Catalytic asymmetric friedel-crafts/protonation of nitroalkenes and N-heteroaromatics

Article abstract of DOI:10.1021/jo200546a

The catalytic asymmetric Friedel-Crafts/protonation of indoles and pyrroles with α-substituted nitroalkenes to give the corresponding adducts in a highly anti-selective manner was achieved by an imidazoline-aminophenol (L2)-Cu complex. The anti-adducts could be successfully transformed to biochemically important α-substituted β-heteroarylalkylamines.

Full text of DOI:10.1021/jo200546a

NOTE
pubs.acs.org/joc
Catalytic Asymmetric FriedelꢀCrafts/Protonation of Nitroalkenes
and N-Heteroaromatics
Takayoshi Arai,*,† Atsuko Awata,† Makiko Wasai,† Naota Yokoyama,† and Hyuma Masu‡
†Department of Chemistry, Graduate School of Science, and ‡Chemical Analysis Center, Chiba University, Inage, Chiba 263-8522, Japan
S Supporting Information
b
ABSTRACT: The catalytic asymmetric FriedelꢀCrafts/pro-
tonation of indoles and pyrroles with R-substituted nitroalkenes
to give the corresponding adducts in a highly anti-selective
manner was achieved by an imidazolineꢀaminophenol
(L2)ꢀCu complex. The anti-adducts could be successfully
transformed to biochemically important R-substituted β-
heteroarylalkylamines.
ptically active indoles and pyrroles, which are common core
structures in natural alkaloids, exhibit significant biological
O
activities.1 For example, R-methyl tryptamines (AMTs) are agonists
of serotonin 5-HT receptors,2 and AJ-9677 is a clinical candidate of
β-adrenergic receptor (β-AR) agonists to treat obesity, a metabolic
syndrome that is often associated with noninsulin dependent
(Type II) diabetes.3 A common structure observed in these com-
pounds is the chiral R-substituted β-indolylalkylamine, as shown
in red in Figure 1. Yohambine, isolated from the root of the
Rauwolfia serpentina Benth (N. O. Apocyanaciae) and utilized in
the treatment of high blood pressure, also has a methyl substituent at
the R-position of the amine.4 Because biological activities are
strongly linked with stereochemistry, much effort has been
invested to construct R-substituted β-indolylalkylamines in a
stereoselective manner.5 One straightforward approach for the
synthesis of chiral R-substituted tryptamines would be the Friedelꢀ
Crafts reaction of indoles and nitroalkenes. However, the catalytic
asymmetric FriedelꢀCrafts reaction of indoles with R-substi-
tuted nitroalkenes is currently unexplored.6ꢀ9
Figure 1. Examples of biologically active chiral R-substituted β-indolyl-
alkylamines.
Even when the more Lewis-acidic L2ꢀCuOTf catalyst was used,
the product was obtained in only 20% yield (entry 2). In contrast,
the L2ꢀCuOTf smoothly catalyzed the reaction using β-nitro-
acrylate to give the adduct in 93% yield with 89:11 diastereo-
selectivity.12 The enantiomeric excess of the major diastereomer
was 79% ee. Although the catalyst structure has not been fully
elucidated, the existence of Cu-phenoxide in the catalyst forma-
tion is suggested by UV spectroscopy. This explains the release of
the strong Brønsted acid TfOH into the reaction media. In order
to study the effects of the proton source on the diastereoselec-
tivity, the reaction was examined without HFIP (entries 5ꢀ6).
When the catalyst solution was treated with base to scavenge the
acids before the catalysis, the diastereoselectivity was improved
to 82:18, and the enantiomeric excess of the major diastereomer
increased to 85% ee (entry 6) (see the detailed experimental
In our program for exploring new asymmetric catalysts and their
application to the synthesis of nitrogen-containing chiral molecules,
we have succeeded in the development of a chiral imidazolineꢀ
aminophenolꢀCu complex for the catalytic asymmetric Friedelꢀ
Crafts reaction of nitroalkenes with indoles and pyrroles.10 More-
over, the imidazolineꢀaminophenolꢀCu complex was success-
fully applied to the tandem FriedelꢀCrafts/Henry (FCH) reac-
tion.11 In the FCH reaction, the intermediate Cu-nitronate is
trapped with an aldehyde for constructing multiple contiguous
stereogenic centers. Here, the chiral imidazolineꢀaminophenolꢀ
-Cu catalyst was applied to the tandem FriedelꢀCrafts reaction/
protonation using R-substituted nitroalkenes to give the chiral
R-substituted β-heteroarylnitroalkanes (Scheme 1).
When the original conditions were applied to the reaction of
indole with R-methylnitrostyrene, the reaction using L1ꢀCuOTf
resulted in only a trace amount of product (Table 1, entry 1).
Received: March 17, 2011
Published: May 20, 2011
r
2011 American Chemical Society
5450
dx.doi.org/10.1021/jo200546a J. Org. Chem. 2011, 76, 5450–5456
|

The Journal of Organic Chemistry
NOTE
Scheme 1. Working Hypothesis of Cu-Catalyzed
Asymmetric FriedelꢀCrafts/Protonation
Table 1. Catalytic Asymmetric FriedelꢀCrafts/Protonation
of Indole with r-Methyl Nitroalkenes
Figure 2. X-ray crystallographic analysis of the FriedelꢀCrafts/proton-
ation adduct obtained in entry 5 of Table 2.
HFIP
ee (%)
entry
R
cat (equiv) time (h) yield (%)
dr
(major/minor)
1
2
3
4
5
Ph
Ph
L1
L2
2
2
2
2
23
46
19
19
44
44
trace
20
65/35
81/19
89/11
79/21
82/18
ND
CO2Et L1
CO2Et L2
CO2Et L2
74
64/32
79/50
84/73
85/73
93
91
6a CO2Et L2
94
Figure 3. X-ray crystallographic analysis of the FriedelꢀCrafts/proton-
a Catalyst was treated with K2CO3 prior to use.
ation adduct obtained in entry 3 of Table 3.
procedure in the Supporting Information). Although the effects
of the additional proton source were reexamined by adding the
reaction mixture after the treatment of catalyst with K2CO3, the
external proton sources examined gave no positive influence on
the diastereoselectivities.
Under the optimized conditions, the generality of the Friedelꢀ
Crafts/protonation of indoles and nitroacrylates was examined,
and the results are shown in Table 2.13
In addition to β-nitroacrylates, β-nitroenone was also effective
in the diastereoselective FriedelꢀCrafts/protonation and main-
tained a high enantiomeric excess (entry 3). Various substituted
indoles were able to be employed to give the products with good
diastereoselectivity, and the major products recorded high enantio-
selectivities. In particular, the 2-methylindole gave a single diastereo-
mer, though the enantiomeric excess remained at 72% ee (entry 5).
