Construction of spiro[indoline]oxindoles through one-pot thermal-induced [3+2] cycloaddition/silica gel-promoted fragmentation sequence between isatin ketonitrones and electron-deficient alkynes

Article abstract of DOI:10.1016/j.tet.2013.03.062

One-pot thermal-induced [3+2] cycloaddition/silica gel-promoted fragmentation sequence between isatin ketonitrones and electron-deficient alkynes affords spiro[indoline]oxindoles in moderate to excellent yields along with good diastereoselectivities. The

Full text of DOI:10.1016/j.tet.2013.03.062

Tetrahedron xxx (2013) 1e10
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Construction of spiro[indoline]oxindoles through one-pot
thermal-induced [3þ2] cycloaddition/silica gel-promoted
fragmentation sequence between isatin ketonitrones
and electron-deficient alkynes
,
y
*
*
Hai-Bin Yang, Yin Wei , Min Shi
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
One-pot thermal-induced [3þ2] cycloaddition/silica gel-promoted fragmentation sequence between
isatin ketonitrones and electron-deficient alkynes affords spiro[indoline]oxindoles in moderate to ex-
cellent yields along with good diastereoselectivities. The detailed mechanism of silica gel-promoted
fragmentation has been clarified by experiment and DFT calculations.
Received 30 January 2013
Received in revised form 11 March 2013
Accepted 15 March 2013
Available online xxx
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Isatin ketonitrone
[
3þ2] Cycloaddition
Silica gel
CeC bond cleavage
Spiro[indoline]oxindoles
1. Introduction
good yields under mild conditions. Therefore, we attempted to use
isatin ketonitrones as substrates to prepare some novel spiroox-
Spirooxindoles are privileged structural motifs found in many
alkaloids and unnatural biologically active compounds. Inspired by
indoles, subsequently enriching the structural motifs of spiroox-
indole cores.
1
these important scaffolds, a variety of synthetic methods for pro-
ducing spirooxindoles, especially applications to natural product
synthesis, have been investigated over the last decade.
In general, nitrones react energetically with electron-deficient
alkynes, such as acetylenedicarboxylate to form 4-isoxazoline as
intermediates and products. However, 4-isoxazolines, due to the
2
8
In organic chemistry much attention has been focused on the
syntheses and reactions of nitrones because of their importance as
synthetic tools. In fact, many reports have appeared on the use of
presence of a weak nitrogeneoxygen bond and the carbonecarbon
p
system, undergo many types of rearrangements to afford dif-
3
9
10
ferent heterocycles, such as 2-acylaziridine, 4-oxazoline,
1H-pyrrole-2,3-dione, and indoline (Scheme 1). The type of
11
12
nitrone as reagents, especially in the 1,3-dipolar cycloaddition re-
actions in which nitrones occupy a uniquely important position due
1
2
3
rearrangements depends on the substituents of R , R , and R .
Among these heterocycles, 2-acylaziridine is unstable and can
rearrange to azomethine ylides through CeC bond cleavage, which
is different from those of simple aziridines, which usually undergo
CeN bond cleavage. Tsuge and co-workers have reported that
2-acylaziridine generated by treating nitrone with acetylenedi-
carboxylate (DMAD) can be trapped by intramolecular alkene
linkage to construct pyrrolidine structural motif (Scheme 2, Eq.
4
to their synthetic significance. However, to the best of our
knowledge, there are a few reports on cycloadditions of isatin
5
ketonitrones because isatin ketonitrones are hard to be prepared
13
by simple condensation reaction between isatin and arylhydrox-
6
ylamine. During our ongoing investigations on the cycloaddition
7
reactions using isatin derivatives, we discovered that trifluoro-
acetic acid can efficiently promote the condensation of isatin with
N-arylhydroxylamine, affording a variety of isatin ketonitrones in
14
1). Recently, Zhang and co-workers have disclosed that aziridine
can react with electron-rich alkene in the presence of Lewis acid
15
through CeC cleavage of aziridine. Inspired by these results, we
envisioned that the combination of isatin ketonitrone 1a, DMAD
2a, and dihydropyran 3 in the presence of Lewis acid or upon
*
y
Corresponding authors. E-mail address: Mshi@mail.sioc.ac.cn (M. Shi).
Fax: þ86 21 64166128.
0
040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.062
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2
H.-B. Yang et al. / Tetrahedron xxx (2013) 1e10
difficulty in analyzing spectroscopic data of the crude product (low
diastereoselectivity) and purification, we decided to adopt a strat-
egy of adding silica gel to the reaction mixture after completion of
thermal-induced [3þ2] cycloaddition. This strategy offered an ef-
ficient and stereoselective access to construct 2-spiroindoline,
which is a privileged structural motif found in many alkaloids and
unnatural biologically active compounds. The closely related
structural motif is mytragynine pseudoindoxyl 2, which is a potent
anti-viral agent that displays promising anticancer properties
16
(
Fig. 1). Although radical dearomatising spirocyclisation onto C-2
Scheme 1. The generation of 4-oxazoline via [3þ2] cycloaddition between nitrone and
electron-deficient alkyne and the related rearrangement.
Fig. 1. The structure of mytragynine pseudoindoxyl.
Δ
Scheme 2. Our original thinking and the experimental result.
heating may produce product 5. After examining the reaction
outcome, interestingly, product 4a was obtained in good yield
along with good diastereoselectivity rather than the anticipated
position of indole can afford this structural motif, this synthetic
procedure must use toxic Bu SnH or air-sensitive SmI and is un-
3
2
17
suitable for substrate containing halides (Br or I). Moreover, C-3
position of the product obtained by radical dearomatising spi-
rocyclisation onto C-2 position of indole cannot be functionalized,
which is unfavorable to a diversity-oriented synthetic strategy.
Herein, further exploration of methodologies for synthesizing this
structural motif is highly desirable and we wish to report our re-
sults in this context.
product 5, and dihydropyran 3 did not participate in the reaction
1
(
Scheme 2, Eq. 2). On the basis of analyzing H NMR spectroscopic
data, we found that compound 4a purified by flash chromatogra-
phy (silica gel) was different from the crude product obtained by
removing the solvent in vacuo, thus we thought that silica gel must
promote some transformation of the crude product. Due to the
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H.-B. Yang et al. / Tetrahedron xxx (2013) 1e10
3
2
. Results and discussion
Initial studies using nitrone 1a as the substrate were aimed at
determining the reaction outcome and subsequently optimizing the
reaction conditions. The results are summarized inTable 1. We found
that compound 4a was formed in 61% yield along with 11:1 dia-
stereoselectivity when 200 mg of 300e400 mesh silica gel was
ꢀ
subjected to the resulting mixture at 80 C for 2 h after 1a (1.0 equiv)
ꢀ
and 2a (1.5 equiv) were stirred in 1,2-dichloroethane (DCE) at 60 C
for 12 h (Table 1, entry 1). The structure of compound 4a was con-
firmed by NMR spectroscopic data and X-ray diffraction. The ORTEP
drawing is shown in Fig. 2 and the CIF data are presented in the
Supplementary data.18 The examination of solvent effects using 1a
(
1.0 equiv) and 2a (1.5 equiv) as substrates revealed that toluene was
the solvent of choice, giving the desired product 4a in 62% yield
along with 12:1 dr value (Table 1, entries 2e8). The temperature has
significant influence in this reaction. Screening of the reaction
ꢀ
temperature revealed that 80 C gave the best result with respect to
yield as well as diastereoselectivity and carrying out the reaction at
ꢀ
1
00 C afforded 4a in 35% yield along with 9:1 dr value (Table 1,
ꢀ
entries 9 and 11). When nitrone 1a, electron-deficient alkyne 2a, 4 A
MS, and 300e400 mesh silica gel were stirred together in 1 mL of
ꢀ
toluene at 80 C for 12 h instead of adding silica gel stepwise, com-
pound 4awas obtained in 60% yield along with 10:1 dr value (Table 1,
entry 10). Increasing the ratio of 1a/2a to 1:3 (3.0 equiv of 2a was
used) indicated that the reaction proceeded smoothly to afford 4a in
Fig. 2. ORTEP drawing of compound 4a.
9
0% yield along with 14:1 dr value (Table 1, entry 12). Because the
intermediate could be completely transformed to compound 4a
with 200 mg silica gel under the mild conditions and the low price of
silica gel, we did not further investigate the effect of the ratio of silica
gel to this reaction. Thus, we have established the optimal reaction
conditions for this reaction: after 1a (1.0 equiv) and 2a (3.0 equiv)
configuration for the major diastereoisomers of products is the
same as that for compound 4a. As for isatin ketonitrones, re-
gardless of whether R is electron-withdrawing group (Cl) or
1
moderately electron-donating group (Me), the corresponding
products 4b,c could be obtained in good yields along with good
diastereoselectivities (Table 2, entries 1 and 2). In the cases of
substrates 1def, the reactions proceeded smoothly to furnish the
desired products 4de4f in higher yields for electron-donating
ꢀ
were stirred in toluene at 80 C for 12 h, 200 mg of 300e400 mesh
silica gel was added to the resulting mixture and the reaction mix-
ꢀ
ture was then further stirred at 80 C for 2 h.
