Atroposelective synthesis of configurationally stable nonbiaryl N-C atropisomers through direct asymmetric aminations of 1,3-benzenediamines

Article abstract of DOI:10.1039/d0cc02368j

A highly atroposelective synthesis of nonbiaryl N-C atropisomers was achievedviadirect aminations of 1,3-benzenediamines with azodicarboxylates enabled by chiral phosphoric acid catalysis. A series ofN-substituents, benzene-substituents and azodicarboxyla

Full text of DOI:10.1039/d0cc02368j

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Atroposelective Synthesis of Configurationally Stable Nonbiaryl N-
C Atropisomers through Direct Asymmetric Aminations of 1,3-
Benzenediamines
Received 00th January 20xx,
Accepted 00th January 20xx
Donglei Wang,a,b Qianwen Jianga and Xiaoyu Yanga,*
DOI: 10.1039/x0xx00000x
a) Tan et al.: asymmetric synthesis of N-C atropisomers via nucleophilc aminations
A highly atroposelective synthesis of nonbiary N-C atropisomers
was achieved via direct aminations of 1,3-benzenediamines with
azodicarboxylates enabled by chiral phosphoric acid catalysis. A
R1
H
N
N
CPA cat
N
COOR2
R1
+
N
N
N
COOR2
R3
series
of
N-substituents,
benzene-substitutions
and
R3
azodicarboxylates were well tolerated, generating N-C
atropisomers with high configurational stability. The facile
derivatizations and utilizations of the chiral products as novel
chiral organocatalysts demonstrate the value of these reactions.
b) Wencel-Delord et al.: asymmetric syntheis of N-C atropisomers via Cu-catalyzed N-C coupling
R2
R2
Mes
R
I
BF4
CONH2
chiral Cu(I) complex
+
N
R1
N
R
CONH2
H
R1
c) JØrgensen et al. and Zhang et al.: asymmetric syntheis of N-C atropisomers via electrophilic
Atropisomerism is stereochemistry arising from restricted
rotation that generates a chiral axis, which is not only widely
present in some biologically active pharmaceuticals1 and
natural products2, but also has been extensively used as
privileged scaffolds of chiral ligands and catalysts in
asymmetric catalysis3. The most representative atropisomers
are axially chiral biaryls, whose asymmetric synthesis has been
extensively studied in recent years.4 In contrast, the
asymmetric synthesis of nonbiaryl atropisomers, such as N-C
atropisomers5, has been less explored. During the last two
decades, a number of practical methods have been developed
for the asymmetric constructions of N-C axial stereogenicity,
via the strategies of asymmetric N-functionalizations of
anilines6, desymmetrization7 and others8. However, most of
these methods are based on the modifications of the existing
achiral N-C bonds, while the more efficient methods of direct
atroposelective construction of the axially chiral N-C bonds
were relatively limited, especially through asymmetric catalytic
methods.9 Recently during the preparation of this manuscript,
Tan and co-workers reported the direct construction of C-N
chiral axis via asymmetric nucleophilic amination of
azonaphthalenes and carbzoles10 (Figure 1, a). Wencel-Delord
and co-workers reported the Cu-catalyzed atroposelective N-C
coupling for the asymmetric synthesis of N-C atropisomers11
(Figure 2, b).
aminationns of 2-naphthols and 2-naphthylamines
COOR2
COOR2
HN
R
N
R
COOR2
XH
chiral organocatalysts
XH
+
R1
R2
N
N
R2OOC
, R = amino group, t1/2 = 5325 h at 25 o
, R = H, t1/2 = 11.4~103.3 h at 25 o
C
1
X = O or N-aryl
2
C
configurationally stable
d) This work: asymmetric synthesis of
amination of 1,3-benzenediamines
N-C atropisomers via electrophilic
COOR2
COOR2
HN
H
N
H
R
N
COOR2
R1
CPA cat.
R
N
+
R1
N
N
R2OOC
NH2
NH2
direct construction of N-C atropisomers of non-naphthalene scaffolds
high configurational stabilities, with t1/2 up to 405 h at 100 o
C
Figure 1. Asymmetric synthesis of N-C atropisomers via
atroposelective direct C-N bond formation.
On the other hand, the asymmetric electrophilic
aminations of 2-naphthols and 2-naphthylamines with
azodicarboxylates have also been well employed in the
asymmetric synthesis of N-C atropisomers (Figure 1, c).