A single recrystallization of the product obtained in entry 5 from
methanol produced racemic crystal to enrich the enantiomeric
excess in the solution up to 90% ee. The single X-ray crystal-
lographic analysis of the rac-crystal revealed the anti-stereochem-
istry as shown in Figure 2.
Next, we attempted the FriedelꢀCrafts/protonation using
pyrrole.14ꢀ16 The reaction was smoothly catalyzed under similar
reaction conditions to give the adducts in a highly enantioselec-
tive manner. The scope of the reaction using pyrroles is
summarized in Table 3.
Although large R2 substituents reduced the diastereoselec-
tivity, each diastereomer showed high enantiomeric excess
(Table 3, entries 5 and 6). The recrystallization of the product
obtained in entry 3 from methanol gave a pure diastereomer.
X-ray crystallographic analysis revealed the anti-stereochemistry
of the major product as shown in Figure 3.
Scheme 2 summarizes why the anti-products are preferably
obtained.17 In previous studies on the asymmetric Friedelꢀ
Crafts reaction catalyzed by the imidazolineꢀaminophenolꢀ
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NOTE
Table 2. L2ꢀCuOTf-Catalyzed Asymmetric FriedelꢀCrafts/Protonation of Indoles with R-Substituted Nitroalkenes
entry
X
R1
R2
temp (°C)
time (h)
yield (%)
dr
ee (%) (major/minor)
1
2
H
H
H
OEt
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
10
10
10
rt
75
92
90
94
92
87
90
62
97
96
84
96
72
80
85/15
90/10
93/7
80/71
87/62
93/83
67/64
72/ND
76/84
87/78
87/65
90/70
67/ND
83/81
66/75
O-t-Bu
Ph
3
67
4
1-Me
2-Me
4-Me
5-Me
5-OMe
5-Br
7-Me
H
O-t-Bu
O-t-Bu
O-t-Bu
O-t-Bu
O-t-Bu
O-t-Bu
O-t-Bu
OEt
69
89/11
>99/<1
52/48
89/11
90/10
91/9
5
rt
45
6
rt
94
7
rt
45
8
rt
46
9
rt
91
10
11
12
rt
88
91/9
rt
120
120
51/49
H
OEt
Ph
0
77/23
a Catalyst was treated with K2CO3 prior to use. b The absolute configuration was determined for the product obtained in entry 9. See details in the
Supporting Information.
Table 3. L2ꢀCuOTf-Catalyzed Asymmetric FriedelꢀCrafts/Protonation of Pyrrole with R-Substituted Nitroalkenes
entry
R1
R2
Me
temp (°C)
time (h)
yield (%)
dr
ee (%) (major/minor)
1
2
3
4
5
6
7
OEt
OMe
O-t-Bu
Ph
0
0
99
96
98
60
41
94
41
93
98
93
80
92
97
98
84/16
80/20
87/13
93/7
87/84
87/86
84/84
80/15
92/86
89/69
91/68
Me
Me
0
Me
0
OEt
OEt
OEt
Et
rt
rt
0
66/34
67/33
53/47
n-C5H11
Ph
a Catalyst was treated with K2CO3 prior to use. b The absolute configuration was determined for the product obtained in entry 3. See the details in the
Supporting Information.
Cu complex, (S,S,S)-L2ꢀCuOTf, both indole and/or pyrrole
nucleophiles attack from the Re face of the activated nitroalkenes
to give the Cu-nitronate intermediates. The acidic proton adjacent
to the nitrogen atom then reacts with the nitronate to give the anti-
adduct. The reduction of diastereoselectivity in the substrates
having bulky R2 groups is also reasonably explained by
considering the steric hindrance between R2 and CO2R1.
The synthetic application of the FriedelꢀCrafts/protonation
product was examined as shown in Scheme 3. After the reduc
tion of the nitro functionality using nickel boride, the Pictetꢀ
Spengler reaction proceeded smoothly to give the bicyclic
compound with good diastereoselectivity. The epimerization of
the product was negligible. The NOE experiments revealed the
stereochemistry of the major PictetꢀSpengler adduct as shown
in Scheme 3.
protonation to give the R-substituted β-heteroarylꢀnitro
adducts in a highly anti-selective manner. This is the first
report on the diastereoselective construction of the chiral acyclic
R-substituted β-indolylalkylamines.18 Because the stereochemi-
cally diverse indole and pyrrole derivatives are fascinating scaffolds
for promoting pharmaceutical research, further application of the
products and studies on the detailed mechanism of the Friedelꢀ
Crafts/protonation reaction are in progress.
’ EXPERIMENTAL SECTION
FriedelꢀCrafts/Protonation (Entry 6, Table 1). Imidazolineꢀ
aminophenol ligand (0.016 mmol) in CH2Cl2 (0.74 mL) was added to
(CuOTf)2 C6H6 (3.7 mg, 0.007 mol) under Ar, and the mixture was
3
stirred for 2 h at room temperature. To the resulting green solution was
added K2CO3 (3.0 mg, 0.022 mmol) and the mixture stirred for 5 min.
After removal of K2CO3 by filtration, the solution was concentrated and
In conclusion, the imidazolineꢀaminophenol (L2)ꢀCu
complex furnished the catalytic asymmetric FriedelꢀCrafts/
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NOTE
Scheme 2. Proposed Mechanism for the Anti-Selective For-
mation of the FriedelꢀCrafts/Protonation Adduct
Scheme 3. Chemical Transformations of the Friedelꢀ
Crafts/Protonation Adduct
2H), 7.30ꢀ7.27 (m, 1H), 7.19ꢀ7.17 (m, 2H), 7.15 (m,1H), 5.55ꢀ5.47
(m, 1H), 5.41 (d, J = 10.0 Hz, 1H), 1.73 (d, J = 6.3 Hz, 3H); minor δ 8.23
(br, 1H), 7.94 (m, 2H), 7.80ꢀ7.79 (m, 1H), 7.48 (m, 1H), 7.36 (m, 2H),
7.30ꢀ7.27 (m, 1H), 7.19ꢀ7.17 (m, 2H), 7.15 (m, 1H), 5.55ꢀ5.47
(m, 1H), 5.41 (d, J = 10.0 Hz, 1H), 1.51 (d, J = 6.6 Hz, 3H); 13C NMR
(125 MHz, CDCl3) major δ 195.7, 136.5, 135.9, 133.7, 128.8, 128.7, 125.8,
124.4, 122.7, 120.7, 118.7, 111.7, 108.6, 86.5, 49.4, 18.9; minor δ 195.7, 136.5,
135.9, 133.7, 128.8, 128.7, 125.6, 124.4, 122.5, 120.8, 118.7, 111.7, 108.6,
86.5, 49.4, 18.9; HRMS calcd for C18H16O3N2Na (M þ Na)þ 331.1053,
found m/z 331.1046; enantiomeric excess was determined by HPLC with a
Chiralpak AS-H column (90:10 hexane/2-propanol, 1.0 mL/min, 254 nm);
major: major enantiomer tR = 16.5 min, minor enantiomer tR = 30.7 min;
93% ee; minor: major enantiomer tR = 18.4 min, minor enantiomer tR =
22.3 min; 83% ee; [R]24.9D = þ223.4 (c = 1.0, CHCl3, dr = 93/7, 93% ee/
dried under reduced pressure. To the resulting green amorphous solid
were subsequently added PhMe (0.37 mL) and nitroalkene (0.147 mmol),
and then indole (0.294 mmol) was added. After being stirred for indicated
time, the reaction mixture was quenched by water. The organic layer was
extracted with AcOEt, and the organic layer was dried over Na2SO4.
