Chiral phosphine-catalyzed asymmetric allylic alkylation of 3-substituted benzofuran-2(3H)-ones or oxindoles with Morita-Baylis-Hillman carbonates

Article abstract of DOI:10.1039/c2ob25694k

An efficient chiral phosphine-catalyzed asymmetric substitution reaction of MBH carbonates with 3-substituted benzofuran-2(3H)-ones or 3-substituted oxindoles has been described in this context, giving the corresponding allylic alkylation products bearing

Full text of DOI:10.1039/c2ob25694k

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PAPER
Chiral phosphine-catalyzed asymmetric allylic alkylation of 3-substituted
benzofuran-2(3H)-ones or oxindoles with Morita–Baylis–Hillman carbonates†
De Wang,a Yuan-Liang Yang,a Jia-Jun Jianga and Min Shi*a,b
Received 9th April 2012, Accepted 11th July 2012
DOI: 10.1039/c2ob25694k
An efficient chiral phosphine-catalyzed asymmetric substitution reaction of MBH carbonates with
3-substituted benzofuran-2(3H)-ones or 3-substituted oxindoles has been described in this context, giving
the corresponding allylic alkylation products bearing adjacent quaternary and tertiary stereogenic centers
in high yields, moderate diastereoselectivities and high enantioselectivities under mild conditions.
have no corresponding natural enantiomers, causing production
of the enantiomers of the corresponding products in the same ee
Introduction
Benzofuran-2(3H)-ones and oxindoles are important motifs
which exist in a broad range of natural products1,2 and pharma-
ceutically relevant compounds.3 Many of them feature a chiral
quaternary stereocenter at the C3 position of the corresponding
heterocyclic rings (Fig. 1).1d,e,2c Therefore, a direct and valuable
strategy for asymmetric synthesis of 3,3-disubstituted benzo-
furan-2(3H)-one or oxindole frameworks is highly desired.
values to be more difficult because for example, (DHQD)2PHAL
is a pseudo-enantiomer of (DHQ)2PHAL. Furthermore, these
organocatalysts cannot be easily modified which limits their
wide application in organic synthesis.
Recently, we have been working on the development of chiral
phosphine-catalyzed asymmetric substitution of Morita–Baylis–
Hillman (MBH) adducts with various pronucleophiles and have
established a chiral phosphine catalyzed asymmetric substitution
reaction of MBH acetates with 2-trimethylsilyloxy furan, afford-
ing the corresponding products in good yields with high ee and
dr values (Scheme 1).9 During our ongoing investigations into
the chiral phosphine catalyzed AAA reactions of MBH adducts
using various nucleophiles,10 we found that these chiral
Thus far, much effort has been devoted to asymmetric reac-
tions using 3-substituted benzofuran-2(3H)-ones4 or oxindoles5
as pronucleophiles. Typically, the asymmetric allylic alkylation
(AAA)6 reaction of benzofuran-2(3H)-ones or oxindoles is fasci-
nating not only because it can be used for the construction of
quaternary stereocenters but also because a double bond can be
induced at the same time, which allows for a number of useful
organic transformations. Chen and his coworkers have presented
the first organocatalytic AAA reaction of 3-substituted ox-
indoles7 by means of a Cinchona alkaloid (DHQD)2AQN as the
catalyst in 2009, giving the desired products in good yields with
86–97% ee values and 62 : 37–92 : 8 diastereoselectivities (dr).
During the preparation of this manuscript, Cheng and Lin’s
group reported the AAA reaction of 3-substituted benzofuran-2
(3H)-ones8 using the same organocatalyst, furnishing the corres-
ponding products in good yields with 67–95% ee values and
68 : 32–98 : 2 dr. Indeed, Cinchona alkaloids and their deriva-
tives are powerful organocatalysts for AAA reactions, but there
are still some limitations in their application. These alkaloids
Fig. 1 Examples of biologically active chiral benzofuran-2(3H)-one
and oxindole.
aKey Laboratory for Advanced Materials and Institute of Fine
Chemicals, East China University of Science and Technology, 130 Mei
Long Road, Shanghai 200237, China
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, China. E-mail: Mshi@mail.sioc.ac.cn;
Fax: +86-21-64166128
†Electronic supplementary information (ESI) available: Experimen-
tal procedures, NMR charts for all compounds. See DOI:
10.1039/c2ob25694k
Scheme 1 Chiral phosphine catalyzed asymmetric substitution of
MBH acetates with 2-trimethylsilyloxy furan.
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phosphines are also effective catalysts for the asymmetric substi-
tution of MBH carbonates with 3-substituted benzofuran-2(3H)-
ones or oxindoles, providing an efficient synthetic protocol for
the preparation of these biologically interesting substances. In
this context, we wish to report the details.
toluene at room temperature in the presence of 10 mol% chiral
phosphines LB1–LB11 (Fig. 2) as Lewis base catalysts for 24 h.
It was found that using catalyst LB1 afforded the desired product
3a in 76% combined yield but with low diastereoselectivity (dr)
as the ratio of two isomers was 55 : 45, with 94% ee value for
the major product and 89% ee value for the minor product
(Table 1, entry 1). Subsequently, we screened the other four
chiral phosphine catalysts LB2–LB5 for this reaction, and the
results are summarized in Table 1 (entries 2–5). As can be seen
from Table 1, catalyst LB1 gave the best result and catalyst LB3
afforded 3a in the lowest yield, diastereo- and enantioselectivity
as compared to the other catalysts. We also used LB6 containing
a sterically bulky group as the catalyst in this reaction and found
that the diastereoselectivity increased to 63 : 37, while the yield
and enantioselectivity declined significantly (Table 1, entry 6).
We also examined the multifunctional chiral phosphine catalysts
LB7–LB10 shown in Fig. 2 in this reaction and the results are
summarized in Table 1 (entries 7–10). Using L8 and L9 as cata-
lysts, the desired products 3a were obtained in 52% and 47%
yields, 51 : 49 and 60 : 40 diastereoselectivities, and 92% (90%)
and 92% (92%) enantioselectivities, respectively (Table 1,
entries 8–9). While using LB7 and LB10 as catalysts afforded
the products 3a in 61 : 39 and 69 : 31 diastereoselectivities,
slightly higher de values than that of LB1, but along with lower
yields and enantioselectivities (Table 1, entries 7 and 10). We
also examined chiral phosphine LB11 derived from a natural
amino acid in this reaction, but it only afforded a trace of product
(Table 1, entry 11). With the identification of LB1 as the best
catalyst for this reaction, the examination of solvent effects
revealed that in dichloromethane (DCM), the desired product 3a
could be obtained in 67% yield along with 57 : 43 dr and 92%
Results and discussion
We initially utilized 3-phenylbenzofuran-2(3H)-one 1a
(0.1 mmol, 1.0 equiv) and MBH carbonate 2a (0.2 mmol, 2.0
equiv) as the substrates to investigate their reaction behavior in
Fig. 2 Chiral phosphine catalysts LB1–LB12.
Table 1 Optimization of chiral phosphine catalyzed AAA reaction of 3-phenylbenzofuran-2(3H)-one 1a and MBH carbonate 2a
Entrya
Cat.*
Solvent
T (°C)
Yieldb (%)
dr (syn : anti)c
ee % (syn/anti)c
1
2
3
4
5
6
7
8
LB1
LB2
LB3
LB4
LB5
LB6
LB7
LB8
LB9
LB10
LB11
LB1
LB1
LB1
LB1
LB1
LB1
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCM
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
76
33
27
53
50
28
60
52
47
37
Trace
67
40
NR
96
95
12
55 : 45
60 : 40
51 : 49
59 : 41
59 : 41
63 : 37
61 : 39
51 : 49
60 : 40
69 : 31
—
57 : 43
55 : 45
—
55 : 45
67 : 33
65 : 35
94/89
83/79
67/65
92/86
92/89
86/85
91/89
92/90
−92/−92d
83/78
—
92/91
91/88
—
94/89
94/91
94/91
9
10
11
12
13
14
15e
16e
17e
THF
CH3CN
Toluene
Toluene
Toluene
−20
a The reactions were carried out with 1a (0.1 mmol), 2a (0.2 mmol), catalyst (0.01 mmol) in solvent (1.0 mL) at room temperature for 24 h. b Isolated
yield by column chromatography. c Determined by chiral HPLC analysis and syn and anti configurations were determined according to previous
literature.8,13 d The absolute configurations of each isomers are opposite to the others. e 0.02 mmol of catalyst was used and the reaction was carried
out for 48 h.
