Formal [4+1] cycloaddition of camphor-derived sulfonium salts with aldimines: Enantioselective synthesis of 2,3-dihydrobenzofurans

Article abstract of DOI:10.1016/j.tet.2013.03.059

An asymmetric formal [4+1] cycloaddition of camphor-derived sulfonium salts with aldimines has been described. The reaction allows for the efficient synthesis of trans-2,3-disubstituted-2,3-dihydrobenzofurans in moderate to good yields with >95:5 dr and u

Full text of DOI:10.1016/j.tet.2013.03.059

Tetrahedron xxx (2013) 1e7
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Formal [4þ1] cycloaddition of camphor-derived sulfonium salts with
aldimines: enantioselective synthesis of 2,3-dihydrobenzofurans
*
Ying Cheng, Xiao-Qiang Hu, Shuang Gao, Liang-Qiu Lu, Jia-Rong Chen, Wen-Jing Xiao
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan,
Hubei 430079, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An asymmetric formal [4þ1] cycloaddition of camphor-derived sulfonium salts with aldimines has been
described. The reaction allows for the efficient synthesis of trans-2,3-disubstituted-2,3-dihydrobenzofurans
in moderate to good yields with >95:5 dr and up to 98% ee under mild reaction conditions.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 9 January 2013
Received in revised form 6 March 2013
Accepted 15 March 2013
Available online xxx
Keywords:
Cycloaddition
Sulfonium salts
Aldimines
2,3-Dihydrobenzofurans
1. Introduction
reaction.6c Notably, the diastereoisomer products are otherwise
difficult to prepare. Alternatively, the group of Jørgensen recently
The 2,3-dihydrobenzofurans (DHBs) are privileged structural
motifs found in many natural products and biologically active com-
pounds.1 These compounds have been shownto exhibit a broad range
of biological activities. For example, neolignans, isolated from sec-
ondary plant metabolites, are a type of important natural products,
which have exhibited high structural diversity and broad bioactivity
profile.1aee The furaquinocins are a class of antibiotics with antihy-
pertensive activity, inhibition of platelet aggregation and coagu-
lation.1feh Moreover, the synthetical cell motility inhibitor shows
good biological effects in cell-based assays (Fig. 1).2 Given the signif-
icance of these valuable DHBs and their potential biological proper-
ties, the development of more efficient synthetic methods for the
constructionofsuchscaffolds represents anareaofintensiveresearch.
During the last few decades, a great deal of research efforts have
been devoted to the development of asymmetric methods for their
synthesis. In this context, the most procedures are mainly based on
the utilization of chiral starting materials,3 kinetic resolution,4 or
chiral auxiliaries.5 Recently, the sporadic examples of catalytic
enantioselective construction of 2,3-dihydrobenzofurans have also
been documented.6 For instance, Hashimoto and co-workers firstly
developed a highly efficient catalytic method for the diastereo- and
enantioselective synthesis of cis-2-aryl-3-methoxycarbonyl-2,3-
dihydrobenzofurans via the Rh(II)-catalyzed CeH insertion
developed a pioneering organocatalytic one-pot reaction cascade,
which provided an efficient entry to trans-2,3-dihydrobenzofurans
bearing three contiguous stereogenic centers in a highly enantio-
selective manner.6e Despite these elegant and creative strategies
toward the construction of 2,3-dihydrobenzofurans, it is still highly
desirable to search for other practical asymmetric process for
the synthesis of optically active trans-2,3-disubstituted-2,3-
dihydrobenzofurans with respect to the functional tolerance and
efficiency.
As part of our ongoing program on carbon- and heterocycle-
oriented methodology development based on sulfur ylides,7,8 we
recently disclosed highly chemo- and stereoselective formal [4þ1]
* Corresponding author. E-mail address: wxiao@mail.ccnu.edu.cn (W.-J. Xiao).
Fig. 1. Representative structures containing 2,3-dihydrobenzofuran motif.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.059
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2
Y. Cheng et al. / Tetrahedron xxx (2013) 1e7
cycloaddition/rearrangement of nitroolefins,7a [4þ1]/[3þ2] cyclo-
addition cascade of alkene-tethered nitroolefins,7b [4þ1] cycload-
Table 1
Condition optimization for asymmetric cycloadditions of camphor-derived sulfo-
nium salt 2a with aldimines 1a
dition of a,b
-unsaturated imines (Scheme 1),7c affording a variety of
structurally diverse nitrogen-containing heterocycles in high
yields. Recently, the versatility of the sulfur ylides was successfully
extended to asymmetric cyclopropanation of
b,g-unsaturated a-
ketoesters9a and [4þ1] cycloaddition of in situ-generated azo-o-
quinodimethane.9b During the course of these studies, we identi-
fied that the electronic and steric effects, and reaction parameters
played an important role on controlling the reaction pathway and
stereoselectivity.7,9 Inspired by these achievements, we wondered
about the possibility of formal asymmetric [4þ1] cycloadditions of
salicyl imines and sulfur ylides, which would provide an efficient
approach to optically active 2,3-dihydrobenzofurans. Herein, we
report a successful realization of such a strategy by a cycloaddition
of camphor-derived sulfonium salts and aldimines, which gives the
trans-2,3-disubstituted-2,3-dihydrobenzofurans with good yields
and enantioselectivities (Scheme 1). Recently, the group of Huang
reported a novel domino annulation between sulfur ylides and
salicyl N-thiophosphinyl imines, in which the bulky thiophosphinyl
group was used to control the reaction pathway and diaster-
eoselectivity.10 Notably, Bolm and co-workers recently described an
enantioselective formal [4þ1] cycloaddition of in situ-derived
azoalkenes and sulfur ylides catalyzed by a chiral copper/Tol-
BINAP complex, providing the biologically important dihydropyr-
azoles with high enantioselectivities in good yields.11
Entry Ar
Solvent/base
Time (h) Yieldb (%) eec,d (%)
1
C6H5
MeCN/KOH
MeCN/KOH
MeCN/KOH
MeCN/KOH
MeCN/KOH
12
7
5
7
7
5
8
5
14
14
14
>24
11
11
48
48
24
21
53
66
43
86
89
70
50
63
51
60
54
Trace
54
56
60
45
63
54
57
62
43
44
59
90
91
87
88
79
d
2
p-OMeC6H4
o-MeC6H4
p-BrC6H4
3e
4
5
p-NO2C6H4
6
7
8
9
3,5-(CF3)2C6H3 MeCN/KOH
3,5-(CF3)2C6H3 THF/Cs2CO3
3,5-(CF3)2C6H3 THF/TMG
3,5-(CF3)2C6H3 THF/KOH
10
11
12
13
14
15
16
17f
18f
3,5-(CF3)2C6H3 THF/CsOH
3,5-(CF3)2C6H3 THF/Ba(OH)2$8H2O
3,5-(CF3)2C6H3 THF/LiOH$H2O
3,5-(CF3)2C6H3 Et2O/TMG
3,5-(CF3)2C6H3 Toluene/TMG
3,5-(CF3)2C6H3 DCM/TMG
3,5-(CF3)2C6H3 MeOH/TMG
3,5-(CF3)2C6H3 Toluene/TMG
96
96
80
47
97
58
p-BrC6H4
MeCN/KOH
82
a
ꢀ
Experimental conditions: a mixture of 1 (0.1 mmol), 2a (0.11 mmol), 4 A MS
(100 mg), and base (0.22 mmol) in solvent (0.5 mL) was stirred at 20 ꢀC for the
indicated time. TMG¼1,1,3,3-tetramethylguanidine.
b
Yield of isolated product.
