Enantioselective synthesis of benzofurans and benzoxazines via an olefin cross-metathesis-intramolecular oxo-Michael reaction

Article abstract of DOI:10.1039/c3cc43937b

Chiral phosphoric acid and Hoveyda-Grubbs II were found to catalyze an olefin cross-metathesis-intramolecular oxo-Michael cascade reaction of the ortho-allylphenols and enones to provide a variety of benzofuran and benzoxazine derivatives in moderate to good yields and enantioselectivity.

Full text of DOI:10.1039/c3cc43937b

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Enantioselective synthesis of benzofurans and
benzoxazines via an olefin cross-metathesis–
intramolecular oxo-Michael reaction†
Jun-Wei Zhang,ab Quan Cai,b Qing Gu,b Xiao-Xin Shia and Shu-Li You*ab
Cite this: Chem. Commun., 2013,
49, 7750
Received 25th May 2013,
Accepted 2nd July 2013
DOI: 10.1039/c3cc43937b
www.rsc.org/chemcomm
Chiral phosphoric acid and Hoveyda–Grubbs II were found to oxo-conjugate cyclization, affording a variety of substituted
catalyze an olefin cross-metathesis–intramolecular oxo-Michael tetrahydropyrans from readily available starting materials. As
cascade reaction of the ortho-allylphenols and enones to provide part of our research program towards the development of
a variety of benzofuran and benzoxazine derivatives in moderate enantioselective metal/organocatalyst sequential catalysis,10
to good yields and enantioselectivity.
we envisaged that a sequential catalysis involving Ru-catalyzed
cross-metathesis and chiral phosphoric acid-catalyzed asymmetric
2,3-Dihydrobenzofuran and 3,4-dihydro-2H-1,4-benzoxazine with a oxo-Michael reactions might be able to construct these chiral cyclic
chiral center at the 2-position are common fragments in a number oxo containing skeletons.
of biologically interesting compounds.1 Asymmetric intramolecular
We began our studies by examining several chiral Brønsted
oxo-Michael reaction2 provides a facile construction of these chiral acids in combination with Hoveyda–Grubbs II in the tandem
skeletons (Fig. 1). Although the first oxo-Michael reaction was reaction of 1a and 2a. As summarized in Table 1, with 5 mol%
reported in 1878,3 surprisingly until recently highly enantioselective chiral phosphoric acids 4 and 5 mol% Hoveyda–Grubbs II in
oxo-Michael reactions employing either chiral organocatalysts4–6 or CH2Cl2 at 40 1C, the reactions all proceeded smoothly to give
chiral Lewis acids7 were not reported. It is mainly due to the the desired product in moderate to good yields and enantio-
intrinsic drawbacks of oxo-Michael reactions such as low reactivity selectivity.11 Chiral phosphoric acid 4b bearing triphenylsilyl
and reversibility, which impede the development of highly enantio- groups proved to be an efficient catalyst, affording product 3a
selective oxo-Michael reactions.
in 56% yield with 78% ee (entry 2). When the corresponding
Recently, the concept of combining transition-metal catalysis stepwise reaction was attempted, we failed to obtain the inter-
and organocatalysis has emerged as a promising strategy for mediate 3a0 due to its facile cyclization during the purification.
developing new transformations beyond the utilization of the single We also found a synergistic effect that the presence of chiral
catalytic system.8 In 2010, Fuwa et al.9 reported a Hoveyda–Grubbs phosphoric acid could accelerate the overall reaction.11
II catalyzed domino olefin cross-metathesis–intramolecular
With 5 mol% (S)-4b and 5 mol% Hoveyda–Grubbs II as the
catalyst, various solvents and other reaction parameters were
further investigated. The results are summarized in Table 2.
Various solvents such as CHCl3, DCE, toluene and o-xylene all
led to the formation of 3a in comparable enantioselectivity but
in decreased yields (entries 2–5). Ether could be used to afford
product 3a in 81% yield with a slightly decreased enantioselectivity
(69% ee, entry 6). However, the reaction in THF or dioxane gave
only a trace amount of desired product (entries 7 and 8). The
addition of molecular sieves (entries 9 and 10) and change in the
substrate concentration and reaction temperature did not give
better results. The enantioselectivity is decreased with prolonged
reaction time or high substrate concentration.
Fig. 1 Chiral benzofuran and benzoxazine derivatives.
a School of Pharmacy, East China University of Science and Technology,
130 Mei-Long Road, Shanghai 200237, China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032,
China. E-mail: slyou@sioc.ac.cn; Fax: +86 21-54925087
Under these optimized conditions [5 mol% (S)-4b in combination
