Yb(NTf2)3-catalyzed [3 + 3] cycloaddition between isatin ketonitrones and cyclopropanes to construct novel spiro[tetrahydro-1,2- oxazine]oxindoles

Article abstract of DOI:10.1039/c2ob26413g

Yb(NTf₂)₃-catalyzed [3 + 3] cycloaddition between isatin ketonitrones and cyclopropanes is described. A variety of spiro[tetrahydro-1,2-oxazine]oxindoles were obtained in moderate to good yields along with good regioselectivities. This is the first example of the intermolecular [3 + 3] cycloaddition between ketone-derived nitrones and cyclopropanes. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob26413g

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ARTICLE TYPE
Yb(NTf2)3-Catalyzed [3+3] Cycloaddition between Isatin Ketonitrones
and Cyclopropanes to Construct Novel Spiro[tetrahydro-1,2-
oxazine]oxindoles
5
Hai-Bin Yang, Min Shi*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
55
Yb(NTf2)3-catalyzed [3+3] cycloaddition between isatin
ketonitrones and cyclopropanes has been described in this
ketonitrone and a few synthetic procedures have been reported
thus far.13 However, the reported synthetic procedures are not
suitable for preparing N-protected isatin derived arylnitrone
due to that N-protected isatin do not react with
60 arylhydroxylamine even under reflux. Therefore, only a few
isatin ketonitrones are prepared and only very limited examples
to use these compounds as substrates to prepare spirooxindoles
have been reported. For example, in 1995, Takashi and co-
10 context. A variety of spiro[tetrahydro-1,2-oxazine]oxindoles
were obtained in moderate to good yields along with good
regioselectivities. This is the first example on the
intermolecular [3+3] cycloaddition between ketone-derived
nitrones and cyclopropanes.
15
Spirooxindoles are privileged structural motifs found in many
alkaloids and unnatural biologically active compounds.1 Inspired
.
workers reported that the MgBr2 Et2O-catalyzed cycloaddition of
by these important scaffolds, a variety of synthetic methods for 65 isatin ketonitrones to allylic alcohols led to exclusive formation
producing spirooxindoles, especially applications to natural
20 product synthesis, have been developed over the last decade.2
Thus far, catalytic one-step construction of spirooxindoles has
attracted much attention due to its high efficiency.3–5 However,
of the exostereoisomers of spiro[isoxazolidine]oxindole.14 In
2011, Mehraad and co-workers discovered that [3+2]
cycloaddition of isatin ketonitrones with alkenes could
proceed smoothly in the absence of any catalyst when the
most of the studies reported to date have focused on the catalytic 70 ionic liquid 1-butyl-3-methylimidazolium was used as the
synthesis of spirooxindoles bearing an all carbon quaternary
25 stereocenter at the C3 position of the oxindole, such as in a
solvent.15 Recently our group reported the first example on the
intramolecular [3+2] cycloaddition of isatin ketonitrones
catalyzed by Yb(OTf)3.16 However, there is no report on [3+3]
cycloaddition of isatin ketonitrones. During our ongoing
spirocycloalkaneoxindole core4 and
a
spiro[pyrrolidin-3,3’-
oxindole] core.5 On the other hand, catalytic methods for
spirooxindoles bearing a nitrogen atom at the C3 position of the 75 research program on the cycloaddition using isatin derivatives,17
oxindole unit are still limited,6-7 despite their importance for the
30 design of medicinally important compounds. Therefore, further
exploration of the scope of available spirooxindole cores is still
highly desirable.
we discovered that trifluoroacetic acid can efficiently promote the
condensation of isatin with N-arylhydroxylamine, affording a
variety of isatin ketonitones in good yields under mild conditions,
and established an efficient and robust synthetic procedure for a
The reactivity of nitrones has been extensively investigated 80 class of novel spiro[tetrahydro-1,2-oxazine]oxindole derivatives.
because they are very useful intermediates in organic synthesis.
35 Nitrone can act as a 1,3-dipole to react with alkene,8 alkyne9 and
O
N
O
O
R
R
cyclopropane10 to form heterocycles, which are also important
structural motifs found in many natural products and unnatural
biologically active compounds.11 Much effort has been devoted to
the aldonitrones, mainly because of their ease of preparation via
40 the condensation of an N-alkylhydroxylamine or N-
arylhydroxylamine with an aldehyde. In contrast, ketonitrones
have not been widely studied because the preparation of
ketonitrones may not always be accomplished by simple
condensation reactions, and occasional reports of synthetic routes
45 toward these compounds often have narrow substrate scope.12 In
addition, ketonitrones have low reactivity caused by steric
hindrance. Isatin-derived nitrones belong to the group of
N
R
N
O
O
O
Other's work
This work
N
N
N
PG
PG
PG
Scheme 1. Isatin-derived nitrone-participating [3+2] and [3+3]
cycloadditions.
85
Herein, we wish to report the first example of a highly
regioselective synthesis of spiro[tetrahydro-1,2-
oxazine]oxindoles by [3+3] cycloaddition of isatin
ketonitrones with cyclopropanes catalyzed by Yb(NTf2)3
90 (Scheme 1).
Initial studies using compound 1a [(E)-configuration, which
a
has been confirmed by NOE NMR spectroscopic analysis of
1l] as the substrate were aimed at determining the reaction
outcome and subsequently optimizing the reaction conditions.
95 The results are summarized in Table 1. The reaction time of
24 h was chosen as a trade off to get a unified procedure. We
found that compound 3a was formed in 47% yield with 28%
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
50 Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, P. R. China. E-mail: mshi@mail.sioc.ac.cn.
† Electronic Supplementary Information (ESI) available: Experimental
procedures, characterization data of new compounds, and CCDC 858690
and 880875. See DOI: 10.1039/b000000x/
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[journal], [year], [vol], 00–00 | 1

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CO2Me
CO2Me
of recovered starting materials 1a using Yb(OTf)3 (45 mol %)
O
N
O
N
O
Ph
O
Ph
Ph
N
CO2Me
CO2Me
as the catalyst in the reaction with cyclopropane 2a in 1,2-
CO2Me
CO2Me
Lewis acid
+
o
O
O
+
dichloroethane (DCE) at 80 C for 24 h (Table 1, entry 1). At
4Å MS
solvent
N
N
N
2a
4a
1a
3a
the same time, we discovered that trace amount of regioisomer
4a which can be separated from compound 3a by silica gel
column chromatography was formed under this condition. The
structure of compound 3a was confirmed by NMR
spectroscopic data and X-ray diffraction. The ORTEP drawing
of 3a is shown in Figure 1 and the CIF data are presented in
T
yield (%)c
5
entry
Lewis acid
solvent
eq (LA)
temp (oC)
3a:4ab Conv
3a
Yb(OTf)3
Cu(OTf)2
Sc(OTf)3
In(OTf)3
Zn(OTf)2
1
2
3
4
5
DCE
DCE
DCE
DCE
DCE
0.45
0.45
0.45
0.45
0.45
11:1
1:0
13:1
33:1
-
72
47
79
31
0
47
20
45
14
0
80
80
80
80
80
Ni(ClO4)2 . 6H2O
6
7
DCE
0.45
-
10
0
80
10 the Supporting Information.18 Using Cu(OTf)2, Sc(OTf)3 or
In(OTf)3 as catalysts gave 3a in 20%, 45% and 14% yields,
respectively (Table 1, entries 2-4). Other Lewis acids did not
improve the yield of 3a (Table 1, entries 5-8 and 10-13). The
combined Lewis acid CuCl2/AgSbF6 did not improve the
15 reaction outcome either (Table 1, entry 9). Changing
Yb(OTf)3 to a more Lewis acidic catalyst Yb(NTf2)3, the yield
of 3a increased to 54% (Table 1, entry 14). Examination of
solvent effects using Yb(OTf)3, Sc(OTf)3 or Yb(NTf2)3 as the
catalyst revealed that DCE was the solvent of choice (Table 1,
20 entries 15-22). Changing the catalyst loading (Yb(NTf2)3) to
0.1, 0.2, or 0.8 equiv., we found that the best result was
obtained in the presence of 0.2 equiv of catalyst, affording 3a
in 85% yield (Table 1, entries 23-25). Prolonging the reaction
time to 48 h, the starting materials 1a could not be consumed
25 completely and the yield of 3a decreased to 70%, suggesting
that this reaction process might be reversible (Table 1, entry
26). Therefore, the optimal reaction conditions have been
Mg(ClO4)2
DCE
DCE
DCE
0.45
0.45
0.45
-
34
53
40
0
80
BF3 . OEt2
CuCl2/AgSbF6
Et2AlCl
8
9
-
0
80
9:1
19
80
10
11
12
13
14
15
16
17
18
19
20
THF
0.45
0.45
0.45
0.45
0.45
0.45
0.45
0.45
0.45
0.45
0.45
0.45
reflux
-
100
24
15
28
92
5
0
TiCl4
DCE
DCE
DCE
DCE
toluene
-
0
80
80
80
La(OTf)3
Eu(OTf)3
-
0
10:1
11:1
-
5
Yb(NTf2
)
3
54
0
80
Yb(OTf)3
Yb(OTf)3
Sc(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
reflux
dioxane
CH3CN
-
3
0
80
1:0
0:1
-
70
100
0
19
26
0
80
TCE
DMF
reflux
80
80
110
80
80
80
o-dichlorobenzene
o-dichlorobenzene
(trifluoromethyl)benzene
DCE
2:1
1:1
65
90
12
(60)
21
22
23
24
Yb(NTf2
)
0.45
0.2
13:1
12:1
1:0
78
36 (34)
85 (85)
53
3
Yb(NTf2
)
90
3
Yb(NTf2
)
DCE
0.8
100
3
Yb(NTf2
Yb(NTf2
)
25
26d
DCE
DCE
0.1
0.2
12:1
12:1
65
95
50
70
3
80
80
)
3
a Nitrone 1a (0.1 mmol), cyclopropane 2a (0.2 mmol), Lewis acid (x mmol) and 4Å MS (80 mg) were stirred in 2
mL of solvents. The reaction time of 24 h was a tradeoff to get a unified procedure. b The ratios of 3a:4a were
determined by 1H NMR spectroscopic data of the crude products. c The yields were determined through analysis
by 1H NMR (1,3,5-trimethoxybenzene) and the values in parentheses were isolated yields. d The reaction time
was prolonged to 48 h.
