Enantioselective friedel-crafts alkylation of N-methylindoles with nitroalkenes catalyzed by chiral bifunctional abietic-acid-derived thiourea-ZnII complexes

Article abstract of DOI:10.1002/ejoc.201200584

The catalytic asymmetric Friedel-Crafts alkylation of N-methylindoles with nitroalkenes catalyzed by bifunctional abietic-acid-derived thiourea-Zn ^II complexes was investigated. Various types of the nitroalkylated indoles were synthesized under

Full text of DOI:10.1002/ejoc.201200584

Job/Unit: O20584
/KAP1
Date: 30-08-12 15:52:21
Pages: 6
FULL PAPER
DOI: 10.1002/ejoc.201200584
Enantioselective Friedel–Crafts Alkylation of N-Methylindoles with
Nitroalkenes Catalyzed by Chiral Bifunctional Abietic-Acid-Derived
Thiourea-ZnII Complexes
Wei-gen Huang,[a] Heng-shan Wang,*[a] Guo-bao Huang,[a] Yong-ming Wu,[a] and
Ying-ming Pan*[a]
Keywords: Asymmetric synthesis / C–C coupling / Friedel–Crafts alkylation / Zinc / Aromatic substitution / Nitroalkenes
The catalytic asymmetric Friedel–Crafts alkylation of N-
thesized under mild conditions and obtained with excellent
methylindoles with nitroalkenes catalyzed by bifunctional yields (up to 99%) and good enantioselectivities (up to
abietic-acid-derived thiourea-ZnII complexes was investi-
gated. Various types of the nitroalkylated indoles were syn-
86%ee). These chiral thiourea catalysts are easily available
from the commercial abietic acid.
Introduction
acid are highly efficient in chiral recognition.[9] Encouraged
by the successful use of abietic acid derivatives, we specu-
lated that the strategy of modifying its functional groups
might be additionally exploited to design a new class of
chiral thiourea catalysts for Friedel–Crafts reactions.
The Friedel–Crafts alkylation[1] of indoles with nitroalk-
enes is one of the most powerful and classical approaches
to carbon–carbon bond formation in asymmetric synthesis
and has become a matter of current interest.[2] As one of
the most ubiquitous scaffolds, the indole skeleton is widely
distributed in a number of natural products and pharma-
ceutical molecules, agrochemicals, and functional materi-
als.[3] Furthermore, nitroalkenes are very attractive Michael
acceptors,[4] and their adducts are amenable to transforma-
tion into a wide range of valuable synthetic building
blocks.[5] Due to the usefulness of nitroalkylated indole
compounds, the development of new strategies to synthesize
indole derivatives remains a challenging topic.
Over the past two decades, many types of chiral thiourea
catalysts,[6] especially bifunctional thiourea catalysts,[6a,7]
have been designed, synthesized, and emerged for asymmet-
ric catalytic reactions. Naturally available commercial abi-
etic acid derivatives promise to be marvelous starting mate-
rials for preparing chiral ligands because of their absolute
optical purities and very stable stereochemistry structures.
