Chiral Bis(oxazolidine)pyridine-copper-catalyzed enantioselective friedel-crafts alkylation of indoles with nitroalkenes

Article abstract of DOI:10.1055/s-0033-1340311

Catalytic asymmetric Friedel-Crafts reaction of indoles with nitroalkenes was catalyzed by the stereochemically tunable bis(oxazolidine)pyridine (PyBodine)-Cu(OTf)₂ complex. Using the PyBodine(Val)-Cu(OTf) ₂ catalyst gave the Friedel-Crafts ?adducts with highly enantioselective manner. For the 1,4-bis[(E)-2-nitrovinyl]benzene, the reaction proceeded in a meso-trick manner to give the chiral double Friedel-Crafts adduct with 97% enantiomeric excess. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340311

LETTER
▌349
lCetther iral Bis(oxazolidine)pyridine–Copper-Catalyzed Enantioselective Friedel–
Crafts Alkylation of Indoles with Nitroalkenes
Enantioselective Friedel–Crafts Alkylation of Indoles
Toru Sato, Takayoshi Arai*
Department of Chemistry, Graduate School of Science, Chiba University, Inage 263-8522, Japan
Fax +81(43)2902889; E-mail: tarai@faculty.chiba-u.jp
Received: 21.10.2013; Accepted after revision: 31.10.2013
Among the most remarkable are the latest examples of
Abstract: Catalytic asymmetric Friedel–Crafts reaction of indoles
bis(oxazolidine)pyridines, abbreviated as N,N,N-triden-
with nitroalkenes was catalyzed by the stereochemically tunable
tate PyBodines, which are analogues of PyBox ligands.7
Based on oxazolidines, which are easily obtained by sim-
bis(oxazolidine)pyridine (PyBodine)–Cu(OTf)2 complex. Using
the PyBodine(Val)–Cu(OTf)2 catalyst gave the Friedel–Crafts
adducts with highly enantioselective manner. For the 1,4-bis[(E)-2- ple condensation of an aldehyde with various chiral β-
nitrovinyl]benzene, the reaction proceeded in a meso-trick manner
to give the chiral double Friedel–Crafts adduct with 97% enantio-
meric excess.
amino alcohols, PyBodines are a new type of tunable chi-
ral ligand. Using a powerful platform of solid-phase catal-
ysis/CD HTS, the PyBodine(Ala)–Cu(OAc)2 complex
was rapidly explored in a tailor-made manner for [3+2]
Key words: oxazolidine, copper, Friedel–Crafts alkylation, indole,
nitroalkene, meso trick
cycloaddition of azomethine imines with propiolates
(Scheme 1).6
The development of novel ligands is a powerful driving
force toward the accomplishment of target metal-cata-
lyzed reactions.1 Particularly, in asymmetric catalysis,
stereo- and electrochemically tunable chiral ligands are
important in the construction of efficient reaction spheres.
Chiral bisoxazoline ligands derived from various natural
and non-natural optically active α-amino acids are repre-
sentative examples of tunable nitrogen ligands, and relat-
ed chiral nitrogen ligands have been widely investigated.2
As part of continuing research efforts in our group, start-
ing from the design of imidazoline-based ligands as
electrochemically tunable variations of oxazolines, we
Ph
Ph
Ph
Ph
NH
HN
N
O
O
N
O
N
PyBodine(Ala) (11 mol%)
Cu(OAc)2 (10 mol%)
N
R1
R1
O
N
+
CO2R2
4 Å MS, –40 °C, CH2Cl2
CO2R
up to 98% ee
Scheme 1 PyBodine(Ala)-Cu(OAc)2-catalyzed [3+2] cycloaddition
have developed a series of stereochemically diversified Here, the potency of N,N,N-tridentate PyBodine–metal
imidazolidine- and oxazolidine-based chiral ligands catalysts is demonstrated in a catalytic asymmetric
(Figure 1).3–6
Ph
Ph
pilot ligand
N
N
Ph
Ph
Ts
OH
R
R
Ph
NTs
Ph
Br
N
N
N
N
N
NTs
O
O
N
Ph
Bn
X
N-tethered bis(imidazoline):
imidazoline-aminophenol:
bis(oxazoline)
Ph
Nb-imidazoline
IAP1 (X = Br), IAP (X = NO2)
Ph
R
R
Ph
Ph
Ph
HN
NH
NH
HN
Ph
Ph
Ph
O
N
N
N
N
O
Bn
Bn
bis(imidazolidine)pyridine:
PyBidine
bis(oxazolidine)pyridine:
PyBodine
Figure 1 Tunable chiral nitrogen ligands: the pilot bis(oxazoline) and our imidazoline-, imidazolidine-, and oxazolidine-based ligands
SYNLETT 2014, 25, 0349–0354
Advanced online publication: 06.12.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340311; Art ID: ST-2013-U0985-L
© Georg Thieme Verlag Stuttgart · New York

350
T. Sato, T. Arai
LETTER
Friedel–Crafts alkylation reaction of indoles with diamines, we moved on to the exploration of appropriate
nitroalkenes.8
ligands among the stereochemically tunable PyBodines.