After removal of the solvent under reduced pressure, the diastereomeric
1
ratio was determined by crude H NMR. The resulting crude mixture
was purified by silica gel column chromatography (hexane/AcOEt = 5:1) to
1
afford adducts: H NMR (500 MHz, CDCl3) major δ 8.18 (br, 1H),
7.70 (d, J = 7.5 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.25ꢀ7.14 (m, 3H),
5.36ꢀ5.28 (m, 1H), 4.89 (d, J = 9.7 Hz, 1H), 4.25ꢀ4.10 (m, 2H), 1.72
(d, J = 6.9 Hz, 3H),1.22 (t, J = 7.5 Hz, 3H); minor δ 8.25 (br, 1H), 7.69
(d, J = 7.5 Hz, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.25ꢀ7.14 (m, 3H), 5.36ꢀ
5.28 (m, 1H), 4.47 (d, J = 11.2 Hz, 1H), 4.25ꢀ4.10 (m, 2H), 1.42 (d, J =
6.9 Hz, 3H), 1.18 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
major δ 170.5, 136,1, 126.1, 123.7,122.7, 120.5, 118.9, 111.6, 108.4, 84.9,
61.8, 47.8, 18.2, 14.1; minor δ 170.5, 136,4, 126.1, 123.7, 122.9, 120.4,
119.0, 111.7, 107.9, 83.5, 61.8, 47.2, 18.4, 14.1; HRMS calcd for C14H16-
O4N2Na (M þ Na)þ 299.1002, found m/z 299.0997. Enantiomeric
excess was determined by HPLC with a Chiralcel OD-H column (90:10
hexane/2-propanol, 1.0 mL/min, 254 nm); major: minor enantiomer
tR = 14.4 min, major enantiomer tR = 17.7 min; 85% ee; minor: minor
enantiomer tR = 13.0 min, major enantiomer tR = 21.5 min; 73% ee;
[R]24.4D = þ129.5 (c = 1.0, CHCl3, dr = 82/18, 85% ee/73% ee); IR
83% ee); IR (neat) 3410, 3059, 1676, 1549, 1449, 1360 cmꢀ1
.
Entry 4, Table 2: white solid; 1H NMR (500 MHz, CDCl3) major δ
7.68 (d, J = 8.0 Hz, 1H), 7.27 (m, 1H), 7.24ꢀ7.21 (m, 1H), 7.15ꢀ7.12
(m, 1H), 7.09 (s, 1H), 5.25ꢀ5.19 (m, 1H), 4.39 (d, J = 9.5 Hz, 1H), 3.74
(s, 3H), 1.70 (d, J = 6.7 Hz, 3H), 1.42 (s, 9H); minor δ 7.68 (d, J = 8.0
Hz, 1H), 7.32 (m, 1H), 7.28ꢀ7.25 (m, 1H), 7.17ꢀ7.13 (m, 1H), 7.04 (s,
1H), 5.25ꢀ5.19 (m, 1H), 4.33 (d, J = 10.9 Hz, 1H), 3.74 (s, 3H), 1.40 (d,
J = 6.7 Hz, 3H), 1.38 (s, 9H); 13C NMR (125 MHz, CDCl3) major δ
169.7, 136.9, 128.0, 126.8, 122.1, 119.7, 119.1, 109.5, 107.1, 85.1, 82.4,
48.6, 33.0, 28.0, 18.0; minor δ 169.7, 136.9, 128.0, 126.8, 122.3, 119.8,
119.3, 109.7, 107.1, 83.8, 82.4, 48.2, 33.0, 27.9, 18.5; HRMS calcd for
C17H22O4N2Na (M þ Na)þ 341.1472, found m/z 341.1465; enantio-
meric excess was determined by HPLC with a Chiralcel OD-H column
(90:10 hexane/2-propanol, 1.0 mL/min, 254 nm); major: major en-
antiomer tR = 6.3 min, minor enantiomer tR = 6.9 min; 67% ee; minor:
major enantiomer tR = 7.4 min, minor enantiomer tR = 9.3 min; 64% ee;
(neat) 3418, 1731, 1555, 1457, 1362 cmꢀ1
.
1
Entry 2, Table 2: yellow oil; H NMR (500 MHz, CDCl3) major δ
8.16 (br, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.23 (m,
1H), 7.12 (t, J = 8.0 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 5.26ꢀ5.20 (m,
1H), 4.41 (d, J = 9.7 Hz, 1H), 1.71 (d, J = 6.9 Hz, 3H), 1.41 (s, 9H);
minor δ 8.22 (br, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H),
7.23 (m, 1H), 7.12 (t, J = 8.0 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 5.26ꢀ5.20
(m, 1H), 4.36 (d, J = 10.9 Hz, 1H), 1.40 (d, J = 6.9 Hz, 3H), 1.37 (s, 9H);
13C NMR (125 MHz, CDCl3) major δ 169.6, 136,1, 126.2, 123.5, 122.6,
120.1, 119.0, 111.5, 108.8, 85.0, 82.6, 48.7, 28.0, 18.0; minor δ 169.6,
136.4, 125.9, 123.5, 122.8, 120.3, 119.1, 111.7, 108.8, 83.7, 82.4, 48.3, 27.9,
18.5; HRMS calcd for C16H20O4N2Na (M þ Na)þ 327.1315, found
m/z 327.1305; enantiomeric excess was determined by HPLC with a
Chiralcel OJ-H column (90:10 hexane/ 2-propanol, 1.0 mL/min, 254 nm);
major: major enantiomer tR = 27.3 min, minor enantiomer tR = 31.7 min;
87% ee; minor: minor enantiomer tR = 15.7 min, minor enantiomer tR =
24.2 min; 62% ee; [R]24.6D = þ60.3 (c = 1.0, CHCl3, dr = 90/10, 87%
[R]22.1 = þ56.7 (c = 1.0, CHCl3, dr = 89/11, 67% ee/64% ee); IR
D
(neat) 2979, 1723, 1550, 1474, 1367 cmꢀ1
.
