Rhodium-Catalyzed Regio- And Enantioselective Allylic Amination of Racemic 1,2-Disubstituted Allylic Phosphates

Article abstract of DOI:10.1021/jacs.1c04016

Alkynylphosphines are rarely used as ligands in asymmetric metal catalysis. We synthesized a series of chiral bis(oxazoline)alkynylphosphine ligands and used them in Rh-catalyzed highly regio- and enantioselective allylic amination reactions of 1,2-disubstituted allylic phosphates. Chiral 1,2-disubstituted allylic amines were synthesized in up to 95% yield with >20:1 branched/linear (b/l) ratio and 99% ee from racemic 1,2-disubstituted allylic precursors. The sterically smaller linear alkynyl group on the P atom in the bis(oxazoline)alkynylphosphine ligands was the key to fit the new requirements of the introduction of bulky 2-R′ groups.

Full text of DOI:10.1021/jacs.1c04016

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Rhodium-Catalyzed Regio- and Enantioselective Allylic Amination of
Racemic 1,2-Disubstituted Allylic Phosphates
Wen-Bin Xu,† Minghe Sun,† Mouhai Shu, and Changkun Li*
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ABSTRACT: Alkynylphosphines are rarely used as ligands in asymmetric metal catalysis. We synthesized a series of chiral
bis(oxazoline)alkynylphosphine ligands and used them in Rh-catalyzed highly regio- and enantioselective allylic amination reactions
of 1,2-disubstituted allylic phosphates. Chiral 1,2-disubstituted allylic amines were synthesized in up to 95% yield with >20:1
branched/linear (b/l) ratio and 99% ee from racemic 1,2-disubstituted allylic precursors. The sterically smaller linear alkynyl group
on the P atom in the bis(oxazoline)alkynylphosphine ligands was the key to fit the new requirements of the introduction of bulky 2-
R′ groups.
Scheme 1. Transition-Metal-Catalyzed Regio- and
Enantioselective Synthesis of Acyclic 1,2-Disubstituted
Allylic Products
ransition-metal-catalyzed asymmetric allylic substitution
of monosubstituted allylic substrates with soft nucleo-
T
philes has been well-established for the regio- and
enantioselective preparation of chiral allylic products in the
presence of Ir, Rh, Pd, Ru, Mo, Co, and other metal
complexes.1 However, the synthesis of chiral acyclic 1,2-
disubstituted allylic products is much less explored and
challenging when an extra 2-alkyl group is introduced (Scheme
1a). In the 1,2-disubstituted π-allylmetal complexes, the energy
difference between the syn π-allylmetal complex A and the anti
complex B becomes smaller because of steric repulsion
between the R and R′ groups.2 Moreover, Z/E control in the
substrate synthesis and the lower reactivity of linear
trisubstituted allylic precursors make it more difficult to get
high efficiency and enantioselectivity (Scheme 1b). Reactions
starting from the more reactive branched racemic allylic
substrates require a challenging dynamic kinetic asymmetric
transformation process after the introduction of the 2-R′
group. To the best of our knowledge, with the well-explored Ir
and Rh catalysts, the only successful example was the allylic
alkylation of dioxinone-derived enol silanes from linear 2-
methyl-substituted allylic precursors reported by Hartwig3
(Scheme 1c). The synthesis of chiral allylic compounds with 2-
alkyl groups bulkier than methyl has rarely been reported.4−7
The development of new efficient catalysts for the preparation
of such compounds is highly desired. In the present work, we
synthesized a series of chiral tridentate bis(oxazoline)-
alkynylphosphine ligands, which could be used in highly
regio- and enantioselective allylic amination of racemic 1,2-
disubstituted allylic phosphates (Scheme 1d). Chiral 1,2-
disubstituted allylic amines could be obtained in up to 95%
yield with >20:1 branched/linear (b/l) ratio and 99% ee.