Among the PyBodines L2–L8 we examined
PyBodine(Val) (L3) gave 3a in 91% yield with the high-
est stereoselectivity of 75% enantiomeric excess. It is
noteworthy that the catalytic activity of the corresponding
bis(oxazoline)pyridine analogue L9–Cu(OTf)2 was low,
giving 3a in 21% yield with only 5% enantiomeric ex-
cess.18
Enantiomerically enriched alkylated indoles have been
the subject of considerable attention in the field of asym-
metric synthesis due to their numerous applications in
medicinal research.9 For example, L-779,97610 and
chaetoglobosin11 contain a β-nitrogen-functionalized
alkyl chain at the 3-position (Figure 2).
NH2
Table 1 Screening of Chiral Tridentate Ligand–Copper Catalysts for
Catalytic Asymmetric Friedel–Crafts Alkylation with β-Nitrostyrene
O
O
O
NH
N
N
H
HN
N
Ph
N
ligand (5.5 mol%)
Cu(OTf)2 (5 mol%)
H
1a
NO2
+
CH2Cl2, r.t., 22–24 h
NO2
HN
Ph
Ph
N
3a
2a
H
L-779,976
(SSTR-2 selective agonist)
R
R
Ph
Ph
H
Ph
Ph
Ph
NH
HN
NH
HN
Ph
N
H
N
O
Ph
N
O
O
N
N
Bn
Bn
H
O
L1 (PyBidine)
PyBodines
HO
L2 (R = Me)
L3 (R = i-Pr)
L4 (R = i-Bu)
L5 (R = s-Bu)
L6 (R = t-Bu)
L7 (R = Ph)
L8 (R = Bn)
OH
N
H
chaetoglobosin-542
(antimicrofilament activity and cytotoxic toward
murine colon and leukemia cancer cell lines)
Figure 2 Biologically important chiral indoles with a β-nitrogen-
functionalized alkyl chain at the 3-position
Ph
Ph
Ph
Ph
N
N
N
O
O
For the introduction of the β-nitrogen-functionalized alkyl
chain onto the indole, Friedel–Crafts alkylation of indoles
with nitroalkenes shows potential, and recent studies have
focused on the catalytic asymmetric variation. In 2005,
Umani-Ronchi et al. achieved first asymmetric Friedel–
Crafts alkylation of indoles with trans-β-nitroalkenes us-
ing the [SalenAuCl] catalyst.12 After this pioneering
work, successful chiral catalytic systems were developed
using zinc,13 copper,14 nickel,15 platinum complexes,16
and organocatalysts.17 N,N,N-Tridentate chiral ligands
have been successfully applied, in particular, in metal-
catalyzed Friedel–Crafts reactions of indoles.13b,e–j
L9
Entry
Ligand
Yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L6
L7
L8
L9
99
87
91
91
96
95
94
99
21
30
23
75
61
31
63
55
60
5
Our group also succeeded in developing a catalytic asym-
metric Friedel–Crafts alkylation reaction of nitroalkenes
with indoles and pyrroles using a chiral imidazoline–ami-
nophenol–Cu complex.4 For example, the reaction of in-
dole 1a with trans-β-nitrostyrene (2a) was catalyzed by
IAP1–CuOTf to give the Friedel–Crafts adduct with an
enantiomeric excess of 74%.4c However, the use of the
N,N,N-tridentate PyBidine ligand (L1) for a copper-cata-
lyzed Friedel–Crafts reaction resulted in only 30% enan-
tiomeric excess (Table 1, entry 1). Because modification
of the structure of the imidazolidine motif is difficult ow-
ing to the limited number of commercially available chiral
a Isolated yield.
b Determined by chiral HPLC analysis of the product using a Daicel
Chiralcel OD-H column [hexane–2-PrOH (70:30), 0.7 mL/min].
