Bifunctional Borane Catalysis of a Hydride Transfer/Enantioselective [2+2] Cycloaddition Cascade

Article abstract of DOI:10.1002/anie.202106168

Herein, we present a mild and efficient method for synthesizing enantioenriched tetrahydroquinoline-fused cyclobutenes through a cascade reaction between 1,2-dihydroquinolines and alkynones with catalysis by chiral spiro-bicyclic bisboranes. The bisborane

Full text of DOI:10.1002/anie.202106168

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Title: Bifunctional Borane Catalysis of a Hydride Transfer/
Enantioselective [2+2] Cycloaddition Cascade
Authors: Ming Zhang and Xiao-Chen Wang
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10.1002/anie.202106168
Angewandte Chemie International Edition
RESEARCH ARTICLE
Bifunctional Borane Catalysis of a Hydride
Transfer/Enantioselective [2+2] Cycloaddition Cascade
Ming Zhang, and Xiao-Chen Wang*
[*]
M. Zhang, Prof. Dr. X.-C. Wang
State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University
94 Weijin Road, Tianjin 300071 (China)
E-mail: xcwang@nankai.edu.cn
Homepage: http://www.wangnankai.com/
Supporting information for this article is given via a link at the end of the document.
Abstract: Herein, we present a mild and efficient method for
occurred via a cascade process promoted by a bifunctional
pentafluorophenyl-substituted chiral borane, which first
facilitated conversion of the 1,2-dihydroquinoline to a 1,4-
dihydroquinoline via a hydride transfer and then activated the
alkynone via monodentate coordination for enantioselective
[2+2] cycloaddition with the 1,4-dihydroquinoline. These are the
first examples of Lewis acid catalyzed enantioselective [2+2]
cycloaddition reactions between electron-rich enamine
intermediates and electron-deficient alkynes. Moreover, this is
also a rare report of a chiral borane Lewis acid acting both as a
conventional Lewis acid (to activate a carbonyl) and as an
unconventional Lewis acid (to catalyze hydride transfer) in a
single reaction.
synthesizing
enantioenriched
tetrahydroquinoline-fused
cyclobutenes through
a
cascade reaction between 1,2-
dihydroquinolines and alkynones with catalysis by chiral spiro-
bicyclic bisboranes. The bisboranes served two functions: first they
catalyzed a hydride transfer to convert the 1,2-dihydroquinoline
substrate to a 1,4-dihydroquinoline, and then they activated the
alkynone substrate for an enantioselective [2+2] cycloaddition
reaction with the 1,4-dihydroquinoline generated in situ.
Introduction
Chiral cyclobutene skeletons are prevalent in natural
products and drugs.[1] The catalytic enantioselective [2+2]
cycloaddition reaction between an alkyne and an alkene is one
of the most direct and atom-economical methods for
synthesizing enantioenriched cyclobutenes. Transition metals
such as Ru, Rh, Ir, and Ni are known to promote these reactions
via a sequential process involving alkene/alkyne oxidative
coupling and reductive elimination, but enantioselective
examples have been confined to highly reactive strained olefins,
such as norbornene, norbornadiene, and aza- or oxa-bridged
cyclic olefins (Scheme 1A).[2] There have also been sporadic
reports of alternative mechanisms for transition-metal-catalyzed
enantioselective cyclobutene formation, including the palladium-
catalyzed Heck reaction[3] and nucleophilic addition of alkenes to
gold-activated alkynes.[4] In addition, photocatalytic [2+2]
cycloaddition is feasible,[5] but enantiocontrol is challenging.
