DDQ-mediated direct cross-dehydrogenative-coupling (CDC) between benzyl ethers and simple ketones

Article abstract of DOI:10.1021/ja060050p

A direct Cross-Dehydrogenative-Coupling (CDC) between benzyl ethers and simple ketones was developed without using any metal catalyst. By using DDQ, various benzyl ethers and simples ketones were coupled together directly to form β-alkoxyl ketones efficie

Full text of DOI:10.1021/ja060050p

Published on Web 03/14/2006
DDQ-Mediated Direct Cross-Dehydrogenative-Coupling (CDC) between Benzyl
Ethers and Simple Ketones
Yuhua Zhang† and Chao-Jun Li*,†,‡
Department of Chemistry, Tulane UniVersity, New Orleans, Louisiana 70118, and Department of Chemistry,
McGill UniVersity, 801 Sherbrooke Street West, Montreal, Quebec H3A 2K6, Canada
Received January 3, 2006; E-mail: cj.li@mcgill.ca
The development of various transition-metal-catalyzed coupling
reactions has greatly advanced state-of-art synthetic methodologies.1
Figure 1. CDC reaction for the formation of C-C bonds.
Scheme 1. CDC Reaction of Ethers with Ketones
On the other hand, there has been enormous interest in developing
metal-free coupling reactions.2 Among the various “newer” synthetic
methodologies, the direct formations of C-C bonds from C-H
bonds have attracted great attention recently.3 Such synthetic meth-
odologies will provide the intrinsic adVantages such as higher atom-
economy, shorter synthetic routes, and requiring more economical
feedstock, which leads to “benign by design” (Green Chemistry).4
Toward the utilization of C-H bonds for forming C-C bonds,
recently, we and others have developed various Cross-Dehydrogena-
tive-Coupling (CDC) reactions for forming new C-C bonds by
utilizing two different C-H bonds (Figure 1).5 In these cases, one
or two metal catalysts are used together with an oxidizing reagent
that can serve as a hydrogen acceptor. Despite the great advantages
of these reactions, there are still certain limitations: (1) one or two
metal catalysts are still required for the reaction (metal catalysts are
sometimes undesirable); (2) less reactive nucleophiles, such as sim-
ple ketones, cannot react under these conditions. To overcome these
limitations, herein we report a highly efficient CDC reaction between
benzyl ethers and simple ketones mediated by 2,3-dichloro-5,6-dicyan-
obenzoquinone (DDQ) without using any metal catalyst (Scheme 1).
To begin this study, we chose isochroman (1a) and acetophenone
(1b) as the standard substrates to search for potential catalysts and
suitable reaction conditions (Table 1). DDQ is a well-known oxidant
in organic chemistry.6 For many years, it has been used for the
oxidation of allylic alcohol7 and allylic ethers8 to R,â-unsaturated
carbonyl compounds. Recently, we reported a In(III)-Cu(II)-cata-
lyzed reaction of bis-activated methylene compounds with benzyl
ethers in methylene chloride, toluene, or acetonitrile.9 However,
simple ketones are unreactive under those conditions. In our initial
experiment, using the ion liquid [BMIM]PF6 as a solvent, the de-
sired product 1c was obtained in about 5% yield at room temper-
ature (rt) in the presence of InCl3 and Cu(OTf)2 as catalysts. After
extensive unsuccessful optimizations, it was found that the desired
product could be generated in low yield under neat conditions at
50 °C (no reaction was observed at rt, entry 2) in the absence of any
metal catalyst (entry 3). Various solvents were tested. No desired
product was detected when CH2Cl2, 1,4-dioxane, or DMSO were
used as solvents (entries 4, 5, and 6). The reaction could proceed
in toluene, MeNO2, H2O, DCE, THF, hexane, and MeCN with
varied efficiency (entries 7-13). Subsequent investigations revealed
