Borane-Catalyzed Direct Asymmetric Vinylogous Mannich Reactions of Acyclic α,β-Unsaturated Ketones

Article abstract of DOI:10.1021/jacs.1c00006

Herein, we report that, by using chiral bicyclic bisborane catalysts, we have achieved the first highly regio-, diastereo-, and enantioselective direct asymmetric vinylogous Mannich reactions of acyclic α,β-unsaturated ketones. The strong Lewis acidity and steric bulk of the bisborane catalysts were essential for the observed high yields and selectivities.

Full text of DOI:10.1021/jacs.1c00006

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Borane-Catalyzed Direct Asymmetric Vinylogous Mannich Reactions
of Acyclic α,β-Unsaturated Ketones
Jun-Jie Tian,† Ning Liu,† Qi-Fei Liu, Wei Sun, and Xiao-Chen Wang*
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ABSTRACT: Herein, we report that, by using chiral bicyclic bisborane catalysts, we have achieved the first highly regio-, diastereo-,
and enantioselective direct asymmetric vinylogous Mannich reactions of acyclic α,β-unsaturated ketones. The strong Lewis acidity
and steric bulk of the bisborane catalysts were essential for the observed high yields and selectivities.
strong base (e.g., LDA or KHMDS), and the silyl dienolate
serves as the nucleophile in the AVMR.1,2 Despite the progress
achieved with this workaround, the preparation of the silyl-
protected nucleophile is an additional step and usually
generates an inseparable mixture of E and Z isomers,3 which
limits the attractiveness of this method. In contrast, “direct”
AVMRs, in which a vinylogous nucleophile is formed in situ by
reaction of an unsaturated compound and a base, are atom-
economical and more convenient. However, to date, the
pronucleophiles used for direct AVMR have been confined
mostly to cyclic compounds, such as α,β-unsaturated γ-
butenolides,4 γ-butyrolactams,5 and cyclic α,α-dicyanoalkenes,6
because the γ protons of these compounds are relatively acidic,
and their rigid cyclic skeletons are considered to be crucial for
controlling the regiochemistry (reaction at the α or γ carbon)
and stereochemistry. Controlling the selectivity of the reactions
of acyclic pronucleophiles is much more challenging.
symmetric vinylogous Mannich reactions (AVMRs) of
Aα,β-unsaturated carbonyl compounds provide efficient
access to optically active amino-functionalized derivatives,
which are useful building blocks for natural product synthesis.1
However, the low acidity of the γ proton of the starting
carbonyl compound has led to the development of many
protocols for “indirect” AVMRs (Scheme 1A) in which the
carbonyl compound is first converted to a silyl dienolate by
reaction with a silyl donor (e.g., TMSCl or TMSOTf) and a
Scheme 1. Asymmetric Vinylogous Mannich Reactions of
Acyclic Dienolates
In a recent breakthrough, the Yin group achieved highly
regio-, diastereo-, and enantioselective direct AVMRs of acyclic
β,γ-unsaturated N-acylpyrazoles and γ-halogenated α,β-unsa-
turated N-acylpyrazoles by using a chiral Cu(I)/diphosphine
complex as a catalyst and triethylamine as a base (Scheme
1B).7 Enhancement of the acidity of the C−H bond by either
the adjacent carbonyl group or the halogen atom facilitates
base-mediated deprotonation. Moreover, the pyrazole auxiliary
is considered to be essential for selectivity, not only because its
steric bulk inhibits reaction at the α position but also because
the group functions as a bidentate auxiliary ligand for the
copper catalyst, forming a complex that decreases the
conformational flexibility of the acyclic compound. There
have been only a few other successful examples of direct
AVMRs of acyclic pronucleophiles.8
Received: January 1, 2021
Published: February 11, 2021
https://dx.doi.org/10.1021/jacs.1c00006
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© 2021 American Chemical Society
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In comparison to β,γ-unsaturated carbonyls whose deproto-
nation was relatively easy to achieve by using organocatalysts9
or soft Lewis acid/Brønsted base catalysts,7c,10 a strong Lewis
acid catalyst would be preferable for unactivated α,β-
unsaturated carbonyls. Theoretically, coordination of the
carbonyl oxygen with a strong Lewis acid catalyst would
facilitate deprotonation by inductively increasing the acidity of
the γ proton and thus favor enolization of the substrate.11
However, strong Lewis acids are more prone to being
quenched by the bases. We reasoned that this problem could
potentially be circumvented by using a frustrated Lewis pair,12
in which quenching of a Lewis acid by a Lewis base is
prohibited by steric hindrance. The most commonly used
Lewis acids in such pairs are fluoroaryl-substituted boranes
because of their strong acidity and sterically hindered boron
center. In principle, the properties of these boranes make them
ideally suited for use as AVMR catalysts. Indeed, in
mechanistically relevant chemistry, the combination of a
fluoroaryl-substituted borane with an amine has been used to
promote ketone enolization for various addition reactions at
the α position.13
Recently, our group developed a series of chiral bicyclic
bisborane catalysts for asymmetric reductions,14 and extending
the use of these catalysts to reactions other than reductions has
been a goal of our research program. Herein, we report that by
combining these boranes with a tertiary amine, we were able to
accomplish direct AVMRs of α,β-unsaturated ketones with
Boc-protected imines with excellent regio-, diastereo-, and
enantioselectivities (Scheme 1C). In these reactions, the Lewis
acid catalyst and the base cooperatively deprotonated the
substrate to generate a borane-ligated vinylogous dienolate and
an ammonium cation, which then presumably served as a
Brønsted acid to activate the imine while the borane controlled
the selectivity of the Mannich reaction. Notably, these
reactions directly used monodentate substrates rather than
substrates containing an auxiliary, which simplified the
procedures. Furthermore, this is the first time that direct
AVMRs of acyclic α,β-unsaturated ketones have been achieved.
