Enantioselective synthesis of highly substituted chromans by a zinc(ii)-catalyzed tandem friedel-crafts alkylation/michael addition reaction

Article abstract of DOI:10.1055/s-0032-1318200

An enantioselective tandem Friedel-Crafts alkylation/ Michael addition reaction of 1-methylindoles with nitroolefin enoates catalyzed by a chiral tridentate bisoxazoline-Zn(II) complex has been described. This method provides an efficient route to highly substituted chromans in good isolated yields with high stereoselectivities (up to 95:5 dr and 91% ee). Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0032-1318200

PAPER
▌601
paper
Enantioselective Synthesis of Highly Substituted Chromans by a Zinc(II)-
Catalyzed Tandem Friedel–Crafts Alkylation/Michael Addition Reaction
Enantioselective Synthesis of Highly Substituted Chromans
Chao Li, Feng-Lei Liu, You-Quan Zou, Liang-Qiu Lu, Jia-Rong Chen, Wen-Jing Xiao*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University,
152 Luoyu Road, Wuhan, Hubei 430079, P. R. of China
Fax +86(27)67862041; E-mail: wxiao@mail.ccnu.edu
Received: 12.12.2012; Accepted after revision: 20.01.2013
have been devoted to the development of versatile, effi-
cient, and practical synthetic approaches to chiral chro-
man derivatives. Representative methods include
asymmetric epoxidations,10 metal-catalyzed cycliza-
Abstract: An enantioselective tandem Friedel–Crafts alkylation/
Michael addition reaction of 1-methylindoles with nitroolefin eno-
ates catalyzed by a chiral tridentate bisoxazoline-Zn(II) complex
has been described. This method provides an efficient route to high-
ly substituted chromans in good isolated yields with high stereose- tions,11 and organocatalytic transformations.12 In this re-
lectivities (up to 95:5 dr and 91% ee).
gard, our research group also developed a bifunctional
amine-thiourea-catalyzed tandem Michael/Michael addi-
tion reaction of thiols and anilines with various nitroolefin
enoates, which gave the corresponding heavily function-
alized chromans, bearing a quaternary stereocenter, in a
highly enantioselective manner.13 Encouraged by this
work, herein, we further advance the use of nitroolefin
enoates to develop a chiral Zn(II) complex-catalyzed en-
antioselective tandem Friedel–Crafts alkylation/Michael
addition reaction of 1-methylindoles. The reaction afford-
ed the highly substituted 4-(indol-3-yl)-3-nitrochromans14
with up to >95:5 dr and 91% ee (Scheme 1).
Key words: tandem reaction, Friedel–Crafts alkylation, 1-methyl-
indole, chroman, nitroolefin enoate
The tandem/domino reactions are a powerful tool in or-
ganic synthetic chemistry that allows for efficient con-
struction of complex molecules from simple starting
materials and combines a variety of transformations in a
single reaction vessel.1 In the presence of the chiral cata-
lyst, complex target compounds with functional diversity
can usually be obtained with high stereoselectivities. In
this context, the Friedel–Crafts reaction2 initiated tandem
reactions have been rarely explored, probably due to the
relatively low activity of the aromatic compounds. For ex-
ample, Yamamoto and co-workers originally applied chi-
ral LBA (Lewis acid assisted Brønsted acid) catalyst to
cascade cyclization reactions.3a–d Then, Arai and Yokoyama
developed an elegant chiral copper(I)-catalyzed three-
component tandem Friedel–Crafts alkylation/Henry reac-
tion of indole, nitroalkenes, and aldehydes to construct
acyclic products bearing three contiguous stereocenters.4
Recently, Feng and co-workers successfully developed a
highly enantioselective tandem chloroamination of α,β-
unsaturated γ-keto esters and chalcones by the use of chi-
ral N,N′-dioxide-Sc(III) complex, giving the desired prod-
ucts with excellent yields and stereoselectivities.5a These
recent achievements paved the way for the development
of novel Lewis acid catalyzed tandem reactions that are
suitable for the assembly of pharmaceutically interesting
chiral compounds.3–5
O
O
O
N
O
O
NC
OH
O
Et
O
O
O
visnadine
cromakalim
HO
O
O
H
H
siccanin
Figure 1 Examples of highly functionalized and bioactive chiral
chroman derivatives
Chroman motifs have been identified as attractive syn-
thetic targets because of their prevalence in many natural-
ly occurring products and due to their medicinally
interesting bioactivities.6 For example, visnadine7 and
cromakalim showed great vasodilatory and antihyperten-
sive effects;8 siccanin was found to be a good antifungal
drug (Figure 1).9 Therefore, considerable research efforts
At the outset, 1-methylindole (1a) and the nitroolefin eno-
ate 2a were selected as the model substrates. Commonly
used Lewis acids were examined together with C2-sym-
metric bisoxazoline 415 as the initial chiral ligand and the
results are highlighted in Table 1. It was found that only
Zn(OTf)2, Sc(OTf)3, and La(OTf)3 gave the desired cyclo-
adduct 3a (Table 1, entries 1–3), and Zn(OTf)2 afforded
the superior results with 55% yield and >95:5 dr and 72%
ee (Table 1, entry 2). A brief screening of common sol-
vents revealed that toluene was the best choice in terms of
SYNTHESIS 2013, 45, 0601–0608
Advanced online publication: 05.02.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1318200; Art ID: SS-2012-F0963-OP
© Georg Thieme Verlag Stuttgart · New York

