Exploiting guanidine as a ligand in cobalt-catalyzed alkyne cyclotrimerizations

Article abstract of DOI:10.1055/s-0030-1259931

The synthesis of polysubstituted arenes is accomplished via the regioselective cyclotrimerization of alkynes utilizing a guanidine-ligated cobalt catalyst. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1259931

LETTER
1109
Exploiting Guanidine as a Ligand in Cobalt-Catalyzed Alkyne
Cyclotrimerizations
G
uanidine-Ligate
h
d
C
obalt Ca
a
A
d
lkyne Cyclotrimeri
C
Evans Chemical Laboratories, The Ohio State University, 100 West 18th Avenue, Columbus, OH 43210, USA
E-mail: stambuli@chemistry.ohio-state.edu
Received 19 February 2011
by Breslow.6 Although guanidine is cheap and abundant,
its use as a ligand in metal-catalyzed reactions has been
limited. For example, only a few palladium-catalyzed pro-
cesses have been developed utilizing guanidines as bases
or ligands.7 Guanidines are attractive in transition-metal
catalysis because they are ambidentate, so binding to the
metal center is possible through the sp2 nitrogen or the two
amino groups. Moreover, metal complexes ligated by
guanidines may provide catalysts that can be employed in
green chemical processes that occur in water instead of or-
ganic solvents. To explore the potential activity of
guanidines as ligands in transition-metal-catalyzed reac-
tions, we investigated the use of these catalyst systems in
the cyclotrimerization of alkynes (Scheme 1).
Abstract: The synthesis of polysubstituted arenes is accomplished
via the regioselective cyclotrimerization of alkynes utilizing a
guanidine-ligated cobalt catalyst.
Key words: alkynes, arenes, cycloaddition, regioselectivity, transi-
tion metals
Guanine is one of nature’s most important natural prod-
ucts as it is a major component of both DNA and RNA.
The degradation of guanine produces various compo-
nents, one of which is guanidine. Guanidine is generated
by the oxidation of guanine and is found in the urine of
mammals. Natural products containing a guanidine moi-
ety exhibit a wide range of biological activity,1 and the in-
teraction of the guanidine motif with proteins leads to
different modes of bioactivity. For example, guanidinium
hydrochloride can act as a protein denaturation agent or it
can stabilize folded proteins.2 Another derivative, hydroxy-
guanidine, was discovered to inhibit the synthesis of DNA
making it a potential antitumor drug.3 Both natural and
unnatural guanidine derivatives possess antiproliferative,
antiviral, and antibacterial properties.1,4 Consequently,
many natural products bearing the guanidine functionality
continue to be active targets of the synthetic organic com-
munity.5
The prevalence of highly substituted benzene derivatives
in natural products prompts the investigations into effi-
cient and reliable methods to generate these moieties. A
useful tactic to create polysubstituted arenes is the
[2+2+2] cyclotrimerization of alkynes.8 Transition-metal
catalysts such as Ti,9 Pd,10 Co,11 Ru,12 Ir,13 and Rh14 have
been employed in this transformation to assist in over-
coming the intrinsic entropic barrier associated with this
reaction. Cobalt-catalyzed processes are particularly at-
tractive due to their low cost and ease of handling. The
ability to catalyze intermolecular cyclotrimerization reac-
tions of unsymmetrical alkynes regioselectively remains a
challenge. Hilt11d and Okamoto11c have shown these reac-
tions proceed with good regioselectivity for the unsym-
metrical arene product and obtained high yields using
cobalt in combination with diimine or iminopyridine
ligands. Typically, these reaction conditions required 5–
10 mol% of cobalt and the corresponding ligand.
DNA or
protein interaction
biologically
useful
transformations
R
N
R
R
N
R
N
R
..
synthetically
useful
transition metal
this work
R2
R1
transformations
R2
R1
R1 R2
R1 R1
R2
R1
CoCl2
R1
Zn, ZnI2
Scheme 1 The diverse utility of guanidine derivatives
R2
Ar
N
R2
R2
= TIPG
H
Ar
A major interest of our research group is the development
of new catalysts for transition-metal-catalyzed reactions.
The use of natural products in catalysis has been exploited
in recent years. The most prominent examples are the
NHC ligands, which were developed in large part because
of the role of naturally occurring thiamine first proposed
N
H
N
Ar
Ar = 2,6-diisopropylphenyl
Scheme 2 Cobalt-catalyzed cyclotrimerization of alkynes
Because of the success of cobalt–imine complexes to cat-
alyze the cyclotrimerization of alkynes, we investigated
the use of guanidine ligands in this reaction (Scheme 2).
As described earlier, guanidine can bind to cobalt as a
SYNLETT 2011, No. 8, pp 1109–1112
Advanced online publication: 30.03.2011
DOI: 10.1055/s-0030-1259931; Art ID: S00211ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
1