In our previous works, we have reported that abietic acid
derivatives have been used in the separations of d/l amino
acids by capillary electrophoresis.[8] Furthermore, our cur-
rent study has shown that crown ethers based on abietic
Extensive studies on the Friedel–Crafts reaction of in-
doles with nitroalkenes have been well documented, how-
ever, the reaction between nitroalkenes and N-blocked in-
doles has only been explored with very limited success. Pre-
vious efforts by Connon[10] and Jørgensen[11] used a chiral
bis-arylthiourea catalyst and a chiral bis-sulfonamide cata-
lyst to improve the reaction between challenging substrates
such as N-methylindole and nitroalkenes. However, only
moderate yields and enantioselectivities (up to 91% and
50%ee, respectively) were obtained and long reaction times
(up to 287 h and 60 h, respectively) and low temperatures
(–30 °C and –24 °C, respectively) were required with the
above catalysts. Recently, Wan and coworkers[2d] investi-
gated a bis-sulfonamide diamine–Cu(OTf)2 complex for the
Friedel–Crafts alkylation of indole with nitroalkenes, af-
fording excellent yields and enantioselectivities except in the
case of substrates of N-methylindole (51% yield, 17%ee),
which suggests that N-blocked indole was not an effective
substrate in the catalytic system. Moreover, Du and co-
workers[12] have developed a more practical and efficient
catalytic asymmetric Friedel–Crafts alkylation of indole de-
rivatives with nitroalkenes using a bifunctional tridentate
bis(oxazoline)–Zn(OTf)2 catalyst. However, the search for
new catalysts for this reaction is still challenging and desir-
able, and to the best of our knowledge, there is no report
on the Friedel–Crafts alkylation of indole with nitroalkene
catalyzed by primary amine–thiourea catalysts. Herein, we
first report the synthesis of chiral thiourea bifunctional
[a] Key Laboratory for the Chemistry and Molecular Engineering
of Medicinal Resources (Ministry of Education of China),
School of Chemistry & Chemical Engineering of Guangxi
Normal University,
Guilin 541004, People’s Republic of China
Fax: +86-773-5803930
E-mail: wang_hengshan@yahoo.com.cn;
panym2004@yahoo.com.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200584.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O20584
/KAP1
Date: 30-08-12 15:52:21
Pages: 6
W.-g. Huang, H.-s. Wang, G.-b. Huang, Y.-m. Wu, Y.-m. Pan
FULL PAPER
based on abietic acid and their metal complexes as catalysts,
We firstly examined the reaction between N-methylindole
and aim to expand the applications of abietic acid deriva- and nitrostyrene with 10 mol-% of thiourea catalysts L1–
tives and promote the asymmetric Friedel–Crafts alkylation L7 in toluene at room temperature, however, the reaction
of N-methylindole with nitroalkenes under mild conditions. proceeded slowly in low yields (16–53%) after 48 h and the
enantiomeric excess of the product was zero or negligible.
Inspired by the ability of a metal complex and an organic
Results and Discussion
molecule to cooperatively catalyze an asymmetric reac-
tion,[2a–2c,12a–12c] we employed Zn(OTf)2 as a Lewis acid. To
Initially, our attention was especially focused on abietic-
acid-derived thioureas containing a primary amine[13] or
amino alcohol[14] moiety as bifunctional catalysts. As
shown in Scheme 1, starting from commercially available
natural abietic acid derivatives, nordehydroabietic isothiocy-
anate (NDHAIC) was designed, and we first synthesized a
novel primary amine-thiourea bifunctional catalyst L3 by
condensation of the chiral (S,S)-1,2-diaminocyclohexane
with NDHAIC. Using the same procedure, thiourea cata-
lysts L1, L2, and L4–L7 were also synthesized[15] (Figure 1)
and evaluated as chiral catalysts for the asymmetric Frie-
del–Crafts alkylation of N-methylindole with nitroalkenes;
the results are summarized in Table 1.
our delight, in the presence of 10 mol-% of Zn(OTf)2, in-
dole reacted smoothly with nitrostyrene (Table 1, Entries 1–
7), giving the product 3a in high yields (up to 99%) and
with good enantioselectivities (up to 78%). In particular,
L3 was found to be the best choice of catalyst and gave a
fast reaction (within 5 h) and excellent yield (99%) (Table 1,
Entry 3). These results indicated that Zn(OTf)2 might ef-
ficiently coordinate with bifunctional thiourea catalysts.
Notably, catalysts L1–L4, which contain a primary amine
moiety, could obtain higher yields and required shorter re-
action times than those of L5–L7 (Table 1, Entries 1–4 vs.
Entries 5–7).
