Cinchona alkaloid-derived thiourea-catalyzed diastereo- and enantioselective [3+2] cycloaddition reaction of isocyanoacetates to isatins: A facile access to optically active spirooxindole oxazolines

Article abstract of DOI:10.1002/adsc.201300077

An efficient diastereo- and enantioselective [3+2] cycloaddition reaction of α-aryl isocyanoacetates to isatins catalyzed by a quinine-derived bifunctional amine-thiourea-bearing sulfonamide as multiple hydrogen-bonding donor catalyst has been investigated. The corresponding adducts, which bear a spirocyclic quaternary stereocenter at the C-3 position of the oxindole, were obtained in good yields (51-95%), high diastereoselectivities (up to >20:1 dr) and good to excellent enantioselectivities (up to 97% ee). Copyright

Full text of DOI:10.1002/adsc.201300077

COMMUNICATIONS
DOI: 10.1002/adsc.201300077
Cinchona Alkaloid-Derived Thiourea-Catalyzed Diastereo-
and Enantioselective [3+2]Cycloaddition Reaction of
Isocyanoacetates to Isatins: A Facile Access to Optically Active
Spirooxindole Oxazolines
Mei-Xin Zhao,a,b,* Hao Zhou,a Wen-Hao Tang,a Wei-Song Qu,a and Min Shia,c,*
a
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and
Technology, 130 Mei Long Road, Shanghai 200237, Peopleꢀs Republic of China
Fax : (+86)-21-3420-1699; e-mail: mxzhao@ecust.edu.cn
CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences,
b
Beijing 100190, Peopleꢀs Republic of China
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
c
Sciences, 354 Fenglin Road, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-21-6416-6128; e-mail: Mshi@mail.sioc.ac.cn
Received: January 28, 2013; Published online: April 30, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300077.
Abstract: An efficient diastereo- and enantioselec-
tive [3+2]cycloaddition reaction of a-aryl isocya-
noacetates to isatins catalyzed by a quinine-derived
bifunctional amine-thiourea-bearing sulfonamide as
multiple hydrogen-bonding donor catalyst has been
investigated. The corresponding adducts, which
bear a spirocyclic quaternary stereocenter at the C-
3 position of the oxindole, were obtained in good
yields (51–95%), high diastereoselectivities (up to
>20:1 dr) and good to excellent enantioselectivities
(up to 97% ee).
cyanao amides with isatins[3a,b] or 3-isothiocyanatoox-
indoles with simple ketones[3c] followed by alkylation
of the thiocarbamates, leading to 2’-alkylthio-substi-
tuted spirooxindole oxazoline derivatives (Figure 1,
left). Herein, we report an efficient catalytic stereose-
lective method to access 2’-unsubstituted spirooxin-
dole oxazolines with two adjacent quaternary stereo-
centers (Figure 1, right) from readily available a-iso-
cyanoacetates 3 and isatins 2.
Isocyanides were found to be irreplaceable building
blocks for the synthesis of numerous important classes
of nitrogen heterocyclic compounds by the virtue of
the fact that the unique divalent features of the iso-
cyano group enable isocyanides to react smoothly
with both electrophiles and nucleophiles.[4] Further-
more, isocyanide-involving multicomponent and cas-
cade reactions have recently been developed.[5] Iso-
cyanoacetate 3, which combines several potential re-
action centers, such as an isocyano group, an acidic
Keywords: cycloaddition; isatins; isocyanoacetates;
organocatalysis; spiro compounds; synthetic meth-
ods
The oxindoles bearing a spirocyclic quaternary stereo- CH fragment and a protected carboxylic acid, have
center at the C-3 position have emerged as attractive shown exceptional reaction diversity and broad syn-
synthetic targets due to their appealing architectural
complexity and their prevalence in numerous natural
products and important biological active molecules.[1,2]
While several methods exist for the enantioselective
synthesis of different class of spirooxindoles, relying
on nucleophilic addition or annulation with alkylidene
oxindoles or isatins as a prochiral electrophilic oxin-
dole,[1] methods for the enantioselective synthesis of
spirooxindole oxazolines are rare.[3] Recently, Wang
and Yuan et al. have reported a convenient method
for the synthesis of spirobrassinin oxazoline analogues
using organocatalyzed aldol/cyclization of a-isothio- line structures by different nucleophiles.
