trace amounts of cycloadducts (entries
10 and 11). Conversely, 1-cyanoadamantane gave a yield of
11% (entry 9) with the macrocyclic product being essentially
just the meta isomer. A silylated nitrile did not undergo
cycloaddition with 3 (entry 12).
a Conditions: molar ratio of nitrile:diyne ) 1:1; 15 mol % CpCo(CO)2,
o-xylene (0.01 M), syringe-pump addition, 100 h, 140 °C, Ar atmosphere,
hν. b Ratios determined from isolated isomeric products.
Scheme 4. Co-cyclotrimerization of ω-Alkynyl Nitrile 28 with
Alkynes
(25) For reviews on heterophanes, see: (a) Newkome, G. R.; Traynham, J. G.;
Baker, G. R. In ComprehensiVe Heterocyclic Chemistry; Lwowski, W.,
Ed.; Pergamon: New York, 1984; Vol. 7, Part 5, pp 763-780. (b)
Newkome, G. R.; Sauer, J. D.; Roper, J. M.; Hager, D. C. Chem. ReV.
1977, 77, 513-597. For reviews on synthesis of pyridinophanes, see: (c)
Shkil, G. P.; Sagitullin, R. S. Chem. Heterocycl. Compds. 1998, 34, 507-
528. (d) Majestic, V. K.; Newkome, G. R. Top. Curr. Chem. 1982, 106,
79-118.
A complementary cyclization strategy could also involve the
reaction of ω-alkynyl nitriles with alkynes,21a,b as exemplified
by the cycloaddition of 28 with aromatic alkynes (Scheme 4).
In contrast to the reaction of diyne 3 with 4-methylbenzonitrile
(Table 2, entry 1), the reaction of 28 with p-tolylacetylene
furnished the 2,4,6-substituted pyridine meta isomer 5m along
with two macrocycles bearing the 2,3,6-substituted pyridines,
(26) Addition of Na+ ion in the form of NaB[1,3-(CF3)2C6H3]4 did not
meaningfully influence the macrocyclization of diyne 8 and p-tolunitrile
via a template effect.
(27) Funk, R. L.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1980, 102, 5245-
5253.
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Synthesis of Macrocycles
A R T I C L E S
Table 3. Optimization of Macrocyclization Conditionsa
in 81% yield. However, when the amount of CpCo(CO)2 was
reduced to a more standard 15 mol %, we obtained only 5%
yield of 7p (7p:7m > 50:1) along with 49% of unreacted 6
(entry 2). We then turned our attention to ether-type solvents
and the use of a CO atmosphere (Table 3). This approach was
based on speculation that catalytic efficiency might be enhanced
(e.g., better catalyst turnover) by providing free ligands to the
cobalt catalyst and intermediates thereof.30 Efficient macrocy-
clizations were attained in reactions conducted in either 1,2-
dimethoxyethane (DME) or 1,4-dioxane (entries 3-6), with the
latter delivering a yield as high as 87% (entry 6); however, the
effect of a CO atmosphere was relatively insignificant.31
As mentioned earlier, the bimolecular macrocyclization
process is associated with an intrinsic paradox. The success of
the reaction simultaneously requires high dilution to favor
macrocyclization and sufficient concentration to favor a bimo-
lecular reaction. Thus, the intermolecular [2 + 2 + 2] cycload-
dition differs inherently from many published metal-mediated
macrocyclizations.8-13 Considering this aspect, one can ap-
preciate why the Vollhardt reaction has been problematic in
forming rings larger than six members.15,18,32 To follow up on
this point, we investigated the effect of concentration on the
macrocyclization to form pyridinophanes via the reaction of 6
with p-tolunitrile to give 7m and 7p (Figure 1). The yield of
product was found to be highly dependent on concentration in
the range of 0.0005-0.1 M,33 and an optimal yield occurs at a
concentration in the vicinity of 0.005 M. Our data indicate that
there is a favorable zone of operation from 0.002 to 0.05 M.
These results are consistent with the following fundamental
point: While fairly high dilution can favor macrocyclization,
this factor cannot be stretched to an extreme because the required
bimolecular process would suffer. At a concentration of 0.005
M, the R,ω-diyne self-trimerized to a minor extent. For example,
the DME reaction without any nitrile present (Table 3, entry 4)
afforded just 6% yield of a dimer of 6 and 62% of unreacted 6.
Given these results, we suggest that an optimal concentration
range for our macrocyclization method would be 0.002-0.05
M.
a Conditions: molar ratio of nitrile:diyne ) ca. 5:1; 15 mol %
CpCo(CO)2; reflux; 24 h; argon, nitrogen, or carbon monoxide atmosphere.
b Ratios determined from isolated isomeric products. c A 2.3 mol equiv
amount of CpCo(CO)2, reflux, 43 h. d Forty-nine percent recovered 6.
29m and 29o. It is interesting that the regioisomeric para
cycloadduct 5p was not observed. Cyclotrimerization of 28 with
1-ethynyl-4-methoxybenzene provided a 1:1:1 ratio of three
isomers of similar substitution pattern: 20m, 30m, and 30o
(entry 2). Despite the R,ω-alkynyl nitrile/alkyne cycloaddition
being nonselective compared with the R,ω-diyne/nitrile cy-
cloaddition, it offers access to other isomeric products that are
not obtainable via the original route.
Improved Reaction Conditions. The reaction conditions
employed by us were adopted from the standard cobalt-catalyzed
alkyne trimerization protocol.15 To generate the macrocyclic
products with reasonable efficiency, we also relied on the high-
dilution technique of syringe-pump addition.5,17 This process
is inconvenient and cumbersome, especially if one were
interested in producing chemical libraries. Thus, we sought to
develop an improved procedure for macrocycle formation via
CpCo(CO)2-catalyzed cyclotrimerizations of diynes and ni-
triles.28 The typical literature procedure entails slow addition
of a xylene or toluene solution of the diyne, nitrile, and cobalt
catalyst into a large volume of refluxing xylene or toluene (either
with or without additional catalyst).15 To minimize the unpro-
ductive oligomerization of reactants,5,17 addition of the reagents
is controlled by using a syringe pump over an extended period
of time while the reaction mixture is irradiated with light.29
High-intensity light (e.g., from a 300-W slide projector lamp)
is commonly used in order to promote decarbonylation of the
cobalt catalyst and release the reactive cobalt species.15,29
Although this classical protocol established the basis for our
early work, we now wanted to perform the co-cyclotrimerization
effectively without a syringe pump, without high-intensity light,
and at a lower reaction temperature.
We pursued further studies with our improved reaction
conditions to assess the scope and limitations (Table 4).
