Copper-catalyzed oxidative coupling of benzylic C-H bonds with 1,3-dicarbonyl compounds

Article abstract of DOI:10.1021/jo801322p

(Chemical Equation Presented) A copper-catalyzed oxidative coupling of benzylic C-H bonds with 1,3-dicarbonyl compounds is described. The reaction utilizes an inexpensive copper catalyst-oxidant system that is suitable for the coupling of a range of benzylic C-H bonds with various 1,3-dicarbonyl compounds. Kinetic isotope studies support a mechanism involving a benzylic hydrogen abstraction.

Full text of DOI:10.1021/jo801322p

SCHEME 1. Direct Oxidative Couplinga
Copper-Catalyzed Oxidative Coupling of Benzylic
C-H Bonds with 1,3-Dicarbonyl Compounds
Nadine Borduas and David A. Powell*
Merck Frosst Centre for Therapeutic Research, 16711 Trans
Canada Highway, Kirkland, Que´bec H9H 3L1, Canada
a Issues: C-H bond selectivity, further oxidation of products.
lished for the oxidative coupling of sp3 C-H bonds require
carbene precursors,4 directing groups,5 and stoichiometric metal
reagents6 or remain limited to R-heteroatomic hydrocarbons.7-9
We were intrigued by the possibility of directly functional-
izing a benzylic C-H bond with concomitant formation of a
new C-C bond (Scheme 1). Realization of such a methodology
would require overcoming the various issues of C-H bond
selectivity and minimizing further functionalization of the
coupling product 1 via competing oxidation (e.g., 2). Our
experience in the copper-catalyzed amidation of allylic and
benzylic C-H bonds established an initial starting point in
where to begin our investigations.10 Recently, Li has reported
a conceptually similar, iron-catalyzed, selective C-C bond
formation by oxidative activation of benzylic C-H bonds.11
Herein we describe our own efforts and proof of principle that
a copper catalyst can effect the selective oxidative functional-
daVid_powell2@merck.com
ReceiVed June 19, 2008
A copper-catalyzed oxidative coupling of benzylic C-H
bonds with 1,3-dicarbonyl compounds is described. The
reaction utilizes an inexpensive copper catalyst-oxidant
system that is suitable for the coupling of a range of benzylic
C-H bonds with various 1,3-dicarbonyl compounds. Kinetic
isotope studies support a mechanism involving a benzylic
hydrogen abstraction.
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The direct functionalization of carbon-hydrogen bonds to
carbon-carbon bonds remains an arduous challenge com-
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and susceptibility toward overoxidation.1 Achieving selectivity
among a range of C-H bonds, including sp3 and sp2 hybridized
C-H bonds, is of particular significance. While new metal
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has been made within the realm of sp3 C-H bond functional-
ization. Despite notable progress,3 most methodologies estab-
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56–57. (d) Shi, L.; Tu, Y.-Q.; Wang, M.; Zhang, F.-M.; Fan, C.-A.; Zhao, Y.-
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7822 J. Org. Chem. 2008, 73, 7822–7825
10.1021/jo801322p CCC: $40.75 2008 American Chemical Society
Published on Web 09/04/2008