Scheme 1. Preparation of abietic-acid-derived thiourea catalysts. Reagents and conditions: (a) SOCl2, dry dichloromethane (DCM), 8 h,
95%; (b) NaN3, H2O; (c) 100 °C; (d) HCl, NaOH, toluene, 24 h, 72%; (e) CS2, N,NЈ-dicyclohexylcarbodiimide (DCC), dry Et2O, 15 h,
92%; (f) CH2Cl2, 16 h, 75%.
Figure 1. Chiral thiourea bifunctional catalysts used in this study.
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20584
/KAP1
Date: 30-08-12 15:52:21
Pages: 6
Alkylation of N-Methylindoles with Nitroalkenes
Table 1. The application of ligands L1–L7/Zn(OTf)2 in the asym-
metric Friedel–Crafts alkylation of indole 1a with nitrostyrene 2a.[a]
Table 3. Effect of ligands in the Zn(OTf)2-catalyzed Friedel–Crafts
alkylation of indole 1a with nitrostyrene 2a.[a]
Entry
Solvent
T [°C] Cat. [mol-%] t [h] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
toluene
EtOAc
CHCl3
DCM
THF
PhCl
toluene
toluene
toluene
toluene
toluene
toluene
toluene
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
–20
0
20
35
45
35
35
10
10
10
10
10
10
10
10
10
10
10
5
5
7
6.5
5
5
9
24
24
8
99
98
98
97
96
98
0
trace
98
99
99
98
99
78
0
8
53
7
48
n.d.
n.d.
73
80
76
72
81
Entry
Ligand
Time [h]
Yield [%][b]
ee [%][c]
9
1
2
3
4
5
6
7
L1
L2
L3
L4
L5
L6
L7
7
6.5
5
98
98
99
98
76
71
86
4 (S)
5 (S)
78 (R)
2 (R)
5 (S)
2 (S)
12 (S)
10
11
12
13
2
1.5
10
2
6
20
24
24
24
[a] Reaction conditions: indole 1a (0.75 mmol) with nitrostyrene 2a
(0.50 mmol) in toluene (2 mL) using 10 mol-% L3/Zn(OTf)2 com-
plex as the catalyst. [b] Isolated yield. [c] Determined by HPLC
with a Daicel Chiracel AS-H column (hexane/2-propanol = 90:10,
1.0 mL/min).
[a] Reaction conditions: indole 1a (0.75 mmol) with nitrostyrene 2a
(0.50 mmol) in 2 mL of toluene using 10 mol-% L1–L7 and 10 mol-
% Zn(OTf)2 as the catalyst at room temp. [b] Isolated yield. [c] The
ee values were determined by HPLC with a Daicel Chiracel AS-H
column (hexane/2-propanol = 90:10, 1.0 mL/min), and the configu-
ration was assigned by comparison of the HPLC data and specific
rotation with literature data.[12a]
more, with a catalyst loading of 5 or 20 mol-%, the result
did not show any beneficial effect to this reaction (En-
tries 12 and 13). Therefore, we finally determined that using
10 mol-% L3/Zn(OTf)2 in toluene at 35 °C to catalyze the
reaction was the most efficient.
Having identified the best catalyst (L3) for the conjugate
addition, we further screened different metal salts, solvents,
temperature, and catalyst loading. As shown in Table 2,
among the Lewis acids used, Zn(OTf)2 gave the best result
(Table 2, Entry 6). On the contrary, when other metallic
triflate salts (Entries 1–5) or other zinc metal Lewis acids
(Entries 7 and 8) were employed as a Lewis acid in situ with
L3, the results were not satisfactory.
