Monodentate n-ligand-directed bifunctional transition-metal catalysis: Highly enantioselective Friedel-Crafts alkylation of indoles with nitroalkenes

Article abstract of DOI:10.1002/chem.201000540

[Chemical equation presented] A role beyond base : A highly efficient, asymmetric Friedel - Crafts alkylation of indoles with nitroalkenes is presented that uses simple nitrogen compounds combined with Schiff base zinc(II) complexes as bifunctional cataly

Full text of DOI:10.1002/chem.201000540

DOI: 10.1002/chem.201000540
Monodentate N-Ligand-Directed Bifunctional Transition-Metal ACTHUNRGTNECNUG atalysis:
Highly Enantioselective Friedel–Crafts Alkylation of Indoles with
Nitroalkenes
Fengfeng Guo, Guoyin Lai, Shunshun Xiong, Sujing Wang, and Zhiyong Wang*[a]
Recently, combinatorial transition-metal catalysis has
been shown to be a promising way to enhance the enantio-,
diastereo-, or regioselectivity of many reactions.[1] By apply-
ing this concept, structurally diverse catalysts can easily be
generated by mixing ligands, without the need to synthesize
any new compounds. Over the past two decades, numerous
well-designed chiral and achiral compounds have been suc-
cessfully applied as combinatorial ligands in many reac-
tions.[1,2] However, the use of simple monodentate N ligands,
such as piperidine, as combinatorial ligands has been less
well explored.[3] Furthermore, understanding the origin of
the enhanced reactivity and selectivity is still a challenge.[1a]
Tridentate Schiff bases 1 (Scheme 1), prepared from a
chiral amino alcohol and 2-hydroxybenzaldehyde deriva-
tives, are considered to be excellent chiral ligands for many
asymmetric transformations, especially those with vanadium,
chromium, aluminum, iron, titanium, and copper.[4] To main-
tain the saturated coordination modes of the central metals,
dimeric structures[4g,h,n] or counteranions that bind directly
to the central metal are generally required in the scaffolds
of complexes. Encouraged by these combinatorial strategies,
we anticipated that the addition of specific N ligands into
the Schiff base metal system could disassemble the dimeric
structure and perhaps provide some new active heterocom-
plexes for use in asymmetric catalysis. Herein, we describe a
highly enantioselective Friedel–Crafts alkylation[5] of indoles
with nitroalkenes that is catalyzed by novel Schiff base
zinc(II) complexes which use piperidine as a crucial combi-
natorial ligand.[6,7]
Initially, we selected the Friedel–Crafts alkylation of
indole with trans-b-nitrostyrene as the model reaction,
which would readily give access to many bioactive indole
derivatives.[7g] The catalyst was formed in situ by mixing
Schiff base 1a and ZnACTHNUTRGNEUNG(OTf)2 (OTf=triflate) in a 1:1 ratio,
in toluene, at room temperature, which gave the product in
88% isolated yield with 52% ee (Table 1, entry 1). Notably,
partial decomposition of 1a was observed due to the strong-
ly acidic HOTf generated during the coordination.[8] This
result provided us with a possible method of further enhanc-
ing the enantioselectivity by using an extra base as an acid
scavenger. However, no increase in ee was obtained after
careful screening of various bases as additives (ratio: Schiff
Scheme 1. Chiral 2-hydroxybenzaldehyde derivatives used as ligands in
this study. Bn=Benzyl.
base 1a/ZnACTHNUGRTENUNG(OTf)2/base=1:1:1). In contrast, a reduction in
ee generally occurred (Table 1, entries 2–10).
With a combinatorial ligand strategy in mind, a library of
achiral monodentate N ligands was introduced to the cata-
lytic system and the ratio of Schiff base 1a, ZnACTHNUGTRENUNG(OTf)2, and
[a] F. Guo, G. Lai, S. Xiong, Dr. S. Wang, Prof. Z. Wang
Hefei National Laboratory for Physical Sciences at the Microscale
CAS Key Laboratory of Soft Matter Chemistry and
Department of Chemistry
achiral ligand was chosen to be 1:1:2. We expected that, in
addition, the nitrogen compounds here could also play a
crucial role as ligands as well as their traditional role as acid
scavengers. Surprisingly, the absolute configuration of the
product was reversed in all cases and significant improve-
ments in reactivity and enantioselectivity were observed. As
shown in Table 2, six-membered ring achiral ligands gave
better selectivities than five-membered ring ligands, al-
University of Science and Technology of China
Hefei, 230026, (China)
Fax : (+86)551-3603-185
E-mail: zwang3@ustc.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000540.
