Cu-Catalyzed Asymmetric Aminoboration of E-Vinylarenes with pivZPhos as the Ligand

Article abstract of DOI:10.1021/acs.orglett.9b03328

A Cu-catalyzed enantioselective aminoboration of E-vinylarenes with ^pivZPhos as a ligand is reported. Enantioenriched aminoborates are prepared with excellent regio- and enantioselectivities up to >99:1 er under the optimized conditions. The ut

Full text of DOI:10.1021/acs.orglett.9b03328

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cu-Catalyzed Asymmetric Aminoboration of E‑Vinylarenes with
pivZPhos as the Ligand
Linglin Wu,*,† Olga Zatolochnaya,† Bo Qu,† Ling Wu,† Lucille A. Wells,‡ Marisa C. Kozlowski,‡
Chris H. Senanayake,†,§ Jinhua J. Song,† and Yongda Zhang*,†
†Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368,
Ridgefield, Connecticut 06877-0368, United States
‡Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
S
* Supporting Information
ABSTRACT: A Cu-catalyzed enantioselective aminoboration of E-vinylarenes with pivZPhos as a ligand is reported.
Enantioenriched aminoborates are prepared with excellent regio- and enantioselectivities up to >99:1 er under the optimized
conditions. The utility of the current method was further established by rapid conversion of an adduct to a chiral
benzo[f ][1,4]oxazepine. A model for the stereochemistry of the asymmetric aminoboration process, which agrees with the
experimental outcomes, was generated by computational analysis of the systems.
lkenes are among the most ubiquitous prochiral func-
borates. Recently, we developed the N-BABIPhos family of
chiral biaryl phosphines, and pivZPhos was found to be an
effective ligand in the Cu-catalyzed asymmetric hydrogenation
of ketones.6 Herein, we report the discovery of pivZPhos as a
highly effective ligand in the Cu-catalyzed asymmetric
aminoboration of various E-vinylarenes, delivering the β-
aminoborates with up to >99:1 er.
Our work commenced with the ligand screening for the
asymmetric aminoboration of the trans-β-methylstyrene 1a
with different bidentate ligands under the reported conditions4
(Scheme 1). The use of (R,R)-Me-DuPhos delivered 4a′ in
72% yield and 93:7 er as reported by the Miura group. The
application of (R)-BINAP gave a low yield of 4a′, and the
enantioselectivity was marginal. When BIBOP was used, the
enantioselectivity was improved to 83:17 er, while the
application of more hindered BIDIME-dimer, encouragingly,
gave 93:7 er and 72% yield.7 O-BABIPhos8 delivered the same
enantioselectivity with lower yield of 42%. Replacing the
heterocyclic oxygen in O-BABIPhos with a nitrogen or
substituted nitrogen provides the opportunity to tune the
electronic and steric properties of the phosphine center. Thus,
we examined the N-BABIPhos series, namely, the ZPhos
ligands. When unsubstituted ZPhos was used, the enantiose-
1
Ational groups,
allowing synthetic chemists to access
chiral compounds in a single step. In this context, asymmetric
difunctionalization reactions of alkenes by addition of two
functional groups to the same double bond are particularly
important and attractive, affording products with highly
complex molecular architectures in an efficient and sustainable
manner.2 Although significant efforts have been devoted to this
area, enantioselective functionalization of alkenes with high
stereoselectivies is still very challenging.3 In 2013, Hirano,
Miura, and coauthors first reported a Cu-catalyzed amino-
boration of styrenes for synthesis of β-aminoalkylboranes by
simultaneous addition of B and N groups to C−C unsaturated
molecules regioselectively under mild conditions.4 Amino
groups are common fragments in natural products and
pharmaceuticals. Organoborons are versatile precursors in
the synthesis of complex natural products, biologically active
compounds, and functional materials. Thus, this approach
affords highly useful building blocks by introducing amino
groups and organoboron groups efficiently in a single step.
