Cobalt-catalyzed cyclotrimerization of alkynes in aqueous solution [10]

Full text of DOI:10.1021/ja9807284

5130
J. Am. Chem. Soc. 1998, 120, 5130-5131
(Cyclopentadienyl)cobalt dicarbonyl [CpCo(CO)2] has been
used in numerous cyclotrimerization reactions. However, no
literature reports exist that describe CpCo catalysis in aqueous
solutions,14 despite the fact that numerous historically significant
examples of transition-metal catalysis in water are known.15 At
the outset we were concerned that low-valent cobalt organome-
tallics would be unstable and become oxidized in the presence
of water. A simple first test of stability in aqueous solutions was
performed on CpCo(CO)2. After 65 h at 75 °C in 60% H2O:
CH3OH16 there was no detectable decomposition of CpCo(CO)2
Cobalt-Catalyzed Cyclotrimerization of Alkynes in
Aqueous Solution
Matthew S. Sigman,†,‡ Anson W. Fatland,† and
Bruce E. Eaton*,†
Department of Chemistry, Washington State UniVersity
P.O. Box 644630, Pullman, Washington 99164-4630
NeXstar Pharmaceuticals, 2860 Wilderness Place
Boulder, Colorado 80301
ReceiVed March 5, 1998
1
by H NMR. Alkyne 1 was added and the sample heated again
for 65 h at 75 °C followed by irradiation with a Kr ion laser (308
Many of the most useful methods for the assembly of cyclic
organic molecules involve transition-metal-catalyzed cycloaddi-
tion. Because aromatic rings are central to many biological,
pharmaceutical, and polymer molecules, alkyne cyclotrimerization
is an important methodology. Vollhardt was first to realize the
potential of cobalt-catalyzed cyclotrimerization in organic syn-
thesis.1 Recent examples that demonstrate the breadth of
chemistry and concomitant diversity in structures that may be
assembled by cobalt-catalyzed cyclotrimerization include steroids,2
carbazoles,3 stemodin,4 illudol,5 phenylenes,6 γ-lycorane,7 and the
ergot alkaloids lysergic acid and lysergene.8 From conducting
oligomers to important medicinal compounds, cyclotrimerization
has had an enormous impact on the synthetic strategies that can
be envisaged.
Our interest in alkyne cyclotrimerization stems from a con-
tinued search for transition-metal catalysts that will perform in
water. For environmental reasons water is a preferred reaction
medium.9 In addition, hydrophobic effects in organic reactions
can provide substantial rate enhancements,10 chemoselectivity,11
and stereoselectivity.12 Another motivation for performing or-
ganometallic catalysis in aqueous solution could entail merging
biochemical13 and organometallic techniques to reveal new
horizons in combinatorial chemistry. Herein we describe a new
cobalt catalyst that performs cyclotrimerization under mild
conditions in water to prepare benzenes with unprotected func-
tional groups.
nm, 175 mJ/pulse) for 1 h. None of the desired cyclotrimerization
1
product could be detected by H NMR.
One problem in using CpCo(CO)2 in water stems from the
difficulty in substituting the CO ligands, which may be due in
part to enhanced back-bonding in this high dielectric solvent. We
reasoned that a CpCo-η4-cyclooctadiene complex was desired,
where the Cp had attached a substituent that aided its water
solubility and a cyclooctadiene that would control access to the
cobalt coordination sphere. From previous reports on the
cyclotrimerization of alkynes in acetonitrile to form pyridines it
was determined that electron-withdrawing groups on the Cp were
desirable.17 Ketone and ester groups appeared most attractive.
The CpzCo catalyst 2 with an appended ester was prepared18 and
treated with alkyne 1. Complex 2 was competent at cyclotrim-
erization of 1, but at 85 °C the half-life was greater than 1 week,
limiting the utility of this catalyst.
* Address correspondence to this author at NeXstar Pharmaceuticals.