602
C. Li et al.
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important role in the reaction. For example, in the cases of
pybox 5 and bisoxazoline 6, no desired product was
formed (Table 2, entries 2, 3). Interestingly, the use of li-
gand 7 did not result in the formation of any desired prod-
uct, probably because of the bulky steric hindrance (Table
2, entry 4). With the use of bisoxazoline 8, the corre-
sponding product 3a was obtained in a yield of 66% with
>95:5 dr but with only 45% ee (Table 2, entry 8). This
may be the result of the relatively lower steric hindrance
of 8. Using chiral ligand 9, the enantiomer of 4, the oppo-
site enantiomeric chroman product was obtained in 57%
yield with >95:5 dr and 73% ee (Table 2, entry 6). A sub-
stantial improvement of the ee and yield was realized
when the catalyst loading was increased from 10 mol% to
15 mol% (Table 2, entry 7). Finally, further screening of
other reaction parameters such as ratio of substrates, tem-
perature, and concentration lead to no further improve-
ment.
R1
Me
R1
N
N
1
Me
Zn(II)-L*
+
R2
∗
up to >95:5 dr
up to 91% ee
NO2
R2
∗
∗
NO2
CO2Et
O
CO2Et
O
3
2
Scheme
Michael addition reaction
1 Zn(II)-catalyzed tandem Friedel–Crafts alkylation/
diastereo- and enantioselectivity (Table 1, entries 2 vs 7–
13).
With the optimal Lewis acid/solvent combination identi-
fied, we screened a series of chiral bisoxazoline ligands 4–
9 (Figure 2).16 As shown in Table 2, the ligands played an
Table 1 Screening of Lewis Acids and Solvents for Tandem Reaction of 1-Methylindole (1a) and Nitroolefin Enoate 2aa
Me
N
M(OTf)n (10 mol%)
NO2
4 (10 mol%)
+
∗
N
solvent, r.t.
CO2Et
NO2
O
∗
∗
Me
CO2Et
O
1a
2a
3a
Entry
M(OTf)n
Solvent
Time (h)
Yield (%)b
drc
ee (%)d
1
Sc(OTf)3
toluene
toluene
toluene
toluene
toluene
toluene
24
24
72
72
72
72
24
24
24
72
72
72
72
45
55
25
0
>95:5
>95:5
>95:5
–
0
Zn(OTf)2
2
72
37
–
3
La(OTf)3
Cu(OTf)2
Yb(OTf)3
Mg(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
4
5
0
–
–
6
0
–
–
7
chlorobenzene
xylenes
benzene
DCE
62
63
44
45
33
0
>95:5
>95:5
>95:5
>95:5
>95:5
–
68
45
58
34
28
–
8
9
10
11
12
13
CHCl3
THF
MeCN
0
–
–
a Reaction conditions: 1a (0.36 mmol), 2a (0.30 mmol), M(OTf)n (10 mol%), and 4 (10 mol%) in toluene (2.0 mL) at r.t. under N2.
b Isolated yield.
c Determined by 1H NMR analysis.
d Determined by chiral HPLC analysis.
Synthesis 2013, 45, 601–608
© Georg Thieme Verlag Stuttgart · New York

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Enantioselective Synthesis of Highly Substituted Chromans
603
With the optimal Lewis acid complex and reaction condi-
tions established, steric and electronic variations on the 1-
methylindoles 1 and nitroolefin enoates 2 were investigat-
ed. As shown in Table 3, both electron-donating and
-withdrawing substituents are well tolerated at the 2, 5, 6,
and 7 positions of indoles and moderate to high yields and
stereoselectivities were obtained (Table 3, entries 1–7).
The scope of nitroolefin enoates was then explored and it
was found that the steric and electronic modifications on
the aromatic ring of nitroolefin enaotes have no adverse
impact on the yield, diastereo-, and enantioselectivity (Ta-
ble 3, entries 8–13, 54–80% yield; 95:5 dr, 64–91% ee).
N
O
O
N
H
Ph
Ph
N
N
O
N
N
O
Ph
Ph
5
Ph
Ph Ph
Ph
4
N
O
O
H
Ph
Ph
N
N
O
N
N
O
Ph
Ph
Ph
Ph
Ph
Ph
6
Bn Bn
7
In conclusion, we have reported a convenient and efficient
tandem Friedel–Crafts alkylation/Michael addition reac-
tion of 1-methylindoles 1 with nitroolefin enoates 2 cata-
lyzed by a chiral Lewis acid. This method provided an
atom economic and straightforward approach to optically
active 4-(indol-3-yl)-3-nitrochromans 3 in moderate to
good yields and stereoselectivities. Further work expand-
ing this reaction to other substrates is ongoing and will be
reported in due course.
