Catalytic Enantioselective Access to Dihydroquinoxalinones via Formal α-Halo Acyl Halide Synthon in One Pot

Article abstract of DOI:10.1002/anie.202110173

An enantioselective one-pot catalytic strategy to dihydroquinoxalinones, featuring novel 1-phenylsulfonyl-1-cyano enantioenriched epoxides as masked α-halo acyl halide synthons, followed by a domino ring-opening cyclization (DROC), is documented. A popula

Full text of DOI:10.1002/anie.202110173

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Angewandte
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Accepted Article
Title: Catalytic Enantioselective Access to Dihydroquinoxalinones via
Formal α-Halo Acyl Halide Synthon in One-Pot
Authors: Volpe Chiara, Sara Meninno, Carlo Crescenzi, Michele
Mancinelli, Andrea Mazzanti, and Alessandra Lattanzi
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10.1002/anie.202110173
Angewandte Chemie International Edition
RESEARCH ARTICLE
Catalytic Enantioselective Access to Dihydroquinoxalinones via
Formal -Halo Acyl Halide Synthon in One-Pot
Chiara Volpe,[a],+ Sara Meninno,[a],+ Carlo Crescenzi,[b] Michele Mancinelli,[c] Andrea Mazzanti,[c] and
Alessandra Lattanzi*[a]
Dedicated to Prof. K. Barry Sharpless on the occasion of his 80th birthday
[a]
C. Volpe, Dr. S. Meninno, Prof. Dr. A. Lattanzi
Dipartimento di Chimica e Biologia “A. Zambelli”
Università di Salerno
Via Giovanni Paolo II 132 - 84084, Fisciano, Italy
E-mail: lattanzi@unisa.it
[b]
[c]
Prof. Dr. C. Crescenzi,
Dipartimento di Farmacia
Università di Salerno
Via Giovanni Paolo II 132 - 84084, Fisciano, Italy
Dr. M. Mancinelli, Prof. Dr. A. Mazzanti
Dipartimento di Chimica Industriale
Università di Bologna
Viale Risorgimento 4 - 40136, Bologna, Italy
[+] These authors contributed equally
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: A first enantioselective one-pot catalytic strategy to
dihydroquinoxalinones, featuring novel 1-phenylsulfonyl-1-cyano
enantioenriched epoxides as masked -halo acyl halide synthon,
and drug discovery, thus resulting particularly appealing from an
industrial perspective.[4]
Chiral dihydroquinoxalinones are recognized as privileged
pharmacophores of broad interest in medicinal chemistry, found
in a variety of bioactive compounds and pharmaceuticals[5]
displaying anti-HIV,[6] antineoplastic,[7] anti-inflammatory[8]
activities, fungicidal properties[9] and used in the control of
cardiovascular disease.[10] Moreover, they can serve as
precursors of enantioenriched tetrahydroquinoxalines, which are
another class of heterocycles endowed with several biological
activities.[11] Expectedly, significant efforts have been devoted to
preparing optically active dihydroquinoxalinones, through the
development of stepwise metal-catalysed and organocatalysed
strategies. The most representative and distinct approaches can
be grouped in chiral pool or auxiliary based methods (Scheme
1a,b) and catalytic enantioselective processes (Scheme 1c,d).
The first ones were based on natural -amino acids as reagents
used in Cu(I)-catalysed coupling with ortho-nitro, or ortho-amino
aryl halides followed by reduction and cyclization (Scheme
1a).[12] (S)-Mandelate -bromoesters were also found to be
followed by
a
domino ring-opening cyclization (DROC), is
documented. A popular quinine-derived urea served as the catalyst
in two, out of the three steps performed in the same solvent, using
commercially available aldehydes, (phenylsulfonyl)acetonitrile, cumyl
hydroperoxide and 1,2-phenylendiamines. Medicinally relevant 3-
aryl/alkyl substituted heterocycles are isolated in generally good to
high overall yield and high enantioselectivity (up to 99% ee). A rare
example of excellent reusability at higher scale of an organocatalyst,
subjected to oxidative conditions, is demonstrated. Mechanistically,
labile -ketosulfone has been detected as the intermediate involved
in the DROC process. Theoretical calculations, on the key
epoxidation step, rationalize the observed stereocontrol, highlighting
the important role played by the sulfone group.