In contrast, Lewis acid catalyzed [2+2] cycloadditions
between alkynes and alkenes show promise for the generation
of cylcobutenes.[6] However, there have been only a few reports
of enantioselective reactions, most of which have involved
substrates capable of bidentate coordination to the Lewis acid[7]
(Scheme 1B). Such coordination facilitates substrate activation
and decreases the conformational flexibility of the substrate, an
effect that is essential for diastereo- and enantioselectivity. So
far, there has been only one report of highly enantioselective
cycloaddition reactions involving monodentate substrates: Feng,
Liu, and co-workers carried out enantioselective [2+2]
cycloaddition reactions of alkynones with cyclic silyl enol ethers
with catalysis by a N,N'-dioxide-zinc(II) complex.[8]
Scheme 1. Enantioselective synthesis of cyclobutenes via
[2+2] cycloaddition reactions
We chose pentafluorophenyl-substituted boranes because
they have many unique and interesting activities attributable to
their strong Lewis acidity and sterically hindered boron center.[10]
For example, B(C6F5)3 can mediate hydride abstraction from the
α carbon of an amine to generate an iminium ion and a
borohydride.[11] Recently, this activity has become a flourishing
platform for the development of catalytic organic reactions,
including transfer hydrogenations,[12] dehydrogenations,[13]
Because of our ongoing interest in catalysis using Lewis
acidic boranes,[9] we reasoned that chiral borane catalysts might
promote enantioselective [2+2] cycloaddition reactions of
alkenes with alkynes. In fact, we herein report a protocol for
mechanistically novel borane-catalyzed reactions between 1,2-
dihydroquinolines and alkynones (Scheme 1C). These reactions
Mannich-type
reactions,[14]
cyclizations,[15]
and
1
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10.1002/anie.202106168
Angewandte Chemie International Edition
RESEARCH ARTICLE
reactions.[16]
8
CAT2
CAT3
CAT4
CAT5
CAT5
CAT5
CAT5
CAT5
CAT5
CAT5
CAT5
toluene
toluene
toluene
toluene
n-hexane
THF
30
30
30
30
30
30
30
30
30
10
0
93
82
79
81
16
n.d.
92
89
90
91
92
56
75
61
85
80
–
dehydrogenation/functionalization
cascade
Intrigued by this activity, we hypothesized that boranes might
perhaps convert 2-alkyl-substituted 1,2-dihydroquinolines (which
can easily be prepared by reaction of an alkyllithium reagent
with an unsubstituted quinoline) to 1,4-dihydroquinolines, which
are much less synthetically accessible, via borane-mediated
hydride transfer. Subsequently, if an alkynone was present, the
boranes could activate the alkynone for an inverse-electron-
demand [2+2] cycloaddition reaction with the 1,4-
dihydroquinoline. Moreover, a chiral borane catalyst might be
able to control the enantioselectivity.
9
10
11
12
13
14
15
16[e]
17[e]
18[e]
DCE
82
87
89
92
93
CHCl3
CHCl3
CHCl3
CHCl3
[a] Unless otherwise noted, all reactions were performed with 5 mol % of a
catalyst, 0.24 mmol of 1a, and 0.20 mmol of 2a in 2 mL of solvent for 2 h. [b]
NMR yields; n.d. = not detected. [c] Determined by HPLC with a chiral column.
[d] The amount of B(C6F5)3 was 10 mol %, and the reaction time was 12 h. [e]
Molecular sieves (4 Å, 50 mg) were added.
Results and Discussion
To test our hypothesis, we began by carrying out reactions
of 1,2-dihydroquinoline 1a with alkynone 2a at 30 °C in toluene
in the presence of various Lewis acid catalysts (Table 1). First,
we tested several commonly used Lewis acids—Sc(OTf)3,
Zn(OTf)2, Mg(OTf)2, FeCl3, and BF3·OEt2—but none of them
were active under these conditions (entries 1–5). Encouragingly,
however, when we used B(C6F5)3 (10 mol %), the desired
hydride transfer/[2+2] cycloaddition cascade occurred to afford
tetrahydroquinoline-fused cyclobutene 3a in 23% yield (entry 6).
We then tested some chiral boranes with the goal of achieving
an enantioselective reaction. Interestingly, chiral spiro-bicyclic
bisborane[17] CAT1 gave 3a in a greatly improved yield (85%)
with an ee of 68% (entry 7). Next, we tested four bisborane
catalysts with substituted aryl rings (CAT2–CAT5, entries 8–11)
and found that the enantioselectivity was markedly improved by
a 4-benzoxyphenyl-substituted catalyst (CAT5), which gave an
81% yield and an 85% ee (entry 11). Changing the solvent to n-
hexane or THF resulted in little to none of the desired product
(entries 12 and 13). The yield was slightly higher in DCE than in
toluene, but the enantioselectivity was slightly lower (entry 14).