Recently, our group developed new catalyst systems based
on Co/Rh and bis(oxazoline)phosphine ligands for highly
branch- and enantioselective synthesis of monosubstituted
allylic compounds.8 The excellent enantioselectivity obtained
for this reaction was assigned to the high exo/endo ratio in the
π-allylmetal intermediate. Analysis of the crystal structure of
Received: April 16, 2021
Published: May 24, 2021
https://doi.org/10.1021/jacs.1c04016
J. Am. Chem. Soc. 2021, 143, 8255−8260
© 2021 American Chemical Society
8255

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Communication
the π-allylrhodium−NPN* complex indicates that the 2-H of
the allyl group is located very close to the ortho hydrogen of
the phenyl group on the P atom (2.024 Å; dashed cyan line in
Figure 1a).8c The introduction of a bulky R2 group to replace
Table 1. Optimization of Rh-Catalyzed Asymmetric Allylic
Amination of Racemic 1,2-Disubstituted Allylic
Phosphates
a
b
c
entry
ligand
yield of 3aa (%)
ee of 3aa (%)
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
L6
39
49
32
41
48
72
52
67
91
47
80
90
90
63
96
82
86
97
Figure 1. Rational modification of the ligand to fit the requirement of
the bulky 2-alkyl group.
d
9
a
Conditions: 1a (0.4 mmol, 1.0 equiv), 2a (0.8 mmol, 2.0 equiv),
Rh(cod)2BF4 (0.01 mmol, 0.025 equiv), and the ligand (0.01 mmol,
0.025 equiv) in CH3CN (2 mL). Isolated yields. Determined by
b
c
the hydrogen atom at the 2-position of the allyl group in the π-
allylrhodium complex may cause repulsion between this R2
group and the phenyl group in the ligand and result in the low
exo/endo selectivity and enantioselectivity (Figure 1b). We
envisioned that rational modification of the phenyl group on
the P atom to a smaller group would lead to a new balance for
the 2-R2 group, giving the same exo/endo selectivity in the new
1,2-disubstituted π-allylrhodium complex as in the monosub-
stituted π-allylrhodium complex. In this work, we present our
result that a smaller alkynyl group on the P atom was identified
to be a perfect solution to realize the dynamic kinetic
asymmetric allylic amination of racemic 1,2-disubstituted
allylic phosphates.
d
HPLC with a chiral column. The reaction time was 40 h.
with a tert-butyl group afforded the 3aa in the highest yield of
72% with 96% ee (entry 6), while L5 with a phenyl group and
L7 with a triisopropylsilyl group led to 62% and 82% ee,
respectively (entries 5 and 7). The substituents on the
oxazoline rings can also influence the enantioselectivity. L8
with tert-butyl groups at R2 led to a lower 86% ee (entry 8).
Finally, when the reaction time was extended to 40 h, 3aa was
isolated in 91% yield with 97% ee (entry 9). In all cases, a
>20:1 b/l ratio was obtained.
With the optimized conditions in hand (Table 1, entry 9),
the reaction scope of anilines and allylic phosphates was
examined. (Scheme 2). The synthesis of 3aa could be
conducted on a 10 mmol scale, and the enantioselectivity
remained at 97% ee. The absolute configuration of 3aa was
assigned to be R by single-crystal X-ray diffraction analysis of
the HCl salt of 3aa. The R configuration of 3aa is consistent
with the hypothesis that the same exo/endo selectivity could
be expected when a smaller alkynyl group is used to fit the size
of the 2-ethyl group. Electron-neutral, electron-donating, and
electron-withdrawing groups could be tolerated at the para
position of the aniline (3ab−af). A high yield was obtained
when o-methoxyaniline (2g) was used as the nucleophile,
although a slightly reduced 92% ee was observed. The allylic
phosphate side was further examined. Besides a 2-ethyl group,
2-methyl-, 2-benzyl-, and 2-n-decanyl-substituted allylic
phosphates reacted smoothly to give the corresponding allylic
amines with high ees (3ba to 3da). However, the allylic
phosphate with a more sterically hindered 2-isopropyl group
failed to give the desired product.11 Functional groups of olefin
and benzyl ether could be tolerated, giving 3ea and 3fa. Cyclic
allylic amine 3ga was prepared in 69% yield with 99% ee by