6438
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 6438 – 6441

COMMUNICATION
Table 1. Effect of bases on the reaction of indole (3a) with trans-b-nitro-
styrene (4a).[a]
proved to be less effective (Table 2, entries 13 and 14).
These results suggest that the combination of Schiff base 1a/
ZnACTHNUGTRENNG(U OTf)2/achiral ligand in a 1:1:3 ratio generates rather
active heterocomplexes for the asymmetric Friedel–Crafts
alkylation of indole (3a) with trans-b-nitrostyrene (4a) with
2b being the best achiral ligand (Table 2, entry 8).[9] Next we
examined the combination of 2b with different Schiff bases,
1a–d, under the same conditions (Table 2, entries 15–17).
Alteration of the Schiff base by changing the substituents on
the 2-hydroxybenzaldehyde structural motif revealed that
the enantioselectivity highly depends upon the electronic
nature and size of the substituents with Schiff base 1a prov-
ing to be the best (Table 2, entry 8).
Under the optimized conditions (Table 2, entry 8), the
scope of the Friedel–Crafts alkylation of indoles with nitro-
alkenes was explored. The results are summarized in
Table 3. Various aromatic nitroalkenes with different sub-
stituents on the aromatic ring were examined. Electron-rich
aromatic nitroalkenes usually gave the corresponding prod-
ucts in slightly better enantioselectivities than electron-poor
ones (Table 3, entries 1–7). The enantioselectivity was found
to be insensitive to the position of the substituent on the
phenyl group of the nitroalkene (Table 3, entries 8–12). It is
notable that the reaction can be extended to disubstituted,
heterocyclic, and fused-ring nitroalkenes with excellent
Entry
Base
Loading
[mol%][b]
Yield
[%][c]
ee
N
[%][d]
1
2
3
4
5
6
7
8
9
–
–
5
5
5
5
5
5
5
5
5
88
73
57
49
68
52
44
45
46
41
52 (S)
52 (S)
33 (S)
30 (S)
20 (S)
23 (S)
34 (S)
50 (S)
31 (S)
33 (S)
Et3N
DIPEA[e]
DBU[e]
tBuOK
PhCOONa
pyrrolidine
piperidine
hexamethyleneimine
2-methylpiperidine
10
[a] Reaction conditions: indole (3a; 0.3 mmol) and trans-b-nitrostyrene
(4a; 0.3 mmol) in toluene (2 mL) at room temperature for 24 h.
[b] Amount of base. [c] Isolated yield. [d] The ee values were determined
by chiral HPLC analysis and the absolute configuration of the products
(in parentheses) was determined by comparison of the optical rotation
with the literature.[6a] [e] DIPEA=ethyldiisopropylamine, DBU=1,8-
diazabicycloACHTUNGTRENNUNG[5.4.0]undec-7-ene.
Table 2. Screening of chiral and achiral ligands.[a]
Entry
Chiral Achiral ligand
ligand
Ratio[b] Yield
[%][c]
Ee
Table 3. Scope of the enantioselective Friedel–Crafts alkylation of in-
doles with nitroalkenes.[a]
[%][d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
pyrrolidine (2a)
piperidine (2b)
hexamethyleneimine (2c) 1:2
2-methylpiperidine (2d)
3-methylpiperidine (2e)
1:2
1:2
87
94
62
43
46
54
90
96
60
43
70
86
91
93
87
91
96
76 (R)
86 (R)
91 (R)
68 (R)
66 (R)
72 (R)
86 (R)
96 (R)
89 (R)
60 (R)
92 (R)
96 (R)
91 (R)
94 (R)
65 (R)
57 (R)
56 (R)
1:2
1:2
1:2
1:3
1:3
1:3
1:3
1:3
1:3
1:4
1:4
1:3
1:3
1:3
4-methylpiperidine (2 f)
2a
2b
2c
2d
2e
2 f
2a
2b
2b
2b
2b
Entry
R1
R2
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20[d]
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3a Ph
4a
4b
4c
4d
4e
4 f
4g
4h
4i
96
95
97
92
99
94
90
96
97
90
96
97
5a
5b
5c
5d
5e
5 f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
96
91
91
92
90
96
95
92