Figure 1. Enantioselective synthesis of spirooxindole oxazo-
Adv. Synth. Catal. 2013, 355, 1277 – 1283
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1277

Mei-Xin Zhao et al.
COMMUNICATIONS
Figure 2. Catalysts screened.
thetic potential.[6] Stimulated by the pioneering works
The addition reaction of isatin 2a with isocyanoace-
of Ito and Hayashi,[7] Gong[8] et al., organometallic or tate 3a in THF at room temperature was selected as
organo-catalyzed asymmetric additions between iso- our model reaction. A variety of Cinchona alkaloid-
cyanoacetates with many electrophiles, including ni- derived catalysts 1a–l (Figure 2) was then tested in
troolefins,[8] aldehydes,[9] imines,[10] azodicarboxy- the model reaction and the results of these experi-
lates[11] and a,b-unsaturated carbonyl compounds,[12] ments are summarized in Table 1. O-Benzoyl-substi-
have been intensively studied in recent years. In most tuted Cinchona alkaloids, including BzQ (1a), BzQD
cases, chiral cyclic compounds were obtained in good (1b), O-Bz-cupreine (BzCPN, 1c) and O-Bz-cuprei-
yields.
dine (BzCPD, 1d), are not suitable catalysts for this
As a part of our ongoing interests in the asymmet- reaction, affording the corresponding product 4aa in
ric addition of isocyanoacetates, we have found that low yields along with low diastereoselectivities and
Ag(I)-Cinchona alkaloid squaramides cooperatively enantioselectivities (Table 1, entries 1–4). Quinine- or
catalyzed the enantioselective formal [3+2]cycloaddi- quinidine-derived bifunctional tertiary amine-thiourea
tion of isocyanoacetates to N-arylmaleimides.[12e] Con- catalysts 1e or 1f gave much better results, higher
sidering that isatin derivatives have emerged as new yields with higher stereoselectivities (Table 1, en-
electrophilic components for a variety of reactions tries 5 and 6). Further examination of Cinchona alka-
due to their high electrophilicity and have been loid-derived bifunctional amine-thiourea-bearing sul-
widely used in the synthesis of various spirooxindoles fonamides as multiple hydrogen-bonding donor cata-
via addition and spirocyclization,[1a–c] we envisaged lysts 1g–l revealed that quinine-derived catalyst 1g,
that the asymmetric addition of a-aryl isocyanoace- which has shown the best efficiency in the enantiose-
tates with isatins could provide a facile access to opti- lective Michael addition of 3-aryloxindoles to phenyl
cally active spirooxindoles with potential biological vinyl sulfone,[13] also exhibited higher catalytic activity
activity. To the best of our knowledge, there is no in this reaction. The reaction proceeded smoothly in
report on the organocatalyzed asymmetric addition of THF at room temperature to afford the desired
isocyanoacetates with isatin derivatives. Herein, we adduct 4aa in 75% yield, >20:1 dr along with 65% ee
wish to report our initial results.
(Table 1, entry 7). Replacing the Ms group of 1g with
the sterically more bulky Ts and 3,5-(CF3)2C6H3SO2
1278
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 1277 – 1283

Cinchona Alkaloid-Derived Thiourea-Catalyzed Diastereo- and Enantioselective [3+2]Cycloaddition
Table 1. Catalysts screening for enantioselective [3+2]cyclo-
addition reaction of isocyanoacetate 3a to isatin 2a.[a]
Table 2. Optimization of reaction conditions for the enantio-
selective [3+2]cycloaddition reaction of isocyanoacetate 3a
to isatin 2a catalyzed by 1g.[a]
Entry Solvent T [8C] t [h] Yield [%][b] dr[c]
ee [%][d]
1
2
3
4
5
6
7
8
THF
Et2O
TBME 20
EtOAc 20
20
20
48
48
48
48
48
48
48
48
48
48
48
48
10
5
75
89
75
70
81
86
76
78
44
80
89
70
63
94
96
87
93
88
75
>20:1 65
9:1 72
>20:1 52
10:1
18:1
19:1
15:1
15:1
12:1
5:1
56
37
34
46
40
53
52
Entry
Catalyst 1
Yield [%][b]
dr[c]
ee [%][d]
DCM
20
CHCl3 20
toluene 20
xylene 20
acetone 20
dioxane 20
CH3CN 20
MeOH 20
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
20
41
19
28
72
74
75
71
66
71
65
64
20:1
2:1
3:1
13
16[e]
13
1:1
31[e]
47
45
65
60
9
10
11
12
13[e]
14[f]
>20:1
15:1
>20:1
20:1
16:1
>20:1
5:1
>20:1 44
20:1
13:1
10:1
30
70
71
Et2O
Et2O
20
20
20
20
20
20
0
9
39
15[f,g] Et2O
16[f,h] Et2O
17[f,i] Et2O
18[f,j] Et2O
19[f,i] Et2O
1
2
24
36
55
>20:1 67
>20:1 76
>20:1 80
>20:1 80
10
11
12
1j
1k
1l
54[e]
63[e]
36[e]
9:1
[a]
Unless noted otherwise, all reactions were carried out
with isatin 2a (0.24 mmol), isocyanoacetate 3a
(0.20 mmol) and catalyst 1 (10 mol%) in THF (1.0 mL)
at 208C for 2 days.
