Trisulfur-Radical-Anion-Triggered C(sp2)-H Amination of Electron-Deficient Alkenes

Article abstract of DOI:10.1021/acs.orglett.0c03846

A trisulfur-radical-anion (S3˙-)-triggered C(sp2)-H amination of α,β-unsaturated carbonyl derivatives with simple amines has been demonstrated. This protocol provides convenient access to a variety of synthetically valuable N-unprotected and secondary β-enaminones with absolute Z selectivity and tertiary β-enaminones with E selectivity. Mechanistic probe and electronic structure theory calculations suggest that S3˙- initiates the nucleophilic attacks via a thiirane intermediate.

Full text of DOI:10.1021/acs.orglett.0c03846

pubs.acs.org/OrgLett
Letter
Trisulfur-Radical-Anion-Triggered C(sp2)−H Amination of Electron-
Deficient Alkenes
Khang X. Nguyen, Phuc H. Pham, Thao T. Nguyen, Chou-Hsun Yang, Hoai T. B. Pham,
Tung T. Nguyen, Haobin Wang,* and Nam T. S. Phan*
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ABSTRACT: A trisulfur-radical-anion (S3 )-triggered C(sp )−H
amination of α,β-unsaturated carbonyl derivatives with simple amines
has been demonstrated. This protocol provides convenient access to a
variety of synthetically valuable N-unprotected and secondary β-
enaminones with absolute Z selectivity and tertiary β-enaminones with
E selectivity. Mechanistic probe and electronic structure theory
−
̇
calculations suggest that S3 initiates the nucleophilic attacks via a
thiirane intermediate.
naminones are 1,3-difunctional frameworks ubiquitously
found in the synthesis of N- and O-containing hetero-
Scheme 1. Intermolecular Alkenyl β-C(sp2)−N Bond
Formation Reactions
E
cycles, natural products, and pharmaceutical targets.1 Owing to
their structural features, β-enaminones are frequently used as
expedient N,O-bidentate ligands in organoboron complexes
and transition-metal catalysis.2 In recent years, the β-enamine
skeleton has been realized via the acid-catalyzed condensation
of 1,3-diketones with amines,3 aza-Michael addition of amines
to ynones,1d,4 aldol-type addition of carbonyl compounds to
nitriles5 or activated isocyanides,6 and reductive ring opening
of heterocycles.7 More recently, several radical coupling
strategies were developed through decarboxylation coupling
of α-keto acids and α-imine radicals.4a,8 However, the available
methods are still arduous tasks due to the tedious multistep
preparations, limited substrate scopes, and unavailability of
starting materials or harsh reaction conditions. Additionally,
practical and efficient syntheses of synthetically useful N-
unprotected enaminones have scarcely been disclosed.
The intermolecular direct oxidative amination of alkenyl
C(sp2)−H bonds represents the most straightforward method
for the synthesis of enamine derivatives (Scheme 1).9 In this
context, most attempts to couple the C(sp2)−H bonds to N−
H bonds were derived from the aza-Wacker process involving
Pd or Rh catalysts.10 These reactions, however, are limited by
the preactivation of amino precursors for which only aromatic
amines, amides, imides, carbamates, and sulfoamides were
reactive substrates.9c,10d Furthermore, the presence of additives
and oxidants is required to either prevent catalyst deactivation
or regenerate the active Pd(II) species. Hence, the oxidative
incorporation of highly nucleophilic amines remains less
explored and hitherto challenging owing to the strong
coordination of the aliphatic amines and precious-metal
catalysts.10f,g Regarding the amido insertions for the con-
struction of β-enamine functions, Xie et al. disclosed a
Ce(OTf)3-catalyzed 1,3-dipolar cycloaddition/N2 extrusion
Received: November 20, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03846
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
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Letter
sequence of benzyl azides with chalcones.11 In addition, Kim
and coworkers reported an Ir(III)-catalyzed direct amidation
of C(sp2)−H bonds involving the carbonyl functionality as a
weakly coordinating directing group.12 The aryl C(sp2)−N
bond formation was found to be highly selective, such that
olefinic amidation was exclusive for the aliphatic and terminal
enone substrates. Therefore, the investigation of a novel system
for the selective amination of the alkenyl C(sp2)−H bonds,
utilizing more versatile amine sources that are accessible and
amount of DMSO to 5.0 equiv. An argon and carbon dioxide
atmosphere could be used for air-sensitive substrates, although
the enhancement was small in the case of 1a and 2a.19 When
other sulfur reagents such as Na2S·9H2O and K2S were applied
in the reaction, 23 and 62% yields of 3a could be achieved,
respectively.