In order to extend the scope of the reaction, a wide range
of nitroalkenes and N-methylindoles were catalyzed by the
L3/Zn(OTf)2 complexes under the optimized reaction con-
ditions (Table 4). In most cases, excellent yields and good
ee values were obtained for the corresponding products (up
to 99% yield and 86%ee). As summarized in Table 4, the
electronic effects were almost negligible, i.e., the electron-
withdrawing systems (Table 4, Entries 2–5) reacted
smoothly, as well as the electron-donating (Table 4, En-
tries 6–8) and neutral systems (Table 4, Entry 1). A het-
eroaromatic nitroalkene was also found to react successfully
with N-methylindole to generate adduct 3j in 99% yield and
79%ee (Table 4, Entry 10). Furthermore, a nitroalkene
bearing a polycyclic aromatic substituent, 2-naphthylni-
troalkene, was treated with N-methylindole to give the cor-
responding product in excellent yields and good enantio-
selectivities (Table 4, Entries 11 and 15). The nitroalkene
derived from 1,3-benzodioxole also gave the adduct in
76%ee (Table 4, Entry 9). However, due to steric hindrance
on ortho substitution of the phenyl group of aromatic nitro-
alkenes, this catalytic system also suffered from lower
enantioselectivities. For example, 2-methoxy-substituted
aromatic nitroalkene and 2-fluoro-substituted aromatic ni-
troalkene were treated with N-methylindole to afford the
Table 2. Asymmetric Friedel–Crafts alkylation of indole 1a with
nitrostyrene 2a catalyzed by chiral L3-Lewis acid complexes.[a]
Entry
Lewis acid
Time [h]
Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
Fe(OTf)3
Cu(OTf)2
AgOTf
Bi(OTf)3
Sc(OTf)3
Zn(OTf)2
Zn(OAc)2
ZnCl2
24
24
24
12
9
5
24
24
86
75
83
98
99
99
trace
48
0
6
1
2
8
78
n.d.[d]
5
[a] Reaction conditions: indole 1a (0.75 mmol) with nitrostyrene 2a
(0.50 mmol) in 2 mL of toluene using 10 mol-% L3 and 10 mol-%
Lewis acid as the catalyst at room temp. [b] Isolated yield. [c] Deter-
mined by HPLC with a Daicel Chiracel AS-H column (hexane/
2-propanol = 90:10, 1.0 mL/min). [d] n.d.: not determined.
Besides toluene, other solvents such as ethyl acetate, desired products in high yields but only 30% and 16%ee,
chloroform, dichloromethane, tetrahydrofuran and chloro- respectively (Table 4, Entries 16 and 17). Furthermore, the
benzene were screened, and the results showed that toluene substituent effects of N-methylindole were also examined
was the best choice (Table 3, Entry 1).
(Table 4, Entries 12–15). The electronic properties of the 5-
As shown in Table 3, increasing the temperature evi- substituent of N-methylindole had little effect on this reac-
dently increased the reaction rate (Entries 7–11). Notably, tion, and the yields and ee values were relatively decreased
nitrostyrene was almost completely converted to adduct at (96–98% yields and 70–72%ee). Meanwhile, we also tried
45 °C after just 1.5 h. When the reaction was performed at other N-blocked indole derivatives such as N-benzylindole,
35 °C, the best result was obtained (Entry 10). Further- and found that it could successfully react with nitroalkene
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O20584
/KAP1
Date: 30-08-12 15:52:21
Pages: 6
W.-g. Huang, H.-s. Wang, G.-b. Huang, Y.-m. Wu, Y.-m. Pan
FULL PAPER
perature overnight. After evaporation of the solvent, the residue
was dissolved in hexane, and the precipitate was collected by fil-
tration. Subsequently, the residue was purified through column
chromatography on silica gel (eluent, hexane) to give nordehyd-
roabietic isothiocyanate (NDHAIC) as a yellow oil (92% yield).
Then NDHAIC (5 mmol, 1.57 g) was added over a period of 1.5 h
to a stirred solution of (S,S)-1,2-diaminocyclohexane (5 mmol,
0.57 g) in dry dichloromethane (40 mL). The reaction mixture was
stirred for a further 15 h at room temperature. The solvent was
removed under reduced pressure. After column chromatography on
silica gel (eluent, ethyl acetate/MeOH = 6:1), the product L3 was
obtained as a white solid in 75% yield.
in 98% yield and 41%ee (Table 4, Entry 18). However, the
reaction was attempted with some nitroalkenes bearing
alkyl groups R that reacted with low yield and ee.