Introduction
competent substrates for
a dynamic kinetic resolution in
Nowadays the development of one-pot routes to heterocyclic
compounds represents a recurrent and convenient strategy, in
line with the principles of green chemistry and the economies of
organic synthesis.[1] Optically active N-heterocycles are of
particular interest, achieving around 60% of FDA approved
drugs, with a relevant portion occupied by simple six-membered
rings and their fused analogues.[2] In the last decades, the one-
pot organocatalytic approach proved to be an excellent and
increasingly applied tool to efficiently prepare important drugs
and natural products under mild conditions at reduced costs,
time and environmental impact.[3] The remarkable examples
reported by the groups of Hayashi,[4a] Zhu,[4b] Aggarwal,[4c]
Paião,[4d] Zhang,[4e] Masson,[4f] Dixon[4g] showed additional key-
features of this tool, in securing wide molecular diversity and
rapid access to libraries of compounds necessary for bioassay
nucleophilic substitution with 1,2-phenylendiamines, followed by
cyclization (Scheme 1b).[13] Both approaches, although based on
cheap chiral sources, somewhat suffered of substrate-
dependent applicability or partial racemization.[14] More recently,
Ir- and Pd-catalysed hydrogenation of quinoxalinones enabled to
achieve consistently high level of asymmetric induction (Scheme
1c,i).[15] The process was also successfully expanded, employing
chiral phosphoric acids/Hantzsch ester systems (Scheme
1c,ii).[16] Leckta and coworkers developed
a
Cinchona
alkaloids/Lewis acid promoted hetero- Diels-Alder reaction of
ketene enolates and ortho-benzoquinone diimides to construct
the heterocycles in excellent enantioselectivity (Scheme 1d).[17]
Epoxides are undoubtedly recognized as highly versatile
intermediates in organic synthesis[18] and those bearing two
identical electron-withdrawing groups with good leaving abilities
1
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10.1002/anie.202110173
Angewandte Chemie International Edition
RESEARCH ARTICLE
(EWG = Cl, CN, SO2R,) positioned at the same carbon atom,
behave as masked -halo acyl halide synthons.[19]
unprecedented. This choice has been guided by the following
considerations: i) the suitability of the Knoevenagel reaction to
access (E)-configured 1-phenylsulfonyl-1-cyano alkenes from
aldehydes under mild reaction conditions,[23] ii) the known strong
hydrogen-bonding acceptor nature of the sulfone group,[24] likely
useful to act as chemical handle for the stereocontrol in the
nucleophilic epoxidation. Herein, we illustrate the results of this
study
to
straightforwardly
access
optically
active
dihydroquinoxalinones, exploiting a readily available quinine-
derived urea as reusable catalyst, commercial aldehydes,
(phenylsulfonyl)acetonitrile, cumyl hydroperoxide (CHP) and 1,2-
phenylendiamines. The DFT study confirmed the crucial role
played by the sulfone group in directing the stereoselectivity of
the epoxidation step.
Results and Discussion
We commenced our study on the enantioselective epoxidation of
model alkene 1a, employing tert-butyl hydroperoxide (TBHP) as
the oxidant and readily available amine-derived thioureas, ureas
and squaramide in toluene at room temperature (Table 1).
Table 1. Optimization of the asymmetric epoxidation reaction on alkene 1a.[a]
cat.
(10 mol%)
O
O
O
O
O
S
S
Ph
Ph
+ TBHP
Ph
1a
Ph
toluene
CN
CN
2a
O
O
S
X
S
Ar
Ar
N
Ar
N
NH
HN
N
N
HN
HN
H
NHAr
N
H
H
N
N
N
N
N
A
OMe
MeO
R
eQDT
eQNT, X = S
eQNS
eQNU, X = O
Ar = 3,5-(CF3)2C6H3
Yield[%][b](Time/h)
62 (4)
Scheme 1. Comparison of the state-of-the-art and this work.