Having these reaction conditions in hand, we then explored
the reaction scope with respect to various primary and
secondary amines, as depicted in Scheme 2. Benzylamines
environmentally benign, is of prodigious synthetic value.9a,c
−
̇
The S-centered, blue radical species S3 has recently
Scheme 2. Substrate Scope for the Reaction of (E)-1,3-
attracted significant interest in organic synthesis.13 Despite
remarkable advances in sulfur-mediated Willgerodt-type C−N
bond formation,14 direct incorporations of the trisulfur radical
g
Diphenylprop-2-en-1-one with Various Amines
into alkenyl double bonds are rare.15 Liu et al. developed a
−
̇
method using K2S/DMF as a S3 generator, which is trapped
by the α,β-unsaturated N-sulfonylimines to produce isothiazo-
les.15b Other groups have employed the K2S/DMSO system to
assemble thiophenes, in which DMSO acts as an oxidant for
the in situ formation of a conjugated system, which was further
15c,d
−
̇
attacked by the reactive radical S3 .
In the course of our
development of efficient strategies for building C−heteroatom
bonds, these results have inspired us to investigate the
possibility of the incorporation of sulfur into enone systems.
We started this research by investigating the β-amination of
(E)-1,3-diphenylprop-2-en-1-one 1a with benzylamine 2a and
elemental sulfur in DMSO at 80 °C (Table 1). To our delight,
a
Table 1. Screening of Reaction Conditions
b
entry
S source (mmol)
solvent
temp (°C) yield of 3a (%)
1
2
3
4
5
6
7
8
9
S8 (1.0)
S8 (1.0)
S8 (1.0)
DMSO
DMSO
DMSO
DMSO
DMSO
neat
rt
83
97
71
n.d.
98
6
88
93
n.d.
98
23
62
40
80
40
40
40
40
40
40
40
40
40
S8 (0.6)
S8 (0.6)
S8 (0.6)
S8 (0.6)
S8 (0.6)
S8 (0.6)
Na2S·9H2O (0.6)
K2S (0.6)
DMF
DMAc
CH3CN
DMSO
DMSO
DMSO
a
b
c
c
2 mmol scale. Under a CO2 atmosphere. NaOAc (2.0 equiv) was
10
11
12
d
c
added. (NH4)2CO3 (0.3 mmol), sulfur (0.6 mmol), DMSO (0.2
mL), under air, 60 °C, 12 h. K2CO3 (0.2 mmol) was added. 80 °C,
12 h. Reaction conditions: 1 (0.20 mmol), 2 (0.40 mmol), sulfur
e
f
c
g
a
Reaction conditions: 1a (0.20 mmol), 2a (0.40 mmol), solvent (0.2
mL), under air, 12 h. n.d. = not detected. Yields are GC yields using
diphenyl ether as the internal standard. DMSO (5.0 equiv) was used.
