Nickel, manganese, cobalt, and iron-catalyzed deprotonative arene dimerization

Article abstract of DOI:10.1021/ol902970z

"Chemical Equation Presented" A number of first-row transition metal salts catalyze deprotonative dimerization of acidic arenes. Under the atmosphere of oxygen, nickel, manganese, cobalt, and iron chlorides have been shown to dimerize five- and six-membered ring heterocycles as well as electron-poor arenes. Both tetramethylpiperidide and dicyclohexylamide bases can be employed; however, the former afford slightly higher yields.

Full text of DOI:10.1021/ol902970z

ORGANIC
LETTERS
2010
Vol. 12, No. 6
1200-1203
Nickel, Manganese, Cobalt, and
Iron-Catalyzed Deprotonative Arene
Dimerization
Thanh Truong, Joseph Alvarado, Ly Dieu Tran, and Olafs Daugulis*
Department of Chemistry, UniVersity of Houston, Houston, Texas 77204-5003
olafs@uh.edu
Received December 28, 2009
ABSTRACT
A number of first-row transition metal salts catalyze deprotonative dimerization of acidic arenes. Under the atmosphere of oxygen, nickel,
manganese, cobalt, and iron chlorides have been shown to dimerize five- and six-membered ring heterocycles as well as electron-poor arenes.
Both tetramethylpiperidide and dicyclohexylamide bases can be employed; however, the former afford slightly higher yields.
Carbon-hydrogen bond activation protocols allow the
utilization of a C-H bond as a functional group, offering a
direct and efficient route for the creation of carbon-carbon
and carbon-heteroatom bonds. Unfortunately, most of the
current methods for functionalization of carbon-hydrogen
bonds employ second or third row transition metal catalysis.1
First-row transition metals such as Fe, Co, Ni, Mn, or Cu
are used relatively rarely.2 These elements are substantially
more abundant compared to their 4d and 5d analogues. For
example, nickel is present at a concentration of 84 g/ton in
the Earth’s crust.3 Its 4d homologue, palladium, is present
at a concentration of 0.015 g/ton while platinum is found at
the concentration of 0.005 g/ton.3 Therefore, the past few
years have witnessed an interest in developing methods that
employ abundant first-row transition metal catalysts. We have
reported a general method for copper-catalyzed arylation of
C-H bonds.4 Recently, we developed a method for copper-
catalyzed, deprotonative arene dimerization by employing
oxygen as the terminal oxidant.5 By analogy with Glaser-Hay
reaction,6 in situ deprotonation is followed by the transmeta-
lation, forming an organocopper species that affords biaryl
under oxygen (Scheme 1). It is known that dimerization of
organometallic species can be catalyzed or promoted by
transition metals other than copper. For example, Mn, Fe,
Co, and Ni salts have been shown to effect the dimerization
of Grignard reagents.7 In some cases, oxygen has been used
(1) (a) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res.
2008, 41, 1013. (b) Campeau, L.-C.; Fagnou, K. Chem. Commun. 2006,
1253. (c) Ackermann, L. Synlett 2007, 507. (d) Chen, X.; Engle, K. M.;
Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (e) Seregin,
I. V.; Gevorgyan, V. Chem. Soc. ReV. 2007, 36, 1173. (f) Dick, A. R.;
Sanford, M. S. Tetrahedron 2006, 62, 2439. (g) Daugulis, O.; Do, H.-Q.;
Shabashov, D. Acc. Chem. Res. 2009, 42, 1074. (h) Alberico, D.; Scott,
M. E.; Lautens, M. Chem. ReV. 2007, 107, 174. (i) McGlacken, G. P.;
Bateman, L. M. Chem. Soc. ReV. 2009, 38, 2447.
(3) Enghag, P. Encyclopedia of the Elements; Wiley: Weinheim,
Germany, 2004.
(4) (a) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404.
(b) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 1128. (c) Do,
H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 15185.
(5) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2009, 131, 17052.
(6) (a) Glaser, C. Ber. Dtsch. Chem. Ges. 1869, 2, 422. (b) Hay, A. S.
J. Org. Chem. 1962, 27, 3320.
(2) Review: (a) Kulkarni, A. A.; Daugulis, O. Synthesis 2009, 4087.
Selected examples: (b) Baslé, O.; Li, C.-J. Chem. Commun. 2009, 4124.
(c) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc.
2006, 128, 6790. (d) Monguchi, D.; Fujiwara, T.; Furukawa, H.; Mori, A.
Org. Lett. 2009, 11, 1607. (e) Brasche, G.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2008, 47, 1932. (f) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127,
6968. (g) Yotphan, S.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2009, 11,
1511.
(7) (a) Bennett, G. M.; Turner, E. E. J. Chem. Soc. 1914, 1057. (b)
Gilman, H.; Lichtenwalter, M. J. Am. Chem. Soc. 1939, 61, 957. (c) Gilman,
H.; Bailie, J. C. J. Org. Chem. 1937, 2, 84.
10.1021/ol902970z  2010 American Chemical Society
Published on Web 03/01/2010