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(91%) ee (Table 1, entry 12). Using tetrahydrofuran (THF) as
solvent gave 3a in 40% yield with 55 : 45 dr and 91% (88%) ee
under identical conditions (Table 1, entry 13). When the solvent
was switched to acetonitrile (CH3CN), no reaction occurred
(Table 1, entry 14). Increasing the catalyst loading to 20 mol%
and carrying out the reaction for 48 h could improve the yield of
3a to 96% in toluene (Table 1, entry 15). Lowering the reaction
temperature to 0 °C with 20 mol% catalyst loading could
improve the yield of 3a to 95% along with 67 : 33 dr and 94%
(91%) ee value in toluene for 48 h (Table 1, entry 16). Further
reducing the reaction temperature to −20 °C did not facilitate the
reaction outcomes (Table 1, entry 17). Thus, we have established
the optimal reaction conditions for this AAA reaction: using
20 mol% LB1 as the catalyst and toluene as the solvent to
perform the reaction at 0 °C for 48 h.
Under these optimized reaction conditions, the reaction gener-
ality was investigated by using various benzofuran-2(3H)-ones 1
in the reaction with several MBH carbonates 2, and the results of
these experiments are summarized in Table 2. All reactions pro-
ceeded smoothly to give the corresponding products 3 in good to
excellent yields with moderate diastereoselectivities and excel-
lent enantioselectivities under the optimal reaction conditions
(Table 2). As can be seen from Table 2, three substituted benzo-
furan-2(3H)-ones 1b–1d were used for the reactions with 2a,
affording the desired allylic-alkylation products 3b–3d in excel-
lent yields (91–93%), with moderate diastereoselectivities
(56 : 44–71 : 29 dr), and high enantioselectivities (90–97% ee for
syn products and 88–92% ee for anti products) (Table 2, entries
1–3). Then, seven different MBH carbonates 2b–2h were tested
in the reactions with 1a (Table 2, entries 4–10). Introducing elec-
tron-withdrawing groups such as 3-Cl, 3-CN, 4-F, or 4-NO2 on
the aromatic ring of MBH carbonates, the corresponding
products 3e–3h were acquired in good yields (84–>99%) with
moderate diastereoselectivities (56 : 44–64 : 36 dr), and excellent
enantioselectivities (90–95% ee for syn products and 88–92% ee
for anti products) (Table 2, entries 4–7). An MBH carbonate
containing the electron-donating group 4-CH3 also gave the
desired product 3i in high yield and ee values (for anti/syn-
stereoisomers) (Table 2, entry 8). Changing the ester moiety of
the MBH carbonate 2 (R3) from Me to Et or the more sterically
bulky tert-Bu provided similar reaction outcomes, affording the
desired products 3j and 3k in 95% and 87% yields, and moder-
ate diastereoselectivities of 55 : 45 and 54 : 46 along with 93%
and 91% ee values for syn products and 88% and 85% ee values
for anti products, respectively (Table 2, entries 9 and 10).
Encouraged by the results above, we attempted to use 3-sub-
stituted oxindoles instead of benzofuran-2(3H)-ones for this
reaction. Thus, we used oxindole 4a and MBH carbonate 2e as
substrates to investigate their AAA reaction behavior. We tested
chiral phosphines LB1, LB4, LB5, and LB12 in this reaction;
the results are summarized in Table 3 (entries 1–4). Gratifyingly,
the catalyst LB1 was also suitable for this system. The results
are indicated in Table 3. Using 20 mol% LB1 as the catalyst
gave 5a in 67% combined yield with 55 : 45 dr and 84% (69%)
ee values in THF for 48 h (Table 3, entry 1). An examination of
solvent effects revealed that in dichloromethane (DCM), the
desired product 5a could be obtained in 80% combined yield
along with 53 : 47 dr and 93% (84%) ee; using other solvents
such as 1,2-dichloroethane (DCE) or toluene gave 5a in 67% or
91% combined yield with 93% (83%) or 98% (89%) ee values
and 45 : 55 or 67 : 33 dr under identical conditions (Table 3,
entries 5, 6, and 8). Notably, no reaction occurred in CH3CN
(Table 3, entry 7). Toluene should be the solvent of choice for
this reaction (Table 3, entry 8). Decreasing the catalyst loading
Table 2 Substrate scope of the reactions of benzofuran-2(3H)-ones 1
and MBH carbonates 2
Table 3 Optimization of the reaction conditions of 3-phenyl oxindole
4a and MBH carbonate 2e in the presence of LB1
ee%
Yieldb
(%)
dr
(syn/
ee%
Entrya 1 (R1)
2 (R2/R3)
(syn : anti)c anti)c
Yieldb
Entrya Cat.* Solvent T (°C) (%)
dr
(anti/
(anti : syn)c syn)c
1
2
3
4
1b (Cl) 2a (H/Me)
1c (Br) 2a (H/Me)
1d (tBu) 2a (H/Me)
3b: 93
3c: 90
3d: 91
3e: >99 56 : 44
3f: 84
3g: 93
56 : 44
71 : 29
63 : 37
92/91
97/92
90/88
94/90
90/88
92/89
95/92
95/92
93/88
91/85 :
1
2
3
4
5
6
7
LB1
LB4
LB5
THF
THF
THF
rt
rt
rt
rt
rt
rt
67
62
57
53
80
67
—
91
77
68
55 : 45
54 : 46
55 : 45
57 : 43
53 : 47
45 : 55
—
67 : 33
64 : 36
66 : 34
84/69
60/52
73/67
82/60
93/84
93/83
—
98/89
94/88
96/85
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
2b (3-Cl/Me)
2c (3-CN/Me)
2d (4-F/Me)
5
56 : 44
64 : 36
58 : 42
56 : 44
55 : 45
54 : 46
LB12 THF
6
LB1
LB1
LB1
LB1
LB1
LB1
DCM
DCE
CH3CN rt
Toluene rt
Toluene rt
7c
8
2e (4-NO2/Me) 3h: 98
2f (4-CH3/Et)
2g (4-NO2/Et)
3i: 85
3j: 95
9
10
8
2h (4-NO2/tBu) 3k: 87
9d
10
Toluene
0
a The reactions were carried out with 1a (0.1 mmol), 2a (0.2 mmol),
catalyst (0.02 mmol) in toluene (1.0 mL) at 0 °C for 48 h. b Isolated
yield by column chromatography and the isomers can not be easily
separated by column chromatography. c Determined by chiral HPLC
analysis and syn and anti configurations were determined according to
previous literature.8,13
a The reactions were carried out with 4a (0.1 mmol), 2e (0.2 mmol),
catalyst (0.02 mmol) in solvent (1.0 mL) at room temperature for 24 h.
b Total isolated yield by column chromatography and the isomers cannot
be easily separated by column chromatography. c Determined by chiral
HPLC analysis. d 0.01 mmol catalyst was used.