Cycloaddition of p-tolunitrile with a series of diynes of different
tether lengths (n ) 1-4) indicated that cyclizations to form
(30) The solvents used in cobalt-mediated alkyne trimerization are normally
aromatic and alkyl hydrocarbons, such as xylene, toluene, and octane.15
An atmosphere of CO has been shown to regenerate the active cobalt
catalyst in the Pauson-Khand reaction, see: (a) Krafft, M. E.; Bon˜aga, L.
V. R.; Hirosawa, C. J. Org. Chem. 2001, 66, 3004-3020 and references
therein. (b) Park, K. H.; Jung, I. G.; Chung, Y. K. Org. Lett. 2004, 6, 1183-
1186.
(31) (a) Under these conditions macrocyclizations of 6 and p-tolunitrile were
achieved in toluene and isooctane to furnish 11m and 11p in 41% (1:8)
and 62% (1:4) yields, respectively. Reactions in 1,2-dichloroethane were
unsatisfactory; only unreacted diyne 6 was isolated. (b) For reference
purposes, we reacted 1,7-octadiyne with p-tolunitrile under our improved
reaction conditions [15 mol % CpCo(CO)2, 0.005 M in 1,4-dioxane, reflux,
24 h, argon atmosphere] and obtained the cycloadduct in 74% yield (69%
yield with an atmosphere of CO). For the reaction of 1,7-octadiyne and
benzonitrile under classical conditions [10 mol % CpCo(CO)2, 0.17 M in
xylene, reflux, syringe pump addition over 5 days, nitrogen atmosphere],
Naiman and Vollhardt obtained a 70% yield of cycloadduct.21a
(32) From an observation of Naiman and Vollhardt the [2 + 2 + 2] reaction of
bis-alkynes with nitriles appears to be intrinsically better than the [2 + 2
+ 2] reaction of bis-alkynes with alkynes.21a In the reaction of 1,8-nonadiyne
with PhCN or C5H11CN under classical conditions, seven-membered
annulated pyridines were obtained in ca. 50% yield.21a
Initially, we examined the reaction of 6 and p-tolunitrile in a
dilute toluene solution (0.005 M) at reflux with a large amount
of CpCo(CO)2 present (Table 3, entry 1). A remarkable result
was realized in that pyridinophanes 7m and 7p were obtained
(28) Bis-alkyne 6 failed to undergo cycloaddition with p-tolunitrile under the
following catalytic systems: (a) RuCl2(imidazolydine)(PCy3)CHPh; (b)
[RhCl(cod)]2, dppe; (c) Ir(cod)Cl2, dppe; and (d) Pd2(dba)3, PPh3. It was
recovered unreacted after prolonged heating, 14-32 h. A similar result
was observed using [RhCl(CO)2]2, dppe, and AgOTf. For references on
diyne-nitrile cycloadditions promoted by transition metals, see ref 19a.
(29) (a) Vollhardt, K. P. C.; Bergman, R. G. J. Am. Chem. Soc. 1974, 96, 4996-
4998. (b) Vollhardt, K. P. C.; Bercaw, J. E.; Bergman, R. G. J. Am. Chem.
Soc. 1974, 96, 4998-5000.
(33) For an example of the effect of reaction concentration on macrocyclization,
see: Yamamoto, K.; Biswas, K.; Gaul, K.; Danishefsky, S. J. Tetrahedron
Lett. 2003, 44, 3297-3299.
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A R T I C L E S
Bon˜aga et al.
point we developed a method for the cobalt(I)-catalyzed [2 +
2 + 2] cycloaddition of R,ω-diynes and nitriles to meta- and
para-pyridinophanes, which is much more convenient than our
original protocol23 and has a reasonable scope for synthetic
applications.
Cyclotrimerization with Cyanamides. Given this procedural
advance, we became interested in the potential utility of
cyanamides as reactants as there is a scarcity of published
information on this aspect.36 Bo¨nnemann and co-workers
reported the reaction of acetylene with cyanamide in the
presence of a η6-borininato cobalt catalyst;37 Heller and co-
workers reported photoinduced cyclotrimerizations of acetylene
with N-cyanopyrrolidine or N-cyanopiperidine in the presence
of CpCo(cod)2;38 and another example of this reaction is
mentioned briefly in a patent.39 We conducted the CpCo(CO)2-
catalyzed cyclotrimerization of R,ω-bis-alkynes with cyan-
amides, under moderate thermal conditions without any photo-
stimulation, to produce various amino-substituted pyridino-
phanes (Table 5).36,40
Figure 1. Reaction efficiency (% yield) vs concentration (0.0005, 0.002,
0.005, 0.01, 0.05, and 0.1 M) for the cobalt-mediated cycloaddition of diyne
6 with p-tolunitrile. The regioisomer ratio is 7m:7p. Unreacted 6 was
recovered in 17% and 23% from the reactions conducted at 0.0005 and
0.002 M, respectively. The abscissa is presented on the log 2 scale. The
dashed line is provided to facilitate visualization of the results (no
mathematical relationship is implied).
Table 4. Cyclotrimerization of R,ω-Diynes with Nitriles Using
Improved Conditionsa
In an early test example the reaction of 3 with N-cyanopyr-
rolidine (34) gave regioisomeric pyrrolidine-substituted pyri-
dinophanes 35m and 35p (1:1 ratio) in 64% yield (eq 2). Several
other reaction of diynes and cyanamides afforded meta- and
para-pyridinophanes in good-to-excellent yields under fairly
mild reaction conditions,36 and some representative examples
are presented in Table 5. Cyclotrimerization of 1,15-bis-alkynes
6, 8, and 10 with cyanamides gave predominantly the corre-
sponding 16-membered para-pyridinophanes (entries 2-5),
whereas 1,17-bis-alkyne 3 provided a mixture (1:1) of the 17-
membered meta- and 18-membered para-pyridinophanes in
good yields (entry 1). Cyanamides disubstituted with alkyl
a Conditions: molar ratio of nitrile:diyne ) ca. 5:1; 15 mol %
CpCo(CO)2, 1,4-dioxane (0.005 M), reflux, ca. 24 h. b Ratios determined
from isolated isomeric products. c See Table 2.
smaller medium-sized rings are not effective (entries 1-4).34
For the reactions of diynes 31 and 33, the anticipated, analogous
13/14-membered and 11/12-membered macrocycles were not
forthcoming (entries 3 and 4); unreacted starting material was
recovered. Cycloaddition of p-tolunitrile with diynes 3, 6, 8,
and 10 furnished the corresponding pyridinophanes in similar
or better yields (entries 1, 2, 5, and 6, respectively) compared
with our original method (cf. Table 1). Macrocyclization of
diyne 3 with 4-bromobenzonitrile provided the pyridinophanes
21m and 21p in 25% yield (entry 7; cf. Table 2, entry 3).