† Washington State University.
Encouraged by these preliminary results, the design of the Cp
ligand was again evaluated. It is well-known that ketones are
more electron withdrawing than esters, but it was unclear whether
this subtle difference in Cp substituents would be sufficient to
enhance the rate of cyclotrimerization.19 It was of interest to
appended a functional group that contained both a carbonyl and
a hydrophilic group. Complex 3 (Cp$Co-COD) was prepared,18
containing a ketone carbonyl to increase catalytic activity and a
hydroxyl to aid in water solubility. The solubility of 3 was
dramatically improved (20 mM in 80% H2O/CH3OH). Gratify-
ingly, 3 gave cyclotrimerization of 1 at an observed rate >50-
fold higher than 2 under identical reaction conditions. After
greater than 3 half-lives no detectable decomposition of 3 was
‡ Current Address: Department of Chemistry and Chemical Biology,
Harvard University, Cambridge, MA 02139.
(1) (a) Vollhardt, K. P. C.; Bergman, R. G. J. Am. Chem. Soc. 1974, 96,
4996. (b) Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1984, 23, 539.
For excellent reviews on metal-mediated cycloaddition, see: (c) Grotjahn, D.
B. In ComprehensiVe Organometallic Chemistry II; Abel, E. W., Stone, F.
G. A., Wilkinson, G., Hegedus, L. S., Eds.; Pergamon: Tarrytown, NY, 1995;
Vol. 12, pp 741-770. (d) Schore, N. E. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon: Elmsford, NY,
1991; Vol. 5, pp 1129-1162.
(2) (a) Funk, R. L.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1980, 102, 5253.
(b) Sternberg, E. D.; Vollhardt, K. P. C. J. Org. Chem. 1984, 49, 1574. (c)
Hillard, R. L., III; Parnell, C. A.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1974,
96, 4996. (d) Lecker, S. H.; Nguyen, N. H.; Vollhardt, K. P. C. J. Am. Chem.
Soc. 1986, 108, 856.
(3) (a) Grotjahn, D. B.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1986, 108,
2091. (b) Boese, R.; Van Sickle, A. P.; Vollhardt, K. P. C. Synthesis 1994,
1374.
(4) Germanas, J.; Aubert, C.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1991,
113, 4006.
(5) Johnson, E. P.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1991, 113, 381.
(6) Schmidt-Radde, R. H.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1992,
114, 9713.
(7) Grotjahn, D. B.; Vollhardt, K. P. C. Synthesis 1993, 579.
(8) Saa´, C.; Crotts, D.; Hsu, G.; Vollhardt, K. P. C. Synlett 1994, 487.
(9) Presidential Green Chemistry Challenge Awards Program: EPA744-
K-96-001, July 1996.
1
observed by H NMR.
Next the scope of alkyne cyclotrimerization via 3 and the
degree of functional group protection required was investigated.
Equation 2 shows the general reaction conditions and Table 1
(14) In supercritical water (374 °C, 3205 psi) alkyne cycloaddition products
have been obtained: Jerome, K. S.; Parsons, E. J. Organometallics 1993, 12,
2991.
(15) Li, C.; Chan, T. Organic Reactions in Aqueous Media; John Wiley
and Sons: New York, 1997; pp 180-189 and references therein.
(16) All samples were degassed by 3 freeze-pump-thaw cycles and sealed
in vacuo.
(17) (a) Bo¨nneman, H.; Brijoux, W.; Brinkmann, R.; Meurers, W.; Mynott,
R.; von Philipsborn, W.; Egolf, T. J. Organomet. Chem. 1984, 272, 231. (b)
Wakatsuki, Y.; Yamazaki, H. Bull. Chem. Soc. 1985, 58, 2715.
(18) See Supporting Information.
(19) Wakatsuki, Y.; Yamazaki, H.; Kobayashi, T.; Sugawara, Y. Organo-
metallics 1987, 6, 1191.