4:1
70
[a]
Unless noted otherwise, all reactions were carried out
with isatin 2a (0.24 mmol), isocyanoacetate 3a
(0.20 mmol) and catalyst 1g (10 mol%) in solvent
(1.0 mL).
[b]
[c]
Yield of isolated product.
The dr of the purified product was determined by
[b]
[c]
1H NMR spectroscopy.
Yield of isolated product.
[d]
[e]
The dr of the purified product was determined by
The ee was determined by HPLC on a chiral stationary
phase.
The opposite enantiomer was obtained.
1H NMR spectroscopy.
[d]
The ee was determined by HPLC on a chiral stationary
phase.
The ratio of 2a/3a was 2:1.
The ratio of 2a/3a was 1:2.
0.5 mL of Et2O was used.
2.0 mL of Et2O were used.
4.0 mL of Et2O were used.
6.0 mL of Et2O were used.
[e]
[f]
[g]
[h]
[i]
groups gave the desired product 4aa in relatively
lower yields as well as lower diastereoselectivities and
enantioselectivities, presumably due to the steric hin-
drance of the hydrogen-bonding donor site of the cat-
alysts 1h and 1i (Table 1, entries 8 and 9). These re-
sults suggest that the strength and steric hindrance of
[j]
the hydrogen bonding donor may play important giving 4aa in good yields with lower enantioselectivi-
roles in the level of enantioselectivity. Quinidine-de- ties (Table 2, entries 4–8). Other polar solvents gave
rived catalysts 1j–l also promoted the reaction, but poor results as well (Table 2, entries 9–12). Upon
gave 4aa with opposite absolute configuration in tuning the ratio of 2a/3a, we found that the use of
much lower dr and ee values than the corresponding 2 equiv. of isocyanoacetate 3a was necessary because
quinine-derived catalysts 1g–i (Table 1, entries 10-12 decreasing the employed amount of 3a led to a longer
vs 7-9).
reaction time, lower yield and lower ee value (Table 2,
Solvent effects were then extensively studied. It entries 14 vs. 13 and 2). The examination of reactant
was found that although the reaction of isatin 2a with concentration revealed that lowering the concentra-
isocyanoacetate 3a proceeded smoothly in a wide tion could significantly improve the enantioselectivity
range of solvents, the ee values obtained varied dra- of 4aa without sacrificing the yield (Table 2, en-
matically (Table 2). Among the various solvents tries 15–18); the best enantioselectivity for 4aa was
screened, good dr and ee values were observed in obtained with a 0.05M solution of isatin 2a (Table 2,
ether solvents (Table 2, entries 1–3). Diethyl ether entry 17). The effect of temperature was also exam-
was found to be the best solvent for this reaction, af- ined, and it was found that lowering the reaction tem-
fording 4aa in up to 89% yield, 9:1 dr and 72% ee perature led to a decrease in enantioselectivity and
(Table 2, entry 2). In less polar solvents such as ethyl yield (Table 2, entry 19). Thus, the optimal reaction
acetate, chlorinated solvents and aromatic hydrocar- conditions have been identified as carrying out the re-
bon solvents, the reactions proceeded smoothly, action with 1.0 equiv. of 2a and 2.0 equiv. of 3a in di-
Adv. Synth. Catal. 2013, 355, 1277 – 1283
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1279

Mei-Xin Zhao et al.