TABLE 1. Exploration of Reaction Parameters on the Oxidative
Coupling of Ethylbenzene with Diphenylpropane-1,3-dione
TABLE 2. Copper-Catalyzed Oxidative Coupling of Benzylic
Hydrocarbons with 1,3-Dicarbonyl Compounds
yield (%)a
reaction conditions
entry
(catalyst, ligand, oxidant, solvent)
1a
3
1
2
3
no catalyst, ligand 4, t-BuOOBz, neat
Cu(ClO4)2, ligand 4, t-BuOOBz, neat
Cu(ClO4)2, ligand 4, t-BuOOBz,
1,2-dichloroethane
Cu(ClO4)2, no ligand, t-BuOOBz,
hexafluoroisopropanol
Cu(ClO4)2, ligand 4, t-BuOOBz, neat
Cu(OTf)2, ligand 4, t-BuOOBz, neat
Cu(ClO4)2, no ligand, t-BuOOBz, neat
Cu(ClO4)2, ligand 4, t-BuOOH, neat
Cu(ClO4)2, ligand 4, t-BuOOBz, neat
<5
47
37
<5
22
<5
4
<5
40b
5c
6c
7c
8c
71
61
57
<5
52
6
<5
<5
<5
<5
c d
,
9
a Yield determined by 1H NMR analysis of the unpurified reaction
mixture versus an internal standard. Average of two runs. b Isolated
yield; 10 mol % copper catalyst was used. c Diphenylpropane-1,3-dione
was added after 6 h. d 2.5 equiv of ethylbenzene was used.
ization of benzylic C-H bonds, leading to the generation of a
new carbon-carbon bond with a 1,3-dicarbonyl compound.
Our initial explorations focused on the oxidative coupling of
ethylbenzene with diphenylpropane-1,3-dione (Table 1). Inves-
tigations on a variety of reaction conditions established that in
the presence of copper(II) perchlorate, ligand 4, and tert-
butylperoxybenzoate (t-BuOOBz) oxidant at 60 °C, the desired
coupling product 1a could be obtained in 47% yield (entry 2).
Despite our efforts, initial attempts to further improve the yield
of 1a were thwarted by the increased production of side product
3. Interestingly, methylation product 3 could be formed pre-
dominately through the judicious choice of solvent (entry 4).
We reasoned that competitive methyl transfer from the tert-
butylperoxybenzoate oxidant to the 1,3-dicarbonyl reaction
partner was contributing to the formation of 3 at the expense
of the desired product 1a.12 It should be noted that a related
palladium-catalyzed methylation of aryl C-H bonds using tert-
butylperoxides as the methylating agent has recently been
disclosed.13 Fortunately, by adding the dicarbonyl component
to the preheated reaction mixture after a period of 6 h, formation
of the methylated product 3 could be suppressed, and reasonable
yields of oxidative coupling product 1a were obtained (entry
5). Overall, we found this procedure to be more convenient and
equally effective, compared to the use of a syringe pump.
Copper(II) triflate (entry 6) was less effective than copper(II)
perchlorate, and other copper salts such as CuCl2 or Cu(OAc)2
gave <5% yield of the desired coupling product. Slightly lower
yields were obtained in the absence of ligand 4 (entry 7), which
we suspect plays a role in increasing the solubility of the copper
catalyst. In general, bidentate nitrogen-based ligands proved to
be superior to other types of ligands, including phosphine
ligands. Other oxidants were ineffective (entry 8),14 while
reduced quantities of the hydrocarbon component led to lower
yields (entry 9). In contrast to other oxidative coupling
a Isolated yield. b Reaction was conducted at room temperature for 5
days.
methodologies,6c no significant quantities of the phenethylidene
compound 2, resulting from further oxidation of 1a, was
detected.
Having established reaction conditions suitable for the
oxidative coupling of ethylbenzene with diphenylpropane-1,3-
dione, we proceeded to investigate the range of 1,3-dicarbonyl
and benzylic hydrocarbon coupling partners that could be
employed (Table 2).
A variety of diketone substrates of varying electronic proper-
ties underwent oxidative coupling under our copper-catalyzed
reaction protocol (entries 1-3, 8-10). In addition to ethylben-
zene and derivatives, diphenylmethane (entries 4, 9, and 10),
indane (entry 5) and allylbenzene (entry 6) are also capable
hydrocarbon reaction components, with the latter substrate
yielding the less sterically hindered terminal phenylpropenyl
product. Attempts to utilize toluene as a hydrocarbon component
have been unsuccessful to date, resulting in the formation of
products in low yields (<20%). Aryl halides (entries 2 and 7),
(14) Significantly lower yields were observed with other oxidants including
CAN and PhI(OAc)2. Use of tert-butylperoxyacetate gave slightly lower yields
than tert-butylperoxybenzoate.
(12) See Supporting Information for details.
(13) Zhang, Y.; Feng, J.; Li, C.-J. J. Am. Chem. Soc. 2008, 130, 2900–2901.
J. Org. Chem. Vol. 73, No. 19, 2008 7823