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Table 4 Substrate scope of the reactions of oxindoles 4 and MBH
carbonates 2
3-substituted benzofuran-2(3H)-ones or oxindoles to give the
corresponding substitution products in high yields with moderate
dr values and high ee values for major and minor diastereomeric
products under mild conditions. For benzofuran-2(3H)-ones, the
desired products could be obtained in high yields (84–>99%)
with moderate diastereoselectivities (syn : anti = 54 : 46–71 : 29)
and excellent ee values (90–97% for major products and
85–92% for minor products). While for oxindoles, the AAA
reactions afforded the products in moderate to high yields
(76–93%) with moderate diastereoselectivities (anti : syn =
51 : 49–67 : 33) and good ee values (91–98% for major products
and 80–89% for minor products). These products bearing adja-
cent quaternary and tertiary stereogenic centers may have poten-
tial biological significance in medicinal chemistry. Our results
suggested that compared to Cinchona alkaloid derived organo-
catalysts, the chiral phosphine catalyst can be also used for this
type of reaction, giving the corresponding products in higher
yields and good ee values. A plausible transition state for this
asymmetric reaction is outlined in the ESI.† Further investi-
gations on the reaction mechanism and improvement of the dia-
stereoselectivity by new chiral phosphine catalyst are ongoing in
our laboratory.
ee%
Yieldb
(%)
dr
(anti/
Entrya 4 (R4/R5)
2 (R2)
(anti : syn)c
syn)c
1
2
3
4
4a (H/H)
4a (H/H)
4a (H/H)
4a (H/H)
4a (H/H)
4a (H/H)
4a (H/H)
4b (H/F)
2e (4-NO2) 5a: 91
2c (3-CN) 5b: 86
67 : 33
62 : 38
51 : 49
59 : 41
58 : 42
60 : 40
57 : 43
60 : 40
61 : 39
56 : 44
64 : 36
98/89
94/80
92/87
93/88
93/85
95/91
93/89
92/89
92/88
91/84
96/94
2b (3-Cl)
2i (4-Cl)
2d (4-F)
5c: 93
5d: 92
5e: 86
5
6
2j (4-CH3) 5f: 81
7c
8
2a (H)
2a (H)
5g: 89
5h: 82
5i: 76
5j: 89
5k: 78
9
10
11
4c (H/CH3) 2a (H)
4d (F/H) 2a (H)
4e (CH3/H) 2a (H)
a The reactions were carried out with 4 (0.1 mmol), 2 (0.2 mmol),
catalyst (0.02 mmol) in toluene (1.0 mL) at room temperature for 48 h.
b Total isolated yield by column chromatography and the isomers cannot
be easily separated by column chromatography. c Determined by chiral
HPLC analysis and syn and anti configurations were determined
according to the previous literature.7,13
Experimental section
General remarks
1H NMR spectra were recorded on a Bruker AM-300 or
AM-400 spectrometer for solutions in CDCl3 with tetramethyl-
silane (TMS) as internal standard; J-values are in Hz. Mass
spectra were recorded with a HP-5989 instrument. All of the
compounds reported in this paper gave satisfactory HRMS ana-
lytic data. Melting points were determined on a digital melting
point apparatus and temperatures were uncorrected. Infrared
spectra were recorded on a Perkin-Elmer PE-983 spectrometer
with absorption in cm−1. THF and toluene were distilled from
sodium (Na) under argon (Ar) atmosphere. CH3CN, 1,2-dichloro-
ethane and dichloromethane were distilled from CaH2 under
argon (Ar) atmosphere. Commercially obtained reagents were
used without further purification. All reactions were monitored
by TLC with Huanghai GF254 silica gel coated plates. Flash
column chromatography was carried out using 300–400 mesh
silica gel at increased pressure.
to 10 mol% afforded 5a in 77% yield (Table 3, entry 9). Lower-
ing the reaction temperature to 0 °C did not improve the result in
toluene (Table 3, entry 10).
Having identified the optimal reaction conditions, we next set
out to examine the scope and limitations of this AAA reaction
catalyzed by LB1 using various substituted oxindoles 4 with
different MBH carbonates 2, and the results are summarized in
Table 4. As can be seen from Table 4, when R2 on the aromatic
group of the MBH carbonates was changed to 3-CN, 3-Cl, 4-Cl,
4-F or 4-CH3 (Table 4, entries 2–6), the desired allylic alkylation
products 5b–5f were obtained in good to excellent yields
(81–93%), with moderate diastereoselectivities (51 : 49–62 : 38
dr), and good enantioselectivities (92–95% ee for anti products
and 80–91% ee for syn products). Subsequently, oxindoles
having no substituent or bearing electron-donating or electron-
withdrawing substituents (R5) at the 3-aryl group were investi-
gated in this reaction, affording the desired products 5g–5i in
76–89% yields, 57 : 43–61 : 39 diastereoselectivities and good
enantioselectivities (92–93% ee for anti products and 88–89%
ee for syn products) (Table 4, entries 7–9). Introducing electron-
donating or electron-withdrawing substituents (R4) at the aryl
ring of the oxindoles, the desire AAA products 5j and 5k were
also formed in good yields, high ee values and moderate diaster-
eoselectivities (Table 4, entries 10 and 11).
Chiral phosphine catalysts LB1–LB12 were synthesized
according to our previous work.9,10 All the 3-substituted benzo-
furan-2(3H)-ones11 or oxindoles5r and MBH carbonates12 were
prepared according to the literature.
General procedure for the preparation of 3 from the reaction of
1 with 2 in the presence of LB1, using 3a as an example
To a mixture of 1a (0.10 mmol, 21.0 mg), 2a (0.20 mmol,
58.0 mg) and LB1 (10.0 mg, 0.02 mmol) was added 1.0 mL of
toluene at 0 °C. The reaction solution was monitored by TLC.
After the reaction was complete, the solution was concentrated
under reduced pressure and the residue was further purified by
silica gel column chromatography (EtOAc–PE = 1 : 10) to give
the target product 3a.
Conclusions
In conclusion, we have established an efficient chiral phosphine-
catalyzed asymmetric allylic alkylation of MBH carbonates with
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Methyl
2-((2-oxo-3-phenyl-2,3-dihydrobenzofuran-3-yl)-
for 90% ee (syn) and 88% ee (anti); Enantiomeric excess was
determined by HPLC with a Chiralcel IC-H column, hexane–
(phenyl)methyl)acrylate 3a. A white solid that is a known com-
pound,8 95% yield, 36 mg (syn : anti = 67 : 33); [α]2D0 = −160.5
(c 0.5, CHCl3) for 94% ee (syn) and 91% ee (anti); Enantiomeric
excess was determined by HPLC with a Chiralcel IC-H column,
hexane–iPrOH = 95 : 5, 0.5 mL min−1, 230 nm, for syn product
iPrOH = 93 : 7, 0.5 mL min−1, 230 nm, for syn product tmajor
=
=
19.627 min, tminor = 26.327 min; for anti product tmajor
1
18.077 min, tminor = 15.177 min. H NMR (400 MHz, CDCl3,
t
t
TMS): δ 1.25 (s, 5.67H, Bu), 1.38 (s, 3.33H, Bu), 3.44 (s,
1.11H, CH3), 3.66 (s, 1.89H, CH3), 5.38 (s, 0.37H, vCH2),
5.40 (s, 0.63H, vCH2), 5.41 (s, 0.67H, vCH2), 5.58 (d, J = 1.2
Hz, 0.33H, vCH2), 6.29 (s, 0.33H, CH), 6.39 (s, 0.67H, CH),
6.76–6.78 (m, 2H, Ar), 6.89–6.98 (m, 2H, Ar), 7.06–7.20 (m,
3H, Ar), 7.25–7.36 (m, 4H, Ar), 7.49–7.63 (m, 2H, Ar); 13C
NMR (CDCl3, 100 MHz): δ 31.39, 31.52, 34.64, 34.71, 51.97,
52.26, 53.00, 53.39, 59.45, 59.67, 110.06, 110.09, 124.59,
125.98, 126.04, 127.29, 127.30, 127.58, 127.64, 127.66, 127.80,
127.90, 127.92, 128.01, 128.44, 128.60, 128.99, 129.61, 129.88,
135.12, 136.69, 137.77, 139.05, 139.78, 146.77, 146.84, 150.68,
150.86, 166.79, 167.71, 176.87, 177.17; IR (neat) ν 2957, 1801,
1720, 1488, 1264, 1145, 1065, 704, 702 cm−1; MS (ESI) m/z
463.5 (M + Na+, 100). HRMS (ESI) Calcd for C29H28O4Na
requires (M + Na+) 463.1889, Found: 463.1880.