40
We next examined the substrate generality of this reaction
under the optimized conditions and the results are shown in
Table 2. As can be seen from Table 2, in the case of substrates
1b and 1c, the reactions proceeded smoothly to furnish the
desired products 3b and 3c in moderate yields, regardless of
o
identified to carry out the reaction in DCE at 80 C for 24 h
using 0.2 equiv Yb(NTf2)3 as the catalyst (Table 1, entry 23).
30
45 whether they have electron-withdrawing, or electron-donating
substituents at the 3-position of aromatic moiety (Ar) along
with moderate to good regioselectivities (Table 2, entries 1-2).
When the 4-position of Ar moiety had an electron-
withdrawing substituent such as Br, the yield decreased to
50 31% (Table 2, entry 3). Substrate 1e having no protecting
group (PG = H) afforded 3e in 63% yield along with 5:1
regioselectivity and changing the N-PG to Bn produced the
corresponding compound 3f in 80% yield along with 15:1
regioselectivity (Table 2, entries
4 and 5). The better
55 regioselectivity for substrate 1f compared to substrate 1e
indicated that protecting group could improve the
regioselectivity although no obvious effect on the overall
yield of 3 and 4 (Table 2, entries 4 and 5). Further
examination of substituent effect of oxindole moiety revealed
60 that the reactions proceeded smoothly to furnish the desired
products in moderate yields along with good regioselectivities
regardless of whether electron-withdrawing or –donating
group was introduced (Table 2, entries 6-11). Changing 1,1-
Figure 1. ORTEP drawing of 3a
Table 1. Optimization of Reaction Conditions for Yb(NTf2)3-
35 catalyzed [3+3] Cycloaddition between Isatin Ketonitrones
and Cyclopropanes.
dimethoxycarbonylcyclopropane
2a
to
1,1-
65 diethoxycarbonylcyclopropane 2b, similar results were
obtained in the reaction with 1a or 1f (Table 2, entries 12-13).
The product structures of 3b-3n were determined by NMR
spectroscopic analysis, mass spectroscopy (MS), and HRMS
(see Supporting Information).
70
Table 2. Substrate Scope for Yb(NTf2)3-catalyzed [3+3]
2
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Cycloaddition between Isatin Ketonitrones and Cyclopropanes.
In this [3+3] cycloaddition, the starting material nitrone could
not be consumed completely, even if prolonging the reaction time
or increasing the amount of cyclopropane. To understand why
25 isatin ketonitrone could not be converted to the desired product
thoroughly, product 3a was treated with Yb(NTf2)3 under the
standard conditions. It was found that 3a was transformed into
isatin ketonitrone 1a in 39% yield and the regioisomer 4a in 5%
yield along with the recovery of 48% of compound 3a (Scheme
30 3). This result suggested that this reaction is a reversible process,
thus the starting material can not be consumed completely and the
choice on the rational reaction time to quench the reaction is
beneficial to improve the overall yield.
O
N
O
O
N
Ar
O
Ar
Ar
N
Yb(NTf2)3 (20 mol%)
CO2R4
CO2R4
CO2R4
CO2R4
R1
R2
CO2R4
R1
R2
R1
R2
Å M
4
S
O
O
+
+
DCE, 80 o
C
N
CO2R4
N
N
R3
R3
1
R3
PG
PG
PG
2
3
4
yield (%)d
3
conv (%)c
entrya
3:4b
R1/R2/R3, PG, Ar
R4
1
2
1b, H/H/H, Me, 3-Cl-Ph
1c, H/H/H, Me, 3-Me-Ph
2a, Me
2a, Me
9:1
5:1
74
92
3b, 55
3c, 50
3
4
5
6
1d, H/H/H, Me, 4-Br-Ph
1e, H/H/H, -, Ph
1f, H/H/H, Bn, Ph
2a, Me
2a, Me
2a, Me
9:1
5:1
15:1
1:0
79
3d, 31
3e, 63
3f, 80
100
93
1g
, H/H/Cl, Me, Ph
2a
3g
, 61
, Me
75
7
8
9
1h, H/H/F, Me, Ph
1i, H/Cl/H, Me, Ph
1j, H/Me/H, Me, Ph
2a, Me
2a, Me
2a, Me
1:0
70
91
94
3h, 60
3i, 60
3j, 52
10:1
11:1
10
1k, Cl/H/H, Me, Ph
1l, Me/H/H, Me, Ph
2a, Me
2a, Me
2b
, Et
14:1
78
3k, 63
3l, 73
3m
, 62
MeO2C
CO2Me
11
14:1
16:1
-
78
93
78
O
O
N
O
N
1a
O
12
, H/H/H, Me, Ph
Ph
Ph
13e
1f, H/H/H, Bn, Ph
2b, Et
3n, 44
N
Ph
Ph
CO2Me
CO2Me
CO2Me
CO2Me
N
Yb(NTf2)3 (20 mol%)
a Nitrones 1 (0.1 mmol), cyclopropane 2a (0.2 mmol), Yb(NTf2
)3 (0.02 mmol) and 4Å MS (80 mg)
O +
O
+
O
O
were stirred in 2 mL of DCE at 80 oC for 24 h. b The ratios of 3a:4a were determined by 1H NMR
spectroscopic data of the crude products. c The conversions were determined from the 1H NMR
spectroscopic data for the crude products by adding internal standard sample 1,3,5-
N
4Å MS
DCE
80 oC, 24 h
N
N
N
3a
4a
, 5%
1a
, 39%
3a
, 48%
35
trimethoxylbenzene. d Isolated yields of 3. e The ratios of 3a:4a could not be determined by 1
H
Scheme 3. The reversibility of the [3+3] cycloaddtion between isatin
NMR spectroscopic data of the crude products.
ketonitrones and cyclopropanes
5
Next, we examined the substituent effect of cyclopropanes and
the results are shown in Scheme 2. Using vinylcyclopropane 2c
afforded the desired product 3o in 51% yield under the standard
conditions. Using cyclopropane 2d as the substrate gave the
corresponding product 3p in 12% yield in the presence of
The obtained cycloadducts 3a, 3g and 3h have been used to
40 synthesize N-Ar-γ-amino alcohols via reductive cleavage of the
N-O bond and the results are shown in Scheme 4. The most
common methods for the reductive cleavage of N-O bond include
zinc in acid,20-22 catalytic hydrogenation,23 TMSI-mediated
reduction,24 as well as SmI2-mediated reduction.25 We found that
45 either complex product mixtures were obtained along with the
recovery of the starting materials or no reaction occurred,
presumably due to that the resulting N-O bond cleaved product is
not stable under such reaction conditions (Scheme 4). The further
examination of the reaction conditions will be carried out in due
50 course.