(0.60 mmol), DMSO (71 μL, 5.0 equiv), under air, 40 °C, 12 h.
b
c
bearing electron-donating groups were reactive toward the
transformation, providing enaminones 3b−e in excellent
yields. Halo- and sulfonyl-substituted benzylamines were also
compatible substrates and upon reactions with chalcone
produced enaminones 3h−k and 3n in 78−95% isolated
yields. Cyano and nitro functionalities remained intact during
the course of the reactions. Unfortunately, reactions of 1a with
benzylamine containing free −OH and −NH2 groups on the
phenyl ring resulted in complex mixtures, presumably due to
competitions between different nucleophilic sites. Additionally,
heterocyclic benzylamines and other 1° aliphatic amines were
well-tolerated, thereby generating the expected β-enaminones
with high efficiency (61−97% isolated yields). Noticeably, the
the enaminone product 3a was obtained in 71% yield, as
detected by GC-MS. Reaction conditions were then intensively
screened to selectively maximize the yield of 3a, with respect to
the amount of sulfur, the additive, the solvent, and the
temperature.16 Absolute selectivity and a 97% yield of 3a could
be achieved by conducting the reaction at 40 °C, whereas a
significant amount of annulation byproduct was observed at
elevated temperatures.17 Different amide-type solvents were
also compatible, which delivered the enaminone products
smoothly, and no traces of the coupling products were
detected when the reaction was carried out in CH3CN.13d,18
Furthermore, the reaction was achievable by reducing the
B
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Letter
synthetically useful and transition-metal-sensitive propargyl-
amine as well as glycine ester were also amenable to this
amination process. The N-unprotected β-enaminone 3q was
successfully prepared from the treatment of chalcone 1a at 60
°C with ammonia. In addition, the reaction conditions could
be altered to achieve the full conversion of the aromatic amine
2t, wherein the addition of K2CO3 (1.0 equiv) was found to be
efficient. It is noteworthy that all secondary enaminones
obtained were Z-selective. This was attributed to the strong
Scheme 4. Substrate Scope for the Reaction of Enones with
Ammonia
d
1
intramolecular hydrogen bonding, as evident from the H
NMR spectroscopy. Secondary amines also exerted high
reactivity, producing tertiary enaminones 3ae−ah in satisfac-
tory yields (77−84%).
The sterically hindered 2,2,6,6-tetramethylpiperidine (TMP)
did not favor the C(sp2)−H amination pathway. Instead it
induced the thienannulation of enone 1a to produce an
inseparable mixture of unsymmetrical (6a) and symmetrical
(6a′) thiophenes, as confirmed by the NMR and HR-MS
analyses. Accordingly, several enone substrates were examined
in reactions with TMP, as summarized in Scheme 3.20 Indeed,
reports on the formation of these thiophene derivatives are rare
in the literature.21
Scheme 3. Trisulfur-Radical-Anion-Triggered
a
Thienannulation of Enones
a
Reaction conditions: 1 (0.20 mmol), amine (0.40 mmol), sulfur
(0.60 mmol), DMSO (0.2 mL), under air, 12 h at 40 °C.
Interestingly, the reaction of chalcone 1a with hydroxyl-
amine produced 3,5-diphenylisoxazole 3ai′ in 82% yield. The
formation of 3ai′ certainly proceeded via a β-amination
followed by a 5-exo-trig cyclization. We note that isoxazole
3ai′ was usually prepared by the oxidation of the
corresponding isoxazoline or by transamination with a
preformed enaminone.8a,22 Likewise, pyrazole 3aj′ was
successfully formed upon reaction with hydrazine hydrate.
Nevertheless, pyrimidine 3ak′ or fused quinoline 3al′ was
generated in good yield from 1-acetylguanidine and 6-
aminouracil under slightly modified conditions.
Considering the importance of β-functionalized N-unsub-
stituted enaminones, the reactions of ammonia with enones
were next investigated (Scheme 4). After extensive screening,
we found that the use of sulfur (3.0 equiv) in DMSO and
(NH4)2CO3 (1.5 equiv) was effective for the direct aminative
C(sp2)−H functionalization. A variety of enones bearing
electron-donating, electron-withdrawing, and heteroaryl sub-
stituents delivered products (4a−ab) in reasonable yields (38−
97%). The reaction of (E)-2-methylchalcone resulted in a
complex mixture, whereas 2-benzoylbenzothiophene 4s′ was
unexpectedly derived from (E)-2-chlorochalcone.23 A cinna-
mate ester was also reactive, whereas attempts to functionalize
a
b
c
2-Chlorochalcone was used as the substrate. 60 °C, 6 h. 80 °C, 12
d
h. Reaction conditions: 1 (0.20 mmol), (NH4)2CO3 (0.30 mmol),
sulfur (0.60 mmol), DMSO (0.2 mL), under air, 12 h at 60 °C.
