Optically active 1,1′-Spirobiindane-7,7′-diol (SPINOL)-based phosphoric acids as highly enantioselective catalysts for asymmetric organocatalysis

Article abstract of DOI:10.1021/jo200302x

The synthesis and application of a series of optically active 1,1′-spirobiindane-7,7′-diol (SPINOL)-based phosphoric acids are described. These SPINOL-based phosphoric acids were prepared from (R)-SPINOL in three steps and exhibited excellent enantioselec

Full text of DOI:10.1021/jo200302x

NOTE
pubs.acs.org/joc
Optically Active 1,10-Spirobiindane-7,70-diol (SPINOL)-Based
Phosphoric Acids as Highly Enantioselective Catalysts for Asymmetric
Organocatalysis
Chun-Hui Xing, Yuan-Xi Liao, Jaclynn Ng, and Qiao-Sheng Hu*
Department of Chemistry, College of Staten Island and the Graduate Center of the City University of New York, Staten Island,
New York 10314, United States
S Supporting Information
b
ABSTRACT: The synthesis and application of a series of
optically active 1,10-spirobiindane-7,70-diol (SPINOL)-based
phosphoric acids are described. These SPINOL-based phos-
phoric acids were prepared from (R)-SPINOL in three steps
and exhibited excellent enantioselectivities for the reactions of
indoles with aldimines and β,γ-unsaturated-R-ketoesters. Our
study provides a family of promising chiral phosphoric acids to
the asymmetric organocatalysis toolbox.
symmetric organocatalysis, the use of optically active organic
compounds as chiral catalysts, has recently attracted much
units for chiral cyclic phosphoric acids and the rigidity of the
spirocyclic framework may render optically active SPINOL-
based phosphoric acids and analogues, as represented by (R)-2
(Chart 2), more enantioselective than reported axially chiral diol-
based phosphoric acids and analogues. Prompted by recent
reports from List and Wang,34 in this communication, we
disclose our results on the preparation of SPINOL-based phos-
phoric acids and their application as highly active and enantio-
selective catalysts for the reaction of indoles with aldimines and
β,γ-unsaturated-R-ketoesters.
Our preparation of optically active SPINOL-based phosphoric
acids 2 started with (R)-SPINOL (1)29ꢀ31 (Scheme 1). As shown
in Scheme 1, reaction of (R)-SPINOL (1) with 2.05 equiv of N-
bromosuccinimide (NBS) at ꢀ20 °C selectively yielded (R)-6,60-
dibromoSPINOL 3 in 70% yield. Pd-catalyzed cross-coupling
reactions of (R)-6,60-dibromoSPINOL 3 with arylboronic acids35
occurred smoothly to yield 6,60-diaryl-substituted SPINOLs (R)-
4aꢀf in high yields. Reaction of (R)-4aꢀf and (R)-3 with POCl3
followed by hydrolysis yielded 6,60-diaryl-substituted SPINOL-
based phosphoric acids (R)-2aꢀg in moderate to good yields.
Phosphoric acids (R)-2aꢀg are soluble in common organic
solvents and are air/moisture-stable.
A
attention.1ꢀ7 Chiral cyclic phosphoric acids, which contain both
a Brønsted acidic site and Lewis basic site, constitute a unique
type of organocatalysts.8ꢀ12 The use of chiral cyclic phosphoric
acids as catalysts for asymmetric organocatalysis was first re-
ported by Terada and Akiyama in 2004.13,14 Since then, the
tremendous potential of chiral cyclic phosphoric acids was
recognized and a number of chiral diol-based phosphoric acids
have been developed (Chart 1).8ꢀ28 Axially chiral diol-based,
including 1,10-binaphthyl(BINOL)-based, phosphoric acids AꢀC
were found to be the most promising chiral phosphoric acids.
While impressive results have been obtained with reported
cyclic phosphoric acids as asymmetric organocatalysts, there exists
ample room for further development of chiral cyclic phosphoric
acids as organocatalysts. For example, the enantioselectivities of
reported chiral phosphoric acids and analogues for a number of
reactions are not high (ranging from 60% ee to low 90% ee). On
the basis of the consideration that the unsatisfactory enantios-
electivity for reported chiral phosphoric acids and analogues might
in part be due to the conformational flexibility of their axially chiral
diol units, such as the BINOL unit, we reasoned that chiral
phosphoric acids based on more rigid chiral backbones might be
more enantioselective than reported phosphoric acids and analogues.
C2-Symmetrical 1,10-spirobiindane-7,70-diol (SPINOL) (1)29ꢀ31
and its derivatives (Chart 2),32,33 which possess very rigid chiral
framework, have been demonstrated to exhibit high enantios-
electivities for transition metal-catalyzed asymmetric reactions.32,33
Significantly, SPINOL-based ligands exhibited higher enantios-
electivities than the corresponding ligands with axially chiral
backbones in most of these reactions, suggesting the unique
chiral inducing ability of spirocyclic structures. We thus envision
that C2-symmetrical SPINOLs might be excellent chiral diol
Optically active SPINOL-based phosphoric acids (R)-2aꢀg
were then tested as organocatalysts for the FriedelꢀCrafts
reaction of indoles with aldimines.36ꢀ38 Such a BINOL-based
phosphoric acid-catalyzed reaction was reported by You.36 Good
to excellent enantioselectivity was obtained with 10 mol % of
catalyst loading at ꢀ60 °C. We found that while (R)-2g showed a
moderate enantioselectivity (Table 1, entry 7), (R)-2aꢀf ex-
hibited good to excellent enantioselectivities for the reaction
Received: February 11, 2011
Published: April 05, 2011
r
2011 American Chemical Society
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|

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NOTE
(Table 1, entries 1ꢀ6), with 2c displaying the highest one (Table 1,
entry 3). Further testing showed that ClCH2CH2Cl was the best
solvent (Table 1, entries 3, 8, and 9). We found that even with 1
mol % of catalyst loading the reaction still occurred with high
enantioselectivity (Table 1, entry 10). By carrying out the reaction
at 0 °C, 98% ee was observed (Table 1, entry 11). In the reported
BINOL-based phosphoric catalyst system, this same enantios-
electivity was achieved by employing 10 mol % of BINOL-based
phosphoric acid catalyst at ꢀ60 °C.36 It should be noted that in
BINOL-based phosphoric acid catalyst system, only 75% ee was
observed with 2 mol % of catalyst loading.14 Under otherwise
identical reaction condition, a much higher enantioselectivity
(94% ee) was observed with SPINOL-based phosphoric acid
2c as the catalyst (Table 1, entry 12). We also examined several
other aldimines and our results are listed in Table 2. As shown in
Table 2, high enantioselectivity (g97% ee) was universally observed
with a 2 mol % of catalyst loading. Significantly, excellent enantios-
electivity was also obtained for substrates where lower enantios-
electivities were observed with BINOL-based phosphoric acids
as catalysts (Table 2, entries 3, 5, and 6). In addition, it was found
that excellent enantioselectivity was observed even with the use
of 1.05 equiv of indole (Table 2, entries 13 and 14). These results
showed that SPINOL-based phosphoric acids are highly efficient
organocatalysts, with enantioselectivity comparable to or higher
than reported chiral phosphoric acids.