COMMUNICATIONS
Table 3. Substrate scope of isatin derivatives 2 for the enan-
tioselective [3+2] cycloaddition reaction with isocyanoace-
tate 3a.[a]
were obtained in good yields along with excellent
enantioselectivities, albeit with lower diastereoselec-
tivities for N-benzyl-substituted substrates 2e and 2f
(Table 3, entries 5, 6, 15 and 16). Other isatin deriva-
tives, whether bearing electron-withdrawing or elec-
tron-donating groups at the 5- or 6-positions, gave the
desired products in moderate to good yields and ste-
reoselectivities, albeit isatins with electron-withdraw-
ing groups could give the corresponding products
Entry 2 [X, R]
4
Yield [%][b] dr[c]
ee [%][d] with much better results than those of the correspond-
ing isatins with electron-donating groups (Table 3, en-
1
2
3
4
5
6
7
8
2a [H, H]
2b [H, Bn]
2c [H, Me]
2d [H, Ph]
2e [4-Cl, Bn]
2f [4-Br, Bn]
2g [5-F, Bn]
2h [5-Cl, Bn]
2i [5-Br, Bn]
2j [5-Me, Bn]
2k [5-OMe, Bn] 4ka 90
2l [6-F, Bn]
2m [6-Cl, Bn]
2n [6-OMe, Bn] 4na 90
2o [4-Cl, H]
2p [4-Br, H]
4aa 93
4ba 74
4ca 69
4da 95
4ea 71
4fa 95
4ga 95
4ha 90
4ia 86
4ja 95
>20:1 80
tries 7–9 and 12–13 vs. entries 10, 11 and 14). It
should be noted that 5-methoxyisatin (2k) led to an
unexpected lower enantioselectivity than that of isatin
2a (Table 3, entry 11).
12:1
14:1
20:1
5:1
86
77
70
95[e]
93 (95)
The substrate scope of various a-substituted isocya-
noacetates was also evaluated (Table 4). For N-
benzyl-substituted isatin 2e, isocyanoacetates with
either an electron-withdrawing or electron-donating
group at the para position of the aromatic ring gave
their corresponding products in excellent yields and
enantioselectivities, but with low diastereoselectivities
(Table 4, entries 1 and 2). However, in the case of N-
unsubstituted isatin 2o, the substituents on phenyl
ring have a great impact on the enantioselectivities.
Isocyanoacetates bearing either an electron-withdraw-
ing or electron-donating groups at para- or meta-posi-
tions afforded the desired products with good yields
(up to 63–95%), excellent diastereoselectivities (up to
>20:1 dr) and lower enantioselectivities (85–94% ee)
than those of isocyanoacetate 3a (Table 4, entries 3–
9). A limitation was observed with an ortho-substitut-
ed aryl group, which showed no conversion (Table 4,
entry 10). Variation on the ester moiety was then con-
sidered. Compared with methyl isocyanoacetate 3a,
tert-butyl and benzyl isocyanoacetate 3j or 3k reacted
smoothly with isatin 2o to afford the desired products
in comparable yields and stereoselectivities, whereas
2:1
>20:1 90
>20:1 88
>20:1 80
9
10
11
12
13
14
15[f]
16
6:1
84
>20:1 73
>20:1 82
>20:1 81
>20:1 80
4la 92
4ma 88
4oa 82
4pa 87
15:1
97
>20:1 94
[a]
Unless noted otherwise, all reactions were carried out
with isatins (0.20 mmol), isocyanoacetate 3a
(0.40 mmol) and catalyst 1g (10 mol%) in Et2O (4.0 mL)
at 208C for 24 h.
2
[b]
[c]
Yield of isolated product.
The dr of the purified product was determined by
1H NMR spectroscopy.
[d]
The ee was determined by HPLC on a chiral stationary
phase; the value in parentheses is the ee of the minor
isomer.
Only for major isomer.
For 48 h
[e]
[f]
ethyl ether (0.05M for 2a) at 208C using 10 mol% of 3j gave the desired product in only moderate yield
1g as the catalyst. (Table 4, entries 11 and 12). The use of aliphatic iso-
The substrate scope of isatin derivatives was then cyanoacetates such as a-benzyl and unsubstituted iso-
examined under the optimized reaction conditions cyanoacetates 3m and 3n was also successful, albeit
and the results of these experiments are summarized with lower stereoselectivities. Using a-isopropyl iso-
in Table 3. In general, all of the isatin derivatives cyanoacetate 3l as the reactant, no reaction occurred
readily undergo this reaction to afford the desired ad- under the standard conditions (Table 4, entries 13–
ducts in moderate to high yields (69–95%) along with 15).
