Copper-catalyzed homodimerization of nitronates and enolates under an oxygen atmosphere

Article abstract of DOI:10.1021/om300393m

A method for copper-catalyzed oxidative dimerization of nitronates and enolates using oxygen as the terminal oxidant has been developed. Cyclization through oxidative intramolecular coupling is also feasible for both nitronates and enolates. The mild reaction conditions lead to good functional group tolerance.

Full text of DOI:10.1021/om300393m

Communication
pubs.acs.org/Organometallics
Copper-Catalyzed Homodimerization of Nitronates and Enolates
under an Oxygen Atmosphere
Hien-Quang Do, Hung Tran-Vu, and Olafs Daugulis*
Department of Chemistry, University of Houston, Houston, Texas 77204-5003, United States
S
* Supporting Information
ABSTRACT: A method for copper-catalyzed oxidative dimerization of nitro-
nates and enolates using oxygen as the terminal oxidant has been developed.
Cyclization through oxidative intramolecular coupling is also feasible for both
nitronates and enolates. The mild reaction conditions lead to good functional
group tolerance.
a
Table 1. Dimerization of Nitroalkanes
xidative dimerization is a useful transformation for the
Oconstruction of many symmetric organic molecules such
as biaryls,1a vicinal dinitroalkanes,1b and 1,4-dicarbonyl
compounds.1c In general, the presence of a stoichiometric
oxidant is essential for achieving good conversions. Both
organic and inorganic oxidants such as 1,2-dihaloethanes,2a,b
benzoquinones,2c,d silver salts,2e,f copper salts,2e,g−j,t ceric
ammonium nitrate,2k,u,v persulfates,2e,f hydrogen peroxide,2e
iron salts,2e,m,n titanium salts,2o,p and halogens2p,s have been
used in these transformations (Scheme 1). However, for both
environmental and economic reasons, it is advantageous if
those stoichiometric oxidants can be replaced by readily
accessible oxygen. Although the involvement of oxygen in the
oxidative dimerization of aromatic compounds has recently
witnessed significant progress,3 the oxidative homocoupling of
Scheme 1. Dimerization of Nitronates and Enolates
a
Conditions: nitroalkane (1.0 mmol), DBU (2.0 mmol), CuCl2 (0.1
mmol), DMF (0.8 mL), room temperature, 1−2 h. Yields are isolated
b
c
yields. CuCl2 (0.15 mmol) was used. DBU (4 mmol) was employed.
aliphatic anions such as nitronates and enolates utilizing oxygen
as terminal oxidant still remains challenging.4a
Vicinal dinitroalkanes are useful intermediates for the
synthesis of vicinal diamines that are employed as ligands for
transition-metal-catalyzed reactions and can be found in many
biologically active compounds.5 Moreover, the nitro group can
also be converted to a wide range of important functionalities
Special Issue: Copper Organometallic Chemistry
Received: May 9, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/om300393m | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
a
counterion from nitronate and ensure a good yield of the
product. We reasoned that since nitroalkanes are fairly acidic
(pKa < 16−17),8 milder bases could be used to generate
nitronates. In addition, the higher compatibility of the base with
the copper catalyst and oxygen should result in a one-step
reaction. A number of bases and solvents were screened for the
dimerization of 2-nitropropane under an oxygen atmosphere
with 10 mol % of copper(II) chloride catalyst. Interestingly,
when DBU was employed as a base, the dimerization
proceeded smoothly at room temperature in most common
solvents such as DMF, THF, dioxane, DCM, acetonitrile, and
methanol to afford the product in good conversion.9 The best
results were obtained in DMF, and the products were isolated
in excellent yields (Table 1). In addition, mild reaction
conditions allow for high tolerance of functional groups. The
optimized conditions were applied to dimerization of nitro-
alkanes bearing various functionalities. Functional groups such
as ether (entry 5), ester (entry 6), and ketone (entry 7) are
tolerated. The reaction was then extended to the cyclization of
dinitroalkanes through an intramolecular oxidative coupling
reaction. A mixture of 2,6-dinitroheptane diastereomers
underwent cyclization to afford cis-1,2-dimethyl-1,2-dinitrocy-
clopentane as the sole product (entry 8). In contrast, nearly
equal amounts (6/4) of cis- and trans-1,2-dimethyl-1,2-
dinitrocyclopentane were observed by Jackson and Bowman
in the cyclization of the same substrate.2m
Table 2. Dimerization of Carbonyl Compounds
The Nef reaction is a competing process under these
conditions and is responsible for the diminished yield of some
substrates by unproductive consumption of starting material.4
The contribution of side reactions becomes significant for
substrates containing at least one large alkyl group (entries 2−
7). About 8% of cyclohexanone was formed in the dimerization
of nitrocyclohexane (analysis by GC). In some cases, an
increase of catalyst amount to 15 mol % improves the yield
(entries 2, 3, 4, and 8).10
a
Conditions: carbonyl compound (1.0 mmol), LDA (1.1 mmol),
ZnCl2 (0.3 mmol), Cu(acac)2 (0.1 mmol), THF (1.0 mL), room
temperature, 10 min. Yields are isolated yields of a diastereomer
b
c
mixture if applicable. Cu(acac)2 (0.15 equiv) was used. 0.5 mmol of
ZnCl2 was employed.
