Catalytic asymmetric [2+2] cycloaddition between quinones and fulvenes and a subsequent stereoselective isomerization to 2,3-dihydrobenzofurans

Article abstract of DOI:10.1039/c7cc03211k

The catalytic enantioselective [2+2] cycloaddition between quinones and fulvenes was achieved, for the first time, by the use of a chiral copper(ii) complex catalyst. The transformation afforded a series of enantiomerically enriched [6,4,5]-tricyclic cyclobutane derivatives in good yields with excellent regio- and stereoselectivities. Furthermore, the [2+2] adducts could be easily converted into formal [3+2] adducts efficiently and stereoselectively.

Full text of DOI:10.1039/c7cc03211k

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
=
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Catalytic Asymmetric [2+2] Cycloaddition between Quinones and
Fulvenes and a Subsequent Stereoselective Isomerization to 2,3-
Dihydrobenzofurans
Received 00th January 20xx,
Accepted 00th January 20xx
Haifeng Zheng,a Chaoran Xu,a Yan Wang,a Tengfei Kang,a Xiaohua Liu,a* Lili Lin,a and Xiaoming
Fenga,b*
DOI: 10.1039/x0xx00000x
www.rsc.org/
The first catalytic enantioselective [2+2] cycloaddition between styrenes. The corresponding cyclobutane adducts were
quinones and fulvenes was addressed by the use of a chiral obtained in good yields and high ee, although stiochiometric
copper(II) complex catalyst. The transformation afforded a series amount catalyst were required (Scheme 1a).8a On the other
of enantiomerically enriched [6,4,5]-tricyclic cyclobutane side, fulvenes are useful synthons as 2π, 4π, and 6π
derivatives in good yields with excellent regio- and components in
a variety of cycloadditions to construct
stereoselectivities. Furthermore, the [2+2] adducts could be easily polycyclic structures.9 [2+2] Cycloaddition of fulvenes was
converted to formal [3+2] adducts efficiently and firstly reported by Huston and coworkers in 1982 using ketene
stereoselectively.
as the electro-poor 2π partner (Scheme 1b).9b In spite of these
efforts, no catalytic enantioselective [2+2] cycloaddition
involving quinones and fulvenes have been reported to date.
The key element is finding an appropriate Lewis acid that could
activate the desired [2+2] cycloaddition, but weaken the
Cyclobutane motif is present in a number of natural
products,1 and is also a type of useful intermediate with
diversity of reactions.2 One of the principal strategies for the
synthesis of enantiomerically enriched cyclobutane derivatives
involves catalytic enantioselective [2+2] cycloadditions.3 Many
variants have been established, such as photochemical
approach,4 polarized [2+2] cycloadditions between α,β-
unsaturated carbonyl compounds or allenes and electron-rich
alkenes catalyzed by sigma Lewis acids5 or π-philic Lewis
acids,6 as well as amine-catalyst-based formal [2+2]
cycloadditions of α,β-unsaturated aldehydes.7 Despite of these
efforts, the π-partners for catalytic enantioselective [2+2]
cycloadditions remain extremely limited, and the scope of the
process is worth of further extending in order to access to
various cyclobutane derivatives.
competitive
formal
[3+2]
cycloaddition,8a,9f,11 [4+2]
cycloaddition,9f polycondensation of quinones10 and
dimerization of fulvenes9e.
a) Enantioselective [2+2] cycloaddition between methoxy-1,4-benzoquinones and styrenes
O
O
R
Ar
R
R
OCH3
CH3
OCH3
H3C
A
B
+
OH
Ar
Ar
H3C
H
O
OCH3
O
O
R = H, CH3
43-88% yield,
64-92% ee, >20:1 d.r.