For the L3–Cu(OTf)2-catalyzed Friedel–Crafts reaction,
the reaction conditions were optimized as shown in Table
2. Although reducing the reaction temperature did not
Synlett 2014, 25, 349–354
© Georg Thieme Verlag Stuttgart · New York

LETTER
Enantioselective Friedel–Crafts Alkylation of Indoles
351
Table 2 Optimization of the Reaction Conditions for PyBodine(Val) (L3)–Cu(OTf)2-Catalyzed Friedel–Crafts Alkylation
Ph
Ph
Ph
Ph
NH
HN
N
O
O
Ph
PyBodine(Val) (L3; 5.5 mol%)
Cu(OTf)2 (5 mol%)
NO2
NO2
+
Ph
CH2Cl2
2a
N
H
HN
1a
3a
Entry
Temp (°C)
Additive
Time (h)
Yield (%)a
ee (%)b
1
2
3
4
5
r.t.
0
–
22
48
47
53
53
91
88
99
99
61
75
70
83
83
79
–
0
HFIPc
HFIPc
HFIPc
–15
–30
a Isolated yield.
b Determined by chiral HPLC analysis of the product using a Daicel Chiralcel OD-H column [hexane–2-PrOH (70:30), 0.7 mL/min].
c Conditions: 2.0 equiv were added.
have a significant effect on the stereoselectivity of 3a, the smoothly with indole at 0 °C with good to high enantiose-
reaction using two equivalents of 1,1,1,3,3,3-hexafluo- lectivity (Table 3, entries 6–9). For aliphatic nitroalkenes,
roisopropanol (HFIP) at 0 °C improved the enantiomeric although hydrocinnamaldehyde 2g could be converted
excess of 3a, with up to 83% (Table 2, entry 3).4c Al- into 3k with 71% enantiomeric excess at 0 °C (Table 3,
though the role of HFIP is not clear, it is thought that the entry 11), the reaction of (E)-(2-nitrovinyl)cyclohexane
addition of HFIP allows smooth protonation of the metal- (2f) was slow at 0 °C, and the reaction at room tempera-
bound intermediate, enforcing a smooth catalytic cycle to ture gave a 90% yield of 3j with 59% enantiomeric excess
release the enantiomerically enriched product.
(Table 3, entry 10).
Under optimized conditions, the scope of the Friedel– Although the detailed mechanism of the PyBodine(Val)
Crafts alkylation reaction of indoles with nitroalkenes was (L3)–Cu(OTf)2-catalyzed Friedel–Crafts reaction was not
investigated, and the results are summarized in Table 3.
elucidated, a plausible reaction model is proposed in
Scheme 2. PyBodine(Val) (L3)–Cu(OTf)2 acts as a Lewis
acid, activating the β-nitrostyrene (2a). When the reaction
proceeds using the upper side of the copper-containing
square planar unit, the indole (1a) approaches the Si face
of 2a from the vacant first quadrant, providing the R-en-
riched Friedel–Crafts adduct 3a.
Electron-donating substitution of the indole enhanced the
reaction rate and resulted in high enantioselectivity in the
products. The use of 5-methyl- or 5-methoxy-1H-indole
resulted in an enantiomeric excess of 87% ee (Table 3, en-
tries 2 and 3), while the use of 7-methyl-1H-indole gave
3e with 80% enantiomeric excess (Table 3, entry 5).19,20
Although the reaction using 5-bromo-1H-indole (1d) pro- As an application of catalysis by PyBodine(Val) (L3)–
ceeded, the enantiomeric excess of 3e was reduced to 69% Cu(OTf)2, a double Friedel–Crafts reaction, shown in
(Table 3, entry 4). Various aromatic nitroalkenes reacted Scheme 3, was demonstrated.
