Atroposelective Haloamidation of Indoles with Amino Acid Derivatives and Hypohalides

Article abstract of DOI:10.1021/acs.orglett.9b03456

An atroposelective coupling of indoles with chiral amino acid-based sulfonamides mediated by hypohalides is described. A series of 2-amido-3-haloindoles with a C-N chiral axis are delivered using this strategy. The C3 halogen atoms can facilitate further

Full text of DOI:10.1021/acs.orglett.9b03456

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Atroposelective Haloamidation of Indoles with Amino Acid
Derivatives and Hypohalides
Zhaojie Li, Menghan Tang, Chenyang Hu, and Shouyun Yu*
State Key Laboratory of Analytical Chemistry for Life Science, Jiangsu Key Laboratory of Advanced Organic Materials, School of
Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China
S
* Supporting Information
ABSTRACT: An atroposelective coupling of indoles with chiral amino acid-based sulfonamides mediated by hypohalides is
described. A series of 2-amido-3-haloindoles with a C−N chiral axis are delivered using this strategy. The C3 halogen atoms can
facilitate further transformation. Various functionalities, such as carbonyl, phosphine, aryl, and alkenyl groups, can be introduced
into the C3 position of indoles. These structurally diverse and axially chiral indole derivatives can find further synthetic utilities.
It can be exemplified with an axially chiral phosphine, which serves as a ligand in Pd-catalyzed cross couplings.
congestion and relatively lower rotation barriers than their
benzene counterparts.11
tropisomers around the C−N chiral axis, which have a
Atypical chiral axis connecting an aryl substituent and the
nitrogen-related hindrance, are one of the most important
classes of nonbiaryl axially chiral compounds.1 Representative
examples with an axially chiral C−N bond are amide-type C−
N axially chiral compounds2 and nitrogen containing aromatic
heterocyclic framework C−N axially chiral compounds3
(Figure 1a). Investigation of these C−N axially chiral
compounds has received increasing attention from the
chemical community due to their widespread appearance in
naturally occurring biologically active compounds4 and
applications toward chiral ligands for asymmetric catalysis.5
Catalytic asymmetric syntheses of these N−C axially chiral
compounds and their applications to asymmetric trans-
formations are of current research interest.6
The indole skeleton is widely apparent in many natural
products and drug molecules.7 Therefore, it is interesting to
introduce axial chirality into the indole skeleton. Uemura3b,c
and Kitagawa3e reported the stereoselective synthesis of axially
chiral indole derivatives possessing a sterically hindered phenyl
group on the nitrogen atom. Catalytic asymmetric synthesis of
indole-based heterobiaryl axially chiral compounds was also
disclosed by the Shi,8 Tan,9 and Gu10 groups. Despite these
elegant achievements, asymmetric synthesis of indole-based
atropisomers, especially with a C−N chiral axis, is still a
synthetic challenge and remains largely unexplored because the
indole-based atropisomers are expected to have less steric
Recently, we have succeeded in constructing a new class of
C−N axial chirality based on N-indole sulfonamides by the
atroposelective coupling of 3-substituted indoles with chiral
amino acid-based sulfonamides (Figure 1b).12 However, the
substituents on the C3 position are mainly limited to alkyl
groups, which are difficult to be functionalized and hamper the
synthesis of these novel, axially chiral indole derivatives in a
structurally diverse manner. We also reported chloroamidation
of indoles with sulfonamides.13 Sulfonamide and chloride were
introduced into the C2 and C3 position, respectively. Using
this 2,3-difunctionalization strategy, we envisage that atropo-
selective halosulfonamidation of indoles could be achieved
using chiral amino acid-based sulfonamides as the coupling
partners (Figure 1c). The halogen atoms are introduced into
the C3 position of indoles, which is expected to increase the
steric hindrance to ensure the thermodynamic stability of the
chiral axis and also facilitate further transformation.
