Catalytic Asymmetric Allylic Amination with Isatins, Sulfonamides, Imides, Amines, and N-Heterocycles

Article abstract of DOI:10.1021/acs.orglett.0c00936

A generally useful palladium-catalyzed method for the asymmetric allylic amination with a large variety of isatins, sulfonamides, imides, amines, and N-heterocycles is introduced. A single protocol with a readily available catalyst accomplishes this reaction at room temperature with high yields and enantioselectivities often exceeding 90%, which is demonstrated with 31 examples.

Full text of DOI:10.1021/acs.orglett.0c00936

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Letter
Catalytic Asymmetric Allylic Amination with Isatins, Sulfonamides,
Imides, Amines, and N‑Heterocycles
Ciaran C. Lynch, Kaluvu Balaraman, and Christian Wolf*
́
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ABSTRACT: A generally useful palladium-catalyzed method for
the asymmetric allylic amination with a large variety of isatins,
sulfonamides, imides, amines, and N-heterocycles is introduced. A
single protocol with a readily available catalyst accomplishes this
reaction at room temperature with high yields and enantioselectiv-
ities often exceeding 90%, which is demonstrated with 31 examples.
he transition-metal-catalyzed asymmetric allylic alkylation
(AAA) has become a popular synthetic tool for the
protocol for diastereoselective N-glycosylation of unsaturated
hexopyranosides with isatin which gives efficient access to both
carbohydrate anomers. Nakazaki described a palladium-
T
5
construction of multifunctional building blocks and bio-
1
logically active compounds. In comparison to the large variety
catalyzed asymmetric intramolecular arylation procedure that
6
of enantioselective carbon−carbon bond formations that have
been achieved with this powerful reaction, relatively few
examples with nitrogen nucleophiles have appeared in the
affords axially chiral N-aryl oxindoles and highly enantiose-
lective organocatalytic aza-Michael additions of isatin deriva-
7
tives to unsaturated diketones were reported by Kanger.
2
literature (Scheme 1). The frequent occurrence of the
Based on the scarcity of catalytic asymmetric C−N bond
formations with N-nucleophilic isatins and oxindoles, we
decided to investigate the possibility of enantioselective allylic
aminations with this important heterocyclic scaffold. We now
wish to report the development of a method that accomplishes
this task with high yields and enantioselectivities. In addition,
we show that this chemistry is widely useful and applicable to
amines, sulfonamides, imides, lactams, amino esters, carba-
mates, aromatic heterocycles, and other N-nucleophiles.
We began our search for an efficient asymmetric allylic
amination protocol by screening the reaction between isatin, 1,
Scheme 1. Asymmetric Allylic Alkylation with Oxindoles
and Isatins
3
and 1,3-diphenylallyl acetate, 2, in the presence 5 mol % of [η -
C H ClPd] , 12 mol % of (S)-4-tert-butyl-2-[2-
3
5
2
(
diphenylphosphino)phenyl]-2-oxazoline and K CO at 25
2 3
°
C in various solvents (Table 1, entries 1−6). We found that
the best results are obtained with chloroform affording 3 in
7% yield and 99% ee (Table 1, entry 6). We then tested a
6
variety of organic and inorganic bases, but the yields did not
improve (Table 1, entries 6−14). Comparison of the
phoshinoxazolines L1, L2, and L3, SEGPHOS (L4), and the
BINAP derivatives L5 and L6 showed that both yields and ee’s
varied considerably when these ligands were used. The
phosphinoxazoline ligand, L1, however, gave superior results,
oxindole ring and derivatives thereof in alkaloids and the
therapeutic potential in a wide range of medicinal applications
have motivated the development of countless asymmetric
carbon−carbon or carbon−heteroatom bond forming reactions
that generate a chiral center at C-3 while the lactam nitrogen is
3
typically protected and not exploited.