10 Yb(OTf)3 but none of 3p could be formed in the presence of
Yb(NTf2)3. The structure of compound 3o has been determined
by X-ray diffraction and the ORTEP drawing is shown in Figure
2 (CIF data see Supporting Information).19
15
Scheme 2. [3+3] cycloaddtion between isatin ketonitrone 1a and
substituted cyclopropane 2c or 2d.
Scheme 3. The examinations for the transformation of spiro[tetrahydro-
1,2-oxazine]oxindole derivatives
55
In summary, we have reported a novel Yb(NTf2)3-catalyzed
[3+3] cycloaddition between isatin ketonitrones and
cyclopropanes to give
a variety of spiro[tetrahydro-1,2-
oxazine]oxindole derivatives in moderate to good yields along
60 with good regioselectivities. Although the yield per pass is
20
Figure 2. ORTEP drawing of 3o
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1
1103, 987, 898 cm-1; H NMR (400 MHz, CDCl3, TMS) δ 3.19
(s, 3H), 6.85 (d, J = 7.6 Hz, 1H), 7.15 (td, J = 7.6 Hz, 0.8 Hz,
60 1H), 7.37 (dd, J = 7.6 Hz, 2.0 Hz, 1H), 7.42-7.53 (m, 4H), 8.44
(dd, J = 7.6 Hz, 1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3, TMS)
δ 26.0, 108.1, 117.7, 122.0, 123.2, 124.2, 125.2, 130.0, 130.7,
132.5, 134.6, 134.8, 142.2, 146.8, 159.3; HRMS (MALDI) Calcd.
for C15H11ClN2O2 requires (M++H): 287.0587, Found: 287.0593.
65
moderate, the overall yield is good because the unconsumed
starting material nitrone can be recovered easily. The choice of
rational reaction time as trade off is critical to improve the
reaction efficiency. In addition, this is the first example of
intermolecular [3+3] cycloaddition between ketone-derived
nitrones and cyclopropanes. Further applications of isatin
ketonitrones to extend the scope of available spirooxindoles and
developing the asymmetric version of [3+3] cycloaddition are
under way in our laboratory.
5
o
Compound 1c: Yield: 63%. A red solid. m. p.: 162-164 C. IR
(neat) ν 3056, 2928, 1702, 1607, 1469, 1375, 1327, 1096, 1023,
985, 873 cm-1; 1H NMR (400 MHz, CDCl3, TMS) δ 2.43 (s, 3H),
3.18 (s, 3H), 6.84 (d, J = 8.0 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H),
70 7.25-7.27 (m, 2H), 7.33-7.44 (m, 3H), 8.46 (d, J = 7.2 Hz, 1H);
13C NMR (100 MHz, CDCl3, TMS) δ 21.3, 26.0, 107.9, 118.0,
120.7, 123.0, 124.0, 125.0, 128.7, 131.3, 132.1, 134.5, 139.3,
142.0, 146.4, 159.5; HRMS (MALDI) Calcd. for C16H14N2O2
requires (M++H): 267.1134, Found: 267.1138.
10 Acknowledgement: We thank the Shanghai Municipal
Committee of Science and Technology (11JC1402600), National
Basic Research Program of China (973)-2010CB833302, and the
National Natural Science Foundation of China for financial
support (21072206, 20472096, 20872162, 20672127, 20732008
15 and 21121062).
75
Experimental Section
1
o
General Remarks. H and 13C NMR spectra were recorded at
Compound 1d: Yield: 58%. A yellow solid. m. p.: 212-214 C.
IR (neat) ν 3093, 3055, 2927, 1698, 1677, 1606, 1466, 1243,
1095, 1067, 1013, 982 cm-1; 1H NMR (300 MHz, CDCl3, TMS) δ
3.19 (s, 3H), 6.85 (d, J = 7.8 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H),
80 7.37 (d, J = 8.4 Hz, 2H), 7.44 (t, J = 7.5 Hz, 1H), 7.64 (d, J = 8.4
Hz, 2H), 8.44 (d, J = 7.5 Hz, 1H); 13C NMR (75 MHz, CDCl3,
TMS) δ 26.0, 108.1, 117.8, 123.2, 124.8, 125.1, 125.4, 132.2,
132.5, 134.7, 142.1, 145.0, 159.4; HRMS (MALDI) Calcd. for
C15H11BrN2O2 requires (M++H): 331.0082, Found: 331.0079.
85
400 (or 300) and 100 (or 75) MHz, respectively. Mass and
20 HRMS spectra were recorded by ESI method. The employed
solvents were dry up by standard methods when necessary.
Commercially obtained reagents were used without further
purification. All reactions were monitored by TLC with silica gel
coated plates. Flash column chromatography was carried out
25 using 300-400 mesh silica gel at increased pressure.
General procedure for preparing isatin ketonitrones. N-
protected isatin (1.0 mmol, 1.0 equiv), N-phenylhydroxylamines
(2.5 mmol, 2.5 equiv), trifluoroacetic acid (0.01 mmol, 0.01
30 equiv) and 4Å MS was stirred in 1,2-dichloromethane until TLC
shows that isatins disappeared completely. The solvent was
removed under reduced pressure and the residue was purified by
a flash column chromatography (SiO2) to give the corresponding
products 1.
o
Compound 1e: Yield: 62%. A yellow solid. m. p.: 258-260 C.
IR (neat) ν 3149, 3066, 3028, 2828, 1701, 1539, 1459, 1351,
1256, 1237, 1139, 925, 857 cm-1; 1H NMR (400 MHz, d6-DMSO,
TMS) δ 6.90 (d, J = 7.6 Hz, 1H), 7.07 (td, J = 7.6 Hz, 0.8 Hz,
90 1H), 7.40 (td, J = 7.6 Hz, 1.2 Hz, 1H), 7.49-7.59 (m, 5H), 8.28 (d,
J = 7.6 Hz, 1H), 10.8 (s, 1H); 13C NMR (100 MHz, d6-DMSO,
TMS) δ 109.8, 118.4, 121.9, 124.0, 124.2, 128.8, 130.2, 132.4,
134.5, 141.0, 146.4, 160.0; HRMS (MALDI) Calcd. for
C14H10N2O2 requires (M++H): 239.0821, Found: 239.0806.
95
35
General procedure for An Yb(NTf2)3-catalyzed [3+3]
cycloaddition between isatin ketonitrones and cyclopropanes
under the standard reaction conditions. Under an argon
o
Compound 1f: Yield: 75%. A yellow solid. m. p.: 208-210 C.
IR (neat) ν 3067, 3030, 2939, 1696, 1605, 1541, 1463, 1258,
atmosphere, isatin ketonitrones
1 (0.1 mmol, 1.0 equiv),
1
1162, 948, 871 cm-1; H NMR (300 MHz, CDCl3, TMS) δ 4.87
40 cyclopropanes 2, Yb(NTf2)3 (0.02 mmol, 0.2 equiv) and 4Å MS
o
(s, 2H), 6.76 (d, J = 7.8 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 7.24-
100 7.34 (m, 6H), 7.51-7.53 (m, 5H), 8.50 (d, J = 7.2 Hz, 1H); 13C
NMR (75 MHz, CDCl3, TMS) δ 43.7, 108.9, 118.2, 123.1, 123.7,
125.1, 127.3, 127.7, 128.8, 129.0, 130.7, 132.1, 134.4, 135.4,
141.3, 146.4, 159.5; HRMS (MALDI) Calcd. for C21H16N2O2
requires (M++H): 329.1290, Found: 329.1280.
was stirred in 1,2-dichloroethane (DCE) (1.0 mL) at 80 C for 24
h. The solvent was removed under reduced pressure and the
residue was purified by a flash column chromatography (SiO2) to
give the corresponding products 3 in moderate to good yields.
45
o
Compound 1a: Yield: 73%. A yellow solid. m. p.: 160-162 C.
105
IR (neat) ν 3059, 3021, 1695, 1608, 1467, 1373, 1328, 1098,
o
1
1080, 983 cm-1; H NMR (400 MHz, CDCl3, TMS) δ 3.18 (s,
Compound 1g: Yield: 64%. A red solid. m. p.: 237-240 C. IR
(neat) ν 3053, 2953, 1702, 1599, 1535, 1450, 1370, 1316, 1110,
3H), 6.84 (d, J = 7.6 Hz, 1H), 7.15 (td, J = 7.6 Hz, 0.8 Hz, 1H),
50 7.43 (td, J = 7.6 Hz, 1.2 Hz, 1H), 7.46-7.55 (m, 5H), 8.47 (dd, J =
7.6 Hz, 1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3, TMS) δ 26.0,
107.9, 118.0, 123.1, 123.6, 125.1, 129.0, 130.6, 132.2, 134.6,
142.0, 146.4, 159.5; HRMS (MALDI) Calcd. for C15H12N2O2
requires (M++H): 253.0977, Found: 253.0976.