t
major = 27.323 min, tminor = 35.282 min; for anti product tmajor =
1
33.532 min, tminor = 25.773 min; H NMR (400 MHz, CDCl3,
TMS): δ 3.43 (s, 0.99H, CH3), 3.65 (s, 2.01H, CH3), 5.38 (s,
0.67H, vCH2), 5.39 (s, 0.33H, vCH2), 5.57 (d, J = 1.2 Hz,
0.33H, vCH2), 5.63 (s, 0.67H, vCH2), 6.27 (s, 0.33H, CH),
6.41 (s, 0.67H, CH), 6.79–6.82 (m, 1H, Ar), 6.90–7.03 (m, 2H,
Ar), 7.07–7.19 (m, 4H, Ar), 7.26–7.39 (m, 5H, Ar), 7.47–7.65
(m, 2H, Ar); MS (ESI) m/z 407.4 (M + Na+, 100). HRMS
(MALDI) Calcd for C25H20O4Na requires (M + Na+) 407.1270,
Found: 407.1254.
Methyl 2-((5-chloro-2-oxo-3-phenyl-2,3-dihydrobenzofuran-3-yl)-
(phenyl)methyl)acrylate 3b. A white solid (41 mg, 93% yield,
syn : anti = 56 : 44); H NMR (400 MHz, CDCl3, TMS) δ 3.46
1
(s, 1.32H, CH3), 3.65 (s, 1.68H, CH3), 5.35 (s, 0.56H, vCH2),
5.39 (s, 0.44H, vCH2), 5.55 (d, J = 1.2 Hz, 0.44H, vCH2),
5.70 (s, 0.56H, vCH2), 6.30 (s, 0.44H, CH), 6.43 (s, 0.56H),
6.81–6.89 (m, 2H, Ar), 6.92–6.98 (m, 2H, Ar), 7.10–7.21 (m,
3H, Ar), 7.25–7.37 (m, 4H, Ar), 7.43–7.61 (m, 2H, Ar) ppm;
13C NMR (CDCl3, 100 MHz, TMS): δ 52.07, 52.31, 53.05,
53.58, 59.84, 60.15, 111.96, 112.16, 126.67, 127.22, 127.36,
127.53, 127.86, 127.87, 128.17, 128.20, 128.25, 128.28, 128.40,
128.69, 128.90, 129.15, 129.38, 129.55, 129.56, 129.63, 129.71,
130.70, 134.63, 135.85, 136.63, 137.19, 138.37, 139.23, 150.98,
151.51, 166.74, 167.49, 175.75, 176.04 ppm; IR (neat) ν 2949,
1805, 1718, 1466, 1262, 1132, 1065, 702 cm−1; MS (ESI) m/z
441.4 (M + Na+). HRMS (MALDI) Calcd for C25H19O4ClNa
requires (M + Na+): 441.0868, Found: 441.0864.
Methyl 2-((3-chlorophenyl)(2-oxo-3-phenyl-2,3-dihydrobenzo-
furan-3-yl)methyl)acrylate 3e. White solid that is a known com-
pound,8 99% yield, 41 mg (syn : anti = 56 : 44); [α]2D0 = −189.6
(c 2.2, CHCl3) for 94% ee (syn) and 90% ee (anti); Enantiomeric
excess was determined by HPLC with a Chiralcel REGIS
column, hexane–iPrOH = 100 : 0.5, 0.5 mL min−1, 230 nm, for
syn product tmajor = 93.710 min, tminor = 68.245 min; for anti
product tmajor = 71.377 min, tminor = 86.127 min; 1H NMR
(400 MHz, CDCl3, TMS): δ 3.46 (s, 1.32H, CH3), 3.67 (s,
1.68H, CH3), 5.33 (s, 0.56H, vCH2), 5.37 (s, 0.44H, vCH2),
5.58 (s, 0.44H, vCH2), 5.60 (s, 0.56H, vCH2), 6.31 (s, 0.44H,
CH), 6.44 (s, 0.56H, CH), 6.67–6.74 (m, 1H, Ar), 6.90 (d, J =
6.8 Hz, 1H, Ar), 7.01–7.18 (m, 4H, Ar), 7.27–7.39 (m, 5H, Ar),
7.47–7.51 (m, 2H, Ar).
Methyl 2-((5-bromo-2-oxo-3-phenyl-2,3-dihydrobenzofuran-3-
yl)(phenyl)methyl)acrylate 3c. Awhite solid, 90% yield, 41 mg,
m.p. 94–95 °C, (syn : anti = 71 : 29); [α]2D0 = −172.7 (c 0.6,
CHCl3) for 97% ee (syn) and 92% ee (anti); Enantiomeric
excess was determined by HPLC with a Chiralcel IC-H column,
hexane–iPrOH = 98 : 2, 0.7 mL min−1, 230 nm, for syn product
Methyl 2-((3-cyanophenyl)(2-oxo-3-phenyl-2,3-dihydrobenzo-
furan-3-yl)methyl)acrylate 3f. A white solid, 84% yield, 34 mg,
m.p. 124–126 °C, (syn : anti = 56 : 44); [α]2D0 = −254.8 (c 1.8,
CHCl3) for 90% ee (syn) and 88% ee (anti); Enantiomeric
excess was determined by HPLC with a Chiralcel IC-H column,
hexane–iPrOH = 93 : 7, 0.5 mL min−1, 230 nm, for syn product
t
major = 19.027 min, tminor = 23.527 min; for anti product tmajor =
1
21.727 min, tminor = 16.977 min. H NMR (400 MHz, CDCl3,
TMS): δ 3.47 (s, 0.87H, CH3), 3.66 (s, 2.13H, CH3), 5.35 (s,
0.71H, vCH2), 5.38 (s, 0.29H, vCH2), 5.55 (s, 0.29H, vCH2),
5.70 (s, 0.71H, vCH2), 6.30 (s, 0.29H, CH), 6.43 (s, 0.71H,
CH), 6.81–7.01 (m, 4H, Ar), 7.13–7.22 (m, 3H, Ar), 7.31–7.36
(m, 3H, Ar), 7.42–7.74 (m, 3H, Ar); 13C NMR (CDCl3,
100 MHz): δ 52.10, 52.32, 53.11, 53.58, 59.81, 60.12, 112.44,
112.64, 116.43, 125.28, 127.24, 127.54, 127.88, 128.21, 128.22,
128.30, 128.72, 128.93, 129.01, 129.54, 129.59, 129.74, 130.10,
130.18, 132.29, 132.56, 134.65, 135.89, 137.22, 138.39, 139.29,
151.50, 152.02, 166.77, 167.50, 175.62, 175.92; IR (neat) ν
2916, 1806, 1719, 1466, 1234, 1135, 1065, 701 cm−1; MS (ESI)
t
major = 55.027 min, tminor = 61.327 min; for anti product tmajor =
1
45.677 min, tminor = 50.477 min; H NMR (400 MHz, CDCl3,
TMS): δ 3.49 (s, 1.32H, CH3), 3.67 (s, 1.68H, CH3), 5.37 (s,
0.56H, vCH2), 5.41 (s, 0.44H, vCH2), 5.63 (d, J = 1.2 Hz,
0.44H, vCH2), 5.71 (s, 0.56H, vCH2), 6.35 (s, 0.44H, CH),
6.48 (s, 0.56H, CH), 6.88–7.08 (m, 2H, Ar), 7.13–7.38 (m, 8H,
Ar), 7.40–7.63 (m, 3H, Ar); 13C NMR (CDCl3, 100 MHz): δ
52.20, 52.41, 52.62, 53.05, 59.24, 59.30, 111.22, 111.85,
111.96, 118.36, 124.17, 124.24, 126.11, 126.79, 127.22, 127.39,
128.06, 128.16, 128.29, 128.33, 128.58, 128.74, 128.77, 128.80,
128.96, 129.37, 129.82, 129.93, 131.00, 131.33, 133.20, 133.23,
134.13, 134.38, 136.03, 137.05, 137.13, 137.59, 138.32, 138.61,
152.52, 152.77, 166.43, 166.95, 176.06, 176.13; IR (neat) ν
2952, 2230, 1800, 1719, 1462, 1271, 1066, 753, 699 cm−1; MS
(ESI) m/z 432.3 (M + Na+, 100). HRMS (ESI) Calcd for
C26H19NO4Na requires (M + Na+) 432.1216, Found: 432.1206.
m/z 485.3 (M
+
Na+, 100). HRMS (ESI) Calcd for
C25H19BrO4Na requires (M + Na+) 485.0366, Found: 485.0359.