While asymmetric aminoborations of different aryl alkenes
were investigated by Hirano, Miura, and coauthors, moderate
to high enantioselectivities were observed with only limited
examples.5 Therefore, it is highly desirable to develop an
efficient catalytic system for asymmetric aminoboration of
various alkenes to afford highly enantioenriched β-amino-
Received: September 20, 2019
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.9b03328
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Letter
Scheme 1. Ligand Screening for Asymmetric Aminoboration
of Alkene 1a
Table 1. Optimization of Reaction Conditions with pivZphos
as the Ligand for Asymmetric Aminoboration of Alkenes
a
a
entry
catalyst
CuCl
CuCl
CuCl
CuCl
CuTc
CuI
CuBr
CuOAc
CuOTf·PhH
CuOTf·Tol
CuOTf
CuCl dimer
CuCl2
CuOTf
CuOTf
CuOTf
CuOTf
CuOTf
base
solvent
yield
er
1
2
3
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
NaOtBu
KOtBu
LiOtBu
LiOtBu
LiOtBu
THF
toluene
dioxane
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
65%
12%
49%
15%
54%
39%
49%
36%
73%
70%
73%
65%
56%
47%
42%
37%
<5%
65%
98:2
96:4
97:3
>99:1
96:4
98:2
90:10
98:2
>99:1
>99:1
>99:1
>99:1
97:3
>99:1
>99:1
>99:1
-
b
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
c
d
e
f
>99:1
a
All the reactions were performed with 1a (0.20 mmol), 2a (0.30
a
All the reactions were performed with 1a (0.20 mmol), 2a (0.30
mmol), pinB−Bpin 3 (0.30 mmol), and MO-t-Bu (0.60 mmol) in
mmol), pinB−Bpin 3 (0.30 mmol), and LiO-t-Bu (0.60 mmol) in
THF (1.5 mL) at rt for 16 h under argon. See ref 4. The yield was
determined by HPLC The er was determined by chiral HPLC.
solvent (1.5 mL) at rt for 16 h under argon as indicated in the table
b
c
b
c
unless noted otherwise. The reaction was run at 0 °C. CuCl dimer:
d
d
e
[Cu(pivZphos)Cl]2. See ref 6. 5 mol % CuOTf was used. Z-alkene
f
was used. 1:1 E and Z-alkene was used and the yield is based on E-
alkene.
lectivity was lost, and only 54:46 er was observed. Switching to
PhZPhos gave none of the desired product. The use of PcZPhos
with the urea led to low enantioselectivity and low yield.
Eventually, we found that the application of sterically hindered
PivZPhos gave the product with 98:2 er and a good yield of
65%. The structure of the product 4a′ was confirmed by NMR
as well as by single crystal X-ray analysis. On the other hand,
the ligand (S,S)-Ph-BPE gave good enantioselectivity (97:3 er)
albeit with lower yield (51%). With these results at hand, we
focused on PivZPhos for further optimization in the amino-
boration of alkenes.
We first investigated the effect of solvent (Table 1) with
PivZPhos as the ligand. When THF, toluene, or 1,4-dioxane was
applied, similar enantioselectivities were observed (Table 1,
entries 1−3). In comparison, THF gave the best yield, and
much lower yield was observed with toluene. This result could
be related to the slower reaction in toluene due to the low
solubility of pinB-Bpin. Thus, THF was selected as the solvent
for the remaining studies. When the reaction was performed at
0 °C, 99:1 er was observed but the yield of 4a′ decreased to
15% after an overnight reaction (Table 1, entry 4). We further
tested different copper catalysts (Table 1, entries 5−13). In
comparison with CuCl, CuTc [copper(I) thiophene-2-
carboxylate], and CuCl2, CuOTf and its complexes with
benzene or toluene were found to work the best. The
enantioselectivity with CuOTf was improved to >99:1 er with
73% yield. CuOTf was then selected as the copper catalyst for
additional studies. Further investigation revealed that LiO-t-Bu
is the base of choice for the aminoboration; NaO-t-Bu and
KO-t-Bu gave the same enantioselectivity, but lower yields
were observed in both cases (Table 1, entries 14 and 15). With
the optimal base, we also ran the reaction with lower catalyst
(5 vs 10 mol %) loading, which caused the reaction to become
much slower, and low yield was observed after an overnight
reaction (Table 1, entry 16). To maintain adequate yields, 10
mol % of the catalyst was retained. We also investigated the
aminoboration of the corresponding Z-alkene under the
optimized conditions. After 16 h, only a trace amount of the
aminoboration product was observed (Table 1, entry 17), and
90% of the alkene was recovered. Clearly, the Z-alkene was
much less active with the optimized catalyst system implying
that a resolution might be viable. When 1:1 E and Z-alkene was
subjected to our reaction conditions, the product 4a′ was
obtained with 99:1 er and 65% yield based on the E-alkene
(Table 1, entry 18).