(10) Rideout, D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102, 7817.
(11) Grotjahn, D. B.; Zhang, X. J. Mol. Catal. A 1997, 116, 99.
(12) (a) Breslow, R.; Maitra, U. Tetrahedron Lett. 1992, 25, 1239. (b) Ward,
D. E.; Gai, Y. Tetrahedron Lett. 1992, 33, 1851. (c) Rizzo, C. J. J. Org. Chem.
1992, 57, 6382.
(13) (a) Tarasow, T. M.; Tarasow, S. L.; Eaton, B. E. Nature 1997, 389,
54. (b) Wiegand, T. W.; Janssen, R. C.; Eaton, B. E. Chem. Biol. 1997, 4,
675.
S0002-7863(98)00728-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/07/1998

Communications to the Editor
J. Am. Chem. Soc., Vol. 120, No. 20, 1998 5131
Table 1. Cyclotrimerization Products from 3 with Functionalized
Alkynes
Scheme 1
alkyne:product
R1
R2
yield, %
a/b
5:12
6:13
H
H
H
H
H
H
H
COCH3
44
67
85
73
81
78
56
0a/44
47/20
62/23b
47/26b
53/28
51/27
36/20
CO2CH3
7:14
(CH2)2OH
CH2NHCH3
C(CH3)2OH
CH2N(CH3)2
(CH2)2CO2H
8:15
9:16
10:17
11:18
a Minor isomer not isolated. b Ratios determined by HPLC.
summarizes the yield data (not optimized) where all reactions
were performed under identical conditions. Good yields were
obtained for both 16a, 17a, 16b, and 17b isomers despite the
fact that for 16 and 17 the substituents in the a isomers must be
ortho and sterically demanding. This is surprising because the
more highly strained products were favored. Table 1 shows that
amine, hydroxyl, ketone, ester, and carboxylic acid groups were
all tolerated in this aqueous [2 + 2 + 2] cycloaddition chemistry.
However, 5 gave only the b isomer product.20
The mechanism of CpCo(CO)2 alkyne cyclotrimerization in
organic solvents has been studied in detail, yet several proposed
steps elude verification or clarification. The accepted mechanism
involves rate determining photochemical or thermal dissociation
of one ligand to allow the first alkyne into the cobalt coordination
sphere.21 To begin to understand alkyne cyclotrimerizations via
3 in water the reaction kinetics were measured to determine the
affect of catalyst 3 and substrate 1 concentration.18 The observed
first-order rate is unaffected by the concentration of 1. As
expected the cyclotrimerization of 1 to give 4 showed a first-
order dependence on the catalyst concentration 3. These data
are consistent with the accepted dissociative mechanisms of
cobalt-catalyzed alkyne cyclotrimerization.
A crucial aspect of the CpCo alkyne cyclotrimerization
mechanism in organic solvents is the dissociative formation of
16 e complexes at several points in the reaction22 to allow the
alkyne access to the metal center. To test if dissociation of either
the Cp or the COD was occurring during the catalytic cycle two
deuterio catalyst isomers were prepared, Cp$Co-COD-d8 (19) and
Cp$-d4Co-COD (20), and double isotopic crossover experiments
were performed in triplicate with an equal mixture of 19:20.18
The cycloaddition was monitored by 1H NMR and ligand
exchange by mass spectrometry. At 60% conversion of 1 (1H
NMR, >5 catalyst cycles) to 4 the mass spectrum of the recovered
catalyst was identical and unchanged in all experiments. These
data rule out rate determining dissociative loss of either the COD
or the Cp and instead would be consistent with alkyne coordina-
tion occurring by ligand slippage of either the COD or the Cp.
