Regioselective Asymmetric Formal (3+2) Cycloadditions of Nitrone Ylides from Isatins and Enals

Article abstract of DOI:10.1002/adsc.201600805

A highly regio-, diastereo- and enantioselective formal (3+2) cycloaddition reaction of nitrone ylides from isatins and α,β-unsaturated aldehydes was developed via iminium catalysis in the presence of an additional base, furnishing a spectrum of 1′-hydroxy-3,2′-pyrrolidinylspirooxindole frameworks. Interestingly, the regioselectivity could be finely switched in the reactions between nitrone ylides and crotonaldehyde by adding catalytic amounts of lithium perchlorate and copper(II) bromide. (Figure presented.).

Full text of DOI:10.1002/adsc.201600805

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DOI: 10.1002/adsc.201600805
Regioselective Asymmetric Formal (3+2) Cycloadditions of
Nitrone Ylides from Isatins and Enals
Yu-Rong Chen,a Gu Zhan,a Wei Du,a,* and Ying-Chun Chena,b,*
a
Key Laboratory of Drug-Targeting and Drug Delivery System of the Ministry of Education, West China School of
Pharmacy, Sichuan University, Chengdu 610041, Peopleꢀs Republic of China
Fax : (+86)-28-8550-1289 (WD) or (+86)-28-8550-2609 (YCC); e-mail: duweiyb@scu.edu.cn or ycchen@scu.edu.cn
College of Pharmacy, Third Military Medical University, Shapingba, Chongqing 400038, Peopleꢀs Republic of China
b
Received: July 23, 2016; Revised: September 25, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201600805.
Abstract: A highly regio-, diastereo- and enantiose-
lective formal (3+2) cycloaddition reaction of ni-
trone ylides from isatins and a,b-unsaturated alde-
hydes was developed via iminium catalysis in the
presence of an additional base, furnishing a spec-
trum of 1’-hydroxy-3,2’-pyrrolidinylspirooxindole
frameworks. Interestingly, the regioselectivity could
be finely switched in the reactions between nitrone
ylides and crotonaldehyde by adding catalytic
amounts of lithium perchlorate and copper(II) bro-
mide.
Eq. (1)].[4] Almost a decade later, the Merino group
presented a complete study on the reaction of similar
nitrone ylides with diverse activated alkenes, and
a full theoretical investigation of the reaction mecha-
nism favored a stepwise process.[5] Furthermore, alde-
hydes were applied to give 3-oxazolines in the pres-
ence of catalytic amounts of n-butyllithium
[Scheme 1, Eq. (2)].[6] As a matter of fact, the current
applicable nitrone ylides are limited to derivatives
from N-hydroxyglycinates. Moreover, to the best of
our knowledge, (3+2) cycloadditions with nitrone
ylides in a catalytic asymmetric manner has rarely
been explored.[7]
The oxindole skeleton is extensively witnessed in
natural products and synthetic bioactive materials,
and the reagents containing an oxindole motif also
provoke continuing attention in organic synthesis.[8]
We are interested in a readily available type of ni-
trone substances 1 between isatins and N-benzylhy-
Keywords: cycloaddition reaction; iminium cataly-
sis; nitrone ylides; regioselectivity; a,b-unsaturated
aldehydes
Nitrone reagents are widely applied as 1,3-dipoles in droxylamines.[9] We envisaged that the acidity of the
concerted (3+2) dipolar cycloaddition reactions, benzyl CH group would be significantly enhanced
given their ease of handling and the usefulness of the owing to the strong electron-withdrawing capacity of
isoxazolidine products.[1] In addition, the C=N double oxindole motif,[10] thus allowing the facile generation
bond in nitrones is a fundamentally electrophilic of nitrone ylide species I only under mild basic condi-
group in organic chemistry, which could be attacked tions. In addition, it is feasible that the umpolung ni-
