Catalytic asymmetric friedel-crafts reaction of activated phenols and 4-oxo-4-arylbutenoates

Article abstract of DOI:10.1002/adsc.201200341

A highly enantioselective Friedel-Crafts reaction of activated phenols with (E)-4-oxo-4-arylbutenoates has been developed with the N,N'-dioxide- scandium(III) complex as the catalyst. A variety of (E)-4-oxo-4-arylbutenoates were found to be suitable substrates for the reaction. The desired products were obtained in moderate to high yields (up to 98%) and excellent enantioselectivities (up to 97% ee). Copyright

Full text of DOI:10.1002/adsc.201200341

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DOI: 10.1002/adsc.201200341
Catalytic Asymmetric Friedel–Crafts Reaction of Activated
Phenols and 4-Oxo-4-arylbutenoates
Sha Bai,a Xiaohua Liu,a Zhen Wang,a Weidi Cao,a Lili Lin,a and Xiaoming Fenga,*
a
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University,
Chengdu 610064, Peopleꢀs Republic of China
Fax : (+86)-28-8541-8249; e-mail: xmfeng@scu.edu.cn
Received: April 21, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200341.
Abstract: A highly enantioselective Friedel–Crafts
reaction of activated phenols with (E)-4-oxo-4-aryl-
butenoates has been developed with the N,N’-diox-
has been conducted in applying a chiral metal com-
plex in the Friedel–Crafts reaction of phenols. Herein,
we describe a readily available chiral N,N’-dioxide-
ide-scandium
G
ScACTHNGUTREN(NUG OTf)3 complex for the catalytic asymmetric Frie-
of (E)-4-oxo-4-arylbutenoates were found to be
suitable substrates for the reaction. The desired
products were obtained in moderate to high yields
(up to 98%) and excellent enantioselectivities (up
to 97% ee).
del–Crafts alkylation of phenol derivatives with (E)-
4-oxo-4-arylbutenoates as option to address this issue.
In our previous study, the highly enantioselective
Friedel–Crafts alkylation of indoles and pyrroles with
a,b-unsaturated ketone derivatives could be achieved
under chiral N,N’-dioxide-metal complex catalysis, as
well as other types of asymmetric transformations.[5]
Therefore, we initially investigated the reaction of
3,4-dimethoxyphenol (2a) with (E)-ethyl 4-oxo-4-phe-
nylbutenoates (1a) promoted by metal complexes of
the chiral N,N’-dioxide ligand L1 derived from l-pro-
line (Table 1, entries 1–4). The combination of Mg-
Keywords: asymmetric catalysis; N,N’-dioxides;
Friedel–Crafts reaction; phenols; scandium
The Friedel–Crafts alkylation of aromatic and hetero-
ACHUTNGTERNG(NU OTf)2 and YACHTUNGTERN(NUGN OTf)3 with L1 gave racemic products in
À
aromatic compounds is an important C C bond form- poor yields (Table 1, entries 1 and 2). The use of L1-
ing process.[1] Over the past few years, several advan- Zn
(BF4)2·6H2O catalyst afforded the desired product
ces have been made in the asymmetric Friedel–Crafts 3a with 49% yield and 11% ee (Table 1, entry 3). Sc-
alkylation of active aromatics, such as indoles, pyr-
ACHTUNGRTEN(NUNG OTf)3 was found to be a suitable Lewis acid, provid-
roles, and naphthols.[2] Comparatively, the use of phe- ing the product 3a in 65% yield and 43% ee (Table 1,
nols as C-nucleophiles was less studied,[3] which is at- entry 4). Encouraged by this result, we explored com-
tributed to their relatively low reactivity. Based on plexes of other N,N’-dioxide ligands (Figure 1) with