2
1
3
With these optimal conditions in hand, we examined the
substrate generality of this reaction to the substituted isatin-de-
rived nitrones and the results are shown in Table 2. The
group (product 4d, R ¼Me, R ¼R ¼H) substituted isatin ketoni-
trones and higher diastereoselectivities for electron-withdrawing
group (product 4e or 4f, R ¼Cl or Br, R ¼R ¼H) substituted isatin
2
1
3
Table 1
Optimization of the reaction conditions
O
Ph
N
HN
CO Me
2
1
2
) 4 MS, solvent, T
) additive, 80 C
O + MeO C
CO Me
O
2
2
o
N
N
2
a
4a
1a
Entrya
1a/2a
Solvent
Temp ( C)
ꢀ
Additive
drb
Yieldc (%)
1
2
3
4
5
6
7
8
9
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:3
DCE
DMF
60
60
60
60
60
60
60
60
80
80
100
80
Silica gel
Silica gel
Silica gel
Silica gel
Silica gel
Silica gel
Silica gel
Silica gel
Silica gel
Silica gel
Silica gel
Silica gel
11:1
d
61
<1
39
32
62
45
35
47
78
60
35
90
Ethanol
Dioxane
Toluene
Acetonitrile
n-Hexane
Chloroform
Toluene
Toluene
Toluene
Toluene
8:1
7:1
12:1
13:1
10:1
12:1
14:1
10:1
9:1
1
1
1
0d
1
2
14:1
Bold signifies optimal conditions.
a
ꢀ
Nitrone 1a (0.1 mmol), alkyne 2a (ꢁmmol), and 4 A MS (100 mg) were stirred in 1 mL of solvent. After 12 h, 200 mg of 300e400 mesh silica gel was added and the resulting
ꢀ
mixtures were stirred for 2 h at 80 C.
b
The dr values were determined by 1H NMR spectroscopic data of the crude products.
c
Isolated yields.
d
ꢀ
Nitrone 1a, alkyne 2a, 4 A MS (100 mg), and 300e400 mesh silica gel (200 mg) were stirred in 1 mL of toluene.
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4
H.-B. Yang et al. / Tetrahedron xxx (2013) 1e10
Table 2
Scope of one-pot thermal-induced [3þ2] cycloaddition/silica gel-promoted fragmentation sequence to the substituted isatins derived nitrones
O
N Ph
O + MeO C
HN
R1
R1
2
CO Me
o
1
) 4Å MS, toluene, 80 C, 12 h
CO Me
O
2
2
o
R2
N
2) 300-400 mesh silica gel, 80 C, 2 h
R2
N
R4
R3
1
R4
2a
R3
4
Entrya
R /R /R /R
1
2
3
4
drb
Yieldc (%)
1
2
3
4
5
6
7
8
9
1b, Me/H/H/Me
1c, Cl/H/H/Me
1d, H/Me/H/Me
1e, H/Cl/H/me
1f, H/Br/H/Me
1g, H/H/Cl/Me
1h, H/H/F/me
1i, H/H/H/Bn
1j, H/H/H/H
17:1
14:1
15:1
25:1
25:1
9:1
8:1
15:1
10:1
4b, 70
4c, 73
4d, 72
4e, 62
4f, 64
4g, 87
4h, 76
4i, 78
4j, 62
a
ꢀ
Nitrone 1a (0.1 mmol), alkyne 2a (3 mmol), and 4 A MS (100 mg) were stirred in 1 mL of toluene. After 12 h, 200 mg of 300e400 mesh silica gel was added and the resulting
ꢀ
mixtures were stirred for 2 h at 80 C.
b
The dr values were determined by 1H NMR spectroscopic data of the crude products.
c
Isolated yields.
ketonitrones (Table 2, entries 3e5). As for isatin ketonitrones with
electron-withdrawing group R , such as Cl and F, the reactions
this reaction and the results are shown in Table 3. It was found that
whether R is an electron-withdrawing group (Cl) or a moderately
3
5
proceeded efficiently to afford the corresponding products 4g,h in
increased yields, albeit with slightly lower diastereoselectivities
electron-donating group (Me), the corresponding products 4k,l
could be formed in moderate yields along with good dr values
(Table 3, entries 1 and 2). Compared with substrate 1n having an
electron-withdrawing group (Cl), the reaction could give better
results in terms of yield and diastereoselectivity for substrate 1m
having electron-donating group (Me) (Table 3, entries 3 and 4).
(
Table 2, entries 6 and 7). Changing the N-PG (PG¼Protecting
Group) to Bn produced the corresponding product 4i in 78% yield
along with 15:1 diastereoselectivity and substrate 1j having no
protecting group (PG¼H) afforded the desired product 4j in 62%
yield along with 10:1 diastereoselectivity. The yield and diaster-
eoselectivity for substrate 1i are better than those of substrate 1j,
indicating that the protecting group could improve the reaction
outcomes (Table 2, entries 8 and 9).
7
Interestingly, when R is an electron-withdrawing group (Br), the
corresponding product 4o was obtained in excellent yield along
with 14:1 dr value (Table 3, entry 5). Subsequently, a variety of
electron-deficient alkynes were tested for this reaction sequence
with isatin ketonitrone 1a. The reaction proceeded smoothly for
electron-deficient alkyne 2b to afford 4p in 78% yield and 21:1 dr
We next investigated the effects of the substituted phenyl-
hydroxylamine derived nitrones and electron-deficient alkynes to
Table 3
Scope of one-pot thermal-induced [3þ2] cycloaddition/silica gel-promoted fragmentation sequence to the substituted phenylhydroxylamine derived nitrones and electron-
deficient alkynes
R6
R7
R6
R5
R5
R7
O
N
HN
9
CO R
o
2
1
) 4Å MS, toluene, 80 C, 12 h
O
+
R8
R9
O
o
2
) 300-400 mesh silica gel, 80 C, 2 h
N
N
1
2
4
Entrya
R /R /R
5
6
7
R8/R9
drb
Yieldc (%)
1
2
3
4
5
6
7
8
1k, Me/H/H
1l, Cl/H/H
2a, CO
2a, CO
2a, CO
2a, CO
2a, CO
2b, CO
2c, H/CO
2d, H/COMe
2
2
2
2
2
Me/CO
Me/CO
Me/CO
Me/CO
Me/CO
2
2
2
2
2
Me
Me
Me
Me
Me
13:1
18:1
15:1
8:1
14:1
21:1
17:1
15:1
4k, 71
4l, 67
1m, H/Me/H
1n, H/Cl/H
1o, H/H/Br
1a, H/H/H
1a, H/H/H
1a, H/H/H
4m, 63
4n, 57
4o, 93
4p, 78
4a, 94
4q, 69
2
2
Et/CO Et
2
Me
a
ꢀ
Nitrone 1a (0.1 mmol), alkyne 2a (3 mmol), and 4 A MS (100 mg) were stirred in 1 mL of toluene. After 12 h, 200 mg of 300e400 mesh silica gel was added and the resulting
ꢀ
mixtures were stirred for 2 h at 80 C.
b
The dr values were determined by 1H NMR spectroscopic data of the crude products.
c
Isolated yields.
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H.-B. Yang et al. / Tetrahedron xxx (2013) 1e10
5
value (Table 3, entry 6). In the case of substrate 2c, the reaction also
proceeded smoothly to furnish the corresponding product 4a in
better yield and diastereoselectivity as compared with that of
substrate 1a and electron-deficient alkyne 2a (Table 3, entry 7).
It was noteworthy that but-3-yn-2-one could be also subjected to
this reaction, providing 4q in 69% yield and 15:1 dr value (Table 3,
entry 8).
To elucidate the detailed mechanism, the crude product before
treating with silica gel was purified by recrystallization using
1
diethyl ether. On the basis of carefully analyzing H NMR spectro-
scopic data and 13C NMR spectroscopic data, the crude product
before treating with silica gel has been identified as compound 6
along with 1.6:1 dr value, and HRMS data further support our
judgment. Treatment of compound 6 with 300e400 mesh silica gel
ꢀ
in toluene at 80 C for 12 h can furnish compound 4a in 92% yield
along with 14:1 diastereoselectivity, strongly supporting that
compound 6 is a key intermediate to the formation of compound 4a
(
Scheme 3). On the basis of the mechanism proposed by Maruoka
12
and co-workers, a plausible mechanism is tentatively outlined in
Scheme 4 to explain the formation of compound 6. The reaction is
initiated by the formation of 4-isoxazoline a via the [3þ2] cyclo-
addition between isatin ketonitrone 1a and electron-deficient al-
kyne, which rearranges to give intermediate b because of the weak
Scheme 5. The proposed reaction mechanism for silica gel-promoted CeC bond
cleavage at the a-position of 2-oxoacetate.
nitrogeneoxygen bond and the carbonecarbon
sequently intermediate b would isomerize into compound 6 via
,3-proton transfer.
p system. Sub-
carbanion c, which accepts one proton to form compound 4a from
silica gel. Due to the change of the dr value from compound 6 to
compound 4a, this mechanism cannot be a concerted process (Path
A). In the other pathway, the ring-opening of indoline via retro-
Mannich reaction process gives intermediate d, which sub-
sequently eliminates 2-oxoacetate at the aid of SieOH of silica gel to
give intermediate e and then intermediate e undergoes intra-
molecular annulation to afford product 4a (Path B).
