Cobalt-Catalyzed Regio- A nd Enantioselective Allylic Alkylation of Malononitriles

Article abstract of DOI:10.1021/acs.orglett.0c00962

Cobalt-catalyzed highly branched- A nd enantioselective allylic alkylation of malononitriles has been developed. Chiral ?,?′-unsaturated malononitriles could be synthesized with >20:1 branched/linear regioselectivity and up to 99% enantiomeric excess from easily accessible racemic allylic carbonates under mild reaction conditions. The electron-rich and sterically less hindered bisoxazolinephosphine ligand is essential to realize the high reactivity in the carbon-carbon bond formation process.

Full text of DOI:10.1021/acs.orglett.0c00962

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Letter
Cobalt-Catalyzed Regio- and Enantioselective Allylic Alkylation of
Malononitriles
Samir Ghorai, Sajid Ur Rehman, Wen-Bin Xu, Wen-Yu Huang, and Changkun Li*
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ABSTRACT: Cobalt-catalyzed highly branched- and enantiose-
lective allylic alkylation of malononitriles has been developed.
Chiral γ,δ-unsaturated malononitriles could be synthesized with
>20:1 branched/linear regioselectivity and up to 99% enantiomeric
excess from easily accessible racemic allylic carbonates under mild
reaction conditions. The electron-rich and sterically less hindered
bisoxazolinephosphine ligand is essential to realize the high
reactivity in the carbon−carbon bond formation process.
Scheme 1. First-Row Transition-Metal-Catalyzed Branch-
Selective Allylic Alkylation of Soft Carbon Nucleophiles
ransition-metal-catalyzed asymmetric allylic substitutions
Tprovide an efficient tool for the selective construction of
carbon−carbon bonds, which is the central task in organic
synthesis.1 From monosubstituted allylic substrates, chiral
allylic products could be synthesized regioselectively and
enantioselectively with suitable catalysts based on Pd,2 Ir,3 Rh,4
Ru,5 or relatively abundant Mo.6 Catalysts based on abundant
and inexpensive first-row transition metals are highly desired,
in terms of sustainability and economics. Cu-catalyzed allylic
substitution of linear allylic substrates provide an elegant
solution for hard carbon nucleophiles (organometallic
reagents).7 Nevertheless, the regiocontrol and enantiocontrol
for soft carbon nucleophiles by first-row transition-metal
catalysts is still very rare. The Plietker group reported the
regiospecific and stereospecific carbon−carbon bond forma-
tion by [Bu4N][Fe(CO)3(NO)] and PPh3 (Scheme 1a).8 A
chiral ligand is not available for the enantioselective version of
this iron catalysis. Recently, Kojima and Matsunaga developed
a cobalt-catalyzed branch-selective allylic alkylation enabled by
photoredox catalysis, for which an enantioselective reaction is
not efficient (Scheme 1b).9 On the other hand, the reaction of
easily accessible racemic branched allylic substrates bearing
alkyl groups is still challenging, with the problems of low
regioselectivities and enantioselectivities. C−N bond formation
has been recently realized by Krische, Nguyen and Breit with Ir
and Rh, respectively.10 The highly selective C−C bond
construction from this type of difficult substrate is very
rare.11 Herein, we report the first-row transition-metal Co-
catalyzed highly regioselective and enantioselective allylic
alkylation of malononitriles to control the chirality in the
allylic moiety.12,13 Chiral γ,δ-unsaturated malononitriles could
be rapidly accessed with branch/linear ratios of >20:1 and up
to 99% enantiomeric excess (ee) using the electron-rich and
sterically less hindered bisoxazolinephosphine (NPN) ligand
(Scheme 1c).
