Regioselective cleavage of unstrained C-C bond and C-H bond: Palladium-copper catalyzed deacetophenonylative arylation of coumarin derivatives

Article abstract of DOI:10.1002/adsc.201200539

A C_α-C_β bond activation of the carbonyl group in unstrained ketones catalyzed cooperatively by palladium and copper(II) with the departure of the acetophenone has been developed, and the subsequent coupling with a variety of aromatics via the formal C-H activation similar to the Friedel-Crafts reaction affords the skeleton-reconstructed coumarin derivatives with high regioselectivity.

Full text of DOI:10.1002/adsc.201200539

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DOI: 10.1002/adsc.201200539
À
À
Regioselective Cleavage of Unstrained C C Bond and C H
Bond: Palladium–Copper Catalyzed Deacetophenonylative
Arylation of Coumarin Derivatives
Manman Sun,a Guodong Shen,a and Weiliang Baoa,*
a
Department of Chemistry, Zhejiang University (Xixi Campus), Hangzhou 310028, Peopleꢀs Republic of China
Fax : (+86)-571-8827-3814; phone: (+86)-571-8827-3814; e-mail: wlbao@css.zju.edu.cn
Received: June 19, 2012; Revised: October 10, 2012; Published online: November 28, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200539.
À
Abstract: A Ca Cb bond activation of the carbonyl
group in unstrained ketones catalyzed cooperatively
by palladium and copper(II) with the departure of
the acetophenone has been developed, and the sub-
sequent coupling with a variety of aromatics via the
formal C H activation similar to the Friedel–Crafts
reaction affords the skeleton-reconstructed coumar-
in derivatives with high regioselectivity.
activate electrophilic centers, may play a key role in
the activation of the C C bond, and the addition of
À
Lewis acids may further induce the potential of transi-
tion metal catalysis[2a,5d,13] (Scheme 1).
À
À
Keywords: C C bond cleavage; copper; coumarins;
palladium
À
Scheme 1. Activation of the Ca Cb bond of the carbonyl
group catalyzed by a transition metal and an LA coopera-
tively.
Coumarin derivatives are of great importance be-
À
The selective C H activation approach, due to its sus- cause of their physiological, photodynamic, anticoagu-
tainable and environmentally benign features, has re- lant, spasmolytic, bacteriostatic, antibiotic, antifungal
ceived substantial attention and success.[1] Selective and rodenticidal activities,[14] for example, warfarin A
catalytic activation of the inert carbon-carbon bond, and the warfarin derivative B used as antithrombotic
owing to its fundamental scientific interest and syn- drugs (Figure 1). Some hydroxycoumarin derivatives
thetic importance, has also received the increasing at- have been reported to possess biological activities
tention of chemists, while it remains an ongoing chal- similar to those of R-glucosidase inhibitors.[15] Addi-
[2]
À
lenge due to the inherent strength of the C C bond.
tionally, chromenes are very common in nature, and
Of the systems developed thus far, two approaches of some chromene skeletons have also elicited pharma-
[3]
À
C C single bond cleavage are oxidative addition
and b-carbon elimination,[4] and most of them have
benefitted from special driving forces, such as the ring
strain,[5] the chelation[6] and the departure of small
ceutical interest as structural elements in drug-like
molecules.[7] The heterolysis of the Ca CC bond in
À
=
O
strained ketones[8] and unstrained ketones with a che-
lating group[9] or without[10] is known to be reasona-
À
ble. On the other hand, the cleavage of the Ca Cb
bond in unstrained ketones is considered to be extra-
À
ordinarily difficult, and only a handful of similar Ca
Cb bond fractures was achieved by hydrogenolysis.[11]
To the best of our knowledge, no example of the frag-
À
mentation of the Ca Cb bond via transition metal cat-
alysis to cleave acetophenone has been reported, al-
though photolysis with cleavage of acetophenone was
known[12]. The Lewis acids (LA), that are assumed to Figure 1. The active coumarin and chromene derivatives.
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Regioselective Cleavage of Unstrained C C Bond and C H Bond
Scheme 2. A new coumarin derivative was obtained.
compounds,[16] such as the 6,7-dimethoxy-4H-chro- Table 1. Optimization of the reaction conditions.[a]
mene C isolated from the plant Wisteria sinensis and
the 2H-chromene derivative D which exhibits the
highest 5-HT1A receptor affinity (Figure 1). Therefore,
it is interesting to prepare and evolve the chromene-
fused coumarin compounds.
Entry
Catalyst
LA
Cu(OTf)2
T [oC]
Yield [%][b]
In the course of our study on modifying the struc-
tures of coumarin derivatives, we accidentally discov-
1
2
–
–
–
–
G
140
140
140
140
140
140
140
140
120
150
27
0
0
25
52
63
53
48
19
59
Cu(OAc)2
FeCl3
Cu(OTf)2
(OTf)2
(OTf)2
(OTf)2
(OTf)2
(OTf)2
(OTf)2
ACHTUNGTRENNUNG
3
À
ered an interesting fragmentation of the Ca Cb bond
4[c]
5
T
near the carbonyl group promoted by a catalytic
system comprised of a transition metal and a Lewis
Pd
PdCl2
Pd(dppf)Cl2
Ru(cod)2Cl2
A
Cu
Cu
Cu
Cu
Cu
Cu
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
6
7
8
9
acid.