1
To testify the existence of imine intermediate d, water is added
to trap imine intermediate d and the results are shown in Scheme 6.
Stirring compound 6 and 300e400 mesh silica gel in water/toluene
ꢀ
(
2
1:1) at 80 C for 12 h can provide N-methyl isatin in 75% yield and
Scheme 3. The isolation of compound 6 and the further transformation.
,3-disubstituted indole 8 in 70% yield along with 4a in 13% yield,
indicating that compound 6 can be easily transformed to imine.
However, compound 6 can be also transformed to N-methyl isatin 7
in 90% yield under the same condition without the addition of silica
gel, indicating that the formation of imine intermediate d did not
require the participation of silica gel. A plausible reaction mecha-
nism for the formation of compound 8 is shown in Scheme 7. The
hydrolysis of imine intermediate d gives the corresponding com-
pound 7 and intermediate f, which is transformed to 2,3-
disubstituted indole 8 via intermediate g through intramolecular
dehydration condensation between amine group and carbonyl
group.
To understand clearly the detailed mechanism of silica gel-
promoted fragmentation, we have theoretically investigated the
reaction pathways as shown in Scheme 5 (for details, see
Supplementary data). All calculations have been performed at the
19
Scheme 4. The proposed reaction mechanism for the reaction between isatin-derived
nitrone and electron-deficient alkyne.
B3LYP/6-31G(d) level of theory with Gaussian 09 program. To take
the effect of the silica gel into account, two silicic acid molecules
(
H
6
Si
2 7
O ) were used to simulate the silica gel surface contacting
2
0,21
with reaction system.
The path A shown in Scheme 5 was ruled
However, to the best of our knowledge, there is no previous
report on the silica gel-promoted CeC bond cleavage at the a-po-
sition of 2-oxoacetate. The proton-catalyzed pathway was excluded
because we found that Brønsted acids, such as trifluoromethane
out since the suggested intermediates and transition states could
not be located. The relative energies of intermediates and transi-
tional states along the suggested path B are shown in Scheme 8. The
compound 6 initially undergoes the intramolecular proton-transfer
via transition state TS1 with an energy barrier of 25.3 kcal/mol,
giving the imine intermediate d. Then, the hydrogen atom of the
hydroxyl groups in silicic acid is hydrogen-bonded to the nitrogen
atom of intermediate d to form a loose complex 10. Subsequently,
the silicic acid is deprotonated to obtain the intermediate 11 via TS2
with an energy barrier of 33.6 kcal/mol. The deprotonated silicic
sulfonic acid (CF
3 3
SO H, 0.4 equiv) and methanesulfonic acid
(
CH SO H, 0.4 equiv), showed no catalytic activity for the trans-
3
3
formation of 1a to 4a. Two possible mechanisms are proposed to
explain the transformation of compound 6 to compound 4a in
Scheme 5. Initially, carbonyl group of compound 6 is attacked by
weak nucleophilic silyl-hydroxyl group of silica gel to afford
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6
H.-B. Yang et al. / Tetrahedron xxx (2013) 1e10
2
Scheme 6. The trap of intermediate d by H O.
gel coated plates. Flash column chromatography was carried out
using 300e400 mesh silica gel at increased pressure.
4.2. General procedure for the one-pot thermal-induced
[
3D2] cycloaddition/silica gel-promoted fragmentation
sequence between isatin ketonitrones and electron-deficient
alkynes
Isatin ketonitrone 1 (0.1 mmol, 1.0 equiv), electron-deficient
ꢀ
alkyne 2 (0.3 mmol, 3.0 equiv), and 4 A MS (100 mg) were stirred
ꢀ
in toluene (1.0 mL) at 80 C. After 12 h, 200 mg of 300e400 mesh
silica gel was added and the resulting mixtures were stirred for 2 h.
The solvent was removed under reduced pressure and the residue
was purified by a flash column chromatography (SiO
corresponding products 4 in moderate to good yields.
2
) to give the
Scheme 7. The proposed mechanism for the formation of compound 8.
ꢀ
Compound 1a: Yield: 73%. A yellow solid. Mp: 160e162 C. IR
(
9
neat) n 3059, 3021, 1695, 1608, 1467, 1373, 1328, 1098, 1080,
ꢂ1
1
3
83 cm ; H NMR (400 MHz, CDCl , TMS) d 3.18 (s, 3H), 6.84 (d,
acid subsequently promotes CeC bond cleavage through TS3 to give
the intermediate 12, which undergoes the intramolecular annula-
tion to form the product complex 13 and then affords the separated
products.
J¼7.6 Hz, 1H), 7.15 (td, J¼7.6, 0.8 Hz, 1H), 7.43 (td, J¼7.6, 1.2 Hz, 1H),
13
7
.46e7.55 (m, 5H), 8.47 (dd, J¼7.6, 1.2 Hz, 1H); C NMR (100 MHz,
CDCl , TMS) 26.0, 107.9, 118.0, 123.1, 123.6, 125.1, 129.0, 130.6,
3
d
1
C
32.2, 134.6, 142.0, 146.4, 159.5; HRMS (MALDI) calcd for
þ
15
H
12
N
2
O
2
requires (M þH): 253.0977, Found: 253.0976.
3
. Conclusion
ꢀ
Compound 1b: Yield: 82%. A red solid. Mp: 190e192 C. IR (neat)
n
3063, 3010, 2911, 1694, 1612, 1538, 1483, 1299, 1101, 1008,
In summary, we have developed a novel one-pot thermal-in-
ꢂ1 1
9
3
8
1
1
30 cm ; H NMR (400 MHz, CDCl
3
, TMS) d 2.39 (s, 3H), 3.16 (s,
duced [3þ2] cycloaddition/silica gel-promoted fragmentation se-
quence between isatin ketonitrones and electron-deficient alkynes,
leading to spiro[indoline]oxindoles in moderate to excellent yields
with good dr values. The unique structure of these products may be
useful for potential drug discovery. This is the first example on silica
gel-promoted elimination of 2-oxoacetate and the detailed mech-
anism of silica gel-promoted fragmentation has been clarified by
experimental and theoretical investigations. Current efforts are in
progress to apply this new methodology to synthesize biologically
active products.
H), 6.74 (d, J¼8.0 Hz, 1H), 7.23 (d, J¼8.0 Hz, 1H), 7.45e7.55 (m, 5H),
13
3
.32 (s, 1H); C NMR (100 MHz, CDCl , TMS) d 21.0, 26.0, 107.7,
18.0, 123.7, 125.7, 129.0, 130.6, 132.6, 132.7, 134.9, 140.0, 146.4,
þ
59.6; HRMS (MALDI) calcd for C16
67.1134, Found: 267.1132.
H
14
N
2
O
2
requires (M þH):
2
ꢀ
Compound 1c: Yield: 59%. A red solid. Mp: 210e212 C. IR (neat)
n
3108, 3084, 3019, 1701, 1536, 1471, 1290, 1234, 1101, 1076,
ꢂ1
1
9
94 cm ; H NMR (400 MHz, CDCl , TMS) d 3.19 (s, 3H), 6.78 (d,
3
J¼8.4 Hz,1H), 7.40 (dd, J¼8.0,1.6 Hz,1H), 7.46e7.58 (m, 5H), 8.48 (d,
13
J¼2.0 Hz, 1H); C NMR (100 MHz, CDCl
3
, TMS) d 26.1, 108.8, 119.1,
1
23.6, 124.8, 128.5, 129.0, 130.9, 131.6, 133.9, 140.3, 146.2, 159.1;
þ
4
4
. Experimental section
HRMS (MALDI) calcd for C15
Found: 287.0587.