To the best of our knowledge, an enantioselective allylic
amination method that utilizes oxindoles or isatins as N-
nucleophiles has not been reported despite the medicinal value
and the widespread presence of the indoline motif in natural
Received: March 13, 2020
4
compounds. A literature search revealed a few examples of
asymmetric carbon−nitrogen bond construction with oxindole
or isatin N-nucleophiles. Liu and co-workers developed a
©
XXXX American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c00936
A
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Letter
Table 1. Optimization of the Asymmetric Allylic Amination
Using Isatin, 1, and Allylic Acetate 2
Scheme 2. Substrate Scope of the Palladium-Catalyzed C−N
a
Bond Formation between Isatins and 1,3-Diarylallyl
a
Acetates
b
c
entry
solvent
THF
DCM
ACN
1,4-dioxane
DMF
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
base
ligand yield (%) ee (%)
1
2
3
4
5
6
7
8
9
K CO
K CO
K CO
K CO
K CO
K CO
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L1
28
60
37
27
67
67
29
67
43
46
50
17
43
44
67
46
45
31
74
63
91
99
80
32
0
2
3
3
3
3
3
3
2
2
2
98
99
99
99
99
99
99
98
37
51
99
91
90
93
81
94
99
2
2
Na CO
2
3
K PO
KO Bu
3
4
t
a
10
11
12
13
14
15
16
17
18
19
20
21
Cs CO
The absolute configuration was assigned based on analogy with the
2
3
e
BSA:KOAc
DBU
DIPEA
tetrazole 4la.
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
positions reacted smoothly toward the corresponding amina-
tion products in 70−90% yield and up to 99% ee. C−N bond
formation, however, was not observed when nitro-substituted
1,3-diphenylallyl acetates were employed in the optimized
protocol. As mentioned above, isatins have not been used in
asymmetric C−N bond formation with 1,3-diphenylallyl
acetates, and to the best of our knowledge all products
shown in Scheme 2 have not been reported to date.
Et N
3
K CO
K CO
K CO
K CO
K CO
K CO
K CO
2
3
3
3
3
3
3
3
2
2
2
2
2
d
2
We were pleased to find that our method can also be applied
to imides, amides, 3,3-disubstituted oxindoles, and sulfona-
mides (Scheme 3). Essentially the same procedure was used
without additional optimization and the desired products were
obtained in 67−99% and with enantioselectivities ranging from
a
Reactions were carried out with 1 (0.2 mmol) and 2 (0.2 mmol) at
5 °C for 48 h under inert atmosphere using 5 mol % of the Pd
2
b
c
complex and 12 mol % of the chiral ligand. Isolated yield. ee values
were determined using a ChiralPak IA column and 95:5 hexanes/IPA
as mobile phase. Acetate/isatin (2:1). BSA/KOAc (3:1).
d
e
94 to 99% ee. The imides 4aa and 4ba, which are both new
compounds, were produced in quantitative yields and with
literally perfect ee’s. Excellent results were also observed with
phthalimide, 3,3-difluoroxindole, and sulfonamides. We note
that the imides may serve as an ammonia surrogate which
would give practical access to chiral primary 1,3-diarylallyl
amines.
Encouraged by the general success, we decided to investigate
the possibility of C−N bond formation with several N-
heterocycles (Scheme 4). The reactions with imidazole and
benzimidazole occurred with high asymmetric induction
producing 4ia and 4ja in 84% yield and 98% ee, and
benzo[d]oxazol-2(3H)-one furnished 4ja with a yield of 89%
and 93% ee. Similar results were obtained with theophylline,
triazole, and 1-methyluracil. Single crystals of the triazole 4la
suitable for X-ray analysis were grown by slow evaporation of a
hexanes−dichloromethane (50:50 v/v) solution, and the
absolute configuration was assigned as R.
and we found that 3 is produced in 91% yield and 99% ee
when 2 equiv of the allylic acetate are employed (Table 1,
entry 21). Interestingly, 3 was formed in only 37% yield from
the corrresponding allylic tert-butyl carbonate under the same
conditions.
