Organocatalytic asymmetric reaction of indol-2-yl carbinols with enamides: Synthesis of chiral 2-indole-substituted 1,1-diarylalkanes

Article abstract of DOI:10.1039/c5cc03345d

The chiral phosphoramide-catalyzed asymmetric reaction of indol-2-yl carbinols with enamides is presented. The method provided an efficient and novel way for the synthesis of chiral 2-indole-substituted 1,1-diarylalkane derivatives.

Full text of DOI:10.1039/c5cc03345d

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ARTICLE TYPE
Organocatalytic Asymmetric Reaction of Indol-2-yl Carbinols with
Enamides: Synthesis of Chiral 2-Indole-Substituted 1,1-Diarylalkanes
Chao-You Liu,a,b and Fu-She Han* a,c
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
The chiral phosphoramide-catalyzed asymmetric reaction of
Previous work: indole substr ates severed as nucleophiles
indol-2-yl carbinols with enamides is presented. The method
a)
R
R
10 provided an efficient and novel way for the synthesis of chiral
2-indole-substituted 1,1-diarylalkane derivatives.
Ar
∗
a) Chiral cat.
b) [O]
Ar
(Ref . 6-8)
EWG
EWG
+
N
EWG
N
P
P
The 1,1-diarylalkane compounds are prevailing structural motifs
in natural products and synthetic molecules for pharmaceuticals
and materials.1 Among them, the heteroaryl-substituted
15 derivatives represent a type of important pharmacophores in
medicinal chemistry, particularly those with incorporation of an
indole core.2,3 More significantly, the indole-containing
compounds are versatile building blocks in numerous natural
products.4 As a consequence, the enantioselective synthesis of
20 indole-based 1,1-diarylalkanes composes a major theme of recent
research in catalytic asymmetric reactions. However, the majority
of the investigations have been concentrated on enantioselective
synthesis of 3-indole-substituted derivatives.3,5 The synthesis of
2-indole-substituted analogues remains underdeveloped due to
25 the poor reactivity at indole C2 position. In early studies, the
groups of You,6 Wang,7 and Du8 reported the synthesis of 2-
indole-substituted 1,1-diarylalkanes by using 4,7-dihydroindole
as nucleophile followed by oxidation of the resulting adducts
(Scheme 1a). More recently, the groups of Xiao,9 Feng,10 and
30 Zhao11 realized the direct asymmetric Friedel-Crafts reaction at
C2 of indole derivatives (Scheme 1b).
R
R
b)
Ar
∗
Ar
Chiral cat.
(Ref . 9-11)
+
N
EWG
N
P
P
This wor k: indole substr ates served as electrophiles
c)
R
R
R
Chiral
organocat.
Nu
Nu
OH
Ar
N
Ar
N
Ar
N
P
A
P
P
40 Scheme 1. Strategies for the asymmetric synthesis of 2-indole-substituted
1,1-diarylalkanes.
With our experiences on the asymmetric synthesis of
diindoylarylmethanes from indol-2-yl carbinols,13c we chose
chiral phosphoric acids or phosphoramides as the potential
45 catalysts because extensive investigations have witnessed that
such Brønsted acids can be versatile catalysts for a wide range of
reactions through various activation modes.14 Moreover, they also
carry with them the added advantages of metal free nature and the
ease of tuning acidity.15
All the extant approaches have employed indoles or analogues
as nucleophiles. As a result of Martin’s12 and our13 recent
advances in indol-2-yl carbinol chemistry, we devised a strategy
35 by utilizing indole derivatives as electrophiles (Scheme 1c). The
new strategy would provide an alternative option for accessing
chiral 2-indole-substituted 1,1-diarylalkanes. The successful
demonstration of this strategy will be presented herein.