N
N
H
H
O
N
N
O
O
N
N
O
Ph Ph
Ph
Ph Ph
Ph
8
9
Figure 2 Chiral bisoxazoline ligands examined in this study
Table 2 Screening of Ligands for Tandem Reaction of 1-Methylindole (1a) and Nitroolefin Enoate 2aa
Me
N
Zn(OTf)2 (X mol%)
NO2
ligand (X mol%)
+
∗
N
toluene, r.t.
CO2Et
NO2
O
∗
∗
Me
CO2Et
O
1a
2a
3a
Entry
Ligand
X
Time (h)
Yield (%)b
drc
ee (%)d
1
4
5
6
7
8
9
9
9
9
9
9
9
9
10
10
10
10
10
10
15
20
15
15
15
15
15
24
72
72
72
72
24
24
24
72
24
24
24
24
55
0
>95:5
–
72
–
2
3
0
–
–
4
0
–
–
5
64
57
66
69
59
43
55
69
56
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
45
73
83
83
83
76
62
64
77
6
7
8
9e
10f
11g
12h
13i
a Reaction conditions: 1a (0.36 mmol), 2a (0.30 mmol), Zn(OTf)2 (X mol%), and chiral ligand (X mol%) in toluene (2.0 mL) at r.t. under N2.
b Isolated yield.
c Determined by 1H NMR analysis.
d Determined by chiral HPLC analysis.
e Reaction was carried out at 0 °C.
f Toluene: 1.5 mL.
g Toluene: 3.0 mL.
h Indole 1a: 1.5 equiv.
i Indole 1a: 1.0 equiv.
© Georg Thieme Verlag Stuttgart · New York
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604
C. Li et al.
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Table 3 Substrate Scopea
Me
R1
N
Zn(OTf)2 (15 mol%)
R2
NO2
CO2Et
9 (15 mol%)
R1
+
R2
∗
N
NO2
toluene, 0.15 M
r.t., N2
O
∗
∗
Me
CO2Et
O
1
2
3
Entry
R1
R2
Yield (%)b
drc
ee (%)d
1
H
H
3a
3b
3c
3d
3e
3f
66
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
15:1
83
75
80
76
74
74
59
73
75
91
73
64
67
2
2-Me
5-Me
6-Me
7-Me
5-F
5-Br
H
H
62
55
65
62
69
55
65
61
63
54
80
77
3
H
4
H
5
H
6
H
7e
8
H
3g
3h
3i
4-F
>95:5
>95:5
95:5
9
H
4-Cl
10
11
12
13
H
4-Br
3j
H
4-MeO
5-MeO
4-Me
3k
3l
>95:5
>95:5
>95:5
H
H
3m
a Reaction conditions: 1a (0.36 mmol), 2a (0.30 mmol), Zn(OTf)2 (15 mol%), and chiral ligand 9 (15 mol%) in toluene (2.0 mL) at r.t. for 24
h under N2.
b Isolated yield.
c Determined by 1H NMR analysis.
d Determined by chiral HPLC analysis.
e Reaction was performed for 72 h.
Zn(II)-Catalyzed Tandem Friedel–Crafts Alkylation/Michael
1H NMR spectra were recorded on Varian Mercury 400/600
(400/600 MHz) spectrometers. Chemical shifts (δ) are reported in
ppm from the solvent resonance as the internal standard (CDCl3:
7.26 ppm). Data are reported as follows: chemical shift, multiplicity
(standard abbreviations were used to define multiplicities), cou-
pling constants (Hz), and integration. 13C NMR spectra were re-
corded on Varian Mercury 400/600 (100/150MHz) with complete
proton decoupling spectrometers (CDCl3: 77.0 ppm). Mass spectra
were measured on API 2000 LC/MS/MS (ESI-MS). Enantiomeric
ratios were determined by chiral HPLC on Agilent 1100 series with
chiral columns (Chiralpak AD-H column) with hexane and i-PrOH
as solvents. Optical rotations were measured with Jasco P-1020 po-
larimeter. Nitroolefin enoates 217 and chiral ligand 915 were pre-
pared according to the reported literature.
Addition Reaction of 1-Methylindoles 1 with Nitroolefin Eno-
ates 2; Ethyl 2-[4-(1-Methyl-1H-indol-3-yl)-3-nitrochroman-2-
yl]acetate (3a); Typical Procedure
To a dried Schlenk tube were added Zn(OTf)2 (16.4 mg, 0.045
mmol) and chiral ligand 9 (27.5 mg, 0.045 mmol) under N2 fol-
lowed by the addition of the toluene (2.0 mL). The solution was
stirred at r.t. for 30 min and nitroolefin enoate 2a (R2 = H) (79.0 mg,
0.30 mmol) was added. The mixture was stirred for 10 min and 1-
methylindole (1a; 47.2 mg, 0.36 mmol) was added. After stirring
for 24 h at r.t., the solvent was removed under vacuum, followed by
flash column chromatography (5% EtOAc in PE) affording the de-
sired product 3a (78.0 mg, 66% yield; 83% ee; >95:5 dr) as a yellow
solid; mp 56–58 °C; [α]D22 –66.63 (c 1.00, CHCl3).