Jørgensen and co-workers reported the landmark work of
atroposelective synthesis of nonbiaryl N-C atropisomers via
asymmetric electrophilic aminations of 2-naphthols with
azodicarboxylates via chiral Brønsted base catalysis, however,
whose substrate scope was limited to 8-amino-2-naphthol
derivatives due to the configurationally instable issues12.
Recently, Zhang and co-workers disclosed the atroposelective
construction of C-N chiral axis via chiral phosphoric acid (CPA)
catalyzed ortho-amination of N-aryl 2-naphthylamines with
azodicarboxylates13. Additionally, Gong and co-workers
disclosed the chiral gold(I) complex catalyzed cascade
cycloisomerization-amination reactions for the synthesis of
a. School of Physical Science and Technology, ShanghaiTech University, Shanghai
201210, China. E-mail: yangxy1@shanghaitech.edu.cn
b. University of Chinese Academy of Sciences, Beijing 100049, China
Electronic Supplementary Information (ESI) available: CCDC 1988838. [details of
any supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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heteroaryl N-C atropisomers14. Despite the fact that these
electrophilic amination methods provided access to N-C
atropisomers via direct N-C bond formation, these methods
still suffered two major limitations: 1) all these examples
constructed N-C atropisomerism at the 1-position of
12
13
14
15
A7
A7
A7
A7
toluene
toluene
toluene
toluene
-40 oC
0 oC
97
98.5:1.5
95:5
97.5:2.5
98.5:1.5
View Article Online
DOI: 10.1039/D0CC02368J
92
95
92
-20 oC
-50 oC
aReactions were performed using 3a (0.1 mmol), 4a (0.12 mmol) and
naphthalene scaffolds; 2) the configurational stabilities of the CPA cat. (0.01 mmol) in solvents (0.5 mL) at designated temperatures.
bIsolated yields. cErs were determined by HPLC analysis on a chiral
generated N-C axial stereogenicity are generally not good (t1/2
stationary phase.
= 11.4~103.3 h at 25 oC for 2), except the 8-amino-2-
naphtols/naphthylamines derived N-C atropisomers 1.
With the optimal conditions in hand, we set out to explore
Recently, we disclosed the asymmetric synthesis of biaryl
the substrate scope of this reaction under the catalysis of (S)-
diamines and amino alcohols via CPA-catalyzed direct para-
A7. The scope regarding to the different N-substituents at the
amination of anilines and phenols15 with azodicarboxylates16.
1-position were firstly investigated (Table 2). A range of
Herein we report the highly atroposelective construction of
aliphatic acyl groups were well tolerated under the optimal
nonbiaryl N-C atropisomers via direct enantioselective
conditions, providing the N-C atropisomers with high
aminations of 1,3-benzenediamines enabled by CPA catalysis17
enantioselectivities (5a-5e). The absolute configurations of the
(Figure 1, d).
products were determined as (R) by analogy to 5a, whose
absolute structure was unambiguously confirmed by X-ray
crystallography18. Switching the acyl groups to benzoyl group
led to the diminishment of enantioselectivity (5f). A series of
N-alkoxylcarbonyl groups at the 1-position were also examined
under the standard conditions, which was also amenable,
providing the N-C atropisomers with comparable
enantioselectivities (5g-5i). The N-tosyl substituted 1,3-
benzenediamine was also well compatible with the standard
conditions (5j). Additionally, the N-Ph substituted substrate
We initiated our study by choosing 5-tBu benzenediamine
derivative 3a as model substrate and dibenzyl
azodicarboxylate 4a as the amination reagent under CPA
catalysis (Table 1). In the presence of TRIP catalyst (cat A1, 10
o
mol %) in CHCl3 at -40 C, the reaction between 3a and 4a
proceeded smoothly to give the aniline para-amination
product 5a in 96% yield with 88.5:11.5 enantiomeric ratio (er),
which possessed the N-C axial stereogenicity due to the
restricted rotation about the N-C bond (entry 1). Next, a
variety of BINOL-derived CPA catalysts were screened in this
afforded the product with high enantioselectivity as well,
reaction (entries 2-9), and encouragingly that the 3,3’-(1-
albeit in moderate yield (42%, 5k). The configurational
pyrenyl)-substituted CPA catalyst A7 provided the optimal
stabilities of these N-C atropisomers were one of the key
results (99% yield, 95.5:4.5 er, entry 7). A range of solvents
issues for their further applications. Although no diminishment
were subsequently investigated (entries 10-12), which
indicated that the reaction in toluene provided improved
of ee of product 5a was detected after storing at -20 oC for five
months, the racemization experiments of these N-C
atropisomers were still performed at 100 oC (in toluene)18. The
results (97% yield, 98.5:1.5 er, entry 12). The reaction
o
temperatures were also examined, which suggested -40 C as
the optimal temperature. Raising the reaction temperature to
Table 2. Substrate scope regarding to different N-
-20 oC or 0 oC led to the diminishment of enantioselectivity and
substituentsa.