further intramolecular amination of the chloride-containing
substrate. The substituent at R2 could be further extended to
We started the investigation with racemic 1-n-propyl-2-
ethylallylic phosphate 1a and 4-methoxyaniline (2a) as the
model substrates (Table 1). In the presence of Rh(cod)2BF4
and NPN ligand L1 with phenyl on the P atom, after 12 h of
heating in CH3CN at 80 °C, the desired product 3aa was
obtained in 39% yield with a moderate 47% ee (entry 1). When
less reactive allylic methyl carbonate 1a′ was used under the
same conditions, no conversion was observed. The extra ethyl
group at the 2-position retards the oxidative addition of the
rhodium complex with allylic carbonates. As predicted, when
the phenyl group on the P atom was replaced by a smaller
methyl group, a higher 80% ee was obtained (entry 2), which
supports our hypothesis that the size of the group on the P
atom has a significant effect on the enantioselectivity. Although
hydrogen is smaller than the methyl group, the possible air
sensitivity of the ligand turned our attention to other less
bulkier groups. Inspired by the triethynylphosphine ligands
developed by the Sawamura group9 and the alkynylP* ligands
reported by Imatomo,10 L3−L8 with an alkynyl group were
synthesized. To our delight, 90% ee was observed with L3 or
L4, although the yields were lower (entries 3 and 4). The
substituent on the alkyne plays a key role in the
enantioselectivity as well. The reaction in the presence of L6
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Communication
a
a
Scheme 2. Scope of Anilines and Allylic Phosphates
Scheme 3. Scope of Other Nucleophiles
a
Conditions: 1 (0.4 mmol, 1.5 equiv), 2 (0.8 mmol, 2.0 equiv),
Rh(cod)2BF4 (0.01 mmol, 0.025 equiv), and L6 (0.01 mmol, 0.025
b
equiv) in CH3CN (2 mL). The methyl allyl carbonate was used.
unoptimized conditions. Finally, malononitrile (4h) could be
utilized as the nucleophile to give 5kh in 70% yield with 94% ee
under neutral conditions.
Some control experiments were conducted to gain
mechanistic insight into the Rh-catalyzed asymmetric allylic
amination. The reactivity of branched 1,2-disubstituted allylic
phosphate 1a toward a stoichiometric amount of Rh-
(cod)2BF4/L6 complex was examined (Scheme 4a). After 12
h of heating in CH3CN, π-allylrhodium complex 6 was isolated
in 97% yield. This complex was characterized as a single isomer
in solution according to 1H and 31P NMR spectroscopy.
Unfortunately, no crystal of 6 suitable for X-ray analysis could
be obtained. The coordination of the OP(O)(OMe)2 group to
the metal center was confirmed by the dd peaks at 26.1 and 2.8
ppm in the 31P NMR spectrum, which were assigned to be the
P atoms in the NPN ligand and the phosphate, respectively.
The reaction of 6 with 2 equiv of 2a afforded 3aa in 84% yield
with 94% ee (Scheme 4b). 6 can also be used as the catalyst to
convert 1a and 2a to 3aa in high yield (Scheme 4c), which
indicates that 6 is involved as the reactive intermediate in the
catalysis. Finally, when bulky nucleophiles are used, the E-
linear product is expected to be formed from the syn-π-
allylrhodium intermediate, while the Z-linear product can be
generated from the anti-π-allylrhodium complex (Scheme
4d).12 N-Methylaniline (2h) reacted with 6 as the nucleophile
to give exclusively E-linear 3ah′ in 80% yield (as confirmed by
NOE experiment). The E configuration of 3ah′, the R
configuration of 3aa, and the nuclear Overhauser effect
spectroscopy (NOESY) analysis of complex 6 (see the
a
Conditions: 1 (0.4 mmol, 1.5 equiv), 2 (0.8 mmol, 2.0 equiv),
Rh(cod)2BF4 (0.01 mmol, 0.025 equiv), and L6 (0.01 mmol, 0.025
b
equiv) in CH3CN (2 mL). The reaction was run on a 10 mmol scale.
c
L8 was used instead of L6.
phenyl and chloride under the identical conditions (3ha and
3ia). In addition to the n-propyl and phenylethyl groups,
substrates bearing methyl, isopropyl, and cyclohexyl groups as
R1 were also converted to allylic amines 3ja−la in high yields
and enantioselectivities.