Initially, we tested this idea using 1-methylindole (1a) and
N-triflyl-(L)-tert-leucine tert-butyl ester (2a) as the model
substrates. When a solution of 1a, 2a, and aqueous NaClO
solution with a ratio of 1:3:2.5 in PhCF3 was stirred at room
temperature for 12 h, the chloroamidation product 4a was
isolated in 11% NMR yield and >20:1 dr (entry 1, Table 1).
Received: September 30, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03456
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Organic Letters
Letter
NMR yield (76% isolated yield) and >20:1 dr (entry 7). After
succeeding in the chloroamidation of the indole 1a, we turned
our attention to bromoamidation of the indole 1a with amino
acid-based sulfonamide 2a using bromine sources instead of
aqueous NaClO solution. A series of common electrophilic
bromine sources, such as NBS, DBDMH, NBP, and Br2, were
tested. However, only a trace amount of the bromoamidation
product 3a could be observed (not shown). Finally, freshly
prepared aqueous NaBrO solution from Br2 and sodium
hydroxide in water was used as the bromine source;14 the
bromoamidation product 3a was obtained in 78% NMR yield
(65% isolated yield) and >20:1 dr (entry 9).
In order to show the generality of this 2,3-difunctionalization
strategy, the couplings of various indoles with amino acid
derivatives were investigated under chloroamidation and
bromoamidation conditions, respectively. First, a series of
substituted indole derivatives at different positions reacted with
2a promoted by NaClO and NaBrO, respectively (Figure 2a).
N-Benzyl indole was less active than its methylated counter-
part. Both chloroamidation (4b, 26% yield) and bromoamida-
tion (3b, 42% yield) resulted in lower yields. Substitutions at
C4−C7 positions did not affect this transformation signifi-
cantly, and chloroamidation (4c−4i, 36−64% yields) and
Figure 1. Establishment of a C−N chiral axis via amidation of indoles
with amino acid derivatives.
a
Table 1. Reaction Conditions Optimization
a
Reaction conditions: a solution of 1a (0.1 mmol), 2a, and NaClO in
b
the indicated solvent (2 mL) for 12 h under air. The yields were
c
d
determined by 1H NMR. Isolated yield in parentheses. The dr
e
values were determined by 19F NMR. Freshly prepared NaBrO
aqueous solution (0.375 mol of NaOH and 0.125 mol of Br2
formulated into 100 mL of aqueous solution at −5 °C) was used
instead of NaClO, and 3a was produced.
Encouraged by this promising result, we explored the solvent
effect of this reaction. It was found that the solvent only
affected the reactivity of this reaction and had no impact on the
stereoselectivity (entries 2−6). Dichloromethane (CH2Cl2)
proved to be the most efficient solvent, giving product 4a in a
59% yield (entry 5). The ratio of 1a:2a:NaClO was then
investigated (entries 7 and 8). The optimal ratio of
1a:2a:NaClO was determined to be 1:3:3, leading to 82%
Figure 2. Substrate scope. Reaction conditions: a solution of 1 (0.1
mmol), 2a (0.3 mmol), and NaClO or [NaBrO] (0.3 mmol, 3.0
equiv) in CH2Cl2 (2 mL) for 12 h under air. The yields were isolated
yields, and the dr values were determined by 19F NMR. aThe reaction
was run in a 4 mmol scale (1a).
B
DOI: 10.1021/acs.orglett.9b03456
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Letter
bromoamidation (3c−3i, 53−70% yields) products were
produced in accepted yields. It is worthy to note that the
diastereoselectivity was excellent (>20:1 dr) in all cases. This
reaction could be scaled up to a gram scale. When 4 mmol of
1a was subjected to the standard bromoamidation conditions,
a comparable isolated yield of 3a (1.2 g, 57% yield) was
achieved without affecting the stereoselectivity (>20:1 dr). We
next sought to investigate the reactivity and stereoselectivity of
the reactions of 1-methylindole (1a) with various amino acid
derivatives (Figure 2b). Generally, the steric hindrance of
amino acid derivatives had a positive influence on the
stereoselectivity without affecting the reactivity. The bulkier
the amino acid derivatives, the better the stereoselectivity. The
stereoselectivity of chloroamidation was better than that of
bromoamidation. Chiral amino alcohol derivative was also
explored and gave the corresponding products with good yield
and stereoselectivity (90% yield and 10.6:1 dr for 3o and 68%
yield and 10.4:1 dr for 4o).
