Double axially chiral bisphosphorylimides catalyzed highly enantioselective and efficient friedel-crafts reaction of indoles with imines

Article abstract of DOI:10.1002/chem.201202900

Cool cats: 1,1′-Bi-2-naphthol and vaulted 3,3′-biphenanthrol- type bisphosphorylimides enabled the atom-economical and highly enantioselective Friedel-Crafts reaction between indoles and N-tosylimines with a low catalyst loading (see scheme). A very small

Full text of DOI:10.1002/chem.201202900

DOI: 10.1002/chem.201202900
Double Axially Chiral BisphosphorylACTHNUTRGNEUNGimides Catalyzed Highly
Enantioselective and Efficient Friedel–Crafts Reaction of Indoles with Imines
Kun Wu, Yi-Jun Jiang,* Yan-Sen Fan, Di Sha, and Suoqin Zhang*[a]
Chiral Brønsted acids derived from 1,1’-bi-2-naphthol
(BINOL) and other axially chiral backbones have been ex-
tensively utilized for a variety of highly setereoselective
transformations during the past decade.[1] Since the pioneer-
ing work of Akiyama[2] and Terada,[3] much effort has been
devoted to modifying the BINOL backbone or developing
new axially chiral backbones to improve the catalytical per-
formance of phosphoric acids. New perspective was opened
by Yamamoto and co-workers by introducing a triflylamide
group into the BINOL phosphate framework to activate
more challenging substrates due to increased catalyst acidi-
ty.[4] Subsequently, pyridinyl phosphoramides[5] and phos-
phinyl phosphoramides[6] were developed by List and co-
workers to further expand the application scope of BINOL
phosphoramide framework through modifying the activation
center with new Brønsted base sites. Very recently, List and
co-workers established a confined imidodiphosphoric acid,
which showed predominant catalytic activity and chiral-con-
trol ability in enantioselective spiroacetalization[7] and sul-
foxidation[8] reactions owing to its enzyme-like deep active-
site pocket and extremely rigid chiral microenvironment.
Meanwhile, we had also reported the synthesis and applica-
tion of bisphosphorylimides 1 (Figure 1) in an asymmetric
three-component Mannich reaction,[9] in which catalyst 1d
displayed significant stereocontrol in providing syn-selective
b-amino ketones exclusively in high yields and with excel-
Figure 1. Double axially chiral bisphosphorylimide catalysts and their ap-
plication in the Friedel–Crafts reaction.
lent enantioselectivities. In view of the attractive features of
this new Brønsted acid framework and the impressive suc-
cess achieved by Antilla and co-workers in catalytic asym-
metric reactions through the use of vaulted 3,3’-biphenan-
throl (VAPOL)-derived phosphoric acid or phosphates,[10]
we further developed VAPOL-type double axially bisphos-
phorylimide 2 and cross-backbone bisphosphorylimide 3 for
the first time to extend the structure diversity and applica-
tion scope of bisphosphorylimides.
and natural-like products.[12,13] A variety of catalytic systems
have been developed using chiral Brønsted acids, including
thioureas,[14] phosphoric acids,[15] N-triflyl phosphoramides,[16]
sulfonimides,[17] squaramides,[18] and tartaric acid deriva-
tives.[19] However, 2–5 equiv of indole or imine substrates
were necessary in all of the reported reactions.[20,21] In addi-
tion, although high enantioselectivity could be achieved for
meta- and para-aldimine substrates, lower stereoselectivities
or yields with limited substrates scope were generally ob-
served for ortho-substituted aldimines. Herein we describe
the highly enantioselective Friedel–Crafts reaction with high
efficiency and extensive substrate scope catalyzed by bi-
sphosphorylimide catalysts, in which BINOL and VAPOL-
type bisphosphorylimides displayed their unique and excel-
lent catalytic properties on aryl imine and alkyl imine sub-
strates, respectively (Figure 1).
In recent years, catalytic asymmetric Friedel–Crafts reac-
tions between indoles and imines have received considerable
attention[11] because 3-indolymethanamine derivatives are
pivotal structural motifs of many biologically active natural
[a] K. Wu, Dr. Y.-J. Jiang, Y.-S. Fan, D. Sha, Prof. Dr. S. Zhang
College of Chemistry, Jilin University
2699 Qianjin Street, Changchun 130012 (P.R. China)
E-mail: jiangyijun@jlu.edu.cn
suoqin@jlu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202900.
474
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Chem. Eur. J. 2013, 19, 474 – 478