Entry
1
cat.
T(°C)
25
ee[%][c]
41
A
This reactivity has been exploited to obtain racemic -
substituted carboxylic acid derivatives from different epoxide
sources. Corey pioneered an interesting asymmetric variant,
involving ring-opening of highly reactive gem-dichloro epoxides,
in situ generated from chiral non racemic trichloromethyl
carbinols as the starting reagent (Scheme 1e).[20] Despite the
undisputed value of the methodologies illustrated in Scheme 1,
multi-step preparation of reagents and heterocyclic precursors
somewhat limited the practicality and pot-economy of the
2
eQNT
eQDT
eQNS
eQNU
eQNU
eQNU
eQNU
eQNU
eQNU
eQNT
eQNU
25
75 (19)
-74
38
3
25
49 (19)
4
25
95 (7)
-64
-70
-86
-91
-93
-92
-92
-91
-89
5
25
90 (3)
6[d]
25
90 (1)
7[d,e]
8[d,e]
9[d,f]
10[d,g]
11[d,g]
12[d,h]
25
95 (4)
catalytic variants. Therefore,
a
one-pot process to
-20
-30
-20
-20
-20
94 (14)
dihydroquinoxalinones, starting from commercially available
compounds and a reusable catalyst, would significantly fill a gap
in addressing these issues. Building on our research interest in
the development of stereocontrolled one-pot methodologies to
prepare heterocyclic compounds,[21] we envisaged the possibility
of setting up a new streamlined catalytic asymmetric strategy
based on Knoevenagel reaction/asymmetric epoxidation/domino
ring-opening cyclization (DROC), trusting in the ability of a chiral
non racemic bifunctional organocatalyst to promote the first two
91 (15)
90 (14)
87 (14)
78 (40)
[a] 1a (0.10 mmol), TBHP (0.12 mmol), catalyst (0.010 mmol) in anhydrous
toluene (0.5 mL). [b] Yields are of isolated product, dr > 95:5. [c] HPLC
analysis on a chiral stationary phase. [d] CHP used as oxidant. [e] Performed
at C = 0.02 M [1a]. [f] Performed at C = 0.05 M [1a]. [g] Performed at C = 0.05
M [1a] with 5 mol% of catalyst. [h] Performed at C = 0.05 M [1a] with 2 mol%
of catalyst.
steps in
a
stereoselective manner (Scheme 1f). 1-
Phenylsulfonyl-1-cyano epoxides were targeted as new potential
masked -halo acyl halide synthons,[22] although either the
epoxidation of 1-phenylsulfonyl-1-cyano alkenes and the
When using 10 mol% of thiourea amine A, we were pleased to
isolate trans-epoxide 2a in 62% yield, with complete
reactivity
of
1-phenylsulfonyl-1-cyano
epoxides
were
2
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10.1002/anie.202110173
Angewandte Chemie International Edition
RESEARCH ARTICLE
diastereoselectivity and 41% ee (entry 1). Interestingly, epi-
quinine derived thiourea (eQNT) provided the epoxide with 74%
ee (entry 2). However, epi-quinidine derived thiourea (eQDT)
proved to be less effective, affording the opposite enantiomer of
2a with 38% ee (entry 3). epi-Quinine derived squaramide
(eQNS) and urea (eQNU) performed more actively, furnishing
the epoxide, after short reaction times, in high yields, with 64%
ee and 70% ee, respectively (entries 4 and 5). eQNU was then
chosen as the catalyst for further optimization in toluene as the
solvent (see Table S1), using CHP as the oxidant. We were
delighted to observe a rapid formation of the epoxide, isolated in
90% yield and 86% ee (entry 6). Dilution of the reaction mixture
was beneficial, leading to the product in 95% yield and 91% ee
(entry 7), with further improvement to 93% ee, observed when
working at -20°C (entry 8). However, no additional enhancement
was detected operating at -30°C (entry 9). The epoxidations
performed at lower catalyst loadings (down to 2 mol%),
proceeded slowly, but with a slightly decreased level of
enantioselectivity, (entries 10 and 12). We proved that, under
the same conditions, eQNU was the catalyst of choice with
respect to eQNT (entries 10 and 11). At this point, sequential
Knoevenagel reaction/epoxidation was performed using eQNU
at 10 mol% under the most effective conditions achieved in
Table 1 for the epoxidation (entry 8), using benzaldehyde and
(phenylsulfonyl)acetonitrile (Scheme 2). To our delight, eQNU
efficiently catalyzed the Knoevenagel reaction in reasonable
time and trans-epoxide 2a was recovered in 85% isolated yield
and 92% ee. The one-pot process performed at 3 or 5 mol%
catalyst loadings, in the presence of molecular sieves to foster
the Knoevenagel step either at 30°C or 50°C, proceeded in a
less effective manner.