good to excellent stereoselectivities (up to >20:1 dr,
The absolute and relative configurations of 4 were
70–97% ee). The electronic and steric properties of unambiguously assigned by X-ray crystallographic
the substituent on the nitrogen and the aromatic ring analysis of the optically pure compound 4pa,[14] which
both played important roles in determining the reac- was obtained by recrystallization from a mixture of
tion outcomes. Isatin 2a and N-benzyl-substituted dichloromethane and hexanes (Table 3, entry 16). The
isatin 2b gave much better results than the corre- structure enabled the (3R,4’S) assignment of the
sponding N-methyl- and N-phenyl-substituted isatins newly formed stereogenic centers in 4pa (Figure 3).
2c and 2d; N-benzyl-substituted isatin 2b afforded the The configurations of other adducts 4 were then as-
best enantioselectivity (Table 3, entries 1–4). In the signed by analogy.
case of 4-substituted isatin derivatives 2e, 2f, 2o and
On the basis of the above results and commonly ac-
2p, the corresponding products 4ea, 4fa, 4oa and 4pa cepted mechanisms, a plausible transition-state model
1280
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 1277 – 1283

Cinchona Alkaloid-Derived Thiourea-Catalyzed Diastereo- and Enantioselective [3+2]Cycloaddition
Table 4. Substrate scope of isocyanoacetates 3 for the enantioselective [3+2]cycloaddition reaction with isatins 2e or 2o.[a]
Entry
2
3 [R2, R3]
4
Yield [%][b]
dr[c]
ee [%][d]
1
2
3
4
2e
2e
2o
2o
2o
2o
2o
2o
2o
2o
2o
2o
2o
2o
2o
3c [4-ClC6H4, Me]
3e [4-MeC6H4, Me]
3b [4-FC6H4, Me]
3c [4-ClC6H4, Me]
3d [4-BrC6H4, Me]
3e [4-MeC6H4, Me]
3f [4-MeOC6H4, Me]
3g [3-FC6H4, Me]
3h [3-MeC6H4, Me]
3i [2-MeC6H4, Me]
3j [Ph, t-Bu]
4ec
4ee
4ob
4oc
4od
4oe
4of
4og
4oh
4oi
4oj
4ok
4ol
4om
4on
94
95
90
88
90
95
95
93
63
–
51
80
–
92
87
7:1
3:1
95 (95)
96 (97)
94
92
92
91
85
92
91
n.d.
85
91
n.d.
80
27 (36)
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
–
>20:1
15:1
–
>20:1
2:1
5
6
7[e]
8
9
10
11[f]
12[e]
13
14[g]
15
3k [Ph, Bn]
3l [i-Pr, Me]
3m [Bn, Me]
3n [H, Et]
[a]
Unless noted otherwise, all reactions were carried out with isatins 2 (0.20 mmol), isocyanoacetates 3 (0.40 mmol) and cat-
alyst 1g (10 mol%) in Et2O (4.0 mL) at 208C for 24 h.
[b]
[c]
[d]
Yield of isolated product.
The dr of the purified product was determined by H NMR spectroscopy.
1
The ee was determined by HPLC on a chiral stationary phase; the data in parentheses are the ee values for the minor iso-
mers.
[e]
[f]
For 48 h.
For 168 h.
For 96 h.
[g]
Scheme 1. Proposed transition state model.
Figure 3. ORTEP drawing of 4pa.
tate and the tertiary amine. Simultaneously, hydrogen
bonds are formed between the two carbonyl groups
is proposed as shown in Scheme 1. The isocyanoace- of isatin and the multi-hydrogen bonding donor thio-
tate is deprotonated by the quinuclidine nitrogen of urea moiety of the catalyst to activate the carbonyl
catalyst 1g, resulting in a single H-bonding interaction group toward enolate attack and direct the orienta-
between the OH group of the enolized isocyanoace- tion of isatin. Additionally, the p–p stacking interac-
Adv. Synth. Catal. 2013, 355, 1277 – 1283
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1281

Mei-Xin Zhao et al.