Table 4. Friedel–Crafts alkylation of indoles 1 with nitroalkene 2
catalyzed by L3/Zn(OTf)2 complexes.[a]
1-[(1S,2S)-2-Aminocyclohexyl]-3-[(1R,4aS,10aR)-7-isopropyl-1,4a-
dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yl]thiourea
(L3): White solid, m.p. 108–110 °C; 75% yield. [α]2D0 = –80.1 (c =
1.02, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.17 (d, J =
8.0 Hz, 1 H), 7.00 (d, J = 8.0 Hz, 1 H), 6.88 (s, 1 H), 5.66 (br., 1
H), 2.97–2.86 (m, 2 H), 2.85–2.76 (m, 1 H), 2.69 (br., 1 H), 2.52
(sep, J = 7.0 Hz, 1 H), 2.26 (d, J = 12.5 Hz, 2 H), 2.03 (d, J =
5.5 Hz, 1 H), 2.00–1.89 (m, 2 H), 1.88–1.78 (m, 2 H), 1.78–1.65 (m,
4 H), 1.64–1.35 (m, 7 H), 1.35–1.04 (m, 14 H) ppm. 13C NMR
(CDCl3, 125 MHz): δ = 181.4, 146.5, 145.7, 134.3, 126.9, 124.4,
124.1, 63.0, 59.7, 56.5, 48.9, 38.4, 37.6, 37.3, 34.7, 33.4, 32.2, 30.4,
Entry
R1
R2
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
MeO
MeO
MeO
Br
H
H
H
Ph
4-FPh
99 (3a)
99 (3b)
99 (3c)
98 (3d)
99 (3e)
99 (3f)
99 (3g)
99 (3h)
96 (3i)
99 (3j)
99 (3k)
96 (3l)
97 (3m)
98 (3n)
98 (3o)
93 (3p)
91 (3q)
98 (3r)
80
79
80
79
81
76
86
82
76
79
81
70
71
72
72
16
30
41
4-ClPh
3-ClPh
4-BrPh
4-MeOPh
3-MeOPh
4-MePh
benzodioxolyl
2-thienyl
2-naphthyl
Ph
4-ClPh
4-BrPh
2-naphthyl
2-FPh
9
10
11
12
13
14
15
16[d]
17[d]
18[e]
25.3, 24.9, 24.6, 23.9, 23.9, 19.5, 19.3 ppm. IR: ν = 3269, 2929,
˜
2862, 1531, 1495, 1382, 1336, 1235, 1103, 908, 820.751, 626 cm–1.
HRMS (ESI): C26H41N3S [M – H]+ calcd. 426.29429; found
426.29430.
Typical Procedure for the Catalytic Asymmetric Friedel–Crafts Re-
action: To a dried Schlenk tube were added Zn(OTf)2 (18.6 mg,
0.05 mmol) and L3 (21.4 mg, 0.05 mmol) under a N2 atmosphere,
followed by toluene (2 mL). The solution was stirred at 35 °C for
1 h under a N2 atmosphere, and the nitroalkene 1a (75 mg,
0.50 mmol) was added followed by N-methylindole (2a) (100 mg,
0.75 mmol). After 3 h, the solvent was removed under vacuum, and
the residue was chromatographed on a silica gel column with ethyl
acetate/hexane (1:8, v/v) to afford pure 3a. Colorless oil; yield 99%.
[α]2D0 = –20.4 (c = 1.20, CH2Cl2); ee was determined by HPLC
analysis (Chiralcel AS-H, iPrOH/hexane = 10:90, 1.0 mL/min,
254 nm): retention times tminor = 22.49 min, tmajor = 16.98 min, ee
= 80%.