With the optimized conditions, we set out to delineate the
scope of the asymmetric aminoboration (Scheme 2). To
facilitate the isolation and determination of the enantiose-
lectivity by chiral HPLC, all the aminoboration products,
except 4a′, were directly oxidized to the corresponding
aminoalcohols with NaBO3. Under the standard conditions,
the product 4a′ was isolated with 70% yield and 99:1 er. The
introduction of electron-rich groups such as MeO on the
aromatic ring gave the products 4b−4d with 97:3 to 99:1 er.
With an electron-withdrawing group CF3 on the phenyl ring,
the reaction delivered the products 4e−4f with 97:3 er. In the
case of 1f, 20 mol % of regioisomer product was observed.9
Sterically hindered alkenes also worked well, and the products
4g−4h were isolated with good yields and 96:4 and 99:1 er,
respectively. For the alkenes with longer alkyl chains, the
B
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products 4i−4j with similar enantioselectivities were obtained.
The current protocol also tolerated multiple labile functional
groups including ester (4k) thioether (4l), chloro (4m),
bromo (4n), and iodo (4o). In all cases, the products were
isolated with moderate yields and excellent er. Compared with
aryl alkenes, heteroaryl alkenes have not been studied as well.
Initial attempts of the aminoboration of the 2-pyridinyl alkene
1p were very challenging. The product 4p was obtained with
less than 10% yield after reaction overnight. Control
experiments indicated that addition of pyridine to the reaction
with 4a did not stall the reaction, ruling out direct coordination
of pyridinyl substituent as the sole issue. We speculated that
the conjugation of the CC bond to the electron-deficient
pyridine ring could prevent its coordination to the Cu catalyst
and inhibit the catalysis.10 In comparison, when 3-pyridyl
alkene 1q was applied, the aminoboration proceeded smoothly,
and the product 4q was obtained with 97:3 er and 53% yield.
Other heteroaryl alkenes 1r and 1s also worked well under our
optimized conditions. For the benzothiophene and the
benzofuran, the products 4r and 4s were obtained with
excellent enantioselectivities and good yields. For methyl
cinnamate 1t, prop-1-en-2-ylbenzene 1u and (E)-(3-methyl-
but-1-en-1-yl) benzene 1v, no reaction was observed. These
outcomes may be related to the steric and electronic properties
of the alkene, which prevent the productive coordination of the
copper catalyst.
Various O-benzoyl-N,N-dialkylhydroxylamines were inves-
tigated under the optimized conditions (Scheme 3). Similar to
O-benzoyl-N,N-dibenzylhydroxylamine 2a, the reaction of
bulky 2b gave the product 4ab with excellent selectivity
(>99:1 dr) and slightly lower yield. For O-benzoyl-N,N-
diethylhydroxylamine 2c, the product 4ac was isolated with
>99:1 er and 61% yield. We also tested O-benzoyl cyclo-
alkylhydroxylamines. Only a trace amount of the product 4ad
was observed with piperidin-1-yl benzoate 2d. In the case of
azepan-1-yl benzoate 2e, 98.5:1.5 er and 52% yield were
obtained.