S3 and Figure S1). -Ketosulfones have been previously
reported to be labile intermediates, prone to react with
nucleophiles.[25] Results reported in Table 1 and Scheme 2
favorably suggested the viability of a sequential one-pot process,
starting
from
commercially
available
aldehydes,
(phenylsulfonyl)acetonitrile, CHP and ortho-phenylendiamines,
to be conveniently conducted in toluene as the sole solvent.
With the optimized conditions in hand, the scope and
limitations of the one-pot approach was firstly studied using
ortho-phenylendiamine (Table 2). Model dihydroquinoxalinone
(R)-3a was isolated in 76% and 89% ee, proving that clean and
high conversions occurred in all steps, with enantioselectivity
essentially maintained, as expected for a SN2 ring-opening
reaction. Aromatic aldehydes, bearing electron-donating or
electron-withdrawing substituents at different positions (para,
meta and ortho), were well tolerated, including sterically
encumbered 1-naphthyl unit, leading to the heterocycles (3b-k)
in high to excellent overall yields (61-81%). High
enantioselectivity was observed (86-96% ee), with the exception
of the ortho-substituted compounds 3g and 3k, isolated
respectively with 62% and 65% ee, likely ascribed to steric
hindrance. To introduce an alkenyl group at the chiral center of
the heterocycle, (E)-cinnamaldehyde was checked as the
starting reagent under usual conditions. Although the alkene
was formed, this challenging substrate proved to be inert under
the epoxidation conditions, even after prolonged reaction time.
The absolute configuration of the stereocenter for compounds 3
was assigned as (R) upon comparison with optical rotations
reported in the literature for known products 3a, 3b,d, 3r,s and
the configuration of the other heterocycles was assigned in
analogy.
Key to the success of the one-pot sequence from aldehydes
to dihydroquinoxalinones, was to attest the feasibility of the
DROC process. Accordingly, the investigation was carried on
racemic 2a using ortho-phenylendiamine and triethyl amine as
acid scavenger in toluene at room temperature (Scheme 2).
Then,
commercially
available
substituted
ortho-
phenylendiamines[26] were coupled with either mono-, di-
substituted, 2-naphthyl and heteroaromatic aldehydes providing
diversely substituted dihydroquinoxalinones (3l-s) with high
yields (60-77%) and high to excellent enantioselectivity (85-99%
ee). The feasibility of DROC process with more sterically
hindered N-methyl ortho-phenylendiamine was next examined,
with a view to directly install typical N-methyl substitution found
in some pharmaceutically active derivatives, thus avoiding a
following sensitive N-alkylation step.[27] Gratifyingly, the
corresponding N-methyl derived dihydroquinoxalinones 3t and
3u were isolated in 68%, 77% yield and with 88% ee, 89% ee,
respectively. When the one-pot process was carried out from the
corresponding alkenes, heterocycles 3t and 3u were isolated
with 92% ee and 96% ee, showing that a slight erosion of the
enantioselectivity occurred when starting from aldehydes.