Scheme 2 Plausible reaction model
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 349–354

352
T. Sato, T. Arai
LETTER
Table 3 General Scheme of Asymmetric Friedel–Crafts Reaction of Indoles with Nitroalkenes Catalyzed by PyBodine(Val) (L3)–Cu(OTf)2
Complex
NH
HN
Ph
Ph
Ph
Ph
N
O
O
PyBodine(Val) (L3; 5.5 mol%)
Cu(OTf)2 (5 mol%)
R1
R2
HFIP (2 equiv)
NO2
NO2
R1
+
R2
CH2Cl2, 0 °C
N
HN
H
1a–e
2a–g
3a–k
Entry
R1
R2
Product
Time (h)
Yield (%)a
ee (%)b
1
2
1a H
2a Ph
3a
3b
3c
3d
3e
3f
23
37
37
80
30
47
47
47
47
12
38
99
99
97
96
99
87
99
94
94
90
90
83
1b 5-Me
2a Ph
87c
87c
69c
80c
76c
78c
84c
84c
59c
71c
3
1c 5-MeO
1d 5-Br
1e 7-Me
1a H
2a Ph
4
2a Ph
5
2a Ph
6
2b 4-O2NC6H4
2c 4-BrC6H4
2d 4-MeOC6H4
2e 2-MeOC6H4
2f c-C6H11
2g PhCH2CH2
7
1a H
3g
3h
3i
8
1a H
9
1a H
10d
11
1a H
3j
1a H
3k
a Isolated yield.
b Determined by chiral HPLC analysis of the product using Daicel Chiralcel OD-H and Chiralpak AD-H columns.
c The absolute configuration is presented by analogy with the product obtained in entry 1.
d The reaction was conducted at r.t.
Using PyBodine(Val) (L3)–Cu(OTf)2 as a catalyst, 1,4- Friedel–Crafts reaction of indoles with nitroalkenes. The
bis[(E)-2-nitrovinyl]benzene (2h) reacted with indole stereochemically tunable PyBodine ligands readily pro-
(1a) smoothly in a meso-trick manner21 to give the chiral vide an appropriate reaction sphere for promoting the tar-
double Friedel–Crafts adduct 3l with an excellent enantio- get reactions. Tailor-made construction of PyBodine–
meric excess of 97%.22
metal catalysts for a wide range of asymmetric catalytic
applications is ongoing in our laboratory.
In conclusion, we demonstrated the catalytic activity of
the newly developed PyBodine–copper catalyst in the
HN
NO2
PyBodine(Val) (L3); (11 mol%)
R
Cu(OTf)2 (10 mol%)
HFIP (2 equiv)
NO2
R
O2N
+
N
CH2Cl2, 0 °C, 69 h
O2N
H
2h
1a
NH
3l
99%
dl/meso = 81:19
97% ee
Scheme 3 Double asymmetric Friedel–Crafts reaction
Synlett 2014, 25, 349–354
© Georg Thieme Verlag Stuttgart · New York

LETTER
Enantioselective Friedel–Crafts Alkylation of Indoles
353
(13) (a) Jia, Y.-X.; Zhu, S.-F.; Yang, Y.; Zhou, Q.-L. J. Org.
Acknowledgment
Chem. 2006, 71, 75. (b) Lu, S.-F.; Du, D.-M.; Xu, J. Org.
