Rhodium-Catalyzed Enantioselective Addition of Arylboroxines to Isatin-Derived N-Boc Ketimines Using Chiral Phosphite-Olefin Ligands: Asymmetric Synthesis of 3-Aryl-3-amino-2-oxindoles

Article abstract of DOI:10.1021/acs.orglett.9b02787

An efficient rhodium-catalyzed enantioselective arylation of isatin-derived N-Boc ketimines with arylboroxines has been developed using H₈-BINOL-derived phosphite-olefin as a chiral ligand. This method allows access to a broad variety of valuab

Full text of DOI:10.1021/acs.orglett.9b02787

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rhodium-Catalyzed Enantioselective Addition of Arylboroxines to
Isatin-Derived N‑Boc Ketimines Using Chiral Phosphite−Olefin
Ligands: Asymmetric Synthesis of 3‑Aryl-3-amino-2-oxindoles
Yue-Na Yu,† Wei-Yi Qi,‡ Chun-Yan Wu,‡ and Ming-Hua Xu*,†,‡
†Shenzhen Grubbs Institute and Department of Chemistry, Southern University of Science and Technology, 1088 Xueyuan
Boulevard, Shenzhen 518055, China
‡State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi
Road, Shanghai 201203, China
S
* Supporting Information
ABSTRACT: An efficient rhodium-catalyzed enantioselective
arylation of isatin-derived N-Boc ketimines with arylboroxines
has been developed using H8-BINOL-derived phosphite-olefin
as a chiral ligand. This method allows access to a broad variety
of valuable tetrasubstituted 3-amino-2-oxindole derivatives in
good yields (up to 98%) with excellent enantioselectivities (up
to 98% ee).
xindoles bearing a tetrasubstituted stereogenic center at
the 3-position constitute a privileged class of hetero-
cyclic frameworks, which are present in a wealth of bioactive
natural products and pharmaceutically active agents.1 Among
them, 3-aryl-3-amino-2-oxindoles are very important structural
motifs found in various drug candidates (Figure 1), including
introduction of indoles, pyrroles, naphthols, or phenols to the
3-position of 2-oxindoles. Alternatively, transition-metal-
catalyzed asymmetric addition of readily available arylboron
reagents to 3-ketimino-2-oxindoles has been recognized to be a
promising method, although only few examples have been
reported. In 2011, Ellman achieved the Rh(I)-catalyzed
diastereoselective addition of arylboroxines to isatin-derived
N-tert-butanesulfinyl chiral imines with up to 92% de.8a In
2016, Zhang and co-workers developed an efficient Pd(II)-
catalyzed highly enantioselective addition of arylboronic acids
to N-tert-butylsufonyl-protected ketimines using Pyrox li-
gands.8b In these two reports, the reactions require the use
of highly activated sulfinyl or sufonyl imines. The widely used
N-Boc imines were found fully inactive under the Pd(II)/
Pyrox catalysis. Notably, Jiang et al. recently reported their
successful development of a new Pd(II)/N-tosyl bisimidazoline
catalytic system that could enable asymmetric addition of
arylboronic acids to isatin-derived N-Boc imines with good to
excellent enantioselectivities (60−96% ee).8c Despite progress,
these Pd-catalyzed reactions have not yet proven effective for
sterically hindered substrates. On the other hand, reactions
involving chiral rhodium complex catalysis remains unex-
ploited. A rhodium(I)-catalyzed enantioselective addition of
arylboronic acids to N-Boc isatin imines was described by
Burke et al.; however, the enantioselectivity was low with only
39% ee when chiral diene ligand was applied.8d Therefore,
developing new effective catalytic systems for enantioselective
arylation of isatin-derived ketimines with a broad scope is still
in high demand.
O
Figure 1. Examples of bioactive 3-aryl-3-amino-2-oxindoles.
SSR-149415, a drug now in clinical trials for treatment of
anxiety depression,2 antimalarial agent NITD609 (also
KAE609 or cipargamin),3 and the ghrelin receptor (GHSR)
antagonists.4 Due to this great importance, the development of
catalytic enantioselective methods for their preparation is a
subject of particular interest to organic and medicinal chemists.