1110
C. C. Eichman et al.
LETTER
neutral donor through the sp2 nitrogen or as an anionic or species to the active catalyst,17 and the Zn/ZnI2 system is
dianionic donor via the amino groups.15 Initially, it was commonplace in most Co-catalyzed cycloaddition reac-
expected that these ligands would coordinate to cobalt tions.11,18 Comparison with the in situ generated catalyst
through the sp2 nitrogen in the same fashion that imines with CoCl2 and TPG provided identical results as the pre-
bind to cobalt. Figure 1 shows the cobalt complex and the formed catalyst. Employment of the more bulky TIPG
guanidine-based ligands that were employed for optimi- ligand gave slightly better regioselectivity (Table 1, entry
zation studies.
3). Reducing the catalyst loading to 5 mol% CoCl2 and 10
mol% TIPG slightly decreased the overall reaction rate as
the reaction required 1 hour to reach completion, but the
regioselectivity was conserved. The reaction also pro-
ceeded with 10 mol% CoCl2 and 10 mol% TIPG in 30
minutes with 95:5 regioselectivity (Table 1, entry 3), sug-
gesting that the active catalytic species only needs to be
supported by a single TIPG ligand. This stoichiometry is
intriguing as previous cobalt imine catalysts required a 1:1
ratio of metal to ligand when bidentate ligands were em-
ployed. Therefore, cobalt likely complexes in a bidentate
fashion to the sp2 nitrogen and one of the sp3 amino groups
of the guanidine. Using this 1:1 metal-to-ligand ratio we
were able to lower the catalyst loading to 2 mol%. The ad-
dition of zinc and zinc iodide was also required for the re-
action to proceed. The final optimized reaction conditions
were 2 mol% CoCl2, 2 mol% TIPG, 4 mol% Zn, and 4
mol% ZnI2 in acetonitrile.
Ph
N
NH
Ar
Ph
Cl
Co
Cl
Ph
N
N
N
H
N
Ph
N
H
Ar
Ph
Ph
N
H
NH
Ar
N
H
NH
Ph
Ph
HN
Ph
Co-TPG
TPG
TIPG
Ar = 2,6-diisopropylphenyl
Figure 1 Cobalt complex and guanidine ligands
A guanidine-ligated cobalt complex15d (Co-TPG) and
triphenylguanidine (TPG) with CoCl2 were subjected to
reaction conditions. To more greatly bias regioselectivity
by crowding the metal center, we also employed the bulky
tris(2,6-diisopropylphenyl) guanidine (TIPG) ligand,
which was easily prepared according to a reported litera-
ture procedure.16
Various alkynes were exposed to the optimized reaction
conditions in order to assess the scope of this new catalyst.
Using only 2 mol% CoCl2 and TIPG, high regioselectivi-
ties and yields were achieved for a variety of functional-
ized alkynes (Table 2). Triphenylbenzene was produced
almost solely as the unsymmetrical product with a 99:1 re-
gioselectivity.19 Electron-deficient alkynes, such as meth-
yl propiolate, underwent cyclotrimerization to give
trimethyl benzene-1,2,4-tricarboxylate as the major prod-
uct (Table 2, entry 3). This catalyst also tolerated silyl-
protected alkynes as trimethylsilylacetylene gave the cor-
responding 1,2,4-trisubstituted arene in high yield
(Table 2, entry 4). Other alkynes such as TBS-protected
propargyl alcohol and 6-chloro-1-hexyne also proceeded
smoothly to afford the corresponding arenes in excellent
yields with good regioselectivities (Table 2, entries 5 and
6). Interestingly, an alkyne containing a pendant nitrile re-
acted to form the benzene product without interference
from the nitrile (Table 2, entry 7). Cobalt-catalyzed cyclo-
trimerizations of alkynes that contain nitrile functional-
ities have been shown to form substituted pyridines.20
However, we did not observe any pyridine side products
during the reaction with this alkyne.
Table 1 Cyclotrimerization of 1-Heptyne Catalyzed by Guanidine-
Ligated Cobalt Catalysta
R
Co source
ligand
R
R
R
Zn, ZnI2
MeCN
23 °C, 30 min
4
R
R
1
2
R = n-pentyl
Entry Co source
(mol%)
Ligand
(mol%)
Zn, ZnI2
(mol%)
Ratio of
1/2b
1
2
3
4
5
6
7
Co-TPG (10)
CoCl2 (10)
CoCl2 (10)
CoCl2 (5)
–
10
10
10
10
10
10
4
94:6
94:6
95:5
95:5c
95:5
95:5
95:5
TPG (20)
TIPG (20)
TIPG (10)
TIPG (10)
TIPG (5)
TIPG (2)
CoCl2 (10)
CoCl2 (5)
CoCl2 (2)
a The alkyne is added after all other reagents are heated at 50 °C for 5
min.
We then tested our reaction conditions on internal alkynes
(Table 2, entries 8–10). Similar to the literature precedent,
this reaction required elevated temperatures to proceed in
high yield. The cyclotrimerization reaction of internal
alkynes with this catalyst system required only two hours
at 80 °C to reach completion. 3-Hexyne was converted to
hexaethylbenzene, while phenyl propyne and tert-
butyldimethylsilyloxy-2-butynol gave near quantitative
yields and high regioselectivities (96:4 and 75:25, respec-
tively) of the corresponding unsymmetrical arene prod-
ucts.
b Regioselectivity was determined by GC analysis.
c Reaction required 1 h to go to completion.
Upon exposure of 1-heptyne to an acetonitrile solution of
10 mol% Co-TPG and a catalytic amount of Zn/ZnI2 the
desired arene is obtained in complete conversion with
high regioselectivity (Table 1, entry 1). Previously, Sny-
der has shown that the addition of zinc and zinc iodide in-
creases reaction rates by effectively reducing the cobalt
Synlett 2011, No. 8, 1109–1112 © Thieme Stuttgart · New York

