Oxathiaborolium: A type of chiral Lewis acid catalyst and its application in catalytic and highly enantioselective Diels-Alder reactions

Article abstract of DOI:10.1021/acs.orglett.6b03147

The first reported sulfur-stabilized borenium cations were synthesized through halide abstraction of a haloborane intermediate by halophilic reagents. Different from the well-known cationic oxazaborolidines, a sulfide instead of an amine was used to not only simplify the preparation of the catalysts but also increase Lewis acidity of the boron atom. The in situ generated borenium salts showed exceptional Lewis acidity and successfully catalyzed asymmetric Diels-Alder reactions of cyclopentadiene and dienophiles in excellent yields and enantioselectivities. The NMR studies of these oxathiaborolium structures were reported as well.

Full text of DOI:10.1021/acs.orglett.6b03147

Letter
pubs.acs.org/OrgLett
Oxathiaborolium: A Type of Chiral Lewis Acid Catalyst and Its
Application in Catalytic and Highly Enantioselective Diels−Alder
Reactions
Singam Naveen Kumar,† Isaac Furay Yu,‡ and Rong-Jie Chein*,†
†Institute of Chemistry, Academia Sinica, Nankang, Taipei 11529, Taiwan
‡Department of Chemistry, National Taiwan University, Taipei 10617, Taiwan
S
* Supporting Information
ABSTRACT: The first reported sulfur-stabilized borenium
cations were synthesized through halide abstraction of a
haloborane intermediate by halophilic reagents. Different from
the well-known cationic oxazaborolidines, a sulfide instead of an
amine was used to not only simplify the preparation of the
catalysts but also increase Lewis acidity of the boron atom. The
in situ generated borenium salts showed exceptional Lewis acidity
and successfully catalyzed asymmetric Diels−Alder reactions of
cyclopentadiene and dienophiles in excellent yields and enantioselectivities. The NMR studies of these oxathiaborolium
structures were reported as well.
he reactive intermediates I, known as borenium cations
according to Noeth’s classification system,1 are three-
coordinate species that comprise two σ-bound substituents (R)
and one dative interaction with a ligand (L) capable of
occupying a third coordination site through π-backbonding
(Figure 1).2 The positive charge can reside on the ligand itself
borenium Lewis acids powerful tools in the field of organic
synthesis. The subsequent flourishing development of activated
cationic oxazaborolidines C and D led by Corey and
Yamamoto, respectively, further highlights the potential for
such species to be used as catalysts for asymmetric organic
transformations5 and the synthesis of many biologically
interesting complex molecules.6 Aside from Diels−Alder
reactions, cyanosilylation,7 [3 + 2] cycloaddition,5g Michael
aldol addition,8 Morita−Baylis−Hillman reaction,9 Mukaiyama
aldol,10 cyclopropanation,11 and Roskamp reactions12 have all
been shown to be amenable to enantioselective catalysis of
cationic oxazaborolidines. This pioneering work inspired us to
explore the possibility of forming chiral borenium complex A.
By using a disubstituted sulfide instead of a secondary amine,
the dative bond of borenium cation can be formed directly,
avoiding the use of a strong Brønsted acid such as triflic acid
(TfOH)13 and triflimide (CF3SO2)2NH14 as activator. The
preparation of catalyst can then be simplified to an one-pot
operation. Furthermore, S is a weaker donor than N, O, and P,
which may increase Lewis acidity of boron atom toward
stronger acid−base interaction, and, to the best of our
knowledge, no intra- or intermolecularly sulfur-stabilized
boreniums have been previously reported. Herein, we report
the syntheses, characterization, and investigation of the
reactivity of type-A sulfur-coordinated aryl oxaborenium
cations. The abilities of these borenium cations to catalyze
asymmetric Diels−Alder reactions are demonstrated.
T
Figure 1. Borenium chemistry from the perspective of organic
chemistry.
or on a boron atom with a dative bond coordinated to a ligand.