We began by testing conditions for direct VMR of α,β-
unsaturated ketone 1a with aldimine 2a (Figure 1A). Initially,
we screened combinations of Et3N (B1, 20 mol %) and a
number of achiral borane Lewis acids (10 mol %) whose Lewis
acidities were determined by means of the Gutmann−Beckett
method.15 The Lewis acidities of these boranes decreased in
the order B(3,4,5-F3C6H2)3 (LA1) > B(C6F5)3 (LA2) >
PhC2H4B(C6F5)2 (LA3) > B(2,4,6-F3C6H2)3 (LA4) > BPh3
(LA5), as indicated by their acceptor numbers (ANs), which
are a quantitative measure of Lewis acidity. The strong Lewis
acids LA1 and LA2 showed excellent activity (87% yield and
91% yield, respectively). LA3 was moderately active, affording
3a in 47% yield with a 3.2/1 diastereomeric ratio (dr). LA4
was poorly active while LA5 was inactive.
We used NMR spectroscopy to elucidate the dienoate
formation process. Addition of Barton’s base (2-tert-butyl-
1,1,3,3-tetramethylguanidine, 2 equiv)16 to the mixture of 1a
and B(C6F5)3 produced two new olefinic proton signals, one at
δ 6.09 (Ha, dd, J = 15.3, 1.5 Hz) and one at δ 5.27 (Hb, dq, J =
15.3, 6.6 Hz) (Figure 1B). The Ha−Hb coupling constant of
15.3 Hz and a 2D-NOESY experiment17 suggest the formation
of an (E, E)-dienolate. In addition, mixing 1a with Barton’s
base in the absence of B(C6F5)3 did not result in dienolate
formation. These experiments clearly demonstrate that a
strongly Lewis acidic borane and an organic base could
efficiently promote dienolate formation.
These results, particularly that of LA3, whose Lewis acidity
should be similar to chiral boranes R−B(C6F5)2, encouraged us
to test chiral boranes in the hopes of achieving enantioselective
reactions (Table 1). Spirobicyclic bisboranes14b LA6−LA9 (5
mol %) exhibited moderate activity and enantioselectivity (up
to 56% ee). Fused bicyclic bisboranes14c generated by
hydroboration of the corresponding diene with HB(C6F5)2 at
25 °C were also tested. Phenyl-substituted catalyst LA10
provided 3a in 80% yield with 5.5/1 dr and 82% ee, whereas 4-
a
Table 1. Optimization of Reaction Conditions
a
Figure 1. (A) Screening of achiral Lewis acids. (B) 1H NMR
spectrum of a mixture of 1a (1 equiv), B(C6F5)3 (1 equiv), and
Barton’s base (2 equiv).
Unless otherwise specified, all reactions were performed with 0.2
mmol of 1a and 0.3 mmol of 2a in 0.5 mL of toluene under N2. NMR
yields are provided. Used 1 mL of PhCF3.
b
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fluorophenyl-, 4-tert-butylphenyl-, and 3,5-di-tert-butylphenyl-
substituted catalysts (LA11−LA13, respectively) gave lower
enantioselectivities. To our delight, bisborane LA14 (a
diastereomer of LA12), which was generated by hydroboration
of the corresponding 4-tert-butylphenyl-substituted diene at 80
°C, gave a dr of 11/1 and an ee of 87%. Similarly, LA15
showed better stereoselectivity than diastereomer LA13 but
was not as selective as LA14.