1
1056, 989 cm-1; H NMR (400 MHz, CDCl3, TMS) δ 3.56 (s,
3H), 7.06 (dd, J = 8.4 Hz, 7.6 Hz, 1H), 7.34 (dd, J = 8.4 Hz, 1.2
110 Hz, 1H), 7.44-7.47 (m, 2H), 7.50-7.58 (m, 3H), 8.48 (dd, J = 8.0
Hz, 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3, TMS) δ 29.2,
115.4, 120.6, 123.3, 123.6, 123.8, 129.0, 130.8, 133.6, 134.1,
137.6, 146.5, 159.7; HRMS (MALDI) Calcd. for C15H11ClN2O2
requires (M++H): 287.0587, Found: 287.0581.
55
o
Compound 1b: Yield: 99%. A yellow solid. m. p.: 209-211 C.
115
IR (neat) ν 3072, 2935, 1704, 1605, 1541, 1468, 1327, 1243,
4
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HRMS (MALDI) Calcd. for C22H22N2O6 requires (M++H):
o
Compound 1h: Yield: 59%. A red solid. m. p.: 170-172 C. IR
(neat) ν 3051, 2937, 1706, 1626, 1548, 1461, 1372, 1230, 791 60 411.1556, Found: 411.1552.
1
cm-1; H NMR (300 MHz, CDCl3, TMS)
3.99-3.40 (m, 3H),
7.03-7.19 (m, 2H), 7.45-7.59 (m, 5H), 8.29 (dd, J = 7.5 Hz, 0.9
Hz, 1H); 13C NMR (75 MHz, CDCl3, TMS) δ 28.6 (d, JC-F = 5.3
Hz), 120.0 (d, JC-F = 19.1 Hz), 120.6 (d, JC-F = 1.6 Hz), 120.9 (d,
Compound 3b: Yield: 24 mg, 55%. A white solid. m. p.: 165-
o
5
167 C. IR (neat) ν 2960, 1740, 1719, 1464, 1264, 1219, 1086,
1
1049, 972, 955 cm-1; H NMR (400 MHz, CDCl3, TMS) δ 2.44
JC-F = 2.9 Hz), 123.6, 123.7, 128.2 (d, JC-F = 9.2 Hz), 129.0, 65 (brs, 1H), 2.74 (brs, 1H), 2.87 (s, 3H), 3.46 (s, 3H), 3.89 (s, 3H),
130.8, 134.1, 146.2, 147.1 (d, JC-F = 242.6 Hz), 159.2; 19F NMR
(282 MHz, CDCl3, CFCl3) δ -136.87 (brs, 1F); HRMS (MALDI)
4.42 (brs, 1H), 4.92 (brs, 1H), 6.50 (d, J = 7.6 Hz, 1H), 6.77 (td, J
= 7.6 Hz, 2.0 Hz, 1H), 6.83 (s, 1H), 6.88-6.95 (m, 2H), 7.03 (dt, J
= 7.6 Hz, 0.8 Hz, 1H), 7.24 (dt, J = 8.0 Hz, 1.2 Hz, 1H), 7.59
(brs, 1H); 13C NMR (100 MHz, CDCl3, TMS) δ 25.9, 27.8, 52.4,
70 52.8, 56.7, 66.6, 107.7, 121.8, 121.9, 123.5, 125.0, 126.2, 126.4,
128.0, 129.8, 132.8, 144.0, 147.0, 169.4, 169.9, 171.5; HRMS
(MALDI) Calcd. for C22H21ClN2O6 requires (M++H): 445.1166,
Found: 445.1164.
10 Calcd. for C15H11FN2O2 requires (M++H): 271.0883, Found:
271.0875.
o
Compound 1i: Yield: 78%. A red solid. m. p.: 218-220 C. IR
(neat) ν 3056, 3015, 1702, 1601, 1531, 1479, 1371, 1284, 1238,
1
15 1107, 1072, 995 cm-1; H NMR (400 MHz, CDCl3, TMS) δ 3.16
(s, 3H), 6.84 (s, 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.46-7.57 (m, 5H),
8.38 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3, TMS) δ 75 Compound 3c: Yield: 21 mg, 50%. A white solid. m. p.: 172-174
26.1, 108.7, 116.5, 122.9, 123.6, 125.7, 129.0, 130.8, 133.7,
137.7, 142.9, 146.2, 159.3; HRMS (MALDI) Calcd. for
20 C15H11ClN2O2 requires (M++H): 287.0587, Found: 287.0578.
oC. IR (neat) ν 2951, 1740, 1717, 1608, 1428, 1371, 1221, 1085,
1
1048, 987, 972 cm-1; H NMR (400 MHz, CDCl3, TMS) δ 2.08
(s, 3H), 2.45 (brs, 1H), 2.74 (brs, 1H), 2.82 (s, 3H), 3.46 (s, 3H),
3.88 (s, 3H), 4.44 (brs, 1H), 4.92 (brs, 1H), 6.46 (d, J = 8.0 Hz,
Compound 1j: Yield: 86%. A red solid. m. p.: 214-216 C. IR 80 1H), 6.61-6.64 (m, 2H), 6.75-6.77 (m, 1H), 6.83 (t, J = 7.6 Hz,
o
(neat) ν 3032, 2916, 2857, 1701, 1614, 1454, 1378, 1244, 1078,
923 cm-1; 1H NMR (300 MHz, CDCl3, TMS) δ 2.45 (s, 3H), 3.18
25 (s, 3H), 6.68 (s, 1H), 6.97 (d, J = 7.8 Hz, 1H), 7.45-7.54 (m, 5H),
8.35 (d, J = 8.1 Hz, 1H); 13C NMR (75 MHz, CDCl3, TMS) δ
1H), 7.00 (t, J = 7.6 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.60 (brs,
1H); 13C NMR (100 MHz, CDCl3, TMS) δ 21.0, 25.7, 28.0, 52.4,
52.7, 56.7, 66.5, 107.4, 120.7, 121.6, 124.1, 125.6, 126.5, 126.9,
127.0, 129.4, 137.0, 144.2, 145.4, 169.6, 170.1, 171.8; HRMS
22.5, 25.9, 108.9, 115.5, 123.6, 123.7, 124.9, 128.9, 130.4, 134.5, 85 (MALDI) Calcd. for C23H24N2O6 requires (M++H): 425.1713,
142.3, 143.4, 146.3, 159.7; HRMS (MALDI) Calcd. for
C16H14N2O2 requires (M++H): 267.1134, Found: 267.1136.
Found: 425.1705.
30
Compound 3d: Yield: 15 mg, 31%. A white solid. m. p.: 194-
o
o
Compound 1k: Yield: 59%. A red solid. m. p.: 210-212 C. IR
196 C. IR (neat) ν 2948, 1741, 1717, 1609, 1483, 1469, 1263,
1
(neat) ν 3108, 3084, 3019, 1701, 1536, 1471, 1290, 1234, 1101, 90 1214, 1096, 1053, 1008, 974 cm-1; H NMR (400 MHz, CDCl3,
1076, 994 cm-1; H NMR (400 MHz, CDCl3, TMS) δ 3.19 (s,
3H), 6.78 (d, J = 8.4 Hz, 1H), 7.40 (dd, J = 8.0 Hz, 1.6 Hz, 1H),
TMS) δ 2.42 (brs, 1H), 2.74 (brs, 1H), 2.86 (s, 3H), 3.45 (s, 3H),
3.89 (s, 3H), 4.40 (brs, 1H), 4.92 (brs, 1H), 6.52 (d, J = 8.0 Hz,
1H), 6.71 (dt, J = 8.8 Hz, 2.4 Hz, 2H), 7.01 (t, J = 7.6 Hz, 1H),
7.08 (dt, J = 8.8 Hz, 2.4 Hz, 2H), 7.24 (td, J = 8.0 Hz, 1.2 Hz,
1
35 7.46-7.58 (m, 5H), 8.48 (d, J = 2.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3, TMS) δ 26.1, 108.8, 119.1, 123.6, 124.8, 128.5, 129.0,
130.9, 131.6, 133.9, 140.3, 146.2, 159.1; HRMS (MALDI) Calcd. 95 1H), 7.60 (brs, 1H); 13C NMR (100 MHz, CDCl3, TMS) δ 25.9,
for C15H11ClN2O2 requires (M++H): 287.0587, Found: 287.0587.