Adamantyl-substituted pyridinophane 27 was obtained in a
similar yield when it was generated using the previous method
(entry 8; cf. Table 2, entry 9). Diyne 3 failed to undergo
cycloaddition with cyanocyclopentane (entry 9, cf. Table 2, entry
10).35 A similar result was also observed in the reaction of 3
with a cyanosilane (entry 10, cf. Table 2, entry 12). At this
(35) For reference purposes we reacted cyanocyclopentane or cyanocyclohexane
with short-tethered diyne i (15 mol % CpCo(CO)2, 0.005 M in DME, reflux,
ca. 18 h) to obtain low yields of benzannulated products iia (25%) or iib
(10%).
(36) For a preliminary report, see: Bon˜aga, L. V. R.; Zhang, H.-C.; Maryanoff,
B. E. Chem. Commun. 2004, 2394-2395.
(37) (a) Bo¨nnemann, H.; Brijoux, W. AdV. Heterocycl. Chem. 1990, 48, 177-
222. (b) Bo¨nnemann, H.; Brijoux, W. Aspects Homogen. Catal. 1984, 5,
75-196. (c) Bo¨nnemann, H.; Brijoux, W.; Brinkmann, R.; Meurers, W.
HelV. Chim. Acta 1984, 67, 1616-1624.
(38) (a) Heller, B.; Sundermann, B.; Buschmann, H.; Drexler, H.-J.; You, J.;
Holzgrabe, U.; Heller, E.; Oehme, G. J. Org. Chem. 2002, 67, 4414-4422.
Heller, B.; Reihsig, J.; Schulz, W.; Oehme, G. Appl. Organomet. Chem.
1993, 7, 641-646. (b) cod ) 1,5-cyclooctadiene.
(39) Vollhardt, K. P. C.; Naiman, A. U.S. Patent 4,328,343, 1982; Chem. Abstr.
1978, 90, 186806.
(40) A survey of cyanamide reactivity with diynes of varying tethered lengths
in given in ref 36.
(34) Strain must be overcome to synthesize medium-sized rings.7g
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Synthesis of Macrocycles
A R T I C L E S
Table 5. Cyclotrimerization of R,ω-Diynes with Cyanamides
cyclization efficiency for the reaction of 1,n-bis-alkynes (n )
6, 7) with isocyanates using catalytic CpCo(CO)2 under typical
reaction conditions (m-xylene, 140 °C, hν, syringe pump, 3-5
h).42a Recently, Yamamoto et al. addressed this shortcoming
by introducing Cp*Ru(cod)Cl for the cycloaddition of 1,6-diynes
and isocyanates to give bicyclic pyridones (58-87% yields).46
a Conditions: molar ratio of cyanamide:diyne ) ca. 5:1; 15 mol %
CpCo(CO)2, 1,4-dioxane (0.005 M), reflux, 18-24 h. b Ratios determined
from isolated isomeric products.
To explore the scope of the isocyanate [2 + 2 + 2] reaction,
several symmetrical acyclic R,ω-diynes were cyclized with
alkylisocyanate 40 (Table 6). 1,15-Bis-alkynes connected to the
ortho positions of a benzene ring possessing ether (entry 2),
bis-ether (entry 5), or ester linkages (entry 6) gave mainly 16-
membered para-2-oxopyridinophanes in good yields. In contrast,
co-cyclotrimerization of the homologous 1,13-alkyne 31 (entry
3) or 1,11-bis-alkyne 33 (entry 4) with 40 proceeded poorly or
not at all. A 1,17-bis-alkyne 46, with a biphenyl scaffold,
provided 17-membered meta- and 18-membered para-2-oxopy-
ridinophanes, 47m and 47p, with the latter predominating (entry
7). Bis-silyl-diyne 18 failed to cyclotrimerize with isocyanate
40 (entry 8), presumably because 18 bears two internal alkyne
groups.
(entries 1-4) or aryl groups (entry 5) were compatible cyclo-
trimerization partners.36 The regiochemical outcome observed
in the reaction of 8 with N-cyanopyrrolidine is noteworthy since
the para isomer was produced exclusively (entry 2; cf. entry
5). Thus, 2-aminopyridinophanes41 can be conveniently formed
in one step through this macrocyclization process.
The reactivity of several isocyanates with bis-alkyne 8 was
studied (Table 6). The scope of isocyanate reactivity in such
cobalt-mediated cycloadditions involving short-chain bis-alkynes
is not known because the reaction has proceeded poorly.42a
Reaction of 8 with unhindered alkyl isocyanates gave fair to
good yields of 2-oxopyridinophanes (entries 9-11). Hindered
aliphatic isocyanates also underwent co-cyclotrimerization
smoothly (entries 12-14). The successful reaction of adamantyl
isocyanate with 8 (entry 14) is particularly significant since tert-
butylisocyanate failed to react with diethyl 2,2-di(prop-2-ynyl)-
malonate under Ru(II) catalysis.46a In contrast to the cyclotri-
merization of R,ω-bis-alkynes with nitriles (viz. Tables 2 and
4), aliphatic isocyanates led to better yields of cycloadducts than
did aromatic isocyanates (cf. entries 1, 2, 5-7, 9-14 with entries
15-17). Similar to the cycloaddition of 1,15-bis-alkyne 6 with
isocyanate 40, only the para-2-oxopyridinophanes were formed
in the cycloadditions of 8 and 10. The low efficiency of
Cyclotrimerization with Heterocumulenes. We were also
interested in the [2 + 2 + 2] cycloaddition of R,ω-diynes and
heterocumulenes using our improved procedure.42,43 Reaction
of diyne 3 with 2-phenylethylisocyanate (40) using 30 mol %
of CpCo(CO)2 furnished a mixture of 2-oxopyridinophanes 41m
and 41p in 68% yield (eq 3).44 Among all possible regioisomeric
products, only two cyclophanes, the 4,6- (meta-) and 3,6- (para-)
substituted 2-pyridones, were obtained in a 1:2 ratio.45 This
result is remarkable considering previous reports on poor
(41) Aminopyridines, which are important as pharmaceutical agents, ligands in
inorganic and organometallic chemistry, and fluorescent dyes, are typically
prepared by the substitution of halogenated pyridines (Thomas, S.; Roberts,
S.; Pasumansky, L.; Gamsey, S.; Singaram, B. Org. Lett. 2003, 5, 3867-
3870 and references therein).
(42) For cobalt-mediated cycloaddition of alkynes with isocyanates, see: (a)
Earl, R. A.; Vollhardt, K. P. C. J. Org. Chem. 1984, 49, 4786-4800. (b)
Earl, R. A.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1983, 105, 6991-6993.
(c) Hong, P.; Yamazaki, H. Tetrahedron Lett. 1977, 1333-1336. (d) Hong,
P.; Yamazaki, H. Synthesis 1977, 50-52. For nickel-mediated cycloaddition
of alkynes with isocyanates, see: (e) Hoberg, H.; Oster, B. W. J.
Organomet. Chem. 1983, 252, 359-364. (f) Hoberg, H.; Oster, B. W. J.