Preliminary investigations were then carried out using ortho-
amino phenol and ortho-amino thiophenol with benzaldehyde as
the reagent. Pleasingly, dihydrobenzoxazinone (R)-3v was
obtained in 60% overall yield and 89% ee.[15c,16b] Even more
relevant, challenging dihydrobenzothiazinone 3w was selectively
recovered in 70% yield, although with 58% ee. However,
racemization was successfully suppressed by using sterically
demanding Hünig’s base in the DROC step (see Table S2). The
enantioselectivity increased to 90% ee, which represents the
highest value reached so far for compound 3w.[13a] Hence, the
mild and tunable reaction conditions employed in the one-pot
protocol, appear to be of wider applicability to access different
families of related enantioenriched heterocycles.
Scheme 2. a) One-pot Knoevenagel/asymmetric epoxidation catalysed by
eQNU. b) DROC of racemic epoxide.
We were delighted to observe a clean conversion to the
expected dihydroquinoxalinone 3a, which was isolated in 94%
1
yield. Reaction progress profile monitored by H-NMR analysis
showed the exclusive presence of compound 3a, supporting fast
ring-opening of the epoxide and intramolecular capture of an
elusive acyl intermediate. Nevertheless, we were able to identify
the involvement of -ketosulfone B species by high resolution
mass spectrometry analysis of the reaction mixture (see Table
3
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RESEARCH ARTICLE
Consequently, the viability of a catalytic one-pot asymmetric
synthesis of 3-alkyl substituted dihydroquinoxalinones was
Table 2. Scope of the enantioselective one-pot catalytic synthesis of
dihydroquinoxalinones[a-d]
investigated starting from alkenes
1 and different ortho-
phenylendiamines (Scheme 3a). This strategy proved to be
versatile, since it could be extended to prepare linear, sterically
encumbered alkyl and cycloalkyl substituted heterocycles 3x-ab
in good to high yields (50-85%) and high enantioselectivity (87-
93% ee).[28] Alkyl moieties, bearing carbon-carbon double and
triple bonds were also installed, offering opportunities for hitherto
unachievable post-functionalizations onto the alkyl chain of
compounds 3. In both examples, the heterocycles 3ac-3ad were
isolated in good yields (50-63%) and excellent enantiocontrol
(93-96% ee).
H
N
H
N
H
N
O
O
O
N
H
N
H
Ph
N
H
t1,t2,t3 = 10 h, 14 h, 6.5 h
3a 76%, 89% ee
t1,t2,t3 = 24 h, 18 h, 18 h
3b 81%, 91% ee
t1,t2,t3 = 26 h, 24 h, 13 h
3c 72%, 91% ee
H
H
H
N
O
N
O
N
O
N
H
N
H
N
H
Cl
F
Br
t1,t2,t3 = 11 h, 13 h, 8.5 h t1,t2,t3 = 11 h, 12 h, 10 h
t1,t2,t3 = 9 h, 12 h, 6.5 h
3d 79%, 90% ee
3e 76%, 96% ee
3f 65%, 91% ee
H
H
H
N
O
N
O
N
O
F
OCH3
N
H
N
H
N
H
SCF3
t1,t2,t3 = 11 h, 13 h, 9 h
3g 65%, 65% ee
t1,t2,t3 = 16 h, 26 h, 12 h
3h 74%, 88% ee
t1,t2,t3 = 16 h, 11 h, 13 h
3i 61%, 86% ee
H
H
H
N
O
N
O
N
O
Br
N
H
N
H
N
H
CN
t1,t2,t3 = 16 h, 144 h, 23 h
3k 75%, 62% ee
t1,t2,t3 = 10 h, 14 h, 8 h
3j 72%, 96% ee
t1,t2,t3 = 11 h, 14 h, 6.5 h
3l 70%, 99% ee
H
H
H
N
O
N
O
N
O
CF3
Cl
Cl
N
H
N
H
N
H
N
t1,t2,t3 = 15 h, 11 h, 6.5 h
3m 64%, 98% ee
CF3
t1,t2,t3 = 14 h, 48 h, 5 h
3o 72%, 86% ee
t1,t2,t3 = 16 h, 11 h, 6.5 h
3n 65%, 92% ee
H
Scheme 3. One-pot asymmetric sequence to 3-alkyl substituted
dihydroquinoxalinones from a) aliphatic alkenes and from b) aldehyde and
(phenylsulfonyl)acetonitrile.