the fact that the phenol unit occurs widespread in bio- ScACHTNUTRGNEUNG(OTf)3. When the amide moiety of the N,N’-dioxide
logically active natural products and pharmaceutically was replaced by aliphatic groups, the enantioselectivi-
useful molecules,[4] an expansion of the scope of phe- ty as well as the reactivity increased dramatically
nols in this kind of reaction is of interest. Recently, (Table 1, entries 4–6). With ligand L2 containing 1-
Nagasawa[3a] et al. reported the catalytic asymmetric adamantyl groups, 87% yield and 90% ee value were
Friedel–Crafts alkylation of sesamol with nitroolefins achieved (Table 1, entry 5). Interestingly, the product
using a bifunctional acyclic guanidine/bisthiourea or- 3a with the opposite configuration was obtained from
ganocatalyst with good results. Other organocatalysts the ligand L3 with 2,6-diisopropylphenyl groups in
were also used for the reaction of active phenol.[3b,c,d] moderate enantioselectivity (Table 1, entry 5 versus
Luo[3c] et al. employed binary-acid catalysis in the re- entry 6). Further optimization of the subunits of the
action of 2-methoxyphenol and b,g-unsaturated a- N,N’-dioxide ligand showed that, with regard to the
keto esters, in which the addition of MgF2 could im- chiral backbone moiety, the l-proline-derived N,N’-di-
prove the reactivity and enantioselectivity. However, oxide achieved higher enantioselectivity and reactivity
the strong interaction of the unprotected hydroxy than the (S)-pipecolic acid- and l-ramipril-derived
group of phenol with a metal center presents a diffi- ones (Table 1, entry 5 versus entries 9 and 10). Steric
culty in chiral Lewis acid catalysis. Limited research hindrance of the ligand played a key role in enhanc-
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Table 1. Optimization of the reaction conditions.[a]
Entry
Ligand
Metal
Mg(OTf)2
X [mol%]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L2
L2
L2
L8
G
5
5
5
5
5
5
5
5
5
5
5
5
1
5
14
27
49
65
87
57
62
60
77
45
92
95
54
88
0
0
Y
Zn
G
.
11 (R)
43 (R)
90 (R)
45 (S)
21 (R)
51 (R)
83 (R)
87 (R)
92 (R)
93 (R)
92 (R)
91 (S)
Sc
Sc
Sc
Sc
Sc
Sc
Sc
Sc
Sc
Sc
Sc
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
9
10
11[d]
12[d,e]
13[d,e]
14[d,e]
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
[a]
Unless otherwise noted, the reactions were performed with 1a (0.15 mmol), metal (0.005 mmol), N,N’-dioxide
(0.005 mmol) under nitrogen in CH2Cl2 (1.0 mL) at 308C for 30 min, then 2a (0.10 mmol) was added at 308C. The reac-
tion mixture was stirred at 308C for 36 h.
Isolated yield.
Determined by chiral HPLC analysis (Chiralcel OD-H).
[b]
[c]
[d]
[e]
Reaction was carried out with L2/Sc
ACHTUNGRTEN(NUNG OTf)3 (1.2/1).
The reaction was carried out in 0.3 mL CH2Cl2.
ing the reactivity and enantioselectivity, and the entry 13). In addition, the corresponding enantiomer
highly sterically demanding ligand L2 turned out to was easily obtained in good enantioselectivity and re-
be the best one. To our delight, when we changed the activity by using the complex N,N’-dioxide L8-
ratio of N,N’-dioxide L2 with Sc
increased the reaction concentration, both the yield Note that the process is air and moisture tolerant.
and the enantioselectivity were slightly increased Under the optimized conditions (Table 1, entry 12),
ACHUTNGTRNENUG(OTf)3 to 1.2:1, and ScACHTUNGTRENN(UGN OTf)3 derived from d-proline (Table 1, entry 14).