H11ClN
2
O
2
requires (M þH): 287.0587,
ꢀ
.1. General remarks
Compound 1d: Yield: 86%. A red solid. Mp: 214e216 C. IR (neat)
ꢂ1
1
n
3032, 2916, 2857, 1701, 1614, 1454, 1378, 1244, 1078, 923 cm ; H
NMR (300 MHz, CDCl , TMS) 2.45 (s, 3H), 3.18 (s, 3H), 6.68 (s, 1H),
6.97 (d, J¼7.8 Hz, 1H), 7.45e7.54 (m, 5H), 8.35 (d, J¼8.1 Hz, 1H);
NMR (75 MHz, CDCl , TMS) 22.5, 25.9, 108.9, 115.5, 123.6, 123.7,
1H and 13C NMR spectra were recorded at 400 (or 300) MHz,
d
3
13
respectively. HRMS spectra were recorded by ESI method. The
employed solvents were dried up by standard methods when
necessary. Commercially obtained reagents were used without
further purification. All reactions were monitored by TLC with silica
C
3
d
124.9, 128.9, 130.4, 134.5, 142.3, 143.4, 146.3, 159.7; HRMS (MALDI)
calcd for C16
þ
H
14
N
2
O
2
requires (M þH): 267.1134, Found: 267.1136.
Please cite this article in press as: Yang, H.-B.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.03.062

H.-B. Yang et al. / Tetrahedron xxx (2013) 1e10
7
Please cite this article in press as: Yang, H.-B.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.03.062

8
H.-B. Yang et al. / Tetrahedron xxx (2013) 1e10
ꢀ
ꢀ
Compound 1e: Yield: 78%. A red solid. Mp: 218e220 C. IR (neat)
Compound 1m: Yield: 63%. A red solid. Mp: 162e164 C. IR (neat)
n
3056, 3015, 1702, 1601, 1531, 1479, 1371, 1284, 1238, 1107, 1072,
n
3056, 2928, 1702, 1607, 1469, 1375, 1327, 1096, 1023, 985,
ꢂ1
1
ꢂ1 1
9
95 cm ; H NMR (400 MHz, CDCl
3
, TMS)
d
3.16 (s, 3H), 6.84 (s,
873 cm ; H NMR (400 MHz, CDCl
3
, TMS) d 2.43 (s, 3H), 3.18 (s,
1
H), 7.11 (d, J¼8.4 Hz, 1H), 7.46e7.57 (m, 5H), 8.38 (d, J¼8.4 Hz, 1H);
3H), 6.84 (d, J¼8.0 Hz, 1H), 7.14 (t, J¼7.6 Hz, 1H), 7.25e7.27 (m, 2H),
13
13
C NMR (100 MHz, CDCl
3
, TMS)
d
26.1, 108.7, 116.5, 122.9, 123.6,
7.33e7.44 (m, 3H), 8.46 (d, J¼7.2 Hz, 1H); C NMR (100 MHz, CDCl
3
,
125.7, 129.0, 130.8, 133.7, 137.7, 142.9, 146.2, 159.3; HRMS (MALDI)
TMS) 21.3, 26.0, 107.9, 118.0, 120.7, 123.0, 124.0, 125.0, 128.7, 131.3,
d
þ
calcd for
2
C
15
H11ClN
2
O
2
requires (M þH): 287.0587, Found:
132.1, 134.5, 139.3, 142.0, 146.4, 159.5; HRMS (MALDI) calcd for
þ
87.0578.
C
16
H
14
N
2
O
2
requires (M þH): 267.1134, Found: 267.1138.
ꢀ
ꢂ1
ꢀ
Compound 1f: Yield: 99%. A red solid. Mp: 233e235 C. IR (neat)
Compound 1n: Yield: 99%. A yellow solid. Mp: 209e211 C. IR
(neat) 3072, 2935, 1704, 1605, 1541, 1468, 1327, 1243, 1103, 987,
898 cm ; H NMR (400 MHz, CDCl
1
n
3060, 2927, 1701, 1599, 1285, 1104, 1060, 990 cm
, TMS)
3.17 (s, 3H), 7.01 (d, J¼1.6 Hz, 1H), 7.28 (dd,
J¼8.4,1.6 Hz,1H), 7.46e7.56 (m, 5H), 8.32 (d, J¼8.0 Hz,1H); C NMR
100 MHz, CDCl , TMS) 26.1, 111.5, 116.9, 123.6, 125.9, 126.0, 129.0,
;
H NMR
n
ꢂ1
1
(
400 MHz, CDCl
3
d
3
, TMS) d 3.19 (s, 3H), 6.85 (d,
13
J¼7.6 Hz, 1H), 7.15 (td, J¼7.6, 0.8 Hz, 1H), 7.37 (dd, J¼7.6, 2.0 Hz, 1H),
13
(
3
d
7.42e7.53 (m, 4H), 8.44 (dd, J¼7.6, 1.2 Hz, 1H); C NMR (100 MHz,
CDCl , TMS) 26.0, 108.1, 117.7, 122.0, 123.2, 124.2, 125.2, 130.0,
130.8, 132.2, 133.9, 142.9, 146.3, 159.3; HRMS (MALDI) calcd for
3
d
þ
C
15
H11BrN
2
O
2
requires (M þH): 331.0082, Found: 331.0062.
130.7, 132.5, 134.6, 134.8, 142.2, 146.8, 159.3; HRMS (MALDI) calcd
ꢀ
þ
Compound 1g: Yield: 64%. A red solid. Mp: 237e240 C. IR (neat)
for C15
H
11ClN
2
O
2
requires (M þH): 287.0587, Found: 287.0593.
ꢀ
n
3053, 2953, 1702, 1599, 1535, 1450, 1370, 1316, 1110, 1056,
Compound 1o: Yield: 58%. A yellow solid. Mp: 212e214 C. IR
ꢂ1
1
9
89 cm ; H NMR (400 MHz, CDCl
3
, TMS)
d
3.56 (s, 3H), 7.06 (dd,
(neat)
1013, 982 cm ; H NMR (300 MHz, CDCl
(d, J¼7.8 Hz, 1H), 7.15 (t, J¼7.5 Hz, 1H), 7.37 (d, J¼8.4 Hz, 2H), 7.44 (t,
n 3093, 3055, 2927, 1698, 1677, 1606, 1466, 1243, 1095, 1067,
ꢂ1
1
J¼8.4, 7.6 Hz, 1H), 7.34 (dd, J¼8.4, 1.2 Hz, 1H), 7.44e7.47 (m, 2H),
3
, TMS) d 3.19 (s, 3H), 6.85
13
7
.50e7.58 (m, 3H), 8.48 (dd, J¼8.0, 1.6 Hz, 1H); C NMR (100 MHz,
13
CDCl , TMS) 29.2, 115.4, 120.6, 123.3, 123.6, 123.8, 129.0, 130.8,
3
d
J¼7.5 Hz, 1H), 7.64 (d, J¼8.4 Hz, 2H), 8.44 (d, J¼7.5 Hz, 1H); C NMR
(75 MHz, CDCl , TMS) 26.0, 108.1, 117.8, 123.2, 124.8, 125.1, 125.4,
133.6, 134.1, 137.6, 146.5, 159.7; HRMS (MALDI) calcd for
3
d
þ
C
15
H11ClN
2
O
2
requires (M þH): 287.0587, Found: 287.0581.
132.2, 132.5, 134.7, 142.1, 145.0, 159.4; HRMS (MALDI) calcd for
ꢀ
þ
Compound 1h: Yield: 59%. A red solid. Mp: 170e172 C. IR (neat)
C
15
H
11BrN
2
O
2
requires (M þH): 331.0082, Found: 331.0079.
ꢂ1
1
ꢀ
n
3051, 2937, 1706, 1626, 1548, 1461, 1372, 1230, 791 cm ; H NMR
, TMS) 3.99e3.40 (m, 3H), 7.03e7.19 (m, 2H),
Compound 4a: Yield: 28 mg, 90%. A white solid. Mp: 187e189 C.
IR (neat) 3365, 3049, 2957,1747, 1708,1608,1487, 1467,1375, 1203,
1006, 744 cm ; H NMR (400 MHz, CDCl
(
300 MHz, CDCl
3
d
n
13
ꢂ1 1
7
CDCl
.45e7.59 (m, 5H), 8.29 (dd, J¼7.5, 0.9 Hz, 1H); C NMR (75 MHz,
3
, TMS) d 3.28 (s, 3H), 3.30
3
, TMS)
d
28.6 (d, JCeF¼5.3 Hz), 120.0 (d, JCeF¼19.1 Hz), 120.6 (d,
(s, 3H), 4.11 (br s, 1H), 4.79 (s, 1H), 6.74 (d, J¼8.0 Hz, 1H), 6.85 (d,
J
CeF¼1.6 Hz), 120.9 (d, JCeF¼2.9 Hz), 123.6, 123.7, 128.2 (d,
J¼8.0 Hz, 1H), 6.92 (t, J¼7.6 Hz, 1H), 7.05 (d, J¼7.2 Hz, 1H), 7.18 (t,
13
JCeF¼9.2 Hz), 129.0, 130.8, 134.1, 146.2, 147.1 (d, JCeF¼242.6 Hz),
J¼7.6 Hz, 1H), 7.30 (t, J¼7.6 Hz, 1H), 7.39 (d, J¼7.6 Hz, 1H); C NMR
19
1
59.2; F NMR (282 MHz, CDCl
3
, CFCl
3
)
d
ꢂ136.87 (br s, 1F); HRMS
3
(75 MHz, CDCl , TMS) d 26.6, 51.6, 56.2, 70.9, 108.1, 110.3, 120.1,
þ
(
MALDI) calcd for C15
H11FN
2
O
2
requires (M þH): 271.0883, Found:
122.9, 123.0, 123.4, 126.3, 128.7, 130.0, 142.9, 149.5, 169.1, 176.9;
þ
271.0875.