Chart 1. Reported Chiral Diol-Based Phosphoric Acids
Scheme 1. Preparationof(R)-SPINOL-Based Phosphoric Acids
Chart 2. 1,10-Spirobiindane-7,70-diol (SPINOL) (1), Its
Derivatives, and SPINOL-Based Phosphoric Acids (2)
Table 1. SPINOL-Based Phosphoric Acid-Catalyzed Reaction of Indole with Benzaldiminea
entry
catalyst
catalyst loading (mol %)
solvent
CH2Cl2
temp
rt
convb (%)
ee (%)c
1
2
(R)-2a
(R)-2b
(R)-2c
(R)-2d
(R)-2e
(R)-2f
(R)-2g
(R)-2c
(R)-2c
(R)-2c
(R)-2c
(R)-2c
10
2
84
69
96
80
84
86
97.5
99
99
96
99
99
91.5
89.5
93
CH2Cl2
rt
3
2
CH2Cl2
rt
4
2
CH2Cl2
rt
86
5
2
CH2Cl2
rt
79
6
2
CH2Cl2
rt
75
7
10
2
CH2Cl2
rt
50
8
ClCH2CH2Cl
toluene
rt
97.5
92
9
2
rt
10
11
12
1
ClCH2CH2Cl
ClCH2CH2Cl
toluene
rt
97
d
2
0 °C
ꢀ60 °C
98.
2
94.(75)e,f
a Reaction conditions: indole (3.0 equiv), imine (1.0 equiv). b Based on 1H NMR analysis. c Based on HPLC (Chiracel OD column) analysis. d Reaction
time: 2 h. e Reaction time: 42 h. f In parentheses: reported ee value with 2 mol % of BINOL-based phosphoric acids in toluene at ꢀ60 °C, see ref 36.
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NOTE
Table 2. SPINOL-Based Phosphoric Acid (R)-2c-Catalyzed
FriedelꢀCrafts Reaction of Indoles with Aldiminesa
Table 3. SPINOL-Based Phosphoric Acid-Catalyzed Reactions
of Indole with a β,γ-Unsaturated-r-ketoestera
entry
R
Ar
yield (%)b
ee (%)c
entry
cat.
cat. loading (mol %)
solvent
temp
rt
ee (%)b
1
2
H
H
H
H
H
H
Br
Br
Br
Br
Br
Br
H
H
Ph
98
98 (98)d
97 (99)d
99 (82)d
99
99 (94)d
99.5 (89)d
99 (98)d
97
1
2
(R)-2a
(R)-2b
(R)-2c
(R)-2d
(R)-2e
(R)-2f
(R)-2b
(R)-2b
(R)-2b
(R)-2b
(R)-2b
(R)-2b
(R)-2b
5
5
5
5
5
5
5
5
5
2
2
2
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
81
90
4-CH3C6H4
4-BrC6H4
3-BrC6H4
4-ClC6H4
3-NO2C6H4
Ph
95
rt
rt
rt
rt
rt
rt
rt
3
99
3
58
4
94.5
98
4
61
5
5
37
6
97
6
76
7
97
7
89
8
4-CH3C6H4
4-BrC6H4
3-BrC6H4
4-ClC6H4
3-NO2C6H4
4-BrC6H4
4-BrC6H4
92
8
toluene
85
9
97
99
9
(CH2Cl)2 rt
91.5
10
11
12
13
14
94
99
10
11
12
13
(CH2Cl)2 rt
92
95
98
(CH2Cl)2 0 °C
(CH2Cl)2 ꢀ10 °C
(CH2Cl)2 ꢀ20 °C
93c
94c
94.5c
93
99.5
99e
99f
94.5
90
a Reaction conditions: indole (1.5 equiv), β,γ-unsaturated-R-ketoester
a Reaction conditions: indole (3.0 equiv), imine (1.0 equiv), 2 mol %
phosphoric acid 2c, ClCH2CHC2Cl, 0 °C, 2 h. b Isolated yields. c Based
on HPLC (Chiracel OD or AD-H column) analysis. d In parentheses:
reported ee value with 10 mol % of BINOL-based phosphoric acids at
ꢀ60 °C, see ref 36. e 1.2 equiv of indole was used. f 1.05 equiv of indole
was used.
(1.0 equiv), 99% conversion was observed for all entries. b Based on
c
HPLC (Chiracel OD or AD-H column) analysis. 3.0 equiv of indole
was used.
Table 4. SPINOL-Based Phosphoric Acid-Catalyzed Reactions
of Indoles with β,γ-Unsaturated-r-ketoestersa
We have also tested the reaction of indoles with β,γ-unsatu-
rated-R-ketoesters.39ꢀ43 This reaction was chosen because it
involves the activation of the carbonyl group, and it was reported
that BINOL-based phosphoric acids cannot catalyze it. More
acidic N-triflylphosphoramides39 or a binary BINOL-based phos-
phoric acidꢀMgF2 catalyst system were needed to realized this
reaction.40 We found not only SPINOL-based phosphoric acids
(R)-2aꢀe can catalyze the reaction (Table 3, entries 1ꢀ5), but
also a 90% ee was observed with (R)-2b as the catalyst (Table 3,
entry 2). Further testing showed that with 2 mol % of phosphoric
acid (R)-2b, ClCH2CH2Cl as the solvent at ꢀ20 °C, a 94.5% ee
could be obtained. The highest percent ee reported for this
substrate with chiral phosphoric acids/phosphoramides as cata-
lysts was 90% ee and was achieved by using 2 mol % BINOL-based
phosphoric acids and 0.5 mol % MgF2 at ꢀ70 °C.40 We also
examined other β,γ-unsaturated-R-ketoesters and our results are
listed in Table 4. We found that excellent enantioselectivity, higher
than reported results with BINOL-based phosphoramides or
phosphoric acidꢀMgF2 as catalysts, was observed (Table 4).