HPLC: Chiralpak AD-H column, hexane–i-PrOH (90:10),
mL/min; 254 nm, 25 °C, t1 = 9.41 min, t2 = 12.90 min.
1
Unless otherwise noted, materials were used as commercially sup-
plied. Solvents were dried according to standard procedures. Petro-
leum ether (PE) used refers to the fraction boiling in the 60–90 °C
range. All reactions were monitored by TLC analysis with silica gel
coated plates. Flash column chromatography was performed using
200–300 mesh silica gel.
1H NMR (600 MHz, CDCl3): δ = 7.31 (d, J = 8.4 Hz, 1 H), 7.21–
7.16 (m, 2 H), 7.02 (s, 1 H), 6.96 (d, J = 6.6 Hz, 4 H), 6.81 (t, J = 7.5
Hz, 1 H), 5.20 (t, J = 10.2 Hz, 1 H), 5.08 (d, J = 10.8 Hz, 1 H), 4.89–
4.91 (m, 1 H), 4.23 (q, J = 6.9 Hz, 2 H), 3.76 (s, 3 H), 2.80 (dd,
J = 15.0, 8.4 Hz, 1 H), 2.72 (dd, J = 16.2, 3.0 Hz, 1 H), 1.29 (t,
J = 7.2 Hz, 3 H).
Synthesis 2013, 45, 601–608
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Enantioselective Synthesis of Highly Substituted Chromans
605
13C NMR (150 MHz, CDCl3): δ = 168.9, 152.6, 137.6, 129.5, 128.9,
128.3, 125.4, 122.2, 122.1, 122.0, 119.4, 119.3, 116.5, 110.3, 109.6,
88.4, 73.2, 61.1, 40.3, 37.2, 32.7, 14.1.
HRMS (ESI): m/z calcd for [C22H22N2O5 + Na+]: 417.1421; found
417.1427.
Ethyl 2-[4-(1,7-Dimethyl-1H-indol-3-yl)-3-nitrochroman-2-
yl]acetate (3e)
Prepared according to the Typical Procedure from 1e (52.2 mg, 0.36
mmol), 2a (79.0 mg, 0.30 mmol), and toluene (2.0 mL) at r.t. for 24
h; white powder (75.5 mg, 62% yield; 74% ee, >95:5 dr); mp 135–
137 °C; [α]D23 –59.80 (c 1.0, CHCl3).
Ethyl 2-[4-(1,2-Dimethyl-1H-indol-3-yl)-3-nitrochroman-2-
yl]acetate (3b)
HPLC: Chiralpak AD-H column, hexane–i-PrOH (90:10), 1.0
mL/min; 254 nm, 25 °C, t1 = 9.31 min, t2 = 14.34 min.
Prepared according to the Typical Procedure from 1b (52.2 mg,
0.36 mmol), 2a (79.0 mg, 0.30 mmol), and toluene (2.0 mL) at r.t.
for 24 h; yellow solid (75.7 mg, 62% yield, 75% ee, >95:5 dr); mp
158–160 °C; [α]D24 –48.69 (c 1.03, CHCl3).
1H NMR (600 MHz, CDCl3): δ = 7.16 (t, J = 7.7 Hz, 1 H), 6.94 (d,
J = 7.8 Hz, 2 H), 6.90 (s, 1 H), 6.87 (d, J = 7.2 Hz, 1 H), 6.81 (t,
J = 7.5 Hz, 2 H), 6.77 (d, J = 7.2 Hz, 1 H), 5.19 (t, J = 10.2 Hz, 1
H), 5.04 (d, J = 10.4 Hz, 1 H), 4.87–4.90 (m, 1 H), 4.22 (q, J = 7.2
Hz, 2 H), 4.02 (s, 3 H), 2.80 (dd, J = 16.2, 8.4 Hz, 1 H), 2.72 (m, 4
H), 1.29 (t, J = 6.9 Hz, 3 H).
HPLC: Chiralpak AD-H column, hexane–i-PrOH (95:5), 0.7
mL/min; 254 nm, 25 °C, t1 = 14.57 min, t2 = 22.74 min.
13C NMR (100 MHz, CDCl3): δ = 169.0, 152.6, 136.4, 130.5, 129.5,
128.3, 126.5, 124.7, 122.2, 122.1, 121.7, 119.7, 117.4, 116.5, 109.9,
88.2, 73.2, 61.1, 40.2, 37.2, 36.8, 19.7, 14.1.
HRMS (ESI): m/z calcd for [C23H24N2O5 + Na+]: 431.1577; found:
431.1580.
