Enantioselective copper-catalyzed intramolecular phenolic O-H bond insertion: Synthesis of chiral 2-carboxy dihydrobenzofurans, dihydrobenzopyrans, and tetrahydrobenzooxepines

Article abstract of DOI:10.1002/anie.201209455

Efficient: A copper-catalyzed enantioselective intramolecular insertion of carbenoids into phenolic O-H bonds has been developed. This method can be used for the synthesis of the title compounds in high yields and excellent enantioselectivities under mild and neutral conditions (see scheme). NaBAr _F=sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate. Copyright

Full text of DOI:10.1002/anie.201209455

Angewandte
Chemie
DOI: 10.1002/anie.201209455
Synthetic Methods
À
Enantioselective Copper-Catalyzed Intramolecular Phenolic O H
Bond Insertion: Synthesis of Chiral 2-Carboxy Dihydrobenzofurans,
Dihydrobenzopyrans, and Tetrahydrobenzooxepines**
Xiao-Guang Song, Shou-Fei Zhu, Xiu-Lan Xie, and Qi-Lin Zhou*
À
The construction of carbon–heteroatom bonds (C X, where
X = N, O, S, etc.) is one of the most widely used methods in
organic synthesis. In particular, catalytic asymmetric forma-
that provides a powerful method for the enantioselective
[7]
À
construction of C O bonds. Herein, we report a copper-
catalyzed enantioselective intramolecular insertion of carbe-
À
À
tion of C X bonds provides a direct method for the synthesis
noids into phenolic O H bonds as a novel strategy for the
of chiral compounds containing heteroatoms,[1] and remark-
able progress on the intramolecular asymmetric formation of
such bonds has been made.[2] However, the known methods
for the synthesis of chiral heterocyclic compounds by means
of intramolecular enantioselective C–X formation are gen-
erally substrate dependent, which limits their utility in organic
synthesis. For instance, chiral 2-carboxy dihydrobenzofuran,
dihydrobenzopyran, and tetrahydrobenzo[b]oxepine, which
are the core structures of numerous natural products and
pharmaceuticals such as (+)-angelmarin,[3] (+)-rutamarin,[4]
synthesis of chiral 2-carboxy dihydrobenzofurans, dihydro-
benzopyrans, and tetrahydrobenzo[b]-oxepines. The method
affords high yields (86–99%) and excellent enantioselectiv-
ities (94–99% ee), proceeds under mild and neutral con-
ditions, and affords cyclic ethers with 5- to 7-membered
rings.[8]
We began our study with intramolecular insertion into the
phenolic O H bond of methyl 2-diazo-3-(2-hydroxyphenyl)-
À
propanoate (2a) catalyzed by a chiral copper catalyst
prepared in situ from copper chloride, ligand (Sa,S,S)-1a,
and sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate
(NaBArF) (Table 1, entry 1). The reaction was complete
within 5 min and afforded 2-methoxycarbonyl 2,3-dihydro-
benzofuran (3a) in 69% yield with 70% ee. To improve the
catalyst reactivity and enantioselectivity, we evaluated a vari-
ety of copper salts as catalyst precursors (Table 1, entries 1–
7). All the tested catalysts promoted the reaction of 2a to
afford desired product 3a, with [Cu(MeCN)4]PF6 giving the
highest enantioselectivity (97% ee, entry 4). The correspond-
ing chiral iron complex, an efficient catalyst for the enantio-
(R,S,S,S)-(À)-nebivolol,[5]
and
(+)-heliannuol D[6]
(Scheme 1), have not been accessed by means of catalytic
À
enantioselective intramolecular C O bond formation reac-
tions. Recently, we developed a highly efficient transition-
metal-catalyzed asymmetric O H bond insertion reaction
À
À
selective intermolecular O H bond insertion of alcohols and
water,[7d] can also promote the present reaction albeit with