including arylbromides, are suitable reaction partners, allowing
for further functionalization through a cross-coupling manifold.
Finally, a heterocycle-containing dicarbonyl compound could
also be employed in the oxidative coupling reaction (entry 10).
This methodology compliments the iron-catalyzed oxidative
coupling of Li,11a allowing for the coupling of the more
challenging ethylbenzene derivatives and overall reducing the
hydrocarbon stoichiometry required.
Based on the copper-catalyzed amidation protocol10a and the
well-established Kharasch-Sosnovsky reaction,15 we propose
a mechanism that involves initial formation of a benzylic radical
A (Figure 1) followed by reaction with the copper(II) species
to generate a phenylalkyl benzoate B. Conversion to 1 may
proceed through a Lewis or Brønsted acid catalyzed nucleophilic
displacement of the benzylic benzoate intermediate B with the
1,3-dicarbonyl nucleophile,16 although alternative mechanisms
cannot be ruled out at this time. Of note, significant quantities
of 1-phenylethyl benzoate B (R1 ) CH3) were observed in the
initial stages of the reaction as determined by 1H NMR analysis
of the unpurified reaction mixture.
FIGURE 1. Proposed mechanistic pathway for the copper-catalyzed
oxidative coupling reaction.
Phenylethyl benzoate B (R1 ) CH3) was synthesized inde-
pendently and demonstrated to be a competent reagent, leading
to the formation of 1a under the copper-catalyzed conditions
(eq 1).12
dicarbonyl compounds, and yields no significant quantities of
over oxidized products.
To provide further insight into the mechanism, a competitive
kinetic isotope experiment was conducted using an excess of a
1:1 mixture of ethylbenzene and d2-ethylbenzene (eq 2). A
kinetic isotope effect of 1.6 was observed (based on the ratio
of remaining starting material), consistent with a mechanism
involving a benzylic hydrogen abstraction.17
Experimental Section
Representative Procedure for the Copper-Catalyzed Oxida-
tive Coupling of Benzylic C-H bonds with 1,3-Dicarbonyl
Compounds. Preparation of 1,3-Diphenyl-2-(1-phenylethyl)pro-
pane-1,3-dione (1a). [CAUTION: Care should be taken when
heating a metal with a peroxide. use of a pressure flask with a
blast shield in a well-Ventilated fumehood is recommended.
HoweVer, no issues were reported by the authors during the
course of these experiments.] Into a 15 mL sealable pressure
flask equipped with a magnetic stir bar and under nitrogen was
weighed copper(II) perchlorate (158 mg, 0.60 mmol, 20 mol%)
and bathophenanthroline (50 mg, 0.15 mmol, 5 mol%). The
solids were suspended in ethylbenzene (1.84 mL, 15.0 mmol, 5
equiv), and tert-butylperoxybenzoate (1.68 mL, 9.0 mmol, 3
equiv) was added dropwise over 5 min. The vial was sealed,
stirred at room temperature for 5 min, and then heated to 60 °C
in an oil bath for 6 h. After this time, the vial was removed
from the oil bath and cooled to room temperature, and 1,3-
diphenylpropane-1,3-dione (673 mg, 3.0 mmol, 1.0 equiv) was
added. The vial was resealed and heated at 60 °C for an
additional 22 h. The resulting mixture was cooled to room