1H NMR (400 MHz, CDCl3): δ = 7.25 (d, J = 6.4 Hz, 1 H), 7.10–
7.17 (m, 2 H), 6.95 (d, J = 7.6 Hz, 1 H), 6.84 (d, J = 6.8 Hz, 2 H),
6.78 (d, J = 7.6 Hz, 1 H), 6.66 (d, J = 7.6 Hz, 1 H), 5.25 (t, J = 9.6
Hz, 1 H), 5.11 (d, J = 10.2 Hz, 1 H), 4.89–4.94 (m, 1 H), 4.23 (q,
J = 7.6 Hz, 2 H), 3.67 (s, 3 H), 2.81 (dd, J = 16.0, 7.9 Hz, 1 H), 2.73
(dd, J = 1.6, 0.4 Hz, 1 H), 2.40 (s, 3 H), 1.29 (t, J = 7.0 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 169.0, 152.7, 137.3, 136.4, 129.3,
128.1, 124.6, 122.2, 122.1, 121.0, 119.2, 118.6, 116.4, 108.9, 106.3,
87.4, 73.4, 61.1, 39.8, 37.2, 29.6, 14.1, 9.90.
HRMS (ESI): m/z calcd for [C23H24N2O5 + Na+]: 431.1577; found:
431.1555.
Ethyl 2-[4-(5-Fluoro-1-methyl-1H-indol-3-yl)-3-nitrochroman-
2-yl]acetate (3f)
Prepared according to the Typical Procedure from 1f (53.6 mg, 0.36
mmol), 2a (79.0 mmol, 0.30 mmol), and toluene (2.0 mL) at r.t. for
24 h; white powder (82.9 mg, 69% yield; 74% ee, >95:5 dr); mp
108–110 °C; [α]D24 –54.23 (c 1.0, CHCl3).
Ethyl 2-[4-(1,5-Dimethyl-1H-indol-3-yl)-3-nitrochroman-2-
yl]acetate (3c)
HPLC: Chiralpak AD-H column, hexane–i-PrOH (90:10), 1.0
mL/min; 254 nm, 25 °C, t1 = 11.25 min, t2 = 14.89 min.
Prepared according to the Typical Procedure from 1c (52.2 mg, 0.36
mmol), 2a (79.0 mg, 0.30 mmol), and toluene (2.0 mL) at r.t. for 24
h; yellow solid (68.8 mg, 55% yield; 80% ee, >95:5 dr); mp 148–
150 °C; [α]D23 –53.48 (c 0.99, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.15–7.24 (m, 2 H), 7.04 (s, 1 H),
6.96–6.90 (m, 3 H), 6.81 (t, J = 7.6 Hz, 1 H), 6.57 (q, J = 2.4 Hz, 1
H) 5.13–5.18 (m, 1 H), 5.02 (d, J = 10.8 Hz, 1 H), 4.85–5.00 (m, 1
H), 4.24 (q, J = 3.0 Hz, 2 H), 3.66 (s, 3 H), 2.80 (dd, J = 15.8, 7.8
Hz, 1 H), 2.72 (dd, J = 16.0, 3.6 Hz, 1 H), 1.26–1.31 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.9, 158.6, 156.3, 152.6, 134.2,
130.5, 129.3, 128.5, 125.7, 125.6, 122.1, 121.6, 116.6, 110.6, 110.5,
110.4, 110.3 110.2, 104.4, 104.1, 88.3, 73.2, 61.1, 40.3, 37.1, 33.0,
14.1.
HPLC: Chiralpak AD-H column, hexane–i-PrOH (95:5), 0.7
mL/min; 254 nm, 25 °C, t1 = 16.84 min, t2 = 21.22 min.
1H NMR (400 MHz, CDCl3): δ = 7.14–7.19 (m, 2 H), 6.95–7.02 (m,
4 H), 6.80 (t, J = 7.4 Hz, 1 H), 6.70 (s, 1 H), 5.18 (t, J = 10.2 Hz, 1
H), 5.04 (d, J = 10.4 Hz, 1 H), 4.88–4.93 (m, 1 H), 4.22 (q, J = 7.1
Hz, 2 H), 3.70 (s, 3 H), 2.80 (dd, J = 15.6, 8.0 Hz, 1 H), 2.72 (dd,
J = 15.8, 3.4 Hz, 1 H), 2.30 (s, 3 H), 1.29 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.0, 152.6, 136.0, 129.5, 128.9,
128.6, 128.3, 125.7, 123.7, 122.3, 122.1, 118.8, 116.5, 109.6, 109.3,
88.4, 73.3, 61.1, 40.3, 37.3, 32.8, 21.4, 14.1.
HRMS (ESI): m/z calcd for [C22H21FN2O5 + Na+]: 435.1327; found:
435.1302.
Ethyl 2-[4-(5-Bromo-1-methyl-1H-indol-3-yl)-3-nitrochroman-
2-yl]acetate (3g)
Prepared according to the Typical Procedure from 1g (75.6 mg, 0.36
mmol), 2a (79.0 mmol, 0.30 mmol), and toluene (2.0 mL) at r.t. for
24 h; white powder (77.7 mg, 55% yield; 59% ee, 15:1 dr); mp 153–
154 °C; [α]D25 –40.82 (c 1.0, CHCl3).
HRMS (ESI): m/z calcd for [C23H24N2O5 + Na+]: 431.1577; found:
431.1574.