H
N
O
H
Cl
Cl
N
O
Cl
Cl
N
O
Br
N
H
N
H
N
H
X
t1,t2,t3 = 10 h, 13 h, 10 h
t1,t2,t3 = 11 h, 14 h, 9.5 h
3p 74%, 95% ee
t1,t2,t3 = 26 h, 24 h, 12 h
3q 77%, 85% ee
3r 62%, 92% ee, X = CN
t1,t2,t3 = 10 h, 14 h, 8.5 h
3s 60%, 91% ee, X = Cl
Finally, the one-pot process was attempted under working
conditions, starting directly from cyclohexanecarboxaldehyde
and (phenylsulfonyl)acetonitrile (Scheme 3b). Predictably, they
sluggishly reacted in the Knoevenagel step, observing a low
conversion to the alkene. Compound 3ab was isolated in 20%
overall yield, although the enantioselectivity was maintained,
showing that the organocatalyst was able to work effectively
under more complex reaction conditions.
To demonstrate the practicality and scalability of this process
as well as the recyclability of eQNU, the synthesis of compound
3l was performed at 1 mmol scale of 3-bromobenzaldehyde and
(phenylsulfonyl)acetonitrile for different runs (Scheme 4a). To
our delight, heterocycle 3l was always isolated in high yields and
99% ee, highlighting complete recovering of eQNU after
[a] i) Knoevenagel step: (phenylsulfonyl)acetonitrile (0.12 mmol), aldehyde
(0.12 mmol), eQNU (0.012 mmol) in anhydrous toluene (0.4 mL). ii)
Epoxidation step: the reaction mixture is diluted with toluene (5.6 mL) placed
at –20 °C and CHP (1.1 equiv., 0.132 mmol) added. DROC step: iii) o-
phenylendiamines or o-amino(thio)phenol (0.132 mmol) and Et3N (0.24 mmol)
added at 20°C. [b] Yields are of isolated product. [c] HPLC analysis on a chiral
stationary phase. [d] Diisopropylethyl amine was used in the DROC.
chromatography and
a
remarkable robustness of this
organocatalyst toward repetitive oxidative conditions up to four
runs. It is interesting to note that eQNU and similar Cinchona
alkaloids derived organocatalysts have been recently classified
according to their E-factor amongst the greenest
organocatalysts to prepare.[29]
Despite the importance of chiral non racemic
tetrahydroquinoxalines as bioactive compounds,[11] to the best of
our knowledge, their synthesis via reduction of enantioenriched
Direct synthesis of compounds 3 from aliphatic aldehydes is
hampered by the occurrence of competitive self-
condensation/oligomerization pathways in the Knoevenagel
reaction.[23]
4
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10.1002/anie.202110173
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RESEARCH ARTICLE
3-aryl substituted dihydroquinoxalinones has not been reported.
Indeed, the most recurrent approach involves metal-catalyzed
enantioselective hydrogenation or transfer hydrogenation of
quinoxalines.[16a,30]
for the addition to both faces of the -carbon, with activation
energies of 8.4 kcal/mol (TS-Si) and 9.3 kcal/mol (TS-Re, see
Figure S3). In both cases, the TS involves the weakening of the
O-H bond by the lone pair on nitrogen, and the simultaneous
formation of the C-O bond. After the formation of the C-O bond,
two intermediates (II-Si and II-Re) were reached by shift of the
hydrogen onto the quinuclidinic nitrogen (see Figure S4). Now
the reaction can fork towards different directions: i) ring closure
by intramolecular SN2 reaction straightforwardly yields the (S,S)
and (R,R) epoxides by release of tert-butanol as the leaving
group; ii) rotation around the C-C bond yields two additional
intermediates (II-S’ and II-R’) with the cyano and the phenyl
groups at opposite side of the original C-C double bond. The
subsequent ring closure step eventually leads to the (S,R) and
(R,S) stereoisomers.