The scope of more basic aliphatic amines was also examined
under the optimized conditions (Scheme 3). Benzylamine and
2-phenylethylamine were good nucleophiles, giving the
secondary amines 5aa and 5ab, respectively, with 99% ee.
Amines with heterocyclic pyridine, 1,3-benzodioxolane, and
thiophene were transformed to the corresponding products
5ac−ae in high yields and ee’s. Chiral (S)-2-amino-3-
phenylpropan-1-ol and (S)-1-phenylethanamine reacted
under the optimized conditions to give amines 5af and 5ag,
respectively, with >20:1 dr. Variation of the group at the R2
position to methyl, benzyl, and n-decanyl as well as olefin- and
ether-containing groups had little influence on the results of
the allylic substitution reaction (5ba−fa). However, the ee of
phenyl-substituted allylic amine 5ha dropped to 88% under the
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Communication
with moderate dr and high ee, which can be used to prepare
molecules with two consecutive chiral centers.
Scheme 4. Control Experiments
In conclusion, we have designed and synthesized novel
bis(oxazoline)phosphine ligands with alkynyl functions on the
P atom after analysis of the monosubstituted allylrhodium−
NPN complex. These ligands could be used to fit the new
requirements of the bulky 2-R′ groups in Rh-catalyzed regio-
and enantioselective allylic amination reactions of challenging
1,2-disubstituted allylic precursors. Chiral 1,2-disubstituted
allylic amines were synthesized in up to 95% yield with >20:1
branched/linear ratio and 99% ee.13 Rational modification of
the NPN ligands to solve the other problems in enantiose-
lective allylic substitution reactions is under investigation in
our group.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c04016.
Detailed experimental procedures, characterization data,
1
and copies of H and 13C NMR and HPLC spectra
(PDF)
Accession Codes
Supporting Information) support that the syn-π-allylrhodium−
NPN* complex exists as the reactive intermediate.
The chiral 1,2-disubstituted allylic amines could be trans-
formed into different chiral products after further functional
group manipulations (Scheme 5). Compound 7 was isolated in
CCDC 2078097 contains the supplementary 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
Scheme 5. Synthetic Applications of Chiral 1,2-
a
Disubstituted Allylic Amine Derivatives
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
Authors
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
Minghe Sun − 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
Mouhai Shu − 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/0000-0002-8556-
7369
a
Conditions: (a) (1) TsCl, pyridine, DCM, 0 °C to rt, 12 h; (2)
NaIO4, RuCl3, 2,6-lutidine, DCM/CH3CN/H2O (1:1:1.5), rt, 12 h.
(b) (1) Acryloyl chloride, pyridine, DCM, 0 °C to rt, 12 h; (2)
Grubbs-II, toluene, 100 °C, 40 h. (c) 9-BBN, 0 °C to rt, 12 h, then
EtOH, NaOH, H2O2 (30%). (d) (1) TsCl, pyridine, DCM, 0 °C to rt,
12 h; (2) m-CPBA, DCM.
79% yield with 94% ee by N-Ts protection and oxidative
cleavage of the C−C double bond (route a). Chiral lactam 8
was produced in 62% overall yield by N-protection with
acryloyl chloride followed by ring-closing metathesis (route b).
Oxidation of the double bond in 3aa with 9-BBN/H2O2 (route
c) and m-CPBA (route d) produced 9 and 10, respectively,
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c04016
Author Contributions
†W.-B. Xu and M. Sun contributed equally.
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Communication
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Grant 21602130) and the startup fund
of Shanghai Jiao Tong University.
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