Determined by chiral HPLC analysis.
The dr values in this table were all >95:5 and determined by chiral HPLC
c
d
analysis and 1H NMR analysis.
e
In this reaction, a byproduct 3-arylaminocinnamamide BP was also isolated.
Please see Supplementary data for more details.
f
The reaction temperature was 0 ꢀC.
afforded the corresponding product in 82% yield but with only 58%
ee (Table 1, entry 18). It is noteworthy that all the reactions gave
exclusively the corresponding trans-2,3-dihydrobenzofurans.
With the optimal conditions in hand (Table 1, entry 17, TMG as
the base in toluene at 0 ꢀC), we firstly investigated the substrate
scope for this asymmetric cascade reaction by employing a range of
aldimines. As summarized in Table 2, various aldimines proved to
be suitable for this asymmetric cyclization reaction. For example,
the aldimine 1b with an electron-donating substituent on the
benzene ring was well tolerated and the corresponding product
was obtained in moderate isolated yield (43%) and with excellent
stereoselectivity (>95:5 dr, 98% ee) (Table 2, entry 2). Surprisingly,
introducing a strong electron-withdrawing group (e.g., NO2) to the
aromatic ring led to a substantial decrease in both yield and
enantioselectivity due to the formation of some unknown side
products (Table 2, entry 3). Note that the aldimines 1de1f bearing
the weak electron-withdrawing groups on the aromatic ring can
participate in this cyclization well to give the desired products in
good yields with good ee’s (Table 2, entries 4e6). The use of di-
substituted aldimines (1g and 1h) resulted in diminished enan-
tioselectivities probably because of the steric hindrance (Table 2,
entries 7 and 8). Importantly, the reaction with heteroaromatic
aldimine, such as 1i, also proceeded smoothly to give the corre-
sponding product 3i in 63% yield with > 95:5 dr and 21% ee (Table
2, entry 9).
Scheme 1. Formal [4þ1] cycloaddition based on sulfur ylides.
2. Result and discussion
Initially, we investigated the desired cycloaddition between
camphor-derived sulfonium salt 2a12 with aldimine 113 bearing
different protecting groups (Table 1). To our delight, treating
camphor-derived sulfonium salt 2a with aldimines 1 (Ar¼C6H5) at
room temperature in dry MeCN for 12 h provided the desired
enantioenriched cycloadduct with 53% yield and 54% ee (Table 1,
entry 1). Then, the effects of the protecting group of the nitrogen on
the reaction efficiency and stereoselectivity were further in-
vestigated under the above conditions. For example, the electron-
donating substituents on the benzene ring of aldimines 1 resulted
in a little of increase in the enantioselectivity (Table 1, entries 2 and
3). In contrast, the electron-withdrawing substituents on the ben-
zene ring of aldimines 1 substantially improved the yield (Table 1,
entries 4e6). Therefore, the 3,5-(CF3)2C6H3 was chosen as the most
suitable protecting group for further optimization study in terms of
the enantioselectivity and yield (Table 1, entry 6). With the use of
aldimine 1 bearing 3,5-(CF3)2C6H3, we then simply examined a se-
ries of bases and it was found that the use of TMG as the base gave
the best results (Table 1, entries 7, 9e12 vs entry 8). Further screen
of the common solvents showed that the use of toluene led to
positive effect on the enantioselectivity (Table 1, entry 14). Finally,
the lowering the reaction temperature to 0 ꢀC further increased the
enantiomeric excess to 97% (Table 1, entry 17). Interestingly, the
annulation reaction with aldimine bearing p-BrC6H4 at 0 ꢀC
Significantly, the encumbered camphor-derived sulfonium salt
2b can also be successfully applied to the desired cycloaddition. As
shown in Table 3, electron-poor and -rich aldimines with different
substitution patterns on the aromatic ring reacted smoothly with
camphor-derived sulfonium salt 2b under optimal conditions,
affording the corresponding cycloadducts 3jel in good yields with
high diastereo- (up to >95:5 dr) and enantioselectivities (up to 93%
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Y. Cheng et al. / Tetrahedron xxx (2013) 1e7
3
Table 2
To gain some insights into the possible mechanism, we tried the
reaction between N-phenyl imine 4 of 2-methoxybenzaldehyde
and sulfonium salt 5 under the optimized conditions (Eq. 1). In
accordance with Huang’s observation, the imine 4 remained intact
and no formation of aziridine product 6 was detected even after
22 h, which was probably because of the steric hindrance of such
type of imine (Eq. 1).
Asymmetric cycloadditions of camphor-derived sulfonium salt 2a with aldimines
1aeia
Entry
1 (R)
1a (H)
1b (5-Me)
1c (5-NO2)
1d (5-F)
1e (5-Cl)
1f (5-Br)
1g (3,5-Cl2)
1h (3,5-Br2)
Time (h)
Yieldc (%)
3a: 63
drd
eee (%)
1
2
3b
4
5
6
7
8
24
96
18
12
24
24
12
18
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
97
98
22
95
88
86
49
43
(1)
3b: 43
3c: 29
3d: 66
3e: 68
3f: 67
3g: 46
3h: 52
Based on the X-ray structure of the product 3e (Fig. 2) and
Huang’s observations,10 we proposed a possible pathway to ac-
count for this formal [4þ1] cycloaddition. As depicted in Scheme
2, for example, camphor-derived sulfonium salt 2a was firstly
transformed into the reactive sulfur ylide in the presence of TMG.