COMMUNICATIONS
tion between the phenyl group of isocyanoacetate and Experimental Section
the isatin moiety might be formed concurrently, which
enables the enolized isocyanoacetate to attack much General Procedure for the Enantioselective
more easily the isatin from the Re-face, leading to the [3+2]Cycloaddition Reaction of Isocyanoacetates 3
formation of two newly generated stereocenters with with Isatins 2 under the Catalysis of 1g
(3R,4’S)-configuration. Subsequently,
a 5-endo-dig
To the solution of isatin 2 (0.2 mmol) and catalyst 1g
(0.02 mmol) in diethyl ether (4.0 mL) was added isocyanoa-
cetate 3 (0.4 mmol) at 208C. The resulting mixture was
stirred at 208C for 1–7 days until the reaction completed
(monitored by TLC). After concentration, the residue was
directly subjected to flash column chromatography on silica
gel (petroleum ether/ethyl acetate=2:1–4:1 or dichlorome-
thane/ethyl acetate=10:1 as eluent) to furnish the corre-
sponding cycloaddition product 4.
cyclization would take place by an intramolecular re-
action between the hydroxy group of the resulting
aldol intermediate and the isocyano group to afford
the observed spirocyclic product 4aa.
To further explore the synthetic utility of the
[3+2]cycloaddition products 4, we next explored their
transformation to the corresponding amino acid deriv-
atives by hydrolysis or reduction with oxazolines.[9]
However, an isatin rather than an amino acid deriva-
tive was obtained due to the decomposition of
adduct, probably owing to the instability of spirooxa-
zoline in the presence of various acids and reductive
reagents.[15] However, spirooxindole oxazolidine 5 can
be obtained from adduct 4ba by Meyers N-methyla-
tion–reduction procedure (MeOTf-NaBH4) in high
yield and without influencing the enantioselectivity
(Scheme 2).[16]
AHCTUNGTREG(NNUN 3R,4’S)-Methyl 2-oxo-4’-phenyl-4’H-spiro[indoline-3, 5’-
oxazole]-4’-carboxylate (4aa): Yield: 59.8 mg (93%); >20:1
dr; white solid; mp 89.3–93.28C; [a]2D5: À31.9 (c=0.5,
CH2Cl2) (80% ee); HPLC (Chiralpak AD-H, hexane/2-prop-
anol=80/20, 0.9 mLminÀ1, 254 nm): tmajor =16.68 min, tminor
=
31.01 min; 1H NMR (400 MHz, CDCl3): d=8.74 (s, 1H),
7.54 (s, 1H), 7.33–7.27 (m, 5H), 7.19 (t, J=7.6 Hz, 1H), 6.90
(d, J=7.6 Hz, 1H), 6.58 (t, J=7.6 Hz, 1H), 5.68 (d, J=
7.6 Hz, 1H), 3.80 (s, 3H); 13C NMR (100 MHz, CDCl3): d=
176.2, 170.8, 155.5, 142.6, 134.5, 131.0, 128.8, 128.1, 127.2,
127.0, 122.7, 122.0, 110.6, 88.3, 85.6, 53.3; IR (film): n=3288,
1751, 1645, 1616, 1590, 1449, 1251, 1179, 1095, 1014 cmÀ1
;
MS (EI): m/z=322 (M+, 21%), 279 (13), 175 (100), 148 (93),
104 (60), 77 (18); HR-MS (EI); m/z=322.0956, calcd. for
C18H14N2O4 (M+): 322.0954.
Acknowledgements
We are grateful for financial support from the National Natu-
ral Science Foundation of China (20772030, 21072056,
21272067), the Fundamental Research Funds for the Central
Universities, Scientific Research Foundation for the Returned
Overseas Chinese Scholars, and State Education Ministry.
Scheme 2. Synthetic transformation of cycloaddition adduct
4ba.
In conclusion, we have developed an efficient dia-
stereo- and enantioselective [3+2]cycloaddition reac-
tion of a-aryl isocyanoacetates to isatins catalyzed by
a quinine-derived bifunctional amine-thiourea-bearing
multiple hydrogen-bonding donor catalyst. A wide va-
riety of substituted isatins and a-aryl isocyanoace-
tates, with different electronic and steric properties,
was tolerated in this catalytic enantioselective
[3+2]cycloaddition reaction, leading to optically
active 2-oxo-4’H-spiro[indoline-3,5’-oxazole] deriva-
tives in high yields (51–95%) along with good to ex-
cellent diastereo- and enantioselectivities (up to
>20:1 dr, up to 97% ee). Investigations aimed at fully
understanding the reaction mechanism and develop-
ing more effective addition reactions of isocyanoace-
tates with other electrophiles are ongoing.
