Enantioselective synthesis of tetrahydropyrano[3,4- b ]indoles catalyzed by chiral N -triflyl phosphoramide via intramolecular friedel-crafts alkylation reaction

Article abstract of DOI:10.1055/s-0030-1260537

A highly efficient intramolecular enantioselective Friedel-Crafts alkylation reaction of indolyl enones utilizing chiral N-triflyl phosphoramide catalyst is described. Various tetrahydropyrano[3,4-b]indoles (THPI) have been afforded with excellent yields and up to 98% ee. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260537

CLUSTER
1239
Enantioselective Synthesis of Tetrahydropyrano[3,4-b]indoles Catalyzed by
Chiral N-Triflyl Phosphoramide via Intramolecular Friedel–Crafts Alkylation
Reaction
E
nantiosel
u
e
ctive Synth
n
e
sis of
T
etra
h
-
ydropyr
W
ano[3,4-
b
]
I
ndoles ei Zhang,a,b Quan Cai,b Xiao-Xin Shi,a Wei Zhang,b Shu-Li You*a,b
a
School of Pharmacy, East China University of Science and Technology, 130 Mei-Long Road, Shanghai 200237, P. R. of China
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Lu, Shanghai 200032, P. R. of China
b
Fax (+86) 21-54925087; E-mail: slyou@sioc.ac.cn
Received 30 January 2011
lyst in the above intramolecular asymmetric Friedel–
Crafts alkylation reaction. In this paper, we report the re-
sults from this study. Chiral N-triflyl phosphoramide was
found an efficient catalyst for asymmetric intramolecular
Friedel–Crafts alkylation reaction of indolyl enones, pro-
viding tetrahydropyrano[3,4-b]indoles in excellent yields
and ee’s. Notably, the catalyst loading could be as low as
1 mol%, and the ketone product could be readily trans-
formed into an ester.
Abstract: A highly efficient intramolecular enantioselective
Friedel–Crafts alkylation reaction of indolyl enones utilizing chiral
N-triflyl phosphoramide catalyst is described. Various tetrahydro-
pyrano[3,4-b]indoles (THPI) have been afforded with excellent
yields and up to 98% ee.
Key words: asymmetric catalysis, chiral Brønsted acids, N-triflyl
phosphoramide, Friedel–Crafts, indoles
Organocatalysts, which have been extensively developed
in the last decade, are still of great research interest due to
their inherent advantages such as robust, environmental
benign, and cheap, but usually require high loading of the
catalysts.1 In the broad research field of organocatalysts,
Brønsted acid is often classified as an important branch,
which typically subdefined as H-bond donor catalysts
such as thioureas2 and stronger Brønsted acid catalysts
(e.g., phosphoric acids).3 Chiral N-triflyl phosphoramides
derived from binaphthyl scaffold, since its first design and
utilization in the asymmetric catalytic Diels–Alder reac-
tion by Yamamoto and co-workers,4 have attracted con-
siderable attention due to their rigid chiral framework and
even stronger acidity than chiral phosphoric acids.5,6 Re-
cently, chiral N-triflyl phosphoramides have been applied
successfully in several asymmetric catalytic reactions by
further broadening the activating mode and reaction
scope.4,5 In 2009, we reported an enantioselective con-
struction of polycyclic indoles by a sequential catalysis of
Ru-catalyzed olefin cross-metathesis and chiral phospho-
ric acid-catalyzed intramolecular Friedel–Crafts alkyla-
tion.7–9 This asymmetric intermolecular Friedel–Crafts
alkylation reaction catalyzed by 5 mol% of chiral phos-
phoric acid led to the facile construction of tetrahydro-
pyrano[3,4-b]indoles in high enantioselectivities
(Scheme 1).
R
O
O
O
P
O
OH
R2
O
R2
R
R = 9-phenanthryl
(S)-CPA
(5 mol%)
O
O
R1
R1
up to 99% yield
98% ee
N
R3
1
N
R3
2
Scheme 1 Enantioselective construction of tetrahydropyrano[3,4-
b]indoles by chiral phosphoric acid catalyzed intramolecular Friedel–
Crafts alkylation
We began our study by examining various chiral phos-
phoramides in the cyclization reaction of 1a in toluene at
–20 °C. The data are summarized in Table 1. To our de-
light, all the phosphoramides, especially N-triflyl phos-
phoramides, proved to be efficient for this intramolecular
Friedel–Crafts alkylation reaction, affording product 2a in
excellent yields within five minutes. This clearly indicates
a better activation of the substrate by N-triflyl phosphor-
amides comparing with their corresponding phosphoric
acids. Among these chiral N-triflyl phosphoramides, (S)-
3j was the optimal one in terms of a combination of yield
and ee (84% yield, 89% ee, Table 1, entry 10).
As part of our ongoing program of developing highly ef-
ficient chiral Brønsted acid catalyzed asymmetric reac-
tions,10,11 we envisaged that the chiral N-triflyl
phosphoramide, a stronger Brønsted acid than its corre-
sponding phosphoric acid, might be a more efficient cata-
With the optimal catalyst (S)-3j in hand, reaction parame-
ters including the reaction temperatures and solvents were
then further optimized. As summarized in Table 2, the re-
action at lower temperature proceeded smoothly with in-
creased enantioselectivity but a longer reaction time
(Table 2, entries 1–5). Reaction at –70 °C provided cy-
clization product 2a in 97% yield and 95% ee (Table 2,
SYNLETT 2011, No. 9, pp 1239–1242
x
x.
x
x.
2
0
1
1
Advanced online publication: 20.04.2011
DOI: 10.1055/s-0030-1260537; Art ID: Y03211ST
© Georg Thieme Verlag Stuttgart · New York