Other than organocatalyzed asymmetric amination of 2-
oxindoles5 and Pd-catalyzed asymmetric intramolecular α-
arylation of amides,6 catalytic asymmetric addition of
nucleophiles to isatin-derived ketimines is among the most
straightforward and efficient approaches to incorporate the
tetrasubstituted carbon stereocenter. However, due to the low
reactivity of ketimines and the difficulty in the stereochemical
control, only a limited number of processes have been
developed.7,8 A commonly employed strategy relies on the
asymmetric aza-Friedel−Crafts reaction, which works well only
with electron-rich π-nucleophilic arenes,7 allowing the sole
Received: August 7, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02787
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Rh-catalyzed enantioselective addition of organoboron
reagents to imines is a particularly useful strategy for
constructing chiral amines.9,10 Previously, we have successfully
synthesized various enantioenriched amines bearing α-
quaternary stereocenters under this strategy using a new series
of chiral sulfur- or phosphorus-based olefin ligands we have
developed.10 On the basis of these successes, we envisioned
that these chiral rhodium complexes might also act as effective
catalysts for the asymmetric addition of arylborons to isatin-
derived ketimines. Herein, we disclose results of our efforts on
the development of a new catalytic system for highly
enantioselective arylation of isatin-derived N-Boc ketimines.
The method allows direct access to a variety of 3-aryl-3-amino-
2-oxindoles in good yields and excellent enantiomeric excesses.
We began our study by examining the arylation of N-Boc
imine 1a derived from N-methyl isatin with boroxine 2a in the
presence of 2.5 mol % of [Rh(COE)2Cl]2 and 5 mol % of
chiral hybrid olefins ligands (L1, L2, L3) in TEA/dioxane at
60 °C. The initial results showed that almost no reaction
occurred with chiral linear sulfur-olefin L1 as a ligand (Table 1,
entry 1), while branched sulfur-olefin L2 gave the desired
product 3a in a very low yield and ee (entry 2). To our delight,
with simple phosphite-olefin ligand L3, the reaction afforded a
promising enantioselectivity (57% ee), albeit in an unsat-
isfactory yield of 16% (entry 3). This result implies that chiral
phosphorus-based olefins might be potential ligands for the
reaction.11 Accordingly, the influence of protecting groups on
the nitrogen of imine oxindole was investigated (entries 3−5).
Interestingly, a significant steric effect of the protecting group
was observed. When the sterically bulky trityl was used as the
protecting group (ketimine 1c), the corresponding product 3c
could be formed in 63% yield with 83% ee (entry 5). Notably,
the reaction could only generate traces of 3c in the absence of
ligand L3 (entry 6). Subsequently, the loading ratio of
rhodium to ligand was examined. The use of 10 mol % of
L3, which corresponds to a ligand-to-metal ratio of 2:1 led to a
sharp decline in both yield and enantioselectivity (entry 7).
Considering the stronger coordinating ability of phosphorus in
comparison with olefin, this result suggests the possible
formation of a less active rhodium diphosphite complex. To
ensure the coordination of rhodium to both the phosphorus
atom and olefinic double bond simultaneously, excess rhodium
was applied and an optimal result was obtained when 2.75 mol
% of [Rh(COE)2Cl]2 was added in the reaction (entry 8).
On the basis of these findings, a series of structurally diverse
phosphite−olefin ligands (L4−9) were evaluated in the same
Rh-catalyzed reaction between 1c and 2a (Table 1, entries 10−
15). First, the influence of the aromatic moiety attached to the
double bond was examined. Introducing a bulky tert-butyl
substituent onto the para-position of phenyl ring was not
beneficial for the stereoselectivity (L4, entry 10). Ligand L5
containing a para-phenyl substituent exhibited lower catalytic
activity (entry 11). Besides, ligand L6 bearing an ortho-methyl
and L7 containing a meta-methyl individually to the olefin
group showed a slight improvement in the catalytic perform-
ance (entries 12−13). In contrast to L3, the presence of two
phenyl substituents at the 3- and 3′-positions of the binaphthyl
moiety led to a clear decrease in yield (50%), albeit with a
somewhat higher ee (89%) (L8, entry 14). To our delight,
with H8-BINOL-derived L9 as the ligand, the addition reaction
proceeded smoothly, giving product 3c in both the highest ee
(95%) and isolated yield (78%) (entry 15). It appears that the
dihedral angle of the two aromatic planes exerts great influence
in the reaction transition state for stereocontrol. Given the ease
of preparation, superior catalytic activity, and enantioselectiv-
ity, L9 was selected as the preferred ligand for further intensive
study.