Condition A: TADDOL:TiCl4:Ti(OiPr)4 (1:1:1, 1.0 equiv), -94 to -78 oC. Condition B: -78 to -30 oC.
b) Thermal ketene-fulvene [2+2] cycloaddition
O
O
R2
C
+
R1
rt, 15 h
R1 R2
R1, R2 = alkene, alkyl
41-69% yield
The use of quinones as the π-component in cycloadditions is
a major advance and challenge since the reactions might result
in several different products, and the quinone subcategory
could transform into densely functionalized aromatic rings.8
Early in 1991, Engler and coworkers used chiral
TADDOL/TiCl4/Ti(OiPr)4 catalyst for the enantioselective [2+2]
cycloaddition between 2-methoxy-1,4-benzoquinones and
c) Catalytic enantioselective quinone-fulvene [2+2] cycloaddition (this work)
O
O
R3
H
CO2R2
H3CO2
HO
C
CO2R2
+
H
Cat*
In(OTf)3
R1
R1
H
O
H
O
H
O
regio-,diastereo-
enantioselectivity
R3
R3
R1
Scheme 1. [2+2] Cycloaddition related to quinones or fulvenes.
Herein, we utilized a chiral N,Nʹ
-dioxide-Cu(OTf)2 catalyst12
a.Key Laboratory of Green Chemistry & Technology, Ministry of Education, College
of Chemistry, Sichuan University, Chengdu 610064, China. E-mail:
liuxh@scu.edu.cn; xmfeng@scu.edu.cn; Fax: + 86 28 85418249; Tel: + 86 28
85418249
for the mentioned [2+2] cycloaddition (Scheme 1c). Moreover,
the formed [6,4,5]-tricyclic structures can be easily and
stereoselectively
converted
into
[6,5,5]-dihydro-1H-
b.Collaborative Innovation Center of Chemical Science and Engineering (Tianjin),
China.
cyclopenta[b]benzofuran structures assisted by In(OTf)3.
Through these ways, the useful cyclobutane and
cylcopenta[b]benzofuran structures both can be obtained in
good yields with excellent regio- and stereoselectivities.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Table 1. Optimization of the [2+2] cycloaddition reaction conditions.a
increase in enantioselectivity (entry 9). Of the solvents tested
for the reaction, CH3CN proved optimal with respect to the
yield (entry 10). Moreover, by adding 3 Å molecular sieves and
changing the ratio of the metal salt and ligand, the best results
of 82% yield, 94:6 dr and 98.5:1.5 er for 3aa were obtained
with trace byproduct 4aa (entry 11).
With the optimal condition in hand, we look into the
substrate scope for the synthesis of various cyclobutane
derivatives (Table 2). Firstly, substituted quinones were
subjected into the [2+2] cycloaddition (entries 1-20). It was
found that the steric hindrance of the ester group at 2-carbon
position had little effect on the stereoselectivity. Quinones
entry
L/Metal salt
Yield (3aa)(%) b
Dr c
Er d
1
2
L-RaPr2/Mg(OTf)2
L-RaPr2/Ni(OTf)2
L-RaPr2/Zn(OTf)2
L-RaPr2/Cu(OTf)2
BOX/Cu(OTf)2
53
62
94:6
73:27
64:36
94:6
-
87:13
72:28
50:50
90:10
-
(
1a-1f) bearing substitutions underwent the reaction well,
resulting in 50-82% yields, 96:4-98.5:1.5 er (entries 1-5). The
naphalene-1,4-dione derivative 1g could deliver the product
3ga in 55% yield, 95:5 dr and 98.5:1.5 er (entry 6). 5-Aryl-
substitued quinones (1h-1m) with electron-withdrawing or
donating substituents on the phenyl group performed the [2+2]
reaction with the electron-deficient double bond, giving the
related cyclobutene derivatives 1ha-1ma in 58-68% yields,
90:10-98.5:1.5 er (entries 7-12). Furthermore, 5-alkyl
substituted quinones (1n-1t) including liner, branched, and
cyclic alkyl groups were tolerated to give the cycloadducts 3na-
3ua with 65-82% yields and up to 99:1 er (entries 13-20).