by diverse nucleophiles, furnishing valuable N-hy- trone ylide intermediates II would be formed through
droxy substances.[2] On the other hand, nitrones bear- simple isomerization [Scheme 1, Eq. (3)].[11,12] As
ing a CH group adjacent to the N-atom can potential- a result, switchable regioselective (3+2) cycloaddi-
ly be deprotonated owing to the electron-withdrawing tions with a,b-unsaturated aldehydes might be accom-
effect of nitrone functionality, giving new different di- plished through the well-established chiral iminium
poles, nitrone ylides, which also can undergo (3+2) catalysis.[13]
cycloadditions with electron-poor alkenes like those
Consequently, we initially investigated the reaction
of the analogous azomethine ylides,[3] whereby poly- between nitrone 1a and cinnamaldehyde 2a in tolu-
substituted 1-hydroxypyrrolidines will be produced. ene, by employing chiral amine[13c] C1 and benzoic
Nevertheless, this kind of transformation is much less acid. However, no reaction occurred after 24 h at
exploited in spite of its potential synthetic utility. In 408C (Table 1, entry 1). Gratifyingly, by replacing the
2002, the Hanessian group successively reported the acid with catalytic amounts of triethylamine, the de-
(3+2) cycloadditions of nitrone ylides derived from sired (3+2) cycloaddition reaction proceeded
ethyl N-hydroxyglycinate with electron-deficient al- smoothly without the aid of a Lewis acid,[4,5] giving
kenes in the presence of LiBr and DBU [Scheme 1, two regioselective products 3a and 4a in a low ratio
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Scheme 1. Formal (3+2) cycloadditions of nitrone ylides.
after reduction with NaBH4,[14] but with excellent dia- was observed for the tested reactions, and the corre-
stereo- and enantioselectivity (major product 3a, sponding spirooxindoles could be directly isolated as
Table 1, entry 2). It should be noted that the direct pure isomers after reduction. At first, a spectrum of
(3+2) dipolar cycloaddition product of nitrone 1a nitrones derived from isatins and diverse N-arylmeth-
and enal 2a has not been detected.[15] Moreover, the yl- or heteroarylmethyl-hydroxylamines was explored
Michael addition adduct from nitrone ylide I and 2a in the reactions with cinnamaldehyde 2a, and prod-
could be detected in the reaction, indicating that the ucts 3a–3j were obtained in moderate to high yields
current (3+2) cycloaddition also proceeded in a step- with outstanding enantioselectivity (Table 2, en-
wise manner.[5,16] Subsequently, the solvent was found tries 1–10). Unfortunately, nitrones with simple N-
to have dramatic effect on the regioselectivity alkyl or N-allyl groups exhibited no reactivity.[18] Simi-
(Table 1, entries 3–6), and the product 3a was pro- lar good results were afforded by nitrones from vari-
duced exclusively in CH3CN in high efficiency ously substituted isatins and N-benzylhydroxylamine
(Table 1, entry 6). On decreasing the catalyst loadings (Table 2, entries 11–14). In addition, a,b-unsaturated
a longer time was required to achieve high conversion aldehydes bearing diverse b-aryl or b-heteroaryl
but with the retained selectivity (Table 1, entry 7). In groups could be well tolerated in the reactions with
addition, similar data were afforded by conducting nitrone 1a (Table 2, entries 15–19). Both 2-pentenal
the reaction at ambient temperature (Table 1, and 4-methyl-2-pentenal could deliver the corre-
entry 8). A few chiral amine catalysts with bulkier sponding products in excellent regioselectivity
groups were tested, whereby slightly inferior results (Table 2, entries 20 and 21); nevertheless, poor regio-
were generally obtained (Table 1, entry 9–12).