With an optimized protocol in hand, we continued with the
evaluation of the isatin substrate scope. We found that a variety
of substituted isatins carrying halogen, alkyl, and alkoxy groups
undergo C−N bond formation with high yields ranging from
8
3 to 99% and remarkable 95−99% ee (Scheme 2). For
example, (R,E)-1-(1,3-diphenylallyl)-5-methylindoline-2,3-
dione, 3ba, was isolated in 95% yield and 99% ee, and the 4-
chloroisatin analogue 3ca was obtained in 88% yield and 99%
ee. It is noteworthy that the reaction with 6-methoxyisatin gave
3
fa in quantitative yield and 99% ee. Substituted 1,3-
diphenylallyl acetates carrying halogens in the meta and para
B
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Scheme 3. Enantioselective Carbon−Nitrogen Bond
Scheme 5. Extension of the Substrate Scope to Amines and
Amino Acid Derivatives
a
a
Formation with Amides and Imides
a
The absolute configuration was assigned based on analogy with the
tetrazole 4la.
a
The absolute configuration was assigned based on analogy with the
tetrazole 4la.
Scheme 4. Asymmetric Allylic Allylation with N-
Heterocycles
a
yields and enantioselectivities using a chiral palladium catalyst
3
generated from commercially available [η -C H ClPd] and 4-
3
5
2
tert-butyl-2-[2-(diphenylphosphino)phenyl]-2-oxazoline and
K CO as base in chloroform at room temperature. A single
2
3
protocol was successfully applied to isatins, sulfonamides,
imides, amines and various N-heterocycles. The general
usefulness was demonstrated with the synthesis of 31 allylic
amination products, including 22 new structures, which were
obtained in 67−99% yields and with enantioselectivities above
90% ee in most cases.
General Procedure
A mixture of (S)-4-tert-butyl-2-[2-(diphenylphosphino)-
3
phenyl]-2-oxazoline (0.12 mmol, 12 mol %) and [η -
C H ClPd] (0.05 mmol, 5 mol %) in dry CHCl (5.0 mL)
3
5
2
3
was stirred at room temperature under N atmosphere for 2 h.
2
(
E)-1,3-Diphenylallyl acetate (502.5 mg, 2.0 mmol) was added
followed by 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (139.2 mg,
.0 mmol) and potassium carbonate (276.5 mg, 2.0 mmol).
1
The resulting mixture was stirred at room temperature for 4
days, and the reaction was monitored by TLC. The crude
product was purified by flash chromatography on silica gel
using 95:5 hexanes−ethyl acetate as the mobile phase. (R,E)-5-
a
The absolute configuration was assigned based on analogy with the
tetrazole 4la.
(
1,3-Bis(2-chlorophenyl)allyl)-4,5,6,7-tetrahydrothieno[3,2-c]-
Finally, we examined amines and amino acid derivatives.
Using benzylamine, N-methylbenzylamine, morpholine, and
allylamine as substrates, 4na, 4oa, 4pa, and 4qa were
synthesized in good yields and high ee’s. The reaction with
glycine methyl ester gave 4ra in 71% yield and 99% ee, which
pyridine was obtained as an orange viscous oil in 90% yield
(361.2 mg, 0.90 mmol). R = 0.71 (hexanes/EtOAc, 8:2). The
f
enantiomeric excess was determined by HPLC (CHIRALPAK
IA, hexanes/i-PrOH 98:2, flow rate 1 mL/min, λ = 254 nm) as
1
90% ee, t (minor) = 4.4 min, t (major) = 5.1 min. H NMR
R
R
8
compares well with previously reported results. The
(400 MHz, chloroform-d): δ = 7.75 (dd, J = 7.9, 1.8 Hz, 1H),
7.54−7.04 (m, 10H), 6.69 (d, J = 5.2 Hz, 1H), 6.20 (dd, J =
15.8, 9.0 Hz, 1H), 4.73 (d, J = 9.0 Hz, 1H), 3.76 (d, J = 14.6
diastereoselective C−N bond formation with alanine methyl
esters revealed that high stereocontrol can be achieved with
matched and mismatched pairs; both 4sa and 4ta were
obtained from (S)- and (R)-alanine methyl ester in yields
greater than 85% and with diastereomeric ratios of 11:1 and
1
3
Hz, 1H), 3.54 (d, J = 14.5 Hz, 1H), 2.93- 2.81 (m, 4H).
C
NMR (100 MHz, chloroform-d): δ = 139.0, 134.8, 133.9,
133.8, 133.6, 133.1, 133.1, 129.8, 129.7, 129.0, 128.6, 128.2,
127.7, 127.4, 126.9, 126.8, 125.5, 122.7, 68.1, 51.8, 48.8, 25.5.