3
25
4
31
5
trace
41
6
L-PiPr2/Cu(OTf)2
L-PrPr2/Cu(OTf)2
L-RaPr3/Cu(OTf)2
L-RaPr3/Cu(OTf)2
L-RaPr3/Cu(OTf)2
L-RaPr3/Cu(OTf)2
72:28
95:5
94:6
94:6
94:6
94:6
50:50
94:6
7
25
8
56
94:6
9e
10e,f
11e–g
56
97:3
74
98.5:1.5
98.5:1.5
82
a Unless otherwise noted, the reactions were performed with L–M (1:1, 10 mol%), 1a
(0.1 mmol) and 2a (0.15 mmol) in CH2Cl2 (1.0 mL) at −10 oC for 36 h. Isolated yield.
The dr value was determined by 1H NMR and HPLC analysis. Determined by HPLC
analysis on chiral stationary phases. At −40 oC. f CH3CN as the solvent. The ratio of
b
c
d
We then examined the substrate scope of fulvenes (Table 2,
e
g
entries 21-34). 6-Aryl substituted fulvenes 2b
substituents performed the [2+2] cycloaddition smoothly to
generate the desired products 3ab 3af in good yields
(61−77%), and excellent enantioselectivity (97.5:2.5–98.5:1.5er)
(entries 21-25). Fulvenes 2g 2h bearingm-tolyl oro-tolyl
–2f bearing para-
M/L was 1:1.1, and 3 Å molecular sieves (10 mg) was added.
–
Initial studies used 6-phenylfluvene 2a and unsubstituted
1,4-benzoquinone as the reactants. After efforts toward
optimization of the chiral catalysts, we got the related [2+2]-
product in moderate yield with poor enantioselectivity (for
detail see Supporting Information). Next, we introduced an
ester group into the quinone structure to enhance the
−
substitution made little influence on both the yields and the
stereoselectivities (entries 26 and 27). Additionally, fulvenes
2i
–2m containing 6-hetero-aromatic and fused-ring
substitutions afforded the corresponding [2+2] products 3ai
–
coordination between the catalyst and quinone via
a
bidentate-binding manner.13 Table 1 summarizes the results
between 2-ester-substituted quinone 1a and fluvene 2a. The
[2+2] cycloaddition occurred from electron-deficient double
bond rather than sterically more accessible double bond
bearing two hydrogens.8a The product 3aa was obtained as the
major product, accompanying trace amount of the formal [3+2]
adduct 4aa11,9f and the [4+2] cycloaddition product was
suppressed in this reaction temperature. By using Mg(OTf)2-L-
RaPr2 catalyst, the [2+2] adduct 3aa was obtained in 53% yield,
94:6 dr and 87:13 er, meanwhile the byproduct 4aa was
obtained in 21% yield with poor enantioselectivity (Table 1,
entry 1). Encouraged by this promising result, a detailed
optimization of metal salts was done firstly. Pleasingly,
Cu(OTf)2 afforded a better result in terms of enantioselectivity
(entries 2-4). Subsequent evaluation focused on various chiral
ligands, including chiral bisoxazoline BOX, and several chiral
N,N′-dioxides (entries 5-8). In the presence of BOX ligand,
3am in satisfied outcomes, with the yields ranging from 61% to
82%, and the er as high as 90:10 to 99:1 (entries 28-32).
Fulvene 2n bearing a 4-acetylphenylgroup was also tolerable,
giving the adduct 3an in 75% yield, as well as 98.5:1.5 er (entry
33). In addition, multi-conjugated alkene substrate 2o could
afford the desired tricyclic product 3ao in 81% yield with 97:3
er (entry 34). It is noteworthy that, the diastereoselectivity
was excellent and only trace amount of formal [3+2]
byproducts
4 were detected in all these cases. Most reaction
achieved up to 20:1 dr, and only a few suffered a slightly
dropped diastereoselectivity, as the lowest dr as 92:8. Other
ortho-substituted quinones, substituted fulvenes were found
sluggish under the optimal reaction conditions. 14 Furthermore
5,5-dimethylcyclopenta-1,3-diene was also used in this
reaction, however the desired [2+2] cycloaddition was not
happened and we detected the [4+2] reaction product.