2-MeOPh
Ph
[a] Reaction conditions: indole 1 (0.75 mmol) with nitroalkene 2
(0.50 mmol) in toluene (2 mL) using 10 mol-% L3/Zn(OTf)2 com-
plexes as the catalyst at 35 °C for 3 h. [b] Isolated yield. [c] Deter-
mined by HPLC with a Daicel Chiracel AS-H column (hexane/2-
propanol = 90:10, 1.0 mL/min). [d] Reaction time: 10 h. [e] Reac-
tion conditions: N-benzyl indole (0.75 mmol) with nitrostyrene
(0.50 mmol) in toluene (2 mL) using 10 mol-% L3/Zn(OTf)2 com-
plexes as the catalyst at 45 °C for 8 h.
Conclusions
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures and characterization data
for chiral catalysts and HPLC chromatograms for all final prod-
ucts.
We have developed a novel and efficient catalytic asym-
metric Friedel–Crafts alkylation of N-methylindole with a
variety of nitroalkenes using bifunctional abietic-acid-
derived thiourea L3/Zn(OTf)2 complexes as catalyst, which
gives high yields (up to 99%) and good enantioselectivities
(up to 86%) for a wide range of aromatic nitroalkenes un-
der mild conditions. Further exploration of the mechanism
and application of the chiral thiourea catalysts to other
asymmetric reactions are in progress in our laboratory.
Acknowledgments
This study was supported by the National Key Basic Research
and Development Program (973 projects, grant number
2011CB512005973), the projects of the Key Laboratory for the
Chemistry and Molecular Engineering of Medicinal Resources
(Guangxi Normal University), Ministry of Education of China
(grant number CMEMR2011-15), and by the Guangxi Natural Sci-
ence Foundation of China (grant numbers 2012GXNSFAA053027,
2011GXNSFD018010, and 2010GXNSFF013001).
Experimental Sections
General Procedure for the Synthesis of Chiral Thiourea: Using the
reported procedures,[14a,16] pure nordehydroabietic amine
(NDHAA) was obtained as a white solid in 72% yield. Carbon
disulfide (15 mmol) and N,NЈ-dicyclohexylcarbodiimide (10 mmol)
were added to a solution of NDHAA (10 mmol) in dry ether
(50 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h
then warmed slowly to room temperature and stirred at room tem-
[1] For reviews, see: a) K. A. Jørgensen, Synthesis 2003, 1117–
1125; b) M. Bandini, A. Melloni, A. Umani-Ronchi, Angew.
Chem. 2004, 116, 560–566; c) M. Bandini, A. Melloni, A. Um-
ani-Ronchi, Angew. Chem. 2004, 116, 560; Angew. Chem. Int.
Ed. 2004, 43, 550–556; d) T. B. Poulsen, K. A. Jørgensen,
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20584
/KAP1
Date: 30-08-12 15:52:21
Pages: 6
Alkylation of N-Methylindoles with Nitroalkenes
Chem. Rev. 2008, 108, 2903–2915; e) S. L. You, Q. Cai, M.
Zeng, Chem. Soc. Rev. 2009, 38, 2190–2201.
Chem. Soc. 2011, 133, 14578–14581; i) Y. Wang, J. Yu, Z. Miao,
R. Chen, Org. Biomol. Chem. 2011, 9, 3050–3054.
[2] For selected examples, see: a) N. Yokoyama, T. Arai, Chem.
Commun. 2009, 3285–3287; b) F. Guo, G. Lai, S. Xiong, S.
Wang, Z. Wang, Chem. Eur. J. 2010, 16, 6438–6441; c) H. Y.
Kim, S. Kim, K. Oh, Angew. Chem. Int. Ed. 2010, 49, 4476–
4478; d) J. Wu, X. C. Li, F. Wu, B. S. Wan, Org. Lett. 2011, 13,
4834–4837; e) E. Marqués-López, A. Alcaine, T. Tejero, R. P.