50
Initially, the reaction of a range of indol-2-yl carbinol
derivatives (1) and vinylsilyl ether (2) was examined, which was
assumed to proceed via the mono activation mode of ion-pairing
or hydrogen-bonding interaction with the presence of phosphoric
acids or phosphoramides (Scheme 2a). Unfortunately, an
55 exhaustive screening of various conditions showed that the
reaction did not proceed (data not shown). In most cases, a rapid
decomposition of 2 was observed. Next, the reaction of indol-2-yl
carbinols 1 with enamides 4 was inspected (Scheme 2b). We
reasoned that replacement of vinylsilyl ethers with enamide
60 nucleophiles could enable the catalyst to activate both reactants
via a bifunctional mode through ion-pairing/H-bonding or H-
bonding/H-bonding interactions.
a
Key Lab of Synthetic Rubber, Changchun Institute of Applied
Chemistry, Chinese Academy of Sciences, 5625 Renmin Street,
Changchun 130022, China. E-mail: fshan@ciac.ac.cn
b The University of Chinese Academy of Sciences, Beijing 100864, China.
c
State Key Lab of Fine Chemicals, Dalian University of Technology,
Dalian, 116024, China.
† Electronic Supplementary Information (ESI) available: Detailed
1
experimental procedures, H-NMR, 13C-NMR, HRMS, and part of X-ray
crystallographic data, and the copies of 1H- and 13C-NMR spectra and
HPLC charts. See DOI: 10.1039/b000000x/
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

ChemComm
Page 2 of 5
Table 1. Optimization of reaction conditions.a
a) Monoactivation mode
Me
Me
Me
5
1) catalyst
Me
View Article Online
OSiR3
Ph
NHR
solvent, rt
conditions
DOI: 10.1039/C5CC03345D
AG
O
Ph
+
∗
+
OH
N
N
∗
Ph
N
2) 48% HBr
MeOH, rt
no reaction
Ph
R = Ac
N
Ph
Ph
O
iPr
4a
Ph
iPr
3a
1
iPr
1a
2
Ph
O
iPr
4b R = Cbz
R = Boc
3a
4c
AG = H, TMS, Ac, et al
O
∗
R
O
4d R = Bz
X
P
5e: R = 3,5-(CF3)2C6H3
5f
O
O
∗
Me
Me
5a: R = H
H
O
: R = 2,4,6-(iPr)3C6H2
5g: R = 9-phenanthryl
5b: R = 4-Ph-phenyl
5c: R = 1-naphthyl
5d: R = 2-naphthyl 5h: R = 9-anthryl
O
X
P
P
O
O
NHTf
AG
O
N
N
O
R
Ph
Ph
OSiR3
Ph
OSiR3
Ph
35
iPr
iPr
H-bonding
entry catalyst
solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
benzene
PhCl
time (h)
10
10
10
10
10
10
10
10
6
yield (%)b
56
ee (%)c
ion-pairing
1
2
(R)-5a
(R)-5b
(R)-5c
(R)-5d
(R)-5e
(R)-5f
(R)-5g
(R)-5h
(R)-5g
(R)-5g
(R)-5g
(R)-5g
(R)-5g
(R)-5g
18
10
54
45
13
16
79
60
81
81
82
76
79
86
62
75
79
77
75
81
9
b) Bifunctional activation modes
51
Me
Me
3
50
NHR
conditions
4
49
+
Ph
AG
∗
O
N
N
5
65
Ph
Ph
O
Ph
Me
Ph
3a
iPr
iPr
1
4
6
29
∗
∗
O
P
7
56
O
O
X
O
8
49
P
Me
H
O
O
9
45
X
OH
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22[d]
3
83
H
N
H
N
N
N
PhF
10
6
75
R
R
iPr
iPr
xylene
CH2Cl2
CHCl3
51
Ph
H-bonding/H-bonding Ph
ion-pairing/H-bonding
3
94
3
89
Scheme 2. Designed activation modes of indol-2-yl carbinol derivatives
with vinlysilyl ethers (a) and enamides (b).