other olefins such as β-nitrostyrenes or styryl sulfones were
unsuccessful (results not shown). Specifically, substituted 2-
hydroxystyryl and 2-aminostyryl ketones could also be
smoothly transformed into the corresponding β-enaminones
(4ad−af) and flavones (4ad′−af′) in an approximately 2:1
ratio. This amination cascade was also amenable to longer
conjugated systems. By moderately increasing the reaction
temperature, the alkaloid piperine and cinnamylideneaceto-
phenone were efficiently converted to the targeted N,N′-
unprotected diamines 4ag and 4ah.
To better understand the reaction pathways, a series of
experiments were conducted to probe the elementary steps of
the amination process (Scheme 5). First, the presence of a
radical scavenger significantly influenced the transformation.
As a further support, a characteristic absorption peak of S3− at
̇
C
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gas-phase and solvation free-energy corrections at the M06-
2X/6-31+G* level of theory. In the Supporting Information,
results from another two DFT functionals, B3LYP and B3LYP
with Grimme’s empirical dispersion correction (B3LYP-
GD3),31 are discussed. On the basis of the calibration
calculations at the MP2/6-311++G** level of theory, we
conclude that the M06-2X functional is more accurate than the
other two functionals for the compounds considered in this
work.
Scheme 5. Mechanistic Studies
The overall reaction from 1a to 3q is exothermic with a free-
energy difference of −4.2 kcal/mol. The reaction mechanism is
illustrated in Scheme 5 and can be summarized as follows.
Initially, a trisulfur radical anion, which is generated from the
base-induced dissociation of elemental sulfur, rapidly attacks
the α- or β-position of the α,β-unsaturated carbonyl 1a and
forms a cyclic transition state TS-I. The reaction then proceeds
−
̇
downhill, dissociating to S2 and a thiirane intermediate 1a-S.
The thiirane ring undergoes nucleophilic attack by NH3 to
form an adduct D, which rearranges to form the second
transition state TS-II and finally dissociates to the product 3q.
Calculations also suggest a possible attack of NH3 on the α-
carbon of 1a-S, which forms a different isomeric adduct D′
(see the Supporting Information for details) with a slightly
higher energy. Nevertheless, both D and D′ go through the
transition state TS-II to reach the final product 3q. Elemental
sulfur or polysulfide anions could be regenerated by the
oxidative nature of DMSO.15c,d Whereas the elimination of
H2S from TS-II leads to the final product 3q, removing NH3
from TS-II goes back to 1a-S, as confirmed by the calculation.
In summary, we have developed a trisulfur radical-enabled
C(sp2)−H amination of enones with simple amines via a
radical sulfuration and sulfur extrusion cascade. Detailed
control experiments and DFT calculations probe the
installation of amine functionalities through the nucleophilic
ring-opening reaction of a thiirane intermediate. This protocol
provides simple access to β-enaminones under mild, oxidant-
and metal-free conditions.
550−700 nm was detected in the UV−visible spectrum of the
reaction mixture.24 These observations suggest that a radical
pathway is likely involved, which may be ascribed to the
13b,25
−
̇
formation of S3 .
Upon adding D2O to the identical
reaction system, the formation of β-deuterated chalcone 1a was
1
observed by GC-MS and H NMR analyses, possibly via a
consecutive H-abstraction/elimination process. From these, we
hypothesize that the amination reaction is triggered by a
radical sulfuration of enone at the α-position.26 In another
control experiment, the thiirane 1l-S was observed using GC-
MS by quenching the reaction of naphthyl chalcone 1l after 1
h, which gave almost full conversion to the enaminone product
4l upon further treatment with (NH4)2CO3.27 These results
support the notion that a mechanism involving a thiirane
intermediate is operative.