Scheme 3. Scope of Asymmetric Aminoboration with O-Bz
a,b
Amines
a
All the reactions were performed with alkene 1a (0.40 mmol), 2a−
2e (0.60 mmol), pinB−Bpin 3 (0.60 mmol), and LiO-t-Bu (1.20
b
mmol) in THF (3.0 mL) at rt for 16 h under argon. The er was
determined by chiral HPLC or SFC.
Scheme 2. Scope of Asymmetric Aminoboration of
Alkenes
The present method was further utilized in the rapid
synthesis of chiral benzo[f ][1,4]oxazepine 7. Seven-membered
nitrogen heterocycles fused to a benzene ring such as
benzo[f ][1,4]oxazepines, and benzo[e][1,4]diazepines are
recognized as privileged motifs in the drug design because of
their wide range of biological activities, providing many
different therapeutic applications.11 However, it is very
challenging to prepare these compounds efficiently in an
asymmetric manner. Treatment of 1a with 2g and 3 under the
optimized conditions, gave the product 5 with 72% yield and
>99:1 er (Scheme 4). Oxidation of 5 with H2O2 followed by
ligand-free Cu-catalyzed intramolecular C−O bond formation
furnished 7 in 70% yield over two steps. Ultimately, the
product 7 was prepared in three steps as a single isomer with
50% overall yield.
a,b
To understand the origin of stereoselectivity of the
aminoboration, we initiated a DFT study of the trans-
formation. According to the proposed mechanism (Figure 1),
a Cu−B species is generated in situ which then undergoes
regioselective 1,2-addition to the alkene.4,12 Subsequent
Scheme 4. Application of Asymmetric Aminoboration to
Synthesis of Chiral benzo[f][1,4]oxazepine 7
a
All the reactions were performed with alkene 1a−v (0.40 mmol), 2a
(0.60 mmol), pinB−Bpin 3 (0.60 mmol), and LiO-t-Bu (1.20 mmol)
b
in THF (3.0 mL) at rt for 16 h under argon. The er was determined
by chiral HPLC or SFC, and the yields are based on E-alkenes.
C
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Cu−B complex, indicating steric interactions between these
portions in the transition state.
The Re-face addition give rise to an energy difference of 1.7
kcal/mol in free energy and 1.6 kcal/mol in enthalpy compared
to the Si-face addition. The majority of the difference between
transition states corresponds to a higher distortion energy of
the Re-face components with this energy calculated at 0.9 kcal/
mol in free energy and 1.3 kcal/mol in enthalpy. Examination
of the structures revealed two steric interactions in the higher-
energy Re-face approach between the phenyl of the alkene and
one of the phosphino tert-butyl groups as well as between the
methyl substituent of the alkene and the other phosphino tert-
butyl group (see Figure 2). The substituents were further apart
in the Si-face approach and there was also a stabilizing CH-π
interaction between the phenyl of the alkene and the
methylene backbone of the chiral ligand.
Experiments showed that the Z-isomer was unreactive in this
system. Computational analysis of the Z-isomer found the
transition state to be higher in energy than that of the E-
isomer. Specifically, the activation energy of the Si-face Z
isomer was calculated to be 9.3 kcal/mol, whereas the
corresponding E-isomer was calculated to be 6.4 kcal/mol
(Figure 3). In both transition states, the coordination geometry
Figure 1. Proposed catalytic cycle of aminoboration.
oxidation and the resultant organocopper intermediate [Cu(I)
to Cu(III)] followed by reductive elimination furnishes the
aminoboration product. The latter oxidative addition and
reductive elimination steps are stereoretentive, rendering syn-
addition of Cu−B species stereodetermining. Previous studies
of Cu-catalyzed aminoboration used PW6B95-D3/def2-
TZVP.13 B3LYP was found to give the same transition state
geometry as PW6B95 and was subsequently employed herein.
Further, similar enantiomeric excesses were calculated with
M06/6-311+G(d,p),Cu:SDD//B3LYP-D3/6-31G(d),Cu:SDD
compared with PW6B95-D3/def2-TZVP//B3LYP-D3/6-31G-
(d),Cu:SDD. As such, the well-known M06/6-311G+(d,p)14
functional was used.