HRMS (MALDI) calcd for C18
Found: 309.1243.
H
16
N
2
O
3
requires (M þH): 309.1239,
ꢀ
Compound 1i: Yield: 75%. A yellow solid. Mp: 208e210 C. IR
ꢀ
(
neat)
n
3067, 3030, 2939, 1696, 1605, 1541, 1463, 1258, 1162, 948,
Compound 4b: Yield: 23 mg, 70%. A white solid. Mp: 163e165 C.
ꢂ1
1
8
71 cm ; H NMR (300 MHz, CDCl
3
, TMS)
d
4.87 (s, 2H), 6.76 (d,
IR (neat)
n 3365, 3051, 2953, 1747, 1710, 1604, 1467, 1364, 1198, 1170,
ꢂ1
1
J¼7.8 Hz, 1H), 7.11 (t, J¼7.5 Hz, 1H), 7.24e7.34 (m, 6H), 7.51e7.53 (m,
1106, 809 cm ; H NMR (300 MHz, CDCl , TMS) d 2.19 (s, 3H), 3.27
3
13
5
H), 8.50 (d, J¼7.2 Hz, 1H); C NMR (75 MHz, CDCl
3
, TMS)
d
43.7,
(s, 3H), 3.29 (s, 3H), 4.12 (s, 1H), 4.77 (s, 1H), 6.74 (d, J¼7.8 Hz, 2H),
6.86 (s, 1H), 6.92 (t, J¼7.8 Hz, 1H), 7.09 (d, J¼7.5 Hz, 1H), 7.18 (t,
108.9, 118.2, 123.1, 123.7, 125.1, 127.3, 127.7, 128.8, 129.0, 130.7, 132.1,
1
3
134.4, 135.4, 141.3, 146.4, 159.5; HRMS (MALDI) calcd for
J¼7.8 Hz, 1H), 7.39 (d, J¼7.5 Hz, 1H); C NMR (75 MHz, CDCl
3
, TMS)
þ
C
21
16
H N
2
O
2
requires (M þH): 329.1290, Found: 329.1280.
d 20.8, 26.7, 51.6, 56.3, 71.0, 107.9, 110.4, 120.2, 123.6, 123.7, 126.3,
ꢀ
Compound 1j: Yield: 62%. A yellow solid. Mp: 258e260 C. IR
128.75, 128.79, 130.3, 132.7, 140.6, 149.5, 169.2, 176.9; HRMS
þ
(
1
neat)
139, 925, 857 cm ; H NMR (400 MHz, DMSO-d
J¼7.6 Hz, 1H), 7.07 (td, J¼7.6, 0.8 Hz, 1H), 7.40 (td, J¼7.6, 1.2 Hz, 1H),
n
3149, 3066, 3028, 2828, 1701, 1539, 1459, 1351, 1256, 1237,
(MALDI) calcd for C19
323.1385.
18
H N
2
O
3
requires (M þH): 323.1396, Found:
ꢂ1
1
6
, TMS) d 6.90 (d,
ꢀ
Compound 4c: Yield: 25 mg, 73%. A white solid. Mp: 180e182 C.
13
7
(
.49e7.59 (m, 5H), 8.28 (d, J¼7.6 Hz, 1H), 10.8 (s, 1H); C NMR
IR (neat)
n 3358, 3056, 2953, 1747, 1708, 1609, 1487, 1467, 1351, 1204,
ꢂ1
1
100 MHz, DMSO-d , TMS) 109.8, 118.4, 121.9, 124.0, 124.2, 128.8,
6
d
1103, 1009, 932 cm ; H NMR (400 MHz, actone-d ) d 3.31 (s, 3H),
6
1
C
30.2, 132.4, 134.5, 141.0, 146.4, 160.0; HRMS (MALDI) calcd for
3.39 (s, 3H), 4.68 (s, 1H), 5.11 (s, 1H), 6.83 (d, J¼7.6 Hz, 1H), 6.95 (t,
þ
14
H
10
N
2
O
2
requires (M þH): 239.0821, Found: 239.0806.
J¼7.6 Hz, 1H), 6.98 (d, J¼2.4 Hz, 1H), 7.04 (d, J¼8.4 Hz, 1H), 7.27 (t,
ꢀ
13
Compound 1k: Yield: 47%. A yellow solid. Mp: 156e158 C. IR
J¼8.0 Hz, 1H), 7.39 (d, J¼7.6 Hz, 1H), 7.45 (dd, J¼8.4, 2.0 Hz, 1H);
C
ꢂ1
(
neat)
n
3079, 2927, 1702, 1606, 1468, 1375, 1244, 1093, 985 cm
H NMR (300 MHz, CDCl , TMS)
J¼7.5 Hz, 1H), 7.16 (t, J¼7.5 Hz, 1H), 7.25 (d, J¼7.8 Hz, 1H), 7.31e7.46
;
NMR (75 MHz, CDCl
3
, TMS) d 26.8, 51.9, 56.4, 70.8, 109.2, 110.5,
1
3
d 2.27 (s, 3H), 3.17 (s, 3H), 6.86 (d,
120.5, 123.1, 123.4, 126.3, 128.2, 129.0, 130.0, 130.4, 141.6, 149.0,
168.9, 176.5; HRMS (MALDI) calcd for C18
H
15ClN
2
O
3
requires
13
þ
(
d
m, 4H), 8.50 (d, J¼7.2 Hz, 1H); C NMR (75 MHz, CDCl
16.4, 25.9, 107.9, 117.4, 123.0, 123.3, 125.0, 126.7, 129.9, 131.1, 131.2,
32.1, 135.0, 142.1,145.9,159.2; HRMS (MALDI) calcd for C16
3
, TMS)
(M þH): 343.0849, Found: 343.0854.
Compound 4d: Yield: 23 mg, 72%. A white solid. Mp:
ꢀ
1
H
14
N
2
O
2
244e246 C. IR (neat)
n
3362, 2903, 1708, 1608, 1484, 1467, 1374,
þ
ꢂ1 1
requires (M þH): 267.1134, Found: 267.1120.
Compound 1l: Yield: 80%. A yellow solid. Mp: 210e212 C. IR
neat) 3097, 3065, 3023, 2935, 1697, 1608, 1467, 1376, 1297, 1108,
1318, 1285, 1263, 1093, 1016, 873 cm ; H NMR (300 MHz, CDCl
TMS) 2.35 (s, 3H), 3.27 (s, 3H), 3.31 (s, 3H), 4.08 (s,1H), 4.75 (s,1H),
6.67 (s, 1H), 6.70e6.74 (m, 2H), 6.88e6.94 (m, 2H), 7.17 (t, J¼7.8 Hz,
3
,
ꢀ
d
(
n
ꢂ1
1
13
9
87 cm ; H NMR (400 MHz, CDCl
3
, TMS)
d
3.17 (s, 3H), 6.86 (d,
1H), 7.38 (d, J¼7.8 Hz, 1H); C NMR (75 MHz, CDCl
3
, TMS) d 21.9,
J¼8.0 Hz, 1H), 7.16 (td, J¼7.6, 0.8 Hz, 1H), 7.39e7.48 (m, 4H), 7.44
26.6, 51.7, 56.2, 70.9, 109.1, 110.4, 120.2, 122.9, 123.4, 123.6, 125.8,
13
(
(
dd, J¼7.2, 1.2 Hz, 1H), 8.47 (dd, J¼8.4, 0.8 Hz, 1H); C NMR
126.3, 128.7, 140.5, 143.1, 149.5, 169.3, 177.3; HRMS (MALDI) calcd
þ
75 MHz, CDCl
3
, TMS)
d
25.9, 108.1, 117.1, 123.1, 125.1, 125.3, 127.4,
for C19
H
18
N
2
O
3
requires (M þH): 323.1396, Found: 323.1385.
ꢀ
127.9, 130.3, 131.0, 132.6, 135.6, 142.4, 144.0, 159.1; HRMS (MALDI)
Compound 4e: Yield: 21 mg, 62%. A white solid. Mp: 190e192 C.
IR (neat) 3288, 3048, 2951,1741,1723,1608,1595,1492,1376,1200,
3
1068, 1001 cm ; H NMR (400 MHz, CDCl , TMS) d 3.27 (s, 3H),
þ
calcd for
2
C
15
H11ClN
2
O
2
requires (M þH): 287.0587, Found:
n
ꢂ1
1
87.0589.