To further explore the reaction mechanisms for the overall
amination process, density functional theory (DFT) calcu-
lations were performed using the quantum chemistry program
packages Q-Chem 5.2 and Gaussian 16.28 The reaction
intermediates considered here include both local minima and
saddle points. Geometry optimizations in the gas phase were
carried out at the M06-2X/6-31+G* level of theory, employing
the M06-2X functional29 and the 6-31+G* basis set. Solvation
free energies were obtained using the polarizable continuum
model (PCM) with DMSO as the solvent. Geometry
optimizations were also performed within the PCM frame-
work, which yielded very similar structures to those obtained in
the gas phase for all of the model compounds. In addition,
second-order Møller−Plesset (MP2) perturbation theory30
was used to recalculate the single-point electronic energies for
the M06-2X/6-31+G* optimized structures using a larger basis
set 6-311++G**. The final free-energy values for all of the
model compounds thus use electronic energies obtained at the
MP2/6-311++G**//M06-2X/6-31+G* level of theory and
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03846.
Experimental procedures, mechanistic study, computa-
1
tional calculation details, characterization data, and H
NMR and 13C NMR spectra for all new products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Nam T. S. Phan − Faculty of Chemical Engineering, Ho Chi
Minh City University of Technology (HCMUT), Ho Chi
Minh City, Vietnam; Vietnam National University Ho Chi
Minh City, Ho Chi Minh City, Vietnam; orcid.org/0000-
0002-5928-7638; Email: ptsnam@hcmut.edu.vn
Haobin Wang − Department of Chemistry, University of
Colorado Denver, Denver, Colorado 80204, United States;
orcid.org/0000-0002-3532-7770; Email: haobin.wang@
ucdenver.edu
Authors
Khang X. Nguyen − Faculty of Chemical Engineering, Ho Chi
Minh City University of Technology (HCMUT), Ho Chi
Minh City, Vietnam; Vietnam National University Ho Chi
D
https://dx.doi.org/10.1021/acs.orglett.0c03846
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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Phuc H. Pham − Faculty of Chemical Engineering, Ho Chi
Minh City University of Technology (HCMUT), Ho Chi
Minh City, Vietnam; Vietnam National University Ho Chi
Minh City, Ho Chi Minh City, Vietnam; orcid.org/0000-
0002-7086-6948
Thao T. Nguyen − Faculty of Chemical Engineering, Ho Chi
Minh City University of Technology (HCMUT), Ho Chi
Minh City, Vietnam; Vietnam National University Ho Chi
Minh City, Ho Chi Minh City, Vietnam; Tra Vinh
University, Tra Vinh City, Tra Vinh Province, Vietnam;
orcid.org/0000-0003-4010-0375
Chou-Hsun Yang − Department of Chemistry, University of
Colorado Denver, Denver, Colorado 80204, United States;
orcid.org/0000-0002-8088-7072
Hoai T. B. Pham − Faculty of Chemical Engineering, Ho Chi
Minh City University of Technology (HCMUT), Ho Chi
Minh City, Vietnam; Vietnam National University Ho Chi
Minh City, Ho Chi Minh City, Vietnam; Department of
Chemistry, University of Colorado Denver, Denver, Colorado
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Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Vietnam National University Ho Chi Minh City
(VNUHCM) is acknowledged for financial support via project
no. NCM2019-20-01. H.W. acknowledges the support from
the National Science Foundation CHE-1954639. This work
used the Extreme Science and Engineering Discovery Environ-
ment (XSEDE), which is supported by National Science
Foundation grant number ACI-1548562. This work was
funded by the Vingroup Joint Stock Company and supported
by the Domestic Master/Ph.D. Scholarship Programme of the
Vingroup Innovation Foundation (VINIF), Vingroup Big Data
Institute (VINBIGDATA) (for K.X.N.).
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E
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Organic Letters
pubs.acs.org/OrgLett
Letter
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