(R)-5g (CH2)2Cl2
3
82
(R)-5g
(R)-5g
(R)-5g
(R)-5g
(R)-5g
(R)-5g
(R)-5g
CCl4
Et2O
3
56
Thus, the reaction of 1a with various enamide 4 (Table 1) was
examined. The results showed that enamides 4a–c were less
effective under various conditions (data not shown). However, 4d
was a promising nucleophile in the presence of phosphoramide
5a to afford the desired product 3a in 56% yield and 18% ee in
toluene at room temperature (entry 1). A further screening of an
10
10
10
10
3
37
5
THF
25
dioxane
tBuOMe
MeCN
CHCl3
32
34
85
12
74
93
10 array of phosphoramide catalysts (entries 1–8) showed that the
BINOL-derived phosphoramide 5g could be a viable catalyst,
providing 3a in 56% yield and 79% ee (entry 7).
a
Unless otherwise noted, the reaction conditions are: 1a (0.1 mmol), 4d
(0.2 mmol, 2.0 equiv), catalyst 5 (10 mol%) in solvent (2 mL) at room
temperature for 10 h; b Isolated yield; c The ee values were determined by
d
40 chiral HPLC on a AD-H column; The reaction was performed with the
With the optimal catalyst 5g, a rich variety of solvents were
evaluated (entries 9–21). CHCl3 provided the best results in terms
15 of yield, enantioselectivity, and reaction time (entry 14). Having
defined the optimal catalyst 5g and solvent CHCl3 in this way, we
optimized the reaction temperature, additives, and concentration
(See details in Table S1). It was found that although the
enantioselectivities could be increased to 94% ee when the
presence of 1.5 equiv of p-nitrobenzoic acid in 2 mL CHCl3 at -5 oC.
With the optimized conditions, we next examined the substrate
scope (Table 2). A range of indol-2-yl carbinols whose aryl group
(Ar) was modified by weak (3b and 3c) or strong (3d–3f)
45 electron-donating groups reacted well with enamide 4d, affording
the corresponding 2-indole-substituted 1,1-diarylalkanes in
moderately high to high yields (57–94%) as well as good
enantioselectivities (88–96%). The para-substituted substrates
were somewhat more reactive and enantioselective than the meta-
50 substituted analogues as shown by a comparison of 3b vs. 3c and
3d vs. 3f. In addition, while a somewhat diminished reactivity
was observed for a substrate substituted with an electron-
withdrawing group (3g), satisfactory yield (67%) and high
enantioinduction (88% ee) could still be obtained by performing
o
20 temperature was lowered from room temperature to -10 C, the
yield was dramatically diminished to lower than 30%. At this
juncture, the effect of a range of acidic additives including
various molecular sieves and Brønsted acids was examined since
some prior literatures have demonstrated that the catalytic
25 efficiency of phosphoric acids could be improved with the
presence of AcOH.16 After extensive screening, we eventually
found that with the use of 1.5 equiv of p-nitrobenzoic acid, the
yield of 3a could be improved substantially to 74% with the
maintenance of an excellent enantioselectivity (93% ee) (entry
30 22). Thus, the optimized conditions for enantioselective synthesis
of 3a are 10 mol% of phosphoramide 5g, 1.5 equiv of p-
nitrobenzoic acid in 2 mL CHCl3 solvent.
o
55 the reaction at 20 C. The reaction also proceeded efficiently for
indol-2-yl carbinols bearing various R groups in indole ring (3h–
3m). High to excellent yields (71–99%) as well as excellent
enantioselectivities (91–99% ee) were observed for all substrates
either by varying the electronic nature or the position of R groups.
2
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Page 3 of 5
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Table 2. Substrate scope by varying Ar, R and R’ group in indol-2-yl
absolute configuration of the products was assigned to be R by X-
carbinols.a-c
ray crytallography by converting 3t into its hydrozone
View Article Online
DOI: 10.1039/C5CC03345D
30 derivative17 (See SI for details).