Performing the reaction in CHCl3 gave the highest
enantioselectivity (87% ee, entry 15). Moreover, adding 4 Å
molecular sieves increased the ee to 89% (entry 16). The
enantioselectivity improved further when we decreased the
reaction temperature; at 0 °C, 3a was obtained in 92% yield and
93% ee (entry 18).[18]
We then explored the substrate scope with respect to the
alkynone by carrying out reactions with 1a (Table 2). Alkynones
with an electron-donating or electron-withdrawing substituent at
the para position of the phenyl ring were well tolerated, giving
the corresponding cyclobutenes (3a–3f) in moderate to high
yields (71–90%) with excellent ee values (91–93%). ortho-
Table 2. Substrate scope with respect to the alkynone[a]
Table 1. Optimization of reaction conditions[a]
entry
catalyst
Sc(OTf)3
Zn(OTf)2
Mg(OTf)2
FeCl3
solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
T (°C )
30
yield (%)[b]
n.d.
ee (%)[c]
1
–
2
30
n.d.
–
3
30
n.d.
–
4
30
n.d.
–
5
6[d]
BF3·OEt2
B(C6F5)3
CAT1
30
n.d.
–
[a] Unless otherwise noted, all reactions were performed with 5 mol % of
CAT5, 0.24 mmol of 1a, 0.20 mmol of 2, and 50 mg of 4 Å molecular sieves in
2 mL of CHCl3 at 0 °C for 2 h; isolated yields are provided. [b] −20 °C. [c] 24 h.
[d] −50 °C. [e] −30 °C. [f] 1 h.
30
23
–
7
30
85
68
2
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RESEARCH ARTICLE
Fluorophenyl-, meta-tolyl- and 2-thienyl-substituted alkynones
were also compatible (3g–3i). When the alkyne was substituted
with a benzyl or styryl group, the reaction occurred, but either
the yield (3j) or the enantioselectivity (3k) decreased. As for the
ketone substituent, substrates with an aryl ring bearing various
groups were reactive, providing cyclobutenes 3l–3s in 78–86%
yields and 91–95% ee.[18] 2-Furyl and 2-thienyl compounds gave
the corresponding products (3t and 3u) with 83% ee and 89%
ee, respectively. Ketones with an alkyl group (methyl, n-pentyl,
or cyclohexyl) were also suitable, affording 3v–3x with excellent
enantioselectivities. Furthermore, the reaction was compatible
with terminal alkynes (3y and 3z).[19] Finally, a gram-scale
reaction between 1a and 2a in the presence of only 2.5 mol % of
catalyst gave 3a in 90% yield with 94% ee.
in 92% yield with 92% ee. A 2-alkynyl 1,2-dihydroquinoline was
less reactive, and the reaction was less selective, affording 4l in
43% yield with 82% ee. When the 2-position was substituted
with an alkyl group bearing a terminal olefin, the reaction gave
4m in 81% yield and 93% ee. A sterically hindered 2-cyclopropyl
substrate was much less reactive (4n, 23% yield), but the high
enantioselectivity was maintained (91% ee). However, any
substituent other than a hydrogen at the 3- or 4-position of the
1,2-dihydroquinoline greatly inhibited the reaction; either no
reaction occurred at all, or only trace of product formed.[19]
Subsequently, we tested six- and five-membered-ring enamines
for the [2+2] cycloaddition, which afforded the corresponding
products (4o and 4p) with 33% ee and 56% ee, respectively.
We then studied the mechanism of the reaction by
performing several control experiments. A reaction of a 2-
deuterium-labeled 1,2-dihydroquinoline (1a-d) with 2l catalyzed
by CAT5 gave 3l-d, the product arising from deuterium transfer
to the 4-position of the N-heterocyclic ring (Scheme 2A). This
Next, we explored the substrate scope with respect to the
1,2-dihydroquinoline by carrying out reactions with alkynone 2a
(Table 3). Substrates with a 6-fluoro, 6-chloro, or 6-methoxy
substituent were tolerated, affording desired products 4b–4d in
good yields (81–96%) with high enantioselectivities (92–94% ee). result demonstrates that the hydride transfer occurred prior to
Notably, unsaturated alkynyl and vinyl substituents were
untouched by the reaction conditions; products 4e and 4f were
obtained in excellent yields and enantioselectivities. Substrates
the cycloaddition. Furthermore, the deuterium in 3l-d was evenly
split between the two faces of the heterocyclic ring, indicating
the absence of enantiocontrol during the hydride transfer. A
competition experiment involving 1a-d and 1e gave 3a-d and 4e-
d in 47% and 46% yields, respectively, with deuterium evenly
distributed to the two products (Scheme 2B); this result suggests
that the hydride transfer proceeds in an intermolecular fashion.