The resulting sulfur ylide 2a0 reacted with aldimine 1a to give the
intermediate A, whereafter the intramolecular hydrogen transfer
to the nitrogen resulted in the formation of intermediate B. Fi-
nally, the intermediate B underwent an intramolecular O-alkyl-
ation (SN2 substitution) to afford the desired product 3a with
release of the chiral sulfide. According to Speziale’s previous
studies on the reaction between carbonyl-stabilized sulfur ylides
and Schiff bases,15 another possible intermediate C might be
formed through a hydride shift to nitrogen followed by the
elimination of chiral sulfide to give the byproduct 3-
arylaminocinnamamide BP-a. Notably, during our optimization
studies with respect to the protecting groups on the nitrogen, we
found that the reaction with aldimine bearing o-MeC6H4 on the
nitrogen gave a mixture of 2,3-dihydrobenzofuran and byproduct
3-arylaminocinnamamide.16 Accordingly, we speculated that such
reaction pathway should be more favored in the cases of aldi-
mines bearing strongly electron-withdrawing groups (e.g., 5-NO2,
3,5-2Cl or 3,5-2Br). The possible equilibrium between the in-
termediates A and C might lead to the decreased enantionse-
lectivity in the desired 2,3-dihydrobenzofuran 3a.
9
16
>95:5
21
3i: 63
1i
a
ꢀ
Experimental conditions: a mixture of 1 (0.2 mmol), 2a (0.22 mmol), 4 A MS
(200 mg), and TMG (0.44 mmol) in toluene (1.0 mL) was stirred at 0 ꢀC for the in-
dicated time.
b
The reaction temperature was 20 ꢀC.
c
Yield of isolated product.
d
Determined by chiral HPLC analysis and 1H NMR analysis.
e
Determined by chiral HPLC analysis.
Table 3
Asymmetric cycloaddition of aldimines 1 with camphor-derived sulfonium salt 2b
ee). In addition, we have also tried some other stable sulfur ylides
such as alkyloxy- and aryl-acyl sulfur ylides.7,9 Unfortunately, only
a complex mixture was observed. Notably, the products 3ael were
fully characterized by NMR analysis and elemental analysis. The
absolute configuration of 3e was unambiguously determined by
X-ray crystal structure analysis (Fig. 2).14
Fig. 2. ORTEP diagram of the X-ray crystal structure of 3e. The thermal ellipsoids are
drawn at the 30% probability level.
Scheme 2. Proposed reaction pathway and transition state.
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4
Y. Cheng et al. / Tetrahedron xxx (2013) 1e7
3. Conclusion
1279, 1180, 1128, 947 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d 13.38 (s, 1H),
8.81 (s,1H), 8.49 (s,1H), 8.34 (d, J¼8.8 Hz,1H), 7.87 (s,1H), 7.76 (s, 2H),
In conclusion, we have developed an asymmetric formal
[4þ1] cycloaddition of camphor-derived sulfonium salts with aldi-
mines to construct optically active trans-2,3-disubstituted-2,3-
dihydrobenzofuran derivatives. The process provided a complemen-
tary method to the precedented metal complex or organocatalyst
catalyzed asymmetric synthesis of 2,3-dihydrobenzofurans.6c,e Al-
though the full substrate scope awaits further improvement, the
current methodology provides a new direction of the use of sulfur
ylides in the carbon and heterocyclic chemistry.17 Additional mech-
anistic studies and applications of this methodology to other func-
tionalized heterocycle synthesis are now ongoing in our laboratory.
7.17 (d, J¼8.9 Hz, 1H). 13C NMR (100 MHz, CDCl3)
d 166.2, 164.2, 148.8,
140.4, 133.9, 133.4, 133.1, 132.7, 129.3, 129.1, 124.2, 121.6, 121.1, 118.6,
117.7. MS: m/z¼378.20 (Mþ). Elemental Anal. Calcd for C15H8F6N2O3:
C, 47.63; H, 2.13; N, 7.41. Found: C, 47.86; H, 2.07; N, 7.48.
4.2.4. (E)-2-(((3,5-Bis(trifluoromethyl)phenyl)imino)methyl)-4-
fluorophenol (1d). Yellow solid, 0.70 g, yield: 40%, mp 95e97 ꢀC
(ethanol). IR (KBr)
1376, 1285, 1133, 947, 894, 682 cmꢁ1
12.41 (s, 1H), 8.60 (s, 1H), 7.82 (s, 1H), 7.69 (s, 2H), 7.21e7.15 (m,
2H), 7.04e7.01 (m, 1H). 13C NMR (100 MHz, CDCl3)
164.5, 157.4,
n
3422, 3091, 2976, 1905, 1801, 1627, 1579, 1485,
.
1H NMR (400 MHz, CDCl3)
d
d
156.8, 154.4, 149.7, 133.5, 133.2, 132.8, 132.5, 127.0, 124.3, 121.6,
121.5, 120.4, 118.8, 118.2, 118.1, 117.7, 117.5. MS: m/z¼351.11 (Mþ).
Elemental Anal. Calcd for C15H8F7NO: C, 51.30; H, 2.30; N, 3.99.
Found: C, 51.56; H, 2.52; N, 4.02.
4. Experimental section
4.1. General information
Unless otherwise noted, materials were purchased from com-
mercial suppliers and used without further purification. All the
solvents were treated according to general methods. Flash column
chromatography (FC) was performed using 200e300 mesh silica gel.
1H NMR spectra were recorded on 400/600 (400/600 MHz) spec-
4.2.5. (E)-2-(((3,5-Bis(trifluoromethyl)phenyl)imino)methyl)-4-
chlorophenol (1e). Yellow solid, 1.27 g, yield: 69%, mp 120e123 ꢀC
(ethanol). IR (KBr)
891, 748 cmꢁ1. 1H NMR (400 MHz, CDCl3)
7.82 (s, 1H), 7.69 (s, 2H), 7.44e7.38 (m, 2H), 7.02 (d, J¼8.8 Hz, 1H).
13C NMR (100 MHz, CDCl3)
164.4, 159.7, 149.6, 134.2, 133.5, 133.2,
n
3446, 1796, 1577, 1477, 1368, 1280, 1173, 947,
d
12.41 (s,1H), 8.60 (s,1H),
trophotometer. Chemical shifts (d) are reported in parts per million
d
(ppm) from the solvent resonance as the internal standard (CDCl3:
7.26 ppm). Data are reported as follows: chemical shift, multiplicity
(s¼singlet, d¼doublet, t¼triplet, m¼multiplet, q¼quarternary), cou-
pling constants (Hz), and integration. 13C NMR spectra were recorded
on 400/600 (100/150 MHz) spectrophotometer (CDCl3: 77.0 ppm)
with complete proton decoupling. Mass spectra were measured on
a Trace MS spectrometer. Elemental analysis was taken on an ele-
mentary analysis instrument.
132.8, 132.5, 131.8, 127.0, 124.3, 124.2, 121.5, 120.5, 119.2, 119.1, 118.9.
MS: m/z¼367.12 (Mþ). Elemental Anal. Calcd for C15H8ClF6NO: C,
49.00; H, 2.19; N, 3.81. Found: C, 49.18; H, 2.38; N, 3.75.