Quinone subcategory has also long served as useful
precursors into functionalized aromatic rings.8a,13 The
rearrangement of the cyclobutane adducts could furnish the
corresponding 2,3-dihydrobenzofurans, another unique
structure in many natural products.15 Therefore, we next
evaluated the condition of the rearrangement from the [2+2]
trace adducts (3aa/4aa) were obtained which was contributed
to the polycondensation of quinone. Luckily, it was found that
the ligand L-RaPr3 provided an obvious increase in terms of
reactivity and enantioselectivity (entry 8). Decreasing the
reaction temperature from −10 to −40 oC led to a further
adduct
3 into the formal [3+2] adduct 4. Preparative scale
2 | J. Name., 2012, 00, 1-3
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synthesis of the [2+2] cycloadduct 3aa were carried out, and either ineffective or less stereoselective (entries 2 and 3). To
there was no change in reactivity and stereoselectivity with our delight, In(OTf)3 led to the product 4aa in 95% yield albeit
the cycloaddition underwent from 5 mmol of the substrate 1a
.
with a little decrease of stereoselectivity (entry 4). Decreasing
o
the reaction temperature from 0 to −20 C and increasing the
Enantiomerically pure product 3aa (99:1 dr and 99.5:0.5 er)
catalyst loading to 15 mol% compensated the loss of
stereocontrol, and the formal [3+2] adduct 4aa could be
generated in 95% yield with maintained stereoselectivity
(entry 5). Therefore, in the assistance of In(OTf)3, several
Table 2. Scope of quinones andfulvenes in [2+2] cycloaddition reaction. a
cyclobutane adducts
cycloaddition reaction could efficiently transformed into the
related 2,3-dihydrobenzofurans . Good yields (81-95%) were
3 obtained from the asymmetric [2+2]
Entry
3(R1, R2, R3)
Yield (%)
Dr
er
4
obtained and the diastereo- and enantioselectivities reduced a
little but remained satisfying (7:1-99:1 dr, 97.5:1.5-99:1 er).
1
2
3
4
5
6
3ba: R2 = Et
67
60
70
50
65
55
97:3
97:3
97:3
97:3
>20:1
95:5
97.5:2.5
97:3
R1 = H
R3 = Ph
3ca: R2 = n-Pr
3da: R2 = n-Bu
3ea: R2 = i-Pr
3fa: R2 = i-Bu
Table 3. Isomerization of cyclobutane adducts into 2,3-dihydrobenzofurans. a
98:2
96:4
O
CO2CH3
98:2
Ph
H
H
H
H3CO2C
HO
98.5:1.5
Lewis Acid (10 mol%)
CH3CN, 0 o
H
C
O
O
3ga
Ph
3aa
99.5:0.5 er, 99:1 dr
H
4aa
7
8
3ha: R1 = Ph
62
68
61
60
50
60
67
66
82
83
78
65
72
60
77
75
63
61
72
72
70
61
75
82
>20:1
>20:1
>20:1
92:8
95:5
98:2
3ia: R1 = 3-MeC6H4
3ja: R1 = 2-MeC6H4
3ka: R1 = 4-t-BuC6H4
3la: R1 = 4-FC6H4
3ma: R1 = 4-EtOC6H4
3na: R1 = Me
entry
Lewis acid
yield of 4aa (%)b
dr of 4aac
er of 4aad
97.5:2.5
-
9
90:10