Please cite this article in press as: Yang, H.-B.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.03.062

H.-B. Yang et al. / Tetrahedron xxx (2013) 1e10
9
3
1
1
.35 (s, 3H), 4.11 (s, 1H), 4.76 (s, 1H), 6.73 (d, J¼7.6 Hz, 1H), 6.85 (s,
H), 6.89 (t, J¼9.6 Hz, 2H), 6.96 (t, J¼8.8 Hz, 1H), 7.17 (t, J¼8.0 Hz,
148.1, 169.2, 177.1; HRMS (MALDI) calcd for C19
H
18
N
2
O
3
requires
þ
(M þH): 323.1396, Found: 323.1392.
13
ꢀ
H), 7.38 (d, J¼7.2 Hz, 1H); C NMR (100 MHz, CDCl
3
, TMS)
d
26.8,
Compound 4l: Yield: 23 mg, 67%. A white solid. Mp: 222e225 C.
51.9, 56.3, 70.5, 109.0, 110.4, 120.4, 122.7, 123.2, 124.1, 126.4, 127.1,
IR (neat) n 3281, 2953, 2864,1742,1715,1607,1465,1207,1092,1020,
ꢂ1
1
128.9, 135.9, 144.3, 149.2, 169.0, 176.9; HRMS (MALDI) calcd for
3
912 cm ; H NMR (400 MHz, CDCl , TMS) d 3.28 (s, 3H), 3.30 (s,
þ
C
18
H15ClN
2
O
3
requires (M þH): 343.0849, Found: 343.0844.
3H), 4.38 (br s, 1H), 4.84 (s, 1H), 6.82e6.87 (m, 2H), 6.85 (dd, J¼7.6,
ꢀ
Compound 4f: Yield: 25 mg, 64%. A white solid. Mp: 195e198 C.
0.8 Hz, 1H), 6.94 (td, J¼7.2, 0.8 Hz, 1H), 7.17 (dt, J¼7.6, 1.0 Hz, 1H),
13
IR (neat)
n
3292, 3048,1740, 1722, 1605, 1592, 1374,1200,1174,1093,
7.28 (d, J¼7.6 Hz,1H), 7.32 (td, J¼7.6,1.2 Hz,1H); C NMR (100 MHz,
ꢂ1
1
9
3
2
99 cm ; H NMR (300 MHz, CDCl
3
, TMS)
d
3.26 (s, 3H), 3.35 (s,
3
CDCl , TMS) d 26.7, 51.8, 56.8, 70.7, 108.3,115.4, 120.9,123.07, 123.13,
H), 4.14 (s, 1H), 4.75 (s, 1H), 6.72 (d, J¼7.8 Hz, 1H), 6.89e6.94 (m,
124.6, 124.8, 128.2, 128.6, 130.4, 142.9, 146.6, 168.6, 176.3; HRMS
þ
H), 7.00e7.05 (m, 2H), 7.17 (t, J¼7.5 Hz, 1H), 7.38 (d, J¼7.2 Hz, 1H);
(MALDI) calcd for C18
Found: 343.0836.
H15ClN
2
O
3
requires (M þH): 343.0849,
1
3
3
C NMR (75 MHz, CDCl , TMS) d 26.8, 51.9, 56.2, 70.6, 110.4, 111.8,
1
20.4, 123.2, 123.7, 124.3, 125.7, 126.3, 127.7, 128.9, 144.3, 149.2,
Compound 4m: Yield: 20 mg, 63%. A white solid. Mp:
ꢀ
169.0, 176.7; HRMS (MALDI) calcd for C18
H15BrN
2
O
3
requires
150e152 C. IR (neat)
1428, 1350, 1248, 1029 cm ; H NMR (300 MHz, CDCl , TMS) d 2.31
3
n
3329, 2946, 2922, 1719, 1707, 1609, 1470,
þ
ꢂ1 1
(
M þH): 387.0344, Found: 387.0338.
ꢀ
Compound 4g: Yield: 33 mg, 87%. A white solid. Mp: 170e172 C.
(s, 3H), 3.27 (s, 3H), 3.28 (s, 3H), 4.07 (br s, 1H), 4.73 (s, 1H), 6.56 (s,
IR (neat)
94, 738 cm ; H NMR (400 MHz, CDCl
s, 3H), 4.15 (br s, 1H), 4.78 (s, 1H), 6.72 (d, J¼7.6 Hz, 1H), 6.81 (t,
J¼7.6 Hz, 1H), 6.89e6.95 (m, 2H), 7.17 (t, J¼7.6 Hz, 1H), 7.21 (dd,
n
3375, 3054, 2957, 1745, 1717, 1605, 1459, 1320, 1205, 1106,
1H), 6.73 (d, J¼7.8 Hz, 1H), 6.84 (d, J¼7.8 Hz, 1H), 6.91 (t, J¼7.8 Hz,
ꢂ1
1
13
7
(
3
, TMS)
d
3.35 (s, 3H), 3.66
1H), 7.06 (d, J¼7.5 Hz, 1H), 7.24e7.32 (m, 2H); C NMR (75 MHz,
3
CDCl , TMS) d 21.5, 26.6, 51.6, 56.1, 71.0, 108.1, 111.2, 120.7, 121.1,
122.9, 123.1, 125.9, 128.9, 130.0, 138.9, 143.0, 149.7, 169.4, 177.0;
13
þ
J¼8.0, 1.2 Hz, 1H), 7.39 (d, J¼7.6 Hz, 1H); C NMR (75 MHz, CDCl
3
,
HRMS (MALDI) calcd for C19
Found: 323.1388.
H
18
N
2
O
3
requires (M þH): 323.1396,
TMS) 30.1, 51.8, 56.7, 70.4, 110.4, 115.6, 120.4, 121.4, 123.2, 123.8,
d
1
26.4, 128.9, 131.7, 132.3, 138.8, 149.2, 168.9, 177.3; HRMS (MALDI)
Compound 4n: Yield: 20 mg, 57%. A white solid. Mp:
þ
ꢀ
calcd for
43.0844.
C
18
H15ClN
2
O
3
requires (M þH): 343.0849, Found:
248e250 C. IR (neat)
n
ꢂ1
3400, 2948, 1748, 1478, 1471, 1436, 1346,
1
3
1179, 1021, 927, 914 cm ; H NMR (400 MHz, CDCl
3
, TMS)
d
3.27 (s,
Compound 4h: Yield: 74 mg, 76%. A white solid. Mp:
3H), 3.28 (s, 3H), 4.24 (br s, 1H), 4.68 (s, 1H), 6.70 (s, 1H), 6.84e6.87
ꢀ
1
1
97e200 C. IR (neat)
n
3370, 3058, 2957, 1745, 1715, 1628, 1608,
(m, 2H), 6.92 (t, J¼7.6 Hz, 1H), 7.04 (d, J¼7.2 Hz, 1H), 7.26e7.33 (m,
ꢂ1
1
13
465, 1371, 1241, 1208, 1013, 901 cm ; H NMR (400 MHz, CDCl
3
,
2H); C NMR (100 MHz, CDCl
3
, TMS)
d
26.7, 51.7, 55.6, 71.2, 108.3,
TMS)
d
3.34 (s, 3H), 3.48 (d, J¼2.4 Hz, 3H), 4.24 (br s, 1H), 4.74 (s,
110.4, 120.0, 122.0, 123.06, 123.08, 127.1, 128.2, 130.3, 134.5, 142.9,
1
H), 6.71 (d, J¼8.0 Hz, 1H), 6.80e6.85 (m, 2H), 6.89 (t, J¼7.2 Hz,
H), 6.99e7.04 (m, 1H), 7.15 (t, J¼7.6 Hz, 1H), 7.38 (d, J¼7.2 Hz, 1H);
150.7, 168.8, 176.4; HRMS (MALDI) calcd for C18
H
15ClN
2
O
3
requires
þ
1
(M þH): 343.0849, Found: 343.0838.
1
3
C NMR (100 MHz, CDCl
3
, TMS)
d
29.1 (d, J¼5.6 Hz), 51.7, 56.5,
Compound 4o: Yield: 36 mg, 93%. A white solid. Mp:
ꢀ
7
0.8 (d, J¼1.9 Hz), 110.3, 117.9 (d, J¼18.9 Hz), 118.8 (d, J¼3.0 Hz),
205e208 C. IR (neat)
n
3324, 2952, 2933, 1724, 1708, 1610, 1470,
ꢂ1
1
1
20.2, 123.1, 123.6 (d, J¼6.3 Hz), 126.3, 128.8, 129.3 (d, J¼8.5 Hz),
3
1246, 1099, 1016, 873 cm ; H NMR (400 MHz, CDCl , TMS) d 3.28
19
131.7 (d, J¼2.6 Hz), 147.4 (d, J¼243.2 Hz), 149.2, 168.9, 176.6;
F
(s, 3H), 3.29 (s, 3H), 4.16 (br s,1H), 4.74 (s,1H), 6.60 (d, J¼8.4 Hz,1H),
NMR (376 MHz, CDCl
3
H
, CFCl
3
)
d
ꢂ135.86e135.80 (m, 1F); HRMS
6.85 (d, J¼7.6 Hz, 1H), 6.93 (td, J¼8.0, 0.8 Hz, 1H), 7.05 (d, J¼7.6 Hz,
þ
13
(
3
MALDI) calcd for C18
27.1144.