1240
J.-W. Zhang et al.
CLUSTER
Table 1 Screening of Chiral Phosphoramides 3a
Table 2 Effects of Reaction Temperatures and Solventsa
O
O
Ph
Ph
O
O
Ph
Ph
O
O
O
O
(S)-3 (5 mol%)
(S)-3j (5 mol%)
solvent
toluene, –20 °C, 5 min
N
N
N
N
Me
Me
Me
Me
1a
2a
1a
2a
R1
Entry
Temp (°C) Solvent
Time
<5 min
<5 min
5 min
5 min
24 h
Yield (%)b ee (%)c
O
O
P
1
2
r.t.
toluene
toluene
toluene
toluene
toluene
CH2Cl2
CHCl3
THF
88
99
84
90
97
99
99
18
17
99
78
79
85
89
92
95
88
78
57
62
66
12
NHR2
O
0
R1
(S)-3
3
–20
–40
–70
–40
–40
–40
–40
–40
–40
Entry
1
3 R1, R2
Yield (%)b ee (%)c
4
5
3a H, SO2C4F9
82
88
95
99
99
99
97
75
85
84
99
94
91
18
62
30
67
20
70
50
52
60
89
85
80
75
6
5 min
8.5 h
3 h
2
3b 3,5-(CF3)2C6H3, SO2C8F17
7
3
3c 2,4,6-(i-Pr)3C6H2, SO2C8F17
3d 3,5-(CF3)2C6H3, Tf
3e 2,4,6-(i-Pr)3C6H2, Tf
3f 3,5-Me2C6H3, Tf
3g 4-biphenyl, Tf
8
4
9
Et2O
18 h
5
10
11
MeCN
hexane
3 h
6
13 h
7
a All the reactions were performed using 1a (0.10 mmol) in 1 mL of
solvent with 5 mol% of catalyst (S)-3j.
b Isolated yield.
8
3h 4¢-[3,5-(CF3)2biphenyl], Tf
3i 4-O2NC6H4, Tf
9
c Determined by HPLC analysis.
10
11
12
13
3j 9-anthryl, Tf
group (OMe) at the 6-position of the indole core were all
cyclized smoothly to provide THPI products with 92–
98% ee (Table 3, entries 1–3). However, substituents (Br,
Me) at the 5-position of the indole slightly lowered the
enantioselectivities (Table 3, entries 4 and 5). When the
N-protected group was switched from Me to Bn, the ee
was maintained to be excellent for the cyclization product
(83% yield, 95% ee, Table 3, entry 6). The indolyl enones
with various substituted phenyl groups were also tested,
and the cyclization products were obtained with good
yields and ee (Table 3, entries 7–12). Interestingly, the
substrate with a free OH group on the phenyl ring could
be tolerated with a complete conversion (Table 3, entry
11). When an aliphatic ketone substrate 1n (R2 = Me) was
tested, the intramolecular Friedel–Crafts alkylation reac-
tion proceeded in 96% yield but with a low enantioselec-
tivity (16% ee) (Table 3, entry 13). Quite remarkably, the
reactions with reduced catalyst loadings (3 mol% and 1
mol%) at –70 °C worked also well without notable loss of
yields and ee (Table 3, entries 14 and 15).
3k 9-phenanthryl, Tf
3l 4-pyrenyl, Tf
3m SiPh3, Tf
a All the reactions were performed using 1a (0.10 mmol) in 1 mL of
toluene with 5 mol% of catalyst (S)-3.
b Isolated yield.
c Determined by HPLC analysis.
entry 5). Screening of various solvents such as toluene,
dichloromethane, chloroform, tetrahydrofuran, diethyl
ether, acetonitrile, and hexane at –40 °C disclosed that tol-
uene was the optimal one (Table 2, entries 4, 6–11). Nota-
bly, the reaction in dichloromethane gave a quantitative
yield with slightly decreased enantioselectivity (88% ee,
Table 2, entry 6).
Under the optimized reaction conditions (Table 2, entry
5), a wide range of substituted indolyl enones were inves-
tigated to test the generality of the reaction.
The results are summarized in Table 3. In general, all the
tested substituted indolyl enones were smoothly convert-
ed into their corresponding cyclization products 2 with
good to excellent yields. Substrates with either an elec-
tron-withdrawing group (Br, Cl) or an electron-donating
To broaden the application of this asymmetric synthetic
methodology, transformation of the product 2b into an es-
ter was carried out, as shown in Scheme 2. Treatment of
ketone 2b with hydroxylamine afforded the oxime, which
was subjected to the Beckmann rearrangement conditions
Synlett 2011, No. 9, 1239–1242 © Thieme Stuttgart · New York