selectivity was observed for the reactions with croto-
With the optimized catalytic conditions in hand, we naldehyde and 2-hexenal, while excellent enantiose-
then investigated a variety of nitrone substrates from lectivity was obtained for both regioisomers (Table 2,
isatins and a,b-unsaturated aldehydes under the catal- entries 22 and 23). An N-MOM-protected nitrone
ysis of amine C1 (20 mol%) and TEA (20 mol%) in substrate also gave the product 3x in good results
CH3CN at 408C. The results are summarized in (Table 2, entry 24). A nitrone derived from isatins and
Table 2. In general, good to excellent regioselectivity N-hydroxyglycinates was also explored, smoothly
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Table 1. Screening studies on the formal (3+2) cycloaddi-
tion of nitrone 1a and cinnamaldehyde 2a.[a]
Table 2. Substrate scope and limitations.[a]
Entry R, R1
R2
Yield[b] [%] ee[c] [%]
1
2
3
4
5
6
7
8
Ph, H
4-MeC6H4, H
4-MeOC6H4, H Ph
Ph
Ph
3a, 90
3b, 85
3c, 80
3d, 81
3e, 82
3f, 85
3g, 73
3h, 71
3i, 71
3j, 87
3k, 80
3l, 69
3m, 72
3n, 68
3o, 80
3p, 75
3q, 75
98[d]
98
97
95
96
92
97
92
89
90
97
95
92
97
94
93
96
96
96
99
98
4-ClC6H4, H
2-BrC6H4, H
3-BrC6H4, H
4-CF3C6H4, H Ph
1-naphthyl, H Ph
3-furyl, H
2-thienyl, H
Ph, 5-Cl
Ph, 5-Br
Ph, 6-Br
Ph, 5-MeO
Ph, H
Ph, H
Ph, H
Ph, H
Ph, H
Ph, H
Ph, H
Ph, H
Ph, H
Ph
Ph
Ph
Entry Cat. Solvent t [h] Yield[b] [%] 3a/4a[c] ee[d] [%]
1
2
3
4
5
6
C1 toluene 24
C1 toluene 24
C1 CH2Cl2 24
C1 CHCl3 24
–
–
–
80
72
77
91
87
85
88
85
80
84
70
3:1
5:1
6:1
9:1
>19:1 98
>19:1 96
>19:1 97
>19:1 98
>19:1 97
>19:1 94
>19:1 95
95
95
94
98
9
Ph
Ph
Ph
Ph
Ph
Ph
3-ClC6H4
4-BrC6H4
3-MeC6H4
3-MeOC6H4 3r, 81
2-furyl
Et
i-Pr
Me
n-Pr
Ph
Ph
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22[e]
23[e]
24[f]
25
26[g]
C1 THF
C1 CH3CN
24
4
7[e]
8[f]
9
C1 CH3CN 13
C1 CH3CN 13
C2 CH3CN
6
10
11
12
C3 CH3CN 10
C4 CH3CN 12
C5 CH3CN 10
3s, 83
3t, 87
3u, 83
[a]
Reaction conditions: 1a (0.05 mmol), 2a (0.06 mmol), cat-
alyst (20 mol%), and TEA (20 mol%) in solvent
(0.5 mL) at 408C. Then the products were reduced with
NaBH4.
3v, 55 (27) 98 (98)
3w, 45 (38) 98 (98)[d]
Ph, H
CO2Et, H
Ph, H
3x, 76
3y, 75
3a, 69
97
93
97
[b]
[c]
[d]
Combined yield of isolated isomers for two steps.
1
Determined by H NMR analysis of crude mixture.
Determined by HPLC analysis on a chiral stationary
[a]
phase for 3a.
With 10 mol% of C1.
At room temperature.
Reaction conditions:
1
(0.15 mmol, PG=Me),
2
[e]
[f]
(0.18 mmol), amine C1 (20 mol%) and TEA (20 mol%)
in CH3CN (1.5 mL) at 40 8C. Then the products were re-
duced with NaBH4.
Isolated yield of 3 for two steps.