medium yield and enantioselectivity (45% and 78% ee,
Table 1, entry 8). Various spiro bisoxazoline ligands were then
compared. The use of ligand (Ra,S,S)-1a substantially reduced
the reaction rate and enantioselectivity (compare entries 9
and 4 in Table 1), thereby implying that the combination of its
chiral components was mismatched. Ligands (Sa,S,S)-1b–1d
exhibited essentially the same yields and enantioselectivities
(91–97% and 96% ee; Table 1, entries 10–12) as (Sa,S,S)-1a;
only ligand (Sa,S,S)-1e, with its bulky tert-butyl groups,
showed substantially low yield and enantioselectivity. These
results indicate that the substituents on the oxazoline rings of
the ligand had a negligible influence on the reactivity and
enantioselectivity of the catalyst. To verify this conclusion, we
tested unsubstituted ligand (Sa)-1 f and found that it afforded
3a in 98% yield with 98% ee (Table 1, entry 14), which
demonstrates that the spiro backbone of the ligand was
crucial for chiral induction. We next evaluated the effects of
various solvents on the reaction. Dichloromethane, chloro-
form, 1,2-dichloroethane, and toluene were all suitable
(Table 1, entries 15–17), whereas the polar, coordinating
solvent acetonitrile markedly slowed the reaction and elim-
inated the enantioselectivity (entry 18). The catalyst was so
Scheme 1. Representative biologically active compounds derived from
chiral 2-carboxy dihydrobenzofuran, dihydrobenzopyran, and tetrahy-
drobenzo[b]oxepine.
[*] X.-G. Song, Prof. S.-F. Zhu, X.-L. Xie, Prof. Q.-L. Zhou
State Key Laboratory and Institute of Elemento-organic Chemistry
Nankai University
Tianjin 300071 (China)
E-mail: qlzhou@nankai.edu.cn
Homepage: http://zhou.nankai.edu.cn
[**] We thank the National Natural Science Foundation of China, the
National Basic Research Program of China (2011CB808600), the
Ministry of Education of China (B06005), and the Program for New
Century Excellent Talents in University (NCET-10-0516) for financial
support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201209455.
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Table 1: Copper-catalyzed asymmetric intramolecular phenolic O–H
insertion of 2a: Optimization of reaction conditions.[a]
Table 2: Copper-catalyzed asymmetric intramolecular phenolic O–H
insertion: Substrate scope.[a]
Entry Diazo compound
Product
Yield ee
[%]
[%]
1
2
3
98
98
98
98
Entry [Cu]
Ligand
Solvent
t
Yield ee
[%][b] [%][c]
99
99
1
CuCl
(Sa,S,S)-1a CH2Cl2 5 min
(Sa,S,S)-1a CH2Cl2 10 h
69
80
92
84
80
74
79
45
70
36
95
97
91
92
36
78
49
96
96
96
61
98
95
95
94
rac
96
2
3
CuCN
CuOTf·1= toluene (Sa,S,S)-1a CH2Cl2 5 min
2
4
[Cu(MeCN)4]PF6 (Sa,S,S)-1a CH2Cl2 5 min
5
CuCl2
(Sa,S,S)-1a CH2Cl2 3 h
(Sa,S,S)-1a CH2Cl2 1 min
(Sa,S,S)-1a CH2Cl2 6 h
(Sa,S,S)-1a CH2Cl2 24 h
6
7
8
Cu(OTf)2
CuSO4
FeCl2
4
5
6
7
99
98
94
99
98
99
97
96
9
[Cu(MeCN)4]PF6 (Ra,S,S)-1a CH2Cl2 30 min 94
[Cu(MeCN)4]PF6 (Sa,S,S)-1b CH2Cl2 5 min 97
[Cu(MeCN)4]PF6 (Sa,S,S)-1c CH2Cl2 20 min 91
[Cu(MeCN)4]PF6 (Sa,S,S)-1d CH2Cl2 15 min 93
10
11
12
13
14
15
16
17
18
19[d]
[Cu(MeCN)4]PF6 (Sa,S,S)-1e CH2Cl2 36 h
80
98
84
98
76
53
95
[Cu(MeCN)4]PF6 (Sa)-1 f
[Cu(MeCN)4]PF6 (Sa)-1 f
[Cu(MeCN)4]PF6 (Sa)-1 f
[Cu(MeCN)4]PF6 (Sa)-1 f
[Cu(MeCN)4]PF6 (Sa)-1 f
[Cu(MeCN)4]PF6 (Sa)-1 f
CH2Cl2 5 min
CHCl3
DCE
toluene 5 min
MeCN 24 h
CH2Cl2 5 min
5 min
5 min
[a] Reaction conditions: [Cu]/ligand/NaBArF/2a=
0.02:0.024:0.024:0.4 mmol, in 4 mL CH2Cl2 at 258C. DCE=1,2-
dichloroethane. [b] Yield of isolated product. [c] Determined by HPLC
using a Chiralcel OD-H column. [d] Using 1 mol% catalyst.