If two diastereoisomers can be produced, for acyclic cases
they are usually generated in equal amounts (dr = 1:1, entries
3−7). The control experiments reveal that copper catalyst is
essential for the formation of the product. Only a trace of
dimerization product was detected if copper(II) chloride is
omitted. Additionally, the reactions can be run in open vials in
the air; however, substantially longer reaction times are
required.11 Unfortunately, all attempts to expand the reaction
to dimerization of primary nitroalkanes led to disappointing
conversions.
The dimerization of enolates is well-established and has been
widely applied in organic synthesis. However, no copper-
catalyzed process has yet been developed.2g−i,n,p,t We were
interested in establishing the conditions for copper-catalyzed
enolate dimerization using oxygen as the terminal oxidant.
Propiophenone was chosen as the model substrate. The lithium
enolate was prepared by treatment of ketone with LDA in THF
at −78 °C. The resulting enolate solution was reacted with
oxygen in the presence of 10% of copper(II) chloride. Only
10% conversion to the dimerization product was observed. We
assumed that lithium enolate is unstable under the reaction
conditions. Consequently, the enolate anion should be
stabilized in the presence of oxygen. A feasible solution for
this issue is the introduction of a more electrophilic zinc or
magnesium salt. We were gratified to find that treatment of
lithium enolate solution with 0.3 equiv of zinc chloride
improves the conversion from 10% to 70%. Increasing the
amount of zinc chloride additive to 1 equiv decreases the
such as amine, carbonyl, nitrile, oxime, hydroxylamine, and
thiol.6
Similarly, the 1,4-dicarbonyl moiety is ubiquitous in organic
molecules, including natural products and numerous medicinal
remedies.2t Therefore, the synthesis of vicinal dinitroalkanes
and 1,4-dicarbonyl compounds is still attracting attention. We
have recently developed a method for copper-catalyzed
dimerization of aromatic compounds employing oxygen as
the terminal oxidant.3h We speculated that the strategy should
be applicable to the oxidative dimerization of nitronates and
enolates. Our speculation was based on the fact that Cu(II)-
promoted enolate dimerization as well as the oxidation of low-
valent copper species to Cu(II) is well precedented.2e−g,j,t,3h
Therefore, we set out to develop conditions for this
transformation employing copper catalysis and oxygen as a
terminal oxidant.
The dimerization of nitroalkanes has been intensively studied
in terms of both method development and mechanism. It can
be performed by both electrochemical and chemical method-
s.2e,f,k−m,r,s,7 In the latter case, several equivalents of chemical
oxidants are employed. Sello and Morin have recently
published an elegant work on the synthesis of pimaricin-
inducing factor.2k The authors have developed a general
procedure for oxidative dimerization of various nitroalkanes
using 2.2 equiv of CAN oxidant and NaH base. However, the
use of NaH base requires 15-crown-5 to decomplex the sodium
B
dx.doi.org/10.1021/om300393m | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
(n) Frazier, R. H., Jr.; Harlow, R. L. J. Org. Chem. 1980, 45, 5408.
(o) Ojima, I.; Brandstadter, S. M.; Donovan, R. J. Chem. Lett. 1992,
1591. (p) Kise, N.; Tokioka, K.; Aoyama, Y.; Matsumura, Y. J. Org.
Chem. 1995, 60, 1100. (q) Ivanoff, D.; Spassoff, A. Bull. Soc. Chim. Fr.
1935, 2, 76. (r) Wade, P. A.; Dailey, W. P.; Carroll, P. J. J. Am. Chem.
Soc. 1987, 109, 5452. (s) Bowman, W. R.; Brown, D. S.; Burns, C. A.;
Crosby, D. J. Chem. Soc., Perkin Trans. 1 1994, 2083. Enolate
heterocoupling: (t) DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am.