4.2.6. (E)-2-(((3,5-Bis(trifluoromethyl)phenyl)imino)methyl)-4-
bromophenol (1f). Orange solid, 1.79 g, yield: 87%, mp 133e135 ꢀC
(ethanol). IR (KBr)
n
3447, 1797, 1601, 1576, 1476, 1376, 1280, 1173,
12.43 (s, 1H),
1127, 947, 798, 681 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d
8.60 (s, 1H), 7.82 (s, 1H), 7.69 (s, 2H), 7.58 (d, J¼2.0 Hz, 1H), 7.52 (dd,
4.2. General procedure for the synthesis of aldimines
J¼8.8, 2.0 Hz, 1H), 6.97 (d, J¼8.8 Hz, 1H). 13C NMR (100 MHz, CDCl3)
d
164.3, 160.2, 149.6, 137.0, 134.9, 133.5, 133.2, 132.9, 132.5, 124.3,
Atroom temperature, 3,5-bis(trifluoromethyl)aniline (5.0 mmol)
was added to a solution of 2-hydroxybenzaldehyde (5.0 mmol) in
ethanol (20 mL). After stirring for 2 h, solid was precipitated. Then
the solid recrystallized with ethanol to obtain the corresponding
pure product 1.
121.5, 120.5, 119.9, 119.5, 111.0. MS: m/z¼413.05 ([MþH]þ). Ele-
mental Anal. Calcd for C15H8BrF6NO: C, 43.72; H, 1.96; N, 3.40.
Found: C, 43.90; H, 1.72; N, 3.19.
4.2.7. (E)-2-(((3,5-Bis(trifluoromethyl)phenyl)imino)methyl)-4,6-
dichlorophenol (1g). Orange solid, 1.21 g, yield: 60%, mp 128e132 ꢀC
4.2.1. (E)-2-(((3,5-Bis(trifluoromethyl)phenyl)imino)methyl) phenol
(1a). Yellow solid, 0.78 g, yield: 47%, mp 87e88 ꢀC (ethanol). IR
(ethanol). IR (KBr)
891, 738 cmꢁ1. 1H NMR (400 MHz, CDCl3)
7.85 (s, 1H), 7.71 (s, 2H), 7.54 (d, J¼2.2 Hz, 1H), 7.39 (d, J¼2.2 Hz, 1H).
13C NMR (100 MHz, CDCl3)
163.8, 155.6, 148.8, 133.9, 133.7, 133.4,
n
3445, 1577, 1444, 1368, 1279, 1177, 1134, 946,
d
13.20 (s,1H), 8.63 (s, 1H),
(KBr)
n
3423, 3098, 2977, 1957, 1795, 1603, 1579, 1382, 1278, 1172,
12.44 (s, 1H), 8.66
1126, 949, 759 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d
d
(s, 1H), 7.79 (s, 1H), 7.69 (s, 2H), 7.46e7.43 (m, 2H), 7.05 (d, J¼8.8 Hz,
133.0, 132.7, 130.4, 126.9, 124.2, 124.0, 123.1, 121.5, 121.0, 119.6. MS:
m/z¼401.13 ([MꢁH]þ). Elemental Anal. Calcd for C15H7Cl2F6NO: C,
44.80; H, 1.75; N, 3.48. Found: C, 45.02; H, 1.63; N, 3.48.
1H), 6.99 (t, J¼7.5 Hz, 1H). 13C NMR (100 MHz, CDCl3)
d 165.6, 161.2,
150.1, 134.5, 133.4, 133.0, 132.7,132.4,124.4,121.7, 121.5, 120.0,119.5,
118.5, 117.5. MS: m/z¼333.15 (Mþ). Elemental Anal. Calcd for
C
15H9F6NO: C, 54.07; H, 2.72; N, 4.20. Found: C, 53.93; H, 2.61; N,
4.2.8. (E)-2-(((3,5-Bis(trifluoromethyl)phenyl)imino)methyl)-4,6-
dibromophenol (1h). Orange solid, 2.14 g, yield: 87%, mp
4.21.
160e162 ꢀC (ethanol). IR (KBr)
n
3446, 3073, 1808, 1599, 1441, 1364,
4.2.2. (E)-2-(((3,5-Bis(trifluoromethyl)phenyl)imino)methyl)-4-
methylphenol (1b). Yellow solid, 0.56 g, yield: 32%, mp 74e75 ꢀC
1278, 1170, 1132, 937, 889, 690 cmꢁ1 1H NMR (400 MHz, CDCl3)
.
d
13.38 (s, 1H), 8.60 (s, 1H), 7.86e7.81 (m, 2H), 7.71 (s, 2H), 7.57 (d,
(ethanol). IR (KBr)
n
3444, 3103, 2922, 2361, 1795, 1629, 1583, 1486,
J¼1.9 Hz, 1H). 13C NMR (100 MHz, CDCl3)
d 163.5, 157.0, 148.6, 139.3,
1374, 1285, 1178, 947, 890, 784 cmꢁ1
.
1H NMR (400 MHz, CDCl3)
134.1, 133.3, 133.0, 124.2, 121.6, 121.5, 121.0, 120.1, 112.3, 110.9. MS:
m/z¼491.08 (Mþ). Elemental Anal. Calcd for C15H7Br2F6NO: C,
36.69; H, 1.44; N, 2.85. Found: C, 36.90; H, 1.66; N, 2.69.
d
12.22 (s, 1H), 8.61 (s, 1H), 7.78 (s, 1H), 7.68 (s, 2H), 7.27 (s, 1H), 7.24
(s, 1H), 6.96 (d, J¼8.3 Hz, 1H), 2.34 (s, 3H). 13C NMR (100 MHz,
CDCl3)
d 165.6, 159.1, 150.3, 135.5, 133.0, 132.9, 132.7, 132.4, 128.7,
124.4, 121.7, 121.5, 119.9, 118.2, 117.3, 20.2. MS: m/z¼347.14 (Mþ).
Elemental Anal. Calcd for C16H11F6NO: C, 55.34; H, 3.19; N, 4.03.
Found: C, 55.14; H, 2.99; N, 4.04.
4.2.9. (E)-2-(((3,5-Bis(trifluoromethyl)phenyl)imino)methyl) pyridin-
3-ol (1i). Yellow solid, 0.35 g, yield: 21%, mp 91e93 ꢀC (ethanol). IR
(KBr)
808 cmꢁ1
8.35e8.32 (m, 1H), 7.84 (s, 1H), 7.77 (s, 2H), 7.43e7.37 (m, 2H). 13
NMR (100 MHz, CDCl3) 167.1, 158.5, 149.2, 142.0, 136.4, 133.5,
133.2, 132.8, 132.5, 127.7, 126.9, 125.3, 124.2, 121.7, 121.5, 120.8. MS:
Please cite this article in press as: Cheng, Y.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.03.059
n
3441, 3068, 1579, 1447, 1377, 1281, 1171, 1126, 946, 845,
.