(95% yield, 93% ee; Table 1, entry 12). However, a variety of (E)-4-oxo-4-arylbutenoates 1 and substi-
when the catalyst loading was reduced from 5 to tuted phenols[6] 2 was investigated. First, the effect of
1 mol%, there was a dramatic decrease in yield, with the ester group of (E)-4-oxo-4-arylbutenoates was
maintenance of the enantioselectivity (Table 1, tested for the asymmetric Friedel–Crafts reaction of
phenol. The ester groups had little influence on the
enantioselectivity, and somewhat decreased yields
were obtained for sterically hindered ester group
(Table 2, entries 1–5). When the electron-donating
group on the phenol was changed, the reactions went
smoothly with good enantioselectivities and yields for
methoxy-, ethoxy-, and isopropoxy-substituted phe-
nols (Table 2, entries 1, 6, and 7). Then, a wide range
of substituted (E)-ethyl 4-oxo-4-arylbutenoates 1 was
tested in the asymmetric Friedel–Crafts reaction with
phenol 2a. Regardless of the electronic and steric
nature, or the position of the substituents on the aro-
matic ring of 1, the asymmetric Friedel–Crafts reac-
tion proceeded smoothly. The desired products were
Figure 1. N,N’-dioxide ligands evaluated in this study.
furnished in high yields (78–98%) and enantioselec-
2
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Catalytic Asymmetric Friedel–Crafts Reaction of Activated Phenols and 4-Oxo-4-arylbutenoates
Table 2. Substrate scope for the asymmetric Friedel–Crafts reaction.[a]
Entry
Ar
R1
R2
Product 3: Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et
Me
i-Pr
t-Bu
Bn
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Me
Me
Me
Me
Et
3a: 95
3b: 97
3c: 78
3d: 87
3e: 96
3f: 93
3g: 92
3h: 92
3i: 97
3j: 78
3k: 93
3l: 84
3m: 87
3n: 88
3o: 93
3p: 93
3q: 95
3r: 90
3s: 98
3t: 87
3u: 92
3v: 86
3w: 92
3a: 87
93 (R)
93 (R)
92 (R)
95 (R)
92 (R)
91 (R)
93 (R)
94 (R)
92 (R)
97 (R)
91 (R)
90 (R)
93 (R)
94 (R)
89 (R)
91 (R)
89 (R)
90 (R)
92 (R)[d]
95 (R)
94 (R)
88 (R)
95 (R)
89 (R)
i-Pr
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
3-MeOC6H4
4-MeOC6H4
3,4-(MeO)2C6H3
3-MeC6H4
4-MeC6H4
3,4-Me2C6H3
2-FC6H4
4-FC6H4
4-BrC6H4
3-ClC6H4
4-ClC6H4
3,4-Cl2C6H3
3-NO2C6H4
4-NO2C6H4
2-furyl
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24[e]
2-thienyl
Ph
[a]
Unless otherwise noted, the reactions were performed with 1 (0.15 mmol), and 2 (0.1 mmol) in the presence of L2/
Sc(OTf)3 (5 mol%, 1.2:1) in CH2Cl2 (0.3 mL) under nitrogen at 308C for 36 h.
Isolated yield.
Determined by HPLC analysis.
The absolute configuration was determined to be R by X-ray crystallographic analysis, and the others were determined
by comparison with the CD spectra.
ACHTUNGTRENNUNG
[b]
[c]
[d]
[e]
3.5 mmol of substrate 2a were used.
tivities (88–97% ee) (Table 2, entries 8–21). It is worth system, giving the adduct with 89% ee and 96% yield
pointing out that the 3,4-dimethoxy-substituted (E)- (Scheme 1).