Eethyl 2-[4-(1,6-Dimethyl-1H-indol-3-yl)-3-nitrochroman-2-
yl]acetate (3d)
Prepared according to the Typical Procedure from 1d (52.2 mg,
0.36 mmol), 2a (79.0 mg, 0.30 mmol), toluene (2.0 mL) at r.t. for
24 h; yellow solid (83.9 mg, 65% yield; 76% ee, >95:5 dr); mp 129–
131 °C; [α]D25 –63.37 (c 0.98, CHCl3).
HPLC: Chiralpak AD-H column, hexane–i-PrOH (95:5), 0.7
mL/min; 254 nm, 25 °C, t1 = 26.73 min, t2 = 33.18 min.
1H NMR (400 MHz, CDCl3): δ = 7.26 (s, 2 H), 7.18 (t, J = 9.2 Hz,
2 H), 7.03 (d, J = 15.6 Hz, 2 H), 6.96 (d, J = 8.8 Hz, 1 H), 6.89 (d,
J = 7.6 Hz, 1 H), 6.80 (t, J = 7.4 Hz, 1 H), 5.15 (t, J = 9.8 Hz, 1 H),
5.03 (d, J = 12.4 Hz, 1 H), 4.89–4.92 (m, 1 H), 4.23 (q, J = 7.2 Hz,
2 H), 3.74 (s, 3 H), 2.80 (dd, J = 16.0, 7.2 Hz, 1 H), 2.72 (dd,
J = 20.0, 3.6 Hz, 1 H), 1.30 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.9, 152.5, 136.3, 130.0, 129.2,
128.6, 127.1, 125.0, 122.2, 121.7, 121.6, 116.7, 112.9, 111.2, 109.9,
88.3, 73.2, 61.2, 40.2, 37.2, 33.0, 14.1.
HPLC: Chiralpak AD-H column, hexane–i-PrOH (95:5), 0.7
mL/min; 254 nm, 25 °C, t1 = 17.35 min, t2 = 24.79 min.
1H NMR (400 MHz, CDCl3): δ = 7.16 (t, J = 7.6 Hz, 1 H), 7.10 (s,
1 H), 7.00–6.91 (m, 3 H), 6.80 (q, J = 7.8 Hz, 3 H), 5.18 (t, J = 10.2
Hz, 1 H), 5.04 (d, J = 10.0 Hz, 1 H), 4.86–4.91 (m, 1 H), 4.22 (q,
J = 7.1 Hz, 2 H), 3.70 (s, 3 H), 2.80 (dd, J = 16.0, 7.8 Hz, 1 H), 2.72
(dd, J = 15.8, 3.4 Hz, 1 H), 2.44 (s, 3 H), 1.29 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.0, 152.6, 138.0, 131.9, 129.5,
128.4, 128.3, 123.3, 122.2, 122.1, 121.2, 119.0, 116.5, 110.1, 109.7,
88.5, 73.2, 61.1, 40.4, 37.2, 32.7, 21.8, 14.1.
HRMS (ESI): m/z calcd for [C22H21BrN2O5 + Na+]: 495.0526;
found: 495.0530.
Ethyl 2-[6-Fluoro-4-(1-methyl-1H-indol-3-yl)-3-nitrochroman-
2-yl]acetate (3h)
Prepared according to the Typical Procedure from 1a (47.2 mg, 0.36
mmol), 2b (84.3 mg, 0.30 mmol), and toluene (2.0 mL) at r.t. for 24
HRMS (ESI): m/z calcd for [C23H24N2O5 + Na+]: 431.1577; found:
431.1577.
© Georg Thieme Verlag Stuttgart · New York
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606
C. Li et al.
PAPER
h; yellow solid (80.7 mg, 65% yield; 73% ee, >95:5 dr); mp 165–
1H NMR (600 MHz, CDCl3): δ = 7.29 (d, J = 7.8 Hz, 1 H), 7.19 (t,
J = 7.2 Hz, 1 H), 6.97–7.02 (m, 3 H), 6.88 (d, J = 9.0 Hz, 1 H), 6.73
(d, J = 8.4 Hz, 1 H), 6.48 (s, 1 H), 5.17 (t, J = 10.2 Hz, 1 H), 5.05
(d, J = 10.2 Hz, 1 H), 4.83 (m, 1 H), 4.22 (d, J = 6.6 Hz, 2 H), 3.75
(s, 3 H), 3.53 (s, 3 H), 2.78 (dd, J = 16.2, 8.4 Hz, 1 H), 2.72 (dd,
J = 16.0, 3.4 Hz, 1 H), 1.29 (t, J = 6.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.0, 154.5, 146.8, 137.6, 128.8,
125.5, 123.2, 121.9, 119.4, 119.3, 117.3, 114.3, 113.9, 110.3, 109.6,
88.8, 73.3, 61.1, 55.6, 40.4, 37.2, 32.7, 14.1.
167 °C; [α] D25 –71.82 (c 0.99, CHCl3).
HPLC: Chiralpak AD-H column, hexane–i-PrOH (90:10), 1.0
mL/min; 254 nm, 25 °C, t1 = 9.39 min, t2 = 15.24 min.