1H NMR (400 MHz, CDCl3)
d
12.30 (s, 1H), 8.90 (s, 1H),
4.2.3. (E)-2-(((3,5-Bis(trifluoromethyl)phenyl)imino)methyl)-4-
nitrophenol (1c). Orange solid, 1.29 g, yield: 68%, mp 166e169 ꢀC
(ethanol). IR (KBr)
C
d
n 3446, 3090, 1804, 1632, 1604, 1579, 1372, 1339,

Y. Cheng et al. / Tetrahedron xxx (2013) 1e7
5
m/z¼334.17 (Mþ). Elemental Anal. Calcd for C14H8F6N2O: C, 50.31;
61.3 mg, yield: 66%, mp 141e143 ꢀC (petroleum ether/ethyl ace-
26
H, 2.41; N, 8.38. Found: C, 50.23; H, 2.32; N, 8.14.
tate), diastereoisomer ratio: >95:5, enantiomeric excess: 95%, [a]
D
ꢁ64.76 (c 1.0, CHCl3). Daicel Chirapak AD-H, hexane/iso-
propanol¼95:5, flow rate 0.7 mL/min, T¼25 ꢀC, 254 nm,
4.3. General procedure for asymmetric cycloaddition of
camphor-derived sulfonium salts with aldimines
tR¼9.84 min (major), tR¼13.01 min (minor). IR (KBr)
n 3315, 3079,
2986, 2941, 1865, 1642, 1549, 1487, 1398, 1277, 1124, 819 cmꢁ1. 1H
NMR (400 MHz, CDCl3)
Aldimine 1 (0.20 mmol), camphor-derived sulfonium salts 2
d
7.23 (s, 1H), 7.08 (s, 2H), 7.04 (d, J¼7.4 Hz,
ꢀ
(0.22 mmol), and 4 A MS (200 mg) were mixed in dry toluene
1H), 7.00e6.95 (m, 1H), 6.80 (dd, J¼8.7, 4.0 Hz, 1H), 6.04e6.01 (m,
(1.0 mL). After stirring at 0 ꢀC for 30 min, TMG (50.7 mg, 0.44 mmol)
was introduced directly. The reaction mixture was stirred at 0 ꢀC for
24 h. After the complete consumption of the aldimine 1 (as moni-
tored by TLC), the mixture was purified by flash column chroma-
tography on silica gel to give the corresponding pure product 3.
1H), 5.08 (d, J¼4.4 Hz, 1H), 4.50 (d, J¼7.6, 1H), 3.53e3.35 (m, 4H),
1.20e1.17 (m, 6H). 13C NMR (100 MHz, CDCl3)
d 166.8, 159.0, 156.6,
154.7, 147.1, 133.1, 132.8, 132.5, 132.1, 127.4, 127.1, 127.0, 124.7, 122.0,
119.3, 117.0, 116.8, 112.5, 112.1, 111.9, 111.1, 110.7, 110.6, 85.7, 58.4,
42.3, 41.0, 14.4, 12.4. MS: m/z¼464.29 (Mþ). Elemental Anal. Calcd
for C21H19F7N2O2: C, 54.31; H, 4.12; N, 6.03. Found: C, 54.22; H, 3.93;
N, 6.05.
4.3.1. 3-((3,5-Bis(trifluoromethyl)phenyl)amino)-N,N-diethyl-2,3-
dihydrobenzofuran-2-carboxamide (3a). White solid, 56.2 mg,
yield: 63%, mp 148e150 ꢀC (petroleum ether/ethyl acetate), di-
4.3.5. 3-((3,5-Bis(trifluoromethyl)phenyl)amino)-5-chloro-N,N-di-
astereoisomer ratio: >95:5, enantiomeric excess: 97%, [
a
]
25 ꢁ64.48
ethyl-2,3-dihydrobenzofuran-2-carboxamide
(3e). White solid,
D
(c 1.0, CHCl3). Daicel Chirapak AD-H, hexane/isopropanol¼95:5,
65.4 mg, yield: 68%, mp 141e142 ꢀC (petroleum ether/ethyl ace-
24
flow rate 0.7 mL/min, T¼25 ꢀC, 254 nm, tR¼10.42 min (major),
tate), diastereoisomer ratio: >95:5, enantiomeric excess: 88%, [a]
D
tR¼11.55 min (minor). IR (KBr)
n
3323, 3076, 2987, 2938, 1642, 1545,
ꢁ48.69 (c 1.0, CHCl3). Daicel Chirapak AD-H, hexane/iso-
propanol¼95:5, flow rate 0.7 mL/min, T¼25 ꢀC, 254 nm,
1479, 1398, 1277, 1187, 1124, 757 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d
7.30 (d, J¼7.4 Hz, 1H), 7.25e7.19 (m, 2H), 7.05 (s, 2H), 6.94 (t,
tR¼10.33 min (major), tR¼11.95 min (minor). IR (KBr)
n
3324, 3077,
1H
7.31 (s, 1H), 7.23 (s, 2H), 7.07 (s, 2H), 6.81
J¼7.4 Hz,1H), 6.84 (d, J¼8.1 Hz,1H), 5.90 (dd, J¼8.2, 4.4 Hz,1H), 5.02
(d, J¼4.4 Hz,1H), 4.74 (d, J¼8.3 Hz,1H), 3.52e3.31 (m, 4H),1.19e1.15
2989, 2941, 1639, 1550, 1475, 1399, 1277, 1190, 1127, 817 cmꢁ1
NMR (400 MHz, CDCl3)
.
d
(m, 7H). 13C NMR (100 MHz, CDCl3)
d
166.9, 158.7, 147.1, 133.1, 132.7,
(d, J¼8.6 Hz, 1H), 6.03e6.00 (m, 1H), 5.08 (d, J¼4.3 Hz, 1H), 4.47 (d,
132.4, 132.1, 130.4, 127.4, 125.7, 125.2, 124.7, 122.0, 121.7, 119.3, 112.4,
110.9, 110.2, 85.2, 58.2, 42.3, 40.9, 14.5, 12.5. MS: m/z¼446.27 (Mþ).
Elemental Anal. Calcd for C21H20F6N2O2: C, 56.50; H, 4.52; N, 6.28.
Found: C, 56.59; H, 4.42; N, 6.27.
J¼8.9 Hz, 1H), 3.52e3.35 (m, 4H), 1.18 (t, J¼7.0 Hz, 6H). 13C NMR
(100 MHz, CDCl3)
d 166.5, 157.3, 147.0, 133.1, 132.8, 132.5, 132.1,
130.3, 127.6, 126.3, 125.2, 124.7, 121.9, 112.4, 111.3, 85.7, 58.1, 42.3,
41.0, 14.5, 12.5. MS: m/z¼480.15 (Mþ). Elemental Anal. Calcd for
C21H19ClF6N2O2: C, 52.46; H, 3.98; N, 5.83. Found: C, 52.58; H, 3.75;
4.3.2. 3-((3,5-Bis(trifluoromethyl)phenyl)amino)-N,N-diethyl-
5-methyl-2,3-dihydrobenzofuran-2-carboxamide (3b). White solid,
39.6 mg, yield: 43%, mp 127e130 ꢀC (petroleum ether/ethyl acetate),
N, 5.75.