The two TS geometries for ring closure to (S,S) and (R,R)
epoxides from II-Si and II-Re were built considering the
assistance of the acidic NH+ site in the protonation of the tert-
butoxide to tert-butanol leaving group. Full optimization and
subsequent frequency analysis yielded the TS-SS and TS-RR
geometries (Figure S5). The TS geometry involves the
simultaneous weakening of the O-O bond, forging of the epoxide
and release of proton from NH+ to tert-butoxide. The C-C-O
bond angles in the TSs are 86° for TS-SS and 81° for TS-RR,
with the O-O distances being very similar (1.92 and 1.97 Å,
respectively). In the TS-SS geometry, a change in the hydrogen
bonding network is required to allow a better geometry for the
ring closure. The two hydrogens of the urea are indeed
hydrogen bonded with the same oxygen of the sulfone moiety
(2.04 and 2.20 Å). Nevertheless, TS-SS (G≠ = 13.9 kcal/mol) is
lower in energy with respect to TS-RR (G≠ = 15.2 kcal/mol).
These energy values suggest that ring closure is the rate-
determining step and the observed enantioselectivity is well
reproduced by calculations (G≠ = 1.3 kcal/mol corresponds to
80% ee vs the experimentally observed 70% ee at 25°C).
To reach a suitable ring closure geometry for the formation
of the R*,S* diastereoisomers, a 180° rotation around the C-C
bond is required, before the intramolecular SN2 reaction occurs.
A stepwise mechanism, involving decomplexation followed by
rotation within the free anion and subsequent complexation
seemed to be unlikely, being toluene the solvent. Two rough TS
geometries for C-C bond rotation were found, using a relaxed
scan of the torsion angle, followed by full optimization (Figure
S6). In TS-Rrot the torsion angle O-C-C-CN is ≈165° and the
activation energy is slightly above TS-RR (15.6 kcal/mol). The
same situation happens on the other direction (TS-Srot = 15.7
kcal/mol). Once II-S’ and II-R’ are formed (Figure S7), the ring
closure TSs across TS-SR and TS-RS leads to the (S,R) and
(R,S) stereoisomers (see Figure S8). Both were found to be
higher in energy with respect to the main pathway within each
branch of the reaction. These findings agree with the observed
formation of trans-epoxide 2a (3D structures of the four
stereoisomers of 2a, complexed with the catalyst, are reported in
Figure S9). Within the branches towards R*,S* stereoisomers,
the transition state energies for the C-C bond rotation and for
the two ring closures are very similar. It is thus difficult to predict
which is the rate-determining transition state for the formation of
the (R*,S*) diastereoisomer.
Scheme 4. a) 1 mmol scale-up one-pot synthesis of dihydroquinoxalinone 3l
with recyclability of eQNU. b) Reduction of compounds
3
to
tetrahydroquinoxalines.
To perform the reduction, enantioenriched NH-free and N-
Me substituted compounds 3a, 3b and 3t, were treated with
BH3-THF complex in THF under reflux (Scheme 4b).[17b] This
reductive procedure proved to be synthetically useful, delivering
the corresponding tetrahydroquinoxalines 4 in good yields and
ee values practically maintained.