27.8, 52.5, 52.8, 56.7, 66.6, 107.8, 119.7, 121.9, 125.1, 125.2,
126.5, 129.8, 130.3, 144.1, 144.8, 169.4, 169.9, 171.6; HRMS
(MALDI) Calcd. for C22H21BrN2O6 requires (M++H): 489.0661,
Found: 489.0656.
o
40 Compound 1l: Yield: 82%. A red solid. m. p.: 190-192 C. IR
(neat) ν 3063, 3010, 2911, 1694, 1612, 1538, 1483, 1299, 1101,
1008, 930 cm-1; H NMR (400 MHz, CDCl3, TMS) δ 2.39 (s, 100
1
3H), 3.16 (s, 3H), 6.74 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz,
1H), 7.45-7.55 (m, 5H), 8.32 (s, 1H); 13C NMR (100 MHz,
45 CDCl3, TMS) δ 21.0, 26.0, 107.7, 118.0, 123.7, 125.7, 129.0,
130.6, 132.6, 132.7, 134.9, 140.0, 146.4, 159.6; HRMS (MALDI)
Compound 3e: Yield: 25 mg, 63%. A white solid. m. p.: 250-252
oC. IR (neat) ν 3092, 2946, 2887, 1744, 1717, 1620, 1467, 1265,
1
1213, 1049, 970 cm-1; H NMR (300 MHz, CDCl3, TMS) δ 2.48
(brs, 1H), 2.72 (brs, 1H), 3.50 (s, 3H), 3.86 (s, 3H), 4.46 (brs,
Calcd. for C16H14N2O2 requires (M++H): 267.1134, Found: 105 1H), 4.90 (brs, 1H), 6.52 (d, J = 7.2 Hz, 1H), 6.88-6.91 (m, 2H),
267.1132.
6.98-7.03 (m, 4H), 7.09 (brs, 1H), 7.16 (t, J = 7.5 Hz, 1H) , 7.60
(brs, 1H); 13C NMR (100 MHz, CDCl3, TMS) δ 27.9, 52.3, 52.7,
57.0, 66.6, 109.4, 121.7, 124.2, 125.9, 126.5, 126.9, 127.4, 129.6,
141.4, 145.5, 169.5, 169.9, 173.4; HRMS (MALDI) Calcd. for
50 Compound 3a: Yield: 34 mg, 82%. A white solid. m. p.: 168-170
oC. IR (neat) ν 2955, 1746, 1714, 1607, 1486, 1433, 1264, 1218,
1046, 990, 973 cm-1; H NMR (400 MHz, CDCl3, TMS) δ 2.43 110 C21H20N2O6 requires (M++H): 397.1400, Found: 397.1394.
1
(brs, 1H), 2.76 (brs, 1H), 2.81 (s, 3H), 3.45 (s, 3H), 3.89 (s, 3H),
4.43 (brs, 1H), 4.93 (brs, 1H), 6.45 (d, J = 7.6 Hz, 1H), 6.80-6.85
55 (m, 2H), 6.94-6.97 (m, 3H), 7.01 (t, J = 7.2 Hz, 1H), 7.21 (t, J =
7.6 Hz, 1H), 7.61 (brs, 1H); 13C NMR (100 MHz, CDCl3, TMS) δ
Compound 3f: Yield: 29 mg, 80%. A white solid. m. p.: 146-148
oC. IR (neat) ν 2954, 2941, 1746, 1720, 1609, 1486, 1365, 1275,
1
1215, 1044, 978 cm-1; H NMR (400 MHz, CDCl3, TMS) δ 2.43
25.8, 27.9, 52.4, 52.7, 56.8, 66.5, 107.5, 121.7, 123.5, 125.4, 115 (brs, 1H), 2.81 (brs, 1H), 3.38 (s, 3H), 3.91 (s, 3H), 4.42-4.49 (m,
126.3, 126.5, 127.1, 129.5, 144.1, 145.5, 169.5, 170.0, 171.7;
2H), 4.74 (d, J = 16.0 Hz, 1H), 4.97 (brs, 1H), 6.32 (d, J = 7.6
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3.89 (s, 3H), 4.45 (brs, 1H), 4.92 (brs, 1H), 6.38 (d, J = 8.4 Hz,
3H), 7.06-7.17 (m, 5H), 7.71 (brs, 1H); 13C NMR (100 MHz, 60 1H), 6.83-6.85 (m, 2H), 6.96-7.03 (m, 3H), 7.20 (dd, J = 8.0 Hz,
Hz, 1H), 6.65-6.67 (m, 2H), 6.88-6.91 (m, 2H), 6.98-7.02 (m,
CDCl3, TMS) δ 28.0, 43.9, 52.3, 52.8, 57.3, 66.7, 108.9, 121.8,
124.5, 125.5, 126.7, 126.8, 127.1, 127.7, 128.5, 129.5, 135.1,
143.8, 145.6, 169.5, 170.0, 171.7; HRMS (MALDI) Calcd. for
C28H26N2O6 requires (M++H): 487.1869, Found: 487.1856.
1.6 Hz, 1H), 7.59 (brs, 1H); 13C NMR (100 MHz, CDCl3, TMS) δ
25.9, 27.8, 52.6, 52.8, 56.7, 66.5, 108.3, 123.4, 126.5, 126.7,
126.9, 127.2, 127.4, 129.3, 142.8, 145.2, 169.4, 169.8, 171.3;
HRMS (MALDI) Calcd. for C22H21ClN2O6 requires (M++H):
65 445.1166, Found: 445.1156.
5
Compound 3g: Yield: 27 mg, 61%. A white solid. m. p.: 136-138
oC. IR (neat) ν 2954, 1747, 1726, 1708, 1463, 1277, 1216, 1111,
Compound 3l: Yield: 31 mg, 73%. A white solid. m. p.: 175-177
oC. IR (neat) ν 2947, 1738, 1717, 1495, 1433, 1353, 1263, 1213,
1
10 1078, 984 cm-1; H NMR (400 MHz, CDCl3, TMS) δ 2.44 (brs,
1
1H), 2.71 (brs, 1H), 3.19 (s, 3H), 3.51 (s, 3H), 3.89 (s, 3H), 4.43
1099, 1045, 989 cm-1; H NMR (400 MHz, CDCl3, TMS) δ 2.36
(brs, 1H), 4.91 (brs, 1H), 6.78-6.80 (m, 2H), 6.93 (t, J = 8.4 Hz, 70 (s, 3H), 2.43 (brs, 1H), 2.78 (brs, 4H), 3.45 (s, 3H), 3.89 (s, 3H),
1H), 6.98-7.03 (m, 3H), 7.15 (d, J = 8.4 Hz, 1H), 7.52 (brs, 1H);
13C NMR (100 MHz, CDCl3, TMS) δ 27.7, 29.4, 52.5, 52.8, 56.9,
15 66.5, 115.1, 122.3, 123.5, 124.8, 126.7, 127.4, 128.3, 131.9,
140.2, 145.2, 169.4, 169.9, 172.2; HRMS (MALDI) Calcd. for
C22H21ClN2O6 requires (M++H): 445.1166, Found: 445.1162.
4.44 (brs, 1H), 4.93 (brs, 1H), 6.34 (d, J = 8.0 Hz, 1H), 6.81-6.83
(m, 2H), 6.94-6.98 (m, 3H), 7.01 (d, J = 7.6 Hz, 1H), 7.43 (brs,
1H); 13C NMR (100 MHz, CDCl3, TMS) δ 21.3, 25.8, 27.9, 52.3,
52.7, 56.7, 66.5, 107.2, 123.6, 125.4, 126.2, 127.1, 127.3, 129.7,
75 131.0, 141.8, 145.5, 169.6, 170.1, 171.6; HRMS (MALDI) Calcd.
for C23H24N2O6 requires (M++H): 425.1713, Found: 425.1717.