4.3.6. 3-((3,5-Bis(trifluoromethyl)phenyl)amino)-5-bromo-N,N-di-
ethyl-2,3-dihydrobenzofuran-2-carboxamide (3f). Yellow solid,
70.4 mg, yield: 67%, mp 134e136 ꢀC (petroleum ether/ethyl ace-
diastereoisomer ratio: >95:5, enantiomeric excess: 98%, [
a
]
25 ꢁ44.12
D
(c 1.0, CHCl3). Daicel Chirapak OD-H, hexane/isopropanol¼95:5, flow
rate 1.0 mL/min, T¼25 ꢀC, 254 nm, tR¼6.70 min (major), tR¼8.74 min
tate), diastereoisomer ratio: >95:5, enantiomeric excess: 86%,
25
(minor). IR (KBr)
n
3326, 3073, 2987, 2940, 2245, 1886, 1641, 1547,
[
a
]
ꢁ36.43 (c 1.0, CHCl3). Daicel Chirapak AD-H, hexane/iso-
D
1491, 1399, 1277, 1188, 1126, 811 cmꢁ1
7.20 (s, 1H), 7.13 (s,1H), 7.07 (s, 3H), 6.76 (d, J¼8.2 Hz, 1H), 5.98e5.95
(m, 1H), 5.03 (d, J¼4.2 Hz, 1H), 4.49 (d, J¼8.1 Hz, 1H), 3.48e3.34 (m,
4H), 2.30 (s, 3H), 1.20e1.16 (m, 6H). 13C NMR (100 MHz, CDCl3)
167.0,
.
1H NMR (400 MHz, CDCl3)
propanol¼95:5, flow rate 0.7 mL/min, T¼25 ꢀC, 254 nm,
d
tR¼10.47 min (major), tR¼11.95 min (minor). IR (KBr)
n 3326,
3076, 2989, 2941, 1638, 1549, 1473, 1398, 1277, 1127, 956, 815,
d
679 cmꢁ1 1H NMR (400 MHz, CDCl3)
.
d
7.45 (s, 1H), 7.37 (d,
156.7, 147.2, 133.0, 132.7, 132.4, 132.1, 131.1, 130.9, 127.5, 125.7, 125.5,
124.7, 122.0, 119.3, 112.4, 110.7, 109.8, 85.3, 58.3, 42.2, 40.9, 20.6, 14.5,
12.5. MS: m/z¼460.31 (Mþ). Elemental Anal. Calcd for C22H22F6N2O2:
C, 57.39; H, 4.82; N, 6.08. Found: C, 57.66; H, 4.54; N, 6.11.
J¼8.5 Hz, 1H), 7.23 (s, 1H), 7.07 (s, 2H), 6.76 (d, J¼8.6 Hz, 1H), 6.01
(dd, J¼8.4, 4.1 Hz, 1H), 5.07 (d, J¼4.3 Hz, 1H), 4.52 (d, J¼8.3 Hz,
1H), 3.521e3.35 (m, 4H), 1.18 (t, J¼7.1 Hz, 6H). 13C NMR (100 MHz,
CDCl3)
d 166.6, 157.9, 147.0, 133.2, 132.8, 132.4, 132.1, 128.2, 128.1,
124.4, 121.9, 113.3, 112.4, 111.8, 111.1, 85.6, 58.1, 42.3, 41.0, 14.5,
4.3.3. 3-((3,5-Bis(trifluoromethyl)phenyl)amino)-N,N-diethyl-5-
nitro-2,3-dihydrobenzofuran-2-carboxamide (3c). Yellow solid,
12.4. MS: m/z¼526.28 ([MþH]þ). Elemental Anal. Calcd for
C
21H19BrF6N2O2: C, 48.02; H, 3.65; N, 5.33. Found: C, 48.27; H,
28.5 mg, yield: 29%, mp 145e147 ꢀC (petroleum ether/ethyl ace-
3.47; N, 5.15.
24
tate), diastereoisomer ratio: >95:5, enantiomeric excess: 22%, [a]
D
ꢁ16.17 (c 1.0, CHCl3). Daicel Chirapak IC-H, hexane/iso-
propanol¼80:20, flow rate 1.0 mL/min, T¼25 ꢀC, 254 nm,
4.3.7. 3-((3,5-Bis(trifluoromethyl)phenyl)amino)-5,7-dichloro-N,N-
diethyl-2,3-dihydrobenzofuran-2-carboxamide (3g). White solid,
47.4 mg, yield: 46%, mp 153e155 ꢀC (petroleum ether/ethyl ace-
tR¼4.84 min (minor), tR¼5.41 min (major). IR (KBr)
n 3322, 3084,
2991, 2944, 2911, 1634, 1548, 1526, 1475, 1398, 1340, 1277, 1172,
tate), diastereoisomer ratio: >95:5, enantiomeric excess: 46%,
957 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d
8.25e8.21 (m, 2H), 7.27 (s,
[
a
]
ꢁ28.59 (c 1.0, CHCl3). Daicel Chirapak AD-H, hexane/iso-
26
D
1H), 7.09 (s, 2H), 6.95 (d, J¼8.8, 1H), 6.06 (t, J¼4.2 Hz, 1H), 5.25 (d,
J¼4.4 Hz, 1H), 4.70 (d, J¼8.8 Hz, 1H), 3.54e3.39 (m, 4H), 1.21e1.18
propanol¼90:10, flow rate 1.0 mL/min, T¼25 ꢀC, 254 nm,
tR¼4.42 min (major), tR¼5.14 min (minor). IR (KBr)
n 3390, 3087,
(m, 6H). 13C NMR (100 MHz, CDCl3)
d
165.7, 163.7,146.6,142.7, 133.0,
2989, 1640, 1589, 1527, 1461, 1393, 1275, 1174, 993, 871, 750 cmꢁ1
1H NMR (400 MHz, CDCl3)
7.29 (s, 1H), 7.25 (s, 1H), 7.22 (s, 1H),
.