References
[1] For recent reviews and references cited therein, see:
a) G. S. Singh, Z. Y. Desta, Chem. Rev. 2012, 112, 6104–
6155; b) L. Hong, R. Wang, Adv. Synth. Catal. 2013,
355, 1023–1052; c) N. R. Ball-Jones, J. J. Badillo, A. K.
Franz, Org. Biomol. Chem. 2012, 10, 5165–5181; d) J. J.
Badillo, N. V. Hanhan, A. K. Franz, Curr. Opin. Drug
Discovery Dev. 2010, 13, 758–776; e) J. S. Russel,
Topics in Heterocyclic Chemistry, 2010, Vol. 26, (Heter-
ocyclic Scaffolds II), pp 397–431; f) F. Zhou, Y.-L. Liu,
J. Zhou, Adv. Synth. Catal. 2010, 352, 1381–1407;
g) B. M. Trost, M. K. Brennan, Synthesis 2009, 3003–
3025; h) C. V. Galliford, K. A. Scheidt, Angew. Chem.
2007, 119, 8902–8912; Angew. Chem. Int. Ed. 2007, 46,
8748–8758; i) R. M. Williams, R. J. Cox, Acc. Chem.
Res. 2003, 36, 127–139; j) H. Lin, S. J. Danishefsky,
Angew. Chem. 2003, 115, 38–53; Angew. Chem. Int. Ed.
2003, 42, 36–51; k) C. Marti, E. M. Carreira, Eur. J.
Org. Chem. 2003, 2209–2219.
1282
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 1277 – 1283

Cinchona Alkaloid-Derived Thiourea-Catalyzed Diastereo- and Enantioselective [3+2]Cycloaddition
[2] For recent examples, see: a) S. M. Rajesh, S. Perumal,
J. C. Menendez, P. Yogeeswari, D. Sriram, MedChem-
Comm 2011, 2, 626–630; b) J. Schonhaber, T. J. J.
Muller, Org. Biomol. Chem. 2011, 9, 6196–6199;
c) B. K. S. Yeung, B. Zou, M. Rottmann, S. B. Lakshmi-
narayana, S. H. Ang, S. Y. Leong, J. Tan, J. Wong, S.
Keller-Maerki, C. Fischli, A. Goh, E. K. Schmitt, P.
Krastel, E. Francotte, K. Kuhen, D. Plouffe, K.
Henson, T. Wagner, E. A. Winzeler, F. Petersen, R.
Brun, V. Dartois, T. T. Diagana, T. H. Keller, J. Med.
Chem. 2010, 53, 5155–5164; d) V. Vintonyak, K. War-
burg, H. Kruse, S. Grimme, K. Hꢂbel, D. Rauh, H.
Waldmann, Angew. Chem. 2010, 122, 6038–6041;
Angew. Chem. Int. Ed. 2010, 49, 5902–5905; e) A. P.
Antonchick, C. Gerding-Reimers, M. Catarinella, M.
Schꢂrmann, H. Preut, S. Ziegler, D. Rauh, H. Wald-
mann, Nat. Chem. 2010, 2, 735–740; f) S. R. Yong, A. T.
Ung, S. G. Pyne, B. W. Skelton, A. H. White, Tetrahe-
dron 2007, 63, 5579–5586.
[3] a) X. Jiang, Y. Cao, Y. Wang, L. Liu, F. Shen, R. Wang,
J. Am. Chem. Soc. 2010, 132, 15328–15333; b) J. Guang,
C.-G. Zhao, Tetrahedron: Asymmetry 2011, 22, 1205–
1211; c) W.-B. Chen, Z.-J. Wu, J. Hu, L.-F. Cun, X.-M.
Zhang, W.-C. Yuan, Org. Lett. 2011, 13, 2472–2475.
[4] For a recent review and references cited therein, see:
A. V. Lygin, A. de Meijere, Angew. Chem. 2010, 122,
9280–9311; Angew. Chem. Int. Ed. 2010, 49, 9094–9124.
[5] For recent reviews, see: a) J. Wu, S. Cao, Curr. Org.
Chem. 2009, 13, 1791–1804; b) L. El Kaim, L. Grimaud,
Tetrahedron 2009, 65, 2153–2171; c) A. Dçmling, Chem.
Rev. 2006, 106, 17–89; d) J. Zhu, Eur. J. Org. Chem.