Organomet. Chem. 1982, 234, C35-C38. (g) Hoberg, H.; Oster, B. W.
Synthesis 1982, 324-325. For the synthesis of pyridone-containing
macrocycles without using transition metals, see: (h) Bradshaw, J. S.;
Nakatsuji, Y.; Huszthy, P.; Wilson, B. E.; Dalley, N. K.; Izatt, R. M. J.
Heterocycl. Chem. 1986, 23, 353-360. For a recent synthesis of 2-pyri-
dones, see: (i) Hachiya, I.; Ogura, K.; Shimizu, M. Org. Lett. 2002, 4,
2755-2757.
(45) Intermolecular cycloaddition of two molecules of an internal alkyne and
one molecule of an isocyanate provides a mixture of regioisomeric
cycloadducts.42a For example:
(43) For a preliminary communication, see: Bon˜aga, L. V. R.; Zhang, H.-C.;
Gauthier, D. A.; Reddy, I.; Maryanoff, B. E. Org. Lett. 2003, 5, 4537-
4540.
(44) The larger amount of the Co(I) catalyst was used to achieve complete
reactions. DME was found to be a better solvent than 1,4-dioxane.
(46) (a) Yamamoto, Y.; Takagishi, H.; Itoh, K. Org. Lett. 2001, 13, 2117-
2119. (b) The analogous cyclotrimerization of isocyanatoalkynes with
monoalkynes to form 2,3-dihydro-5(1H)-indolizinones appears to be more
synthetically useful.42a,b (c) cod ) 1,5-cyclooctadiene; Cp* ) pentameth-
ylcyclopentadienide.
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A R T I C L E S
Bon˜aga et al.
Table 6. 2-Oxopyridinophanes of R,ω-Diynes and Isocyanates
cyclotrimerization with the aromatic isocyanates (entries 15-
17) may be due to some self-condensation of the isocyanate to
give a symmetrical urea.47 In the reaction of 8 with 4-meth-
oxybenzylisocyanate, N,N′-bis(4-methoxybenzyl)urea (56) was
obtained along with 44 (entry 10), but the yield of 44 could be
improved by using excess isocyanate (5-10 mol equiv).
Similarly, excess isocyanate (4 mol equiv) was used (added in
two batches) to favor the cycloaddition in a Ru(II)-catalyzed
reaction of 1,6-diynes.46a
To expand on the product diversity, we attempted reactions
with other heterocumulenes such as isothiocyanates and
carbodiimides.42c,d In the presence of a catalytic amount of
CpCo(CO)2 the reaction of diyne 6 with p-tolylisothiocyanate
or cyclohexylisothiocyanate did not yield the desired macro-
cycles bearing 2-pyridinethiones. Similarly, the reactions of
diyne 8 with 1,3-di-(p-tolyl)carbodiimide or 1,3-dicyclohexyl-
carbodiimide did not produce the corresponding macrocycles
bearing 2-imino-1,2-dihydropyridines. Negative results were also
obtained in Cp2Co-catalyzed cycloadditions of diynes 8 or
dimethyl 2,2-di(prop-2-ynyl)malonate with 1,3-di-(p-tolyl)-
carbodiimide.42d
Cyclotrimerization of Alkynes. Our favorable results for
cyclotrimerizations of R,ω-diynes with nitriles and isocyanates
to yield macrocycles, under convenient reaction conditions,
encouraged us to reevaluate the corresponding reaction with
alkynes (“Vollhardt reaction”). In our hands and in the hands
of others,18,23 transition-metal-mediated cyclotrimerizations of
alkynes for macrocycle production have not yielded positive
results.48,49 A study of reactions of short-chain diynes and
a Conditions: molar ratio of isocyanate:diyne ) 5-10:1; 30 mol %
CpCo(CO)2, DME (0.005 M), 85 °C, ca. 24 h. b Ratios determined from
isolated isomeric products. c See Table 4. d See Table 1.
(47) (a) Ulrich, H. Cycloaddition Reactions of Heterocummulenes; Academic
Press: New York, 1967. (b) The Chemistry of Cyanates and Their Thio
DeriVatiVes; Patai, S., Ed.; Wiley-Interscience: New York, 1977; Parts 1
and 2. (c) Ozaki, S. Chem. ReV. 1972, 72, 457-496.
(48) Bis-alkyne 6 failed to co-cyclotrimerize with an excess of 1-hexyne (20-
65 mol equiv) under thermal conditions using various catalytic systems:
(a) RuCl2(imidazolidine)(PCy3)CHPh; (b) RuCl2(PCy3)2CHPh; (c) [RhCl-
(CO)2]2, dppe, AgOTf; (d) RhCl(PPh3)3; (e) [RhCl(cod)]2, dppe; (f) Ni-
(cod)2, dppe; (g) Ni(acac)2, PPh3, (i-Bu)2AlH; (h) [Ir(cod)Cl]2, dppe; (i)
Pd2(dba)3, PPh3. The diyne was recovered unreacted after prolonged heating
(ca. 32 h) except in the last two systems, where it was consumed without
yielding cyclophane products. A similar result occurred when 6 was reacted
with 4-octyne using RhCl(PPh3)3.
(49) References on alkyne cyclotrimerization with other transition metals.
RuCl2(PCy3)2CHPh: (a) Peters, J.-U.; Blechert, S. Chem. Commun. 1997,
1983-1984. (b) Witulski, B.; Stengel, T.; Fernandez-Hernandez, J. M.
Chem. Commun. 2000, 1965-1966. RhCl(PPh3)3: (c) Sun, Q.; Zhou, X.;
Islam, K.; Kyle, D. J. Tetrahedron Lett. 2001, 42, 6495-6497. (d) Grigg,
R.; Scott, R.; Stevenson, P. J. Chem. Soc., Perkin Trans. 1 1988, 1357-
1363. (e) McDonald, F. E.; Zhu, H. Y. H.; Holmquist, C. R. J. Am. Chem.