Entry 5, Table 2: yellow solid; 1H NMR (500 MHz, CDCl3); δ 7.85
(br, 1H), 7.71ꢀ7.67 (m, 1H), 7.25ꢀ7.20 (m, 2H), 7.11ꢀ7.04 (m, 1H),
5.49ꢀ5.41 (m, 1H), 4.23 (d, J = 10.9 Hz, 1H), 2.40 (s, 3H), 1.76 (d, J =
6.6 Hz, 3H), 1.37 (s, 9H); 13C NMR (125 MHz, CDCl3) δ169.4, 135.2,
134.1, 126.6, 121.4, 120.0, 119.0, 110.6, 104.3, 83.7, 82.4, 49.1, 28.0, 18.3,
11.7; HRMS calcd for C17H22O4N2Na (M þ Na)þ 341.1472, found m/
z 341.1461; enantiomeric excess was determined by HPLC with a
Chiralpak AD-H column (90:10 hexane/2-propanol, 0.5 mL/min,
254 nm); major enantiomer tR = 12.3 min, minor enantiomer tR
=
13.1 min; 72% ee; [R]20.3D = þ72.0 (c = 1.0, CHCl3, dr = >99/<1, 72%
ee/62% ee); IR (neat) 3413, 2981, 1724, 1553, 1457, 1368 cmꢀ1
.
ee); IR (neat) 3400, 2979, 1721, 1551, 1458, 1367 cmꢀ1
.
Entry 3, Table 2: yellow solid; 1H NMR(500 MHz, CDCl3) major δ
8.16 (br, 1H), 7.98 (m, 2H), 7.78ꢀ7.74 (m, 1H), 7.48 (m, 1H), 7.36 (m,
Entry 6, Table 2: yellow oil; 1H NMR (500 MHz, CDCl3) major δ 8.20
(br, 1H),7.32ꢀ6.86(m, 4H), 5.18ꢀ5.08 (m, 1H), 4.82 (d, J=10.0Hz, 1H),
5453
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NOTE
2.80 (s, 3H), 1.72 (d, J = 6.6 Hz, 3H), 1.40 (s, 9H); minor δ 8.26 (br,
1H), 7.32ꢀ6.86(m, 4H), 5.18ꢀ5.08 (m, 1H), 4.82 (d, J = 10.0 Hz, 1H),
2.82 (s, 3H), 1.46 (d, J = 6.6 Hz, 3H), 1.36 (s, 9H); 13C NMR (125 MHz,
CDCl3) major δ 170.3, 136.0, 130.5, 125.0, 122.7, 122.5, 122.3, 109.7,
109.5, 86.1, 82.4, 48.4, 27.9, 20.6, 18.2; minor δ 171.2, 136.2, 130.4, 125.0,
122.8, 122.5, 122.2, 110.2, 109.8, 85.5, 82.1, 47.3, 27.8, 21.1, 18.3; HRMS
calcd for C17H22O4N2Na (M þ Na)þ 341.1472, found m/z 341.1467;
enantiomeric excess was determined by HPLC with a Chiralcel OD-H þ
Chiralpak AS-H column (90:10 hexane/2-propanol, 1.0 mL/min, 254 nm);
major: minor enantiomer tR = 14.9 min, major enantiomer tR = 16.9 min;
76% ee; minor: minor enantiomer tR = 13.5 min, major enantiomer tR =
20.5 min; 84% ee; [R]21.8D = þ138.8 (c=1.0, CHCl3, d.r.=52/48, 76% ee/
Entry 10, Table 2: yellow oil; 1H NMR (500 MHz, CDCl3) major δ
8.13 (br, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 2.6 Hz, 1H),
7.08ꢀ7.05 (m, 1H), 6.99 (d, J = 7.2 Hz, 1H), 5.27ꢀ5.21 (m, 1H), 4.40
(d, J = 9.7 Hz, 1H), 2.43 (s, 3H), 1.71 (d, J = 6.6 Hz, 3H), 1.42 (s, 9H);
minor δ 8.20 (br, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 2.6 Hz, 1H),
7.10ꢀ7.03 (m, 1H), 6.99 (d, J = 7.2 Hz, 1H), 5.27ꢀ5.21 (m, 1H), 4.35
(d, J = 10.6 Hz, 1H), 2.48 (s, 3H), 1.40 (d, J = 6.9 Hz, 3H), 1.38 (s, 9H);
13C NMR (125 MHz, CDCl3) major δ 169.8, 135.9, 128.5, 126.0, 123.3,
120.9, 120.5, 116.9, 109.4, 85.2, 82.7, 49.1, 28.2, 18.2, 16.7; minor
δ 169.8, 136.1, 128.5, 126.0, 123.3, 121.1, 120.7, 117.1, 109.4, 84.0, 82.7,
49.1, 28.1, 18.7, 16.7; HRMS calcd for C17H22O4N2Na (M þ Na)þ
341.1472, found: m/z 341.1466; enantiomeric excess was determined by
HPLC with a Chiralcel OD-H þ Chiralpak AS-H column (95:5 hexane/
84% ee); IR (neat) 3404, 2978, 1720, 1549, 1455, 1359 cmꢀ1
.
1
Entry 7, Table 2: yellow solid; H NMR (500 MHz, CDCl3) major
2-propanol, 1.0 mL/min, 254 nm); major: minor enantiomer tR
=
31.8 min, major enantiomer tR = 34.7 min; 67% ee; [R]22.0D = þ49.8
δ 8.08 (br, 1H), 7.48 (s, 1H), 7.27ꢀ7.17 (m, 2H), 7.02 (m, 1H), 5.26ꢀ
5.19 (m, 1H), 4.39 (d, J = 9.5 Hz, 1H), 2.46 (s, 3H), 1.71 (d, J = 6.6 Hz,
3H), 1.42 (s, 9H); minor δ 8.13 (br, 1H), 7.48 (s, 1H), 7.27ꢀ7.17 (m,
2H), 7.06 (m, 1H), 5.26ꢀ5.19 (m, 1H), 4.33 (d, J = 10.9 Hz, 1H), 2.47
(s, 3H), 1.40 (d, J = 6.6 Hz, 3H), 1.38 (s, 9H); 13C NMR (125 MHz,
CDCl3) major δ 169.3, 134.4, 129.3, 126.5, 124.2, 123.5, 118.6, 111.1,
108.3, 85.0, 82.5, 48.7, 28.0, 21.7, 17.9; minor δ 170.5, 134.7, 129.2,
126.5, 124.4, 123.5, 118.7, 111.3, 108.3, 83.8, 82.3, 48.3, 27.9, 21.7, 18.6;
HRMS calcd for C17H22O4N2Na (M þ Na)þ 341.1472, found m/z
341.1466; enantiomeric excess was determined by HPLC with a Chiralpak
AD-H column (90:10 hexane/2-propanol, 1.0 mL/min, 254 nm); major:
minor enantiomer tR = 8.4 min, major enantiomer tR = 9.2 min; 87% ee;
minor: minor enantiomer tR = 7.2 min, major enantiomer tR = 12.5 min;
(c = 1.0, CHCl3, dr = 91/9, 67% ee/ND); IR (neat) 3414, 2979, 1720,
1550, 1455, 1367 cmꢀ1
.