R'
R
R'
R
5g
1)
(10 mol%)
CHCl , temp
Ar
Table 3. Substrate scope by varying R1 in indol-2-yl carbinols and Ar1 in
enamides.a-c
NHBz
Ph
3
+
Ar
N
N
2) 48% HBr
MeOH, rt
i
O
Pr
i
OH
Pr
4d
3
1
Ph
R
Me
R
Me
OH
1) 5g (10 mol%)
CHCl3, temp
NHBz
Ar1
Ar1
O
By varying Ar and R group in indol-2-yl carbinol
Me
O
+
Ar
N
N
Me
Me
2) 48% HBr
MeOH, rt
Me
Me
R1
R1
1
Ar1
4
3
N
N
N
i
i
i
Pr
O
O
Pr
By varying Ar1 group in enamide
Pr
Ph
Ph
3c: -5 C, 12 h
Ph
Me
Me
Me
OMe
OMe
OMe
o
o
o
3a: -5 C, 12 h
74%, 93% ee
R
3b: -25 C, 9 h
82%, 93% ee
57%, 89% ee
N
N
iPr
N
iPr
OMe
OMe
i
Me
Me
O
O
O
Pr
Cl
N
i
C6H4-m-Me
3o: -40 oC, 3 h
99%, 96% ee
p
C6H4- -F
C6H4-p-OMe
N
N
: -40 oC, 24 h
O
Pr
3p
3n
: -40 oC, 3 h
i
i
O
O
Pr
Pr
93%, 97% ee
70%, 82% ee
Ph
o
3d: R = Me, -40 C, 6 h
94%, 96% ee
3e: R = Et, -40 C, 23 h
Ph
-5 C, 6 h
71%, 91% ee
Ph
Me
Me
Me
o
o
OMe
OMe
3f
3g: 20 C, 3 h
67%, 88% ee
:
F
o
N
iPr
N
N
iPr
90%, 91% ee
O
C6H4-p-Cl
3r: -5 oC, 12 h
iPr
O
O
By varying R group in indol-2-yl carbinol
Me
Me
Me
C6H4-p-Cl
3q: -40 oC, 3 h
C6H4-p-Cl
3s: -40 oC, 3 h
Me
Me
Me
OMe
OMe
66%, 93% ee
95%, 98% ee
94%, 97% ee
Me
Br
N
N
N
Me
i
i
i
OMe
Me
O
O
Me
Pr
O
OMe
OMe
Pr
Pr
Ph
3h: -5 C, 9 h
Ph
Ph
N
iPr
o
N
iPr
N
iPr
o
o
3i: -40 C, 3 h
3j : -40 C, 3 h
O
71%, 92% ee
O
O
92%, 96% ee
99%, 99% ee
Me
Br
MeO
p
C6H4- -Br
3t: -40 oC, 3 h
C6H4-p-Br
p
C6H4- -Br
OMe
3u: -40 oC, 3 h
3v: -40 oC, 3 h
Me
Me
OMe
F
96%, 98% ee
99%, 97% ee
99%, 98% ee
N
N
N
By varying R1 group of indole N1
i
O
i
Pr
i
O
O
Pr
Pr
Ph
o
Me
Me
OMe
Me
Ph
Ph
OMe
OMe
F
o
o
3k
:
-5 C, 9 h
3m: -40 C, 3 h
3l: -40 C, 3 h
98%, 97% ee
71%, 91% ee
99%, 97% ee
N
N
N
iPr
R1
O
O
Me
O
a
Unless otherwise noted, the reaction conditions are: 1a (0.1 mmol), 4d
C6H4-p-Br
: -40 oC, 3 h
96%, 98% ee
Ph
3x: -60 oC, 6 h
98%, 81% ee
Ph
5 (0.2 mmol, 2.0 equiv), catalyst 5g (10 mol%), p-nitrobenzoic acid (0.15
mmol, 1.5 equiv) in CHCl3 (2 mL); b Isolated yield; c The ee values were
determined by chiral HPLC.