Soc. 1995, 117, 6605-6606. (f) Witulski, B.; Stengel, T. Angew. Chem.,
Int. Ed. Engl. 1999, 38, 2426-2430. (g) Grigg, R.; Sridharan, V.; Wang,
J.; Xu, J. Tetrahedron 2000, 56, 8967-8976. [Ir(cod)Cl]2/dppe: (h)
Takeuchi, R.; Tanaka, S.; Nakaya, Y. Tetrahedron Lett. 2001, 42, 2991-
2994. Cp*Ru(cod)Cl: (i) Yamamoto, Y.; Ogawa, R.; Itoh, K. Chem.
Commun. 2000, 269-270. Pd2(dba)3/PPh3: (j) Yamamoto, Y.; Nagata, A.;
Itoh, K. Tetrahedron Lett. 1999, 40, 5035-5038. (k) Yamamoto, Y.; Nagata,
A.; Arikawa, Y.; Tatsumi, K.; Itoh, K. Organometallics 2000, 19, 2403-
2405. Ni(acac)2/PPh3/(i-Bu)2AlH: (l) Sato, Y.; Ohashi, K.; Mori, M.
Tetrahedron Lett. 1999, 40, 5231-5234. (m) Sato, Y.; Nishimata, T.; Mori,
M. J. Org. Chem. 1994, 59, 6133-6135. [RhCl(cod)]2/tppts: (n) ref 16b.
alkynes under our improved reaction conditions50 prompted us
to pursue reactions of R,ω-diynes with selected alkynes (Table
7). Under the conditions shown in Table 7, bis-cobaltacyclo-
butadiene complex 4 was not formed on reacting 1,17-diyne 3
with 100 mol equiv of BTMSA under argon or carbon monoxide
(unreacted 3 was recovered). By employing 50 mol equiv of
BTMSA under argon or 5 mol equiv of BTMSA under argon
or CO, 3 was consumed and a complex mixture of unidentified
products was observed. A similar result was noted when 1,15-
diyne 6 was reacted with 5 mol equiv of BTMSA (Ar
atmosphere). Also, (trimethylsilyl)acetylene, 2-ethynylpyridine,
1-ethynylcyclohexene, but-1-ynylcyclohexane, trimethyl(phe-
nylethynyl)silane, and trimethyl(phenylethynyl)stannane did not
(50) In studying the effect of solvent and reaction atmosphere on the cycload-
dition of a short-tethered diyne, we found that cyclotrimerization is more
efficient in DME than in 1,4-dioxane and that it is not influenced by a CO
atmosphere. The observed low yields, which reflect the poor efficiency of
such alkyne cyclotrimerizations, are comparable to those reported for
cyclizations of analogous substrates conducted with traditional reaction
conditions (3 mol % CpCo(CO)2, 0.5 M in octane, reflux, syringe-pump
addition, 36 h; 14-50% yields).15 See Supporting Information.
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Synthesis of Macrocycles
A R T I C L E S
details of the process.19b Presumably, these findings are also
applicable to the related reactions of a bis-alkyne with a nitrile
or an isocyanate.19a The catalytic cycle would be initiated by
sequential exchange of the ligands, L, in the cobalt catalyst for
two alkyne units. Oxidative coupling of the alkynes would
generate the coordinatively unsaturated cobaltacyclopentadiene
intermediate, which would readily coordinate to the third
reactive component, be it a nitrile or an isocyanate, or an alkyne
in the classical process. In the case of an alkyne reactant direct
cycloaddition would produce an η4-benzene complex that would
undergo decomplexation to liberate the arene product and the
CpCo catalyst with further cycling of the reaction. Whereas an
alternative pathway involving insertion and reductive elimination
steps is energetically less favorable according to density-
functional theory (DFT) calculations, it may still be possible
for the related reactions of a cobaltacyclopentadiene complex
with a nitrile or an isocyanate to proceed via either pathway.42a,d
Table 7. Cobalt-Mediated Alkyne Cyclotrimerization
a Conditions: 15 mol % CpCo(CO)2, DME (0.005 M), reflux, argon or
carbon monoxide atmosphere. b Ratios determined from isolated isomeric
products. c Also, 9% yield of 59. d Also, 7% yield of 59. e Also, 11% yield
of 61. f A 27% yield of 62 with 1,4-dioxane as the solvent.
Although we were able to effect the cobalt(I)-mediated [2 +
2 + 2] alkyne cycloaddition for the preparation of macrocycles
(benzannulenes or cyclophanes), this route does not appear to
be very efficient or general. The most notable previous successes
with the bimolecular cyclotrimerization of R,ω-diynes and
monoalkynes have been for reactions of 1,6-, 1,7-, and 1,8-
diynes with BTMSA, the latter being present in a large excess.15
However, with long-chain R,ω-diynes the side reactions depicted
in Scheme 3 tend to dominate, leading to an unsatisfactory
macrocyclization process.
cyclotrimerize with diyne 6 to give macrocycles. After many
negative results in pursuit of this reaction class, we were
delighted to find that 4-octyne underwent macrocyclization with
diyne 6, albeit in low yields (entry 1). Interestingly, different
regiochemistry was observed in this benzannulation depending
on whether we used an atmosphere of argon or carbon
monoxide. The cycloaddition of diyne 6 and 4-octyne under
argon provided paracyclophane 57p almost exclusively, whereas
the reaction under CO provided a mixture of ortho and para
isomers, 57o and 57p (cf. entries 1 and 2). The cyclization of
diyne 6 with dimethyl acetylenedicarboxylate (DMAD) under
argon yielded benzannulene 58o (entry 3); however, under
carbon monoxide the reaction provided the meta and ortho
isomers, 58m and 58o, in a ratio of 1:11 (entry 4). Similarly,
macrocyclizations of DMAD with bis-alkynes 3 and 8 furnished
only the benzannulenes 60 and 62, respectively (entries 5 and
6). Macrocyclizations in DME and 1,4-dioxane gave similar
yields and regiochemistry (entry 6). Undesired cycloadducts
derived from the incorporation of two molecules of DMAD and
only one of the alkyne moieties of the R,ω-diyne, such as 59
and 61, were also isolated.51
A similar trend in the regiochemical product distribution was
observed in our cyclotrimerizations that furnished macrocycles
containing pyridine and 2-oxopyridine moieties. On this basis
we suggest that cobaltacyclopentadiene formation may be the
regiochemistry-determining step with common intermediates
being involved (Scheme 5). Three different regiochemical
permutations are possible in the oxidative addition of the alkyne
moieties in long-chain acyclic diynes, which implicates inter-
mediates I (head-to-head reaction), II (head-to-tail reaction),
and III (tail-to-tail reaction). To probe the reaction outcomes
we performed DFT52 calculations (B3LYP with LACVP basis
set for cobalt53 and 6-31G for the other atoms54) on key
intermediates I, II, and III derived from a series of related bis-
alkynes, 3, 6, 31, and 33 as well as from bis-alkynes 1, 8, and
13. In general, such DFT methodology has proven to be accurate
and useful to study the energetics and reaction mechanisms for
organometallic compounds.55
In the case of 1,17-diyne 3, our DFT calculations indicate
that R,R′-substituted cobaltacycle I is favored by only 0.5 kcal/
mol over R,â-substituted cobaltacycle intermediate II but by
7.5 kcal/mol over â,â′-substituted cobaltacycle III. This result
suggests that the cycloaddition of 3 would generally yield a
mixture of regioisomeric products IV/VII and V/VIII in a ratio
of approximately 1:1, as observed in the reaction of 3 with
nitriles (Table 1, entry 2; Table 2, entries 1-8; Table 4, entries
Regiochemical and Mechanistic Considerations. Cobalt-
(I)-mediated [2 + 2 + 2] cycloadditions of bis-alkynes with
nitriles, isocyanates, and alkynes proceed through a similar
catalytic cycle (Scheme 3).19 Mechanistic studies, along with
the isolation of intermediate complexes, for CpCoL2-catalyzed
(L ) CO, PR3, olefin) cyclotrimerizations of three alkyne units,
to form a benzene ring, have supplied crucial information about
(51) Dimethyl 2,2-di(prop-2-ynyl)malonate and maleic anhydride gave no
cycloadduct under these reaction conditions; mostly unreacted diyne was
observed at the end of the reaction.
