Axially Chiral Cyclic Phosphoric Acid Enabled Enantioselective Sequential Additions

Article abstract of DOI:10.1021/acs.orglett.8b04012

Efficient axially chiral cyclic phosphoric acid catalyzed enantioselective sequential additions of 2-aryl-3H-indol-3-ones, aldehydes, and diethyl 2-aminomalonate have been developed, and a new type of nitrogen-containing heterocyclic compounds, 2,3-dihydro-1H-imidazo[1,5-a]indol-9(9aH)-one derivatives, were prepared in good yields and excellent ee values with a wide functional group tolerance, in which the reactivity and enantioselectivity of the substrates were enabled by our newly developed axially chiral cyclic phosphoric acid, (R)-CYC-9-CPA. Furthermore, the corresponding 1H-imidazo[1,5-a]indol-9(9aH)-ones were constructed through the easy oxidation of 2,3-dihydro-1H-imidazo[1,5-a]indol-9(9aH)-one derivatives.

Full text of DOI:10.1021/acs.orglett.8b04012

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Axially Chiral Cyclic Phosphoric Acid Enabled Enantioselective
Sequential Additions
Xi Yuan,†,‡ Xudong Wu,‡ Pengxiang Zhang,‡ Fei Peng,‡ Can Liu,†,‡ Haijun Yang,‡ Changjin Zhu,†
and Hua Fu*,†,‡
†School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081, China
‡Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, China
S
* Supporting Information
ABSTRACT: Efficient axially chiral cyclic phosphoric acid catalyzed
enantioselective sequential additions of 2-aryl-3H-indol-3-ones, alde-
hydes, and diethyl 2-aminomalonate have been developed, and a new
type of nitrogen-containing heterocyclic compounds, 2,3-dihydro-1H-
imidazo[1,5-a]indol-9(9aH)-one derivatives, were prepared in good
yields and excellent ee values with a wide functional group tolerance, in
which the reactivity and enantioselectivity of the substrates were
enabled by our newly developed axially chiral cyclic phosphoric acid,
(R)-CYC-9-CPA. Furthermore, the corresponding 1H-imidazo[1,5-a]indol-9(9aH)-ones were constructed through the easy
oxidation of 2,3-dihydro-1H-imidazo[1,5-a]indol-9(9aH)-one derivatives.
he construction of nitrogen-containing heterocycles is an
important goal in organic synthesis because they are
whelming, and the catalytic reactivity and enantioselectivity
usually depend on structures of chiral ligands or organo-
catalysts. Therefore, the development of chiral ligands and
organocatalysts has been an important task for organic
chemists. Very recently, a kind of novel axially chiral
cyclo[1,1′-biphenyl]-2,2′-diol (CYCNOL) core structure has
been developed in our research group.11 Furthermore, the
chiral cyclic phosphoramidite12 and diphosphine ligands13
derived from CYCNOLs were prepared and used in iridium- or
palladium-catalyzed enantioselective synthesis.12,13 Since the
pioneering works from the research groups of Akiyama14a and
Terada14b in 2004, chiral phosphoric acids have become
powerful organocatalysts in the enantioselective synthesis of
chiral molecules,15 and the previous chiral phosphoric acid
catalysts mainly are derivatives based on naphenyl]-2,2′-diol
(BINOL)14 and 1,1′-spirobiindane-7,7′-diol (SPINOL).16
Inspired by these excellent achievements,14−16 we herein
report a newly developed axially chiral cyclic phosphoric acid
derived from CYCNOLs and their application in catalytic
enantioselective sequential additions.
T
ubiquitous in nature and the chemical, agrochemical, and
pharmaceutical industries.1 In particular, N-heterocycles have
been assigned as privileged structures in drug development.2
For example, imidazoles are often used as core structures of
some enzyme inhibitors3 and drugs,4 and indolones are
important pharmaceutical intermediates.5 However, molecules
having both imidazole and indolone frameworks, 2,3-dihydro-
1H-imidazo[1,5-a]indol-9(9aH)-one and 1H-imidazo[1,5-a]-
indol-9(9aH)-one (Figure 1), have not been developed thus
Figure 1. Structures of 2,3-dihydro-1H-imidazo[1,5-a]indol-9(9aH)-
ones and 1H-imidazo[1,5-a]indol-9(9aH)-ones.