132.7, 127.5, 127.3, 124.6, 121.9, 112.6, 111.7, 110.5, 87.0, 57.5, 42.4,
d
41.2, 14.6, 12.5. MS: m/z¼491.21 (Mþ). Elemental Anal. Calcd for
7.10 (s, 2H), 6.15e6.12 (m, 1H), 5.16 (d, J¼4.3 Hz, 1H), 4.51 (d,
J¼8.6 Hz, 1H), 3.56e3.52 (m, 2H), 3.45e3.28 (m, 2H), 1.25 (t,
J¼7.2 Hz, 3H), 1.18 (t, J¼7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3)
C
21H19F6N3O4: C, 51.33; H, 3.90; N, 8.55. Found: C, 51.55; H, 3.72; N,
8.40.
d
165.8, 153.7, 146.9, 133.7, 133.4, 133.1, 132.7, 130.5, 129.1, 127.5,
4.3.4. 3-((3,5-Bis(trifluoromethyl)phenyl)amino)-N,N-diethyl-
5-fluoro-2,3-dihydrobenzofuran-2-carboxamide (3d). White solid,
127.2, 124.8, 123.8, 122.1, 116.8, 113.0, 112.0, 86.8, 59.0, 42.5, 41.2,
14.5, 12.5. MS: m/z¼516.34 ([MþH]þ). Elemental Anal. Calcd for
Please cite this article in press as: Cheng, Y.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.03.059

6
Y. Cheng et al. / Tetrahedron xxx (2013) 1e7
C21H18Cl2F6N2O2: C, 48.95; H, 3.52; N, 5.44. Found: C, 49.18; H,
3.76; N, 5.42.
3H), 1.97e1.89 (m, 4H). 13C NMR (100 MHz, CDCl3)
d 166.6, 156.8,
147.1, 133.1, 132.8, 132.4, 132.1, 131.3, 131.0, 125.6, 124.7, 122.0, 112.4,
110.9, 109.9, 86.6, 58.6, 46.9, 46.7, 26.2, 23.8, 20.7. MS: m/z¼458.24
(Mþ). Elemental Anal. Calcd for C22H20F6N2O2: C, 57.64; H, 4.40; N,
6.11. Found: C, 57.68; H, 4.15; N, 6.39.
4.3.8. 3-((3,5-Bis(trifluoromethyl)phenyl)amino)-5,7-dibromo-N,N-
diethyl-2,3-dihydrobenzofuran-2-carboxamide (3h). Yellow solid,
62.8 mg, yield: 52%, mp 167e169 ꢀC (petroleum ether/ethyl ace-
26
tate), diastereoisomer ratio: >95:5, enantiomeric excess: 43%, [
a
]
4.3.12. (3-((3,5-Bis(trifluoromethyl)phenyl)amino)-5-fluoro-2,3-
D
ꢁ19.87 (c 1.0, CHCl3). Daicel Chirapak AD-H, hexane/iso-
dihydrobenzofuran-2-yl)(pyrrolidin-1-yl)methanone
(3l). White
propanol¼90:10, flow rate 1.0 mL/min, T¼25 ꢀC, 254 nm,
solid, 72.1 mg, yield: 78%, mp 144e148 ꢀC (petroleum ether/ethyl
tR¼4.54 min (major), tR¼5.72 min (minor). IR (KBr)
n
3403, 3322,
acetate), diastereoisomer ratio: >95:5, enantiomeric excess: 73%,
26
3082, 2988, 2944, 1653, 1626, 1454, 1397, 1277, 1181, 1129, 863,
[a
]
ꢁ56.17 (c 1.0, CHCl3). Daicel Chirapak AD-H, hexane/iso-
D
681 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d
7.58 (s, 1H), 7.40 (s, 1H), 7.25
propanol¼95:5, flow rate 0.7 mL/min, T¼25 ꢀC, 254 nm,
(s, 1H), 7.11 (s, 2H), 6.19 (dd, J¼8.6, 4.2 Hz,1H), 5.15 (d, J¼4.4 Hz,1H),
4.47 (d, J¼8.3 Hz,1H), 3.59e3.53 (m, 2H), 3.41e3.29 (m, 2H), 1.27 (d,
J¼7.1 Hz, 3H), 1.19 (d, J¼7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3)
tR¼11.99 min (major), tR¼18.27 min (minor). IR (KBr)
n 3292, 3085,
2988, 2888,1644,1559,1484,1453,1400,1277,1194,1129, 818 cmꢁ1
1H NMR (400 MHz, CDCl3)
7.23 (s, 1H), 7.13 (s, 2H), 7.04e6.96 (m,
.
d
d
165.7, 155.3, 146.7, 135.5, 132.9, 132.6, 128.9, 127.3, 124.6, 121.9,
2H), 6.83e6.80 (m, 1H), 5.94e5.90 (m, 1H), 5.03 (d, J¼4.3 Hz, 1H),
113.7, 112.6, 111.5, 104.0, 86.2, 58.7, 42.5, 41.0, 14.4, 12.4. MS: m/
z¼604.08 (Mþ). Elemental Anal. Calcd for C21H18Br2F6N2O2: C,
41.75; H, 3.00; N, 4.64. Found: C, 41.94; H, 3.29; N, 4.44.
4.52 (d, J¼8.5 Hz, 1H), 3.72e3.67 (m, 1H), 3.58e3.46 (m, 3H),
2.04e1.87 (m, 4H). 13C NMR (100 MHz, CDCl3)
d 166.2, 159.0, 156.7,
154.7, 146.9, 132.8, 132.4, 126.9,126.8, 124.7, 122.0,117.1, 116.9, 112.5,
112.2, 112.0, 111.2, 110.7, 110.7, 86.9, 58.4, 46.8, 46.6, 26.0, 23.8. MS:
m/z¼462.44 (Mþ). Elemental Anal. Calcd for C21H17F7N2O2: C,
54.55; H, 3.71; N, 6.06. Found: C, 54.37; H, 3.92; N, 5.89.
4.3.9. 3-((3,5-Bis(trifluoromethyl)phenyl)amino)-N,N-diethyl-
2,3-dihydrofuro[3,2-b]pyridine-2-carboxamide (3i). White solid,
56.3 mg, yield: 63%, mp 182e185 ꢀC (petroleum ether/ethyl ace-
tate), diastereoisomer ratio: >95:5, enantiomeric excess: 21%,
4.3.13. (Z)-N,N-Diethyl-3-(2-hydroxyphenyl)-3-(o-tolylamino) acryl-
24
[
a
]
11.12 (c 1.0, CHCl3). Daicel Chirapak AD-H, hexane/iso-
amide (BP). 1H NMR (400 MHz, CDCl3)
d 11.26 (s, 1H), 7.25e7.13 (m,
D
propanol¼70:30, flow rate 1.0 mL/min, T¼25 ꢀC, 254 nm,
2H), 7.10e7.08 (m, 3H), 6.94e6.89 (m, 2H), 6.85e6.82 (m, 1H), 6.11
(d, J¼12.5 Hz, 1H), 3.58 (d, J¼5.9 Hz, 4H), 1.95 (s, 3H), 1.26e1.22 (m,
tR¼4.88 min (minor), tR¼5.93 min (major). IR (KBr)
n 3319, 3078,
2989, 2941, 1635, 1580, 1473, 1397, 1278, 1188, 1125, 952, 854,
6H). 13C NMR (100 MHz, CDCl3)
d 173.5, 156.5, 139.3, 130.9, 130.1,
797 cmꢁ1 1H NMR (400 MHz, CDCl3)
.
d
8.20 (d, J¼3.3 Hz, 1H),
129.9, 127.3, 123.8, 121.0, 120.4, 119.7, 119.2, 112.1, 105.9, 16.9, 13.8,
13.7.