(52) Parr, R. G.; Yang, W. Density-Functional Theory of Atoms and Molecules;
Oxford University Press: Oxford, 1989.
(53) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785-789.
(54) Jaguar 4.2; Schrodinger, LLC: Portland, OR, 2002.
(55) An issue of Chem. ReV. is devoted to computational transition-metal
chemistry: (a) Chem. ReV. 2000, 100, 351-818. (b) Davidson, E. R. Chem.
ReV. 2000, 100, 351-352. See also ref 19.
9
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A R T I C L E S
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Scheme 5. Permutations for Cyclopentadiene Formation Leading to Regioisomeric Pyridinophanes and 2-Oxopyridinophanes (Co )
CoCpL)
Scheme 6. Nitrile/Isocyanate Addition to a Disubstituted
Cobaltacycle (Co ) CoCpL)
Scheme 7. Cyclophanes from ω-Alkynyl Nitrile 28 (X ) N) or
R,ω-Diynes (X ) CH) and External Alkynes
1 and 7; Table 5, entry 1) and an isocyanate (Table 6, entry 1).
In the case of 1,15-diyne 6, cobaltacycle I is favored over
cobaltacycle II by 1.4 kcal/mol and over cobaltacycle III by
3.6 kcal/mol. This result suggests that cycloaddition of 6 would
generally yield a mixture of regioisomeric products IV/VII and
V/VIII biased toward paracyclophanes IV/VII, as observed in
the reactions of 6, and its analogues 8 and 10, with nitriles (Table
1, entries 1, 3, and 4; Table 3, entries 3-6; Table 4, entries 2,
5, and 6; Table 5, entries 2-5) and isocyanates (Table 6, entries
2, 5, 6, 9-16). This effect is evidently much more pronounced
in the cycloadditions of 1,15-diyne 8 with cyanamides (Table
5, entries 2 and 5) and isocyanates (Table 6, entries 5, 9-16)
where the para-pyridinophane isomer (IV/VII) generally pre-
dominated. For 1,15-diyne 8, our DFT calculations indicate that
cobaltacycle I is preferred over cobaltacycles II and III by 4.5
and 14.2 kcal/mol, respectively (cf. 1,15-diyne 6). With the more
conformationally flexible diynes 1 and 13 (Table 1) the energy
differences for intermediates I-III were less pronounced, as
reflected in the products (Table 1, entries 5 and 6). Cobaltacycle
I derived from 1,15-diyne 1 was preferred over II by only 0.9
kcal/mol and over III by 6.2 kcal/mol (cf. 1,15-diyne 6). The
shorter chain homologues 31 and 33 (Table 4) incur higher strain
energies in the formation of cobaltacycles I-III, as evidenced
from the low-to-nonexistent yields from their cyclizations
(Tables 4 and 6, entries 3 and 4). In the case of 1,13-diyne 31,
DFT calculations indicated that I is preferred over II and III
by 0.6 and 4.4 kcal/mol; however, for 1,11-diyne 33, III was
preferred over II and I by 5.8 and 8.8 kcal/mol, respectively.
In the addition of nitriles to cobaltacycle II, meta-pyridi-
nophanes of form Va, rather than form Vb, were invariably
obtained (Scheme 6). Of the two possible modes of nitrile
addition, pathway a is strongly favored over pathway b,
probably because of steric interactions that govern the direction
of addition (as illustrated). In the addition of an isocyanate to
cobaltacycle II, meta-pyridinophanes of form VIIIb, rather than
form VIIIa, were obtained (e.g., Table 6, entries 1-3). Of the
two possible modes of isocyanate insertion, pathway d is
strongly favored over pathway c, perhaps because of an
electronic effect associated with the isocyanate 1,3-dipole and
the charge distribution at the R-carbons of the cobaltacycle. In
any event, no steric aspect is apparent to explain this preference
for pathway d.
In the cyclotrimerization of a long-chain R,ω-alkynyl nitrile,
such as 28, with an alkyne there would be four possible
cobaltacyclopentadiene intermediates, X-XIII, which would
lead to eight possible products, XIVa/b-XVIIa/b (Scheme 7,
X ) N, R1 * R2). The cyclotrimerization of R,ω-alkynyl nitrile
28 with an aromatic alkyne (Scheme 4) provided three regio-
isomeric macrocycles in a even distribution: a 2,4,6-substituted
meta-pyridinophane (5m, 20m), a 2,3,6-substituted meta-
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Synthesis of Macrocycles
A R T I C L E S
pyridinophane (29m, 30m), and a 2,3,6-substituted pyridino-
annulene (29o, 30o). The three observed products, represented
by XIVa, XVIa, and XVIb (X ) N, R1 ) Ar, R2 ) H), arise
from the corresponding cobaltacycles, X and XII (Scheme 7,
X ) N, R1 ) Ar, R2 ) H). The preference for intermediates X
and XII relative to XI and XIII in this situation is presumably
caused by stabilization that is imparted by the aromatic group
being positioned R on the cobaltacycle. Then, the absence of
XVIb relates to a predilection for nitrile addition in cobaltacycle
X head-to-head (a-e bond formation) rather than head-to-tail
(c-e bond formation). The two products from nitrile addition
in cobaltacycle XII, XVIa and XVIb, arise from head-to-head
(b-e bond formation) and head-to-tail (c-e bond formation)
modes, respectively.
Figure 2. Observed NOEs for regioisomeric pyridine-containing macro-
cycles, e.g., 5p (para) and 5m (meta).
(5 mol equiv) in the presence of 15 mol % of complex 4 (viz.
Scheme 2) in refluxing 1,4-dioxane over 4 days (CO atmo-
sphere; unreacted 3 was recovered), and complex 6318,56 failed
to react with p-tolunitrile (5 mol equiv) in refluxing 1,4-dioxane
over 3 days (CO or Ar atmosphere; unreacted 63 was recovered).
Consistent with this point, Vollhardt found that harsh conditions,
such as flash-vacuum pyrolysis (∼10-5 Torr, 540-650 °C), are
required for cobaltacyclobutadiene complexes to undergo retro-
[2 + 2] cycloaddition.57 Also, Gleiter demonstrated that higher
temperatures, such as 140 °C (refluxing xylene) or 200 °C
(without solvent), are needed for the cobaltacyclobutadiene
complexes to undergo cyclotrimerization with nitriles.20 There-
fore, under our milder reaction protocol for cobalt-mediated
alkyne cyclotrimerizations, any cobaltacyclobutadiene com-
plexes that form should not revert into the reaction manifold.