temperature and poured into a 125 mL separatory funnel
containing aqueous sodium carbonate (75 mL), and the mixture
was extracted with ethyl acetate (3 × 30 mL). The combined
organic layers were washed with brine (30 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure.
Purification by column chromatography through silica gel, eluting
with a gradient of 100% hexanes to 10% ethyl acetate in hexanes,
afforded the desired product 1a as a white solid (651 mg, 66%
In summary, we have developed a copper-catalyzed oxidative
functionalization of benzylic C-H bonds with 1,3-dicarbonyl
compounds that results in the formation of a new C-C bond.
The reaction utilizes an inexpensive copper catalyst-oxidant
system18 in the absence of added solvent, is suitable for the
coupling of a range of benzylic C-H bonds with various 1,3-
1
yield). Mp 126-127 °C; H NMR (400 MHz, CDCl3) δ 8.06
(2H, d, J ) 7.5 Hz), 7.76 (2H, d, J ) 7.5 Hz), 7.59 (1H, t, J )
7.5 Hz), 7.49-7.43 (3H, m), 7.32-7.28 (4H, m), 7.20 (2H, t, J
) 7.5 Hz), 7.10 (1H, t, J ) 7.5 Hz), 5.63 (1H, d, J ) 10.0 Hz),
4.10 (1H, dq, J ) 10.0, 7.0 Hz), 1.37 (3H, d, J ) 7.0 Hz); 13C
NMR (100 MHz, CDCl3) δ 195.0, 194.6, 143.8, 137.2, 136.9,
133.6, 133.0, 128.9, 128.8, 128.52, 128.46, 128.42, 127.8, 126.6,
64.9, 41.2, 20.2; IR (KBr) ν 1694, 1595, 1447, 1267, 1197, 972,
756 cm-1; HRMS (ESI+) m/z calcd for C23H21O2 [M + H]+
329.1536, found 329.1529.
(15) (a) Andrus, M. B.; Lashley, J. C. Tetrahedron 2002, 58, 845–866. (b)
Eames, J.; Watkinson, M. Angew. Chem., Int. Ed. 2001, 40, 3567–3571. (c)
Kharasch, M. S.; Sosnovsky, G. J. Am. Chem. Soc. 1958, 80, 756.
(16) (a) Noji, M.; Konno, Y.; Ishii, K. J. Org. Chem. 2007, 72, 5161–5167.
´
(b) Sanz, R.; Mart´ınez, A.; Miguel, D.; Alvarez-Gutie´rrez, J. M.; Rodr´ıguez, F.
AdV. Synth. Catal. 2006, 348, 1841–1845.
(17) Kinetic deuterium isotope effects of 2.9 and 4.3 have previously been
observed for the copper-catalyzed reaction of tert-butylperoxyesters with
allylbenzene. The lower value observed here with ethylbenzene may be a result
of a more linear H-transfer process, or an early transition state; see: (a) Denney,
D. B.; Denney, D. Z.; Feig, G. Tetrahedron Lett. 1959, 15, 19–23. (b) Kwart,
H.; Benko, D. A.; Bromberg, M. E. J. Am. Chem. Soc. 1978, 100, 7093–7094.
(c) Kwart, H. Acc. Chem. Res. 1982, 15, 401–408. (d) Lykakis, I. N.;
Orfanopoulos, M. Tetrahedron Lett. 2005, 46, 7835–7839.
(18) Copper(II) perchlorate hexahydrate: $0.33 per gram (Aldrich). tert-
Butylperoxybenzoate: $0.13 per gram (Aldrich).
7824 J. Org. Chem. Vol. 73, No. 19, 2008

Acknowledgment. We thank Wayne Mullet for analytical
assistance with the GCMS, Geoffrey Tranmer for assistance with
the vacuum apparatus, Merck Frosst for providing financial
support to N.B. during her undergraduate work term, and
colleagues for helpful discussions, in particular Austin Chen,
Jason Burch, Ernest Lee, Rick Friesen and Robert DeVita.
Supporting Information Available: Experimental proce-
dures and compound characterization data for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO801322P
J. Org. Chem. Vol. 73, No. 19, 2008 7825