Axially chiral cyclo[1,1′-biphenyl]-2,2′-diols, (R)-CYC-8-
NOL, (R)-CYC-9-NOL, and (R)-CYC-10-NOL, were pre-
pared according to our previous procedures.11 Subsequently,
synthesis of our axially chiral cyclic phosphoric acids, (R)-
CYC-8-CPA (K), (R)-CYC-9-CPA (L), and (R)-CYC-10-
CPA (M), were carried out as shown in Scheme 1 (see the
Supporting Information for details). First, reaction of (R)-
CYC-8-NOL, (R)-CYC-9-NOL, or (R)-CYC-10-NOL with
chloro(methoxy)methane (MOMCl) in the presence of NaH
far. Therefore, we herein design and construct the poly-N-
heterocycles by using readily available starting materials.
Transition-metal or organo-catalyzed asymmetric 1,3-dipolar
cycloadditions (1,3-DCs) of azomethine ylides with dipolar-
ophiles have become a powerful strategy for synthesis of chiral
five-membered N-heterocycles,6−9 and the 1,3-DCs have been
well investigated by using electron-deficient alkenes7 or
alkynes9 as the dipolarophiles. However, the catalytic
asymmetric 1,3-DCs of azomethine ylides with imines have
seldom been reported.10
In previous catalytic asymmetric synthesis, transition-metal
and organo-catalyzed enantioselective reactions are over-
Received: December 16, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b04012
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
coupling of M-2 with M-3 under catalysis of Pd(PPh3)4
afforded M-4, and deprotection of MOM in concd HCl led
to M-5. Finally, phosphorylation of M-5 afforded the
corresponding chiral phosphoric acid (R)-CYC-8-CPA (K),
(R)-CYC-9-CPA (L), or (R)-CYC-10-CPA (M).
Scheme 1. Synthesis of Axially Chiral Cyclic Phosphoric
Acids
Sequential additions of 2-phenyl-3H-indol-3-one (1a), 4-
nitrobenzaldehyde (2a), and diethyl 2-aminomalonate (3)
were used as the model to optimize conditions including
catalysts, solvents, ratios of the three substrates, and additives.
As shown in Table 1, the reactions were divided into two steps
under the catalysis of chiral phosphoric acid: (a) coupling of 4-
nitrobenzaldehyde (2a) with diethyl 2-aminomalonate (3) to
the corresponding imine Ia and (b) asymmetric 1,3-dipolar
cycloaddition of Ia with 2-phenyl-3H-indol-3-one (1a) leading
to the target product (4a). Initially, 13 chiral phosphoric acids
including 10 common organocatalysts (A−J) and our newly
developed cyclic phosphoric acids, (R)-CYC-8-CPA (K), (R)-
CYC-9-CPA (L), and (R)-CYC-10-CPA (M), were screened
using MgSO4 as the additive with a 1:1.1:1 ratio of 1a/2a/3 in
toluene under an argon atmosphere at room temperature
(entries 1−13), and we found that our newly developed axially
chiral cyclic phosphoric acid, (R)-CYC-9-CPA (L), provided
the highest ee value (entry 12). The absolute configuration of
in THF provided M-1, and then sequential lithiation of M-1
with nBuLi in the presence of N,N,N′,N’-tetramethylethylene-
diamine (TMEDA) and iodination with I2 gave M-2. Suzuki
Table 1. Optimization of Conditions for Chiral Phosphoric Acid Catalyzed Enantioselective Sequential additions of 1a, 2a, and
a
3
b
c
b
c
entry cat.
solvent ratio of 1a/2a/3 yield of 4a (%) ee of 4a (%) entry cat.
solvent
DCE
DCE
THF
ratio of 1a/2a/3 yield of 4a (%) ee of 4a (%)
1
2
3
4
5
6
A
B
C
D
E
F
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
CH2Cl2
1:1.1:1
1:1.1:1
1:1.1:1
1:1.1:1
1:1.1:1
1:1.1:1
1:1.1:1
1:1.1:1
1:1.1:1
1:1.1:1
1:1.1:1
1:1.1:1
1:1.1:1
1:1.1:1
1:1.1:1
1:1.1:1
38
15
17
2
10
12
9
10
17
7
90
66
79
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
A
L
L
L
L
L
L
A
K
M
L
L
L
L
L
1:1.1:1
1:1.1:1
1:1.1:1
1:1.1:1
1:2.2:2
1:2.75:2.5
1:3.3:3
1:3.3:3
1:3.3:3
1:3.3:3
1:3.3:3
1:3.3:3
1:3.3:3
1:3.3:3
1:3.3:3
32
33
7
15
50
68
69
94
ND
40
94
95
96
71
92
92
ND
58
1,4-dioxane
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
67
d
7
8
9
G
H
I
ND
67
77 (71 )
72
14
43
67
NR
trace
51
10
11
12
13
14
15
16
J
ND
92
e
f
K
L
M
9
21
19
NR
36
32
94
88
g
h
i
80
78
79
45
46
A
L
35
92
a
Reaction conditions: under argon atmosphere, 2-phenyl-3H-indol-3-one (1a) (0.1 mmol, 1.0 equiv), 4-nitrobenzaldehyde (2a) (0.11−0.33 mmol,
1.1−3.3 equiv), diethyl 2-aminomalonate (3) (0.1−0.30 mmol, 1.0−3.0 equiv), catalyst (A−M) (10 μmol, 10 mol %), solvent (2.0 mL), MgSO4
b
(300 mg), temperature (rt, ∼25 °C), time (1 h for the first step; 24 h for the second step) in a sealed Schlenk tube. Conversion yield determined
c