Structural Assignments by NMR and X-ray Crystal-
lography. Structures of the macrocycles were unambiguously
In the cyclotrimerization of a long-chain R,ω-bis-alkyne with
an alkyne there would be up to seven possible cobaltacyclo-
pentadiene intermediates from the pairwise oxidative addition
of alkyne units: I-III (Scheme 5) and X-XIII (Scheme 7, X
) CR, R1 * R2), which would lead to eight possible products,
XIVa/b-XVIIa/b (Scheme 7, X ) CR, R1 * R2). Our
successful cyclotrimerization of symmetrical R,ω-diynes with
an identically substituted alkyne (R1 ) R2) provided three
distinct types of macrocycles (Table 7). 1,15-Diyne 6 combined
with dipropylacetylene under argon to give paracyclophane 57p
(Scheme 7; XIVb/XVb, X ) CH, R1 ) R2 ) Pr) or under CO
to give 57p and benzannulene 57o (XVIa/XVIIa, X ) CH, R1
) R2 ) Pr). With DMAD, 1,15-diyne 6 gave benzannulene 58o
under argon (XVIa/XVIIa, X ) CH, R1 ) R2 ) CO2Me) or
58o and metacyclophane 58m under CO (XIVa/XVa/XVIb/
XVIIb, X ) CH, R1 ) R2 ) CO2Me); 1,15-diyne 8 gave
benzannulene 62 under argon (XVIa/XVIIa, X ) CH, R1 )
R2 ) CO2Me). It is also evident that the regiochemistry in the
reaction of long-chain bis-alkynes with an alkyne can be
influenced by the electronic nature of the monoalkyne, such as
nonpolar vs polar substituents, to switch between paracyclo-
phane, metacyclophane, and benzannulene products (Table 7,
entries 1-4). The formation of side products 59 and 61 in the
reactions of DMAD with 3 and 6 points to another possible
mechanism other than those depicted in Scheme 5, such as a
Diels-Alder-type cycloaddition. This pathway could be re-
sponsible in part for the formation of the benzannulenes.
However, no cycloadducts were produced in a control experi-
ment that probed possible Diels-Alder reactivity.51
1
assigned from one- and two-dimensional H and 13C NMR
experiments, such as COSY, NOESY, HMQC, and HMBC (see
Supporting Information). The regioisomeric pyridinophanes
1
were easily identified by H NMR from the protons on the
pyridine ring, which appears as a pair of singlets for the meta
isomer and a pair of doublets for the para isomer (JAB ≈ 8.0
Hz) in the aromatic region (5-8 ppm). Regioisomers, such as
5m and 5p, were also identified from 1H NOESY spectra, where
the sets of benzylic protons, Ha and Hb, exhibited strong NOEs
with the pyridine protons in a distinct pattern for each isomer
(Figure 2). For 5p an NOE was observed between the benzylic
protons Ha and H5 (doublet), while for 5m an NOE was observed
between the benzylic protons Ha and H5 (singlet). The other
set of benzylic protons, Hb, for 5p has an NOE with H4 (doublet)
and the aromatic protons of the tolyl group, Hc. The benzylic
protons Hb for 5m have NOE’s with the pyridine protons H3
We thought that a breakdown of the catalytic cycle (i.e., low
turnover numbers) might be behind the low yields and preva-
lence of side products (viz. Scheme 3) in our all-alkyne
cyclotrimerizations. An atmosphere of carbon monoxide, instead
of argon, was explored in an attempt to enhance the catalytic
cycle from this standpoint. Although the yields for the argon
and carbon monoxide are not meaningfully different, the reaction
products were surprisingly affected (Table 7). For example, the
cyclotrimerization of 6 with 4-octyne gave 57p under argon
but 57o and 57p under carbon monoxide. At this time we do
not have an adequate explanation for these observations.
and H5 (singlets). The HMBC experiment, optimized for 3JHC
,
was also used to confirm both structures. C2 was easily identified
by its chemical shift (158.8 ppm) and correlations with the Hc
protons of the p-tolyl ring. Additional correlations for C2 derive
from a one-proton doublet integrating in the aromatic region
(56) Complex 63 was prepared by a modification of the literature method18
without the use of syringe-pump addition or high-intensity light (see
equation below).
We also wondered about the possibility of reversal of
cobaltacyclobutadiene complexes as a source of active cobalt
species in the cyclotrimerization and any effect that carbon
monoxide might exert. In this regard, we found no evidence
for the reactivity of a cobaltacyclobutadiene complex from two
separate experiments. Diyne 3 failed to react with p-tolunitrile
(57) This conversion presumably occurs via a retrocyclization, rotation, and ring-
closure sequence. (a) Ville, G.; Vollhardt, K. P. C.; Winter, M. J. J. Am.
Chem. Soc. 1981, 103, 5267-5269. (b) Fritch, J. R.; Vollhardt, K. P. C.
Angew. Chem., Int. Ed. Engl. 1979, 18, 9-11.
(58) See the Supporting Information for general experimental methods.
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A R T I C L E S
Bon˜aga et al.
Figure 3. View of 15-membered meta-pyridinophane 7m from the X-ray
crystal structure showing the atom-labeling scheme.
Figure 5. View of 14-membered benzannulene 62 from the X-ray crystal
structure showing the atom-labeling scheme.
in the NOESY experiments were helpful in characterizing the
regioisomers (see Supporting Information). The structure of a
14-membered benzannulene 62 was confirmed by single-crystal
X-ray diffraction (Figure 5).
Conclusion
Figure 4. Observed NOEs for regioisomeric 2-oxopyridine-containing
macrocycles, e.g., 41p (para) and 41m (meta).
We developed the cobalt-mediated [2 + 2 + 2] cycloaddition
of R,ω-diynes with nitriles, cyanamides, and isocyanates as a
facile, flexible macrocyclization approach to meta- and para-
pyridinophanes. We have also been able to effect the related
co-cyclotrimerization of R,ω-diynes and alkynes, but this
reaction type is much less general, with low efficiency and
predictability. The regioselectivity of the pyridinophane reactions
was impacted by the length and type of the tether as well as by
stereoelectronic factors. The nitrile macrocyclizations could be
achieved in an optimal concentration range of 2-50 mM, which
is consistent with a balance of the requisite unimolecular and
bimolecular processes. By producing a macrocycle and a
pyridine ring simultaneously, the co-cyclotrimerization process
affords substantial molecular complexity in a single step. In the
area of metal-mediated [2 + 2 + 2] cycloadditions, it is
particularly noteworthy to be able to incorporate an external
nitrile or isocyanate in a bimolecular process under convenient
reaction conditions.