8
86
99
94
98
98
97
active that the reaction could be carried out at a catalyst
loading of 1 mol% without diminishing the yield or enantio-
selectivity (Table 1, entry 19).
9
Under the optimal reaction conditions, we explored the
À
substrate scope of the intramolecular phenolic O H bond
insertion (Table 2). The variation of the ester groups had
a negligible influence on the reactivity and enantioselectivity
of the reaction (Table 2, entries 1–3). The steric and electronic
properties of the substituents on the benzene ring of
diazoesters 2 slightly affected both the reactivity and enan-
tioselectivity of reaction. With diazoesters 2d–2l, the reac-
tions were complete within 5 min and afforded the desired
dihydrobenzofuran products in good yields (86–99%) with
excellent enantioselectivities (94–99% ee, Table 2, entries 4–
12). The reaction could be extended to the syntheses of chiral
dihydrobenzopyrans and even chiral tetrahydrobenzo[b]ox-
epines; however the Cu-(Sa,S,S)-1a became the catalyst of
choice. When using this catalyst, the intramolecular phenolic
O–H insertions of diazo compounds 2m, 2n, and 2o were
accomplished under mild reaction conditions to afford the
chiral dihydrobenzopyrans 3m and 3n, and tetrahydroben-
zo[b]oxepine 3o in high yields with excellent enantioselectiv-
ities (Table 2, entries 13–15). These results demonstrate that
10
11
97
97
12
13
99
95
94
48
(95)[b] (96)[b]
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À
Table 2: (Continued)
asymmetric X H bond insertion reactions in organic syn-
thesis.
Entry Diazo compound
Product
Yield ee
[%]
[%]
Experimental Section
95
45
14
15
(95)[b] (96)[b]
General procedure for intramolecular asymmetric phenolic O–H
insertion: [Cu(MeCN)4]PF6 (7.5 mg, 0.02 mmol, 5 mol%), (Sa)-1 f
(8.6 mg, 0.024 mmol, 6 mol%), and NaBArF (22.6 mg, 0.024 mmol,
6 mol%) were combined in an oven-dried Schlenk tube in an argon-
filled glovebox. CH2Cl2 (3 mL) was injected by using a syringe. After
the mixture was stirred at 258C for 2 h, diazo compound 2 (0.4 mmol,
dissolved in 1 mL of CH2Cl2) was added, and the resulting mixture
was stirred until 2 was completely consumed, as indicated by TLC.
The crude product was purified by chromatography on silica gel
(petroleum ether/ethyl acetate = 8:1), and the ee value was deter-
mined by HPLC with a chiral column.
95
98
(99)[b] (99)[b]
[a] The reaction conditions were the same as those in Table 1, entry 14.
All the reactions reached full conversion within 5 min. For analyses of
products, see the Supporting Information. [b] Using (Sa,S,S)-1a.
the present reaction has a high potential for wide application
in the synthesis of chiral benzo hetereocyclic compounds.
To demonstrate the utility of the reaction, we conducted
a formal synthesis of (R,S,S,S)-(À)-nebivolol, an antihyper-
tensive drug (Scheme 2). We found that two enantiomeric
Received: November 27, 2012
Published online: January 31, 2013
Keywords: asymmetric catalysis · bisoxazoline ligands ·
.
carbenes · copper · heterocycles
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