by 1H NMR using 1,3,5-trimethoxybenzene as the internal standard. The ee values were determined by HPLC analysis on a chiral stationary phase
d
e
f
g
using a Daicel Chiralpak IF column. Isolated yield. In the presence of 4 Å molecular sieves (300 mg). In the presence of Na2SO4 (300 mg). In
h
i
the presence of CaCl2 (300 mg). In the presence of CaSO4 (300 mg). In the absence of MgSO4. The dr was determined by 1H NMR analysis of
the crude reaction mixture after the sequential removal of MgSO4 and solvent, and the results showed dr > 20:1. Absolute configuration of (R,R)-4a
was determined by comparing the structure of (R,R)-4j (absolute configuration of (R,R)-4j was assigned by X-ray diffraction analysis). DCE = 1,2-
dichloroethane. ND = no detection. NR = no reaction.
B
DOI: 10.1021/acs.orglett.8b04012
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4a was determined to be the (R,R)-form by comparing the
structure of (R,R)-4j (absolute configuration of (R,R)-4j was
assigned by X-ray diffraction analysis (see Figure 2 and
Table 2. Substrate Scope for the Axially Chiral Cyclic
Phosphoric Acid Catalyzed Enantioselective Sequential
a
Additions
Figure 2. Crystal structure of (R,R)-4j.
Supporting Information for details)). The cycloaddition did
not work in the absence of chiral phosphoric acid (entry 14).
The effect of solvents was investigated using A or L as the
catalyst (compare entries 12, 15−20), and the experiments
indicated that 1,2-dichloroethane (DCE) was a suitable solvent
(entry 18). We attempted different ratios of 1a/2a/3 using L
as the catalyst (compare entries 21−23), and the results
showed that the ratio, 1a/2a/3 = 1:3.3:3, was optimal (entry
23). Catalysts A, K, and M were tested with the ratio 1a/2a/3
= 1:3.3:3 (entries 24−26), and they did not provide better
results. We explored the effect of additives (entries 27−29); 4
Å molecular sieves and Na2SO4 gave bad results (entries 27
and 28), and CaCl2 (entry 29) or CaSO4 (entry 30) afforded
lower enantioselectivity than MgSO4. The reactivity and
enantioselectivity decreased in the absence of MgSO4 (entry
31). The results above showed that MgSO4 promoted the
present reaction. Unfortunately, an exact mechanism on the
role of MgSO4 has been unknown until now.
After the optimized conditions were obtained, the substrate
scope for the sequential additions of 2-aryl-3H-indol-3-ones
(1), aldehydes (2), and diethyl 2-aminomalonate (3) was
investigated using our axially chiral cyclic phosphoric acid, (R)-
CYC-9-CPA (L), as the organocatalyst. As shown in Table 2,
we first surveyed different substituted aromatic Ar1 in 1 and
found that steric hindrance of para-position substituents in
phenyl rings of Ar1 was obvious for enantioselectivity. The
substrates containing the smaller groups (see 4a and 4b)
exhibited higher enantioselectivity than those containing the
bigger groups (see 4c, 4f, 4g, and 4h). When Ar1 owned meta-
position substituents, higher ee values were provided (see 4d
and 4e). We attempted variation of R1 substituents in 1 and
found that fluoro, chloro, bromo, and methyl were feasible, and
the reactions provided good reactivity (60−66% yields) and
excellent enantioselectivity (91−96% ee) (see 4i−l). For
different aromatic aldehydes 2, the substrates containing the
strong electron-withdrawing groups showed higher reactivity
and enantioselectivity (see 4a, 4u, 4v, and 4w). We found that
the steric hindrance of para-position substituents in aromatic
aldehydes 2 was influential for enantioselectivity, and 4-
iodobenzaldehyde with slightly larger steric hindrance at the
para-position provided higher ee values than 4-fluorobenzal-
dehyde and 4-chlorobenzaldehyde (see 4m−o). In addition,
the substrates containing m,p-dihalobenzaldehydes all afforded
a
Reaction conditions: under argon atmosphere, substituted 3H-indol-
3-one (1) (0.1 mmol, 1.0 equiv), aryl aldehyde (2) (0.33 mmol, 3.3
equiv), diethyl 2-aminomalonate (3) (0.30 mmol, 3.0 equiv), (R)-
CYC-9-CPA (L) (10 μmol, 10 mol %), DCE (2.0 mL), MgSO4 (300
mg), temperature (rt, ∼25 °C), time (1 h for the first step; 24 h for
the second step) in a sealed Schlenk tube. Isolated yield, and the ee
values were determined by HPLC analysis on a chiral stationary phase
1
using a Daicel Chiralpak IF column. The dr was determined by H
NMR analysis of the crude reaction mixture after the sequential
removal of MgSO4 and solvent, and the results showed dr > 20:1.