15FN
2
O
3
requires (M þH): 327.1145, Found:
1H), 7.25e7.28 (m, 1H), 7.31 (td, J¼7.6, 1.6 Hz,1H), 7.51 (br s, 1H);
C
NMR (100 MHz, CDCl
3
, TMS) d 26.7, 51.8, 55.9, 71.2, 108.3, 111.5,
ꢀ
Compound 4i: Yield: 30 mg, 78%. A white solid. Mp: 133e136 C.
112.0, 123.0, 123.1, 125.7, 128.3, 129.4, 130.3, 131.6, 142.9, 148.6,
IR (neat)
n
3335, 3055, 3032, 2949, 1717, 1608, 1484, 1465, 1434,
168.5, 176.4; HRMS (MALDI) calcd for C18
H
15BrN
2
O
3
requires
ꢂ1
1
þ
1170, 1011, 918 cm ; H NMR (400 MHz, CDCl
3
, TMS)
d
3.11 (s, 3H),
(M þH): 387.0344, Found: 387.0345.
ꢀ
4
.19 (br s, 1H), 4.70 (d, J¼16.0 Hz, 1H), 4.87 (s, 1H), 5.24 (d,
Compound 4p: Yield: 25 mg, 78%. A white solid. Mp: 145e147 C.
J¼16.0 Hz, 1H), 6.74 (d, J¼7.6 Hz, 2H), 6.85 (t, J¼7.6 Hz, 1H), 6.92 (t,
J¼7.6 Hz, 1H), 7.03 (d, J¼7.6 Hz, 1H), 7.14e7.20 (m, 2H), 7.27e7.31
IR (neat)
n 3395, 3050, 1744, 1714, 1608, 1462, 1376, 1322, 1187, 1092,
ꢂ1
1
1033, 793 cm ; H NMR (300 MHz, CDCl
3
, TMS)
d
0.76 (t, J¼7.2 Hz,
13
(
m, 1H), 7.34 (t, J¼7.6 Hz, 2H), 7.40e7.42 (m, 1H); C NMR (75 MHz,
3H), 3.29 (s, 3H), 3.75 (q, J¼7.2 Hz, 2H), 4.15 (br s, 1H), 4.76 (s, 1H),
CDCl
3
, TMS) d 44.3, 51.4, 56.1, 70.9, 109.2, 110.4, 120.3, 123.0, 123.1,
6.72 (d, J¼7.8 Hz, 1H), 6.83e6.93 (m, 3H), 7.03 (d, J¼7.5 Hz, 1H), 7.16
13
123.5, 126.5, 127.6, 127.8, 128.7, 128.8, 128.9, 130.0, 135.5, 142.0,
(t, J¼7.8 Hz, 1H), 7.30 (t, J¼7.8 Hz, 1H), 7.43 (d, J¼7.8 Hz, 1H);
C
1
49.4, 169.1, 177.1; HRMS (MALDI) calcd for C24
H
20
N
2
O
3
requires
3
NMR (100 MHz, CDCl , TMS) d 13.4, 26.6, 55.8, 60.5, 70.9, 108.1,
þ
(
M þH): 385.1552, Found: 385.1553.
110.3, 120.1, 122.9, 123.5, 126.4, 128.6, 128.8, 130.0, 143.0, 149.4,
ꢀ
þ
Compound 4j: Yield: 18 mg, 62%. A white solid. Mp: 205e208 C.
168.5, 176.9; HRMS (MALDI) calcd for C19
323.1396, Found: 323.1385.
18
H N
2
O
3
requires (M þH):
IR (neat) n 3347, 3156, 3096, 2951, 1749, 1706, 1602, 1465, 1171, 1112,
ꢂ1
1
ꢀ
8
72 cm ; H NMR (400 MHz, CDCl
3
, TMS)
d
3.31 (s, 3H), 4.24 (br s,
Compound 4q: Yield: 20 mg, 69%. A white solid. Mp: 154e156 C.
1
H), 4.79 (s, 1H), 6.73 (d, J¼8.0 Hz, 1H), 6.85e6.94 (m, 3H), 7.02 (d,
IR (neat)
n 3344, 3052, 2923, 1708, 1608, 1484, 1467, 1349, 1090,
ꢂ1
1
J¼7.2 Hz, 1H), 7.16e7.22 (m, 2H), 7.40 (d, J¼7.2 Hz, 1H), 9.45 (br s,
780 cm ; H NMR (300 MHz, CDCl , TMS) d 1.81 (s, 3H), 3.32 (s,
3
13
1
H); C NMR (75 MHz, CDCl
3
, TMS)
d
51.7, 56.1, 71.5, 110.46, 110.49,
3H), 4.12 (br s, 1H), 4.78 (s, 1H), 6.75 (d, J¼8.1 Hz, 1H), 6.87e6.98 (m,
3H), 7.06 (d, J¼7.2 Hz, 1H), 7.18 (t, J¼7.8 Hz, 1H), 7.25 (d, J¼9.0 Hz,
120.3, 122.9, 123.38, 123.41, 126.4, 128.8, 129.1, 130.1, 140.3, 149.4,
13
169.2, 179.9; HRMS (MALDI) calcd for C17
H
14
N
2
O
3
requires
1H), 7.33 (t, J¼7.8 Hz, 1H); C NMR (75 MHz, CDCl
3
, TMS) d 26.7,
þ
(
M þNa): 317.0902, Found: 317.0901.
29.8, 63.6, 70.6, 108.6, 110.5, 120.3, 123.5, 124.2, 124.3, 126.6, 128.0,
ꢀ
Compound 4k: Yield: 23 mg, 71%. A white solid. Mp: 169e172 C.
128.8, 130.4, 142.6, 149.6, 177.4, 203.1; HRMS (MALDI) calcd for
þ
IR (neat)
n
3298, 3054, 2951, 2853, 1714, 1610, 1598, 1466, 1375,
C
18
H
16
N
2
O
2
requires (M þH): 293.1290, Found: 293.1281.
ꢂ1
1
ꢀ
1209, 1089, 1030, 1013, 924 cm ; H NMR (400 MHz, CDCl
3
, TMS)
Compound 6: A yellow solid. Mp: 88e95 C. IR (neat)
n
3339,
ꢂ1
d
2.14 (s, 3H), 3.28 (s, 3H), 3.30 (s, 3H), 3.97 (br s, 1H), 4.80 (s, 1H),
.83e6.87 (m, 2H), 6.91 (td, J¼7.6, 0.8 Hz, 1H), 7.01 (d, J¼7.6 Hz, 1H),
2952, 1736, 1713, 1607, 1484, 1469, 1258, 1098, 1037, 983, 908 cm
;
1
6
3
H NMR (400 MHz, CDCl , TMS) d 3.21 (s, 3H) (minor isomer), 3.26
7
1
7
.04 (dd, J¼7.6, 0.8 Hz, 1H), 7.24 (d, J¼7.6 Hz, 1H), 7.30 (td, J¼7.6,
(s, 3H), 3.50 (s, 3H) (minor isomer), 3.59 (s, 3H), 3.77 (s, 3H), 3.81 (s,
3H) (minor isomer), 4.03 (br s, 1H), 6.82e7.07 (m, 5H), 7.23e7.40
(m, 3H); C NMR (100 MHz, CDCl , TMS) d 26.4, 26.5, 52.4, 52.97,
3
.2 Hz, 1H); 13C NMR (100 MHz, CDCl
0.8, 108.1, 119.7, 120.4, 122.9, 123.0, 123.8, 129.2, 129.7, 130.1, 143.0,
Please cite this article in press as: Yang, H.-B.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.03.062
, TMS)
d
16.6, 26.7, 51.6, 56.6,
3
13

10
H.-B. Yang et al. / Tetrahedron xxx (2013) 1e10
5
1
1
3.01, 53.1, 70.7, 72.49, 72.54, 74.4, 108.4, 111.5, 111.8, 120.8, 120.9,
22.5, 123.0, 123.4, 124.0, 124.1, 124.5, 126.3, 126.4, 126.7, 128.9,
30.0, 130.2, 130.3, 130.7, 143.2, 143.9, 150.0, 150.4, 160.2, 160.7,
2007, 94, 1; (j) Merino, P.; Mannucci, V.; Tejero, T. Eur. J. Org. Chem. 2008, 3943;
k) Merino, P.; Delso, I.; Tejero, T. Eur. J. Org. Chem. 2008, 2929.
. (a) Shuji, K.; Takashi, T. Chem. Lett. 1995, 49; (b) Mehrdad, M.; Faraji, L.; Jadidi,
K.; Eslami, P.; Sureni, H. Monatsh. Chem. 2011, 142, 917; (c) Pei, C.-K.; Jiang, Y.;
Shi, M. Eur. J. Org. Chem. 2012, 4206.