Despite early interest in the chemistry of borenium cations,
especially in the field of enantioselective synthesis, their
applications have been slow to unfold until recently. In 1996,
Corey and co-workers3 successfully introduced bicyclic
oxazaborinane B (Figure 1) as a highly efficient catalyst for
enantioselective Diels−Alder reactions,4 which made chiral
Heterolysis of boron−halogen bonds is the most widely used
and successful method for preparing borenium ions; other
Received: October 23, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03147
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
methods include electrophilic activation by protonation or
Lewis acids, nucleophilic displacement, electrophilic attack at
boron−nitrogen bonds, and metathesis.1,2,5b On the basis of
these methods, we planned a straightforward approach to
synthesize borenium cation A through halide abstraction of
haloborane E using a halophile (Scheme 1); the sulfur−boron
boron−halogen bond. The presence of borenium complex 3
was examined by experimentally determining the ability for
asymmetric catalysis in the Diels−Alder reaction of cyclo-
pentadiene and 2,2,2-trifluoroethyl acrylate.
Both TMSOTf and the control reaction (entries 1 and 2)
showed no reaction and did not generate the Diels−Alder
adduct. Although tribromoborane, trichloroborane, antimony
pentachloride, and silver tetrafluoroborate afforded product 4 in
31%, 25%, 17%, and 26% yields after 2 days, respectively, no
enantioselective induction was observed (entries 3−6). When
AgOTf was used as a halophile (entry 7), 7% of product 4 was
isolated with 75% ee. The use of AlCl3 further improved the
enantiomeric excess to 91% with a small increase in the reaction
rate (entry 8). Because AlCl3 is only slightly soluble in
dichloromethane, the dissolution of AlCl3 indicated the
successful reaction of this halophile with phenyl boron chloride
2. These results encouraged us to use a larger amount (20 mol
%) of catalyst 3a or 3b (entries 9 and 10), which generated a
satisfactory outcome. Product 4 was synthesized in 96% yield
with excellent endo/exo selectivity (98:2) and almost perfect
enantioselectivity (>99% ee) after 24 h of reaction in
dichloromethane at −78 °C. The use of dichloromethane as
a solvent was also critical for achieving high reactivity and
enantioselectivity in comparison with reactions conducted in
toluene (entry 11).
Scheme 1. Retrosynthetic Route for the Synthesis of Type A
Oxathiaborolium
bond was expected to form in the presence of an internal
tetrahydrothiophene ligand. Intermediate E could be readily
synthesized through the nucleophilic displacement of dihalo-
(phenyl)borane by (thiolan-2-yl)diphenylmethanol 1, which is
a very useful sulfur ligand for asymmetric organocatalysis and
has been reported by our research group several times.15
Accordingly, ligand 1 was first treated with commercially
available dichloro(phenyl)borane, and N,N-diisopropylethyl-
The successful use of oxathiaborolium 3b in the catalytic
asymmetric Diels−Alder reaction of cyclopentadiene and 2,2,2-
trifluoroethyl acrylate prompted us to examine the scope of the
dienophile substrates, especially the less reactive ester ones; the
outcomes are highlighted in Table 2. Compound 3b effectively
catalyzed the reaction of cyclopentadiene with less active
acrylates (entries 1−4) at a higher temperature (−20 °C) in a
highly stereoselective manner, generating dominant endo
Diels−Alder adducts 4a−d in excellent yields (>92%) and
excellent enantiomeric excess (96%−97%). Reactions with
dialkyl fumarates (entries 5 and 6) and cyclohexenone (entry
7) also generated products 4e−g in excellent yields (>90%) and
excellent enantioselectivities (92%, 97%, and 95%, respec-
tively). When cycloheptenone (entry 8) was used as dienophile,
high yield (93%) and good enantioselectivities (87%) were
obtained; nevertheless, the enantioselectivity decreased to 60%
when cyclopentenone was employed as dienophile (entry 9).