COMMUNICATION
Table 2. Screening of additives.[a]
As shown in Figure 1, BINOL-derived double axially bi-
sphosphorylimides 1a–d were synthesized according to the
procedure reported in our previous work.[9] The VAPOL-
type backbone was employed into this new Brønsted acid
framework for the first time and bisphosphorylimide 2 was
achieved successfully. Bisphosphorylimides 3 composed with
two different axial backbones were also synthesized. Opti-
cally active bisphosphorylimides 1–3 were then tested for
the Friedel–Crafts reaction of indoles and aryl/alkyl N-tosyl
imines.
Entry
Additives
[mol%]
t
Yield
[%][b]
ee
U
A
[%][c]
1
2
3
4
5
6
7
8
9
–
15
30
60
60
60
60
74
55
72
75
75
70
95
<1
99
>99
73
diethylamine (1)
piperidine (1)
pyrrolidine (1)
triethylamine (1)
pyridine (1)
DMAP (1)
97
97
97
95
Initial studies were carried out with imine 5a (0.1 mmol)
and 5 equivalents of indole 4a to avoid the generation of
side product 7a according to literature procedures (Ta-
ble 1).[15c,d] Generally, for catalysts 1a–d, the yield and enan-
120
–
98
DMAP (2)
DMAP (0.2)
N/A
>99
60
Table 1. Screening of bisphosphorylimide catalysts.[a]
[a] Reaction conditions: 4a (0.1 mmol), 5a (0.1 mmol), 1d (2 mol%), tol-
uene (1 mL), RT. [b] Yield of the isolated product. [c] Determined by
HPLC analysis on a Chiralcel OD-H column.
a poor selective reaction with a fast catalyst could be slowed
down by adding a second catalyst, thus to suppress the un-
wanted side reactions.[24] Considering that four extra equiva-
lents of indole used in Table 1 might make the catalytic
system less acidic and keep 6aa from consuming to 7a, we
decided to investigate different basic additives. Amines and
pyridine were examined, which did not improve the yield
but decreased the ee value (Table 2, entries 2–6). Inspired
by the reports of using 4-(dimethylamino)pyridine (DMAP)
as an efficient additive in chiral Brønsted acid-catalyzed
asymmetric transformations,[25] DMAP (1 mol%) was used
in combination with 1d (2 mol%) to test the efficiency of
Friedel–Crafts reaction (Table 2, entry 7). Gratifyingly, the
yield of 6aa was improved significantly and the formation of
the side product 7a had been successfully suppressed. Mean-
while, the reaction time was extended to 120 min, indicating
that the reaction proceeded more slowly and more chemose-
lectively by adding DMAP. However, virtually no conver-
sion occurred when the amount of DMAP was increased to
2 mol% (Table 2, entry 8). Surprisingly, the best result was
observed when the amount of DMAP was reduced to
0.2 mol% (Table 2, entry 9). This process was more efficient
and atom-economical than all of the previous reports in
which 1–4 equivalents excess of indoles or imines were
needed.[14–18,20,21]
With the optimized conditions in hand, the scope of the
reaction was explored (Table 3). A wide range of aryl imines
bearing either electron-withdrawing or electron-donating
groups on the meta- and para-position of the phenyl ring
furnished the resulting chiral 3-indolymethanamines 6ab–
6ao with high yields and excellent enatioselectivities in all
cases (Table 3, entries 2–15). Aryl imines derived from 1-
napthylaldehyde and 2-napthylaldehyde were also exam-
ined. Both of the reactions proceeded smoothly and afford-
ed the products with excellent enantioselectivities and yields
(Table 3, entries 16 and 17).
Entry
Catalyst
[mol%]
t
Yield
[%][b]
ee
G
A
[%][c]
1
2
3
4
5
6
7
1a (5)
1b (5)
1c (5)
1d (5)
2 (5)
15
15
15
15
60
30
30
80
83
85
98
76
78
99
10
90
93
>99
83
3 (5)
1d (2)
93
>99
[a] Reaction conditions: 4a (0.5 mmol), 5a (0.1 mmol), toluene (1 mL),
RT. Ts =p-toluenesulfonyl. [b] Yield of the isolated product. [c] Deter-
mined by HPLC analysis on Chiralcel OD-H column. Absolute configu-
ration determined by comparing the retention time of HPLC of products
with those of literature data (see the Supporting Information).
tioselectivity of 6aa were both improved by magnifying the
steric hindrance on the 3,3’-position of BINOL (Table 1, en-
tries 1–4). Among the catalysts examined, bisphosphoryli-
mide 1d was found to be most effective for both yield and
enantiomeric excess (ee; Table 1, entry 4). VAPOL-derived
bisphosphorylimide 2 proved to be much less effective and
led to dramatic decrease of stereochemical induction and
yield (Table 1, entry 5). Bisphosphorylimide 3 was more ster-
eoselective than 2, but only performed to give a moderate
yield of the product (Table 1, entry 6). To our delight, reduc-
ing the catalyst loading of 1d to 2 mol% did not affect the
catalytic profile or stereochemical outcome (Table 1,
entry 7).
Having identified the optimal catalyst 1d (Table 1,
entry 7), a screen of additives was carried out in an attempt
to minimize the mole ratio of 4a and 5a. When equimolar
amounts of 4a and 5a were used without adding additive,
product 6aa was obtained in 15 min, along with rapid con-
version to side product 7a (Table 2, entry 1).[22,23] The poor
chemoselectivity implied an excess of strong acidity of cata-
lyst 1d in this process. It has been reported that the rate of
Chem. Eur. J. 2013, 19, 474 – 478
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475