Herrera, Eur. J. Org. Chem. 2011, 3700–3705.
[8]
a) F. G. Ye, H. S. Wang, B. J. Huang, S. L. Zhao, Electrophore-
sis 2010, 31, 1488–1492; b) S. L. Zhao, H. S. Wang, Y. M. Pan,
M. He, Z. C. Zhao, J. Chromatogr. A 2007, 1145, 246–249; c)
H. S. Wang, S. L. Zhao, M. He, Z. C. Zhao, Y. M. Pan, Q.
Liang, J. Sep. Sci. 2007, 30, 2748–2753; d) S. L. Zhao, H. S.
Wang, R. C. Zhang, L. D. Tang, Y. M. Liu, Electrophoresis
2006, 27, 3428–3433.
[3] a) D. J. Faulkner, Nat. Prod. Rep. 2001, 18, 1–49; b) K. S.
Jandu, V. Barrett, M. Brockwell, D. Cambridge, D. R. Farrant,
C. Foster, H. Giles, R. C. Glen, A. P. Hill, H. Hobbs, J. Med.
Chem. 2001, 44, 681–693; c) K. H. Lim, O. Hiraku, K. Komi-
yama, T. Koyano, M. Hayashi, T. S. Kam, J. Nat. Prod. 2007,
70, 1302–1307.
[9]
H. S. Wang, X. Y. Tian, D. Yang, Y. M. Pan, Q. Wu, C. H. He,
Tetrahedron: Asymmetry 2011, 22, 381–386.
E. M. Fleming, T. McCabe, S. J. Connon, Tetrahedron Lett.
2006, 47, 7037–7042.
W. Zhuang, R. G. Hazell, K. A. Jorgensen, Org. Biomol. Chem.
2005, 3, 2566–2571.
a) S. F. Lu, D.-M. Du, J. Xu, Org. Lett. 2006, 8, 2115–2118; b)
H. Liu, S. F. Lu, J. Xu, D.-M. Du, Chem. Asian J. 2008, 3,
1111–1121; c) H. Liu, D.-M. Du, Adv. Synth. Catal. 2010, 352,
1113–1118; d) H. Liu, D.-M. Du, Eur. J. Org. Chem. 2010,
2121–2131.
[10]
[11]
[12]
[4] O. M. Berner, L. Tedeschi, D. Enders, Eur. J. Org. Chem. 2002,
1877–1894.
[5] N. Ono, The Nitro Group in Organic Synthesis, Wiley-VCH,
Weinheim, Germany, 2001.
[6] For reviews, see: a) S. H. McCooey, S. J. Connon, Angew.
Chem. 2005, 117, 6525–6528; Angew. Chem. Int. Ed. 2005, 44,
6367–6370; b) Y. Takemoto, Org. Biomol. Chem. 2005, 3, 4299–
4306; c) S. J. Connon, Chem. Eur. J. 2006, 12, 5418–5427; d)
M. S. Taylor, E. N. Jacobsen, Angew. Chem. 2006, 118, 1550;
Angew. Chem. Int. Ed. 2006, 45, 1520–1543; e) A. G. Doyle,
E. N. Jacobsen, Chem. Rev. 2007, 107, 5713–5743; f) Y. Ya-
maoka, H. Miyabe, Y. Takemoto, J. Am. Chem. Soc. 2007, 129,
6686–6687; g) Z. Zhang, P. R. Schreiner, Chem. Soc. Rev. 2009,
38, 1187–1198; h) R. R. Knowles, S. Lin, E. N. Jacobsen, J.
Am. Chem. Soc. 2010, 132, 5030–5032.
[7] For selected examples, see: a) C. Rabalakos, W. D. Wulff, J.