Methyl 2-((5-(tert-butyl)-2-oxo-3-phenyl-2,3-dihydrobenzo-
furan-3-yl)(phenyl)methyl)acrylate 3d. A colorless oil, 91%
yield, 40 mg (syn : anti = 63 : 37); [α]2D0 = −134.6 (c 2.0, CHCl3)
7162 | Org. Biomol. Chem., 2012, 10, 7158–7166
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Methyl 2-((4-fluorophenyl)(2-oxo-3-phenyl-2,3-dihydrobenzo-
furan-3-yl)methyl)acrylate 3g. A white solid that is a known
excess was determined by HPLC with a Chiralcel AD-H
column, hexane–iPrOH = 95 : 5, 0.8 mL min−1, 230 nm, for syn
product tmajor = 15.727 min, tminor = 19.227 min; for anti product
compound,8 93% yield, 37 mg (syn : anti = 64 : 36); [α]2D0
=
1
−228.7 (c 1.85, CHCl3) for 92% ee (syn) and 89% ee (anti);
Enantiomeric excess was determined by HPLC with a Chiralcel
AD-H column, hexane–iPrOH = 97 : 3, 0.5 mL min−1, 210 nm,
for syn product tmajor = 17.460 min, tminor = 31.167 min; for anti
product tmajor = 26.322 min, tminor = 43.432 min; 1H NMR
(400 MHz, CDCl3, TMS): δ 3.46 (s, 1.08H, CH3), 3.66 (s,
1.92H, CH3), 5.34 (s, 0.64H, vCH2), 5.38 (s, 0.36H, vCH2),
5.57 (d, J = 1.2 Hz, 0.36H, vCH2), 5.65 (s, 0.64H, vCH2),
6.27 (s, 0.36H, CH), 6.40 (s, 0.64H, CH), 6.76–6.80 (m, 3H,
Ar), 6.92–6.96 (m, 1H, Ar), 6.99–7.16 (m, 2H, Ar), 7.23–7.35
(m, 5H, Ar), 7.46–7.51 (m, 2H, Ar); 19F NMR (CDCl3,
376 MHz, CFCl3): δ −114.83, −114.69.
tmajor = 34.527 min, tminor = 31.077 min; H NMR (400 MHz,
CDCl3, TMS): δ 1.08 (t, J = 6.8 Hz, 1.35H, CH3), 1.18 (t, J =
6.8 Hz, 1.65H, CH3), 3.86–4.00 (m, 0.90H, CH2), 4.03–4.17 (m,
1.10H, CH2), 5.45 (s, 0.55H, vCH2), 5.53 (s, 0.45H, vCH2),
5.65 (d, J = 1.2 Hz, 0.45H, vCH2), 5.72 (s, 0.55H, vCH2),
6.37 (s, 0.45H, CH), 6.49 (s, 0.55H, CH), 6.95–7.06 (m, 3H,
Ar), 7.15–7.37 (m, 6H, Ar), 7.43–7.49 (m, 2H, Ar), 7.61–7.97
(m, 2H, Ar); 13C NMR (CDCl3, 100 MHz): δ 13.88, 13.93,
52.87, 52.91, 59.25, 59.45, 61.34, 61.43, 111.26, 111.28,
122.78, 123.01, 124.15, 124.27, 126.19, 126.79, 127.23, 127.30,
128.10, 128.31, 128.33, 128.88, 129.00, 129.12, 129.83, 129.93,
130.71, 130.75, 136.29, 137.06, 137.93, 138.54, 143.34, 144.99,
146.90, 147.27, 152.53, 152.75, 165.95, 176.13; IR (neat)
ν 2981, 1800, 1716, 1597, 1521, 1347, 1065, 757, 699 cm−1
;
Methyl 2-((4-nitrophenyl)(2-oxo-3-phenyl-2,3-dihydrobenzo-
furan-3-yl)methyl)acrylate 3h. A white solid that is a known
compound,8 98% yield, 42 mg (syn : = 58 : 42); [α]2D0 = −171.4
(c 2.8, CHCl3) for 95% ee (syn) and 92% ee (anti); Enantiomeric
excess was determined by HPLC with a Chiralcel AD-H
column, hexane–iPrOH = 90 : 10, 1.0 mL min−1, 210 nm, for
syn product tmajor = 22.917 min, tminor = 28.935 min; for anti
product tmajor = 51.235 min, tminor = 44.657 min; 1H NMR
(400 MHz, CDCl3, TMS): δ 3.49 (s, 1.26H, CH3), 3.66 (s,
1.74H, CH3), 5.45 (s, 0.58H,vCH2), 5.52 (s, 0.42H,vCH2),
5.65 (d, J = 1.2 Hz, 0.42H,vCH2), 5.75 (s, 0.58H,vCH2), 6.37
(s, 0.42H, CH), 6.49 (s, 0.58H, CH), 6.95–7.05 (m, 3H, Ar),
7.15–7.19 (m, 1H, Ar), 7.22–7.25 (m, 1H, Ar), 7.29–7.38 (m,
4H, Ar), 7.44–7.49 (m, 2H, Ar), 7.95–7.97 (m, 2H, Ar).
MS (ESI) m/z 466.4 (M + Na+, 100). HRMS (ESI) Calcd for
C26H21NO6Na requires (M + Na+) 466.1268, Found: 466.1261.