Received: March 16, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00962
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Recently, our group successfully developed the cobalt-
catalyzed highly regioselective and enantioselective allylic
amination from anilines and aliphatic amines,14,15 in which
the use of chiral bisoxazolinephosphine ligand is the key to
control the regioselectivities and enantioselectivities. Com-
pared to nitrogen nucleophiles, the reaction of soft carbon
nucleophiles is more challenging for two reasons. First, the
carbon pronucleophiles are not basic and nucleophilic
themselves. An extra base or the released alkoxide from the
carbonate substrate to deprotonate the pronucleophiles before
the nucleophilic attack is likely to be incompatible with the
cobalt catalyst. Second, the carbon nucleophiles are sterically
more hindered than nitrogen nucleophiles, which may lead to
difficulty in C−C bond formation and the enantiocontrol
process, because of the relatively small size of the Co metal
atom. The modular synthesis of the chiral NPN ligands
encouraged us to modify the electronic and steric nature of the
catalyst.
2−4). In contrast, L5 with the smaller methyl group makes the
reaction more reactive and 33% of 3aa was isolated (Table 1,
entry 5). To our delight, the enantiomeric excess of 3aa is 99%
with all the ligands examined. Higher yield could be obtained
when the ratio of 1a and 2a was changed to 1:2 (Table 1, entry
6). The yield was further improved to 60% when 10 mol %
bis(trimethylsilyl)acetamide (BSA) was added as extra base
(Table 1, entry 7), which was used to increase the
concentration of the malononitrile anion. The effect of the
R1 group in the ligand then was investigated. 60% of 3aa was
isolated when L6 with electron-donating and bulkier 4-MeO-
3,5-tBu2C6H2 (DTBM) groups was used in the presence of 5
mol % cobalt catalyst (Table 1, entry 8). 86% yield was
obtained when two more methoxy groups were introduced at
the R3 position para to the phosphine, which further indicated
the beneficial effect of electron-donating group in the ligand
(Table 1, entry 9). Considering the size effect of ligands, L8
and L9 with a smaller methyl group at R1 were examined. High
conversions could also be realized (Table 1, entries 10 and 11).
Keeping the challenges in mind, we commenced our study
on allylic alkylation of malononitrile, which was selected as the
model substrate for its versatile functional group manipulation
(Table 1).16,17 Starting from 1.5 equiv racemic allylic
1
No linear regiomer of 3aa could be observed in the H NMR
of crude reaction mixture and 99% ee was obtained with all the
ligands tested.
With the optimized condition in hand (Table 1, entry 11),
the substrate scope of malononitriles of the Co-catalyzed
asymmetric allylic alkylation was evaluated (Scheme 2). First,
the reaction of simple malononitrile 2a was conducted at 5
mmol scale with 2.5 mol % Co catalyst. 930 mg of 3aa was
Table 1. Optimization for Co-Catalyzed Asymmetric Allylic
Alkylation of Malononitrile
a
a
Scheme 2. Scope of Malononitrile
b
c
entry
1a:2a
ligand
yield (%)
enantiomeric excess, ee (%)
1
2
3
4
5
6
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1:2
1:2
1:2
1:2
1:2
L1
L2
L3
L4
L5
L5
L5
L6
L7
L8
L9
30
15
<5
20
33
38
60
60
86
86
87
99
99
−
99
99
99
99
99
99
99
99
d
7
de
,
8
9
10
11
de
,
de
,
de
,
1:2
a
Conditions: The reactions were performed in 0.25 mmol scale in
b
c
CH3CN (1 mL). Isolate yield. The enantiomeric excess of 3aa was
determined by HPLC with a chiral column. 10 mol % bis-
(trimethylsilyl)acetamide (BSA) was added as a base. 5 mol %
d
e
Co(BF4)2·6H2O, 7.5 mol % of ligand, and 10 mol % of Zn were used.