Am. Chem. Soc. 2008, 130, 13524–13525; b) X. Han, J. Kwiat-
kowski, F. Xue, K. W. Huang, Y. Lu, Angew. Chem. 2009, 121,
7740; Angew. Chem. Int. Ed. 2009, 48, 7604–7607; c) H. Ue-
hara, C. F. Barbas, Angew. Chem. 2009, 121, 10032; Angew.
Chem. Int. Ed. 2009, 48, 9848–9852; d) Y. Wang, H. Yang, J.
Yu, Z. Miao, R. Chen, Adv. Synth. Catal. 2009, 351, 3057–
3062; e) F. Xue, L. Liu, S. Zhang, W. Duan, W. Wang, Chem.
Eur. J. 2010, 16, 7979–7982; f) F. Yu, Z. Jin, H. Huang, T. Ye,
X. Liang, J. Ye, Org. Biomol. Chem. 2010, 8, 4767–4774; g) K.
Asano, S. Matsubara, J. Am. Chem. Soc. 2011, 133, 16711–
16713; h) N. Z. Burns, M. R. Witten, E. N. Jacobsen, J. Am.
[13] For selected examples, see: a) K. Mei, M. Jin, S. Zhang, P. Li,
W. Liu, X. Chen, F. Xue, W. Duan, W. Wang, Org. Lett. 2009,
11, 2864–2867; b) P. Li, S. Wen, F. Yu, Q. Liu, W. Li, Y. Wang,
X. Liang, J. Ye, Org. Lett. 2009, 11, 753–756; c) K. Liu, H. F.
Cui, J. Nie, K. Y. Dong, X. J. Li, J. A. Ma, Org. Lett. 2007, 9,
923–925; d) M. P. Lalonde, Y. Chen, E. N. Jacobsen, Angew.
Chem. 2006, 118, 6514; Angew. Chem. Int. Ed. 2006, 45, 6366–
6370.
[14] For selected examples, see: a) R. P. Herrera, V. Sgarzani, L.
Bernardi, A. Ricci, Angew. Chem. 2005, 117, 6734; Angew.
Chem. Int. Ed. 2005, 44, 6576–6579; b) M. Ganesh, D. Seidel,
J. Am. Chem. Soc. 2008, 130, 16464–16465.
[15] Owing to steric hindrance, the NDHAIC did not react with
(S)-(–)-1,1Ј-bi(2-naphthylamine). Therefore, dehydroabietic iso-
thiocyanate (DHAIC) was used to synthesize L4 instead of
NDHAIC.
[16] a) X. Jiang, Y. Zhang, A. S. C. Chan, R. Wang, Org. Lett. 2008,
10, 153–156; b) B. K. Tayana, N. K. Nikalai, V. T. Olga, G. T.
Alexander, Chirality 2004, 16, 40–50.
Received: May 3, 2012
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O20584
/KAP1
Date: 30-08-12 15:52:21
Pages: 6
W.-g. Huang, H.-s. Wang, G.-b. Huang, Y.-m. Wu, Y.-m. Pan
FULL PAPER
Asymmetric Catalysis
W.-g. Huang, H.-s. Wang,* G.-b. Huang,
Y.-m. Wu, Y.-m. Pan* ....................... 1–6
Enantioselective Friedel–Crafts Alkylation
of N-Methylindoles with Nitroalkenes Cat-
alyzed by Chiral Bifunctional Abietic-
Acid-Derived Thiourea-ZnII Complexes
Keywords: Asymmetric synthesis / C–C
coupling / Friedel–Crafts alkylation / Zinc /
Aromatic substitution / Nitroalkenes
The catalytic asymmetric Friedel–Crafts
alkylation of N-methylindoles with nitro-
alkenes catalyzed by abietic-acid-derived
thiourea-ZnII complexes was investigated.
Nitroalkylated indoles were synthesized in
excellent yields (up to 99%) and good en-
antioselectivities (up to 86%ee) under mild
conditions. These chiral thiourea catalysts
are easily available from the commercial
abietic acid.
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0