Chem. Soc. 2008, 130, 11546. Oxidative carbon−carbon bond
formation via silyl bis-enol ethers: (u) Clift, M. D.; Taylor, C. N.;
Thomson, R. J. Org. Lett. 2007, 9, 4667. (v) Avetta, C. T., Jr.; Konkol,
L. C.; Taylor, C. N.; Dugan, K. C.; Stern, C. L.; Thomson, R. J. Org.
Lett. 2008, 10, 5621.
(3) Pd-catalyzed arene intermolecular homo-/heterodimerization:
(a) Okamoto, M.; Yamaji, T. Chem. Lett. 2001, 212. (b) Brasche, G.;
García-Fortanet, J.; Buchwald, S. L. Org. Lett. 2008, 10, 2207.
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Grignard homodimerization under O2: (d) Cahiez, G.; Moyeux, A.;
Buendia, J.; Duplais, C. J. Am. Chem. Soc. 2007, 129, 13788. (e) Maji,
M. S.; Pfeifer, T.; Studer, A. Angew. Chem., Int. Ed. 2008, 47, 9547.
Phenol dimerization under Cu/O2: (f) Sakamoto, T.; Yonehara, H.;
Pac, C. J. Org. Chem. 1994, 59, 6859. (g) Hewgley, J. B.; Stahl, S. S.;
Kozlowski, M. C. J. Am. Chem. Soc. 2008, 130, 12232. Arene
dimerization: (h) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2009, 131,
17052. (i) Truong, T.; Alvarado, J.; Tran, L. D.; Daugulis, O. Org. Lett.
2010, 12, 1200. (j) Niu, T.; Zhang, Y. Tetrahedron Lett. 2010, 51,
6847. (k) Li, Y.; Jin, J.; Qian, W.; Bao, W. Org. Biomol. Chem. 2010, 8,
326. (l) Monguchi, D.; Yamamura, A.; Fujiwara, T.; Somete, T.; Mori,
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conversion. Further optimization led to the use of copper(II)
acetylacetonate catalyst. The optimized conditions involve 10
mol % of Cu(acac)2 catalyst, 0.3−0.5 equiv of ZnCl2 additive,
and 1 atm of oxygen, affording the desired product in 68%
isolated yield. The conditions work well for a variety of
carbonyl compounds such as ketones (Table 2, entries 1−4, 7),
esters (entry 5), and amides (entry 6).
Good results can be obtained for both primary and
secondary ketones (entries 1−3), although tertiary ketone
afforded diminished yield, presumably due to steric effects
(entry 4). For chiral or prochiral secondary ketones, two
diastereoisomers are produced with preferential formation of
the syn (dl) diastereoisomer (entries 2 and 3). Analogous
outcomes have also been observed in stoichiometric dimer-
izations.2i,n,t The cyclization through intramolecular oxidative
coupling was also successful, and a mixture of cis- and trans-1,2-
dibenzoylcyclohexane was obtained if 1,8-diphenyloctane-1,8-
dione was subjected to the general conditions. As expected, the
trans isomer was formed predominantly (entry 7). In general,
the yields in the catalytic reactions parallel those previously
described in stoichiometric reactions.2g−i
In conclusion, we have developed two copper-catalyzed
methods for oxidative dimerization of nitroalkanes and carbonyl
compounds that employ oxygen as the terminal oxidant. Mild
reaction conditions in the homocoupling of nitroalkanes lead to
good functional group tolerance.
ASSOCIATED CONTENT
* Supporting Information
■
S
(4) One example of dimerizing nitroethane by employing oxygen as a
terminal oxidant has been reported: (a) Clark, J. H.; Cork, D. G.;
Gibbs, H. W. J. Chem. Soc., Perkin Trans. 1 1983, 2253. (b) Ballini, R.;
Bosica, G.; Fiorini, D.; Petrini, M. Tetrahedron Lett. 2002, 43, 5233.
(5) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed.
1998, 37, 2580.
Text, figures, and tables giving experimental details, data, and
spectra for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: olafs@uh.edu.
■
(6) Ono, N. The Nitro Group in Organic Synthesis; Wiley: New York,
2001.
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(9) Please see the Supporting Information for optimization data.
(10) An increase of CuCl2 loading increases the dimerization product
yield; however, the effect becomes smaller with higher Cu(II) loading.
Please see the Supporting Information for details.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Welch Foundation (Grant No. E-1571), the
NIGMS (Grant No. R01GM077635), the Norman Hackerman
Advanced Research Program, and the Camille and Henry
Dreyfus Foundation for supporting this research.
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dx.doi.org/10.1021/om300393m | Organometallics XXXX, XXX, XXX−XXX