CLUSTER
Enantioselective Synthesis of Tetrahydropyrano[3,4-b] Indoles
1241
the chiral center will make the current synthetic method-
ology potentially useful in organic synthesis.
Table 3 Substrate Scope of the Intramolecular Friedel–Crafts
Alkylation Reactiona
O
In conclusion, we found that chiral N-triflyl phosphor-
amide was an efficient catalyst for the asymmetric in-
tramolecular Friedel–Crafts alkylation reaction of indolyl
enones. With 1–5 mol% of the optimized catalyst, the sub-
stituted tetrahydropyrano[3,4-b]indoles were obtained in
excellent yields and ee’s. The transformation of the ke-
tone moiety into an ester functionality was also success-
fully demonstrated.
R2
O
R2
O
O
(S)-3j (5 mol%)
R1
R1
toluene, –70 °C
N
N
R3
R3
1
2
Entry
1
1 R1, R2, R3
Time (h) Yield (%)b ee (%)c
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
1b 6-Br, Ph, Me
24
24
24
42
24
24
24
24
24
24
108
32
60
24
24
99
96
83
81
99
83
49
94
92
99
99
96
96
99
98
98
92
92
63
87
95
86
96
94
97
63
91
16
98
98
2
1c 6-Cl, Ph, Me
Acknowledgment
3
1d 6-MeO, Ph, Me
1e 5-Br, Ph, Me
We thank the NSFC (20732006, 21025209) and MOST (973 Pro-
gram 2010CB833300) for financial support.
4
5
1f 5-Me, Ph, Me
1g H, Ph, Bn
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O
O
O
Ph
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O
OMe
O
(a), (b)
(c), (d), (e)
65% yield
O
79% yield
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N
N
Br
Br
Br
Me
Me
Me
2b
98% ee
4
5
98% ee
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reflux; (c) Boc2O, Et3N, DMAP, CH2Cl2; (d) LiOH, THF–H2O (5:1); (e) TMSCHN2, MeOH–benzene (1:1).
Synlett 2011, No. 9, 1239–1242 © Thieme Stuttgart · New York

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J.-W. Zhang et al.
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Synlett 2011, No. 9, 1239–1242 © Thieme Stuttgart · New York