For a comparison purpose, an addition reaction with 2b as the
catalyst was also examined under the reaction condition reported
by Chen (toluene, ꢀ70 °C).40 We found higher enantioselectivity
was observed for 2b (93% ee) than BINOL-based phosphoric
acidꢀMgF2 catalyst (83% ee)40 (Table 4, entry 7). These results
also showed that SPINOL-based phosphoric acids are a family of
promising chiral phosphoric acids, with their enantioselectivity
higher than those of BINOL-based phosphoric acids.
entry
R
R0
yield (%)b
ee (%)c
1
2
3
4
5
6
7
H
H
H
Br
Br
H
H
H
84
94.5 (90)d
98 (94)d
94 (87)d
91
2-F
96
4-Me
H
89.5
82
2-F
92
97
4-Cl
4-Cl
94
94 (83)d
93 (83)d
e
84.
a Reaction conditions: indole (3.0 equiv), β,γ-unsaturated-R-ketoester
(1.0 equiv). b Isolated yields. c Based on HPLC (Chiracel OD or AD-H
column) analysis. d In parentheses: reported ee for β,γ-unsaturated-R-
ketoesters (methyl esters) with 2 mol % of BINOL-based phosphoric
acidꢀ0.5 mol % of MgF2 catalyst at ꢀ70 °C, see ref 40. e The reaction
was carried out in toluene at ꢀ70 °C for 48 h.
acids more enantioselective than reported axially chiral diol-
based phosphoric acids, a series of optically active (R)-SPINOL-
based phosphoric acids were prepared from readily available (R)-
SPINOL in three steps. These SPINOL-based phosphoric acids
In summary, based on the consideration that the rigidity of the
spirocyclic framework may render SPINOL-based phosphoric
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NOTE
were employed as organocatalysts for the reactions of indoles with
aldimines and β,γ-unsaturated-R-ketoesters. They exhibited excel-
lent enantioselectivity in these reactions, comparable to or higher
than those reported for phosphoric acids. Our study adds a new
family of promising chiral phosphoric acids to the asymmetric
organocatalysis toolbox and paves the road for the development of
other SPINOL-based phosphoric acids and related Brønsted acidic
analogues such as SPINOL-based N-triflylphosphoramides.44ꢀ47
Work toward this direction is actively underway.
7.44ꢀ7.48 (m, 4H), 7.30 (d, J = 7.8 Hz, 2H), 6.99 (d, J = 7.8 Hz, 4H),
5.20 (s, 2H), 3.08ꢀ3.16 (m, 4H), 2.39ꢀ2.50 (m, 4H); 13C NMR δ
149.7, 145.4, 135.0, 133.5, 132.4, 132.1, 130.8, 128.1, 128.0, 127.8,
127.62, 127.60, 126.8, 126.2, 126.0, 117.6, 58.5, 37.8, 31.2; HRMS
(ESIþ) m/z calcd for C37H32NO2 ([M þ NH4]þ) 522.2428, found
522.2434.
(R)-4d:48 97% yield; mp 93ꢀ94 °C; 1H NMR δ 7.15 (d, J = 7.8 Hz,
2H), 7.07 (s, 4H), 6.94 (s, 2H), 6.90 (d, J = 7.2 Hz, 2H), 5.13 (s, 2H),
3.03ꢀ3.10 (m, 4H), 2.40ꢀ2.45 (m, 2H), 2.32ꢀ2.36 (m, 14H); 13C
NMR δ 149.4, 145.0, 138.2, 137.3, 132.3, 130.2, 128.9, 126.96, 126.93,
117.1, 58.5, 37.8, 31.2, 21.3; HRMS (ESIþ) m/z calcd for C33H36NO2
([M þ NH4]þ) 478.2741, found 478.2737.
’ EXPERIMENTAL SECTION
(R)-4e: 95% yield; mp 222ꢀ223 °C; 1H NMR δ 7.97 (s, 4H), 7.79 (s,
2H), 7.29 (d, J = 7.8 Hz, 2H), 7.04 (d, J = 7.8 Hz, 2H), 4.92 (s, 2H),
3.10ꢀ3.17 (m, 4H), 2.44ꢀ2.47 (m, 2H), 2.33ꢀ2.38 (m, 2H); 13C NMR
δ 149.8, 147.0, 139.6, 131.6, 131.5 (q, J = 33.3 Hz), 130.6, 129.50,
129.48, 124.6, 123.4 (q, J = 273 Hz), 120.7(m), 118.6, 57.9, 37.6, 31.20,
31.15; HRMS (ESIꢀ) m/z calcd for C33H19F12O2 ([M ꢀ H]ꢀ)
675.1199, found 675.1209.
General. NMR spectra were recorded on 300 or 600 MHz spectro-
meters (300 or 600 MHz for 1H NMR, 150 M Hz for 13C NMR, and 121
MHz for 31P NMR) with CDCl3 as the solvent. The enantioselectivities
were determined by using a HPLC instrument (analysis condition:
hexanes/IPA = 70/30 to 90/10, flow rate at 1.0 mL/min, and UV
detector λ = 254 nm).
(R)-6,60-Dibromo-1,10-spirobiindane-7,70-diol, (R)-3. In a
round flask, (R)-SPINOL (R)-1 (1 g, 4 mmol) and KHCO3 (0.8 g, 8
mmol) were mixed with dichloromethane (40 mL), and the mixture was
stirred and cooled to ꢀ20 °C. Then, NBS (1.46 g, 8.2 mmol) was added.
After being stirred at ꢀ20 °C for 2 h, the reaction mixture was poured
into HCl (2 N). The reaction mixture was then extracted with dichlor-
omethane. After removal of solvent by rota-evaporation, the residue was
subjected to column chromatography (silica gel, hexanes/ethyl acetate
(v/v = 20/1ꢀ15/1) as eluent), affording the expected compound (R)-3
as a white solid (70% yield). Mp 159ꢀ160 °C; 1H NMR δ 7.31 (d, J =
7.8 Hz, 2H), 6.75 (d, J = 8.4 Hz, 2H), 5.26 (s, 2H), 2.95ꢀ3.06 (m, 4H),
2.36ꢀ2.41 (m, 2H), 2.21ꢀ2.25 (m, 2H); 13C NMR δ 148.6, 145.5,
134.3, 131.0, 118.0, 108.0, 59.8, 38.2, 31.2; HRMS (ESIþ) m/z calcd for
C17H18Br2NO2 ([M þ NH4]þ) 427.9679, found 427.9684.
(R)-4f: 92% yield; mp 193ꢀ194 °C; 1H NMR δ 7.56ꢀ7.63 (m, 10H),
7.43(t, J = 7.2 Hz, 4H), 7.34 (t, J = 7.8 Hz, 2H), 7.25ꢀ7.26 (m, 4H), 6.97
(d, J = 7.2 Hz, 2H), 5.11 (s, 2H), 3.06ꢀ3.16 (m, 4H), 2.38- 2.47
(m, 4H); 13C NMR δ 149.6, 145.3, 140.8, 140.0, 136.4, 131.9, 130.6,
129.7, 128.8, 127.3, 127.1, 126.6, 117.6, 58.4, 37.8, 31.2; HRMS (ESIþ)
m/z calcd for C41H36NO2 ([M þ NH4]þ) 574.2741, found 574.2747.
General Procedure for the Preparation of SPINOL-Based
Phosphoric Acids. In a vial, (R)-3 or (R)-4 (0.25 mmol) was dis-
solved in anhydrous pyridine (0.5ꢀ1.0 mL) and the mixture was stirred
under N2. POCl3 (77 mg, 0.5 mmol) was added dropwise. The reaction
mixture was stirred at room temperature or 80 °C for 6ꢀ24 h. After
being cooled to room temperature, the reaction mixture was transferred
to HCl (6 N) carefully and extracted with dichloromethane three times.