Compound 3h: Yield: 51 mg, 60%. A white solid. m. p.: 190-
o
20 192 C. IR (neat) ν 2949, 1725, 1719, 1626, 1596, 1476, 1432,
Compound 3m: Yield: 29 mg, 62%. A white solid. m. p.: 140-
1337, 1282, 1214, 1119, 1041, 870 cm-1; H NMR (300 MHz,
142 C. IR (neat) ν 2974, 2939, 2892, 1725, 1712, 1612, 1491,
1
o
CDCl3, TMS) δ 2.44 (brs, 1H), 2.71 (brs, 1H), 3.03 (d, J = 2.1 80 1468, 1260, 1214, 1044, 990 cm-1; H NMR (400 MHz, CDCl3,
1
Hz, 3H), 3.51 (s, 3H), 3.89 (s, 3H), 4.42 (brs, 1H), 4.92 (brs, 1H),
6.79-6.83 (m, 2H), 6.93-6.96 (m, 2H), 6.99-7.02 (m, 3H), 7.41
25 (brs, 1H); 13C NMR (75 MHz, CDCl3, TMS) δ 27.7, 28.3 (d, J =
6.8 Hz), 52.5, 52.8, 56.8, 66.4, 117.6 (d, J = 18.8 Hz), 122.1 (d, J
TMS) δ 0.89 (t, J = 6.4 Hz, 3H), 1.37 (t, J = 6.8 Hz, 3H), 2.41
(brs, 1H), 2.78 (brs, 4H), 3.91 (brs, 2H), 4.31-4.41 (m, 3H), 4.94
(brs, 1H), 6.44 (d, J = 8.0 Hz, 1H), 6.81-6.83 (m, 2H), 6.94-6.98
(m, 3H), 7.01 (t, J = 7.6 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H), 7.64
= 6.3 Hz), 122.3, 123.4, 126.6, 127.3, 128.3 (d, J = 2.3 Hz), 130.9 85 (brs, 1H); 13C NMR (100 MHz, CDCl3, TMS) δ 13.3, 14.0, 25.7,
(d, J = 8.0 Hz), 145.2, 147.1 (d, J = 241.8 Hz), 169.4, 169.8,
171.4; 19F NMR (282 MHz, CDCl3, CFCl3) δ -136.83--136.90
30 (m, 1F); HRMS (MALDI) Calcd. for C22H21FN2O6 requires
(M++H): 429.1462, Found: 429.1455.
27.9, 56.6, 61.3, 61.7, 66.7, 107.3, 121.6, 123.5, 125.6, 126.3,
126.6, 127.1, 129.4, 144.2, 145.6, 169.1, 169.8, 171.7; HRMS
(MALDI) Calcd. for C24H26N2O6 requires (M++H): 439.1869,
Found: 439.1858.
90
Compound 3i: Yield: 27 mg, 60%. A white solid. m. p.: 200-202
oC. IR (neat) ν 2956, 1725, 1605, 1592, 1432, 1372, 1250, 1211,
Compound 3n: Yield: 23 mg, 44%. A white solid. m. p.: 192-
o
194 C. IR (neat) ν 2969, 2927, 2849, 1721, 1711, 1609, 1466,
35 1073, 968 cm-1; H NMR (400 MHz, CDCl3, TMS) δ 2.45 (brs,
1367, 1226, 1047, 1022 cm-1; 1H NMR (400 MHz, CDCl3, TMS)
1
1H), 2.68 (brs, 1H), 2.80 (s, 3H), 3.50 (s, 3H), 3.89 (s, 3H), 4.42
δ 0.84 (t, J = 6.0 Hz, 3H), 1.39 (t, J = 7.2 Hz, 3H), 2.42 (brs, 1H),
(brs, 1H), 4.91 (brs, 1H), 6.47 (d, J = 2.0 Hz, 1H), 6.82-6.84 (m, 95 2.82 (brs, 1H), 3.87 (brs, 2H), 4.34-4.42 (m, 4H), 4.81 (d, J =
2H), 6.99-7.00 (m, 4H), 7.53 (brs, 1H); 13C NMR (100 MHz,
CDCl3, TMS) δ 25.9, 27.8, 52.5, 52.8, 56.8, 66.5, 108.3, 121.5,
40 123.4, 123.9, 126.5, 127.3, 127.4, 135.4, 145.2, 145.4, 169.4,
169.8, 171.7; HRMS (MALDI) Calcd. for C22H21ClN2O6 requires
(M++H): 445.1166, Found: 445.1157.
16.0 Hz, 1H), 4.99 (brs, 1H), 6.32 (d, J = 7.6 Hz, 1H), 6.60 (d, J
= 5.2 Hz, 2H), 6.88-6.90 (m, 2H), 6.98-7.03 (m, 3H), 7.07-7.18
(m, 5H), 7.73 (brs, 1H); 13C NMR (100 MHz, CDCl3, TMS) δ
13.4, 14.0, 28.0, 43.9, 57.2, 61.3, 61.8, 66.9, 108.8, 121.8, 124.6,
100 125.7, 126.7, 126.8, 126.9, 127.1, 127.8, 128.4, 129.4, 135.0,
143.9, 145.7, 169.1, 169.7, 171.7; HRMS (MALDI) Calcd. for
C30H30N2O6 requires (M++H): 515.2182, Found: 515.2186.
Compound 3j: Yield: 22mg, 52%. A white solid. m. p.: 178-180
45 oC. IR (neat) ν 3008, 2955, 1732, 1718, 1618, 1594, 1438, 1379,
1279, 1201, 1084, 969 cm-1; 1H NMR (400 MHz, CDCl3, TMS) δ
Compound 3o: Yield: 22 mg, 51%. A white solid. m. p.: 164-166
2.29 (s, 3H), 2.45 (brs, 1H), 2.73 (brs, 1H), 2.79 (s, 3H), 3.47 (s, 105 oC. IR (neat) ν 2953, 1750, 1725, 1610, 1471, 1254, 1200, 1043,
3H), 3.88 (s, 3H), 4.43 (brs, 1H), 4.90 (brs, 1H), 6.28 (s, 1H),
6.79-6.85 (m, 3H), 6.95-6.98 (m, 3H), 7.47 (brs, 1H); 13C NMR
50 (100 MHz, CDCl3, TMS) δ 21.7, 25.7, 27.9, 52.4, 52.7, 56.8,
66.4, 108.5, 122.2, 122.4, 123.6, 126.2, 127.1, 139.7, 144.1,
973, 949 cm-1; 1H NMR (400 MHz, CDCl3, TMS) δ 2.40 (dd, J =
14.8 Hz, 3.2 Hz, 1H), 2.55 (dd, J = 14.8 Hz, 12.0 Hz, 1H), 2.79
(s, 3H), 3.37 (s, 3H), 3.96 (s, 3H), 5.31 (dt, J = 10.8 Hz, 1.2 Hz,
1H), 5.46 (dt, J = 17.2 Hz, 1.2 Hz, 1H), 5.50-5.55 (m, 1H), 6.01
145.6, 169.6, 170.1, 172.0; HRMS (MALDI) Calcd. for 110 (ddd, J = 17.2 Hz, 10.8 Hz, 5.2 Hz, 1H), 6.47 (d, J = 8.0 Hz, 1H),
C23H24N2O6 requires (M++H): 425.1713, Found: 425.1706.
6.81-6.85 (m, 2H), 6.95-6.98 (m, 3H), 7.02 (td, J = 7.6 Hz, 1.2
Hz, 1H), 7.23 (td, J = 7.6 Hz, 1.2 Hz, 1H), 7.64 (d, J = 7.6 Hz,
1H); 13C NMR (100 MHz, CDCl3, TMS) δ 25.9, 33.0, 52.4, 52.9,
57.9, 72.9, 75.8, 107.5, 117.2, 121.9, 123.3, 125.4, 126.2, 126.7,
55 Compound 3k: Yield: 28 mg, 63%. A white solid. m. p.: 196-
o
198 C. IR (neat) ν 2951, 1756, 1736, 1716, 1609, 1488, 1428,
1
1279, 1202, 1086, 977, 944 cm-1; H NMR (400 MHz, CDCl3, 115 127.2, 129.5, 135.9, 144.0, 145.5, 169.4, 170.1, 171.6; HRMS
TMS) δ 2.47 (brs, 1H), 2.68 (brs, 1H), 2.80 (s, 3H), 3.53 (s, 3H),
6
| Journal Name, [year], [vol], 00–00
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(MALDI) Calcd. for C24H24N2O6 requires (M++H): 437.1713,
Found: 437.1705.
70
75
80
85
90
95
Chem. Soc. 2006, 128, 9626; (c) C. Palomo, M. Oiarbide, E. Arceo, J.
M. Garcia, R. Lopez, A. Gonzalez, Angew. Chem. Int. Ed. 2005, 44,
6187; (d) M. P. Sibi, Z.-H. Ma, C. P. Jasperse, J. Am. Chem. Soc.
2004, 126, 718; (e) W. S. Jen, J. M. Wiener, D. W. MacMillian, J. Am.