with 5 mol% Hoveyda–Grubbs II in CH2Cl2 at 40 1C], the
substrate scope for the synthesis of 2,3-dihydrobenzofuran
derivatives was investigated. The results are summarized in
Table 3. Substituted phenols bearing an electron-donating
† Electronic supplementary information (ESI) available: Experimental procedures
and analysis data for new compounds, CIF files of 3m and 7. CCDC 937446 and
937447. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c3cc43937b
c
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Table 1 Screening of the chiral phosphoric acidsa
Table 3 Scope of the enantioselective oxo-Michael reaction for the synthesis of
benzofuransa
Entry
3: R, Ar
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
3a: H, C6H5
48
12
12
23
12
12
24
12
24
12
12
12
12
12
12
56
49
72
64
53
52
46
59
40
49
38
51
61
75
49
78
79
78
76
76
74
80
66
79
81
76
79
77
50
79
3b: 4-Me, C6H5
3c: 4-iPr, C6H5
3d: 4-tBu, C6H5
3e: 4-Ph, C6H5
3f: 4-OMe, C6H5
3g: 5-OMe, C6H5
3h: 6-OMe, C6H5
3i: 4-Br, C6H5
3j: H, 4-MeC6H4
3k: H, 4-MeOC6H4
3l: H, 4-ClC6H4
3m: H, 4-BrC6H4
3n: H, 4-NO2C6H4
3o: H, 2-naphthyl
9
Entry 4, Ar
Time (h) Yieldb (%) eec (%)
10
11
12
13
14
15
1
2
3
4
5
6
7
8
9
4a, 2,4,6-(iPr)3-C6H2
4b, SiPh3
4c, 1-Naphthyl
4d, 9-Anthryl
47
48
66
24
24
47
45
45
82
56
67
33
62
43
39
70
88
90
6
78
ꢀ3
ꢀ30
ꢀ31
23
4e, 9-Phenanthryl
4f, 2,6-(iPr)2-4-anthryl-C6H2
4g, 3,5-(CF3)2-C6H3
4h, 4-Biphenyl
a
b
c
Reaction conditions as in entry 1, Table 2. Isolated yield. Deter-
mined by HPLC.
ꢀ19
ꢀ2
4i, 4-(30,50-(CF3)2-C6H3)-C6H4 45
15
10
4j, 4-NO2-C6H4
45
ꢀ13
good yields and enantioselectivity (entries 10–13). 2-Naphthyl
enone could also be tolerated to afford 3o in 49% yield and 79%
ee (entry 15). However, para-nitro substituted enone gave the
product in 50% ee (entry 14). The absolute configuration of the
product was determined by an X-ray crystallographic analysis of
the single crystal of enantiopure 3m as (S).
a
Reaction conditions: 1a (0.2 mmol), 2a (0.30 mmol), Hoveyda–Grubbs
II (5 mol%) and chiral phosphoric acid (5 mol%) in CH2Cl2 (2 mL) at
40 1C. Isolated yield. Determined by HPLC.
b
c
Table 2 Optimization of the reaction conditions for the tandem reactiona
In addition to allyl phenols that afforded chiral 2,3-dihydro-
benzofuran derivatives, the 2-N-allyl substituted phenols were
also examined to yield chiral oxazine derivatives. The results
are summarized in Table 4. When the N-benzyl allyl substituted
phenol was used, various aromatic enones could react smoothly
under the optimized conditions affording the desired products
in 44–65% yields and 67–77% ee (Table 4, entries 1–8). It is
Entry
Solvent
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
DCM
CHCl3
DCE
Toluene
o-Xylene
Ether
THF
Dioxane
DCM
48
67
88
83
88
96
67
96
5
56
14
21
20
21
81
15
Trace
63
78
75
69
80
82
69
1
nd
75
75
Table 4 Scope of the enantioselective oxo-Michael reaction for the synthesis of
benzoxazinesa
8
9d
10e
DCM
15
54
a
Reaction conditions: 1a (0.20 mmol), 2a (0.30 mmol), Hoveyda–Grubbs
II (5 mol%) and (S)-4b (5 mol%) in solvent (2 mL, c = 0.1 mol Lꢀ1 for 1a)
at 40 1C. Isolated yield. Determined by HPLC. 4 Å MS (100 mg) was
added. 5 Å MS (100 mg) was added.
b
c
d
e
Entry
6: R, Ar
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
6a: C6H5, C6H5
24
10
24
11
11
8
5
12
5
12
12
12
14
65
54
64
44
52
48
52
51
76
81
67
58
63
77
74
67
69
76
73
75
76
76
78
82
79
64
6b: 4-MeC6H4, C6H5
6c: 4-MeOC6H4, C6H5
6d: 2-BrC6H4, C6H5
6e: 4-BrC6H4, C6H5
6f: 4-ClC6H4, C6H5
6g: 4-NO2C6H4, C6H5
6h: 2-naphthyl, C6H5
6i: Me, C6H5
group (4-Me, 4-iPr, 4-tBu, 4-Ph, 4-OMe, 5-OMe and 6-OMe,
entries 2–8) or an electron-withdrawing group (4-Br, entry 9)
were well tolerated, and their corresponding cross-metathesis
and oxo-Michael adducts were obtained in good yields (40–72%)
and enantioselectivity (66–80% ee). The ortho substituted phenol
(6-OMe) could also be tolerated but with slightly decreased
enantioselectivity (66% ee, entry 8). In addition, the reaction is
also general for the enones bearing different aromatic groups.
The enones containing either an electron-donating group (4-Me,
4-OMe) or an electron-withdrawing group (4-Cl, 4-Br) on the
phenyl ring all led to the formation of the desired products in
9
10
11
12
13
6j: Et, C6H5
6k: nPr, C6H5
6l: Me, 1-naphthyl
6m: Me, 2-naphthyl
a
b
c
Reaction conditions as in entry 1, Table 2. Isolated yield. Deter-
mined by HPLC.
c
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We thank the National Basic Research Program of China
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c
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