3w
3y: R = PMB, -60 oC, 6 h
87%, 50% ee
3z: R = Bn, -60 oC, 6h
88%, 38% ee
To extend the scope of the protocol, we further evaluated the
reaction by altering the enamide component (Table 3). While a
10 relatively lower yield (70%) and enantioselectivity (82% ee) was
observed for the enamide modified by an electron-rich substituent
(3n, Ar1 = p-MeO-C6H4), other enamides with weak electron-
donating Me (3o) and electron-withdrawing groups in the phenyl
ring periphery such as F (3p), Cl (3q–3s), and Br (3t–3w) reacted
15 very effectively with different indol-2-yl carbinols. Finally, an
examination of the R1 substituents at indole N1 revealed that both
the reactivity and enantioinduction were sensitive to the
electronic and steric nature of R1. For instance, replacement of iPr
group (3d) by electron-rich Me (3x,) PMB (3y), and Bn (3z)
20 showed that the enantioselectivities were irregularly decreased,
but high yields were still obtained. These observations indicate
a
Unless otherwise noted, the reaction conditions are: 1a (0.1 mmol), 4
35 (0.2 mmol, 2.0 equiv), catalyst 5g (10 mol%), p-nitrobenzoic acid (0.15
mmol, 1.5 equiv) in CHCl3 (2 mL); b Isolated yield; c The ee values were
determined by chiral HPLC.
We also demonstrated that the use of secondary enamides, i.e.,
40 containing N–H bond is vital for this reaction. As illustrated in
Scheme 3, 1d and secondary enamide 4d could react very
smoothly to afford 3d in excellent yield and enantioinduction. In
sharp contrast, ineffective reaction was observed when tertiary
enamide 4e was used in place of 4d. These results are in good
45 agreement with our proposed bifunctional work mode (Scheme
2b).
i
that Pr group was suitable for obtaining good enantioinduction
under the temporarily optimized conditions. In stark contrast, the
reaction was entirely suppressed when an electron-deficient Boc
25 group was attached. The reliablity of the methodology was
further exemplified by the gram-scale (up to 1.6 g) synthesis of
3d and 3t (3d: 95% yield, 95% ee; 3t: 94% yield, 97% ee). The
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3

ChemComm
Page 4 of 5
OMe
+
5
For some selected examples, see: (a) T. C. Fessard, S. P. Andrews, H.
Motoyoshi and E. R. Carreira, Angew. Chem. Int. Ed., 2007, 46,
9331; (b) D. A. Evans, K. R. Fandrick, H.-J. Song, K. A. Scheidt,
5g
1)
(10 mol%)
Me
OMe
R
p-NO2C6H4CO2H
CHCl3, temp
Me
View Article Online
NBz
Ph
N
iPr
DOI: 10.1039/C5CC03345D
and R. Xu, J. Am. Chem. Soc. 2007, 129, 10029; (c) M. Rueping, B.
50
55
60
65
70
75
2) 48% HBr (aq)
MeOH, rt
O
N
OH
J. Nachtsheim, S. A. Moreth and M. Bolte, Angew. Chem. Int. Ed.,
2008, 47, 593; (d) J. Itoh, K. Fuchibe and T. Akiyama, Angew.
Chem. Int. Ed., 2008, 47, 4106; (e) Y.-F. Sheng, Q. Gu, A.-J. Zhang
and S.-L. You, J. Org. Chem., 2009, 74, 6899; (f) Q.-X. Guo, Y.-G.
Peng, J.-W. Zhang, L. Song, Z. Feng and L.-Z. Gong, Org. Lett.,
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(a) M. Zeng, Q. Kang, Q.-L. He and S.-L. You, Adv. Synth. Catal.,
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iPr
4d
R = H
4e R = Me
Ph
3d
1d
for 4d, -40 oC: 94%, 96% ee
for 4e, -40 oC to rt: no reaction
Scheme 3. Comparison of the reactivity of 4d and 4e.