tert-Butyl 2-((4-nitrophenyl)(2-oxo-3-phenyl-2,3-dihydroben-
zofuran-3-yl)methyl)acrylate 3k. A white solid, 87% yield,
41 mg, m.p. 147–149 °C, (syn : anti = 54 : 46); [α]2D0 = −119.7 (c
1.8, CHCl3) for 91% ee (syn) and 85% ee (anti); Enantiomeric
excess was determined by HPLC with a Chiralcel AD-H
column, hexane–iPrOH = 93 : 7, 0.5 mL min−1, 230 nm, for syn
product tmajor = 17.477 min, tminor = 14.977 min; for anti product
1
tmajor = 19.777 min, tminor = 16.177 min; H NMR (400 MHz,
t
t
CDCl3, TMS): δ 1.22 (s, 4.14H, Bu), 1.34 (s, 4.86H, Bu), 5.41
(s, 0.54H, vCH2), 5.52 (s, 0.46H, vCH2), 5.55 (s, 0.54H,
vCH2), 5.61 (s, 0.46H, vCH2), 6.33 (s, 0.46H, CH), 6.40 (s,
0.54H, CH), 6.90–7.07 (m, 3H, Ar), 7.15–7.49 (m, 8H, Ar),
7.96 (d, J = 7.2 Hz, 2H, Ar); 13C NMR (CDCl3, 100 MHz): δ
27.64, 27.78, 52.41, 52.79, 59.00, 59.71, 81.69, 81.77, 111.18,
111.27, 122.68, 122.90, 124.04, 124.29, 126.33, 126.83, 127.16,
127.31, 127.85, 128.13, 128.25, 128.32, 128.45, 128.93, 129.77,
129.87, 130.66, 130.73, 136.58, 137.04, 139.21, 139.50, 143.72,
145.52, 146.72, 147.14, 152.58, 152.69, 165.00, 165.51, 176.10,
176.29; IR (neat) ν 2978, 1801, 1709, 1604, 1524, 1347, 1146,
1065, 757 cm−1; MS (ESI) m/z 494.5 (M + Na+, 100). HRMS
Ethyl 2-((2-oxo-3-phenyl-2,3-dihydrobenzofuran-3-yl)(p-tolyl)-
methyl)acrylate 3i. A colorless oil, 85% yield, 35 mg (syn : anti
= 56 : 44); [α]2D0 = −187.7 (c 1.2, CHCl3) for 95% ee (syn) and
92% ee (anti); Enantiomeric excess was determined by HPLC
with a Chiralcel OD-H column, hexane–iPrOH = 98 : 2, 1.0 mL
min−1, 210 nm, for syn product tmajor = 14.540 min, tminor
=
=
29.405 min; for anti product tmajor = 33.103 min, tminor
1
42.455 min; H NMR (400 MHz, CDCl3, TMS): δ 1.07 (t, J =
9.6 Hz, 1.32H, CH3), 1.18 (t, J = 9.6 Hz, 1.68H, CH3), 2.20 (s,
1.32H, CH3), 2.24 (s, 1.68H, CH3), 3.75–3.96 (m, 0.88H, CH2),
4.00–4.17 (m, 1.12H, CH2), 5.35 (s, 0.56H, vCH2), 5.37 (s,
0.44H, vCH2), 5.55 (s, 0.44H, vCH2), 5.56 (s, 0.56H, vCH2),
6.25 (s, 0.44H, CH), 6.38 (s, 0.56H, CH), 6.67–6.84 (m, 2H,
Ar), 6.88–7.04 (m, 3H, Ar), 7.23–7.37 (m, 5H, Ar), 7.48–7.66
(m, 2H, Ar); 13C NMR (CDCl3, 100 MHz): δ 13.86, 13.95,
20.99, 21.43, 52.65, 53.21, 59.51, 59.59, 60.95, 61.09, 110.84,
111.00, 123.67, 123.72, 125.26, 126.85, 127.41, 127.47, 127.54,
127.71, 127.83, 127.96, 128.19, 128.36, 128.48, 128.61, 128.73,
128.99, 129.23, 129.45, 129.50, 129.71, 132.06, 133.99, 136.64,
136.90, 137.15, 137.91, 139.13, 139.92, 152.69, 153.17, 166.39,
167.35, 176.50, 176.79; IR (neat) ν 2980, 1796, 1712, 1460,
1232, 1127, 1061, 734, 696 cm−1; MS (ESI) m/z 413.1 (M + H+,
100). HRMS (ESI) Calcd for C27H25O4 requires (M + H+)
413.1675, Found: 413.1738.
(MALDI) Calcd for C28H25NO6Na requires (M
494.1579, Found: 494.1574.
+
Na+)
General procedure for the preparation of 5 from the reaction of
4a with 2e in the presence of LB1, using 5a as an example
To a mixture of 1a (0.10 mmol, 31.0 mg), 2a (0.20 mmol,
67.0 mg) and LB1 (10.0 mg, 0.02 mmol) was added 1.0 mL of
toluene at room temperature. The reaction solution was moni-
tored by TLC. After the reaction was complete, the solution was
concentrated under reduced pressure and the residue was further
purified by silica gel column chromatography (EtOAc–PE =
1 : 10) to give the target product 5a.
tert-Butyl 3-(2-(methoxycarbonyl)-1-(4-nitrophenyl)allyl)-2-
oxo-3-phenylindoline-1-carboxylate 5a. A white solid, 91%
Ethyl 2-((4-nitrophenyl)(2-oxo-3-phenyl-2,3-dihydrobenzo-
furan-3-yl)methyl)acrylate 3j. A yellowish solid, 95% yield,
42 mg, m.p. 65–67 °C, (syn : anti = 55 : 45); [α]2D0 = −229.1 (c
2.0, CHCl3) for 93% (syn) and 88% (anti) ee; Enantiomeric
yield, 48 mg, m.p. 90–92 °C, (anti : syn = 67 : 33); [α]D20
=
−200.0 (c 0.1, CHCl3) for 98% ee (anti) and 89% ee (syn);
Enantiomeric excess was determined by HPLC with a Chiralcel
This journal is © The Royal Society of Chemistry 2012
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AD-H column, hexane–iPrOH = 80 : 20, 0.7 mL min−1, 230 nm,
for anti product tmajor = 7.057 min, tminor = 8.517 min; for syn
product tmajor = 9.900 min, tminor = 17.785 min; 1H NMR
(400 MHz, CDCl3, TMS): δ 1.56 (s, 9.00H, for syn and anti,
Boc), 3.48 (s, 0.99H, CH3), 3.64 (s, 2.01H, CH3), 5.40 (s,
0.67H, vCH2), 5.53 (s, 0.33H, vCH2), 5.59 (s, 0.33H, vCH2),
5.97 (s, 0.67H, vCH2), 6.32 (s, 0.33H, CH), 6.49 (s, 0.67H,
CH), 6.99 (d, J = 8.8 Hz, 2H, Ar), 7.13–7.21 (m, 1H, Ar),
7.25–7.35 (m, 5H, Ar), 7.39–7.44 (m, 2H, Ar), 7.60–7.66 (m,
1H, Ar), 7.91 (d, J = 8.8 Hz, 2H, Ar); 13C NMR (100 MHz,
CDCl3): δ 27.88, 28.03, 52.15, 52.31, 53.17, 53.26, 60.15,
60.28, 84.76, 115.05, 115.19, 122.54, 122.72, 124.17, 124.27,
125.53, 126.60, 127.57, 127.80, 127.86, 127.96, 128.60, 128.80,
128.95, 129.03, 129.20, 130.70, 130.82, 136.95, 137.36, 137.99,
138.74, 138.94, 139.60, 143.88, 145.37, 146.75, 147.09, 148.40,
166.75, 167.25, 175.19, 175.43; IR (neat) ν 2982, 1793, 1762,
1719, 1604, 1522, 1251, 1147, 738 cm−1; MS (ESI) m/z 551.4
(M + Na+, 100). HRMS (ESI) Calcd for C30H28N2O7Na requires
(M + Na+) 551.1797, Found: 551.1789.
3.69H, Boc), 1.57 (s, 5.31H, Boc), 3.44 (s, 1.23H, CH3), 3.64
(s, 1.77H, CH3), 5.28 (s, 0.59H, vCH2), 5.39 (s, 0.41H,
vCH2), 5.51 (d, J = 1.2 Hz, 0.41H, vCH2), 5.88 (s, 0.59H,
vCH2), 6.22 (s, 0.41H, CH), 6.41 (s, 0.59H, CH), 6.72–6.89
(m, 2H, Ar), 6.98–7.14 (m, 3H, Ar), 7.22–7.37 (m, 5H, Ar),
7.42–7.46 (m, 2H, Ar), 7.59–7.73 (m, 1H, Ar); 13C NMR
(100 MHz, CDCl3): δ 27.94, 27.98, 51.96, 52.19, 52.88, 53.09,
60.25, 60.48, 84.37, 84.45, 114.93, 115.14, 123.85, 124.06,
125.74, 126.99, 127.65, 127.70, 127.77, 127.83, 127.91, 128.07,
128.37, 128.61, 128.69, 128.96, 131.12, 131.20, 132.94, 133.28,
134.34, 135.87, 137.10, 138.08, 138.51, 139.07, 139.66, 140.00,
148.55, 148.61, 167.03, 167.82, 175.32, 175.83; IR (neat) ν
2927, 1793, 1762, 1735, 1491, 1368, 1287, 1148, 738 cm−1
MS (ESI) m/z 494.5 (M + Na+, 100). HRMS (ESI) Calcd for
;
C30H28ClNO5Na requires (M
540.1548.