Table 2. Scope with Respect to the α,β-Unsaturated
Ketone
a
Using LA14 as the Lewis acid, we screened various bases.
When N-methylpiperidine (B2) was the base, reaction in
toluene gave 3a with an ee of 92%, but the yield decreased to
63%. N-Ethylpiperidine (B3) was more active but slightly less
selective. Bulky amines (diisopropylethylamine [B4] and
1,2,2,6,6-pentamethylpiperidine [B5]) markedly reduced the
yield and had a deleterious effect on the enantioselectivity.
Barton’s base (B6) increased the yield to 93% but decreased
the ee to 83%. In contrast, DBU (B7) shut down the reaction
completely, perhaps because of coordination of the imine to
the borane catalyst. 2,6-Di-tert-butylpyridine (B8) and N,N-
diethylaniline (B9) also did not give the desired product,
probably because these bases were too weak to remove the γ
proton. Similarly, in the absence of a base, the borane was
unable to catalyze the reaction. To further optimize the
reaction conditions, we tested the combination of LA14 and
B2 in various solvents. p-Xylene, PhCF3, mesitylene, and
cyclohexane improved the yield to >90%, but only PhCF3
maintained the high enantioselectivity (92% ee) that was
observed in toluene. The polar solvent CHCl3 was detrimental
to both the yield and the stereoselectivity. Taken together, the
results of our experiments indicated that the optimal reaction
conditions involved the use of 5 mol % LA14, and 20 mol %
B2 in PhCF3 at 10 °C (for optimization of reaction
temperature, see the Supporting Information). Notably, the
formation of the α-addition product was not observed at any
point during the optimization of the conditions for reaction of
1a with 2a.
Next, we used imines 2a and 2c to investigate the scope of
the reaction with respect to the α,β-unsaturated ketone (Table
2). First, we tested ketones with various substituted aryl groups
connected to the carbonyl carbon. Compounds with an
electron-donating group (e.g., methoxy) or an electron-
withdrawing group (e.g., trifluoromethyl) at the para, ortho,
or meta position of the phenyl ring were suitable, giving the
desired products (3b−3q) in high isolated yields (82−98%)
with excellent diastereoselectivity (>10/1 dr) and enantiose-
lectivity (>90% ee). Substrates with a halogen atom (F, Cl, or
Br; 3e−3g, 3n, and 3o), an alkenyl group (3i), or an alkynyl
group (3j) were well tolerated. Moreover, the phenyl ring
could be replaced by a 2-thienyl (3r) or 5-benzofuranyl (3s)
ring without decreasing the selectivities.
a
Unless otherwise specified, all reactions were performed with 0.2
mmol of 1 and 0.3 mmol of 2 in 1 mL of PhCF3 under N2. Isolated
yields are provided. At 0 °C. Used 0.4 mmol of 2. Used 10 mol %
b
c
d
e
f
of LA14 and 40 mol % of B2. Used 1.5 mL of PhCF3. At −20 °C.
g
h
At −10 °C. 36 h.
Subsequently, the γ methyl group was changed to ethyl (3t),
n-propyl (3u), n-butyl (3v), or benzyl (3w) as well as to a
linear alkyl group with a terminal OTBS (3x) or olefin (3y);
the corresponding products were obtained in 67−88% yields
with excellent diastereo- and enantioselectivities. However,
when the γ carbon was unsubstituted (3z), both the yield and
the enantioselectivity decreased (to 55% and 85% ee,
respectively).
Substrates with various α substituents were studied as well.
When there was no α substituent, the diastereoselectivity was
poor (3aa, dr = 2.9/1), and the enantioselectivity was
moderate (78% ee for the trans isomer, 83% ee for the cis
isomer). In contrast, reactions of α-bromo (3bb), α-ethyl
(3cc), α-n-propyl (3dd), and α-CH2TMS (3ee) substrates
provided high diastereoselectivities and 82−88% ee. The
reaction of an α-cyclopropyl-substituted compound gave 3ff
with moderate diastereoselectivity and enantioselectivity.
It is worth mentioning that none of the α,β-unsaturated
ketones shown in Table 2 gave any α-addition products. This
result may be attributable to blocking of the α position by the
bulky chiral bisborane. Furthermore, we also evaluated less
acidic pronucleophiles, such as α,β-unsaturated esters and α,β-
unsaturated amides, but they failed to give the corresponding
products.17
Next, an array of aldimine electrophiles were studied in
reactions with 1a as the pronucleophile (Table 3). Electron-
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a
removed easily by treatment with trifluoroacetic acid to afford
chiral δ-amino-α,β-unsaturated ketone 5 in 88% yield with
retention of the ee value.