Entry 11, Table 2: yellow oil; 1H NMR (500 MHz, CDCl3) major δ
8.24 (br, 1H), 7.72 (t, J = 7.45 Hz, 1H), 7.40 (d, J = 8.02 Hz, 1H), 7.26ꢀ
7.13 (m, 3H), 5.26ꢀ5.17 (m, 1H), 4.44 (d, J = 10.9 Hz, 1H), 4.23ꢀ4.02
(m, 2H), 2.17ꢀ2.00 (m, 1H), 1.82ꢀ1.66 (m, 1H), 1.21 (t, J = 6.9 Hz,
3H), 0.87 (t, J = 7.5 Hz, 3H); minor δ 8.16 (br, 1H), 7.72 (t, J = 7.45 Hz,
1H), 7.33 (d, J = 8.02 Hz, 1H), 7.26ꢀ7.13 (m, 3H), 5.26ꢀ5.17 (m, 1H),
4.53 (d, J = 10.9 Hz, 1H), 4.23ꢀ4.02 (m, 2H), 2.17ꢀ2.00 (m, 1H),
1.82ꢀ1.66 (m,1H), 1.16 (t, J = 7.5 Hz, 3H), 1.04 (t, J = 6.9 Hz, 3H); 13C
NMR (125 MHz, CDCl3, diastereomixture) δ 171.4, 170.7, 136,4, 136,1,
126.0(2C), 123.6(2C), 122.9, 122.7, 120.5, 120.3, 119.1(2C), 111.7, 111.5,
108.5, 108.2, 91.5, 89.3, 61.7(2C), 47.2, 45.8, 31.7, 26.3, 25.1, 22.7, 10.5,
9.6; HRMS calcd for C15H18O4N2Na (M þ Na)þ 313.1159, found m/z
313.1154; enantiomeric excess was determined by HPLC with a Chiralpak
AS-H column (90:10 hexane/2-propanol, 1.0 mL/min, 254 nm); major:
major enantiomer tR = 11.7 min, minor enantiomer tR = 12.9 min; 87% ee;
minor: minor enantiomer tR = 8.5 min, major enantiomer tR = 9.4 min;
65% ee; [R]25.1D = þ65.1 (c = 1.0, CHCl3, dr = 51/49, 88% ee/81% ee);
[R]21.5 = þ75.5 (c = 1.0, CHCl3, dr = 89/11, 87% ee/78% ee); IR
D
(neat) 3410, 2979, 1721, 1550, 1455, 1367 cmꢀ1
.
Entry 8, Table 2: yellow solid; 1H NMR (500 MHz, CDCl3) major δ
8.14 (br, 1H), 7.27ꢀ7.11 (m, 3H), 6.84 (dd, J = 8.6, 2.3 Hz, 1H), 5.25ꢀ
5.19 (m, 1H), 4.39 (d, J = 9.7 Hz, 1H), 3,87 (s, 3H), 1.72 (d, J = 6.6 Hz,
3H), 1.42 (s, 9H); minor δ 8.21 (br, 1H), 7.27ꢀ7.11 (m, 3H), 6.88 (dd,
J = 8.8, 2.3 Hz, 1H), 5.25ꢀ5.19 (m, 1H), 4.32 (d, J = 10.0 Hz, 1H), 3,86
(s, 3H), 1.40(d, J = 7.2 Hz, 3H), 1.39 (s, 9H); 13C NMR (125 MHz,
CDCl3) major δ 169.6, 154.4, 131,2, 126.7, 124.0, 112.9, 112.2, 108.5,
100.6, 84.9, 82.5, 55.9, 48.7, 28.0, 18.1; minor δ 169.6, 154.4, 131,2,
126.7, 124.2, 113.2, 112.4, 108.3, 100.6, 84.9, 82.4, 55.9, 48.7, 27.9, 18.5;
HRMS calcd for C17H22O5N2Na (M þ Na)þ 357.1421, found m/z
357.1414; enantiomeric excess was determined by HPLC with a
Chiralcel OD-H þ Chiralpak AD-H column (90:10 hexane/2-propanol,
0.8 mL/min, 254 nm); major: major enantiomer tR = 30.7 min, minor
enantiomer tR = 43.1 min; 87% ee; minor: minor enantiomer tR = 43.1
min, minor enantiomer tR = 44.8 min; 65% ee; [R]24.9D = þ85.9 (c = 1.0,
CHCl3, dr = 90/10, 87% ee/65% ee); IR (neat) 3423, 2986, 1724, 1554,
IR (neat) 3414, 2979, 1729, 1552, 1458, 1374 cmꢀ1
.
Entry 12, Table 2: yellow solid; 1H NMR (500 MHz, CDCl3) major δ
8.24 (br, 1H), 7.91ꢀ7.07 (m, 10H), 6.27 (d, J = 11.7 Hz, 1H), 5.12 (d,
J = 11.7 Hz, 1H), 3.97ꢀ3.84 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H); minor δ
8.02 (br, 1H), 7.91ꢀ7.07 (m, 10H), 7.27 (d, J = 11.7 Hz, 1H), 4.97 (d,
J = 11.5 Hz, 1H), 4.30ꢀ4.23 (m, 1H), 4.15ꢀ4.09 (m, 1H), 1.22 (t, J =
7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) major δ 169.7, 136.2, 132.9,
130.5, 129.1, 128.4, 126.1, 123.6, 122.8, 120.4, 119.3, 111.6, 108.6, 92.5,
61.5, 47.7, 13.8; minor δ 169.7, 136.2, 132.9, 130.5, 128.9, 127.7, 126.1,
124.0, 122.6, 120.3, 119.0, 111.5, 108.6, 90.2, 62.0, 47.6, 14.1; HRMS
calcd for C19H18O4N2Na (M þ Na)þ 361.1159, found m/z 361.1153;
enantiomeric excess was determined by HPLC with a Chiralpak AD-H
column (90:10 hexane/2-propanol, 1.0 mL/min, 254 nm); major: major
enantiomer tR = 33.6 min, minor enantiomer tR = 37.0 min; 66% ee;
minor: minor enantiomer tR = 20.4 min, major enantiomer tR = 22.8
min; 75% ee; [R]25.1D = þ114.8 (c = 1.0, CHCl3, dr = 77/23, 66% ee/
1457, 1368, 1153 cmꢀ1
.