1H NMR (600 MHz, CDCl3): δ = 7.32 (d, J = 6.4 Hz, 1 H), 7.21 (t,
J = 7.2 Hz, 1 H), 7.02–6.98 (m, 3 H), 6.92–6.86 (m, 2 H), 6.65 (d,
J = 8.4 Hz, 1 H), 5.20 (t, J = 9.9 Hz, 1 H), 5.04 (d, J = 10.8 Hz, 1
H), 4.85–4.87 (m, 1 H), 4.22 (q, J = 7.5 Hz, 2 H), 3.77 (s, 3 H), 2.80
(dd, J = 16.2, 7.8 Hz, 1 H), 2.72 (dd, J = 16.2, 3.6 Hz, 1 H), 1.29 (t,
J = 7.2 Hz, 3 H).
HRMS (ESI): m/z calcd for [C23H24N2O6 + Na+]: 447.1527; found:
447.1514.
13C NMR (100 MHz, CDCl3): δ = 168.9, 158.9, 156.5, 148.7, 137.6,
128.9, 125.2, 123.9, 123.8, 122.1, 119.6, 119.1, 117.8, 117.7, 115.5,
115.3, 109.8, 109.7, 88.0, 73.4, 61.1, 40.3, 37.1, 32.8, 14.1.
HRMS (ESI): m/z calcd for [C22H21FN2O5 + Na+]: 435.1327; found:
435.1307.
Ethyl 2-[7-Methoxy-4-(1-methyl-1H-indol-3-yl)-3-nitrochro-
man-2-yl]acetate (3l)
Prepared according to the Typical Procedure from 1a (47.2 mg, 0.36
mmol), 2f (87.9 mg, 0.30 mmol), and toluene (2.0 mL) at r.t. for 24
h; yellow solid (102.3 mg, 80% yield; 64% ee, >95:5 dr); mp 100–
102 °C; [α]D25 –55.32 (c 1.0, CHCl3).
Ethyl 2-[6-Chloro-4-(1-methyl-1H-indol-3-yl)-3-nitrochroman-
2-yl]acetate (3i)
Prepared according to the Typical Procedure from 1a (47.2 mg, 0.36
mmol), 2c (89.3 mg, 0.30 mmol), and toluene (2.0 mL) at r.t. for 24
h; yellow solid (77.9 mg, 61% yield; 75% ee, >95:5 dr); mp 165–
167 °C; [α]D25 –7.05 (c 1.0, CHCl3).
HPLC: Chiralpak AD-H column, hexane–i-PrOH (90:10), 1.0
mL/min; 254 nm, 25 °C, t1 = 11.35 min, t2 = 16.21 min.
1H NMR (400 MHz, CDCl3): δ = 7.28 (d, J = 8.4 Hz, 1 H), 7.18 (m,
1 H), 6.92–6.97 (m, 3 H), 6.81 (d, J = 8.4 Hz, 1 H), 6.49 (d, J = 2.4
Hz, 1 H), 6.38 (m, 1 H), 5.16 (t, J = 10.0 Hz, 1 H), 4.98 (d, J = 10.4
Hz, 1 H), 4.87–4.92 (m, 1 H), 4.20 (q, J = 7.4 Hz, 2 H), 3.69 (s, 3
H), 3.66 (s, 3 H), 2.79 (dd, J = 16.0, 8.0 Hz, 1 H), 2.70 (dd,
J = 16.0.0, 5.4 Hz, 1 H), 1.29 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.9, 159.7, 153.3, 137.6, 130.1,
128.8, 125.4, 121.9, 119.4, 119.3, 114.0, 110.4, 109.6, 109.2, 101.0,
88.5, 73.3, 61.1, 55.3, 40.0, 37.1, 32.7, 14.1.
HPLC: Chiralpak AD-H column, hexane–i-PrOH (90:10), 1.0
mL/min; 254 nm, 25 °C, t1 = 10.57 min, t2 = 18.28 min.
1H NMR (600 MHz, CDCl3): δ = 7.32 (d, J = 6.4 Hz, 1 H), 7.23 (s,
1 H), 7.21 (t, J = 3.6 Hz, 1 H), 7.12 (d, J = 9.0 Hz, 1 H), 7.00 (d,
J = 12.0 Hz, 3 H), 6.93 (s, 1 H), 6.89 (d, J = 6.4 Hz, 1 H), 5.20 (t,
J = 10.2 Hz, 1 H), 5.03 (d, J = 10.8 Hz, 1 H), 4.85–4.89 (m, 1 H),
4.22 (q, J = 6.6 Hz, 2 H), 3.77 (s, 3 H), 2.79 (dd, J = 16.2, 8.4 Hz, 1
H), 2.72 (dd, J = 15.9, 3.3 Hz, 1 H), 1.29 (t, J = 7.2 Hz, 3 H).
HRMS (ESI): m/z calcd for [C23H24N2O5 + Na+]: 447.1527; found:
447.1510.
13C NMR (100 MHz, CDCl3): δ = 168.8, 151.2, 137.6, 128.9, 128.5,
127.1, 125.2, 124.1, 122.1, 119.6, 119.0, 118.0, 109.8, 109.4, 87.8,
73.4, 61.2, 40.1, 37.0, 32.8, 14.1.