After removal of the solvent, a white solid was obtained. The white solid
was then mixed with acetic acid, 1,2-dichloromethane, and HCl (6 N),
and heated to reflux for 5 h to 7 days (monitored by 31P NMR). After the
reaction mixture was cooled to room temperature, a white solid was
formed. The mixture was poured into HCl (4 N) and extracted with
dichloromethane (three times). The organic solution was combined and
washed with HCl (2 N) once, followed by filtration through a short silica
gel column with dichloromethane/methanol (v/v 20/1) as eluent. The
obtained solution was concentrated by rota-evaporation. A few milliliters
of methanol was added to dissolve the residue. Then, HCl (2 N) was
added slowly with swirling and the precipitate was formed. After
standing in a refrigerator for a few hours, the final product was harvested
as a white or pale pink solid by filtration, which was washed with water
and then dried under vacuum for 2ꢀ6 h.
General Procedure for the Preparation of (R)-6,60-Diaryl-
1,10-spirobiindane-7,70-diol, (R)-4aꢀf. Under N2, to a round flask
containing (R)-3 (205 mg, 0.5 mmol), arylboronic acid (2ꢀ3 mmol),
Pd2(dba)3 (9.2 mg, 2 mol %), S-Phos (16.5 mg, 8 mol %) or t-Bu3P (12 mg,
12 mol %), and K3PO4 (3ꢀ4 mmol) was added toluene (5 mL) or
dioxane (5 mL). The reaction mixture was stirred and heated to
105ꢀ110 °C for 8ꢀ12 h. After being cooled to room temperature,
HCl (2 N) was added to the reaction mixture. The mixture was then
extracted with dichloromethane. After removal of solvent by rota-
evaporation, the residue was subjected to column chromatography
[silica gel, hexanes/ethyl acetate (v/v = 20/1ꢀ15/1) or hexanes/
dichloromethane (v/v = 1/1) as eluent], affording the expected product
as a white solid.
(R)-4a:48 98% yield; mp 200ꢀ201 °C; 1H NMR δ 7.47 (d, J = 7.8 Hz,
4H), 7.39 (t, J = 7.2 Hz, 4H), 7.30 (t, J = 7.8 Hz, 2H), 7.19 (d, J = 7.8 Hz,
2H), 6.93 (d, J = 7.8 Hz, 2H), 5.06 (s, 2H), 3.04ꢀ3.13 (m, 4H),
2.35ꢀ2.45 (m, 4H); 13C NMR δ 149.5, 145.2, 137.5, 132.1, 130.5,
129.3, 128.6, 127.2, 126.9, 117.4, 58.4, 37.8, 31.2; HRMS (ESIþ) m/z
calcd for C29H28NO2 ([M þ NH4]þ) 422.2115, found 422.2119.
(R)-4b: 88% yield; mp > 300 °C; 1H NMR δ 7.68ꢀ7.92 (m, 5H),
7.31ꢀ7.60 (m, 8H), 6.61ꢀ7.22 (m, 5H), 4.71ꢀ4.90 (m, 2H),
3.05ꢀ3.20 (m, 4H), 2.41ꢀ2.55 (m, 4H); 13C NMR δ 150.02, 149.98,
149.96, 149.91, 145.54, 145.47, 145.4, 135.2, 135.1, 134.8, 133.9, 133.70,
133.66, 133.60, 132.8, 132.7, 132.4, 132.2, 132.0, 131.9, 131.8, 131.2,
131.0, 130.9, 130.7, 128.4, 128.33, 128.29, 128.25, 128.18, 128.14,
128.11, 128.09, 128.0, 127.95, 126.7, 126.3, 126.22, 126.16, 126.10,
126.05, 126.0, 125.91, 125.88, 125.73, 126.64, 125.59, 125.50, 125.45,
125.21, 125.15, 125.07, 124.96, 116.99, 116.94, 116.84, 116.78, 58.6,
58.5, 38.3, 38.1, 37.8, 37.6, 31.41, 31.36; HRMS (ESIꢀ) m/z calcd for
C37H27O2 ([M ꢀ H]ꢀ) 503.2017, found 503.2020.
(R)-2a:34b 59% yield; mp >300 °C; 1H NMR δ 7.36ꢀ7.39 (m, 4H),
7.26 (d, J = 7.8 Hz, 2H), 7.17 (d, J = 7.8 Hz, 2H), 7.02ꢀ7.07 (m, 6H),
3.60 (br, OH), 3.08ꢀ3.19 (m, 2H), 2.92 (dd, J = 7.8, 16.2 Hz, 2H), 2.35
(dd, J = 6.3, 11.7 Hz, 2H), 1.97 (dd, J = 10.8, 18.9 Hz, 2H); 13C NMR δ
145.3, 142.31, 142.26, 140.53, 140.51, 137.8, 134.25, 134.23, 130.3, 129.5,
128.3, 126.9, 122.6, 60.03, 60.04, 38.6, 30.2; 31P NMR δ ꢀ10.4; HRMS
(ESIþ) m/zcalcd for C29H24O4P([Mþ H]þ) 467.1407, found 467.1414.
(R)-2b:34b 50% yield; mp 169ꢀ172 °C; 1H NMR δ 7.65ꢀ7.77 (m,
2H), 6.76ꢀ7.48 (m, 16H), 4.2 (br, OH), 2.92ꢀ3.34 (m, 4H),
2.26ꢀ2.53 (m, 4H); 13C NMR δ 145.4, 145.1, 145.0, 143.25, 143.19,
142.9, 142.7, 140.8, 140.6, 140.08, 140.06, 139.8, 135.1, 134.9, 134.3,
134.1, 133.8, 133.5, 133.0, 132.8, 132.7, 132.5, 132.3, 132.1, 132.0, 131.9,
131.8, 131.7, 131.5, 131.3, 128.9, 128.8, 128.6, 128.5, 128.0, 127.9, 127.6,
127.35, 127.28, 126.7, 126.4, 125.72, 125.66, 125.58, 125.4, 125.11,
125.07, 125.03, 124.97, 124.94, 124.8, 124.7, 122.4, 121.4, 60.2, 60.0,
59.8, 39.15, 39.06, 38.74, 38.69, 30.53, 30.44, 30.40, 30.32; 31P NMR
δ ꢀ10.1; HRMS (ESIꢀ) m/z calcd for C37H26O4P ([M ꢀ H]ꢀ)
565.1574, found 565.1576.