Entry 9, Table 2: yellow solid; 1H NMR (500 MHz, CDCl3) major δ
8.20 (br, 1H), 7.86 (d, J = 1.7 Hz, 1H), 7.27 (dd, J = 10.3, 1.7 Hz, 1H),
7.20 (s, 1H), 7.20 (d, J = 10.3 Hz, 1H), 5.25ꢀ5.19 (m, 1H), 4.30 (d, J =
9.7 Hz, 1H), 1.71 (d, J = 6.6 Hz, 3H), 1.42 (s, 9H); minor δ 8.25 (br,
1H), 7.85 (d, J = 1.7 Hz, 1H), 7.32 (dd, J = 9.1, 1.7 Hz, 1H), 7.26 (d, J =
9.1 Hz, 1H), 7.20 (m, 1H), 5.24ꢀ5.18 (m, 1H), 4.30 (d, J = 10.6 Hz,
1H), 1.40 (d, J = 7.2 Hz, 3H), 1.38 (s, 9H); 13C NMR (125 MHz,
CDCl3) major δ 169.2, 134.7, 127.8, 125.5, 124.7, 121.7, 113.5, 113.0,
108.5, 84.8, 82.9, 48.9, 28.0, 18.2; minor δ 170.0, 135.0, 127.8, 125.8,
124.7, 121.8, 113.7, 113.2, 108.2, 83.4, 82.8, 48.2, 27.9, 18.5; HRMS calcd
for C16H19O4N2BrNa (M þ Na)þ 405.0420, found m/z 405.0411;
enantiomeric excess was determined by HPLC with a Chiralcel OD-H þ
OD-H column (90:10 hexane/2-propanol, 1.0 mL/min, 254 nm);
major: major enantiomer tR = 18.4 min, minor enantiomer tR = 22.0 min;
90% ee; minor: minor enantiomer tR = 17.3 min, major enantiomer tR =
19.5 min; 70% ee; major [R]25.0D = þ70.2 (c = 1.0, CHCl3, major only,
90% ee); minor [R]25.0D = þ56.8 (c = 1.0, CHCl3, minor only, 70% ee);
75% ee); IR (neat) 3412, 3062, 1728, 1554, 1457, 1368 cmꢀ1
.
Entry 1, Table 3: yellow oil; 1H NMR (500 MHz, CDCl3) major δ 8.70
(br, 1H), 6.75ꢀ6.74 (m, 1H), 6.13ꢀ6.11 (m, 1H), 6.10ꢀ6.08 (m, 1H),
5.08ꢀ5.02 (m, 1H), 4.28ꢀ4.10 (m, 1H), 1.60 (d, J = 6.6 Hz, 3H), 1.28
(t, J = 7.2 Hz, 3H); minor δ8.47 (br, 1H), 6.77ꢀ6.76 (m,1H), 6.17ꢀ
6.15 (m, 1H), 6.13ꢀ6.11 (m, 1H), 5.08ꢀ5.02 (m, 1H), 4.28ꢀ4.10 (m,
3H), 1.43 (d, J= 6.9 Hz, 3H), 1.23 (t, J= 7.2 Hz, 3H); 13C NMR (125 MHz,
CDCl3) major δ 169.9, 122.3, 119.1, 109.1, 108.8, 85.1, 62.2, 49.1, 17.7,
14.1; minor δ 169.9, 121.2, 119.2, 109.2, 108.8, 83.5, 62.2, 49.0, 17.8,
14.0; HRMS calcd for C10H14O4N2Na (M þ Na)þ 249.0846, found m/z
249.0845; enantiomeric excess was determined by HPLC with a
Chiralpak AD-Hþ Chiralcel OD-H column (98:2 hexane/2-propanol,
0.8 mL/min, 254 nm); major: minor enantiomer tR = 55.4 min, major
enantiomer tR = 64.6 min; 87% ee; minor: minor enantiomer tR = 53.0 min,
IR (neat) 3421, 1717, 1556, 1456, 1362, 1154 cmꢀ1
.
5454
dx.doi.org/10.1021/jo200546a |J. Org. Chem. 2011, 76, 5450–5456

The Journal of Organic Chemistry
NOTE
major enantiomer tR = 75.6 min; 84% ee; [R]24.3 = þ52.8 (c = 1.0,
(c = 1.0, CHCl3, dr = 66/34, 92% ee/86% ee); IR (neat) 3393, 2980,
D
CHCl3, dr = 84/16, 87% ee/84% ee); IR (neat) 3409, 2989, 1730, 1554,
1727, 1553, 1374 cmꢀ1
.
1361 cmꢀ1
.
Entry 6, Table 3: yellow oil; 1H NMR (500 MHz, CDCl3) major δ
8.46 (br, 1H), 6.77ꢀ6.76 (m, 1H), 6.17ꢀ6.15 (m, 1H), 6.13ꢀ6.10 (m,
1H), 5.00ꢀ4.93 (m, 1H), 4.27ꢀ4.07 (m, 3H), 1.76ꢀ1.63 (m, 2H), 1.42ꢀ
1.09 (m, 9H), 0.82 (t, J = 6.9 Hz, 3H); minor δ 8.54 (br, 1H), 6.74ꢀ6.73
(m, 1H), 6.13ꢀ6.10 (m, 1H), 6.09ꢀ6.07 (m, 1H), 5.00ꢀ4.93 (m, 1H),
4.27ꢀ4.07 (m, 3H), 2.05ꢀ1.98 (m, 2H), 1.42ꢀ1.09 (m, 9H), 0.87 (t, J =
6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) major δ 170.8, 122.1, 119.2,
109.2 (2C), 88.3, 62.2, 48.3, 32.2, 30.9, 24.7, 22.3, 14.0, 13.9; minor δ
170.0, 122.3, 119.1, 109.0, 108.9, 90.5, 62.2, 48.7, 31.5, 29.8, 25.5, 22.3, 14.2,
14.1; HRMS calcd for C14H22O4N2Na (M þ Na)þ 305.1472, found m/z
305.1466; enantiomeric excess was determined by HPLC with a Chiralpak
AS-H column (90:10 hexane/2-propanol, 1.0 mL/min, 254 nm); major:
minor enantiomer tR = 8.6 min, major enantiomer tR = 11.2 min; 89% ee;
minor: major enantiomer tR = 7.1 min, minor enantiomer tR = 7.8 min; 69%
ee; [R]22.2D = þ58.5 (c = 1.0, CHCl3, dr = 67/33, 89% ee/69% ee); IR
1
Entry 2, Table 3: yellow oil; H NMR (500 MHz, CDCl3) major δ
8.56 (br, 1H), 6.76ꢀ6.75 (m, 1H), 6.14ꢀ6.11 (m, 1H), 6.10ꢀ6.08 (m,
1H), 5.09ꢀ5.02 (m, 1H), 4.24 (d, J = 8.6 Hz, 1H), 3.76 (s, 3H), 1.60 (d, J
= 6.9 Hz, 3H); minor δ 8.41 (br, 1H), 6.78ꢀ6.76 (m, 1H), 6.14ꢀ6.11
(m, 1H), 6.10ꢀ6.08 (m, 1H), 5.09ꢀ5.02 (m, 1H), 4.26 (d, J = 9.7 Hz,
1H), 3.72 (s, 3H), 1.44 (d, J = 6.9 Hz, 3H); 13C NMR (125 MHz,
CDCl3) major δ 170.4, 122.2, 119.2, 109.2, 108.9, 85.0, 53.0, 48.9, 17.8;
minor δ 170.4, 122.2, 119.3, 109.3, 109.1, 83.3, 53.0, 48.8, 17.8; HRMS
calcd for C9H12O4N2Na (M þ Na)þ 235.0689, found m/z 235.0689;
enantiomeric excess was determined by HPLC with a Chiralpak AD-Hþ
Chiralcel OJ-H column (90:10 hexane/2-propanol, 1.0 mL/min, 254 nm);
major: minor enantiomer tR = 45.9 min, major enantiomer tR = 52.9 min;
87% ee; minor: minor enantiomer tR = 25.5 min, major enantiomer tR =
28.7min;86% ee; [R]24.6D = þ72.2 (c = 1.0, CHCl3, dr = 80/20, 87% ee/
(neat) 3395, 2928, 1723, 1550, 1372 cmꢀ1
.