7.23e7.17 (m, 3H), 7.07 (s, 2H), 5.95e5.91 (m, 1H), 5.17 (d, J¼5.3 Hz,
1H), 4.90 (d, J¼5.8 Hz, 1H), 3.56e3.43 (m, 4H), 1.24e1.19 (m, 6H).
13C NMR (100 MHz, CDCl3)
d 166.3, 152.8, 147.5, 147.5, 143.0, 133.0,
Acknowledgements
132.6, 132.3, 132.0, 124.7, 124.5, 122.0, 117.3, 112.4, 111.1, 85.0, 58.4,
42.3, 41.1, 14.7, 12.6. MS: m/z¼447.27 (Mþ). Elemental Anal. Calcd
for C20H19F6N3O2: C, 53.69; H, 4.28; N, 9.39. Found: C, 53.87; H,
4.12; N, 9.11.
We are grateful to the National Natural Science Foundation of
China (No. 21072069 and 21002036) and the National Basic Re-
search Program of China (2011CB808603) for financial support of
this research.
4.3.10. (3-((3,5-Bis(trifluoromethyl)phenyl)amino)-2,3-dihydro ben-
zofuran-2-yl)(pyrrolidin-1-yl)methanone (3j). White solid, 59.5 mg,
yield: 67%, mp 163e164 ꢀC (petroleum ether/ethyl acetate), di-
Supplementary data
astereoisomer ratio: >95:5, enantiomeric excess: 84%, [
a
]
25 ꢁ57.99
D
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.03.059.
(c 1.0, CHCl3). Daicel Chirapak AD-H, hexane/isopropanol¼95:5,
flow rate 1.0 mL/min, T¼25 ꢀC, 254 nm, tR¼13.36 min (major),
tR¼14.61 min (minor). IR (KBr)
n 3288, 3176, 3099, 2965, 2891,1648,
1620, 1456, 1397, 1275, 1187, 1121, 853, 753 cmꢁ1
.
1H NMR
References and notes
(600 MHz, CDCl3)
d
7.34 (d, J¼7.4 Hz, 1H), 7.29 (t, J¼7.8 Hz, 1H), 7.22
1. For selected examples, see: (a) Sefkow, M. Synthesis 2003, 2595e2625; (b)
(s, 1H), 7.15 (s, 2H), 6.99 (t, J¼7.4 Hz, 1H), 6.90 (d, J¼8.1 Hz, 1H),
5.92e5.90 (m, 1H), 5.00 (d, J¼3.9 Hz, 1H), 4.50 (d, J¼8.3 Hz, 1H),
3.71e3.69 (m, 1H), 3.58e3.54 (m, 3H), 2.00e1.87 (m, 4H). 13C NMR
ꢁ
~
ꢁ
ꢁ
~
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(150 MHz, CDCl3)
d 166.5, 158.8, 147.1, 133.0, 132.7, 132.4, 132.1,
130.5, 125.7, 125.3, 124.7, 122.0, 121.7, 112.4, 110.9, 110.2, 86.4, 58.4,
46.9, 46.6, 26.1, 23.8. MS: m/z¼444.28 (Mþ). Elemental Anal. Calcd
for C21H18F6N2O2: C, 56.76; H, 4.08; N, 6.30. Found: C, 56.91; H,
4.25; N, 6.04.
4.3.11. (3-((3,5-Bis(trifluoromethyl)phenyl)amino)-5-methyl-2,3-
2. Nandy, J. P.; Rakic, B.; Sarma, B. V. N. B.; Babu, N.; Lefrance, M.; Enright, G. D.;
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dihydrobenzofuran-2-yl)(pyrrolidin-1-yl)methanone
(3k). White
solid, 65.1 mg, yield: 71%, mp 203e206 ꢀC (petroleum ether/ethyl
ꢁ
ꢁ
ꢁ
ꢁ
Antus, S.; Kurtan, T.; Juhasz, L.; Kiss, L.; Hollosi, M.; Majer, Z. S. Chirality 2001, 13,
acetate), diastereoisomer ratio: >95:5, enantiomeric excess: 93%,
493e506.
24
ꢂ
4. For examples, see: (a) Van Dyck, S. M. O.; Lemiere, G. L. F.; Jonckers, T. H. M.;
[
a]
ꢁ49.77 (c 1.0, CHCl3). Daicel Chirapak AD-H, hexane/iso-
D
Dommisse, R.; Pieters, L.; Buss, V. Tetrahedron: Asymmetry 2001, 12, 785e789;
propanol¼95:5, flow rate 1.0 mL/min, T¼25 ꢀC, 254 nm,
ꢁ
(b) Juhasz, L.; Visy, J.; Simonyi, M.; Krohn, K.; Antus, S. Tetrahedron: Asymmetry
tR¼14.37 min (major), tR¼16.46 min (minor). IR (KBr)
n 3304, 3081,
2002, 13, 1219e1222; (c) Itoh, T.; Kawai, K.; Hayase, S.; Ohara, H. Tetrahedron
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(c) Orlandi, M.; Rindone, B.; Molteni, G.; Rummakko, P.; Brunow, G. Tetrahedron
2971, 2892, 1642, 1576, 1450, 1401, 1276, 1190, 1129, 815 cmꢁ1. 1H
NMR (400 MHz, CDCl3)
d
7.21 (s, 1H), 7.14 (s, 3H), 7.08 (d, J¼8.7 Hz,
1H), 6.78 (d, J¼8.2 Hz,1H), 5.87e5.84 (m, 1H), 4.98 (d, J¼4.0 Hz,1H),
4.46 (d, J¼8.3 Hz, 1H), 3.71e3.67 (m, 1H), 3.57e3.53 (m, 3H), 2.31 (s,
Please cite this article in press as: Cheng, Y.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.03.059

Y. Cheng et al. / Tetrahedron xxx (2013) 1e7
7
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ꢁ
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16. See Supplementary data for more details.
17. Actually, we have extensively tried some chiral H-Bonding catalysts, such
as urea and thiourea. Unfortunately, all the attempts met failure. For ex-
ample, the use of C2-symmetric urea catalyst 7 resulted in the formation of
the corresponding product 3j in excellent yield and dr, but with no
enantioselectivity.
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Please cite this article in press as: Cheng, Y.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.03.059