6. Aurich, H. G.; Weiss, W. Tetrahedron 1976, 32, 159.
. (a) Guan, X.-Y.; Wei, Y.; Shi, M. Chem.dEur. J. 2011, 16, 13617; (b) Zhang, X.-C.;
Cao, X.-H.; Wei, Y.; Shi, M. Chem. Commun. 2011, 1548; (c) Zhang, X.-C.; Cao, X.-
H.; Wei, Y.; Shi, M. Org. Lett. 2011, 13, 1142; (d) Cao, S.-H.; Zhang, X.-C.; Wei, Y.;
Shi, M. Eur. J. Org. Chem. 2011, 2668; (e) Liu, Z.; Gu, P.; Shi, M. Org. Lett. 2011, 13,
(
5
166.5, 168.1, 174.4, 174.5, 186.1, 186.4; HRMS (MALDI) calcd for
þ
C
21
H
18
N
2
O
6
requires (M þH): 395.1243, Found: 395.1239.
7
1
1
Compound 8: This is a known compound. H NMR (400 MHz,
CDCl
3
, TMS)
d
3.98 (s, 3H), 3.99 (s, 3H), 7.27 (t, J¼8.4 Hz, 1H), 7.37 (t,
J¼8.4 Hz, 1H), 7.45 (d, J¼8.4 Hz, 1H), 8.06 (d, J¼8.4 Hz, 1H), 9.55 (br
2314; (f) Wang, D.; Jiang, J.-J.; Zhang, R.; Shi, M. Tetrahedron: Asymmetry 2011,
13
s, 1H); C NMR (100 MHz, CDCl , TMS) 51.9, 52.7, 111.9, 122.6,
3
d
22, 1133; (g) Zhao, M.-X.; Zhang, Z.-W.; Chen, M.-X. Eur. J. Org. Chem. 2011, 3001;
1
22.7, 125.9, 126.8, 128.0, 134.8, 161.4, 164.6; HRMS (MALDI) calcd
(h) Deng, H.-P.; Wei, Y.; Shi, M. Org. Lett. 2011, 13, 3348; (i) Lian, Z.; Shi, M. Eur. J.
Org. Chem. 2012, 581; (j) Lian, Z.; Wei, Y.; Shi, M. Tetrahedron 2012, 68, 2401; (k)
Yang, H.-B.; Guan, X.-Y.; Wei, Y.; Shi, M. Eur. J. Org. Chem. 2012, 2792.
. (a) Takeuchi, Y. Adv. Heterocycl. Chem. 1977, 21, 207; (b) Freeman, J. P. Chem. Rev.
1983, 83, 261.
þ
for C12
H11NO
4
requires (M þH): 234.0766, Found: 234.0756.
8
9
Acknowledgements
. Baldwin, J. E.; Pudussery, R. G.; Qureshi, A. K.; Sklarz, B. J. Am. Chem. Soc. 1968,
9
0, 5325.
0. Damavandy, J. A.; Jones, R. A. Y. J. Chem. Soc., Perkin Trans. 1 1981, 712.
11. Huisgen, R.; Seidl, H.; Bruning, I. Chem. Ber. 1969, 102, 1102.
2. Tomioka, Y.; Nagahiro, C.; Nomura, Y.; Maruoka, H. J. Heterocycl. Chem. 2003,
0, 121.
3. (a) Unhureanu, I.; Klotz, P.; Mann, A. Angew. Chem., Int. Ed. 2000, 39, 4615; (b)
We thank the Shanghai Municipal Committee of Science and
Technology (11JC1602600), National Basic Research Program of
China (973)-2009CB825300, and the National Natural Science
Foundation of China for financial support (21072206, 21102166,
1
1
4
1
2
0672096, 20872162, 20672127, 21121062, and 20732008).
Wender, P. A.; Strand, D. J. Am. Chem. Soc. 2009, 131, 7528; (c) Yadav, V. K.;
Sriramurthy, V. J. Am. Chem. Soc. 2005, 127, 16366; (d) Munegumi, T.; Azumaya,
I.; Kato, T.; Masu, H.; Saito, S. Org. Lett. 2006, 8, 379.
Supplementary data
14. Tsuge, O.; Ueno, K.; Kanemasa, S. Chem. Lett. 1986, 797.
5. Li, L.; Wu, X.-X.; Zhang, J.-L. Chem. Commun. 2011, 5049.
1
1H NMR and 13C NMR spectroscopic and analytic data of isatin
16. (a) Takayama, H.; Hurihara, M.; Subhadhisakul, S.; Kitajima, M.; Aimi, N.; Sakai,
S. I. Heterocycles 1996, 42, 87; (b) Takayama, H.; Ishikawa, H.; Kurihara, M.;
Kitajima, M.; Aimi, N.; Ponglux, D.; Koyama, F.; Matsumoto, K.; Moriyama, T.;
Yamamoto, L. T.; Watanabe, K. J. Med. Chem. 2002, 45, 1949.
ketonitrones 1aeo, products 4aeq, and intermediate 6 as well as
the X-ray data of compound 4a are included in the Supplementary
data. Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2013.03.062.
1
7. Kyei, A. S.; Tchabanenko, K.; Baldwin, J. E.; Adlington, R. M. Tetrahedron Lett.
004, 45, 8931.
8. The crystal data of 4a have been deposited in CCDC with number 865933.
Empirical Formula: C18 ; Formula Weight: 308.33; Crystal Color, Habit:
colorless; Crystal Dimensions: 0.360ꢁ0.258ꢁ0.160 mm; Crystal System:
2
1
16 2 3
H N O
References and notes
ꢀ
ꢀ
monoclinic; Lattice parameters: a¼12.0894(12) A, b¼8.4383(8) A, c¼15.
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
3
2
650(14) A,
a
¼90 ,
b
¼92.784(2) ,
g
¼90 , V¼1555.4(3) A ; Space group: P2(1)/
3
1
. For a review, see: Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46,
n; Z¼4; Dcalcd¼1.317 g/cm ; F000¼648; Final R indices [I>2
wR2¼0.1183
s
(I)] R1¼0.0491,
8748.
2
. For reviews, see: (a) Trost, B. M.; Brennan, M. K. Synthesis 2009, 3003; (b) Lin,
H.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 36; (c) Williams, R. M.; Cox,
R. J. Acc. Chem. Res. 2003, 36, 127; (d) Marti, C.; Carreira, E. M. Eur. J. Org. Chem.
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Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Na-
katsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng,
G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery,
J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.;
Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.;
Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene,
M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.;
Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dan-
2003, 2209.
3
4
. (a) Holzapfel, C. W.; Crous, R. Heterocycles 1988, 68, 1337; (b) Kiguchi, T.;
Shirakawa, M.; Ninomiya, I.; Naito, T. Chem. Pharm. Bull. 1996, 66, 1282; (c)
Hamer, J.; Macaluso, A. Chem. Rev. 1966, 66, 673; (d) Delpierre, G. R.; Lamchen,
M. Quart. Rev. 1965, 19, 329.
. (a) Breuer, E. In The Chemistry of Functional Group, Supplement F, Part 1; Patai, S.,
Ed.; John Wiley: New York, NY, 1982; p 659; (b) Black, D. S.; Crozier, R. F.; Davis,
V. C. Synthesis 1975, 205; (c) Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chem-
istry; Padwa, A., Ed.; John Wiley: New York, NY, 1986; Vol. 2, p 83; (d) Torssell,
K. B. G. Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis; VCH,: New
York, NY, 1988; (e) Tamura, O.; Mita, N.; Gotanda, K.; Yamada, K.; Nakano, T.;
Katagiri, R.; Sakamoto, M. Heterocycles 1997, 66, 95; (f) Chiacchio, U.; Casuscelli,
F.; Corsaro, A.; Rescifina, A.; Romeo, G.; Uccella, N. Tetrahedron 1996, 50, 6671;
€
nenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.;
Cioslowski, J.; Fox, D. J. Gaussian 09, Revision A.1; Gaussian: Wallingford CT,
2009.
20. For computational studies on the silica gel participated reactions, see: Shao, L.-
X.; Li, Y.-X.; Shi, M. Chem.dEur. J. 2007, 13, 862.
(
g) Brandi, A.; Cardona, F.; Cicchi, S. Chem.dEur. J. 2009, 15, 7808; (h) Padwa, A.;
21. Jiao, N.; Shi, Z.-S.; Zhang, C.; Li, S.; Pan, D.-L.; Ding, S.-T.; Cui, Y.-X. Angew. Chem.,
Int. Ed. 2009, 48, 4572.
Bur, S. Tetrahedron 2007, 63, 5341; (i) Bur, S.; Padwa, A. Adv. Heterocycl. Chem.
Please cite this article in press as: Yang, H.-B.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.03.062