86% ee); IR (neat) 3404, 2956, 1735, 1554, 1360 cmꢀ1
.
Entry 7, Table 3: yellow oil; 1H NMR (500 MHz, CDCl3) major δ
7.97 (br, 1H), 7.57 (m, 1H), 7.45ꢀ7.23 (m, 4H), 6.58ꢀ6.56 (m, 1H),
5.99ꢀ5.97 (m, 1H), 5.93 (d, J = 11.5 Hz, 1H), 5.84ꢀ5.82 (m, 1H), 4.71
(d, J = 11.5 Hz, 1H), 4.32ꢀ4.14 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H); minor
δ 8.58 (br, 1H), 7.57 (m, 1H), 7.45ꢀ7.23 (m, 4H), 6.78ꢀ6.77 (m, 1H),
6.22ꢀ6.21 (m, 1H), 6.16ꢀ6.14 (m, 1H), 5.91 (d, J = 11.7 Hz, 1H), 4.84
(d, J = 11.5 Hz, 1H), 3.98ꢀ3.86 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H); 13C
NMR (125 MHz, CDCl3) major δ 169.1, 132.1, 130.1, 129.1, 127.7,
121.1, 118.8, 109.1, 108.9, 90.9, 62.3, 49.3, 14.0; minor δ 170.6, 132.6,
130.6, 129.1, 128.3, 122.6, 119.3, 109.2, 109.0, 93.1, 61.9, 49.3, 13.7;
HRMS calcd for C15H16O4N2Na (M þ Na)þ 311.1002, found m/z
311.0996; enantiomeric excess was determined by HPLC with a Chiralpak
AS-H column (90:10 hexane/2-propanol, 0.5 mL/min, 254 nm); major:
minor enantiomer tR = 33.6 min, major enantiomer tR = 53.6 min; 91%
Entry 3, Table 3: white solid; 1H NMR (500 MHz, CDCl3) major δ
8.65 (br, 1H), 6.75ꢀ6.74 (m, 1H), 6.13ꢀ6.11 (m, 1H), 6.08ꢀ6.06 (m,
1H), 5.00ꢀ4.95 (m, 1H), 4.14 (d, J = 8.6 Hz, 1H), 1.59 (d, J = 6.9 Hz, 3H),
1.46 (s, 9H); minor δ 8.45 (br, 1H), 6.76ꢀ6.75 (m, 1H), 6.17ꢀ6.15 (m,
1H), 6.09ꢀ6.08 (m, 1H), 5.00ꢀ4.95 (m, 1H), 4.11 (d, J = 10.3 Hz, 1H),
1.42 (d, J = 6.6 Hz, 3H), 1.41 (s, 9H); 13C NMR (125 MHz, CDCl3)
major δ 168.9, 122.8, 118.9, 108.9, 108.7, 85.4, 83.3, 49.9, 27.9 17.5;
minor δ 169.8, 122.5, 118.9, 109.1, 108.9, 83.7, 83.1, 49.9, 27.8 17.8
HRMS calcd for C12H18O4N2Na (M þ Na)þ 277.1159, found m/z
277.1151; enantiomeric excess was determined by HPLC with a Chiralpak
AD-H þ Chiralcel OD-H column (95:5 hexane/2-propanol, 0.8 mL/min,
254 nm); major: minor enantiomer tR = 21.4 min, major enantiomer tR =
22.6 min; 84% ee; minor: minor enantiomer tR = 20.0 min, major
enantiomer tR = 33.5 min; 84% ee; [R]24.8D = þ31.3 (c = 1.0, CHCl3, dr =
87/13, 84% ee/84% ee); IR (neat) 3411, 2981, 1722, 1553, 1369 cmꢀ1
.
ee; minor: major enantiomer tR = 22.1 min, minor enantiomer tR
=
23.7 min; 68% ee; [R]25.6D = þ149.8 (c = 1.0, CHCl3, dr = 53/47, 91%
1
Entry 4, Table 3: yellow oil; H NMR (500 MHz, CDCl3) major δ
8.33 (br, 1H), 7.98 (m, 2H), 7.59 (t, J = 7.5 Hz, 1H), 7.46 (t, J = 7.5 Hz,
2H), 6.72ꢀ6.71 (m, 1H), 6.12ꢀ6.10 (m, 1H), 6.09ꢀ 6.07 (m, 1H),
5.32ꢀ5.22 (m, 2H), 1.61 (d, J = 6.3 Hz, 3H); minor δ 8.25 (br, 1H), 7.98
(m, 2H), 7.59 (t, J = 7.5 Hz, 1H), 7.46 (t, J = 7.5 Hz, 2H), 6.74ꢀ6.73 (m,
1H), 6.22ꢀ6.20 (m, 1H), 6.15ꢀ6.13 (m, 1H), 5.32ꢀ5.22 (m, 2H), 1.52
(d, J = 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) major δ 195.9, 135.9,
134.3, 129.1, 128.9, 122.6, 119.8, 109.8, 109.4, 86.5, 50.6, 18.6; minor δ
195.9, 135.9, 134.3, 129.1, 128.9, 122.6, 119.8, 109.8, 109.4, 86.5, 50.6,
18.6; HRMS calcd for C14H14O3N2Na (M þ Na)þ 281.0897, found
m/z 281.0891; enantiomeric excess was determined by HPLC with a
Chiralcel OJ-H column (95:5 hexane/2-propanol, 1.0 mL/min, 254 nm);
major: minor enantiomer tR = 48.5 min, major enantiomer tR = 62.3 min;
80% ee; minor: minor enantiomer tR = 22.2 min, major enantiomer tR =
30.2 min; 15% ee; [R]25.7D = þ72.5 (c = 0.25, CHCl3, dr = 93/7, 80%
ee/68% ee); IR (neat) 3401, 3037, 1727, 1554, 1370 cmꢀ1
.