+
Na+) 540.1563, Found:
tert-Butyl 3-(1-(4-fluorophenyl)-2-(methoxycarbonyl)allyl)-2-
oxo-3-phenylindoline-1-carboxylate 5e. A white solid that is a
known compound.7 86% yield, 43 mg (anti : syn = 58 : 42); [α]2D0
= −236.0 (c 1.9, CHCl3) for 93% ee (anti) and 85% ee (syn);
Enantiomeric excess was determined by HPLC with a Chiralcel
OD-H column, hexane–iPrOH = 99 : 1, 1.0 mL min−1, 254 nm,
for anti product tmajor = 6.793 min, tminor = 35.273 min; for syn
product tmajor = 8.958 min, tminor = 52.310 min; 1H NMR
(400 MHz, CDCl3, TMS) δ 1.54 (s, 3.78H, Boc), 1.57 (s, 5.22H,
Boc), 3.44 (s, 1.26H, CH3), 3.64 (s, 1.74H, CH3), 5.30 (s,
0.58H, vCH2), 5.40 (s, 0.42H, vCH2), 5.52 (d, J = 1.2 Hz,
0.42H, vCH2), 5.90 (s, 0.58H, vCH2), 6.21 (s, 0.42H, CH),
6.40 (s, 0.58H, CH), 6.71–6.79 (m, 3H, Ar), 6.88–7.14 (m, 2H,
Ar), 7.22–7.36 (m, 5H, Ar), 7.42–7.47 (m, 2H, Ar), 7.61–7.72
(m, 1H, Ar).
tert-Butyl 3-(1-(3-cyanophenyl)-2-(methoxycarbonyl)allyl)-2-
oxo-3-phenylindoline-1-carboxylate 5b. A white solid that is a
known compound.7 86% yield, 43 mg (anti : syn = 62 : 38); [α]2D0
= −98.0 (c 0.15, CHCl3) for 94% ee (anti) and 80% ee (syn);
Enantiomeric excess was determined by HPLC with a Chiralcel
AD-H column, hexane–iPrOH = 90 : 10, 1.0 mL min−1, 254 nm,
for anti product tmajor = 5.607 min, tminor = 6.290 min; for syn
product tmajor = 7.147 min, tminor = 8.542 min; 1H NMR
(400 MHz, CDCl3, TMS): δ 1.57 (s, 3.42H, Boc), 1.59 (s,
5.58H, Boc), 3.49 (s, 1.14H, CH3), 3.65 (s, 1.86H, CH3), 5.32
(s, 0.62H, vCH2), 5.43 (s, 0.38H, vCH2), 5.59 (d, J = 1.6 Hz,
0.38H, vCH2), 5.98 (s, 0.62H, vCH2), 6.32 (s, 0.38H, CH),
6.48 (s, 0.62H, CH), 6.95–7.03 (m, 1H, Ar), 7.10–7.17 (m, 2H,
Ar), 7.22–7.45 (m, 9H, Ar), 7.59–7.71 (m, 1H, Ar).
tert-Butyl
3-(2-(methoxycarbonyl)-1-(p-tolyl)allyl)-2-oxo-3-
phenylindoline-1-carboxylate 5f. A white solid, 81% yield,
39 mg, m.p. 82–84 °C, (anti : syn = 60 : 40); [α]2D0 = −89.5 (c
1.2, CHCl3) for 95% ee (anti) and 91% ee (syn); Enantiomeric
excess was determined by HPLC with a Chiralcel IC-H column,
hexane–iPrOH = 90 : 10, 0.7 mL min−1, 214 nm, for anti
product tmajor = 11.627 min, tminor = 25.043 min; for syn product
tert-Butyl 3-(1-(3-chlorophenyl)-2-(methoxycarbonyl)allyl)-2-
oxo-3-phenylindoline-1-carboxylate 5c. A white solid that is a
known compound.7 93% yield, 48 mg (anti : syn = 51 : 49); [α]2D0
= −254.6 (c 1.85, CHCl3) for 92% ee (anti) and 87% ee (syn);
Enantiomeric excess was determined by HPLC with a Chiralcel
OD-H column, hexane–iPrOH = 95 : 5, 0.9 mL min−1, 254 nm,
for anti product tmajor = 4.915 min, tminor = 14.830 min; for syn
product tmajor = 5.487 min, tminor = 16.798 min; 1H NMR
(400 MHz, CDCl3, TMS): δ 1.55 (s, 4.41H, Boc), 1.58 (s,
4.59H, Boc), 3.46 (s, 1.47H, CH3), 3.65 (s, 1.53H, CH3), 5.29
(s, 0.51H, vCH2), 5.39 (s, 0.49H, vCH2), 5.54 (d, J = 1.2 Hz,
0.49H, vCH2), 5.88 (s, 0.51H, vCH2), 6.26 (s, 0.49H, CH),
6.43 (s, 0.51H, CH), 6.64–6.82 (m, 1H, Ar), 6.94–7.15 (m, 4H,
Ar), 7.23–7.36 (m, 5H, Ar), 7.42–7.46 (m, 2H, Ar), 7.59–7.74
(m, 1H, Ar).
1
tmajor = 15.877 min, tminor = 22.543 min; H NMR (300 MHz,
CDCl3, TMS): δ 1.52 (s, 3.60H, Boc), 1.57 (s, 5.40H, Boc),
2.19 (s, 1.20H, CH3), 2.22 (s, 1.80H, CH3), 3.42 (s, 1.20H,
CH3), 3.64 (s, 1.80H, CH3), 5.31 (s, 0.60H, vCH2), 5.38 (s,
0.40H, vCH2), 5.51 (s, 0.40H, vCH2), 5.79 (s, 0.60H, vCH2),
6.18 (s, 0.40H, CH), 6.38 (s, 0.60H, CH), 6.66–6.79 (m, 2H,
Ar), 6.84–7.14 (m, 3H, Ar), 7.25–7.34 (m, 5H, Ar), 7.35–7.51
(m, 2H, Ar), 7.62–7.74 (m, 1H, Ar); 13C NMR (CDCl3,
75 MHz): δ 20.97, 27.93, 27.99, 51.89, 52.15, 53.02, 53.51,
60.33, 60.57, 84.03, 84.17, 114.82, 115.06, 123.65, 123.84,
126.13, 127.24, 127.42, 127.55, 127.63, 127.86, 128.22, 128.46,
128.72, 129.60, 129.69, 132.44, 134.05, 136.54, 136.79, 137.27,
138.67, 138.84, 139.18, 140.18, 140.26, 148.74, 167.21, 168.24,
175.43, 176.05; IR (neat) ν 2981, 1759, 1724, 1463, 1345,
1287, 1146, 1098, 734, 697 cm−1; MS (ESI) m/z 520.2
(M + Na+, 100). HRMS (ESI) Calcd for C31H31O5Na requires
(M + Na+) 520.2202, Found: 520.2086.
tert-Butyl 3-(1-(4-chlorophenyl)-2-(methoxycarbonyl)allyl)-2-
oxo-3-phenylindoline-1-carboxylate 5d. A white solid that is a
known compound.7 92% yield, 47 mg, m.p. 134–136 °C, (anti :
syn = 59 : 41); [α]2D0 = −203.0 (c 0.1, CHCl3) for 93% ee (anti)
and 88% ee (syn); Enantiomeric excess was determined by
HPLC with a Chiralcel AD-H column, hexane–iPrOH = 90 : 10,
0.7 mL min−1, 230 nm, for anti product tmajor = 6.652 min, tminor
= 7.385 min; for syn product tmajor = 7.985 min, tminor
=
tert-Butyl 3-(2-(methoxycarbonyl)-1-phenylallyl)-2-oxo-3-phe-
nylindoline-1-carboxylate 5g. A white solid that is a known
13.052 min; 1H NMR (400 MHz, CDCl3, TMS): δ 1.54 (s,
7164 | Org. Biomol. Chem., 2012, 10, 7158–7166
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compound.7 89% yield, 42 mg (anti : syn = 57 : 43); [α]2D0
=
Ar), 7.04–7.12 (m, 3H, Ar), 7.28–7.38 (m, 4H, Ar), 7.41–7.47
(m, 2H, Ar), 7.62–7.72 (m, 1H, Ar).