Chem. Soc. 2000, 122, 9874; (f) S. Kanemasa, Y. Oderaotoshi, J.
Tanaka, E. Wada, J. Am. Chem. Soc. 1998, 120, 12355
Compound 3p: Yield: 12 mg, 12%. A white solid. m. p.: 190-
o
5
192 C. IR (neat) ν 2952, 2917, 1750, 1724, 1611, 1514, 1246,
9
For selected examples of [3+2] cycloaddition and rearrangement
between nitrone and alkyne, see: (a) M. Buchlovic, S. Hebanova, M.
Potacek, Tetrahedron 2012, 68, 3117; (b) G. Mloston, M. Jasinski, H.
Heimgartner, Eur. J. Org. Chem. 2011, 2542; (c) S. A. Popov, N. V.
Chukanov, G. V. Romanenko, T. V. Rybalova, Y. V. Gatilov, V. A.
Reznikov, J. Heterocycl. Chem. 2006, 43, 277; (d) A. A. Aly, H.
Hopf, L. Ernst, I. Dix, P. G. Jones, Eur. J. Org. Chem. 2006, 3001; (e)
N. Coskun, A. Oeztuerk, Tetrahedron 2006, 62, 12057; (f) N. Coskun,
B. Yilmaz, Synth. Commun. 2004, 34, 1617; (g) A. V. Varlamov, A. I.
Chernyshev, F. I. Zubkov, K. F. Turchin, A. N. Levov, Chemistry of
Heterocyclic Compounds, 2004, 40, 364; (h) H. Valizadeh, E.
Vesally, L. Dinparast, J. Heterocycl. Chem. 2012, 49, 106.
1
1178, 1030, 972 cm-1; H NMR (400 MHz, CDCl3, TMS) δ 2.57
(dd, J = 14.8 Hz, 2.8 Hz, 1H), 2.78-2.85 (m, 4H), 3.37 (s, 3H),
3.83 (s, 3H), 3.99 (s, 3H), 6.06 (dd, J = 12.0 Hz, 2.8 Hz, 1H),
6.49 (d, J = 7.6 Hz, 1H), 6.85-6.88 (m, 2H), 6.94-6.97 (m, 5H),
10 7.05 (t, J = 7.6 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.46 (d, J = 8.8
Hz, 2H), 7.76 (d, J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3,
TMS) δ 25.9, 34.6, 52.5, 53.0, 55.3, 58.3, 73.0, 76.8, 107.6,
113.9, 121.9, 123.3, 125.6, 126.2, 126.5, 127.2, 127.7, 129.5,
131.9, 144.1, 145.6, 159.4, 169.5, 170.2, 171.7; HRMS (MALDI)
15 Calcd. for C29H28N2O7 requires (M++H): 517.1975, Found:
517.1964.
10 For selected examples of [3+3] cycloaddition between nitrone and
cylcopropane, see: (a) B. Hu, J.-L. Zhu, S.-Y. Xing, J. Fang, D. Du,
Z.-W. Wang, Chem. Eur. J. 2009, 15, 324; (b) C. A. Carson, I. S.
Young, M. A. Kerr, Synthesis 2008, 3, 485; (c) Y.-B. Kang, X.-L. Sun,
Y. Tang, Angew. Chem. Int. Ed. 2007, 46, 3918; (d) K. Sapeta, M. A.
Kerr, J. Org. Chem. 2007, 72, 8597; (e) A. Karadeolian. A, M. A.
Kerr, J. Org. Chem. 2007, 72, 10251; (f) T. P. Lebold, C. A. Carson,
M. A. Kerr, Synlett 2006, 3, 364; (g) M. P. Sibi, Z. Ma, C. P. Jasperse,
J. Am. Chem. Soc. 2005, 127, 5764; (h) I. S. Young, J. L.Williams, M.
A. Kerr, Org. Lett. 2005, 7, 953; (i) I. S. Young, M. A. Kerr, Org. Lett.
2004, 6, 139; (j) I. S. Young, M. A. Kerr, Angew. Chem. Int. Ed. 2003,
42, 3023.
Notes and references
1
For a review, see: C. V. Galliford, K. A. Scheidt, Angew. Chem. Int.
Ed. 2007, 46, 8748.
20
25
30
35
40
45
50
55
60
65
2
For reviews, see: (a) B. M. Trost, M. K. Brennan, Synthesis 2009,
3003; (b) H. Lin, S. J. Danishefsky, Angew. Chem. Int. Ed. 2003, 42,
36; (c) R. M.Williams, R. J. Cox, Acc. Chem. Res. 2003, 12, 36, 127;
(d) C. Marti, E. M. Carreira, Eur. J. Org. Chem. 2003, 2209.
3
4
For a general review on the enantioselective synthesis of
tetrasubstituted oxindoles, see: F. Zhou, Y.-L. Liu, J. Zhou, Adv.
Synth. Catal. 2010, 352, 1381.
100 11. (a) M. A. Voinov, T. G. Shevelev, T. V. Rybalova, Y. V. Gatilov, N.
V. Pervukhina, A. B. Burdukov, I. A. Grigorev, Organometallics
2007, 26, 1607; (b) J. M. Macdonald, H. T. Horsley, J. H. Ryan, S.
Saubern, A. B. Holmes, Org Lett. 2008, 10, 4227.
For selected leading examples of catalytic asymmetric synthesis of
spirooxindoles bearing a carbocyclic ring, see: (a) B. M. Trost, N.
Cramer, S. M. Silverman, J. Am. Chem. Soc. 2007, 129, 12396; (b) B.
K. Corkey, F. D. Toste, J. Am. Chem. Soc. 2007, 129, 2764; (c) G.
Bencivenni, L.-Y. Wu, A. Mazzanti, B. Giannichi, F. Pesciaioli, M.-P.
Song, G. Bartoli, P. Melchiorre, Angew. Chem. Int. Ed. 2009, 48,
7200; (d) K. Jiang, Z.-J. Jia, S. Chen, L. Wu, Y.-C. Chen, Chem. Eur.
J. 2010, 16, 2852; (e) A. P. Antonchick, C. Gerding-Reimers, M.
Catarinella, M. Schürmann, H. Preut, S. Ziegler, D. Rauh, H.
Waldmann, Nat. Chem. 2010, 2, 735; (f) B. Tan, N. R. Candeias, C.-F.
Barbas III, J. Am. Chem. Soc. 2011, 133, 4672; (g) B. Tan, N. R.
Candeias, C. F. Barbas III, Nat. Chem. 2011, 3, 473; (h) F. Zhong, X.
Han, Y. Wang, Y. Lu, Angew. Chem. Int. Ed. 2011, 50, 7837; (i) Z.-J.
Jia, H. Jiang, J.-L. Li, B. Gschwend, Q.-Z. Li, X. Yin, J. Grouleff, Y.-
C. Chen, K.-A. Jorgensen, J. Am. Chem. Soc. 2011, 133, 5053; (j) J.
Peng, X. Huang, L. Jiang, H.-L. Cui, Y.-C. Chen, Org. Lett. 2011, 13,
4584; (k) Y. Liu, M. Nappi, E. Arceo, S. Vera, P. Melchiorre, J. Am.
Chem. Soc. 2011, 133, 15212.
12 (a) S. Franco, F. L. Merchan, P. Merino, T. Tejero, Synth Commun.
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1995, 25, 2275; (b) E. Hulsbos, J. Marcus, J. Brussee, A. Vandergen,
Tetrahedron: Asymmetry 1997, 8, 1061; (c) Y. Tomioka, C. Nagahiro,
Y. Nomura, H. Maruoka, J. Heterocycl. Chem. 2003, 40, 121; (d) S.
Torrente, B. Noya, V. Branchadell, R. Alonso, J. Org. Chem. 2003,
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13 H. G. Aurich, W. Weiss, Tetrahedron 1976, 32, 159.
14 K. Shuji, T. Takashi, Chem. Lett. 1995, 1, 49.
15 M. Mehrdad, L. Faraji, K. Jadidi, P. Eslami, H. Sureni, Monatsh Chem.
2011, 142, 917.
115 16 C.-K. Pei, Y. Jiang, M. Shi, Eur. J. Org. Chem. DOI:
10.1002/ejoc.201200511.
17 (a) X.–Y. Guan, Y. Wei, M. Shi, Chem. Eur. J. 2011, 16, 13617; (b)
X.–C. Zhang, X.–H. Cao, Y. Wei, M. Shi, Chem. Commun. 2011, 47,
1548; (c) X.–C. Zhang, X.–H. Cao, Y. Wei, M. Shi, Org. Lett. 2011, 13,
5
6
7
8
For selected examples of the catalytic asymmetric synthesis of a
spiro[pyrrolidin-3,3’-oxindole] core, see: (a) L. E. Overman, M. D.