Treatment of 1a with 5 mol % CAT5 for 5 min gave 1,4-
dihydroquinoline 5 in 83% yield, accompanied by decomposition
of the remainder of the starting material (Scheme 2C).
Interestingly, when we tested the more acidic borane B(C6F5)3
(10 mol %) in a reaction with 1a, the hydride transfer product
was not detected; instead, quinolinium borohydride intermediate
6 was generated in 6% yield, along with unchanged starting
material (Scheme 2D). When the amount of B(C6F5)3 was
increased to 1 equiv, 6 was produced in 82% yield after 30 min
with
a
5-methyl, 7-methyl, 7-trifluoromethyl, or 8-fluoro
substituent reacted smoothly to give desired products 4g–4j,
respectively, in 88–97% yields with 92–93% ee. Changing the 2-
methyl group to a 2-butyl group was tolerated; 4k was obtained
Table 3. Substrate scope with respect to the 1,2-dihydroquinoline[a]
[a] Unless otherwise noted, all reactions were performed with 5 mol % of
CAT5, 0.24 mmol of 1, 0.20 mmol of 2a, and 50 mg of 4 Å molecular sieves in
2 mL of CHCl3 at 0 °C for 2 h; isolated yields are provided. [b] 24 h. [c] 20 °C .
[d] 0.3 mmol of 1. [e] 4 h. [f] 25 °C .
Scheme 2. Control experiments
3
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10.1002/anie.202106168
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RESEARCH ARTICLE
(Scheme 2E). These results show that the chiral boranes
efficiently promoted the hydride transfer; whereas B(C6F5)3 was
effective for hydride abstraction but not for hydride addition.
To improve our understanding of the hydride transfer
process, we performed density functional theory (DFT)
calculations for processes involving CAT1 and B(C6F5)3 (Figure
1).[20] Because 1a is racemic, the hydride abstraction catalyzed
by chiral borane CAT1 can proceed via one of two transition
states (TSA-R or TSA-S), each derived from one of the two
enantiomers. These transition states had similar moderate
energies (14.8 kcal/mol for TSA-R and 15.1 kcal/mol for TSA-S),
which explains the efficient hydride abstraction for both
enantiomers. The free energy of the resulting prochiral
quinolinium intermediate stabilized by CAT1–hydride anion (7,
−0.4 kcal/mol) was similar to the energy of 1a. The subsequent
hydride addition reaction (formation of 5 from 7) was exothermic
(−1.8 kcal/mol), and the energy barriers to addition from the top
and bottom faces were almost the same (TSB-1, 12.2 kcal/mol;
TSB-2, 12.6 kcal/mol); these results agree qualitatively with the
observed absence of enantiocontrol during the hydride addition
(Scheme 2A). The thermodynamic stability of 5 may have been
the driving force for hydride transfer. In contrast, when B(C6F5)3
was used as the catalyst, the hydride abstraction proceeded via
TSA' (15.2 kcal/mol), a process that was very exothermic
because the quinolinium intermediate stabilized by the B(C6F5)3–
hydride anion (6) had a relatively low energy (−3.9 kcal/mol).
This result is qualitatively in agreement with our experimental
results showing that the reaction of 1a with B(C6F5)3
predominantly produced 6 instead of 5 (Scheme 2E) because 6
is thermodynamically more stable than 5. Formation of the
cycloaddition product with B(C6F5)3 (Table 1, entry 6) may have
resulted from a trace amount of 5, and the cycloaddition reaction
would shift the equilibrium between 6 and 5 toward 5.