o
decreasing the temperature to -50 C gave the product with
H
H
H
N
N
N
Cbz
Cbz
Cbz
Cbz
Cbz
tBu
diminished yield (entries 13-15).
Cbz
tBu
N
N
N
H
N
H
N
H
N
tBu
Cy
tBu
iPr
O
O
O
Table 1. Optimizations of reaction conditionsa.
NH2
NH2
NH2
Cbz
Ar
A1,
A2
Ar = 2,4,6-(iPr)3C6H2
, Ar = Ph
5bb
5a
5a
5c
, 95% yield, 93:7 er
, 97%, 98.5:1.5 er
100
X-Ray structure of
H
, 94%, 93.5:6.5 er
100
Cbz
N
HN
H
1
N
Cbz
N
Cbz
100
tBu
N
O
O
O
A3, Ar = 1-naphthyl
A4
(t1/2 rac = 370 h)
(t1/2 rac = 405 h)
(t1/2 rac = 340 h)
Piv
4a
H
N
5
P
, Ar = 2-naphthyl
tBu
OH
Piv
A5,
Ar = 9-phenylanthracenyl
, Ar = 9-anthracenyl
, Ar = 1-pyrenyl
3
CPA cat (10%mol)
solvents (0.2 M)
N
H
Cbz
H
A6
A7
A8
A9
Cbz
tBu
H
NH2
N
Cbz
N
Ar
N
Cbz
Cbz
tBu
N
Cbz
tBu
Cbz
H
N
N
N
5a
, Ar = 2,4,6-(Me)3C6H2
, Ar = 2,4,6-(Cy)3C6H2
Cbz
tBu
NH2
temperature
Me
H
N
3a
H
N
N
CPA catalyst
Et
H
N
O
Boc
O
O
NH2
Entry Cat.
Sol.
Temp.
Yield (%)b
erc
NH2
NH2
5fb
NH2
5d
5e
5g
, 90% yield, 91:9 er
, 72% yield, 93.5:6.5 er
100
,
97% yield, 88:12 er
100
, 99% yield, 92:8 er
100
1
2
A1
A2
A3
A4
A5
A6
A7
A8
A9
A7
A7
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
DCM
Et2O
-40 oC
-40 oC
-40 oC
-40 oC
-40 oC
-40 oC
-40 oC
-40 oC
-40 oC
-40 oC
-40 oC
96
67
96
88
93
77
99
96
99
95
84
88.5:11.5
62.5:37.5
91:9
94:6
92:8
100
(t1/2 rac = 321 h)
(t1/2 rac = 246 h)
(t1/2 rac = 226 h)
(t1/2 rac = 84 h)
H
H
H
H
N
Cbz
N
3
4
5
6
Cbz
N
Cbz
N
Cbz
Cbz
tBu
Cbz
tBu
Cbz
tBu
N
Cbz
tBu
N
N
N
H
N
H
H
N
H
N
N
O
Ph
iPr
Cbz
Ts
O
NH2
NH2
NH2
NH2
90:10
5h
, 99% yield, 94.5:5.5 er
5i
, 99% yield, 93.5:6.5 er
5k
, 42% yield, 93.5:6.5er
5j
, 99% yield, 96:4 er
100
100
70
70
7
8
95.5:4.5
86.5:13.5
86:14
96.5:3.5
97.5:2.5
(t1/2 rac = 116 h)
(t1/2 rac = 85 h)
(t1/2 rac = 313 h)
(t1/2 rac = 129 h)
aReactions were performed using 3 (0.2 mmol), 4a (0.24 mmol) and (S)-
cat A7 (0.02 mmol) in toluene (1 mL) at –40 oC for 3 h. Yields were
isolated yield. Ers were determined by HPLC analysis on a chiral
stationary phase. bWith (R)-A1 catalyst.