carbonate 1a, different bisoxazolinephosphine ligands were
examined with 10 mol % Co(BF4)2·6H2O catalyst precursor
and 20 mol % Zn. Reaction with L1, which is the best ligand
for the allylic amination, gave the product 3aa in 30% yield,
which demonstrated the reactivity difference of malononitrile
(Table 1, entry 1). Reactions with bulkier L2−L4 were more
sluggish and lower conversions were observed (Table 1, entries
a
Conditions: 1a (0.25 mmol, 1.0 equiv), 2 (0.5 mmol, 2.0 equiv),
Co(BF4)2·6H2O (0.0125 mmol, 0.05 equiv), L9 (0.019 mmol, 0.075
equiv), Zn dust (0.025 mmol, 0.1 equiv), BSA (0.025 mmol, 0.1
equiv) and CH3CN (1 mL). Reaction at 5 mmol scale with 2.5
mol % Co(BF4)2·6H2O and 3.5 mol % L9.
b
B
https://dx.doi.org/10.1021/acs.orglett.0c00962
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pubs.acs.org/OrgLett
Letter
isolated in 89% yield and 99% ee, which indicated that this
reaction could be performed in a gram scale. The absolute
configuration of 3aa was assigned to be R by comparison with
that reported in literature.17b A variety of malononitriles with
α-alkyl groups were examined in the reaction. Benzyl and
substituted benzyl groups could be tolerated. 3ab−3ad with
vicinal quaternary and tertiary carbon centers could be
prepared in high yields and enantiomeric excesses. Malononi-
triles with 2-naphthyl, 2-pyrryl, 2-furyl and simple cyclohexyl
groups were also converted to the allylation products 3ae−3ah
smoothly. Allyl and propargyl groups can also be introduced
into the products 3ai and 3aj successfully without erosion of
regio- and enantioselectivities, which allows further synthetic
manipulations. Methyl cyanoacetate and bis(phenylsulfonyl)-
methane were utilized to prepare 3ak and 3al in moderate
yields under the identical condition.
Scheme 4. Reaction of Z-Linear Allylic Carbonate and
Kinetic Resolution Study
was not regiospecific and a π-allyl cobalt intermediate might be
involved. Kinetic resolution reaction was conducted as shown
in eq 2 in Scheme 4. When 1 equiv of racemic 1a reacts with
0.5 equiv 2a in the presence of 5 mol % of cobalt catalyst, 30%
of 3aa was isolated with 99% ee. Meanwhile, the unreacted 1a
was recovered in 64% yield and only 6% ee, indicating no
kinetic resolution of the substrate in the reaction.
The scope of the allylic carbonates was further examined as
shown in Scheme 3. With 2-benzylmalononitrile 2b as the
a
Scheme 3. Scope of Allylic Carbonates
The chiral malononitrile products could be transformed to
different chiral compounds (see Scheme 5). A simple oxidation
Scheme 5. Synthetic Application of the Chiral γ,δ-
a
Unsaturated Malononitriles
a
a
Conditions are described as follows: (a) for eq (1): magnesium
Conditions: 1 (0.25 mmol, 1.0 equiv), 2b (0.5 mmol, 2.0 equiv),
monoperoxyphthalate hexahydrate (MMPP, 0.92 equiv) and Li2CO3
(1.5 equiv), MeOH, 0 °C, 3 h; for eq (2): LiAlH4 (4 equiv), THF, 0
°C to rt, 5 h; (b) Grubbs II (0.1 equiv), 40 °C, DCM, 16 h; (c) PtCl2
(0.04 equiv), 80 °C, toluene, 4 h; and (d) guanidine hydrochloride
Co(BF4)2·6H2O (0.0125 mmol, 0.05 equiv), L9 (0.019 mmol, 0.075
equiv), Zn dust (0.025 mmol, 0.1 equiv), BSA (0.025 mmol, 0.1
equiv) and CH3CN (1 mL).
b
(1.25 equiv), NaOEt (1.5 equiv), EtOH, reflux, 12 h. 7 could not be
model substrate, a variety of branched allyl methyl carbonates
react smoothly to give the branched products in high yields.
Simple methyl, n-propyl, and alkyl group with TBS-protected
hydroxyl, as well as the β-branched isobutyl group, could be
tolerated in this transformation (3bb−3eb). Carbonate with a
cyclopropyl group was converted to the product 3fb in 95%
yield without ring opening, which implied that an allyl radical
mechanism might not be involved. The reactions of α-
branched isopropyl and cyclohexyl containing carbonates are
relatively sluggish. 3gb and 3hb were isolated in moderate
yields. Finally, the aromatic phenyl group could be tolerated
and 89% of the product 3ib was isolated with 99% ee.