(R)-4c: 90% yield; mp 227ꢀ228 °C; 1H NMR δ 7.93 (s, 2H), 7.86
(d, J = 8.4 Hz, 2H), 7.80ꢀ7.83 (m, 4H), 7.61 (dd, J = 7.2, 8.4 Hz, 2H),
4128
dx.doi.org/10.1021/jo200302x |J. Org. Chem. 2011, 76, 4125–4131

The Journal of Organic Chemistry
NOTE
(R)-2c: 57% yield; mp >300 °C; 1H NMR δ 7.67 (s, 2H), 7.53 (d, J =
7.8 Hz, 2H), 7.50 (d, J = 7.8 Hz, 2H), 7.33 (d, J = 7.2 Hz, 2H), 7.21ꢀ7.25
(m, 10H), 4.77 (br, OH), 3.14ꢀ3.20 (m, 2H), 2.98 (dd, J = 7.8, 16.2 Hz,
2H), 2.37 (dd, J = 6.6, 12.0 Hz, 2H), 2.23 (dd, J = 10.8, 19.8 Hz, 2H); 13C
NMR δ 145.29, 145.28, 142.43, 142.38, 140.58, 140.56, 135.2, 134.46,
134.44, 133.1, 132.2, 130.3, 128.0, 127.8, 127.5, 127.4, 127.2, 125.44,
125.37, 122.5, 59.91, 59.90, 38.7, 30.4; 31P NMR δ ꢀ11.1; HRMS
(ESIþ) m/z calcd for C37H31NO4P ([M þ NH4]þ) 584.1985, found
584.1989.
129.0, 127.2, 127.1, 125.4, 123.7, 122.5, 119.9, 119.3, 116.6, 111.2, 54.9,
21.5, 21.1.
N-((4-Bromophenyl)(1H-indol-3-yl)methyl)-4-methylben-
zenesulfonamide:36. white solid, 99% yield, 99% ee (Chiralcel OD,
1
t(minor) = 12.95 min, t(major) = 20.04 min); mp 201ꢀ202 °C; H
NMR δ 8.00 (br, 1H), 7.56 (d, J = 7.8 Hz, 2H), 7.32 (t, J = 9.0 Hz, 3H),
7.17ꢀ7.21 (m, 2H), 7.13 (t, J = 7.8 Hz, 4H), 7.01 (t, J = 7.8 Hz, 1H), 6.63
(d, J = 1.8 Hz, 1H), 5.80 (d, J = 6.6 Hz, 1H), 5.05 (d, J = 6.6 Hz, 1H), 2.40
(s, 3H); 13C NMR δ 143.3, 139.3, 137.3, 136.5, 131.4, 129.4, 129.0,
127.2, 125.1, 123.7, 122.8, 121.3, 120.2, 119.1, 115.9, 111.3, 54.5, 21.5.
N-((3-Bromophenyl)(1H-indol-3-yl)methyl)-4-methylben-
zenesulfonamide:41. white solid, 94.5% yield, 99% ee (Chiralpak
AD-H, t(minor) = 19.89 min, t(major) = 22.77 min); mp 142ꢀ143 °C;
1H NMR δ 8.00 (br, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz,
2H), 7.26ꢀ7.28 (m, 2H), 7.18ꢀ7.21 (m, 2H), 7.15 (d, J = 7.8 Hz, 2H),
7.08 (t, J = 7.8 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.64 (s, 1H), 5.82 (d, J =
6.0 Hz, 1H), 5.01 (d, J = 6.0 Hz, 1H), 2.39 (s, 3H); 13C NMR δ 143.4,
142.4, 137.2, 136.5, 130.5, 130.2, 129.9, 129.4, 127.2, 126.0, 125.1, 123.7,
122.8, 122.4, 120.2, 119.1, 115.8, 111.3, 54.5, 21.5.
(R)-2d: 60% yield; mp 235ꢀ240 °C; 1H NMR δ 7.23 (d, J = 7.8 Hz,
2H), 7.13 (t, J = 7.8 Hz, 2H), 7.00 (s, 4H), 6.78 (s, 2H), 3.24 (br, OH),
3.08ꢀ3.14 (m, 2H), 2.88 (dd, J = 7.8, 16.2 Hz, 2H), 2.32 (dd, J = 6.0,
12.0 Hz, 2H), 2.18 (dd, J = 10.8, 19.2 Hz, 2H), 2.12 (s, 12H); 13C NMR
δ 145.04, 145.03, 142.9, 140.8, 138.4, 137.5, 134.9, 130.0, 127.9, 127.6,
122.0, 59.87, 59.86, 38.7, 30.3, 21.0; 31P NMR δ ꢀ11.2; HRMS (ESIþ)
m/z calcd for C33H32O4P ([M þ H]þ) 523.2033, found 523.2030.
(R)-2e:34b 62% yield; mp >300 °C; 1H NMR δ 7.66 (s, 4H), 7.44 (s,
2H), 7.26 (s, 2H), 7.16 (d, J = 7.8 Hz, 2H), 3.14ꢀ3.20 (m, 2H), 2.99 (dd,
J = 7.2, 16.2 Hz, 2H), 2.37 (dd, J = 7.2, 12.0 Hz, 2H), 2.22 (dd, J = 10.2,
19.2 Hz, 2H); 13C NMR δ: 147.15, 147.13, 141.53, 141.48, 140.58,
140.56, 139.4, 132.19, 132.16, 131.4, 131.2, 131.0, 130.8, 130.7, 129.4,
126.0, 124.2, 123.2, 122.4, 120.6, 59.9, 38.5, 30.4; 31P NMR δ ꢀ6.8;
HRMS (ESIþ) m/z calcd for C33H23F12NO4P ([M þ NH4]þ)
756.1168, found 756.1167.
N-((4-Chlorophenyl)(1H-indol-3-yl)methyl)-4-methylben-
zenesulfonamide:36. white solid, 98% yield, 99% ee (Chiralcel OD,
1
t(minor) = 12.34 min, t(major) = 18.93 min); mp 189ꢀ190 °C; H
NMR δ 7.99 (br, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 7.8 Hz, 1H),
7.17ꢀ7.21 (m, 6H), 7.15 (d, J = 7.8 Hz, 2H), 7.01 (t, J = 7.8 Hz, 1H),
6.64 (d, J = 2.4 Hz, 1H), 5.82 (d, J = 6.6 Hz, 1H), 5.02 (d, J = 7.2 Hz, 1H),
2.40 (s, 3H); 13C NMR δ 143.3, 138.8, 137.3, 136.5, 133.2, 129.3, 128.6,
128.4, 127.2, 125.1, 123.7, 122.8, 120.2, 119.1, 116.0, 111.3, 54.4, 21.5.
N-((1H-Indol-3-yl)(3-nitrophenyl)methyl)-4-methylbenzene-
sulfonamide:36. white solid, 97% yield, 99.5% ee (Chiralcel OD,
(R)-2f:34b 62% yield; mp 282ꢀ290 °C; 1H NMR δ 7.35 (d, J = 7.8 Hz,
4H), 7.27 (d, J = 7.8 Hz, 2H), 7.16ꢀ7.24 (m, 16H), 3.67 (br, OH),
3.10ꢀ3.16 (m, 2H), 2.92 (dd, J = 7.8, 15.6 Hz, 2H), 2.32 (dd, J = 6.6,
12.0 Hz, 2H), 2.14 (dd, J = 11.4, 19.2 Hz, 2H); 13C NMR δ 145.2, 142.3,
141.1, 140.52, 140.50, 139.8, 136.6, 134.2, 130.1, 129.7, 128.3, 127.2,
127.0, 126.7, 122.6, 60.0, 38.5, 30.3; 31P NMR δ ꢀ9.2; HRMS (ESIþ)
m/z calcd for C41H32O4P ([M þ H]þ) 619.2033, found 619.2037.