vestigated by Knochel for a variety of deprotonation/
functionalization procedures.11 It was found that optimal
yields are obtained if a combination of zinc and magnesium
bases is used.
Scheme 1. Copper-Catalyzed Arene Dimerization
as the terminal oxidant.8 As a consequence, one should be
able to perform the deprotonation/oxidative dimerization
sequences by employing first-row transition metals other than
copper. Potential benefits of their use include relative
nontoxicity of iron and manganese complexes. We report
here a method for cobalt-, iron-, nickel-, and manganese-
catalyzed arene deprotonative dimerization by using oxygen
as the terminal oxidant.
Scheme 3. Base Synthesis
Our initial attempts were directed toward developing
optimized conditions for arene dimerization under nickel
catalysis. In copper-catalyzed arene dimerization, the best
product yields were obtained by employing magnesium or
zinc amide bases.5 Use of lithium or potassium alkoxide
bases led to formation of major amounts of phenol byproduct.
Similar results were obtained if NiCl2 catalyst was employed
(Scheme 2). By analogy with copper catalysis chemistry,9
The rationale for the use of base mixtures is as follows.
Combination of magnesium bases 1 and 2 with zinc bases 3
and 4 allows for a relatively rapid deprotonation (provided
by Mg amides) and higher substrate stability (provided by
Zn amides; enhanced functional group tolerance and phenol
byproduct formation prevented). If Mg bases are used for
sensitive substrates, lower yields are obtained.
The optimal results for nickel-catalyzed dimerization were
obtained by employing 5 mol % of NiCl2 catalyst at 0-60 °C
in THF solvent under 1 atm of oxygen (Table 1). The scope
of the reaction is similar to the scope of copper-catalyzed
dimerization. Electron-rich heterocycles such as thiazole
(entry 1) and benzofuran (entry 2) can be dimerized.
3-Chloropyridine is reactive, affording the dimer in 33%
yield (entry 3). Electron-deficient 1,3-difluorobenzene and
difluoronitrobenzene (entries 4 and 5) are reactive and the
most acidic C-H bonds, those flanked by fluoro and nitro
substituents, are functionalized. Entries 1 and 4 were run
with both tetramethylpiperidide and dicyclohexylamide bases.
The substantialy cheaper dicyclohexylamide is almost as
efficient as the tetramethylpiperidide base.12
Scheme 2. Phenol Byproducts in Dimerization
phenol byproduct can be formed either by the direct reaction
of arylalkali metal intermediate with oxygen or by reaction
of a high-valent arylnickel with hydroxide derived from
water. Thus, a less polarized C-metal bond in the intermedi-
ate that should decrease the reactivity of arylmetal with
oxygen and would bind hydroxide byproduct was needed.
As observed for copper-catalyzed dimerization, zinc or
magnesium bases of hindered amines were shown to be
efficient. Synthesis of the bases is presented in Scheme 3.
Both tetramethylpiperidides and dicyclohexylamides can be
used; however, the more expensive tetramethylpiperidides
afford somewhat higher yields as shown below. Magnesium
tetramethylpiperidides were introducted by Eaton.10 Numer-
ous tetramethylpiperidide bases have been extensively in-
Manganese salts are known to promote Grignard
dimerizations.7c,8a Selective cross-dimerization of organo-
magnesium species can be achieved by employing manga-
nese catalysis.8c Manganese salts are less toxic than copper
or nickel complexes.13 As shown in Table 2, manganese(II)
chloride catalyzes arene deprotonative dimerization under
conditions that are similar to the ones described for nickel.
Thiazole and 2-chlorothiophene are dimerized in good yields
(entries 1 and 2). Electron-deficient methoxypyrazine is also
reactive, affording the product in acceptable yield (entry 3).
1,2,4-Trifluorobenzene and ethyl 3,4-difluorobenzoate are
converted into dimers in good yields (entries 4 and 5). Entries
(8) (a) Cahiez, G.; Moyeux, A.; Buendia, J.; Duplais, C. J. Am. Chem.
Soc. 2007, 129, 13788. (b) Maji, M. S.; Pfeifer, T.; Studer, A. Angew. Chem.,
Int. Ed. 2008, 47, 9547. (c) Cahiez, G.; Duplais, C.; Buendia, J. Angew.
Chem., Int. Ed. 2009, 48, 6731. (d) Liu, W.; Lei, A. Tetrahedron Lett. 2008,
610. (e) Chen, S.-Y.; Zhang, J.; Li, Y.-H.; Wen, J.; Bian, S.-Q.; Yu, X.-Q.
Tetrahedron Lett. 2009, 6795. (f) Hwang, D.-R.; Chen, C.-P.; Uang, B.-J.
Chem. Commun. 1999, 1207. (g) Sakamoto, T.; Yonehara, H.; Pac, C. J.
Org. Chem. 1994, 59, 6859.
(10) Eaton, P. E.; Lee, C.-H.; Xiong, Y. J. Am. Chem. Soc. 1989, 111,
8016.
(11) (a) Mosrin, M.; Knochel, P. Org. Lett. 2009, 11, 1837. (b) Dubbaka,
S. R.; Kienle, M.; Mayr, H.; Knochel, P. Angew. Chem., Int. Ed. 2007, 46,
9093. (c) Wunderlich, S. H.; Knochel, P. Angew. Chem., Int. Ed. 2007, 46,
7685.
(12) 2,2,6,6-Tetramethylpiperidine is available at $524/mol, while
dicyclohexylamine costs $4.7/mol (Aldrich).
(13) NIOSH Pocket Guide to Chemical Hazards, DHHS (NIOSH);
Department of Health and Human Services, Centers for Disease Control
and Prevention, National Institute for Occupational Safety and Health:
Cincinnati, OH, 2007; Publication No. 2005-149.
(9) (a) King, A. E.; Brunold, T. C.; Stahl, S. S. J. Am. Chem. Soc. 2009,
131, 5044. (b) Lam, P. Y. S.; Bonne, D.; Vincent, G.; Clark, C. G.; Combs,
¨
A. P. Tetrahedron Lett. 2003, 44, 1691. (c) Demir, A. S.; Reis, O.;
Emruallahoglu, M. J. Org. Chem. 2003, 68, 10130.
Org. Lett., Vol. 12, No. 6, 2010
1201