that the desired product could be obtained in 76% yield without
using any solvent at 100 °C (entry 14). Further increase in the
reaction temperature (entry 15) resulted in a slight decrease in yield.
Switching the ratio of ether/ketone diminished the yield (entry 16).
Both increase and decrease the amount of DDQ reduced the yield
(entries 17 and 18). No product was detected without DDQ.
Table 1. CDC Reaction of Isochroman with Acetophenonea
ether/ketone/DDQ
(mmol)
temp
C)
yield
(%)c
entry
solventb
(
°
1d
2e
3
0.2/0.4/0.24
0.2/0.4/0.24
0.2/0.4/0.24
0.2/0.4/0.24
0.2/0.4/0.24
0.2/0.4/0.24
0.2/0.4/0.24
0.2/0.4/0.24
0.2/0.4/0.24
0.2/0.4/0.24
0.2/0.4/0.24
0.2/0.4/0.24
0.2/0.4/0.24
0.2/0.4/0.24
0.2/0.4/0.24
0.4/0.2/0.24
0.2/0.4/0.2
[BMIM]PF6
neat
neat
CH2Cl2
1,4-dioxane
DMSO
PhMe
MeNO2
H2O
DCE
THF
hexane
MeCN
neat
rt
rt
50
reflux
reflux
100
reflux
reflux
reflux
reflux
reflux
reflux
reflux
100
5
ndf
10
ndf
ndf
ndf
40
60
45
38
10
10
35
76
71
37
66
62
4
5
6g
7
8
9
10
11
12
13
14
15
16h
17
18
neat
neat
neat
neat
125
100
100
100
0.2/0.4/0.3
a Reaction time: 2 h. b Solvent (0.5 mL) was used. c 1H NMR yields
using an internal standard. d Reaction time: overnight, InCl3/Cu(OTf)2 as
catalyst. e Reaction time: overnight. f Not detected by 1H NMR. g Isoch-
roman (60%) remained after the reaction. h Yield was based on ketone.
Thus, under the optimized neat conditions, various ketones were
reacted with isochroman, 3-methylisochroman, and benzyl methyl
ether, and the corresponding results are listed in Table 2. Both
aliphatic and aromatic ketones are effective for the current reaction.
Benzyl ether is found to be less reactive than isochroman (compare
entries 2, 10, 14, and 15). There is little difference in the reactivity
between aliphatic ketones and aromatic ketones (compare entries
1-6, 10, and 11). When unsymmetrical 2-pentanone was reacted
with isochroman (Scheme 2), a 1:1.5 mixture of the coupling
products was obtained with the major isomer corresponding to the
coupling at the more substituted carbon.
A tentative mechanism for the coupling is proposed in Scheme
3. A single electron transfer from the benzyl ether to DDQ generates a
radical cation and a DDQ radical anion. The radical oxygen of the
DDQ radical anion then abstracts a H-atom from the radical cation
† Department of Chemistry, Tulane University, New Orleans, Louisiana 70118.
‡ Department of Chemistry, McGill University, Quebec H3A 2K6, Canada.
9
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J. AM. CHEM. SOC. 2006, 128, 4242-4243
10.1021/ja060050p CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. CDC Reaction of Isochroman with 2-pentanone
Table 2. CDC Reaction of Benzyl Ethers with Ketonesa
Scheme 3. Tentative Mechanism for the CDC Reaction of Benzyl
Ethers with Ketones Mediated by DDQ
by using DDQ as a dehydrogenating reagent and an organomediator.
The new method has several advantages: (1) simple benzyl ethers
and ketones can be used directly; (2) no metal is needed for the
reaction; (3) no additional reagent is required. The scope, mecha-
nism, and application of this method are under investigation.
Acknowledgment. We are grateful to Canada Research Chair
(Tier I) foundation (to C.J.L.) and the NSF-EPA joint program for a
Sustainable Environment for support of our research. Y.Z. thanks Mc-
Gill University for the hospitality during the aftermath of Hurricane
Katrina.
Supporting Information Available: Representative experimental
procedure and characterization of all new compounds (PDF). This
material is available free of charge via the Internet at http:/pubs.acs.org.
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