Computational analysis of the corresponding diastereose-
lective transition states for the reaction catalyzed by ligand O-
BABIPhos, replacing the NPiv with O to simplify the
calculations, indicated an energetic preference for addition to
the Si-face of the alkene (Figure 2). The difference of 1.6 kcal/
mol corresponds to a predicted ratio of 94:6 S:R, which is in a
good agreement with the experimentally measured value of
93:7 S:R.
Figure 3. Energy profile of the 1,2-insertion of the isomeric alkene
insertions. The red and blue pathways correspond to the Z- and E-
alkene isomer Cu−B insertions, respectively. Free energy and
enthalpy (in brackets) were computed using M06/6-311+G-
(d,p),Cu:SDD//B3LYP-D3/6-31G(d),Cu:SDD. Values are given in
kcal/mol.
of the alkene to the copper is approximately the same, and the
main difference is that the E-alkene methyl substituent is
oriented into an empty groove defined by the catalyst, whereas
the Z-alkene methyl substituent undergoes a steric interaction
with the pinacol backbone. This steric interaction leads to the
sensitivity toward alkene geometry not seen with the ligand in
Miura’s system.4 The two lowest-energy transition states from
the Z- and E-isomers differ by 2.9 kcal/mol, which leads to a
relative rate ratio of 130. This calculated difference is in accord
with the reactivity observed.
Figure 2. Structures of the 1,2-insertion to the two stereofaces of the
alkene. Distances are the distance between the methyl group of the
alkene and the tert-butyl group as well as the distances between the
phenyl and the other tert-butyl group. Free energy and enthalpies (in
brackets) were computed using M06/6-311+G(d,p),Cu:SDD//
B3LYP-D3/6-31G(d),Cu:SDD. Values are given in kcal/mol.
In summary, PivZPhos was identified as a highly effective
ligand for Cu-catalyzed aminoboration of E-vinylarenes. The
protocol herein provides an efficient approach to chiral β-
aminoborates, which could be further transformed to
interesting enantioenriched chiral molecules with two adjacent
stereocenters. Under the optimized conditions, up to >99:1 er
values were achieved. For the first time, the substrate scope
was extended to heteroaryl alkenes such as 3-pyridiyl alkenes,
and excellent enantioselectivities were observed. The current
method was also incorporated into a facile synthesis of chiral
seven-membered nitrogen heterocycles such as benzo[f][1,4]-
The cores of the diastereomeric transition state were very
similar (RMSD ∼ 0.2 A), suggesting that the energy
differentiation is mainly due to interactions between the ligand
and the alkene. A distortion interaction analysis confirmed this
hypothesis. The energy difference between the Si-face and the
Re-face arises primarily from distortion of the alkene and of the
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L. Angew. Chem., Int. Ed. 2018, 57, 8714. (e) Whyte, A.; Burton, K. I.;
Zhang, J.; Lautens, M. Angew. Chem., Int. Ed. 2018, 57, 13927. (f) Li,
H.; Shen, S.-J.; Zhu, C.-L.; Xu, H. J. Am. Chem. Soc. 2018, 140, 10619.
(4) Matsuda, N.; Hirano, K.; Satoh, T.; Miura, M. J. Am. Chem. Soc.
2013, 135, 4934.
(5) For asymmetric aminoboration of styrenes, see: (a) Nishikawa,
D.; Hirano, K.; Miura, M. Org. Lett. 2016, 18, 4856. (b) Jiang, H.-C.;
Tang, X.-Y.; Shi, M. Chem. Commun. 2016, 52, 5273. For asymmetric
aminoboration of unactivated terminal alkenes, see: Kato, K.; Hirano,
K.; Miura, M. Chem. Eur. J. 2018, 24, 5775.
oxazepine 7. A model for the stereochemical outcome of the
asymmetric aminoboration was developed on the basis of
computational studies, which indicates that a combination of
stabilizing and destabilizing interactions provides the differ-
entiation between the enantiomeric outcomes. This model is
further supported by its ability to differentiate the relative
reactivity of E vs Z alkenes. Further application of the current
catalyst system to functionalization of alkenes is under
investigation and will be reported in due course.