ethyl)chromeno
xylene (2a) in the presence of CuAHCNUTGTRENNUNG
After
treatment
[4,3-b]chromen-6(7H)-one (1a) in p-
(OTf)2 as catalyst at
of
7-(2-oxo-2-phenyl-
N
N
ACHTUNGTRENNUNG
U
PdCl2
PdCl2
1408C for 16 h, to our surprise, a new coumarin deriv-
ative (3a) was isolated in 27% yield. After the struc-
ture had been characterized, it was realized that the
10
[a]
Reaction
conditions:
catalyst
(0.01 mmol),
LA
(0.02 mmol) and substrate 1a (0.2 mmol) in p-xylene
(2.0 mL) for 16 h.
Yield of isolated product.
À
Ca Cb bond near the carbonyl group was cut and
a new C C bond with p-xylene was formed as shown
À
[b]
[c]
À
in Scheme 2. There have been few reports on new C
C bond formation via C H activation after C C bond
Stoichiometric CuACHTNUGTRENUNG(OTf)2 was used.
À
À
À
cleavage, but most were limited to C X bond activa-
tion[10,17]
.
With the optimal conditions in hand, a series of
Then various reaction conditions were studied to coumarin derivatives and different aromatics were
À
help to understand the details of the reaction subjected to this C C cleavage and coupling reaction
(Table 1). Firstly, different Lewis acids were used to (Table 2). Firstly, a variety of aromatics was exam-
promote the reaction, however, no product was de- ined. Obviously the reaction depends mainly on the
tected, no matter whether a weak salt like Cu
or a strong Lewis acid like FeCl3 was used (Table 1, density such as 2a, 2b, 2d, 2f, 2h and 2i, reacted well
entries 2 and3). When stoichiometric Cu(OTf)2 was (Table 2, entries 1, 2, 4, 6, 8–10); with low electron
ACHTUNGRTEN(NNUG OAc)2 electronic effects, and aromatics with high electron
AHCTUNGTRENNUNG
used, the yield changed slightly (Table 1, entry 4). density such as 2c, 2e and 2g, did not work so well
Then several transition metal catalysts such as (Table 2, entries 3, 5 and 7). However, chlorobenzene
PdACHTUNGTRENNUNG(OAc)2, PdCl2, PdACHTUNRTEGN(GNUN dppf)Cl2 and RuACHTNUGTREN(NUGN cod)2Cl2 were and N,N-dimethylaniline both failed to furnish the
employed. Excitingly, the yields were greatly im- corresponding products, maybe the chlorobenzene
proved, ranging from 48% to 63%, and PdCl2 gave was not active enough and the N,N-dimethylaniline
the best result (Table 1, entries 5–8). Further screen- reacted with itself[18] (Table 2, entries 11 and 12). The
ing showed that the optimized reaction conditions molecular structure of 3i was unambiguously elucidat-
were to carry out the reaction at 1408C using both ed by X-ray crystallography (Figure 2). Interestingly,
PdCl2 and Cu
may play a key role. Generally, the C C bond cleav- single product 3g or 3h could be obtained in moderate
age by the way of oxidative addition is often promot- yield by controlling the amount of Cu(OTf)2 and the
ed by rhodium complexes, whereas catalysis by palla- temperature (Table 2, entries 8 and 9). Then various
ACHTUNGTRENNUNG(OTf)2 as catalysts, in which the PdCl2 when 1a reacted with the substrate 2h, the unexpected
À
AHCTUNGTRENNUNG
dium complexes is rare[5e]
.
coumarin derivatives with functional groups such as
CH3 (R1), OMe, C6H5 (R2) and CH3, Cl (R3) were ex-
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Manman Sun et al.
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amined and moderate yields were obtained (Table 2, cleaved product 5a and acetophenone in 34% yield
entries 13–18). together with the recovered substrates (reaction i,
However, when benzene (2l) was heated with 1a in Scheme 3). On the other hand 5a could couple with
a sealed tube, the reaction only gave the simple diphenyl ether to give corresponding product 3f in
[a]
À
À
Table 2. Synthesis of coumarin derivatives by C C bond and C H bond activation.
Entry
1
1
2
3
Yield [%][b]
1a
2a
2b
3a
3b
63
2
70
45
80
3[c]
2c
3c
4
2d
3d
5
2e
3e
30
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Regioselective Cleavage of Unstrained C C Bond and C H Bond
Table 2. (Continued)
Entry
1
2
3
Yield [%][b]
6
2f
3f
85
7
8
2g
2h
3g
3g
38
65
9[d]
2h
2i
3h
3i
55
81
10
11
12
2j
–
–
–
–
2k
13
1b
2a
3a
51
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Manman Sun et al.
Yield [%][b]
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Table 2. (Continued)
Entry
1
2
3
14
1c
2a
3a
42
15
16
1d
1e
2b
2b
3j
65
76
3k
17
1f
2a
3l
61
18
1f
2b
3m
64
[a]
Reaction conditions: PdCl2 (0.01 mmol), Cu
1408C for 16 h.
Yield of isolated product.
ACHTUNGRTEN(NUGN OTf)2 (0.02 mmol) and substrate 1 (0.2 mmol) in 2 (2.0 mL or 10 mmol) at
[b]
[c]
[d]
Cu
Cu
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
91% yield (reaction ii, Scheme 3). According to all
Then with the assistant of CuACTHUNGTERNNU(G OTf)2, the oxidative
the above results, a plausible mechanism was pro- addition of Pd(0) formed the Pd-coordinated cation
posed as shown in Scheme 4. Firstly, Pd(0) and intermediate B based on the five-membered ring
CuACHTUNGTRENNUNG
(OTf)2 were coordinated with the carbonyl groups, structure theory[19] via the cleavage of the acetophen-
respectively.
ACHTUNGTRENoNGNU ne part. Only aromatics with high electron density
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Adv. Synth. Catal. 2012, 354, 3468 – 3474