(H4) and triplets integrating for two protons in the aliphatic
region (Hb), which relate to three-bond JCH couplings, consistent
with a para substitution pattern. In contrast, regioisomer 5m
showed an additional two-bond JCH coupling correlating a one-
proton aromatic singlet (H3) to C2, which is consistent with a
meta substitution pattern. The structure of 17-membered meta-
pyridinophane 7m was confirmed by single-crystal X-ray
diffraction (Figure 3).
Regioisomeric 2-oxopyridinophanes were identified from the
2-pyridone protons, which are observed as distinct pairs of
singlet (in the meta isomer) and doublet resonances (for the
para isomer, JAB ) 5.5-7.0 Hz) in the olefinic and aromatic
1
regions in H NMR spectra. NOESY data were also used to
establish the structures of these regioisomers (Figure 4). The
para isomer showed a one-proton doublet in the aromatic region
(H4 or H5), which exhibited an NOE to a set of triplet in the
aliphatic region (Ha or Hb). Another doublet aromatic proton
showed an NOE with a different set of triplet aliphatic protons.
On the contrary, the meta isomer showed a singlet aromatic
proton (H5) exhibiting an NOE with two sets of aliphatic triplet
protons (Ha and Hb). Another singlet aromatic proton (H3)
indicated an NOE with only one of the two sets of aliphatic
triplet protons (Hb). HMBC data were used to confirm the
structures of the isomers. The C2 carbonyl carbon was easily
recognized by its chemical shift (163.5 ppm) and a three-bond
JCH correlation to the triplet aliphatic phenethyl protons (Hc).
Three-bond JCH correlations from a doublet aromatic proton (H4)
and a set of triplet aliphatic proton (Ha) to C2 were observed in
the para isomer. A two-bond JCH correlation from the singlet
aromatic proton (H3) to C2 was observed in the meta isomer.
The structure of 16-membered 2-oxo-para-pyridinophane 44p
was confirmed by single-crystal X-ray diffraction, as previously
described.43
Experimental Section58
Procedure for the Synthesis of Pyridinophanes by Using Classical
Reaction Conditions.23 In a 50-mL round-bottom flask, equipped with
a magnetic stirring bar and a condenser under argon, was added 25
mL of o-xylene. A 300-W slide projector lamp, connected to a Variac
set at 30 V, was mounted 3 cm from the reaction flask. The solvent
was purged with argon for 20 min and then heated in a 140 °C oil
bath. With the aid of an automatic syringe pump, a solution of o-xylene
(10 mL), diyne (2 mmol), nitrile (1 mol equiv), and CpCo(CO)2 (0.15
mol equiv) was added into the solvent over 100 h using a gastight
syringe wrapped in aluminum foil. The black mixture was then cooled
to room temperature. Subsequent removal of the solvents in vacuo,
followed by MPLC (0-40% ethyl acetate in hexanes), afforded the
meta and para regioisomeric products. In the case of the synthesis of
7m and 7p, diyne 6 (500 mg, 1.85 mmol, 1 mol equiv), p-tolunitrile
(217 mg, 1.85 mmol, 1 mol equiv), and CpCo(CO)2 (50 mg, 0.28 mmol,
15 mol %) in 9 mL of o-xylenes were added into the reaction flask
over 100 h. Purification by MPLC afforded 72 mg of meta-pyridi-
nophane 7m (10%) and 366 mg of the para-pyridinophane 7p (51%).
Note: A similar procedure was followed in the cyclotrimerization of
ω-alkynylnitriles with the aromatic alkynes.
For the cyclophanes or benzannulenes the protons of the
newly generated benzene rings were observed as a singlet (ortho
and para isomers) or a pair of singlets (meta isomer) in the
aromatic region in the 1H NMR spectra. Similar trends as above
9
3484 J. AM. CHEM. SOC. VOL. 127, NO. 10, 2005

Synthesis of Macrocycles
A R T I C L E S
Improved Procedure for the Synthesis of Pyridinophanes. Into
a 100-mL round-bottom flask, equipped with a condenser and a three-
way stopper connected to an argon-filled balloon, a mixture of diyne
6 (100 mg, 0.37 mmol) and p-tolunitrile (246 mg, 2.10 mmol, 5.7 mol
equiv) was pumped briefly and the vessel purged three times with argon.
1,4-Dioxane (50 mL) was added, followed by 10 mL of a 1,4-dioxane
solution of CpCo(CO)2 (7.0 µL, 0.056 mmol, 15 mol %), and the
remaining solvent (19 mL) to provide a final concentration of 0.005
M (relative to diyne 6). The resulting solution was heated at reflux for
ca. 24 h, and the light-brown mixture was cooled to room temperature.
Subsequent removal of the solvents in vacuo, followed by flash
chromatography (silica gel; ethyl acetate/hexanes, 1:10, followed by
ethyl acetate/hexanes, 1:4), afforded 16 mg of meta-pyridinophane 7m
(11%) and 109 mg of the para-pyridinophane 7p (76%). For best results,
newly opened bottles of DME, 1,4-dioxane, and CpCo(CO)2 (Strem
Chemicals) were used. A similar procedure was followed in the
cycloadditions of R,ω-diynes or short-tethered diynes with cyan-
amides,36 isocyanates,43 and alkynes.
47m, 47p, 48-55 (ref 43); 8, 35m, 35p, 36p (ref 36); 63 (ref 18).
Additional experimental details and compound characterization data
are presented in the Supporting Information.
Acknowledgment. We thank Dr. Indrasena Reddy for techni-
cal assistance, William Jones for HRMS data, and Dr. Victor
Day (Crystalytics) for X-ray structure determinations.
Supporting Information Available: Data for the cyclotri-
merization of dimethyl 2,2-di(prop-2-ynyl)malonate and 4-oc-
tyne; characterization data for the compounds described in refs
32, 35, and 50 and for 9m, 9p, 21m, 21p, 24m, 24p, 25m,
25p, 27, 29m, 29o, 30o, 31, 32m, 32p, 33, 37, 38p, 39m, 39p,
43p, 57o, 57p, 58m, 58o, 59, 60, 61, and 62; 2-D NMR
experiments on 58m and 58o; X-ray crystallographic details for
1
macrocycles 7m and 62; H NMR spectra of ii, iii, 9m, 9p,
21m, 21p, 29m, 29o, 30o, 32m, 32p, 37p, 38p, 39m, 39p, 43p,
57o, 57p, 58m, 58o, 59, 60, 61, and 62. This material is
available free of charge via the Internet at http://pubs.acs.org.
The following compounds were synthesized and fully characterized
in our previous reports: 1, 3, 4, 5m, 5p, 6, 7m, 7p, 10, 11m, 11p,
12m, 12p, 15, 16m, 16p, 28 (ref 23); 41m, 41p, 42m, 42p, 44, 45, 46,
JA045001W
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