We next examined the Co-catalyzed allylic alkylation from
linear cinnamyl methyl carbonate 1j (see Scheme 4, eq 1).
Compared to the branched carbonate 1i, the reaction of 1j was
slower. 45% of 3ja was isolated, even in the presence of 10
mol % of cobalt catalyst at higher temperature (60 °C).
However, the same level of regioselectivity and enantioselec-
tivity were observed. This result also indicated that the reaction
separated in high-performance liquid chromatography (HPLC).
and reduction manipulation of monosubstituted malononitrile
3aa delivered the chiral homoallylic alcohol 4 in 68% yield
without any erosion of enantioselectivity (99% ee). The
availability of the chiral 1,6-diene 3ai and enyne 3aj allowed
the rapid construction of chiral carbon cycles 5 and 6 by ring-
closing metathesis with Grubbs-II catalyst or cycloisomeriza-
tion with PtCl2, respectively. Furthermore, addition reaction of
guanidine to 3aa under basic conditions afforded the chiral
heterocyclic compound 7 in 82% yield.
In conclusion, we have developed cobalt-catalyzed highly
regioselective and enantioselective allylic alkylation of stabi-
lized carbon nucleophiles to control the chirality in the allyl
moiety. Chiral γ,δ-unsaturated malononitriles could be
synthesized with >20:1 branched/linear regioselectivity and
up to 99% ee from easily accessible racemic allylic carbonates
under mild reaction conditions. The modular synthesis of the
C
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Int. Ed. 2008, 47, 258−297. For a recent book, see: (d) Transition
Metal Catalyzed Enantioselective Allylic Substitution in Organic
Synthesis; Kazmaier, U., Ed.; Springer Verlag: Berlin and Heidelberg,
Germany, 2012.
chiral bisoxazolinephosphine ligands allows the easy mod-
ification of the electronic and steric nature of the catalyst to fit
the requirement of the bulky carbon nucleophiles. Further
investigation on novel nucleophiles under the cobalt/
bisoxazolinephosphine system is underway in our group.
(2) For selected examples on Pd-catalyzed highly branched and
enantioselective allylations, see: (a) You, S.-L.; Zhu, X.-Z.; Luo, Y.-M.;
Hou, X.-L.; Dai, L.-X. Highly Regio- and Enantioselective Pd-
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Hou, X.-L. Highly Regio-, Diastereo-, and Enantioselective Pd-
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7718−7719. (c) Katcher, M. H.; Sha, A.; Doyle, A. G. Palladium-
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Cai, A.; Xie, J.; Kleij, A. W. Asymmetric Synthesis of α,α-
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A.; Kleij, A. W. Regio- and Enantioselective Preparation of Chiral
Allylic Sulfones Featuring Elusive Quaternary Stereocenters. Angew.
Chem., Int. Ed. 2019, 58, 14944−14949.
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00962.
Detailed experimental procedures, characterization data,
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copies of H, 13C NMR spectra, HPLC spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Changkun Li − Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs, School of Chemistry and Chemical
Engineering, Frontiers Science Center for Transformative
Molecules, Shanghai Jiao Tong University, Shanghai 200240,
China; orcid.org/0000-0002-4277-830X; Email: chkli@
sjtu.edu.cn
(3) For selected reviews on Ir, see: (a) Hartwig, J. F.; Stanley, L. M.
Mechanistically Driven Development of Iridium Catalysts for
Asymmetric Allylic Substitution. Acc. Chem. Res. 2010, 43, 1461−
1475. (b) Hethcox, J. C.; Shockley, S. E.; Stoltz, B. M. Iridium-
Catalyzed Diastereo-, Enantio-, and Regioselective Allylic Alkylation
with Prochiral Enolates. ACS Catal. 2016, 6, 6207−6213. (c) Qu, J.;
Helmchen, G. Applications of Iridium-Catalyzed Asymmetric Allylic
Substitution Reactions in Target-Oriented Synthesis. Acc. Chem. Res.