Slippage of Cp ligands in associative substitution reactions has
been suggested previously for isoelectronic CpRh complexes,22
but we are unaware of any previous examples for ligand slippage
in cobalt complexes. While clearly more research is needed to
elucidate the mechanism of alkyne cyclotrimerization via 3 in
aqueous solutions, the crossover experiments may explain why
3 shows remarkable stability in water because coordinatively
unsaturated intermediates are not necessary. One possible
mechanistic alternative is shown in Scheme 1.
Complex 3 could undergo slippage of the Cp ligand from η5
to η3 as in A and subsequent coordination of the first alkyne.23
A
second alkyne could enter the metal binding sphere by further
Cp slippage to η1 giving B. Cp ring slippage from η5 to η1 has
been reported previously for CpRe24 and CpPd25 complexes.
Oxidative coupling of the alkyne ligands in B with Cp slippage
back from η1 to η3 as in C could provide a driving force for
metallacycle formation and maintain a filled cobalt valence (18
e). The most direct path to the product could involve Diels-
Alder addition of the cobalt bound third alkyne to the metallacycle
in D,26 or prior to metal coordination by direct reaction on C by
the third alkyne to give the η2-benzene complex E.27 Reductive
elimination of the η2-benzene from the cobalt would give the
product, and slippage of the Cp from η1 to η5 would regenerate
the resting state of the catalyst.
In summary a new cobalt catalyst has been prepared that
performs alkyne cyclotrimerization in water solutions under mild
conditions. Protection of the alkyne functional groups is not
required even for amines and carboxylic acids. The kinetic and
double isotopic crossover data gave some surprising results
consistent with rate determining dissociative coordination of
alkyne, which implies ligand slippage to allow access of the
alkyne to the metal center. Further investigations are in progress
to better define the scope and mechanism of this new alkyne
cyclotrimerization chemistry in water.
Acknowledgment. We are grateful for financial support from NeXstar
Pharmaceuticals and stimulating discussions with T. Dewey and T.
Tarasow. Insightful comments regarding this work from WSU professors
S. Wherland and D. Matteson are also appreciated. Some NMR data were
obtained from the WSU NMR Center supported in part by NIH
(RR0631401) and NSF (CHE-9115282).
Supporting Information Available: Experimental details and chemi-
cal characterization data (10 pages, print/PDF). See any current masthead
page for ordering information and Web access instructions.
JA9807284
(23) This regioisomer of the η3-Cp is suggested by previous X-ray and 1H
NMR data on formyl-CpRh-diene complexes. Arthurs, M.; Karodia, H.;
Sedwick, M.; Morton-Blake, D. A.; Cardin, C. J.; Parge, H. J. Organomet.
Chem. 1985, 291, 231.
(24) (a) Werner, H.; Tune, D.; Parker, G.; Kru¨ger, C.; Brauer, D. J. Angew.
Chem. 1975, 87, 205. (b) Werner, H.; Kuhn, A. Angew. Chem. 1979, 91,
447.
(20) Only traces of the a isomer could be detected by mass spectral analysis.
(21) Collman, J. P.; Hegedus, L. S.; Norton, J. R.; Finke, R. G. Principles
and Applications of Organotransition Metal Chemistry; University Science
Books: Mill Valley, 1988; pp 870-871 and references therein.
(22) (a) Schuster-Woldan, H. G.; Basolo, F. J. Am. Chem. Soc. 1966, 88,
1657. (b) Vest, P.; Anhaus, J.; Bajaj, H. C.; van Eldik, R. Organometallics
1991, 10, 818.
(25) (a) Casey, C. P.; Jones, W. D. J. Am. Chem. Soc. 1980, 102, 6156.
(b) Casey, C. P.; O'Connor, J. M.; Haller, K. J. J. Am. Chem. Soc. 1985, 107,
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(26) Eaton, B. E. Ph.D. Dissertation, University of California, Berkeley,
1988.
(27) McAlister, D. R.; Bercaw, J. E.; Bergman, R. G. J. Am. Chem. Soc.
1997, 99, 1666.