a
Table 1. Initial Screening of Reaction Conditions
b
c
entry
1
[Rh] (mol %) ligand PG
3
yield (%) ee (%)
With the above results in hand, we proceeded to further
optimize the reaction parameters. As shown in Table 2, a
survey of base additives was performed first. In view of organic
base additives examined (TEA, DBU, DABCO, and DIPEA)
(entries 1−4), the use of 3 equiv of DIPEA was identified as
the best choice, giving the adduct in 82% yield and 96% ee
(entry 4). It was found that the N-Boc ketimines 1 are very
sensitive to water and suffered serious hydrolysis in aqueous
base K3PO4 and KF, resulting in much lower yields (enteis 5−
6). Next, we turned our attention toward investigating the
influence of solvent. When the reaction was carried out in THF
and DCE, it afforded the desired product in a lower yield while
maintaining excellent enantioselectivity (entries 7−8). How-
ever, in toluene or Et2O, a drop in both yield and
enantioselectivity was found (entries 9−10). Thus, dioxane
was chosen as the best solvent. Additionally, it was found that
the presence of 4 Å molecular sieves (MS) in the reaction
system would be helpful for suppressing the hydrolysis of
imines (entry 11). We also investigated the use of other
organoboron reagents instead of arylboroxine. Surprisingly,
when phenylboronic acid was employed under the same
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a
1a
1a
1b
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
5
5
5
5
5
5
5
5.5
6
5.5
5.5
5.5
5.5
5.5
5.5
L1
L2
L3
L3
L3
−
L3
L3
L3
L4
L5
L6
L7
L8
L9
Me
Me
Me
Bn
Tr
Tr
Tr
Tr
Tr
Tr
Tr
Tr
Tr
Tr
Tr
3a
3a
3a
3b
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
trace
9
−
14
57
77
83
−
63
85
85
73
87
86
89
89
95
16
30
63
trace
23
63
64
71
43
68
64
50
78
d
a
Reaction conditions: 1 (0.2 mmol), (p-TolBO)3 (1 equiv),
[Rh(COE)2Cl]2, ligand (5 mol %), and TEA (3 equiv) in 1.0 mL
of dioxane were stirred at 60 °C for 12 h, unless otherwise noted.
Isolated yield. Determined by chiral HPLC analysis. 10 mol % of
L3
b
c
d
B
DOI: 10.1021/acs.orglett.9b02787
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Optimization of the Reaction Conditions
Scheme 1. Rh-Catalyzed Asymmetric 1,2-Addition of
a b c
,
,
Arylboroxines to Isatin-Derived N-Boc Ketimines
b
c
entry
solvent
base
yield (%)
ee (%)
1
2
3
4
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
THF
DCE
toluene
Et2O
TEA
DBU
DABCO
DIPEA
K3PO4 (1.5 M)
KF (1.5 M)
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
78
95
−
−
n.r.
trace
82
50
44
63
75
88
56
96
96
96
95
96
88
85
97
d
5
6
d
7
8
9
10
e
11
dioxane
83
a
Reaction conditions: 1c (0.2 mmol), (p-TolBO)3 (1 equiv),
[Rh(COE)2Cl]2 (2.75 mol %), L9 (5 mol %), and base (3 equiv)
b
in 1.0 mL of solvent were stirred at 60 °C for 12 h. Isolated yield.
c
d
Determined by chiral HPLC analysis. 3 equiv of aqueous base were
e
used. 100 mg of 4 Å molecular sieves were added.
conditions, the reaction gave the corresponding product in
only 45% yield with 89% ee. With phenylboronate (5,5-
dimethyl-2-phenyl-1,3,2-dioxaborinane), no reaction occurred.