Overall, the reactivity and stereoselectivity of compound 3b are
not only universal but also comparable with type C and D
catalysts in adducts 4,5c,e,14a including 4a,5d,f 4f,5c−e,14a and
4g5c,e (entries 1, 6, and 7). Entries 2−5 are not covered by the
previously reported cationic oxazaborolidine catalysts. With less
reactive dienophiles such as ethyl crotonate (entry 10), no
reaction was observed at 0 °C.
amine (DIPEA, Hunig’s base) was used as the base to prepare
intermediate 2. The resulting solution was then mixed with a
range of halophilic Lewis acids, as listed in Table 1, to break the
̈
Table 1. Screening of Halophiles in an Oxathiaborolium-
Catalyzed Asymmetric Diels−Alder Reaction
a
b
d
cat. loading
(mol %)
time
(h)
yield (%)
ee
(%)
c
entry halophile
(endo/exo)
e
f
1
none
10
10
10
10
10
10
10
10
20
20
20
48
16
48
48
48
48
16
16
44
24
24
NR
NA
NA
0
e
f
2
TMSOTf
BBr3
NR
To further characterize oxathiaborolium 3b, a series of NMR
studies were carried out at various temperatures, as summarized
in Scheme 2. The reaction of ligand 1 with dichloro(phenyl)-
borane and DIPEA in CD2Cl2 partially converted the ligand to
3
31 (99:1)
25 (97:3)
17 (96:4)
26 (92:8)
7 (>99:1)
13 (97:3)
4
BCl3
2
5
SbCl5
AgBF4
AgOTf
AlCl3
0
6
0
1
chloro(methoxy)(phenyl)borane 2, as determined by H and
7
75
91
97
>99
60
11B NMR analyses. The lower field shift of Ha (δ = 4.97 ppm)
on 2 suggests that the combination of formally positive sulfur
and tetracoordinate boron (δ 11B = 17.6 ppm) was responsible
for deshielding the proton on the adjacent carbon atom (Δδ =
0.25 ppm). When the solution was further treated with AlCl3 at
−78 °C, a new broad peak that appeared at δ 5.61 ppm was
assigned to borenium structure 3b; this chemical shift is greater
than the reported Ha chemical shifts of cationic oxazabor-
olidines C and D (δ Ha = 4.85−5.44 ppm),5b which support the
8
9
AgOTf
AlCl3
78 (>99:1)
96 (98:2)
82 (99:1)
10
11
g
AlCl3
a
b
c
Ratio of halophile/ligand/PhBCl2 = 0.9:1:1. Isolated yield. Exo/
d
endo ratios were determined by 1H NMR. ee was determined by GC
with a Hydrodex β-6TBDM column. No reaction occurred. Not
available. Toluene was used as the solvent.
e
f
g
B
DOI: 10.1021/acs.orglett.6b03147
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Scope of Dienophile Substrates
Scheme 2. NMR Studies of Oxathiaborolium 3b in CD2Cl2
experiments were increased to above −10 °C, the equilibrium
gradually collapsed. Enhanced quadrupolar relaxation at low
temperatures is a recurring issue with most of the cationic
oxazaborolidine catalysts;2,16 thus, no information could be
obtained from the 11B NMR experiment of 3b. We then turned
to 27Al NMR, and the resulting spectrum showed a sharp signal
−
for AlCl4 (δ 27Al = 103.63 ppm, h(1/2) = 51 Hz, see the
Supporting Information).
Finally, we aimed to further demonstrate that the formation
of a sulfur−boron dative bond was critical for the catalytic
ability of this novel oxathiaborolium species. When sulfoxides
5a and 5b (see SI) were used to prepare catalysts, both of
which contained sulfur atoms masked by oxygen atoms, the
Diels−Alder reactions of cyclopentadiene and 2,2,2-trifluor-
oethyl acrylate proceeded slowly, and only a 15% racemic
mixture of compound 4 was isolated after 24 h at −78 °C.
These data, the absolute stereochemical outcome of the
catalytic reaction, and the NMR results all support the
hypothesis that the highly enantioselective formation of the
Diels−Alder adducts resulted from the preferred pre-transition-
state assembly 6 (see the SI), which was similar to the activity
of chiral oxazaborolidium cations proposed by Corey et al.3,5h,17
The complexation of the catalyst with acrylate involved the
coordination of the carbonyl oxygen to boron and a synergistic
electronic interaction between the α-C−H group and the
oxygen on boron from the less hindered, convex face of the
bicyclic borenium core, which led to face selectivity.