Finally, to demonstrate the synthetic utility of our newly
synthesized chiral 2-indole-substituted 1,1-diarylalkanes, 3d and
3l were converted into the corresponding amides 6a and 6b via a
two-step procedure involving oximation of ketone functionality
followed by Beckmann rearrangement (Scheme 4). High overall
yields were obtained for both compounds. More significantly, the
5
10 reactions proceeded uneventfully without compromising the
enantiomeric purities.
6
7
R
R
Me
OMe
Me
OMe
1) NH2OH·HCl, NaOAc
MeOH, reflux, 12 h
N
N
2) TsCl, Et3N
DMAP (cat)
CH2Cl2, rt, 12 h
iPr
iPr
O
O
Ph
NHPh
3d R = H (96% ee)
3l R = Br (97% ee)
6a R = H (76%, 95% ee)
6b R = Br (80%, 96% ee)
8
9
Y. Liu, Z. Cao and H. Du, J. Org. Chem., 2012, 77, 4479.
H. G. Cheng, L. Q. Lu, T. Wang, Q.-Q. Yang, X.-P. Liu, Y. Li, Q.-H.
Deng, J.-R. Chen and W.-J. Xiao, Angew. Chem. Int. Ed., 2013, 52,
3250.
Scheme 4. Further derivatization of the synthesized chiral 2-indole-
substituted 1,1-diarylalkanes
80 10 Y. Zhang, X. Liu, X. Zhao, J. Zhang, L. Zhou, L. Lin and X. Feng,
Chem. Commun., 2013, 49, 11311.
11 B. Bi, Q.-X. Lou, Y.-Y. Ding, S.-W. Chen, S.-S. Zhang, W.-H. Hu
and J.-L. Zhao, Org. Lett., 2015, 17, 540.
15
In conclusion, we have established an organocatalytic protocol
for enantioselective synthesis of 2-indole-substituted 1,1-
diarylalkanes. The new protocol is compatible with a wide variety
of indol-2-yl carbinols and various enamides. Contrary to the
reported methods, our strategy has utilized indole derivatives as
12 (a) T.-H. Fu, A. Bonaparte and S. F. Martin, Tetrahedron Lett., 2009,
85
90
50, 3253; (b) B. A. Granger, I. T. Jewett, J. D. Butler, B. Hua, C. E.
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20 electrophiles, and thereby offering a new method for accessing
chiral 2-indole-substituted 1,1-diarylalkanes. In addition, the
synthetic utility of the chiral compounds was also exemplified.
An investigation of the biological property of chiral 2-indole-
substituted 1,1-diarylalkanes is currently underway.
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X. Zhong, Y. Li, J. Zhang, W.-X. Zhang, S.-X., Wang and F.-S. Han,
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25
Financial support from NSFC (21272225), and State Key
Laboratory of Fine Chemicals, Dalian University of Technology
(KF 1201) is acknowledged.
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Notes and references
1
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17 CCDC 1404860 contains the supplementary crystallographic data of
2
3
For a recent comprehensive review, see: S. Safe, S. Papineni and S.
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N-tosylhydrazone derivative of 3t.
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4
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 5 of 5
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Table of Graphical Abstract
View Article Online
DOI: 10.1039/C5CC03345D
The chiral phosphoramide-catalyzed asymmetric reaction of indol-2-yl carbinols with enamides is presented.
R
9-phenanthryl
O
O
Me
1) cat (10 mol%)
p-NO2C6H4CO2H
CHCl3, temp
R
Me
Ar1
NHBz
∗
N
cat =
P
Ar +
O
NHTf
N
Ar1
2) 48% HBr
MeOH, rt
O
Ar
R1
OH
26 examples
R1
9-phenanthryl
up to 99% yield and 99% ee
5
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 5