Grignard dimerization under cobalt catalysis is
known.7b,8e We were pleased to find out that cobalt-catalyzed
deprotonative arene dimerization is also successful (Table
3). The thiazole dimerization efficiency is virtually the same
as that for nickel and manganese catalysis, affording the
dimer in 86% yield (entry 1). Benzothiophene (entry 2) and
N-butylimidazole (entry 3) can be dimerized in excellent
yields. Electron-poor tetrafluoroanisole (entry 4) and difluo-
robenzonitrile (entry 5) afford deprotonative dimerization
products in 90% and 80% yields, respectively. As shown
before for nickel and manganese catalysis, dicyclohexyla-
mides afford results comparable to those of tetramethylpi-
peridide amides.
Table 1. Nickel Catalysisa
Table 3. Cobalt Catalysisa
a Substrate (1 equiv), base (1.2-1.4 equiv). Yields are isolated yields.
See the Supporting Information for details. b Dicyclohexylamide base.
1, 2, and 4 were run with both tetramethylpiperidide and
dicyclohexylamide bases, with tetramethylpiperidides af-
fording slightly higher yields.
Table 2. Manganese Catalysisa
a Substrate (1 equiv), base (1.1-1.7 equiv). Yields are isolated yields.
See the Supporting Information for details. b Dicyclohexylamide base.
Iron is the fourth most abundant element in the Earths’
crust.3 Iron salts are relatively nontoxic.13 Iron-promoted
or catalyzed Grignard dimerizations have been
reported.7a,b,8a,e We show that iron trichloride catalyzes
deprotonative arene dimerization under an atmosphere of
oxygen (Table 4). In general, the dimerization efficiency is
lower compared to that of nickel, manganese, and cobalt
catalysis. Somewhat higher catalyst loading (10 mol % as
opposed to 5-7 mol %) is required for optimal results.
Thiazole is dimerized in 59% yield (entry 1). Other five-
membered-ring heterocycles such as 4,5-dimethylthiazole
(entry 2) and N-methylbenzimidazole (entry 3) are also
reactive. Tetrafluoropyridine, tetrafluoroanisole, and ethyl-
2,4-difluorobenzoate (entries 4-6) afford dimerization prod-
ucts in good yields.
We ran several control experiments to determine if a trace
of another transition metal might be catalyzing the dimer-
ization (Scheme 4).14 With reagent grade or ultrapure
a Substrate (1 equiv), base (1.2-1.4 equiv). Yields are isolated yields.
See the Supporting Information for details. b Dicyclohexylamide base.
1202
Org. Lett., Vol. 12, No. 6, 2010

Table 4. Iron Catalysisa
Scheme 4. Control Experiments (% conversion reported)
oxygen as the terminal oxidant. Electron-rich and electron-
poor heterocycles as well as electron-poor arenes can be
dimerized.
a Substrate (1 equiv), base (1.1-1.3 equiv). Yields are isolated yields.
See the Supporting Information for details.
Acknowledgment. We thank the Welch Foundation (Grant
No. E-1571), NIGMS (Grant No. R01GM077635), the A. P.
Sloan Foundation, the Camille and Henry Dreyfus Founda-
tion, and the Norman Hackerman Advanced Research
Program for supporting this research.
transition metal salts similar results were obtained, showing
that catalysis by contaminants is unlikely. If the metal salt
was omitted, only minor amounts of arene dimer were
formed.
In conclusion, we have shown that transition metal-
catalyzed deprotonative arene dimerization can be achieved
by cobalt, iron, nickel, and manganese catalysis employing
Supporting Information Available: Experimental details,
data, and spectra for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(14) Buchwald, S. L.; Bolm, C. Angew. Chem., Int. Ed. 2009, 48, 5586.
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