91
97
91
95
95
92
94
95
3a 4-FPh
3a 4-ClPh
3a 4-BrPh
3a 4-CF3Ph
3a 4-MePh
3a 4-OMePh
3a 3-ClPh
3a 3-OMePh
3a 3,4-(OMe)2Ph 4j
3a 2-ClPh
[a] Reaction conditions: indole (3a; 0.3 mmol) and trans-b-nitrostyrene
(4a; 0.3 mmol) in toluene (2 mL) at room temperature for 24 h. [b] Ratio
of chiral ligand to achiral ligand. [c] Isolated yield. [d] The ee values were
determined by chiral HPLC analysis and the absolute configuration of
the products (in parentheses) was determined by comparison of the opti-
cal rotation with the literature.[6a]
4k
4l
4m 96
4n
4o
4p
4a
4a
4a
4a
3a 2-OMePh
3a 2-furyl
3a 2-thienyl
3a 1-napthyl
3a 2-napthyl
99
92
91
96
91
89
90
4-OMe 3b Ph
5-Br 3c Ph
5-OMe 3d Ph
3a Ph
93
93
96
5s
5a
though a low yield was obtained if hexamethyleneACTHNUTRGNEUGiN mine was
H
83 (>99)[e]
utilized (Table 2, entries 1–3). More sterically hindered li-
gands gave lower yields and moderate enantioselectivities
(Table 2, entries 4–6). Interestingly, if the ratio of chiral
ligand to achiral ligand was increased to 1:3, higher reactivi-
ty and enantioselectivity was obtained (Table 2, entries 7–
12). A further increase in the amount of achiral ligand
[a] Reaction conditions: indole (3, 0.3 mmol) and nitroalkene (4,
0.3 mmol) in toluene (2 mL) at room temperature for 24 h. [b] Isolated
yield. [c] Determined by chiral HPLC analysis. [d] Performed on
a
5 mmol scale under 1 mol% catalyst in toluene (10 mL) at room temper-
ature for 24 h. [e] The ee value after a single recrystallization is given in
parentheses.
Chem. Eur. J. 2010, 16, 6438 – 6441
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6439

Z. Wang et al.
enantioselectivities (Table 3, entries 10 and 13–16). Several
substituted indoles, containing either electron-withdrawing
or electron-donating groups, have also been tested in the re-
action with trans-b-nitrostyrene. In all cases, high yields and
excellent enantioselectivities were achieved (93–96% ee,
Table 3, entries 17–19). To our delight, this reaction can be
performed, on a gram scale, with a lower catalyst loading
(1 mol%), which results in the product in good yield with
>99% enantiopurity after a single recrystallization (Table 3,
entry 20).[10]
To get an insight into the reaction mechanism and a
better understanding of the role of the achiral N ligands, we
obtained the single-crystal X-ray structure of the optimum
catalyst (Figure 1).[11] In the solid state, the catalyst exists in
Figure 2. Proposed bifunctional mode of action in the transition state.
binatorial achiral ligands in asymmetric transition-metal cat-
alysis. Efforts to apply a combinatorial strategy to other
asymmetric transformations are underway in our group.
Experimental Section
General procedure: ZnACTHNUTRGNE(NUG OTf)2 (5.4 mg, 0.015 mmol) and piperidine (2b;
4.5 mL, 0.045 mmol) were added to a solution of 1a (6.7 mg, 0.015 mmol)
in toluene (2 mL). The solution was stirred at room temperature for
30 min, before adding trans-b-nitrostyrene (4a; 44.7 mg, 0.3 mmol) and
indole (3a; 35.1 mg, 0.3 mmol). After stirring for 24 h, the solvent was re-
moved under vacuum. Column chromatography on silica gel (petroleum
ether/ethyl acetate=6:1) was performed to give the pure product 5a as a
white solid.
Figure 1. X-ray single-crystal structure of the catalyst 1a/ZnACTHNUTRGNEUNG(OTf)2/2b.
The triflate counteranion and all hydrogen atoms are omitted for clarity.