3
2:1, respectively (Scheme 5).
In conclusion, we have developed an efficient method that
+
HRMS (ESI-TOF) m/z: [M + H] calcd for C H Cl NSNa
2
2
19
2
allows asymmetric allylic C−N bond formation with high
400.0693, found 400.0687.
C
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00936.
Detailed experimental procedures, compound character-
ization, NMR spectra, chiral HPLC chromatograms, and
crystallographic information (PDF)
9
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CCDC 1983652 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.
5
823. (n) Kita, Y.; Kavthe, R. D.; Oda, H.; Mashima, K. Asymmetric
AUTHOR INFORMATION
Corresponding Author
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allylic alkylation of β-ketoesters with allylic alcohols by a nickel/
diphosphine catalyst. Angew. Chem., Int. Ed. 2016, 55, 1098−1101.
(o) Balaraman, K.; Wolf, C. Catalytic enantioselective and
diastereoselective allylic alkylation with fluoroenolates: efficient access
to C3-fluorinated and all-carbon quaternary oxindoles. Angew. Chem.,
Int. Ed. 2017, 56, 1390−1395. (p) Huo, X.; He, R.; Fu, J.; Zhang, J.;
Yang, G.; Zhang, W. Stereoselective and site-specific allylic alkylation
of amino acids and small peptides via a Pd/Cu dual catalysis. J. Am.
Chem. Soc. 2017, 139, 9819−9822. (q) Wei, L.; Zhu, Q.; Xu, S.-M.;
Chang, X.; Wang, C.-J. Stereodivergent synthesis of α,α-disubstituted
α-amino acids via synergistic Cu/Ir catalysis. J. Am. Chem. Soc. 2018,
Christian Wolf − Department of Chemistry, Georgetown
University, Washington, DC 20057, United States;
orcid.org/0000-0002-4447-3753; Email: cw27@
georgetown.edu
Authors
Ciaran C. Lynch − Department of Chemistry, Georgetown
́
University, Washington, DC 20057, United States
Kaluvu Balaraman − Department of Chemistry, Georgetown
University, Washington, DC 20057, United States;
orcid.org/0000-0003-2020-269X
1
40, 1508−1513. (r) Trost, B. M.; Schultz, J. E.; Bai, Y. Development
of chemo- and enantioselective palladium-catalyzed decarboxylative
asymmetric allylic alkylation of α-nitroesters. Angew. Chem., Int. Ed.
2
019, 58, 11820−11825. (s) Alexy, E. J.; Zhang, H.; Stoltz, B. M.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00936
Catalytic enantioselective synthesis of acyclic quaternary centers:
palladium-catalyzed decarboxylative allylic alkylation of fully sub-
stituted acyclic enol carbonates. J. Am. Chem. Soc. 2018, 140, 10109−
Notes
10112. (t) Sempere, Y.; Alfke, J. L.; Roessler, S. L.; Carreira, E. M.
The authors declare no competing financial interest.
Morpholine ketene aminal as amide enolate surrogate in iridium-
catalyzed asymmetric allylic alkylation. Angew. Chem., Int. Ed. 2019,
5
8, 9537−9541. (u) Sandmeier, T.; Goetzke, F. W.; Krautwald, S.;
ACKNOWLEDGMENTS
We gratefully acknowledge financial support from NIH
GM106260).
■
(
Carreira, E. M. Iridium-catalyzed enantioselective allylic substitution
with aqueous solutions of nucleophiles. J. Am. Chem. Soc. 2019, 141,
1
2212−12218. (v) Ran, G.-Y.; Yang, X.-X.; Yue, J.-F.; Du, W.; Chen,
Y.-C. Asymmetric allylic alkylation with deconjugated carbonyl
compounds: direct vinylogous Umpolung strategy. Angew. Chem.,
Int. Ed. 2019, 58, 9210−9214. (w) Sun, W.; Hess, S. N.; Stoltz, B. M.
Enantioselective synthesis of gem-disubstituted N-Boc diazahetero-
cycles via decarboxylative asymmetric allylic alkylation. Chem. Sci.
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