2003, 1133–1144; e) V. Nair, C. Rajesh, A. U. Vinod, S.
Sreekanth, A. R. Bindu, J. S. Mathen, L. Balagopal,
Acc. Chem. Res. 2003, 36, 899–907; f) A. Dçmling, I.
Ugi, Angew. Chem. 2000, 112, 3300–3344; Angew.
Chem. Int. Ed. 2000, 39, 3168–3210.
wamura, H. Hamashima, Y. Ito, Tetrahedron Lett. 1991,
32, 2799–2802.
[8] C. Guo, M.-X. Xue, M.-K. Zhu, L.-Z. Gong, Angew.
Chem. 2008, 120, 3462–3465; Angew. Chem. Int. Ed.
2008, 47, 3414–3417.
[9] a) M.-X. Xue, C. Guo, L.-Z. Gong, Synlett 2009, 2191–
2197; b) F. Sladojevich, A. Trabocchi, A. Guarna, D. J.
Dixon, J. Am. Chem. Soc. 2011, 133, 1710–1713;
c) H. Y. Kim, K. Oh, Org. Lett. 2011, 13, 1306–1309.
[10] a) Z.-W. Zhang, G. Lu, M.-M. Chen, N. Lin, Y.-B. Li, T.
Hayashi, A. S. C. Chan, Tetrahedron: Asymmetry 2010,
21, 1715–1721; b) S. Nakamura, Y. Maeno, M. Ohara,
A. Yamamura, Y. Funahashi, N. Shibata, Org. Lett.
2012, 14, 2960–2963.
[11] D. Monge, K. L. Jensen, I. Marꢃn, K. A. Jørgensen,
Org. Lett. 2011, 13, 328–331.
[12] a) C. Arrꢄniz, A. Gil-Gonzꢅlez, V. Semak, C. Escolano,
J. Bosch, M. Amat, Eur. J. Org. Chem. 2011, 3755–
3760; b) J. Song, C. Guo, P.-H. Chen, J. Yu, S.-W. Luo,
L.-Z. Gong, Chem. Eur. J. 2011, 17, 7786–7790; c) L.-L.
Wang, J.-F. Bai, L. Peng, L.-W. Qi, L.-N. Jia, Y.-L. Guo,
X.-Y. Luo, X. Xu, L.-X. Wang, Chem. Commun. 2012,
48, 5175–5177; d) S. Padilla, J. Adrio, J. C. Carretero, J.
Org. Chem. 2012, 77, 4161–4166; e) M.-X. Zhao, D.-K.
Wei, F.-H. Ji, X.-L. Zhao, M. Shi, Chem. Asian J. 2012,
7, 2777–2781; f) J.-F. Bai, L.-L. Wang, L. Peng, Y.-L.
Guo, L.-N. Jia, F. Tian, G.-Y. He, X.-Y. Xu, L.-X.
Wang, J. Org. Chem. 2012, 77, 2947–2953.
[13] M.-X. Zhao, W.-H. Tang, M.-X. Chen, D.-K. Wei, T.-L.
Dai, M. Shi, Eur. J. Org. Chem. 2011, 6078–6084.
[14] CCDC 913186 (for 4pa) contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
[15] Isatin was obtained in low yields when treating the
adduct 4 with SOCl2-MeOH, HCl-MeOH, silica gel,
wet chloroform, etc. Moreover, a complex reaction
mixture was obtained in the presence of LiAlH4 or
Pd/C.
[16] C. Alvarez-Ibarra, A. G. Csꢅkꢆ, E. Martꢃnez-Santos,
M. L. Quiroga, J. L. Tejedor, Tetrahedron 1999, 55,
3041–3060.
[6] For a recent review on isocyanoacetates, see: A. V. Gu-
levich, A. G. Zhdanko, R. V. A. Orru, V. G. Nenajden-
ko, Chem. Rev. 2010, 110, 5235–5331.
[7] a) Y. Ito, M. Sawamura, T. Hayashi, J. Am. Chem. Soc.
1986, 108, 6405–6406; b) Y. Ito, M. Sawamura, T. Haya-
shi, Tetrahedron Lett. 1987, 28, 6215–6218; c) T. Haya-
shi, M. Sawamura, Y. Ito, Tetrahedron 1992, 48, 1999–
2012; d) T. Hayashi, Y. Uozumi, A. Yamazaki, M. Sa-
Adv. Synth. Catal. 2013, 355, 1277 – 1283
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1283