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This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science and Tech-
nology (Japan), by the Chiba University Iodine Research Project
and by the Workshop on Chirality in Chiba University (WCCU).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
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Analytical Data of PyBodine(Val) (L3)
1H NMR (400 MHz, DMSO-d6): δ = 8.06 (t, J = 7.6 Hz, 1 H),
7.76 (d, J = 7.6 Hz, 2 H), 7.44–7.36 (m, 8 H), 7.31–7.28 (m,
2 H), 7.23–7.19 (m, 4 H), 7.13–7.11 (m, 6 H), 5.54 (d, J =
12.5 Hz, 2 H), 3.89 (dd, J = 12.5, 3.4 Hz, 2 H), 3.75 (t, J =
12.5 Hz, 2 H), 1.92–1.85 (m, 2 H), 1.08 (d, J = 6.7 Hz, 6 H),
0.15 (d, J = 6.7 Hz, 6 H). 13C NMR (125 MHz, CDCl3): δ =
155.0, 146.4, 143.8, 138.1, 128.1, 127.8, 127.6, 127.5,
127.2, 126.7, 124.6, 90.2, 88.0, 73.0, 28.6, 23.3, 16.8. ESI-
FTMS: m/z calcd for C41H44N3O2+ [M + H]+: 610.3428;
found: 610.3434. [α]D26 –42.9 (c 1.05, CHCl3). FTIR: 2956,
2924, 2854, 1456, 1377, 1003, 938, 813, 755, 728, 700 cm–1.
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PyBodine(Val) (L3, 0.011 mmol) and Cu(OAc)2 (0.01
mmol) were added to a round flask containing a stir bar
under Ar. CH2Cl2 (1 mL) was added to the flask, and the
mixture was stirred for 1 h. After cooling to 0 °C to the
mixture was added nitroalkene (0.4 mmol), indole (0.2
mmol), and HFIP. After being stirred for appropriate time,
the reaction mixture was purified by silica gel column
chromatography (hexane–EtOAc; 9:1 to 2:1) to afford the
Friedel–Crafts adduct.
Analytical Data of 3b
1H NMR (400 MHz, CDCl3): δ = 7.99 (br s, 1 H), 7.36–7.30
(m, 4 H), 7.28–7.23 (m, 3 H), 7.02 (dd, J = 8.5 Hz, 1.4 Hz, 1
H) 6.96 (d, J = 1.8 Hz, 1 H), 5.16 (t, J = 8.4 Hz, 1 H), 5.05
(dd, J = 12.6, 8.4 Hz, 1 H), 4.93 (dd, J = 12.6, 8.4 Hz, 1 H),
2.17 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 139.2, 134.8,
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 349–354

354
T. Sato, T. Arai
LETTER
129.3, 128.9, 127.7, 127.5, 126.3, 124.3, 121.8, 118.4,
113.9, 111.0, 79.5, 41.5, 21.5. ESI-FTMS: m/z calcd for
C17H15N2O2– [M – H]–: 279.1139; found: 279.1148; the
enantiomeric excess was determined by HPLC with a
Chiralcel OD-H column [hexane–2-PrOH (85:15), 0.7
mL/min, 254 nm]: tR (major enantiomer) = 50.0 min; tR
(minor enantiomer) = 71.7 min. [α]D20 +13.5 (c 1.0, CH2Cl2,
87% ee). FTIR: 3412, 2974, 1556, 1377 cm–1.
(22) Analytical Data of 3l
1H NMR (400 MHz, acetone-d6): δ = 10.23 (br s, 2 H), 7.51–
7.46 (m, 2 H), 7.43 (s, 4 H), 7.38–7.36 (m, 4 H), 7.10–7.06
(m, 2 H), 6.97–6.93 (m, 2 H), 5.30–5.14 (m, 6 H). 13C NMR
(100 MHz, acetone-d6): δ = 140.0, 137.4, 128.7, 127.0,
122.7, 122.3, 119.6, 119.2, 114.4, 112.0, 79.8, 41.5. ESI-
FTMS: m/z calcd for C26H21N4O4– [M – H]–: 453.1568;
found: 453.1588; the enantiomeric excess was determined
by HPLC with a Chiralcel AD-H column [hexane–2-PrOH
(80:20), 1.0 mL/min, 254 nm]: tR (major enantiomer) = 44.7
min; tR (minor enantiomer) = 48.2 min. [α]D20 +19.0 (c 1.0,
CH2Cl2, 97% ee). FTIR: 3412, 2921, 1546, 1457, 741 cm–1.
(21) (a) Laumen, K.; Schneider, M. Tetrahedron Lett. 1984, 25,
5875. (b) Wang, Y.-F.; Chen, C.-S.; Girdaukas, G.; Sih, C. J.
J. Am. Chem. Soc. 1984, 106, 3695.
Synlett 2014, 25, 349–354
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