98.5:1.5
98.5:1.5
98.5:1.5
98:2
1
2
Cu(OTf)2
BF3·Et2O
Yb(OTf)3
In(OTf)3
In(OTf)3
7
trace
36
90:10
-
10
11
12
>20:1
>20:1
97:3
3
85:15
97:3
99:1
54:46
4
5[e]
95
98.5:1.5
99.5:0.5
13 R2 = Me
14 R3 = Ph
95
3oa: R1 = Et
95:5
98:2
Ar
H
[e] 4pa:
4qa:
H3CO2C
HO
Ph
H
15
16
17
18
19
20
21
22
23
24
25
26
3pa: R1 =i-Pr
93:7
99:1
R = Pr, 82% yield, 7:1 dr, 99:1 er
i-
i-
R = Bu, 81%, 7:1 dr, 97.5:2.5 er
H3CO2C
HO
3qa: R1 =i-Bu
98:2
99:1
4sa: R = c-Pentyl, 80% yield, 9:1 dr, 97.5:2.5 er
4ha: R = Ph, 90% yield, 9:1 dr, 98.5:1.5 er
4ua: R = PhCH2CH2,
O
3ra: R1 =t-Bu
95:5
98:2
O
H
[e]4an: Ar = p-OAc-C6H4
H
3sa: R1 =c-pentyl
3ta: R1 =c-hexyl
3ua: R1 = PhCH2CH2
3ab: R3 = 4-FC6H4
3ac: R3 = 4-ClC6H4
3ad: R3 = 4-BrC6H4
3ae: R3 = 4-IC6H4
3af: R3 = 4-MeC6H4
3ag: R3 = 3-MeC6H4
3ah: R3 = 2-MeC6H4
3ai: R3 = 2-furyl
3aj: R3 = 3-thienyl
3ak: R3 = 2-
98:2
99:1
R
85% yield, 7:1 dr, 97.5:2.5 er
95% yield, 99:1 dr, 99:1 er
3an
(from enantiomeric pure
)
>20:1
95:5
98.5:1.5
98:2
a
Unless otherwise noted, the reactions were performed with Lewis acid (10 mol%), 3
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
94:6
98.5:1.5
97.5:2.5
97.5:2.5
97.5:2.5
98:2
(0.1 mmol) in CH3CN (1.0 mL) at 0 oC for 0.5 h. b Isolated yield. c Determined by 1H NMR
and HPLC analysis. d Determined by HPLC analysis on chiral stationary phases. e In(OTf)3
(15 mol%) at −20 oC for 15 min.
To demonstrate the utility of the [2+2] cycloaddition
reaction, preparative scale synthesis of the cycloadducts
carried out. The scale synthesis of ent-3an was also successful
when the enantiomer of the ligand L-RaPr3 was used instead.
The optical pure product ent-3an was acquired in a 66%
totalyield. Next, the catalytic isomerization of the [2+2] adduct
ent-3an at a gram scale performed well, generating the related
benzofuranderivative ent-4an in 95% yield with maintained
enantioselectvity. The absolute configuration of ent-4an was
determined after single crystal X-ray analysis.16 After highly
regioselective hydrogenation reaction, the product ent-6an
was obtained in 99% yield (see Supporting Information).
98.5:1.5
97:3
27
R1 = H
28
99.5:0.5
90:10
98:2
R2 = Me
29
97:3
30
>20:1
benzo[b]thiophenyl
3al: R3 = 1-naphthyl
3am: R3 = 2-naphthyl
3an: R3 = 4-AcOC6H4
3ao: R3 =PhCH=CH-
31
32
33
34
65
78
75
81
>20:1
>20:1
96:4
97:3
99:1
98.5:1.5
97:3
>20:1
a
L-RaPr3–Cu(OTf)2 (1.1:1, 10 mol%), 1 (0.1 mmol), 2 (1.5 equiv.), 3 Å MS (10 mg) in
CH3CN (1.0 mL) at −40 oC for 36 h. The yield is the isolated yield. The dr was determined
by 1H NMR and HPLC analysis, and the er value was determined by HPLC analysis on
chiral stationary phases.