2017, 50, 2539−2555. (d) Cheng, Q.; Tu, H.-F.; Zheng, C.; Qu, J.-P.;
Helmchen, G.; You, S.-L. Iridium-Catalyzed Asymmetric Allylic
Substitution Reactions. Chem. Rev. 2019, 119, 1855−1969.
Authors
Samir Ghorai − Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs, School of Chemistry and Chemical
Engineering, Frontiers Science Center for Transformative
Molecules, Shanghai Jiao Tong University, Shanghai 200240,
China
Sajid Ur Rehman − Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs, School of Chemistry and Chemical
Engineering, Frontiers Science Center for Transformative
Molecules, Shanghai Jiao Tong University, Shanghai 200240,
China
̈
(e) Rossler, S. L.; Petrone, D. A.; Carreira, E. M. Iridium-Catalyzed
Asymmetric Synthesis of Functionally Rich Molecules Enabled by
(Phosphoramidite, Olefin) Ligands. Acc. Chem. Res. 2019, 52, 2657−
2672.
(4) For recent reviews on rhodium-catalyzed asymmetric allylations,
see: (a) Turnbull, B. W. H.; Evans, P. A. Asymmetric Rhodium-
Catalyzed Allylic Substitution Reactions: Discovery, Development
and Applications to Target-Directed Synthesis. J. Org. Chem. 2018,
83, 11463−11479. (b) Thoke, M. B.; Kang, Q. Rhodium-Catalyzed
Allylation Reactions. Synthesis 2019, 51, 2585−2631. (c) Koschker,
P.; Breit, B. Branching Out: Rhodium-Catalyzed Allylation with
Alkynes and Allenes. Acc. Chem. Res. 2016, 49, 1524−1536.
(5) For selected examples on Ru, see: (a) Onitsuka, K.; Okuda, H.;
Sasai, H. Regio- and Enantioselective O-Allylation of Phenol and
Alcohol Catalyzed by a Planar-Chiral Cyclopentadienyl Ruthenium
Complex. Angew. Chem., Int. Ed. 2008, 47, 1454−1457. (b) Kanbaya-
shi, N.; Onitsuka, K. Enantioselective Synthesis of Allylic Esters via
Asymmetric Allylic Substitution with Metal Carboxylates Using
Planar-Chiral Cyclopentadienyl Ruthenium Catalysts. J. Am. Chem.
Soc. 2010, 132, 1206−1207. (c) Trost, B. M.; Rao, M.; Dieskau, A. P.
A Chiral Sulfoxide-Ligated Ruthenium Complex for Asymmetric
Catalysis: Enantio- and Regioselective Allylic Substitution. J. Am.
Chem. Soc. 2013, 135, 18697−18704.
Wen-Bin Xu − Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs, School of Chemistry and Chemical
Engineering, Frontiers Science Center for Transformative
Molecules, Shanghai Jiao Tong University, Shanghai 200240,
China
Wen-Yu Huang − Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs, School of Chemistry and Chemical
Engineering, Frontiers Science Center for Transformative
Molecules, Shanghai Jiao Tong University, Shanghai 200240,
China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00962
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(6) For reviews on Mo, see: (a) Belda, O.; Moberg, C.
Molybdenum-Catalyzed Asymmetric Allylic Alkylations. Acc. Chem.
Res. 2004, 37, 159−167. (b) Moberg, C. Molybdenum-Catalyzed and
Tungsten-Catalyzed Enantioselective Allylic Substitutions. Top.
Organomet. Chem. 2011, 38, 209−234.
■
This work is supported National Natural Science Foundation
of China (NSFC) (Grant No. 21602130) and the starting fund
of Shanghai Jiao Tong University.
̈
(7) For recent reviews on Cu, see: (a) Alexakis, A.; Backvall, J. E.;
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