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Regioselective Cleavage of Unstrained C C Bond and C H Bond
Figure 2. Molecular structure of 3i.
can coordinate to [Pd], and the reductive elimination
of the intermediates C produced the products 3a and
4a, and regenerated the Pd(0) and the CuACTHNURGTNEUNG(OTf)2. As
for the mechanism of 5a with diphenyl ether
(Scheme 4), it is a little bit different from the above,
and this may be the reason why the yields were great-
ly improved when Pd catalysts were used.
À
In summary, we have developed a Ca Cb bond acti-
vation of the unstrained carbonyl group catalyzed co-
operatively by palladium and copper(II) with the de-
parture of acetophenone. The formed Pd-coordinated
À
cation intermediate undergoes the new C C bond for-
mation with a variety of aromatics via the formal C
À
H activation similar to the Friedel–Crafts reaction to
obtain the skeleton-reconstructed coumarin deriva-
tives in moderate to excellent yields with high regio-
selectivity, which might be potentially applicable in
Scheme 4. Plausible mechanisms.
the pharmaceutical and biochemical areas. This sp3- become a general way and may be useful in organic
3
À
sp C C bond cleavage method may be developed to synthesis.
Scheme 3. Simple cleavage of the substrate.
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Manman Sun et al.
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Experimental Section
General Procedure
An oven-dried Schlenk tube equipped with a Teflon valve
was charged with a magnetic stir bar, PdCl2 (0.01 mmol),
CuACHTUNGTRENNUNG(OTf)2 (0.02 mmol), substrates 1 (0.2 mmol), 2 (2.0 mL or
10 mmol). The reaction vessel was sealed and the mixture
stirred at 1408C for 16 h. The reaction was monitored by
TLC. After the starting material had been consumed com-
pletely, the resulting suspension was cooled to room temper-
ature and filtered through a pad of filter paper with the help
of 50 mL of ethyl acetate. After evaporating the solvent
under reduced pressure, the residue was purified by column
chromatography on silica gel to give the pure product
(AcOEt/petroleum ether v/v=1/10). For more details, see
the Supporting Information.
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CCDC 905151 contains the supplementary crystallograph-
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Acknowledgements
This work is financially supported by the Natural Science
Foundation of China (No. 21072168).
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