Y.-J. Jiang, S. Zhang et al.
Table 3. Enantioselective Friedel–Crafts reaction of indoles with aldimines catalyzed by 1d.[a]
Entry
R4
Ar
Product
t
Yield
[%][b]
ee
Entry
R4
Ar
Product
t
Yield
[%][b]
ee
[h]
[%][c]
[h]
[%][c]
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
3-FC6H4
4-FC6H4
6aa
6ab
6ac
6ad
6ae
6af
6ag
6ah
6ai
6aj
6ak
6al
6am
6an
1
1
1
1
1
1
1
1
1
1
2
1.5
1.5
0.5
99
97
92
99
99
98
97
98
90
99
97
92
95
94
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
99
15
16
17
18
19
20
21
22
23
24
25
26
27
28
H
H
H
H
H
H
H
H
H
H
2-Me
5-Me
5-OMe
5-Br
4-OMeC6H4
1-Nap
2-Nap
6ao
6ap
6aq
6ar
6as
6at
6au
6av
6aw
6ax
6bt
6ct
2
2
1.5
1
1
1
0.5
2
0.5
0.5
3
0.5
1
90
96
91
98
99
99
98
96
99
92
92
98
91
98
99
99
99
>99
>99
>99
>99
98
98
>99
98
>99
>99
98
3-ClC6H4
4-ClC6H4
3-BrC6H4
4-BrC6H4
3-NO2C6H4
4-NO2C6H4
4-CF3C6H4
3-Me C6H4
4-Me C6H4
4-iPrC6H4
3-OMeC6H4
2-FC6H4
2-ClC6H4
2-BrC6H4
2-NO2C6H4
2-MeC6H4
2-OMeC6H4
2,4-Cl C6H3
2-BrC6H4
2-BrC6H4
2-BrC6H4
2-BrC6H4
9
10
11
12
13
14
>99
>99
6dt
6et
3
[a] Reaction conditions: 4a (0.1 mmol), 5a (0.1 mmol), catalyst (2 mol%), DMAP (0.2 mol%), toluene (1 mL), RT; Nap=Napthyl. [b] Yield of the iso-
lated product. [c] Determined by HPLC analysis on Chiralcel OD-H or AD-H column.
Remarkably, our catalytic system was capable of promot-
ing the Friedel–Crafts reaction of ortho-substituted aldi-
mines with high efficiency and selectivity, whereas systems
in previous reports showed considerable chemo- or stereose-
lective limitations.[14–18,20] The ortho-substituted aldimines
with various electron-withdrawing or electron-donating
groups were tested and 3-indolymethanamines 6ar–6ax
were obtained in high yields and with excellent enantiose-
lectivities (Table 3, entries 18–24). The ortho-bromo-substi-
tuted aldimine was further applied to examine substituted
indoles (Table 3, entries 25–28). To our delight, high yields
and excellent enantioselectivities were observed for the cor-
responding products 6bt–6et.
hexacyl imine 8a was then selected for further optimization
of the reaction conditions. Increasing the amount of imine
8a to 4 equivalents improved the yield to 80% effectively
with a moderate ee value (Table 4, entry 2). Gratifyingly,
VAPOL-derived bisphosphorylimide 2 was found to be
more efficient in this process and 9aa was obtained with ex-
cellent enantioselectivity and high yield (Table 4, entry 3).
Meanwhile, 0.2 mol% DMAP was still found necessary for
improving the yield and enantioselectivity (Table 4, entry 4).
Bisphosphorylimide 3 afforded the product with only mod-
erate yield and low enatioselectivity (Table 4, entry 5). It
was exciting to note that even using
a loading of
0.25 mol%[26] of catalyst 2, the reaction proceeded equally
well and the optimal result was achieved at a lower temper-
ature (Table 4, entry 6).
The Friedel–Crafts reactions of indole and alkyl imines
were also evaluated under the same conditions (Table 1,
entry 7) but gave inferior results (Table 4, entry 1). Cyclo-
Other alkyl imines were also examined with the optimized
conditions (Table 4, entry 6) and the results are listed in
Table 5. In these processes, our catalyst loading
(0.25 mol%) was much lower than that reported by Deng
et al. (10 mol%).[14a] For the same substrates, VAPOL-de-
rived bisphosphorylimide 2 gave higher yield and enantiose-
lectivity than Dengꢁs method.
Table 4. Optimization of the reaction conditions for alkyl imines.[a]
To demonstrate the utility of the present Friedel–Crafts
reaction, experiments were performed on gram scales, at
which the bisphosphorylimide catalysts showed even better
performance. When indole 4a (10 mmol, 1.18 g) was treated
with aldimine 5t, the catalyst loading of 1d could be further
reduced to 0.5 mol% and 6at (4.49 g) was obtained without
any loss of enantioselectivity and yield. When indole 4a
(10 mmol, 1.18 g) was treated with alkyl imine 8d, com-
pound 9ad (3.35 g) was obtained with retention of the enan-
tioselectivity and in a dramatically increased yield (com-
pared with the result in Table 5, entry 5). 3-Indolymethana-
mines 6at and 9ad in Scheme 1 were obtained in almost
Entry
Catalyst
[mol%]
DMAP
[mol%]
Yield
[%][b]
ee
G
G
[%][c]
1
2
3
4
5
6
1d (2)
1d (2)
2 (2)
2 (2)
3 (2)
0.2
0.2
0.2
–
0.2
0.025
14
80
93
80
82
93
À66[d,e]
À73[e]
96
87
25
2 (0.25)
97[f]
[a] Reaction conditions: 4a (0.1 mmol), 8a (0.4 mmol), toluene (1 mL),
RT. [b] Yield of the isolated product. [c] Determined by HPLC analysis
on Chiralcel OD-H column. [d] The reaction was run with 0.1 mmol 4a
and 0.1 mmol 5a. [e] Reversed absolute configuration with 9aa. [f] Reac-
tion was run at 08C over 6 h.
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Chem. Eur. J. 2013, 19, 474 – 478