with n-BuLi leading to lithium−halogen exchange, the
resultant anion was trapped by HCO2Et and ClPPh2, giving
aldehyde (5, 58% yield, >20:1 dr)- and phosphine (6, 52%
yield, >20:1 dr)-derived indoles, respectively (Figure 3a).
All atropisomers prepared in this work are thermodynami-
cally stable, and no obvious epimerization was observed at
room temperature. However, upon heating, significant
epimerization could be observed. In the case of 3l, the half-
lives and energy barriers for epimerization in toluene were
measured experimentally at 50 °C (323.15 K) and 70 °C
(343.15 K), respectively (Table 2; see the Supporting
Table 2. Half-Lives and Energy Barriers for the
Epimerization of 3l in Toluene
Figure 3. Synthetic application of axially chiral 3-bromoindole
derivatives.
Bromide 3a could also undergo a Suzuki−Miyaura coupling
reaction with arylboronic acid and alkenylboronic acid to give
arylation and alkenylation products 7 (48% yield, >20:1 dr)
and 8 (53% yield, >20:1 dr), respectively (Figure 3a). All ee
values of these compounds were determined to be more than
99%. No racemization was observed during these trans-
formations.
These structurally interesting and novel axially chiral indole
derivatives can find further synthetic utilities, which could be
exemplified with the axially chiral phosphine 6 (Figure 3b).
Phosphine 6 could serve as a chiral ligand in Pd-catalyzed
asymmetric allylic alkylation of acetate 9 with malonate 10 to
give the allylation product 11 in 51% yield and 69:31 er. Bulky
and electron-rich phosphine 6 was also an effective ligand in
the Pd-catalyzed Suzuki−Miyaura coupling reaction (87%
yield for 14) of the less reactive aryl chloride 12 with
arylboronic acid 13. As a contrast, PPh3 was an ineffective
ligand in the same reaction (<5% yield). These results
showcased that these C−N chiral axes were a good skeleton
as ligands in Pd-catalyzed cross couplings.
To obtain more details of these haloamidation reactions, a
series of control experiments were conducted, as shown in
Figure 4. It is known that N-chlorosulfonamides generated
from sulfonamides and NaClO are good chlorinating
reagents.13 However, treatment of sulfonamide 2a with
NaClO could not provide N-chlorosulfonamide 15, which
ruled out N-chlorosulfonamide 15 serving as the chlorinating
reagent (Figure 4a). 1-Methylindole 1a reacted with NaClO
could give chlorination product 16 and dichlorination product
17 but in low yields (8% yield for 16 and 6% yield for 17). It
was found that the overall yield for chlorination products 17
τ1/2rac
ΔG⧧kf
ΔG⧧kb
T
(h)
(kcal/mol)
(kcal/mol)
Keq
323.15 K (50 °C)
343.15 K (70 °C)
3.45
0.25
26.98
26.78
25.29
25.12
0.072
0.088
Information for more details). It was found that the half-lives
for the epimerization of axially chiral indole 3l were 3.45 h at
50 °C and 0.25 h at 70 °C, respectively. The rotational barriers
for the forward and reverse directions were 26.98 kcal/mol
(ΔG⧧kf) and 25.29 kcal/mol (ΔG⧧kb) at 50 °C and 26.78
kcal/mol (ΔG⧧kf) and 25.12 kcal/mol (ΔG⧧kb) at 70 °C.
Chiral indole 3a is thermodynamically more stable than 3l.