Acknowledgements
We are grateful for financial support from the National Science Founda-
tion of China (20932002, 20972144, 90813008, and 20628202).
monomeric form as we proposed previously. Interestingly,
the tridentate Schiff base ligand coordinates in a bidentate
mode; the OH of the amino alcohol structural motif does
not coordinate to zinc.[12] Two piperidine molecules occupy
two of the coordination sites of the central metal, which
generates a distorted-tetrahedral structure. We envision that
the catalyst acts in a bifunctional fashion with the OH of the
amino alcohol structural motif acting as a hydrogen-bond
donor to direct the indole to attack the nitroalkene on the
Re face,[13] while the nitroalkene is activated by zinc from its
position within the tetrahedron (Figure 2). The heterocom-
plex does not split during the catalytic process, as no free pi-
Keywords: asymmetric catalysis · combinatorial chemistry ·
indoles · N ligands · Schiff bases
[1] For recent reviews of combinatorial transition-metal catalysis, see:
a) M. T. Reetz, Angew. Chem. 2008, 120, 2592–2626; Angew. Chem.
Int. Ed. 2008, 47, 2556–2588; b) A. J. Sandee, J. N. H. Reek, Dalton
Trans. 2006, 3385–3391; c) B. Breit, Angew. Chem. 2005, 117, 6976–
6986; Angew. Chem. Int. Ed. 2005, 44, 6816–6825; d) K. L. Ding,
H. F. Du, Y. Yuan, J. Long, Chem. Eur. J. 2004, 10, 2872–2884.
[2] For a review of achiral and meso ligands in asymmetric catalysis,
see: P. J. Walsh, A. E. Lurain, J. Balsells, Chem. Rev. 2003, 103,
3297–3344.
1
peridine was detected by H NMR analysis.[14]
[3] For selected examples, see: a) S. Kobayashi, M. Kawamura, J. Am.
Chem. Soc. 1998, 120, 5840–5841; b) S. Kobayashi, H. Ishitani, J.
Am. Chem. Soc. 1994, 116, 4083–4084.
In conclusion, we have developed a new, efficient combi-
natorial catalyst for the asymmetric Friedel–Crafts alkyla-
tion of indoles with nitroalkenes. A crucial achiral ligand
effect was disclosed, which was further confirmed by single-
crystal structural analysis of the catalyst. We also proposed a
bifunctional mode of action for this catalytic process. To the
best of our knowledge, this is the first example of a system-
atic evaluation of monodentate nitrogen compounds as com-
[4] a) S. H. Hsieh, Y. P. Kuo, H. M. Gau, Dalton Trans. 2007, 97–106;
b) A. Blanc, F. D. Toste, Angew. Chem. 2006, 118, 2150–2153;
Angew. Chem. Int. Ed. 2006, 45, 2096–2099; c) C. Bolm, F. Biene-
wald, Angew. Chem. 1995, 107, 2883–2885; Angew. Chem. Int. Ed.
Engl. 1995, 34, 2640–2642; d) M. L. Grachan, M. T. Tudge, E. N. Ja-
cobsen, Angew. Chem. 2008, 120, 1491–1494; Angew. Chem. Int. Ed.
2008, 47, 1469–1472; e) E. R. Jarvo, B. M. Lawrence, E. N. Jacobsen,
Angew. Chem. 2005, 117, 6197–6200; Angew. Chem. Int. Ed. 2005,
6440
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 6438 – 6441

Bifunctional Transition-Metal Catalysis
COMMUNICATION
44, 6043–6046; f) R. T. Ruck, E. N. Jacobsen, Angew. Chem. 2003,
115, 4919–4922; Angew. Chem. Int. Ed. 2003, 42, 4771–4774;
g) R. T. Ruck, E. N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 2882–
2883; h) K. Gademann, D. E. Chavez, E. N. Jacobsen, Angew. Chem.
2002, 114, 3185–3187; Angew. Chem. Int. Ed. 2002, 41, 3059–3061;
i) A. G. Dossetter, T. F. Jamison, E. N. Jacobsen, Angew. Chem.
1999, 111, 2549–2552; Angew. Chem. Int. Ed. 1999, 38, 2398–2400;
j) X. Zhou, X. H. Liu, X. Yang, D. J. Shang, J. G. Xin, X. M. Feng,
Angew. Chem. 2008, 120, 398–400; Angew. Chem. Int. Ed. 2008, 47,
392–394; k) J. Legros, C. Bolm, Angew. Chem. 2003, 115, 5645–
5647; Angew. Chem. Int. Ed. 2003, 42, 5487–5489; l) Q. Fan, L. L.
Lin, J. Liu, Y. Z. Huang, X. M. Feng, G. L. Zhang, Org. Lett. 2004,
6, 2185–2188; m) M. Hayashi, T. Inoue, N. Oguni, J. Chem. Soc.