To summarize, we have reported the development of a novel
oxathiaborolium catalyst that was readily synthesized in a single
step using chiral tetrahydrothiophene ligand 1 and commercial
materials (see SI); this catalyst exhibits excellent catalysis of
asymmetric Diels−Alder reactions at low temperatures.
Oxathiaborolium type A compounds functioning as potent
chiral Lewis acids have strong potential to be used in other
Lewis acid catalyzed reactions where borenium cations serve as
activating agents.18 Although further developments are required
for better stability at higher temperature, compounds 3a and 3b
are the first sulfur-stabilized borenium Lewis acids reported to
date, which paves the way for expanding the applications of
chiral sulfur ligands in organic syntheses.
a
b
c
1
Isolated yield. Exo/endo ratios were determined by H NMR. ee
d
was determined by GC with a Hydrodex β-6TBDM column. 1 M
e
concentration, 5 equiv cyclopentadiene used. No reaction occurred.
f
Not available.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03147.
■
higher Lewis acidity of oxathiaborolium 3b. The 1H NMR data
also suggest that the catalytically active and super Lewis acidic
borenium cation 3b was present in equilibrium with the
tetracoordinate boron complex 2 and that only approximately
20% of compound 1 was converted into 3b; as observed, the
intrinsic catalytic reactivity was sufficiently large to catalyze the
Diels−Alder reaction. When the temperatures of the NMR
S
Detailed experimental procedures, characterization data,
and NMR spectra for all products (PDF)
C
DOI: 10.1021/acs.orglett.6b03147
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(11) Gao, L.; Hwang, G.-S.; Ryu, D. H. J. Am. Chem. Soc. 2011, 133,
20708−20711.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: rjchein@chem.sinica.edu.tw.
ORCID
(12) Gao, L.; Kang, B. C.; Hwang, G.-S.; Ryu, D. H. Angew. Chem.,
Int. Ed. 2012, 51, 8322−8325.
(13) Corey, E. J.; Shibata, T.; Lee, T. W. J. Am. Chem. Soc. 2002, 124,
3808−3809.
(14) (a) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 6388−
6390. (b) Zhou, G.; Hu, Q.-Y.; Corey, E. J. Org. Lett. 2003, 5, 3979−
3982.
Rong-Jie Chein: 0000-0002-0119-8288
Notes
(15) (a) Wang, S.-H.; Chein, R.-J. Tetrahedron 2016, 72, 2607−2615.
(b) Huang, M.-T.; Wu, H.-Y.; Chein, R.-J. Chem. Commun. 2014, 50,
1101−1103. (c) Wu, H.-Y.; Chang, C.-W.; Chein, R.-J. J. Org. Chem.
2013, 78, 5788−5793.
(16) (a) Beall, H.; Bushweller, C. H.; Dewkett, W. J.; Grace, M. J.
Am. Chem. Soc. 1970, 92, 3484−3486. (b) Bacon, J.; Gillespie, R. J.;
Hartman, J. S.; Rao, U. R. K. Mol. Phys. 1970, 18, 561−570.
(17) Corey, E. J.; Lee, T. W. Chem. Commun. 2001, 1321−1329.
(18) Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.; Wiley-
VCH: New York, 2000; Vols. 1 and 2.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by Academia Sinica and
the Ministry of Science and Technology (Taiwan) (103-2113-
M-001-027, 104-2113-M-001-011). We greatly thank Prof. E. J.
Corey of Harvard University for inspiring this work. We also
acknowledge Prof. Ching-Wen Chiu of National Taiwan
University for discussions regarding borenium synthesis, Ms.
Su-Ching Lin of the Institute of Chemistry of Academia Sinica
for assistance with the NMR experiments, and the MS lab at the
Institute of Chemistry of Academia Sinica for assistance with
mass spectrometric analyses.
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DOI: 10.1021/acs.orglett.6b03147
Org. Lett. XXXX, XXX, XXX−XXX