Double Axially Chiral Bisphosphorylimides
COMMUNICATION
Table 5. Enantioselective Friedel–Crafts reaction of indole with alkyl
of the reaction mechanism and extension of the reaction
scope are currently underway in our laboratory.
imines catalyzed by 2.[a]
Experimental Section
R5
Product
t
Yield
[%][b]
ee
General procedure for aryl imines: Aryl imine 5 (0.1 mmol), bisphos-
phorylimide 1d (2.4 mg, 0.002 mmol, 2 mol%) and DMAP (10 mL of
2.44 mgmLÀ1 solution in toluene, 0.0002 mmol, 0.2 mol%) were dissolved
in toluene (1 mL), the solution was stirred for 5 min at room temperature
and indole 4 (0.1 mmol) was added. After the reaction was complete
(monitored by TLC), the mixture was purified by silica gel chromatogra-
phy (ethyl acetate/petroleum ether, 1:3) directly to afford the product 6.
Entry
[h]
[%][c]
1
2
9aa
9ab
6
8
93
88
97[d]
96
General procedure for alkyl imines: Alkyl imine 8 (0.4 mmol), bisphos-
phorylimide 2 (10 mL of 30 mgmLÀ1 solution in toluene, 0.00025 mmol,
0.25 mol%) and DMAP (10 mL of 0.31 mgmLÀ1 solution in toluene,
0.000025 mmol, 0.025 mol%) were dissolved in toluene (1 mL), the solu-
tion was stirred for 15 min at À408C and indole 4a (0.1 mmol) was
added. After the reaction was complete (monitored by TLC), the mixture
was purified by flash chromatography (ethyl acetate/petroleum ether,
1:3) directly to afford the product 9.
3
4
9ac
9ad
8
92
93
98
18
>99
5
9ae
8
90
97
[a] Reaction conditions: 4a (0.1 mmol), 8a (0.4 mmol), catalyst
(0.25 mol%), DMAP (0.025 mol%), toluene (1 mL), À408C. [b] Yield of
the isolated product. [c] Determined by HPLC analysis on Chiralcel OD-
H column. [d] The reaction was run at 08C.
Acknowledgements
We thank the National Natural Science Foundation of China (21202059)
and the Jilin Province Science & Technology Development Program
(20100538, 20120315) for financial support.
Keywords: asymmetric catalysis
· bisphosphorylimides ·
enantioselectivity · Friedel–Crafts reaction · indoles
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very small amount of DMAP was found to be crucial for the
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Received: August 13, 2012
Published online: December 5, 2012
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