9
10
11
2 | J. Name., 2012, 00, 1-3
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half-lives of racemization of all these N-C atropisomers were reactions, some control experiments were conducted (Scheme
View Article Online
DOI: 10.1039/D0CC02368J
measured, which suggested that the N-acyl substituted 1, a). Subjection of the 3-iPr aniline derivative 6a into the
products possessed the highest configurational stabilities (with standard conditions didn’t lead to the formation of any desired
t1/2 ranging from 226 to 405 h at 100 oC) and N-alkoxylcarbonyl amination product. Using the N-Me substituted 1,3-
substituted ones showed relatively lower configurational benzenediamine 6b as substrate under the standard
o
stability (with t1/2 ranging from 84 to 116 h at 100 C)19. The conditions provided the product in 86% yield with 72:28 er,
racemization experiments suggested that N-tosyl and N-Ph while the N,N-di-Me substituted substrate 6c also afforded the
substituted products possessed comparable configurational product in 94% yield with 81:19 er. Based on these results, a
stabilities as well.
plausible reaction mechanism was proposed: 1) the CPA
With the well compatibility of different N-substituents in catalyst activated both reactants by forming dual H-bonding
5-tBu-1,3-benzenediamine substrates, we next explored the with azodicarboxylates and benzenediamines (with their 1-
substrate scope regarding to a variety of 5-substitutions of 1,3- amino group), which underwent the addition reaction to
benzenediamines (Table 3). Switching the 5-substitutions from provide the dearomatized product INT A, possessing a chiral
–tBu group to secondary alkyl groups (both acyclic and cyclic) centre. The 3-amino groups of the substrates played the role
were well tolerated with the optimal conditions, generating of the electron-donating activation groups to ensure sufficient
the N-C atropisomers with high enantioselectivities (5l-5n). nucleophilicity of its para-position; 2) subsequent
Replacing the substituents with primary alkyl groups were also aromatization of INT A underwent central-to-axial chirality
amenable, affording comparable results (5o-5p). However, the transfer20 to provide the N-C atropisomers (Scheme 1, b).
configurational stabilities of these products were relatively
a) control experiments
Cbz
HN
lower compared to the 5-tBu-substituted products, which
were attributed to the obvious less steric hindrance of these
groups. The half-lives of racemization were ranged from 413 h
to 617 h for secondary alkyl-substituted products and ranged
from 11 h to 91 h for primary alkyl-substituted products at 50
oC (in toluene), which suggested that these atropisomers still
Cbz
H
N
5
iPr
N
tBu
H
N
A7
(S)-cat
toluene (0.2 M)
-40 o
(10%mol)
1
Cbz
iPr
tBu
N
+
N
Cbz
O
3
O
R
C
4a
R
6a
6b
6c
, R = H
, R = NHMe
, R = NMe2
7a,
NR;
7b
7c
, 87%, 72:28 er
, 94%, 81:19 er
b) plausible reaction mechanism
hold
suitable
configurational
stabilities18.
Different
Cbz
Cbz
R1
N
R1
Cbz
Cbz
Cbz
Cbz
H
N
HN
N
N
N
R1
azodicarboxylates were also examined in these reactions;
using diethyl and diisopropyl azodicarboxylates as amination
reagents generated the products with excellent yields and
enantioselectivities, which possessed excellent configurational
stabilities as well (5q-5s).
aromatization
H
H
addition
*
O
central-to-axial
chirality transfer
N
H2N
H
P
O
NH
R2
R2
N
R2
O
H2N
H2N
O
INT A
*
Dual H-bonding activation
Scheme 1. Control experiments and proposed reaction
mechanism.
Table 3. Substrate scope for regarding to substituents at the 5-
position and the azodicarboxylatesa.