Table 3. Scope with Respect to the Imine
In conclusion, we have developed the first protocol for direct
AVMRs of acyclic α,β-unsaturated ketones. The protocol
efficiently and atom-economically affords optically active δ-
amino-α,β-unsaturated carbonyl derivatives. The strong Lewis
acidity of the borane catalysts was crucial for deprotonation of
the poorly acidic γ-C−H bond of the substrates by the tertiary
amine, and the steric bulk and structural rigidity of the catalysts
were pivotal for achieving selectivities. Currently, we are
investigating other α,β-unsaturated carbonyl compounds and
other electrophiles in borane-catalyzed asymmetric addition
reactions to determine whether chiral borane catalysts can
overcome the limitations of existing catalytic systems.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c00006.
■
sı
a
Unless otherwise specified, all reactions were performed with 0.2
Experimental procedures, characterization data for new
compounds, NMR spectra, and HPLC traces (PDF)
mmol of 1a and 0.4 mmol of 2 in 1 mL of PhCF3 under N2. Isolated
b
c
d
yields are provided. At −10 °C. Used 2 mL of PhCF3. Used 1.5
e
mL of PhCF3. At 0 °C.
Accession Codes
CCDC 2052961−2052962 and 2052994 contain the supple-
mentary 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 Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
donating and electron-withdrawing groups on the phenyl rings
were tolerated, and the corresponding products (3gg−3oo)
were obtained in high yields with excellent dr and ee values.
Notably, ester (3kk), methylthio (3ll), and trifluoromethoxy
(3mm) functional groups had no effect on the yield or
stereoselectivity. Furthermore, 2-naphthyl (3pp), 3-furyl
(3qq), 3-thienyl (3rr), and 2-benzothienyl (3ss) moieties
were compatible with the reaction conditions. In contrast,
aliphatic imines were poorly reactive or completely un-
reactive.17
To demonstrate the utility of our AVMR protocol, we
performed a gram-scale reaction of 1a with 2c in the presence
of LA14 (2.5 mol %) and B2 (10 mol %), which afforded 3hh
in 80% yield with 12/1 dr and 90% ee (Scheme 2A).
Subsequently, the major diastereomer of 3hh was purified and
subjected to two transformations (Scheme 2B). First, treat-
ment with NaBH4 and CeCl3 reduced the carbonyl group to
give allyl alcohol 4 in 90% yield with 5.1/1 dr and 90% ee; the
olefin remained intact. Second, the Boc protecting group was
AUTHOR INFORMATION
Corresponding Author
■
Xiao-Chen Wang − State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China; orcid.org/0000-
0001-5863-0804; Email: xcwang@nankai.edu.cn
Authors
Jun-Jie Tian − State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China
Ning Liu − State Key Laboratory and Institute of Elemento-
Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China
Qi-Fei Liu − State Key Laboratory and Institute of Elemento-
Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China
Scheme 2. Synthetic Applications
Wei Sun − State Key Laboratory and Institute of Elemento-
Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c00006
Author Contributions
†J.-J.T. and N.L. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (Nos. 91956106 and 21871147),
the Natural Science Foundation of Tianjin (Nos. 20JCZDJC-
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(7) (a) Zhang, H.-J.; Zhong, F.; Xie, Y.-C.; Yin, L. Catalytic
Asymmetric Mannich-Type Reaction Enabled by Efficient Dienoliza-
tion of α,β-Unsaturated Pyrazoleamides. Chin. J. Chem. 2021, 39, 55−
61. (b) Zhong, F.; Yue, W.-J.; Zhang, H.-J.; Zhang, C.-Y.; Yin, L.
Catalytic Asymmetric Construction of Halogenated Stereogenic
Carbon Centers by Direct Vinylogous Mannich-Type Reaction. J.
Am. Chem. Soc. 2018, 140, 15170−15175. (c) Zhang, H.-J.; Shi, C.-Y.;
Zhong, F.; Yin, L. Direct Asymmetric Vinylogous and Bisvinylogous
Mannich-Type Reaction Catalyzed by a Copper(I) Complex. J. Am.
Chem. Soc. 2017, 139, 2196−2199.
00720 and 20JCJQJC00030), the NCC Fund (No. NCC2020-
PY10), and the Fundamental Research Funds for Central
Universities (No. 2122018165). X.-C.W. thanks the Tencent
Foundation for support via the Xplorer Prize. This paper is
dedicated to the 100th anniversary of Chemistry at Nankai
University.
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model is included in the Supporting Information.
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