ethyl 4-oxo-4-arylbutenoate 1j afforded excellent
The reaction provided an efficient approach to the
enantioselectivity (97% ee), although the yield was synthesis of 6-phenyl-5-substituted-4,5-dihydro-3(2H)-
slightly reduced in comparison with those of the pyridazinone 4a (Scheme 2). In the presence of a cata-
mono-methoxy-substituted ones (Table 2, entry 10 lytic amount of trifluoroacetic acid, 3a reacted with
versus entries 8 and 9). Notably, substrates bearing hydrazine hydrate in EtOH at 308C for 12 h, giving
heteroaryl units proved to be competent candidates the corresponding pyridazinone 4a in good yield with-
for the catalytic asymmetric Friedel–Crafts reaction out any loss of the enantioselectivity (70% yield, 93%
(Table 2, entries 22 and 23). Additionally, the absolute ee). The derived moiety represents a potentially
configuration of the product 3s was confirmed to be useful biological agent[7] with activities such as antihy-
R. The others were also determined to be R in com- pertension, platelet aggregation, as well as positive in-
parison with the Cotton effect in the CD spectra (see otropic action.
the Supporting Information for details).
To our delight, (E)-1,4-diphenyl-2-butene-1,4-dione and the N,N’-dioxide-Sc
1x was also well tolerated in the current catalytic catalytic model for the Friedel–Crafts reaction of 3,4-
In light of the X-ray structures of the product 3s[8]
(III) complex,[9] a possible
AHCTUNGTRENNUNG
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Si face, generating the R-configured product 3s. The
strong interaction of multiple O-donors of the ligand
with the scandium complex overwhelms the coordina-
tion of phenol. Therefore, Lewis acid catalysis in the
Friedel–Crafts reaction of phenol was achieved.
In summary, we have developed a direct, highly
enantioselective catalytic asymmetric Friedel–Crafts
reaction of 3,4-disubstituted phenols with (E)-4-oxo-
4-arylbutenoates promoted by the N,N’-dioxide L2-
ScACTHUNTRGENNG(U OTf)3 complex. Excellent enantioselectivities (up
to 97% ee) and good yields (78–97%) were obtained
by using a 5 mol% catalyst loading under mild reac-
tion conditions. The corresponding products can be
easily converted to pyridazinone derivatives. Further
investigation of the catalyst system in the synthesis of
biologically interesting molecules is ongoing.
Scheme 1. The asymmetric Friedel–Crafts reaction of 1x
with phenol 2a.
Experimental Section
General Procedure for Catalytic Asymmetric Friedel–
Crafts Reactions
A solution of N,N’-dioxide L2 (3.4 mg, 0.006 mmol), scandi-
um triflate (2.5 mg, 0.005 mmol) and (E)-ethyl 4-oxo-4-aryl-
butenoate 1 (0.15 mmol) in CH2Cl2 (0.3 mL) was stirred at
308C for 0.5 h. Subsequently, 3,4-disubstituted phenol 2
(0.10 mmol) was added. The reaction mixture was stirred at
308C for 36 h. The mixture was directly purified via flash
chromatography (petroleum ether: ethyl ether=3/1–2/1) on
silica gel to afford the desired product.
Scheme 2. The transformation of the product 3a.
dimethoxyphenol with (E)-ethyl 4-oxo-4-arylbuten-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
radentate manner to form two six-membered chelate
rings. The (E)-ethyl 4-oxo-4-arylbutenoates 2s could
coordinate to ScACHTUNGTRENNUNG(III) with the oxygen of the ketone
Acknowledgements
moiety, in which the b-Re face is shielded by the
nearby adamantyl group of the N,N’-dioxide L2.
Then, 3,4-dimethoxyphenol could undergo bonding to
the scandium complex in an upright position. The C-2
We appreciate the National Natural Science Foundation of
China (Nos. 21021001 and 21172151), the Ministry of Educa-
tion (No. 20110181130014), and the Basic Research Program
of China (973 Program: 2011CB808600) for financial sup-
attacks 4-oxo-4-arylbutenoates 2s preferably from the port.
Figure 2. Proposed catalytic model and the X-ray structure of the product 3s.
4
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6 Catalytic Asymmetric Friedel–Crafts Reaction of Activated
Phenols and 4-Oxo-4-arylbutenoates
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Sha Bai, Xiaohua Liu, Zhen Wang, Weidi Cao, Lili Lin,
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