(6) Zatolochnaya, O. V.; Rodríguez, S.; Zhang, Y.; Lao, K. S.;
Tcyrulnikov, S.; Li, G.; Wang, X. J.; Qu, B.; Biswas, S.; Mangunuru, H.
P. R.; Rivalti, D.; Sieber, J. D.; Desrosiers, J. N.; Leung, J. C.;
Grinberg, N.; Lee, H.; Haddad, N.; Yee, N. K.; Song, J. J.; Kozlowski,
M. C.; Senanayake, C. H. Chem. Sci. 2018, 9, 4505.
(7) Chong, E.; Qu, B.; Zhang, Y.; Cannone, Z. P.; Leung, J. C.;
Tcyrulnikov, S.; Nguyen, K. D.; Haddad, N.; Biswas, S.; Hou, X.;
Kaczanowska, K.; Chwalba, M.; Tracz, A.; Czarnocki, S.; Song, J. J.;
Kozlowski, M.; Senanayake, C. H. Chem. Sci. 2019, 10, 4339.
(8) Li, G.; Zatolochnaya, O. V.; Wang, X.-J.; Rodríguez, S.; Qu, B.;
Desrosiers, J.-N.; Mangunuru, H. P. R.; Biswas, S.; Rivalti, D.;
Karyakarte, S. D.; Sieber, J. D.; Grinberg, N.; Wu, L.; Lee, H.;
Haddad, N.; Fandrick, D. R.; Yee, N. K.; Song, J. J.; Senanayake, C. H.
Org. Lett. 2018, 20, 1725.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03328.
■
S
Complete experimental details, DFT calculations, X-ray
crystallographic data (PDF)
Accession Codes
CCDC 1954567 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, UK; fax: +44 1223 336033.
(9) The reason for the formation of the regioisomer product was not
clear and could be related to the polarization of the alkene 1f.
(10) Similar results were obtained for the 4-pyridinyl alkene.
(11) Bakulina, O.; Chizhova, M.; Dar’in, D.; Krasavin, M. Eur. J. Org.
Chem. 2018, 2018, 362.
(12) Semba, K.; Fujihara, T.; Terao, J.; Tsuji, Y. Tetrahedron 2015,
71, 2183.
(13) Tobisch, S. Chem. Eur. J. 2017, 23, 17800.
(14) Desrosiers, J. N.; Wen, J.; Tcyrulnikov, S.; Biswas, S.; Qu, B.;
Hie, L.; Kurouski, D.; Wu, L.; Grinberg, N.; Haddad, N.; Busacca, C.
A.; Yee, N. K.; Song, J. J.; Garg, N. K.; Zhang, X.; Kozlowski, M. C.;
Senanayake, C. H. Org. Lett. 2017, 19, 3338.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: linglin.wu@boehringer-ingelheim.com.
*E-mail: yongda.zhang@boehringer-ingelheim.com.
ORCID
Linglin Wu: 0000-0003-1773-5524
Olga Zatolochnaya: 0000-0003-3680-2913
Bo Qu: 0000-0001-7347-0108
Marisa C. Kozlowski: 0000-0002-4225-7125
Yongda Zhang: 0000-0002-2575-7590
Present Address
§C.H.S.: Astatech BioPharmaceutical Corporation, 488 Kelin
West Road, Wenjiang Dist., Chengdu, Sichuan 611130, P. R.
China
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Scott Pennino and Keith McKellop of Boehringer
Ingelheim Pharmaceuticals for HRMS analysis and Qi Jiang of
Boehringer Ingelheim Pharmaceuticals for the single-crystal X-
ray analysis. M.C.K. thanks the NIH (GM087605 to M.C.K.)
and Boehringer Ingelheim Pharmaceuticals for financial
support. Computational support was provided by XSEDE
(TG-CHE120052).
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DOI: 10.1021/acs.orglett.9b03328
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