Figure 2. Optimized transition states in the stereo-determining step of the [2+2]
cycloaddition reaction between 5 and 2l catalyzed by CAT1 at 273 K. The DFT
calculations
were
performed
using
ω-B97XD/def2-
TZVPP/SMD(chloroform)//ω-B97XD/6-31G(d). Energies are given in kcal/mol.
Bond lengths are given in Å.
In addition, we also studied the CAT1-catalyzed
enantioselective [2+2] cycloaddition reaction between 5 and 2l
by means of DFT calculations (Figure 2). The two most stable
transition states for generation of the two enantiomers were
TS1-R and TS1-S, which differ in free energy by 1.4 kcal/mol, a
result that is in good agreement with the observed 86% ee of 3l
(with CAT1). After coordination to one of the boron atoms, an
alkynone would occupy the open space between a BArF group
2
of one cyclopentane ring and a phenyl group of the other
cyclopentane ring. The position of the alkynone would be fixed
by a π–π stacking interaction between the phenyl ring adjacent
to the alkyne and an ArF group. The 1,4-dihydroquinoline would
react with the alkynone at a position fixed by the π–π stacking
interaction with the alkynone (TS1-R); the reaction with a flipped
1,4-dihydroquinoline would be disfavored by the absence of the
π–π stacking interaction and by steric repulsion (TS1-S).
Furthermore, we evaluated the possibility of cooperation
between two boron atoms of one catalyst molecule (e.g., one
boron atom activates the alkynone while the other captures the
1,4-dihydroquinoline). However, the sterics of the catalyst would
prevent such interactions (the DFT calculations showed no
viable models). Because the catalyst is C2-symmetric, the two
boron atoms are equivalent and presumably function
independently. Indeed, racemic monocyclic trans-2-phenyl-1-
B(C6F5)2-cyclopentane was also found to be very active for this
cascade reaction (see Supporting Information).
Conclusion
In summary, we have developed
a
protocol for
enantioselective synthesis of fully substituted cyclobutenes by
means of a cascade process comprising a borane-catalyzed
hydride transfer and an enantioselective [2+2] cycloaddition.
This protocol has the following advantages due to the use of a
chiral spiro-bicyclic bisborane catalyst: the strong Lewis acidity
of the catalyst activated the substrates, enabling reactions with
sterically hindered compounds (internal alkynes and
trisubstituted alkene); the combination of the steric bulk of the
catalyst and its strong Lewis acidity resulted in excellent
enantiocontrol of the reactions of monodentate substrates
(alkynones). In addition, the catalyst showed unique activity; that
Figure 1. Energy profiles of hydride transfer reactions catalyzed by CAT1 and
B(C6F5)3 at 298 K. The DFT calculations were performed using ω-B97XD/def2-
TZVPP/SMD(chloroform)//ω-B97XD/6-31G(d).
4
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10.1002/anie.202106168
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RESEARCH ARTICLE
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chiral borane catalysts in additional enantioselective reactions
that are traditionally catalyzed by conventional Lewis acids to
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Acknowledgements
We are grateful for financial support from the National Natural
Science Foundation of China (91956106 and 21871147), the
Natural Science Foundation of Tianjin (20JCZDJC00720 and
20JCJQJC00030), the NCC Fund (NCC2020PY10), and the
Fundamental Research Funds for Central Universities
(2122018165). We thank Prof. Qi-Lin Zhou and Prof. Xiao-Song
Xue for helpful discussions. X.-C.W. thanks the Tencent
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Keywords: asymmetric catalysis • boron • hydride transfer •
cycloaddition • heterocycles
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a discussion of the limitations of this cascade reaction, see
Supporting Information.
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CAT1 instead of CAT5. The reactions in Scheme 2A and 2C were also
tested with CAT1; they gave similar results as CAT5. See Supporting
Information for details.
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5
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10.1002/anie.202106168
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
Bifunctional Borane Catalyst. A borane-catalyzed cascade reaction between a benzyl-protected 1,2-dihydroquinoline and an
alkynone has been developed. The reaction consists of hydride transfer and enantioselective [2+2] cycloaddition, which are both
promoted by the spiro-bicyclic bisborane catalysts.
6
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