Rosen, Angew. Chem. Int. Ed. 2000, 39, 4596; (b) M. Bella, S.
Kobbelgaard, K. A. Jogensen, J. Am. Chem. Soc. 2005, 127, 3670; (c)
X.-H. Chen, Q. Wei, S.-W. Luo, H. Xiao, L.-Z. Gong, J. Am. Chem.
Soc. 2009, 131, 13819; (d) Y. Cao, X. Jiang, L. Liu, F. Shen, F. Zhang,
R. Wang, Angew. Chem. Int. Ed. 2011, 50, 9124.
For selected examples of the catalytic asymmetric synthesis of a
spiro[pyrrolidin-3,3’-oxindole] core, see: (a) L. E. Overman, M. D.
Rosen, Angew. Chem. Int. Ed. 2000, 39, 4596; (b) M. Bella, S.
Kobbelgaard, K. A. Jogensen, J. Am. Chem. Soc. 2005, 127, 3670; (c)
X.-H. Chen, Q. Wei, S.-W. Luo, H. Xiao, L.-Z. Gong, J. Am. Chem.
Soc. 2009, 131, 13819; (d) Y. Cao, X. Jiang, L. Liu, F. Shen, F. Zhang,
R. Wang, Angew. Chem. Int. Ed. 2011, 50, 9124.
For related works on spirooxindoles with an oxygen atom at C3’
position of the oxindole unit, see: (a) D. Hojo, K. Noguchi, M. Hirano,
K. Tanaka, Angew. Chem. Int. Ed. 2008, 47, 5820; (b) X. Jiang, Y.
Cao, Y. Wang, L. Liu, F. Shen, R. Wang, J. Am. Chem. Soc. 2010,
132, 15328; (c) L.-T. Shen, P.-L. Shao, S. Ye, Adv. Synth. Catal. 2011,
353, 1943; (d) G. Bergonzini, P. Melchiorre, Angew. Chem. Int. Ed.
2012, 51, 971.
For selected examples of [3+2] cycloaddition between nitrone and
alkene, see: (a) P. Jiao, D. Nakashima, H. Yamamoto, Angew. Chem.
Int. Ed. 2008, 47, 2411; (b) D. Nakashima, H. Yamamoto, J. Am.
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Wang, J.-J. Jiang, R. Zhang, M. Shi, Tetrahedron: Asymmetry 2011, 22,
1133; (g) M.-X. Zhao, Z.-W. Zhang, M.-X. Chen, Eur. J. Org. Chem.
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18 The crystal data of 3a have been deposited in CCDC with number
858690.
130 19 The crystal data of 3o have been deposited in CCDC with number
880875.
20 D. A. Dias, M. A. Kerr, Org. Lett. 2009, 11, 3694.
21 Y, Li, A, Studer, Angew. Chem. Int. Ed. 2012, 51, 8221.
22 S. Kumarn, A. J. Oelke, D. M. Shaw, D. A. Longbottom, S. V. Ley,
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Journal Name, [year], [vol], 00–00 |
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7

Organic & Biomolecular Chemistry
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A highly regioselective Yb(NTf2)3-catalyzed [3+3] cycloaddition
Yb(NTf2)3-catalyzed [3+3] Cycloaddition between Isatin
Ketonitrones and Cyclopropanes to Construct Novel
Spirooxindoles
between isatin ketonitrones and cyclopropanes to construct
spiro[tetrahydro-1,2-oxazine]oxindoles in moderate to good
yields
Hai-bin Yang, Min Shi*
8
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

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Table 1. Optimization of Reaction Conditions for Yb(NTf2)3-catalyzed [3+3]
Cycloaddition between Isatin Ketonitrones and Cyclopropanes.
yield
(%)[c]
3a
entry[a]
Lewis acid
solvent
eq (LA) temp (oC) 3a:4a[b] Conv
1
2
3
4
5
6
7
8
Yb(OTf)3
Cu(OTf)2
Sc(OTf)3
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
THF
DCE
DCE
DCE
DCE
toluene
dioxane
0.45
0.45
0.45
0.45
0.45
0.45
0.45
0.45
0.45
0.45
0.45
0.45
0.45
0.45
0.45
0.45
0.45
0.45
0.45
0.45
0.45
0.45
0.2
80
80
80
80
80
80
80
80
80
reflux
80
80
80
80
reflux
80
80
reflux
80
80
11:1
1:0
13:1
33:1
-
-
-
-
9:1
-
72
47
79
31
0
10
34
53
40
100
24
15
28
92
5
47
20
45
14
0
0
0
0
19
0
0
0
5
54
0
0
19
In(OTf)3
Zn(OTf)2
Ni(ClO4)2 . 6H2O
Mg(ClO4)2
BF3 . OEt2
CuCl2/AgSbF6
Et2AlCl
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
TiCl4
La(OTf)3
-
-
Eu(OTf)3
Yb(NTf2)3
Yb(OTf)3
Yb(OTf)3
Sc(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(NTf2)3
Yb(NTf2)3
Yb(NTf2)3
Yb(NTf2)3
Yb(NTf2)3
10:1
11:1
-
-
3
CH3CN
TCE
1:0
0:1
-
2:1
1:1
13:1
12:1
1:0
12:1
12:1
70
100
0
65
90
78
90
100
65
95
26
0
12
DMF
o-dichlorobenzene
o-dichlorobenzene
(trifluoromethyl)benzene
DCE
80
80
80
80
80
80
(60)
36 (34)
85 (85)
53
DCE
DCE
DCE
0.8
0.1
0.2
50
70
[a] Nitrone 1a (0.1 mmol), cyclopropane 2a (0.2 mmol), Lewis acid (x mmol) and 4Å MS (80
mg) were stirred in 2 mL of solvents. The reaction time of 24 h was a tradeoff to get a unified
procedure. [b] The ratios of 3a:4a were determined by 1H NMR spectroscopic data of the crude

Organic & Biomolecular Chemistry
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[c]
products.
The yields were determined through analysis by 1H NMR
(1,3,5-trimethoxybenzene) and the values in parentheses were isolated yields. [d] The reaction
time was prolonged to 48 h.

Page 11 of 11
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Table 2. Substrate Scope for Yb(NTf2)3-catalyzed [3+3] Cycloaddition between Isatin
Ketonitrones and Cyclopropanes.
yield (%)[d]
entry[a]
R1/R2/R3, PG, Ar
R4
3:4[b] conv (%)[c]
3
1
2
3
4
5
1b, H/H/H, Me, 3-Cl-Ph 2a, Me 9:1
1c, H/H/H, Me, 3-Me-Ph 2a, Me 5:1
1d, H/H/H, Me, 4-Br-Ph 2a, Me 9:1
74
92
79
100
93
75
70
91
94
78
78
93
78
3b, 55
3c, 50
3d, 31
3e, 63
3f, 80
3g, 61
3h, 60
3i, 60
3j, 52
3k, 63
3l, 73
3m, 62
3n, 44
1e, H/H/H, -, Ph
1f, H/H/H, Bn, Ph
1g, H/H/Cl, Me, Ph
1h, H/H/F, Me, Ph
1i, H/Cl/H, Me, Ph
1j, H/Me/H, Me, Ph
1k, Cl/H/H, Me, Ph
1l, Me/H/H, Me, Ph
1a, H/H/H, Me, Ph
1f, H/H/H, Bn, Ph
2a, Me 5:1
2a, Me 15:1
2a, Me 1:0
2a, Me 1:0
2a, Me 10:1
2a, Me 11:1
2a, Me 14:1
2a, Me 14:1
2b, Et 16:1
6
7c
8
9
10
11
12
13[e]
2b, Et
-
[a]
Nitrones 1 (0.1 mmol), cyclopropane 2a (0.2 mmol), Yb(NTf2)3 (0.02 mmol) and 4Å MS (80
mg) were stirred in 2 mL of DCE at 80 oC for 24 h. [b] The ratios of 3a:4a were determined by 1H
[c]
1
NMR spectroscopic data of the crude products. The conversions were determined from the H
NMR spectroscopic data for the crude products by adding internal standard sample
1,3,5-trimethoxylbenzene. [d] Isolated yields of 3. The ratios of 3a:4a could not be determined
[e]
by 1H NMR spectroscopic data of the crude products.