(R)-2g: 80% yield; mp >300 °C; 1H NMR δ 7.45 (d, J = 7.8 Hz, 2H),
6.99 (d, J = 7.8 Hz, 2H), 5.14 (br s, OH), 2.98ꢀ3.04 (m, 2H), 2.78ꢀ2.82
(m, 2H), 2.19ꢀ2.22 (m, 2H), 2.03ꢀ2.08 (m, 2H); 13C NMR δ 145.3,
142.2, 140.7, 133.0, 123.8, 114.7, 60.7, 38.4, 30.1; 31P NMR δ ꢀ9.0;
HRMS (ESIþ) m/z calcd for C17H17Br2NO4P ([M þ NH4]þ)
489.9237, found 489.9239.
1
t(minor) = 9.97 min, t(major) = 19.55 min); mp 203ꢀ204 °C; H
NMR (DMSO-d6) δ 10.96 (br, 1H), 8.64 (d, J = 7.8 Hz, 1H), 8.06 (s,
1H), 7.97 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.43ꢀ7.46 (m,
3H), 7.38 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.05ꢀ7.08 (m,
3H), 6.92 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 2.4 Hz, 1H), 5.90 (d, J = 7.2 Hz,
1H), 2.22 (s, 3H); 13C NMR (DMSO-d6) δ 147.7, 143.7, 142.3, 138.6,
136.6, 134.2, 129.6, 129.2, 126.6, 125.5, 124.2, 121.9, 121.8, 121.7,
119.01, 118.97, 114.9, 111.8, 54.0, 21.0.
General Procedure for SPINOL-Based Phosphoric Acids-
Catalyzed Reaction of Indoles with Aldimines. In a vial,
aldimine (0.2 mmol, 1.0 equiv) and SPINOL-based phosphoric acid
(R)-2c (2.0 mol %) were dissolved in 1,2-dichloroethane (1.6 mL). The
mixture was stirred and cooled to 0 °C with an ice-bath. Then, indole
(0.6 mmol, 3.0 equiv) was added in one portion. The reaction mixture
was stirred at this temperature for 2ꢀ6 h until all aldimine was converted
N-((5-Bromo-1H-indol-3-yl)(phenyl)methyl)-4-methylben-
zenesulfonamide:36. white solid, 97% yield, 99% ee (Chiralcel OD,
t(minor) = 7.30 min, t(major) = 15.14 min); mp 202ꢀ203 °C; 1H NMR
δ 8.04 (br, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.22ꢀ7.26 (m, 6H), 7.15ꢀ7.19
(m, 3H), 7.11 (s, 1H), 6.74 (d, J = 2.4 Hz, 1H), 5.74 (d, J = 6.0 Hz, 1H),
4.95 (d, J = 6.6 Hz, 1H), 2.40 (s, 3H); 13C NMR δ 143.4, 140.1, 137.0,
135.1, 129.5, 128.5, 127.7, 127.15, 127.08, 127.06, 125.5, 125.1, 121.6,
116.2, 113.3, 112.7, 54.6, 21.6.
1
(monitored by H NMR). Column chromatography on silica gel with
dichloromethane as eluent removed excessive indole, with dichloro-
methane/ethyl acetate (v/v = 20/1) eluent afforded the product, and
with dichloromethane/methanol (v/v = 15/1) as eluent recovered the
catalyst (R)-2c.
N-((5-Bromo-1H-indol-3-yl)(p-tolyl)methyl)-4-methylben-
zenesulfonamide: white solid, 92% yield, 97% ee (Chiralcel OD,
t(minor) = 8.39 min, t(major) = 19.83 min); mp 183ꢀ185 °C; H NMR
δ 8.04 (br, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.21 (dd, J = 1.8, 8.4 Hz, 1H),
7.14ꢀ7.19 (m, 3H), 7.10ꢀ7.13 (m, 3H), 7.05 (d, J = 7.8 Hz, 2H), 6.78
(d, J = 2.4 Hz, 1H), 5.68 (d, J = 6.0 Hz, 1H), 4.92 (d, J = 5.4 Hz, 1H), 2.40
(s, 3H), 2.31 (s, 3H); 13C NMR δ 143.3, 137.4, 137.2, 137.0, 135.1,
129.5, 129.2, 127.14, 127.07, 126.98, 125.4, 125.1, 121.6, 116.2, 113.2,
112.7, 54.5, 21.6, 21.1; HRMS (ESIꢀ) m/z calcd for C23H20BrN2O2S
([M ꢀ H]ꢀ) 467.0434, found 467.0439.
N-((1H-Indol-3-yl)(phenyl)methyl)-4-methylbenzenesulfon-
amide:36. white solid, 98% yield, 98% ee (Chiralcel OD, t(minor) =
10.9 min, t(major) = 17.2 min); mp 141ꢀ142 °C; 1H NMR δ 7.97 (br,
1H), 7.57 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 7.8 Hz, 1H), 7.20ꢀ7.25 (m,
5H), 7.17 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 7.8 Hz, 2H), 7.00 (t, J = 7.8 Hz,
2H), 6.69 (d, J = 1.8 Hz, 1H), 5.86 (d, J = 6.6 Hz, 1H), 4.99 (d, J = 6.6 Hz,
1H), 2.37 (s, 3H); 13C NMR δ 143.0, 140.2, 137.4, 136.5, 129.2, 128.3,
127.4, 127.2, 125.3, 123.7, 122.6, 120.0, 119.3, 116.5, 111.2, 55.0, 21.5.