The half-lives for the epimerization of 3a were 11.87 h at 50
°C, and the rotational barriers for the forward and reverse
directions were 26.98 kcal/mol (ΔG⧧kf) and 26.20 kcal/mol
(ΔG⧧kb) at 50 °C. The structures and stereochemistry of 3l
and 3l′ were confirmed unambiguously by single crystal X-ray
diffraction analysis. The absolute stereochemistry of 3l and 3l′
was assigned as (S, P) and (S, M), respectively.15
The C3 halogen atoms are expected to facilitate further
transformation, which can generate structurally diverse indoles
with a C−N chiral axis. Upon the treatment of bromide 3a
C
DOI: 10.1021/acs.orglett.9b03456
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Letter
Figure 5. Plausible reaction mechanism.
20 is then trapped by sulfonamide 2a. After antiperiplanar
elimination of HCl with the help of a base, the
chlorosulfonamidation product 4a is finally afforded. The
axial chirality is established by a point-to-axial chirality transfer
process. Alternatively, the iminium intermediate 20 can be
trapped by water in the absence of 2a to provide the
intermediate 22. Intermediate 22 can either be oxidized to
furnish the 3,3-dichloroindolinone 17 or lose HCl to give the
3-chloroindolinone 18.
In summary, we have reported an atroposelective coupling of
indoles with chiral amino acid-based sulfonamides mediated by
hypohalides. This reaction delivers 2-amido-3-haloindoles with
a C−N chiral axis. The C3 halogen atoms can facilitate further
transformation, which can introduce various functionalities,
such as carbonyl, phosphine, aryl, and alkenyl groups, into the
C3 position of indoles. These structurally diverse and axially
chiral indole derivatives can find further synthetic utilities. It
can be exemplified with an axially chiral phosphine, which
serves as a ligand in Pd-catalyzed couplings. Further
investigation on the structural diversity and the application
of these novel axially chiral indoles is underway in our
laboratory.
Figure 4. Control experiments.
and 18 could be improved 89% when HOAc was added into
the reaction mixture of 1a and NaClO. Besides, 1-methylindole
1a reacted with sulfonamide 2a (1equiv) and NaClO (1
equiv), giving 3-chloroindole 16 in good yield (93%) (Figure
4b). Given that trifluoromethanesulfonamide is about 3 pK
units more acidic than acetic acid in DMSO,16 sulfonamide 2a
was believed to act not only as an amide source but also as an
acid to promote the chlorine transfer from NaClO to indole
1a.17 When 3-chloroindole 16 replacing indole 1a was
subjected to the standard chloroamidation conditions, the
desired chloroamidation product 4a was isolated in a 60% yield
(Figure 4c). However, C2 sulfomidated indole 19 could not be
further chlorinated with the sole NaClO. Interestingly, when
C2 sulfomidated indole 19 was treated with the combination
of NaClO and sulfonamide 2a, a new chloroamidation product
4a′ (90% yield, 9:1 dr), which was determined to be the
diastereomer of 4a, was produced (Figure 4d). These
phenomena indicated that 3-chloroindole 16 was the key
intermediate of this chloroamidation reaction.
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.9b03456.
Experimental details, NMR spectra, and details of
experiments (PDF)
Accession Codes
CCDC 1955748 and 1955749 contain 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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yushouyun@nju.edu.cn.
ORCID
Based on the aforementioned experimental phenomena as
well as our previous works,12,13 a plausible mechanism for this
transformation is posited. As shown in Figure 5, electrophilic
chlorination of indole 1a with NaClO in the assistance of
acidic sulfonamide 2a gives the 3-chloroindole 16. 3-
Chloroindole 16 is further chlorinated with NaClO to give
the dichlorinated iminium intermediate 20. The iminium ion
Shouyun Yu: 0000-0003-4292-4714
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.9b03456
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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ACKNOWLEDGMENTS
■
Financial support from National Key Research and Develop-
ment Program of China (2018YFC0310900) and Fundamental
Research Funds for the Central Universities (020814380092)
is acknowledged.
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DOI: 10.1021/acs.orglett.9b03456
Org. Lett. XXXX, XXX, XXX−XXX