HRMS (ESI): m/z calcd for [C22H21ClN2O5 + Na+]: 451.1031;
found: 451.1035.
Ethyl 2-[6-Methyl-4-(1-methyl-1H-indol-3-yl)-3-nitrochroman-
2-yl]acetate (3m)
Prepared according to the Typical Procedure from 1a (47.2 mg, 0.36
mmol), 2g (83.1 mg, 0.30 mmol), and toluene (2.0 mL) at r.t. for 24
h; yellow solid (94.9 mg, 77% yield; 67% ee, >95:5 dr); mp 164–
167 °C; [α]D25 –25.75 (c 1.0, CHCl3).
Ethyl 2-[6-Bromo-4-(1-methyl-1H-indol-3-yl)-3-nitrochroman-
2-yl]acetate (3j)
Prepared according to the general procedure from 1a (47.2 mg, 0.36
mmol), 2d (1.03 g, 0.30 mmol), and toluene (2.0 mL) at r.t. for 24
h; yellow solid (89.4 mg, 63% yield; 91% ee, 95:5 dr); mp 87–88
°C; [α]D22 +16.25 (c 0.99, CHCl3).
HPLC: Chiralpak AD-H column, hexane–i-PrOH (90:10), 1.0
mL/min; 254 nm, 25 °C, t1 = 10.04 min, t2 = 15.48 min.
1H NMR (600 MHz, CDCl3): δ = 7.16 (d, J = 8.4 Hz, 1 H), 7.20 (t,
J = 7.5 Hz, 1 H), 6.95–7.01 (m, 4 H), 6.84 (d, J = 8.4 Hz, 1 H), 6.75
(s, 1 H), 5.17 (t, J = 9.9 Hz, 1 H), 5.03 (d, J = 10.8 Hz, 1 H), 4.84–
4.86 (m, 1 H), 4.22 (q, J = 7.2 Hz, 2 H), 3.76 (s, 3 H), 2.78 (dd,
J = 15.9, 7.5 Hz, 1 H), 2.70 (dd, J = 15.9, 3.3 Hz, 1 H), 2.01 (s, 3 H),
1.29 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.0, 150.5, 137.6, 131.4, 129.5,
129.0, 128.7, 125.6, 121.9, 119.4, 119.3, 116.3, 110.5, 109.6, 88.7,
73.2, 61.0, 40.2, 37.2, 32.7, 20.5, 14.1.
HPLC: Chiralpak AD-H column, hexane–i-PrOH (90:10), 1.0
mL/min; 254 nm, 25 °C, t1 = 11.45 min, t2 = 20.01 min.
1H NMR (600 MHz, CDCl3): δ = 7.32 (d, J = 7.8 Hz, 1 H), 7.21–
7.27 (m, 3 H), 7.10 (s, 1 H), 7.00 (d, J = 6.0 Hz, 3 H), 6.80 (d,
J = 8.4 Hz, 1 H), 5.20 (t, J = 10.2 Hz, 1 H), 5.03 (d, J = 10.2 Hz, 1
H), 4.85–4.88 (m, 1 H), 4.22 (q, J = 7.2 Hz, 2 H), 3.77 (s, 3 H), 2.79
(dd, J = 15.9, 8.1 Hz, 1 H), 2.72 (dd, J = 16.2, 3.0 Hz, 1 H), 1.29 (t,
J = 7.2 Hz, 3 H).
HRMS (ESI): m/z calcd for [C23H24N2O5 + Na+]: 431.1577; found:
431.1566.
13C NMR (150 MHz, CDCl3): δ = 168.8, 151.8, 137.6, 131.9, 131.4,
128.9, 125.2, 124.6, 122.1, 119.7, 119.0, 118.4, 114.4, 109.8, 109.4,
87.8, 73.4, 61.2, 40.0, 37.0, 32.8, 14.1.
Acknowledgment
HRMS (ESI): m/z calcd for [C22H21BrN2O5 + Na+]: 497.0511;
We are grateful to the National Science Foundation of China (NO.
21002036, 21072069, 21232003 and 21202053) and the National
Basic Research Program of China (2011CB808600) for support of
this research. We thank Dr. Richard Pederson at Materia, Inc. for
fruitful discussions.
found: 497.0508.
Ethyl 2-[6-Methoxy-4-(1-methyl-1H-indol-3-yl)-3-nitrochro-
man-2-yl]acetate (3k)
Prepared according to the Typical Procedure from 1a (47.2 mg, 0.36
mmol), 2e (87.9 mg, 0.30 mmol), and toluene (2.0 mL) at r.t. for 24
h; yellow solid (68.3 mg, 54% yield; 73% ee, >95:5 dr); mp 67–69
°C; [α]D24 –26.10 (c 1.0, CHCl3).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
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HPLC: Chiralpak AD-H column, hexane–i-PrOH (90:10), 1.0
mL/min; 254 nm, 25 °C, t1 = 14.55 min, t2 = 22.98 min.
Synthesis 2013, 45, 601–608
© Georg Thieme Verlag Stuttgart · New York

PAPER
Enantioselective Synthesis of Highly Substituted Chromans
607
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