−196.0 (c 0.1, CHCl3) for 93% ee (anti) and 89% ee (syn);
Enantiomeric excess was determined by HPLC with a Chiralcel
OD-H column, hexane–iPrOH = 95 : 5, 0.9 mL min−1, 254 nm,
for anti product tmajor = 6.295 min, tminor = 12.578 min; for syn
product tmajor = 8.940 min, tminor = 18.340 min; 1H NMR
(400 MHz, CDCl3, TMS): δ 1.52 (s, 3.87H, Boc), 1.57 (s,
5.13H, Boc), 3.43 (s, 1.29H, CH3), 3.63 (s, 1.71H, CH3), 5.34
(s, 0.57H, vCH2), 5.42 (s, 0.43H, vCH2), 5.53 (d, J = 0.8 Hz,
0.43H, vCH2), 5.85 (s, 0.57H, vCH2), 6.22 (s, 0.43H, CH),
6.40 (s, 0.57H, CH), 6.79–6.92 (m, 2H, Ar), 6.95–7.12 (m, 4H,
Ar), 7.24–7.33 (m, 5H, Ar), 7.44–7.50 (m, 2H, Ar), 7.61–7.72
(m, 1H, Ar).
tert-Butyl 3-(2-(methoxycarbonyl)-1-phenylallyl)-5-methyl-2-
oxo-3-phenylindoline-1-carboxylate 5k. A colorless oil that is a
known compound.7 78% yield, 38 mg (anti : syn = 64 : 36); [α]2D0
= −32.7 (c 0.25, CHCl3) for 96% ee (anti) and 94% ee (syn);
Enantiomeric excess was determined by HPLC with a Chiralcel
AD-H column, hexane–iPrOH = 95 : 5, 1.0 mL min−1, 254 nm,
for anti product tmajor = 7.887 min, tminor = 11.732 min; for syn
product tmajor = 9.095 min, tminor = 13.745 min; 1H NMR
(400 MHz, CDCl3, TMS): δ 1.51 (s, 3.24H, Boc), 1.55 (s,
5.78H, Boc), 2.29 (s, 1.92H, CH3), 2.42 (s, 1.08H, CH3), 3.44
(s, 1.08H, CH3), 3.64 (s, 1.92H, CH3), 5.31 (s, 0.64H, vCH2),
5.40 (s, 0.36H, vCH2), 5.53 (d, J = 1.2 Hz, 0.36H, vCH2),
5.90 (s, 0.64H, vCH2), 6.22 (s, 0.36H, CH), 6.40 (s, 0.64H,
CH), 6.73–6.93 (m, 2H, Ar), 7.03–7.14 (m, 4H, Ar), 7.24–7.33
(m, 4H, Ar), 7.40–7.59 (m, 3H, Ar).
tert-Butyl 3-(4-fluorophenyl)-3-(2-(methoxycarbonyl)-1-phenyl-
allyl)-2-oxoindoline-1-carboxylate 5h. A white solid that is a
known compound.7 82% yield, 41 mg (anti : syn = 60 : 40); [α]2D0
= −147.7 (c 1.1, CHCl3) for 92% ee (anti) and 89% ee (syn);
Enantiomeric excess was determined by HPLC with a Chiralcel
AD-H column, hexane–iPrOH = 95 : 5, 1.0 mL min−1, 254 nm,
for anti product tmajor = 5.468 min, tminor = 7.813 min; for syn
product tmajor = 5.998 min, tminor = 8.328 min; 1H NMR
(400 MHz, CDCl3, TMS): δ 1.52 (s, 3.60H, Boc), 1.57 (s,
5.40H, Boc), 3.46 (s, 1.20H, CH3), 3.64 (s, 1.80H, CH3), 5.30
(s, 0.60H, vCH2), 5.35 (s, 0.40H, vCH2), 5.52 (s, 0.40H,
vCH2), 5.72 (s, 0.60H, vCH2), 6.22 (s, 0.40H, CH), 6.39 (s,
0.60H, CH), 6.78–6.89 (m, 3H, Ar), 6.94–7.14 (m, 5H, Ar),
7.25–7.37 (m, 2H, Ar), 7.41–7.49 (m, 2H, Ar), 7.59–7.73 (m,
1H, Ar).
Acknowledgements
We thank the Shanghai Municipal Committee of Science and
Technology (11JC1402600), National Basic Research Program
of China (973)-2009CB825300, the Fundamental Research
Funds for the Central Universities and the National Natural
Science Foundation of China for financial support (21072206,
20472096, 20872162, 20672127, 21121062 and 20732008).
References
tert-Butyl 3-(2-(methoxycarbonyl)-1-phenylallyl)-2-oxo-3-(p-
tolyl)indoline-1-carboxylate 5i. A white solid that is a known
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compound.7 76% yield, 38 mg (anti : syn = 61 : 39); [α]2D0
=
−177.8 (c 1.85, CHCl3) for 92% ee (anti) and 88% ee (syn);
Enantiomeric excess was determined by HPLC with a Chiralcel
AD-H column, hexane–iPrOH = 95 : 5, 0.8 mL min−1, 254 nm,
for anti product tmajor = 6.902 min, tminor = 8.437 min; for syn
product tmajor = 7.322 min, tminor = 18.025 min; 1H NMR
(400 MHz, CDCl3, TMS): δ 1.51 (s, 3.51H, Boc), 1.56 (s,
5.49H, Boc), 2.29 (s, 1.17H, CH3), 2.31 (s, 1.83H, CH3), 3.43
(s, 1.13H, CH3), 3.63 (s, 1.87H, CH3), 5.31 (s, 0.61H, vCH2),
5.39 (s, 0.39H, vCH2), 5.54 (d, J = 1.2 Hz, 0.39H, vCH2),
5.86 (s, 0.61H, vCH2), 6.22 (s, 0.39H, CH), 6.40 (s, 0.61H,
CH), 6.81 (d, J = 7.2 Hz, 1H, Ar), 6.92 (t, J = 8.4 Hz, 1H, Ar),
7.01–7.14 (m, 6H, Ar), 7.22–7.36 (m, 4H, Ar), 7.60–7.71 (m,
1H, Ar).
tert-Butyl 5-fluoro-3-(2-(methoxycarbonyl)-1-phenylallyl)-2-
oxo-3-phenylindoline-1-carboxylate 5j. A white soli that is a
known compound.7 82% yield, 41 mg (anti : syn = 56 : 44); [α]2D0
= −155.0 (c 0.25, CHCl3) for 97% ee (anti) and 84% ee (syn);
Enantiomeric excess was determined by HPLC with a Chiralcel
OD-H column, hexane–iPrOH = 95 : 5, 0.9 mL min−1, 254 nm,
for anti product tmajor = 5.585 min, tminor = 12.665 min; for syn
product tmajor = 6.605 min, tminor = 9.740 min; 1H NMR
(400 MHz, CDCl3, TMS): δ 1.52 (s, 3.96H, Boc), 1.56 (s,
5.04H, Boc), 3.44 (s, 1.32H, CH3), 3.64 (s, 1.68H, CH3), 5.31
(s, 0.56H, vCH2), 5.41 (s, 0.44H, vCH2), 5.49 (d, J = 1.6 Hz,
0.44H, vCH2), 5.87 (s, 0.56H, vCH2), 6.23 (s, 0.44H, CH),
6.41 (s, 0.56H, CH), 6.67–6.83 (m, 2H, Ar), 6.91–6.96 (m, 1H,
This journal is © The Royal Society of Chemistry 2012
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7166 | Org. Biomol. Chem., 2012, 10, 7158–7166
This journal is © The Royal Society of Chemistry 2012