Chemical Transformation of the FriedelꢀCrafts/Proton-
ation Adduct (Scheme 3). Reduction of the FriedelꢀCrafts/pro-
tonation adduct: see the procedure in ref 10b. The product obtained in
entry 3 of Table 3 was recrystallized from MeOH to give pure anti isomer
with 96% ee: 1H NMR (500 MHz, CDCl3) δ 9.23 (br, 1H), 6.73 (m,
1H), 6.13ꢀ6.11 (m, 1H), 6.03 (m, 1H), 3.35ꢀ3.27 (m, 2H), 1.44 (s, 9H),
1.11 (d, J = 5.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 172.7, 126.4,
117.7, 108.2, 107.9, 81.5, 54.1, 50.2, 28.1, 21.5; HRMS calcd for C12H21-
O2N2 (M þ H)þ 225.1598, found m/z 225.1593; enantiomeric excess
was determined by HPLC with a Chiralpak AD-H þ AS-H column
(100:1 hexane/2-propanol, 1.0 mL/min, 254 nm); major enantiomer
tR = 72.9 min, minor enantiomer tR = 97.3 min; [R]22.2D = þ12.9 (c =
0.167, CHCl3, 97% ee); IR (neat) 3385, 3186, 2977, 1719 cmꢀ1
.
ee/15% ee); IR (neat) 3410, 2931, 1675, 1551, 1361 cmꢀ1
.
PictetꢀSpengler reaction: see the procedure in ref 10b. Major
1
1
Entry 5, Table 3: yellow oil; H NMR (500 MHz, CDCl3) major δ
8.47 (br, 1H), 6.77ꢀ6.76 (m, 1H), 6.17ꢀ6.15 (m, 1H), 6.14ꢀ6.12 (m,
1H), 4.97ꢀ4.87 (m, 1H), 4.30ꢀ4.07 (m, 3H), 1.83ꢀ1.68 (m, 2H), 1.22
(t, J = 7.2 Hz, 3H), 0.89 (t, J = 7.5 Hz, 3H); minor δ 8.55 (br, 1H),
6.75ꢀ6.73 (m, 1H), 6.12ꢀ6.10 (m, 1H), 6.09ꢀ6.08 (m, 1H), 4.97ꢀ
4.87 (m, 1H), 4.30ꢀ4.07 (m, 3H), 2.08ꢀ1.99 (m, 1H), 1.84ꢀ1.71 (m,
1H), 1.27 (t, J = 7.2 Hz, 3H), 0.99 (t, J = 7.5 Hz, 3H); 13C NMR (125
MHz, CDCl3) major δ 170.8, 122.0, 119.2, 109.2(2C), 89.4, 62.2, 47.6,
24.9, 14.0, 9.5; minor δ 170.0, 122.3, 119.1, 109.0, 108.9, 91.8, 62.2, 48.4,
25.8, 14.1, 10.4; HRMS calcd for C11H16O4N2Na (M þ Na)þ 263.1002,
found m/z 263.0998; enantiomeric excess was determined by HPLC
with a Chiralcel OJ-Hþ Chiralpak AS-H column (90:10 hexane/2-propanol,
1.0 mL/min, 254 nm); major: minor enantiomer tR = 17.9 min, major
product: H NMR (500 MHz, CDCl3) δ 8.25 (br, 1H), 7.44 (d, J =
8.3 Hz, 2H), 7.24 (d, J = 8.3 Hz, 2H), 6.62ꢀ6.61 (m, 1H), 5.63ꢀ5.62
(m, 1H), 4.97 (s, 1H), 3.48ꢀ3.42 (m, 2H), 1.52 (s, 9H), 1.32 (d, J = 5.7
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 170.7, 131.7, 131.6, 130.2,
130.1, 123.0, 121.3, 117.1, 106.1, 82.1, 58.5, 52.1, 49.1, 28.3, 21.1; HRMS
calcd for C19H24O2N2Br (M þ H)þ 391.1016, found m/z 391.1006;
[R]21.9 = ꢀ14.0 (c = 0.5, CHCl3); IR (neat) 2972, 2929, 1718,
D
1156 cmꢀ1. Minor product: 1H NMR (500 MHz, CDCl3) δ 8.14 (br,
1H), 7.42 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 8.6 Hz, 2H), 6.71ꢀ6.70 (m,
1H), 5.84ꢀ5.83 (m, 1H), 4.98 (s, 1H), 3.46ꢀ3.41 (m, 1H), 3.31 (d, J =
6.3 Hz, 1H), 1.47 (s, 9H), 1.21 (d, J = 6.3 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 171.5, 131.4 (2C), 130.2 (2C), 123.2, 121.1, 117.7, 106.3,
81.9, 54.3, 48.0, 47.0, 28.3, 20.0; HRMS calcd for C19H24O2N2Br (M þ
H)þ 391.1016, found m/z 391.1006; [R]21.9D = ꢀ13.9 (c = 0.5, CHCl3);
enantiomer tR = 20.1 min; 92% ee; minor: minor enantiomer tR
=
25.6 min, major enantiomer tR = 28.1 min; 86% ee; [R]25.2D = þ80.9
IR (neat) 2971, 2925, 1716, 1152 cmꢀ1
.
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The Journal of Organic Chemistry
NOTE
’ ASSOCIATED CONTENT
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(b) Arai, T.; Wasai, M.; Yokoyama, N. J. Org. Chem. 2011, 76, 2909–2912.
(12) Catalytic asymmetric conjugate additions to nitroacrylates: (a)
Zhang, F.-G.; Yang, Q.-Q.; Xuan, J.; Lu, H.-H.; Duan, S.-W.; Chen, J.-R.;
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Supporting Information. 1H and 13C NMR spectra of
S
b
products in the FriedelꢀCrafts/protonation and in the deriva-
tization in Scheme 3. Structural determination of the Pictetꢀ
Spengler product obtained in Scheme 3. CIF files of Figures 2
and 3. This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Email: tarai@faculty.chiba-u.jp.
’ ACKNOWLEDGMENT
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan, and the Takeda Science
Foundation.
(13) Under the current optimized conditions using (S,S,S)-L2-
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99% yield with 66% ee (rt, 20 h), though the product was obtained in
99% yield with 72% ee (rt, 5 h) in.10b
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