Having established the optimal reaction conditions, the
scope of the reaction was then explored with diverse substrates.
As summarized in Scheme 1, a wide range of arylboroxines and
N-Boc ketimines bearing different substituents were examined.
Gratifyingly, most transformations proceeded smoothly to give
a variety of tetrasubstituted 3-aryl-3-aminooxindoles in
moderate to good yields with high levels of enantioselectivity
(90−98% ee). The overall yield and enantioselectivity are
influenced by the nature of the reactants. Electron-rich
arylboroxines reacted faster in comparison with phenyl-
boroxine (3c−g vs 3i), while in cases with electron-deficient
arylboroxines, the reaction needs to be performed at 80 °C
with solid K3PO4 as the base additive and displayed a modest
decrease in yield and enantiocontrol (3j−l, 90−92% ee).
Remarkably, ortho-substituted arylboroxines are also compat-
ible in this reaction, affording product 3g and 3h in good yield
and enantioselectivity. It is worth noting that the employment
of a sterically hindered arylboron reagent remains problematic
under palladium catalysis.8b,c Subsequently, various 3-ketimi-
no-2-oxindoles bearing either electron-withdrawing or elec-
tron-donating substituents at the C4, C5, C6, or C7 position
were found to be tolerated, and in most cases the
corresponding products (3m, 3n, 3p−v) could be obtained
in moderate to good yields with high enantioselectivities (92−
96% ee). With 4-fluoro-substituted substrate, the yield was
slightly reduced when phenylboroxine was employed (3m,
56% yield), while electron-rich arylboroxine could give
excellent yield (3n, 98% yield). However, when bulky bromine
was introduced at the C4 position, a sharp decrease in both
yield and enantioselectivity was observed due to the difficulty
in overcoming the steric encumbrance (3o, 26% yield, 54%
ee).
a
Reaction conditions: imine substrate 1 (0.20 mmol), arylboroxine 3
(1.0 equiv), [Rh(COE)2Cl]2 (2.75 mol %), L9 (5.0 mol %), and
DIPEA (3.0 equiv), 100 mg of 4 Å MS in 1.0 mL of dioxane were
b
stirred at 60 °C for 12 h, unless otherwise noted. Isolated yield.
c
d
Determined by chiral HPLC analysis. One mmol scale, stirred for
e
24 h. The reaction was carried out with 3 equiv of K3PO4 at 80 °C.
diffraction analysis (CCDC 1403781), and the stereochemistry
of the quaternary carbon center was determined to be S
(Scheme 1).
We next explored the synthetic utility of the current
enantioselective arylation (Scheme 2). The tert-butoxycarbonyl
Scheme 2. Transformation of Addition Products
(Boc) and trityl (Tr) group of addition products 3 could be
easily removed in one step with trifluoroacetic acid in 1,2-
dichloroethane at 50 °C, giving optically active quaternary
carbon-containing 3-aryl-3-aminooxindole in good yield with-
out loss of enantiopurity, as exemplified by 4a and 4b. Notably,
nonprotecting chiral 3-aryl-3-aminooxindoles 4 are critical
synthetic intermediates for a series of GHSR antagonists.4a In
the other case, NBS/AIBN-mediated bromination and
cyclization of product 3g in CCl4 furnished an interesting
Reaction at 1 mmol scale with 1 and tris(4-methoxyphenyl)-
boroxin was carried out successfully and gave 3e in 88% yield
and 92% ee. The structure of 3t was confirmed by X-ray
C
DOI: 10.1021/acs.orglett.9b02787
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
B. K. S.; Lee, M. C. S.; Zou, B.; Russell, B.; Seitz, P.; Plouffe, D. M.;
spirocyclic compound 5. The Boc group could be selectively
deprotected with 3 N HCl in dioxane at 60 °C to deliver the
corresponding (S)-spiro[indoline-3,1′-isoindolin]-2-one 6 with
no erosion of optical purity. This showcases a unique
advantage of our method, as such spirocyclic molecules are
otherwise difficult to access particularly in a highly stereo-
selective manner.