Determined by HPLC analysis on a chiral stationary
[b]
[c]
giving the corresponding product 3y in good outcome
(Table 2, entry 25). Finally, the reaction of 1a and 2a
was tested at a gram scale, and a moderate yield with
retained stereocontrol was observed after 24 h
(Table 2, entry 26). It should be noted that poor reac-
tivity was observed for the nitrone used by the
Merino group.[18]
Subsequently, we turned our attention to the poten-
tially switchable formal cycloaddition reaction via ni-
trone ylide II.[19] While all attempts were unsatisfacto-
phase.
[d]
[e]
The absolute configuration of 3a and 4w was determined
by X-ray analysis.[17] The other products were assigned by
analogy.
Data in parentheses referred to the isolated regioisomers
4.
PG=MOM.
With 3.76 mmol (1.0 g) of 1a, for 24 h.
[f]
[g]
ry for the reaction of nitrone 1a and cinnamaldehyde amounts of CuBr2 (0.3 mol%) could dramatically
2a,[18] we selected crotonaldehyde 2b as the electro- switch the regioselectivity, delivering the desired
phile since regioisomer 4v was apparently generated product 4v in high regio- and enantioselectivity
under the previously used conditions. We screened an (Table 3, entry 5). It should be noted that the amount
array of Lewis acids (Table 3, entries 1–5), and found of CuBr2 was crucial for the reaction, as the inferior
that the combination of LiClO4 (20 mol%) and small results were observed with lower or higher loadings
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Table 3. Screening studies on switchable formal (3+2) cy-
cloaddition of nitrone 1a and crotonaldehyde 2b.[a]
Table 4. Substrate scope and limitations of switchable formal
(3+2) cycloadditions of nitrones 1 and crotonaldehyde 2b.[a]
Entry x R, R1
t [h] 3/4[b] Yield[c] [%] ee[d] [%]
1
2
3
4
5
6
0.3 Ph, H
32
1:11 4v, 64
1:12 4z, 65
1:7 4a’, 56
1:15 4b’, 56
1:11 4c’, 63
1:7 4d’, 58
1:12 4e’, 60
1:8 4v, 51
94
93
96
86
95
95
94
92
Entry Additive
(mol%)
t
Yield[b]
3v/
ee[d]
[%]
0.5 4-ClC6H4, H 21
1.0 3-BrC6H4, H 25
0.5 1-naphthyl, H 72
0.3 3-furyl, H
0.5 Ph, 5-Cl
0.8 Ph, 5-OMe
0.3 Ph, H
[h] [%]
4v[c]
1
2
3
4
5
LiClO4 (20)
LiBF4 (20)
LiBr (20)
30 73
36 69
72 ND
72 ND
32 71
1:1.6
1:1.4
ND
ND
1:11
ND[e]
ND
ND
ND
92
22
22
22
72
7
CuBr2 (20)
LiClO4 (20)
CuBr2 (0.3)
LiClO4 (20)
CuBr2 (0.1)
LiClO4 (20)
CuBr2 (0.5)
LiClO4 (20)
CuCl2 (0.3)
LiClO4 (20)
Cu(OAc)2 (0.3)
LiClO4 (20)
Zn(OAc)2 (0.3)
LiClO4 (10)
CuBr2 (0.3)
8[e]
[a]
Reaction conditions: 1 (0.15 mmol), 2b (0.3 mmol), amine
C1 (20 mol%), TEA (40 mol%), LiClO4 (10 mol%) and
CuBr2 (x mol%) in toluene (1.5 mL) at 408C. Then the
products were reduced with NaBH4.
6
48 73
34 68
60 63
28 74
26 72
32 70
1:2
1:8
1:3
1:9
1:2
1:11
ND
92
7
[b]
[c]
[d]
1
Determined by H NMR analysis of crude mixture.
8
95
Yield of the isolated isomer 4 for two steps.
Determined by HPLC analysis on a chiral stationary
phase.
9
94
[e]
With 3.76 mmol (1.0 g) of 1a.