To shed light on the experimental stereocontrol achieved in
the epoxidation step, a theoretical study was performed by DFT
calculations, using 2a as model compound. To reduce the
conformational space, CHP was replaced by TBHP and the vinyl
group of eQNU was omitted. Optimization of the ground states
(GS) and transition states (TS) geometries was obtained at the
B3LYP-GD3(BJ)/6-311+g(2d,p)//B3LYP/6-31G(d) level of theory,
including toluene with the IEF-PCM solvent approach[31] (see the
Supporting Information for further details). The nucleophilic
epoxidation pathway was modelled considering three steps: i)
formation of the electrophilic complex from eQNU and alkene, ii)
oxa-Michael addition of the alkyl hydroperoxide to yield the
peroxyenolate complexed with protonated catalyst; iii) ring
closure by intramolecular SN2 reaction with release of tert-
butanol (see Figure 1 for the whole catalytic cycle).
Being toluene the reaction solvent, the formation of the
reactive complex between catalyst and the alkene should be
driven mainly by hydrogen bonding between the urea group with
the sulfone moiety,[24] leaving the quinuclidinic basic nitrogen
free to assist the addition of TBHP within the subsequent
reaction step. GS geometries of the complex were built following
this bias and by orienting the complexed alkene in such a way to
expose the two enantiotopic faces of the -carbon (see Figure
S2) to the nucleophilic attack. A conformational analysis was
performed to search for the best catalyst geometry, being the
lowest energy conformation found in agreement with a similar
case.[32] The addition of TBHP to the -carbon was modelled
assuming assistance of the quinuclidinic lone pair nitrogen to
boost TBHP nucleophilicity.[33] Two geometries were optimized
5
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10.1002/anie.202110173
Angewandte Chemie International Edition
RESEARCH ARTICLE
Figure 1. Full reaction pathway for the asymmetric epoxidation of alkene 1a to epoxide 2a with TBHP. Free energies are relative to reagents, in kcal/mol at IEF-
PCM B3LYP-GD3(BJ)/6-311+G(2d,p)//B3LYP/6-31G(d) level of theory. Structures in blue boxes are the two TSs for the formation of the S,S stereoisomer.
for international attraction and mobility call for researchers
funded by PON RI 2014-2020. A.M. and M.M. thank the
University of Bologna (RFO funds 2020).
In conclusion, we developed a first catalytic and scalable
Conclusion
single-pot process to efficiently prepare dihydroquinoxalinones
in enantioselective and practical manner, capitalizing on optically
active 1-phenylsulfonyl-1-cyano epoxides, as novel masked -
Conflict of Interest
halo acyl halide synthons. This attractive protocol is further
simplified by using toluene as the sole reaction solvent,
commercial reagents and completely recyclable and readily
available organocatalyst. The approach demonstrated to be
versatile, giving facile access to differently aryl/alkyl 3-
substituted dihydroquinoxalinones in high enantioselectivity and
the potential to access other important related heterocycles has
been assessed. Computational investigation suggests that the
enantioselectivity is driven by a network of hydrogen bonding
between the urea and the sulfone moieties, with the key
involvement of the basic tertiary nitrogen to activate the oxidant
and to assist ring closure by protonation of the leaving group.
The ring closure step of the catalytic oxidative cycle, has been
found to be rate-determining. We believe this strategy will open
up opportunities for convenient one-pot asymmetric syntheses of
other biologically active heterocycles and carboxylic acid
derivatives. Current investigations along this line are ongoing
and the results will be reported in due course.
The authors declare no conflict of interest.
Keywords: asymmetric catalysis
•
one-pot reaction
•
epoxidation • domino ring-opening cyclization • heterocycles
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10.1002/anie.202110173
Angewandte Chemie International Edition
RESEARCH ARTICLE
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7
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10.1002/anie.202110173
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
One-pot catalytic and scalable Knoevenagel/asymmetric epoxidation/DROC strategy, to medicinally significant dihydroquinoxalinones,
featuring 1-phenylsulfonyl-1-cyano epoxides as new masked -halo acyl halide synthons, is reported. Two, out of the three steps, are
catalysed by highly robust, recyclable and easily available quinine-derived urea. This practical approach paves the way for useful
asymmetric syntheses of other carboxylic acid derivatives.
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