N-((1H-Indol-3-yl)(p-tolyl)methyl)-4-methylbenzenesulfon-
amide:36. white solid, 95% yield, 97% ee (Chiralcel OD, t(minor) =
9.97 min, t(major) = 17.18 min); mp 143ꢀ145 °C; 1H NMR δ 7.97 (br,
1H), 7.57 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 7.8 Hz,
1H), 7.15 (t, J = 7.8 Hz, 1H), 7.10ꢀ7.12 (m, 4H), 7.97ꢀ7.01 (m, 3H),
6.72 (s, 1H), 5.80 (d, J = 6.6 Hz, 1H), 4.99 (d, J = 6.6 Hz, 1H), 2.38 (s,
3H), 2.29 (s, 3H); 13C NMR δ 143.0, 137.5, 137.3, 137.1, 136.6, 129.2,
N-((5-Bromo-1H-indol-3-yl)(4-bromophenyl)methyl)-4-
methylbenzenesulfonamide: white solid, 97% yield, 99% ee
(Chiralcel OD, t(minor) = 7.16 min, t(major) = 17.84 min); mp
1
220ꢀ221 °C; H NMR (DMSO-d6) δ 11.12 (br, 1H), 8.48 (d, J =
8.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.35 7.37 (m, 3H), 7.26 (d, J = 8.4
Hz, 1H), 7.21 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 9.0 Hz, 3H), 6.78 (d, J = 2.4
Hz, 1H), 5.67 (d, J = 8.4 Hz, 1H), 2.30 (s, 3H); 13C NMR (DMSO-d6) δ
142.2, 140.9, 138.3, 135.1, 130.8, 129.34, 129.29, 129.14, 129.08, 127.1,
126.4, 125.8, 125.7, 123.9, 123.8, 119.9, 114.8, 113.5, 111.4, 53.42, 53.39,
4129
dx.doi.org/10.1021/jo200302x |J. Org. Chem. 2011, 76, 4125–4131

The Journal of Organic Chemistry
NOTE
21.05, 21.02; HRMS (ESIꢀ) m/z calcd for C22H17Br2N2O2S ([M þ
HCOO]ꢀ) 530.9383, found 530.9381.
Ethyl 4-(4-chlorophenyl)-4-(1H-indol-3-yl)-2-oxobutano-
ate: 94% yield, 94% ee (Chiralpak AD-H, t(major) = 17.44 min,
1
t(minor) = 24.99 min); mp 80ꢀ82 °C; H NMR δ 8.02 (br, 1H),
N-((5-Bromo-1H-indol-3-yl)(3-bromophenyl)methyl)-4-
methylbenzenesulfonamide: white solid, 94% yield, 99% ee
(Chiralcel OD, t(minor) = 7.12 min, t(major) = 12.04 min); mp
7.37 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.22ꢀ7.27 (m, 4H),
7.17 (t, J = 7.2 Hz, 1H), 7.02ꢀ7.04 (m, 2H), 4.89 (t, J = 7.2 Hz, 1H),
4.21ꢀ4.25 (m, 2H), 3.65 (dd, J = 7.2, 17.4 Hz, 1H), 3.57 (dd, J = 8.4,
17.4 Hz, 1H), 1.29 (t, J = 7.2 Hz, 3H); 13C NMR δ 192.7, 160.9, 141.8,
136.6, 132.3, 129.2, 128.7, 126.2, 122.5, 121.4, 119.7, 119.3, 117.9, 111.2,
62.6, 45.4, 37.1, 13.9; HRMS (ESIꢀ) m/z calcd for C20H17ClNO3
([M ꢀ H]ꢀ) 354.0902, found 354.0909.
1
187ꢀ188 °C; H NMR δ 8.06 (br, 1H), 7.63 (d, J = 8.4 Hz, 2H),
7.37 (d, J = 7.8 Hz, 1H), 7.33 (s, 1H), 7.23ꢀ7.25 (m, 4H), 7.19 (d, J = 8.4
Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 7.11 (s, 1H), 6.69 (d, J = 2.4 Hz, 1H),
5.71 (d, J = 5.4 Hz, 1H), 4.88 (d, J = 6.0 Hz, 1H), 2.43 (s, 3H); 13C NMR
δ 143.8, 142.4, 136.8, 135.0, 130.7, 130.2, 130.0, 129.7, 127.1, 126.9,
125.83, 125.81, 125.2, 122.6, 121.3, 115.6, 113.6, 112.8, 54.0, 21.7;
HRMS (ESIꢀ) m/z calcd for C22H17Br2N2O2S ([M ꢀ H]ꢀ) 530.9383,
found 530.9388.
Ethyl 4-(2-fluorophenyl)-4-(1H-indol-3-yl)-2-oxobutano-
ate: 96% yield, 98% ee (Chiralpak AD-H, t(major) = 15.55 min,
1
t(minor) = 21.48 min); mp 99ꢀ101 °C; H NMR δ 8.02 (br, 1H),
7.49 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.23ꢀ7.26 (m, 1H),
7.14ꢀ7.18 (m, 2H), 7.09 (d, J = 2.4 Hz, 1H), 7.00ꢀ7.07 (m, 3H), 5.22
(t, J = 7.8 Hz, 1H), 4.22ꢀ4.27 (m, 2H), 3.74 (dd, J = 7.2, 16.8 Hz, 1H),
3.59 (dd, J = 7.8, 17.4 Hz, 1H), 1.29 (t, J = 7.2 Hz, 3H); 13C NMR δ
192.6, 161.3, 160.9, 159.7, 136.4, 130.04, 129.95, 129.33, 129.31, 128.27,
128.22, 126.4, 124.19, 124.17, 122.4, 121.7, 119.6, 119.1, 117.0, 115.7,
115.5, 111.1, 62.5, 44.4, 31.04, 31.02, 13.9; HRMS (ESIꢀ) m/z calcd for
C20H17FNO3 ([M ꢀ H]ꢀ) 338.1198, found 338.1203.
N-((5-Bromo-1H-indol-3-yl)(4-chlorophenyl)methyl)-4-
methylbenzenesulfonamide: white solid, 95% yield, 98% ee
(Chiralcel OD, t(minor) = 6.85 min, t(major) = 16.10 min); mp
1
196ꢀ197 °C; H NMR δ 8.09 (br, 1H), 7.61 (d, J = 7.8 Hz, 2H),
7.20ꢀ7.25 (m, 7H), 7.16 (d, J = 8.4 Hz, 1H), 7.07 (s, 1H), 6.66 (d, J = 1.8
Hz, 1H), 5.69 (d, J = 6.6 Hz, 1H), 5.00 (d, J = 6.6 Hz, 1H), 2.43 (s, 3H);
13C NMR δ 143.7, 138.7, 136.8, 135.0, 133.4, 129.7, 128.6, 128.5, 127.1,
126.9, 125.7, 125.1, 121.3, 115.7, 113.5, 112.8, 54.0, 21.6; HRMS
(ESIꢀ) m/z calcd for C22H17BrClN2O2S ([M ꢀ H]ꢀ) 486.9888, found
486.9894.
Ethyl 4-(5-bromo-1H-indol-3-yl)-2-oxo-4-phenylbutano-
ate: 82% yield, 91% ee (Chiralpak AD-H, t(major) = 40.45 min,
t(minor) = 50.83 min); 1H NMR δ 8.06 (br, 1H), 7.54 (s, 1H),
7.26ꢀ7.30 (m, 4H), 7.17ꢀ7.23 (m, 3H), 7.04 (m, 1H), 4.85 (t, J =
7.8 Hz, 1H), 4.21ꢀ4.25 (m, 2H), 3.64 (dd, J = 7.8, 17.4 Hz, 1H), 3.57
(dd, J = 7.8, 16.8 Hz, 1H), 1.29 (t, J = 7.2 Hz, 3H); 13C NMR δ 192.8,
160.9, 142.7, 135.1, 128.6, 128.2, 127.6, 126.8, 125.2, 122.7, 121.9, 118.0,
112.8, 112.6, 62.5, 45.6, 37.5, 13.9; HRMS (ESIꢀ) m/z calcd for
C20H17BrNO3 ([M ꢀ H]ꢀ) 398.0397, found 398.0404.