10
11
97
94
hyde 2b still proceeded smoothly at a gram scale,
albeit slightly decreased yields and stereoselectivity
were obtained (Table 4, entry 8). Unfortunately, a ni-
trone with an N-CH2CO2Et group showed poor reac-
tivity in the reaction with crotonaldehyde. In addition,
poor regioselectivity or reactivity was observed when
other enals were applied.[18]
In addition, the cycloaddition product 3a could be
diastereoselectively converted to the fused tetrahy-
drofuro[2,3-b]indole 5[20] in moderate yield with re-
tained ee value. Interestingly, by treatment with 10%
Pd/C, product 5 could be readily dehydrogenated to
[a]
Reaction conditions: 1a (0.05 mmol), 2b (0.1 mmol),
amine C1 (20 mol%), and TEA (40 mol%) and additive
in toluene (0.5 mL) at 408C. Then the products were re-
duced with NaBH4.
Combined yield of isolated isomers for two steps.
Determined by H NMR analysis of crude mixture.
[b]
[c]
[d]
1
Determined by HPLC analysis on a chiral stationary
phase for 4v.
ND=not determined.
[e]
of CuBr2 (Table 3, entries 6 and 7). Poorer results a new nitrone substance 6 in an excellent yield
were obtained when other Cu(II) and Zn(II) salts (Scheme 2). Unfortunately, attempts to reduce the hy-
were used (Table 3, entries 8–10). In addition, similar droxylamino group of 3a to give the corresponding
results could be achieved by decreasing the loadings pyrrolidine derivative failed, probably due to the
of LiClO4 (Table 3, entry 11).
steric hindrance.[18]
As a result, a few nitrones 1 were explored in the
In conclusion, we have explored the asymmetric
reactions with crontonaldehyde 2b under the opti- and regioselective formal (3+2) cycloadditions of ni-
mized catalytic conditions. The results are summar- trones from isatins and a,b-unsaturated aldehydes
ized in Table 4. The loadings of CuBr2 had to be through the in situ formation of nitrone ylides under
slightly modified to give optimal regioselectivity in mild basic conditions. The substrate scope was gener-
most cases, while good to high ratios could be gener- ally substantial, and a spectrum of highly enantioen-
ally obtained (Table 4, entries 1–7). The asymmetric riched 1’-hydroxy-3,2’-pyrrolidinylspiro-oxindoles was
cycloaddition reaction of nitrone 1a with crotonalde- constructed in moderate to good yields by employing
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were washed with brine and dried with anhydrous Na2SO4,
filtered and concentrated. The resulting crude product was
purified by chromatography on silica gel eluting with petro-
leum ether/ethyl acetate (6:1 to 3:1) to afford the product 4.
Acknowledgements
We are grateful for the financial support from the NSFC
(21125206, 21372160 and 21321061), and the Starting Foun-
dation for Young Teachers of Sichuan University
(2016SCU11009).
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(0.03 mmol) in MeCN (1.5 mL) was stirred at 408C for 12 h.
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Cycloaddition of 1 and 2b
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(0.3 mmol), triethylamine (0.06 mmol), secondary amine cat-
alyst C1 (0.03 mmol), LiClO4 (0.015 mmol) and CuBr2 (x
mmol) in toluene (1.5 mL) was stirred at 408C. After com-
pletion (monitored by TLC), the solvent was removed
under reduced pressure and the residue was directly dis-
solved in CH2Cl2 (1.5 mL). Then NaBH4 (0.45 mmol) was
added in one portion, and the mixture was stirred at room
temperature for 12 h. After completion (monitored by
TLC), the reaction was quenched with water and the mix-
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Supporting Information.
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These data can be obtained free of charge from The
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Adv. Synth. Catal. 0000, 000, 0 – 0
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ÞÞ
These are not the final page numbers!

COMMUNICATIONS
Regioselective Asymmetric Formal (3+2) Cycloadditions of
7
Nitrone Ylides from Isatins and Enals
Adv. Synth. Catal. 2016, 358, 1 – 7
Yu-Rong Chen, Gu Zhan, Wei Du,* Ying-Chun Chen*
Adv. Synth. Catal. 0000, 000, 0 – 0
7
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!