To obtain information about the [2+2] cycloaddition process,
static state and Operando IR experiments were carried out (for
detail see Supporting Information). As peaks related to the two
was obtained after simple recrystallization. The absolute
configuration of 3aa was determined to be (3aR,3bR,7aR,7bS)
by X-ray crystal analysis.16 Resubjecting 3aa to various Lewis
reactants depleted gradually, the signals of the [2+2] product
3
and the formal [3+2] byproduct 4 increased nearly
simultaneously. It indicates that two catalytic reactions
occurred synchronal and competitively. The [6,5,5]-tricyclic
acid catalysts at
0
oC afforded the related 2,3-
dihydrobenzofuran 4aa (Table 3). Cu(OTf)2 gave only 7% yield,
and both the diastereoselectivity and the enantioselectivity of
4aa dropped a little (entry 1). BF3·Et2O and Yb(OTf)3 proved
product
4 is not generated from the isomerization of the
[6,4,5]-tricyclic product
3
in the circumstance of the chiral
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5
6
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catalytic system. Based on the results mentioned above and
our previous work,12 we proposed possible pathways for the
generation of the cycloadducts. As shown in Scheme 3, the
chiral L-RaPr3-Cu(II) complex bonds the two carbonyl groups of
quinone substrate
nucleophilic ability of the fulvene
-position of , forming the intermediate
through two reaction pathways to give the cycloadducts. The
nucleophilic approach of the α-position of quinone is
preferable resulting in enantioselective [2+2] cycloaddition
1
, activating the
enables the addition to the
, which can get
β-position. Then the
2
β
1
A
1
7
a)K. Ishihara, K. Nakano, J. Am. Chem. Soc. 2007, 129, 8930;
b) L. Albrecht, G. Dickmeiss, F. C. Acosta, C. R. Escrich, R. L.
Davis, K. A. JØrgenson, J. Am. Chem. Soc. 2012, 134, 2543; c)
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C. Luo, P. F. Xu, Chem. Commun. 2013, 49, 4625; e) L. W. Qi,
Y. Yang, Y. Y. Gui, Y. Zhang, F. Chen, F. Tian, L. Peng, L. X.
Wang, Org. Lett. 2014, 16, 6436;
product of [6,4,5]-tricyclic derivative 3 (path a). The
8
9
a) T. A. Engler, M. A. Letavic, J. P. Reddy, J. Am. Chem. Soc.
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6913.
,
For review on fulvenes: a) P. Preethalayam, K. S. Krishnan, S.
Thulasi, S. S. Chand, J. Joseph, V. Nair, F. Jaroschik, K. V.
Radhakrishnan, Chem. Rev. 2017, 117, 3930; As 2π
Scheme 3. The proposed reaction processes.
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accompanying enantioselective oxygen-nucleophilic addition
might be hampered due to the delayed aromatization process
(path b), thus the formal [3+2]-product
minor adduct. Moreover, in the presence of In(OTf)3, the ring-
opening of cyclobutane moiety gives the intermediate , which
undergoes oxa-addition efficiently and enantioselectively to
afford the [6,5,5]-tricyclic product
4 was detected as the
,
B
Org. Lett. 2002,
Bhunia, A. T. Biju, Org. Lett. 2012, 14
4
, 663; g) S. S. Bhojgude, T. Kaicharla, A.
,
4.
4098; As 6π
In summary, we have developed the catalytic
enantioselective [2+2] cycloaddition between quinones and
fulvenes. Under a chiral N,N′-dioxide-copper(II) complex, a
variety of quniones and fulvenes smoothly afforded the
[6,4,5]-tricyclic cyclobutane derivatives in good yields with
excellent regio- and stereoselectivities. Furthermore, the
cyclobutane derivatives can be easily, diastereo- and
enantioselectively converted into cyclopenta[b]benzofuran
structures catalyzed by In(OTf)3. Additionally, based on
Operando IR experiments, a conceivable reaction mechanism
was also proposed to comprehend the reaction process.
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14 Other o-substituted quinones (such as o-methyl-, o-
methoxyl-, o-bromo- and o-chloro quinone), substituted
fulvene (such as cyclohexyl substituted fulvene and 6,6-
dimethylfulvene) are sluggish for the [2+2] cycloaddition.
Notes and references
1
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16 CCDC 1476945 (3aa) and CCDC 1476944 (ent-4an).
4 | J. Name., 2012, 00, 1-3
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