In summary, we have developed an efficient rhodium-
catalyzed enantioselective arylation of isatin-derived N-Boc
ketimines using an exceptionally simple chiral phosphite-olefin
as ligand. The method exhibits broad substrate generality and
functional group tolerance, enabling ready access to a wide
variety of valuable 3-aryl-3-aminooxindoles bearing a stereo-
defined quaternary carbon center in moderate to good yields
(up to 98%) with excellent enantioselectivities (up to 98% ee).
Significantly, these versatile products can be conveniently
transformed into a range of biologically interesting complex
molecules. Further efforts on exploring the application of this
practical method in related biological and drug discovery
studies are underway in our laboratory.
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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.9b02787.
Experimental procedures and spectroscopic data of all
new compounds (PDF)
Accession Codes
CCDC 1403781 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.
(6) (a) Jia, Y. X.; Hillgren, J. M.; Watson, E. L.; Marsden, S. P.;
Kundig, E. P. Chem. Commun. 2008, 44, 4040. (b) Tolstoy, P.; Lee, S.
̈
AUTHOR INFORMATION
Corresponding Author
X. Y.; Sparr, C.; Ley, S. V. Org. Lett. 2012, 14, 4810.
■
(7) (a) Feng, J.; Yan, W.; Wang, D.; Li, P.; Sun, Q.; Wang, R. Chem.
Commun. 2012, 48, 8003. (b) Chen, J.-P.; Chen, W.-W.; Li, Y.; Xu,
M.-H. Org. Biomol. Chem. 2015, 13, 3363. (c) Montesinos-Magraner,
*E-mail: xumh@sustech.edu.cn; xumh@simm.ac.cn.
ORCID
́
́
M.; Vila, C.; Cantyn, R.; Blay, G.; Fernnadez, I.; Mun
Pedro, J. R. Angew. Chem., Int. Ed. 2015, 54, 6320. (d) Montesinos-
̃
oz, M. C.;
Ming-Hua Xu: 0000-0002-1692-2718
Notes
́
́
̃
o, A.; Blay, G.; Fernandez, I.;
Magraner, M.; Vila, C.; Rendon-Patin
Munoz, M. C.; Pedro, J. R. ACS Catal. 2016, 6, 2689. (e) Zhang, X.;
̃
The authors declare no competing financial interest.
Zhang, J.; Lin, L.; Zheng, H.; Wu, W.; Liu, X.; Feng, X. Adv. Synth.
Catal. 2016, 358, 3021. (f) Kaur, J.; Chimni, S. S. Org. Biomol. Chem.
2018, 16, 3328.
ACKNOWLEDGMENTS
■
(8) (a) Jung, H. H.; Buesking, A. W.; Ellman, J. A. Org. Lett. 2011,
13, 3912. (b) He, Q.; Wu, L.; Kou, X.; Butt, N.; Yang, G.; Zhang, W.
Org. Lett. 2016, 18, 288. (c) Wang, J.-Y.; Li, M.-W.; Li, M.-F.; Hao,
W.-J.; Li, G.; Tu, S.-J.; Jiang, B. Org. Lett. 2018, 20, 6616. (d) Marques,
C. S.; Burke, A. J. Eur. J. Org. Chem. 2016, 2016, 806.
(9) For recent reviews, see: (a) Marques, C. S.; Burke, A. J.
ChemCatChem 2011, 3, 635. (b) Friestad, G. K.; Mathies, A. K.
Tetrahedron 2007, 63, 2541. (c) Chen, D.; Xu, M.-H. Chin. J. Org.
Chem. 2017, 37, 1589. For representative examples of Rh/Pd/Ni-
catalyzed addition of organoboron reagents to ketimines from other
groups, see: (d) Shintani, R.; Takeda, M.; Tsuji, T.; Hayashi, T. J. Am.
Chem. Soc. 2010, 132, 13168. (e) Nishimura, T.; Noishiki, A.; Tsui, G.
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We thank the National Science & Technology Major Project
“Key New Drug Creation and Manufacturing Program”, China
(2018ZX09711002-006) and the National Natural Science
Foundation of China (81521005, 21472205, 21325209) for
financial support.
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