Chem. Commun. 1994, 341–342; n) G. Y. Lai, S. J. Wang, Z. Y.
Wang, Tetrahedron: Asymmetry 2008, 19, 1813–1819; o) L. L. Lin,
Q. Fan, B. Qin, X. M. Feng, J. Org. Chem. 2006, 71, 4141–4146;
p) C. S. Gan, G. Y. Lai, Z. H. Zhang, Z. Y. Wang, M. M. Zhou, Tet-
rahedron: Asymmetry 2006, 17, 725–728.
[7] For previous asymmetric metal catalyzed versions of this reaction,
see: a) S. C. McKeon, H. Muller-Bunz, P. J. Guiry, Eur. J. Org.
Chem. 2009, 4833–4841; b) S. Z. Lin, T. P. You, Tetrahedron 2009,
65, 1010–1016; c) Z. L. Yuan, Z. Y. Lei, M. Shi, Tetrahedron: Asym-
metry 2008, 19, 1339–1346; d) P. K. Singh, A. Bisai, V. K. Singh, Tet-
rahedron Lett. 2007, 48, 1127–1129; e) S. F. Lu, D. M. Du, J. X. Xu,
Org. Lett. 2006, 8, 2115–2118; f) Y. X. Jia, S. F. Zhu, Y. Yang, Q. L.
Zhou, J. Org. Chem. 2006, 71, 75–80; g) M. Bandini, A. Garelli, M.
Rovinetti, S. Tommasi, A. Umani-Ronchi, Chirality 2005, 17, 522–
529.
[8] The amount of HOTf generated was proven to be one equivalent,
with 1a as the chiral ligand, by the fact that aging a mixture of 1a
and ZnACHTNURGTNE(NUG OTf)2 in Et2O for two days gave crystals of the amino alco-
hol triflate as colorless needles.
[9] We anticipated that 1/3 of the achiral ligand added would act as an
acid scavenger, while the other 2/3 might serve as ligands, which was
further confirmed by the single-crystal structure of the catalyst.
[10] If 4-methyl-1-nitropent-1-ene was applied as an aliphatic nitroalkene
under the standard conditions a relatively low yield (73%) and re-
duced enantioselectivity (60% ee) was obtained.
[11] Details of the crystal structure analysis are provided as Supporting
Information. CCDC-763966 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[5] For reviews of stereoselective Friedel–Crafts alkylation, see: a) S.-L.
You, Q. Cai, M. Zeng, Chem. Soc. Rev. 2009, 38, 2190–2201; b) T. B.
Poulsen, K. A. Jørgensen, Chem. Rev. 2008, 108, 2903–2915; c) M.
Bandini, A. Melloni, A. Umani-Ronchi, Angew. Chem. 2004, 116,
560–566; Angew. Chem. Int. Ed. 2004, 43, 550–556; d) K. A. Jør-
gensen, Synthesis 2003, 1117–1125;.
[6] For previous asymmetric organocatalytic versions of this reaction,
see: a) J. Itoh, K. Fuchibe, T. Akiyama, Angew. Chem. 2008, 120,
4080–4082; Angew. Chem. Int. Ed. 2008, 47, 4016–4018; b) M.
Ganesh, D. Seidel, J. Am. Chem. Soc. 2008, 130, 16464–16465;
c) E. M. Fleming, T. McCabe, S. J. Connon, Tetrahedron Lett. 2006,
47, 7037–7042; d) W. Zhuang, R. G. Hazell, K. A. Jørgensen, Org.
Biomol. Chem. 2005, 3, 2566–2571; e) R. P. Herrera, V. Sgarzani, L.
Bernardi, A. Ricci, Angew. Chem. 2005, 117, 6734–6737; Angew.
Chem. Int. Ed. 2005, 44, 6576–6579.
[12] The distance between Zn1 and O1 was measured to be 2.519 ꢁ and
therefore an interaction between them can be ruled out.
[13] When N-methylindole was applied to the reaction very little product
was formed under the standard conditions.
[14] By comparing the 1H NMR spectrum of the reaction mixture to the
standard spectrum of piperidine, no characteristic signal at 2.80 ppm
was observed.
Received: March 2, 2010
Published online: May 3, 2010
Chem. Eur. J. 2010, 16, 6438 – 6441
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6441