To demonstrate the utilities of these reactions,
derivations of the axially chiral products were performed
(Scheme 2). The free –NH2 group of 5a was converted into an
iodide group in 79% yield via diazotization with NaNO2
followed by treatment of NaI, which could be utilized in
transition metal catalyzed cross-coupling reactions for further
derivatizations (Scheme 2, a). Deamination of 5s using the
combination of NaNO2 and H3PO2 gave the product 9s in 75%
yield, which could then underwent catalytic hydrogenation to
Cbz
HN
Cbz
HN
Cbz
HN
CH3
Cbz
HN
Cbz
Cbz
Cbz
Cbz
N
N
N
N
H
N
H
N
H
N
H
N
H3C
H3C
Piv
Piv
Piv
Piv
NH2
NH2
NH2
NH2
5l
5m
5n
5o
, 99% yield, 96.5:3.5 er
, 96% yield, 97.5:2.5 er
, 99% yield, 97.5:2.5 er
50
, 99% yield, 97:3 er
50
50
50
(t1/2 rac = 617 h)
(t1/2 rac = 413 h)
(t1/2 rac = 448 h)
(t1/2 rac = 91 h)
Cbz
COOiPr
COOiPr
COOEt
HN
HN
HN
HN
Cbz
COOiPr
N
H
COOiPr
N
H
COOEt
N
H
N
H
tBu
N
H3C
N
tBu
N
tBu
N
Piv
Piv
Piv
Cbz
H
H
NH2
NH2
NH2
NH2
N
Cbz
N
Cbz
Cbz
tBu
Cbz
tBu
N
NaNO2, NaI
TsOH
N
H
N
H
N
5pb
5q
5r
5s
, 96% yield, 97.5:2.5 er
, 99% yield, 96.5:3.5 er
, 99% yield, 97.5:2.5 er
100
, 99% yield, 96.5:3.5 er
50
tBu
tBu
(a)
100
100
(t1/2 rac = 11 h)
(t1/2 rac = 321 h)
(t1/2 rac = 325 h)
(t1/2 rac = 185 h)
O
MeCN/H2O
O
aThe same conditions as indicated in Table 2. bWith (R)-A1 catalyst.
I
NH2
5a
8a
, 98.5:1.5 er
, 79%, 96.5:3.5 er
COOiPr
COOiPr
COOiPr
In the CPA catalyzed Friedel-Craft-type amination
reactions with azodicarboxylates, a well-accepted asymmetric
induction model is that the CPA catalyst reacted as the
bifunctional catalyst, which activated both the nucleophile and
HN
COOiPr
HN
COOiPr
HN
COOiPr
N
NaNO2,
H3PO2
N
N
H
N
H
H2, Pd/C
NH2
tBu
(b)
tBu
tBu
N
Cbz
Cbz
10s
, 99%, 97:3 er
70
9s
, 75%, 97:3 er
5s
, 97.5:2.5 er
NH2
(t1/2 rac = 200 h)
15
electrophile via dual hydrogen bonding activation.13,
Me
F
10s
(10 mol %)
NaBH4
EtOH
However, in these 1,3-benzenediamine substrates, there are
two N-H groups that can reacted as the potential H-bonding
donor with the CPA catalyst. In order to figure out which
OH
(c)
CHO
NFSI, -10 o
DCM
C
11a
(±)-
12a
, 63%, 91:9 er
amino group actually played as H-bonding donor in these Scheme 2. Derivatizations of the chiral products.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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The application of this chiral aniline in asymmetric catalysis was also
preliminarily studied, which could catalyse the enantioselective
21
electrophilic fluorination of α-branched aldehyde12a,
with high
enantioselectivity (63%, 91:9 er, Scheme 2, c).
7
In conclusion, we report
a highly efficient method for
asymmetric synthesis of nonbiary N-C atropisomers via direct
enantioselective aminations of 1,3-benzenediamine derivatives with
azodicarboxylates enabled by chiral phosphoric acid catalysis. This
method features broad substrates scope and generating N-C
atropisomeric products with high configurational stabilities (with
racemization half-lives up to 405
h
at 100 oC). The facile
derivatizations of the chiral products and their application as novel
chiral aniline catalyst demonstrate the potential of this method.
We gratefully acknowledge ShanghaiTech University start-
up funding for financial support. The authors thank the support
from Analytical Instrumentation Center (#SPST-AIC10112914),
SPST, ShanghaiTech University.
8
9
Conflicts of interest
There are no conflicts to declare.
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18 For details see supporting informations.
19 The rotation barriers of each N-C atropisomers were
calculated, with ΔG≠ up to 33.3 kcal/mol.
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4 | J. Name., 2012, 00, 1-3
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R2
DOI: 10.1039/D0CC02368J
R2
HN
R2
HN
R2
H
N
H
N
R
N
R2
R1
R
N
CPA cat.
R1
NH2
R
N N
R2
+
NH2
NH2
novel chiral aniline catalyst
19 examples, up to 98.5:1.5 er
high configurational stabilities
racemization t1/2 up to 405 h at 100 oC
An atroposelective synthesis of configurationally stable nonbiaryl N-C atropisomers through
direct asymmetric aminations of 1,3-benzenediamines has been developed.