LETTER
Guanidine-Ligated Cobalt Catalyst for Alkyne Cyclotrimerizations
1111
Table 2 Cyclotrimerization of Terminal and Internal Alkynes
Acknowledgment
..
R1
We acknowledge financial support of this research from The Ohio
State University.
R2
R1
R2
R1
R1 R2
R1 R1
R2
R1
CoCl2
TIPG
R2
Zn, ZnI2
MeCN
References and Notes
R2
3
R2
4
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Entry Alkynea
CoCl2, TIPG Zn,
(mol%)
Ratio of Yield
ZnI2 3/4b
(%)c
1
2
4
95:5
87
4
2
2
2
4
4
99:1
74
98
Ph
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3
85:15
MeO2C
4
2
2
4
4
81:19
85:15
89
94
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5
TBSO
6
2
4
94:6
94
Cl
4
7
8
2
4
4
4
4
8
8
8
93:7
–
98
93
98
98
NC
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3
9
96:4
75:25
Ph
10
TBSO
a The alkyne is added after all other reagents are heated at 50 °C for 5
min.
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c Isolated yield is an average of two 1 mmol experiments.
In summary, we have reported a rare example of a guani-
dine-ligated transition-metal-catalyzed reaction. Our cat-
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cyclotrimerization reaction conditions, while still provid-
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ligated complexes in an aqueous medium. Unfortunately,
the initial reactions to perform the guanidine-ligated co-
balt-catalyzed cyclotrimerization in water or a water–
THF mixture proved fruitless and ligand modification is
under way.
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http://www.thieme-connect.com/ejournals/toc/synlett.
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Synlett 2011, No. 8, 1109–1112 © Thieme Stuttgart · New York