Absolute configurations of products 4a−i and 4k−z were determined
by comparing the structure of (R,R)-4j (absolute configuration of
(R,R)-4j was assigned by X-ray diffraction analysis).
C
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Letter
good reactivity (60−64% yields) and excellent enantioselec-
tivity (90−94% ee) (see 4p−t). Unfortunately, we found that
aromatic aldehydes without electron-withdrawing groups did
not give satisfactory results (see 4x−z), and aliphatic aldehydes
were not suitable substrates.
5a and 5b with a quaternary stereocenter were prepared in
78% and 83% yields, respectively (Scheme 4). Therefore,
another kind of N-heterocycle was constructed through this
strategy.
We attempted the scale experiments using the synthesis of
(R,R)-4r and (R,R)-4t as examples. As shown in Scheme 2, the
Scheme 4. Oxidation of (R,R)-4r and (R,R)-4t with
tBuOOH Leading to (R)-5a and (R)-5b
Scheme 2. Scale Synthesis of (R,R)-4r and (R,R)-4t
In summary, we have developed the efficient axially chiral
cyclic phosphoric acid catalyzed enantioselective sequential
additions of 2-aryl-3H-indol-3-ones, aryl aldehydes, and diethyl
2-aminomalonate, and a new kind of N-heterocycles, 2,3-
dihydro-1H-imidazo[1,5-a]indol-9(9aH)-one derivatives, was
prepared in good yields and excellent ee values with a wide
functional group tolerance, in which the reactivity and
enantioselectivity of the substrates were enabled by our
newly developed axially chiral cyclic phosphoric acid, (R)-
CYC-9-CPA. Furthermore, easy oxidation of 2,3-dihydro-1H-
imidazo[1,5-a]indol-9(9aH)-one derivatives led to the corre-
sponding 1H-imidazo[1,5-a]indol-9(9aH)-one derivatives with
a quaternary stereocenter.
reactions under the standard conditions afforded (R,R)-4r and
(R,R)-4t without loss of reactivity and enantioselectivity. The
results indicated that the present method was very effective and
practical for the synthesis of 2,3-dihydro-1H-imidazo[1,5-
a]indol-9(9aH)-one derivatives.
On the basis of the experiments above, a possible
mechanism on the reactions is suggested in Scheme 3.
Scheme 3. Possible Mechanism for the Chiral Cyclic
Phosphoric Acid Catalyzed Enantioselective Sequential
Additions
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b04012.
Experimental details, NMR data (PDF)
Accession Codes
CCDC 1882580 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Reaction of aldehyde (2) with diethyl 2-aminomalonate (3)
in the presence of (R)-CYC-9-CPA (L) affords imine I, which
acts as the precursor of azomethine ylide (II).7,17 Simultaneous
treatment of axially chiral cyclic phosphoric acid, (R)-CYC-9-
CPA (L), with both the azomethine ylide (II) and 1 via dual
hydrogen-bonding interaction leads to a complex of L, II, and
1, which is favorable to an enantioselective [3 + 2]
cycloaddition of II and 1 to provide the desired product 4.
In the present chiral cyclic phosphoric acid catalyzed
enantioselective sequential additions, (R)-CYC-9-CPA (L)
provided higher enantioselectivity than other catalysts, which
could be attributed to its suitable dihedral angle in the
reactions.11−13
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: fuhua@mail.tsinghua.edu.cn.
ORCID
Hua Fu: 0000-0001-7250-0053
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Haifang Li (Department of Chemistry, Tsinghua
University) for her help with high-resolution mass spectro-
metric analysis and the National Natural Science Foundation
of China (Grant No. 21772108) for financial support.
Oxidation of 4r and 4t with tBuOOH in the presence of KI
in MeCN was performed at room temperature, and the
corresponding 1H-imidazo[1,5-a]indol-9(9aH)-one derivatives
D
DOI: 10.1021/acs.orglett.8b04012
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Organic Letters
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