N-((5-Bromo-1H-indol-3-yl)(3-nitrophenyl)methyl)-4-methyl-
benzenesulfonamide: white solid, 93% yield, 99.5% ee (Chiralcel OD,
t(minor) = 9.22 min, t(major) = 16.66 min); mp 221ꢀ223 °C; 1H NMR
(DMSO-d6) δ 11.17 (br, 1H), 8.65 (d, J = 8.4 Hz, 1H), 8.11 (s, 1H), 8.00
(dd, J = 2.4, 8.4 Hz, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.47ꢀ7.50 (m, 3H), 7.43
(d, J = 1.2 Hz, 1H), 7.28 (d, J = 9.0 Hz, 1H), 7.16 (dd, J = 1.2, 8.4 Hz, 1H),
7.11 (d, J = 7.8 Hz, 2H), 6.77 (d, J = 2.4 Hz, 1H), 5.89 (d, J = 7.8 Hz, 1H),
2.25 (s, 3H); 13C NMR (DMSO-d6) δ 147.6, 143.5, 142.3, 138.1, 135.1,
134.0, 133.9, 129.5, 129.2, 129.1, 127.1, 126.5, 126.1, 125.9, 124.1, 124.0,
121.8, 121.7, 121.1, 114.5, 113.64, 113.61, 111.6, 53.19, 53.17, 20.94, 20.90;
HRMS (ESIꢀ) m/z calcd for C22H17BrN3O4S ([M ꢀ H]ꢀ) 498.0129,
found 498.0135.
General Procedure for SPINOL-Based Phosphoric Acids-
Catalyzed Reaction of Indoles with β,γ-Unsaturated-r-ke-
toesters. In a vial, β,γ-unsaturated-R-ketoester (0.2 mmol, 1.0 equiv)
and SPINOL-based phosphoric acid (R)-2b (2.0 mol %) were dissolved
in 1,2- dichloroethane (1 mL). The mixture was stirred and cooled
to ꢀ20 °C. Then, indole (0.6 mmol, 3.0 equiv) was added in one portion.
The reaction mixture was stirred at this temperature for 2ꢀ5 h until
β,γ-unsaturated-R-ketoester was fully reacted (monitored by 1H NMR).
Column chromatography on silica gel with hexanes/ethyl acetate (v/v =
3/1) afforded the product and with dichloromethane/methanol (v/v =
15/1) as eluent recovered the catalyst (R)-2b.
Ethyl 4-(5-bromo-1H-indol-3-yl)-4-(2-fluorophenyl)-2-ox-
obutanoate: 92% yield, 97% ee (Chiralcel OD, t(major) = 17.42 min,
t(minor) = 22.15 min); mp 139ꢀ140 °C; 1H NMR (DMSO-d6) δ 11.17
(br, 1H), 7.55 (s, 1H), 7.40 (t, J = 7.2 Hz, 1H), 7.30ꢀ7.32 (m, 2H),
7.21ꢀ7.24 (m, 1H),7.13ꢀ7.17 (m, 2H), 7.11 (t, J = 7.8 Hz, 1H), 4.94 (t,
J = 7.8 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 3.77 (dd, J = 7.2, 18.6 Hz, 1H),
3.61 (dd, J = 7.8, 18.0 Hz, 1H), 1.24 (t, J = 7.2 Hz, 3H); 13C NMR
(DMSO-d6) δ 192.2, 160.6, 160.3, 158.9, 134.9, 130.6, 130.5, 129.2, 128.2,
127.8, 124.47, 124.43, 124.22, 124.18, 123.7, 123.6, 120.3, 115.8, 115.4, 115.3,
113.58, 113.56, 111.2, 61.8, 43.7, 29.4, 29.3, 13.78, 13.72; HRMS (ESIꢀ) m/z
calcd for C20H16BrFNO3 ([M ꢀ H]ꢀ) 416.0303, found 416.0310.
’ ASSOCIATED CONTENT
S
Supporting Information. General procedures and char-
b
acterization of SPINOL-based phosphoric acids and products of
their catalyzed reactions. This material is available free of charge
via the Internet at http://pubs.acs.org.
Ethyl 4-(1H-indol-3-yl)-2-oxo-4-phenylbutanoate:38. 84%
yield, 94.5% ee (Chiralcel OD, t(major) = 37.72 min, t(minor) =
44.68 min); 1H NMR δ 8.01 (br, 1H), 7.42 (d, J = 7.8 Hz, 1H),
7.32ꢀ7.33 (m, 3H), 7.25ꢀ7.27 (m, 2H), 7.14ꢀ7.19 (m, 2H),
7.01ꢀ7.04 (m, 2H), 4.92 (t, J = 7.8 Hz, 1H), 4.19ꢀ4,24 (m, 2H),
3.68 (dd, J = 7.2, 17.4 Hz, 1H), 3.60 (dd, J = 7.8, 16.8 Hz, 1H), 1.27 (t, J =
7.2 Hz, 3H); 13C NMR δ 193.0, 160.9, 143.2, 136.5, 128.5, 127.8, 126.6,
126.4, 122.3, 121.5, 119.5, 119.4, 118.4, 111.1, 62.4, 45.6, 37.8, 13.9.
Ethyl 4-(1H-indol-3-yl)-2-oxo-4-p-tolylbutanoate: 89.5%
yield, 94% ee (Chiralpak AD-H, t(major) = 17.06 min, t(minor) =
20.95 min); 1H NMR δ 7.98 (br, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.32
(d, J = 8.4 Hz, 1H), 7.21 (d, J = 7.8 Hz, 2H), 7.15 (t, J = 7.2 Hz, 1H), 7.07
(d, J = 7.8 Hz, 2H), 7.02 (t, J = 7.2 Hz, 2H), 4.88 (t, J = 7.8 Hz, 1H),
4.19ꢀ4,23 (m, 2H), 3.66 (dd, J = 7.2, 16.8 Hz, 1H), 3.57 (dd, J = 7.8,
16.8 Hz, 1H), 2.28 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H); 13C NMR δ 193.2,
161.0, 140.2, 136.5, 136.0, 129.2, 127.6, 126.4, 122.2, 121.4, 119.5, 119.4,
118.6, 111.1, 62.4, 45.7, 37.4, 21.0, 13.9; HRMS (ESIꢀ) m/z calcd for
C21H20NO3 ([M ꢀ H]ꢀ) 334.1449, found 334.1454.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: qiaosheng.hu@csi.cuny.edu.
’ ACKNOWLEDGMENT
Partial support from PSCꢀCUNY Research Award Programs
is gratefully acknowledged. We also thank Frontier Scientific for its
generous gifts of palladium(II) acetate and arylboronic acids.
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