Asymmetric Synthesis of β-Aryl β-Imido Sulfones Using Rhodium Catalysts with Chiral Diene Ligands: Synthesis of Apremilast

Article abstract of DOI:10.1021/acs.orglett.9b01513

A chiral rhodium(I)-diene catalyst enabled the one-step synthesis of β-aryl β-imido sulfones under mild reaction conditions. By selection of the chiral diene ligand L1a or L2, each enantiomer of the chiral β-aryl β-imido sulfone target can be accessed with high stereoselectivity. Demonstration of the scope of the reaction, which includes the synthesis of an N-protected chiral β-amino β-phenyl sulfone, culminated with the efficient synthesis of the heteroatom-rich active pharmaceutical ingredient apremilast.

Full text of DOI:10.1021/acs.orglett.9b01513

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Asymmetric Synthesis of β‑Aryl β‑Imido Sulfones Using Rhodium
Catalysts with Chiral Diene Ligands: Synthesis of Apremilast
Jin-Fong Syu,† Balraj Gopula,† Jia-Hong Jian,† Wei-Sian Li,† Ting-Shen Kuo,† Ping-Yu Wu,‡
Julian P. Henschke,† Meng-Chi Hsieh,† Ming-Kang Tsai,† and Hsyueh-Liang Wu*,†
†Department of Chemistry, National Taiwan Normal University, No. 88, Section 4, Tingzhou Road, Taipei 11677, Taiwan
‡Oleader Technologies, Co., Ltd., 1F, No. 8, Aly. 29, Ln. 335, Chenggong Road, Hukou Township, Hsinchu 30345, Taiwan
S
* Supporting Information
ABSTRACT: A chiral rhodium(I)−diene catalyst enabled
the one-step synthesis of β-aryl β-imido sulfones under mild
reaction conditions. By selection of the chiral diene ligand L1a
or L2, each enantiomer of the chiral β-aryl β-imido sulfone
target can be accessed with high stereoselectivity. Demon-
stration of the scope of the reaction, which includes the
synthesis of an N-protected chiral β-amino β-phenyl sulfone,
culminated with the efficient synthesis of the heteroatom-rich active pharmaceutical ingredient apremilast.
nantioenriched β-amino sulfone derivatives are versatile
vinyl sulfone Michael acceptor substrates. The Rh(I)-catalyzed
asymmetric addition of organoboron reagents to electron-
deficient conjugated alkenes, known as the Hayashi−Miyaura
reaction, has emerged as the method of choice for the
preparation of homochiral β-alkenyl- or β-aryl-substituted
carbonyl compounds and electronic equivalents such as nitro-
and phosphonyl alkenes, among others.7 The first reported
asymmetric addition of arylboronic acids to α,β-unsaturated
sulfones was catalyzed by Rh(I)−diphosphine catalysts and
relied, crucially, on the chelating effect of a strategically
positioned S-(2-pyridyl) group directly adjacent to the sulfur
atom.8 Without the 2-pyridyl group, or a less effective 2,6-
pyrimidyl or imidazoyl group, the vinyl sulfones were inert
toward 1,4-addition8c or underwent nucleophilic cine-sub-
stitution when aryltitanium triisopropoxide reagents were
used.9 The recent development of chiral Rh(I)−diene
catalysis,7e−i however, has paved the way for the arylation of
unsaturated cyclic and acyclic sulfonates and sulfones without
the necessity for a 2-pyridyl group.10
Despite these advances, to the best of our knowledge, no
examples of 1,4-additions of arylboronic acids to β-imido vinyl
sulfones catalyzed by Rh(I) salts have been reported. By
analogy to the corresponding carbonyl compounds,11 we
envisioned that chiral β-aryl β-amino sulfone derivatives, such
as apremilast, could be accessed by the Rh(I)-catalyzed
arylation of α,β-unsaturated β-imido sulfones.12 Here we
describe a general approach that provides access to
enantioenriched β-aryl β-phthalimido and -succinimido
sulfones, which can be readily converted to β-amino sulfone
derivatives, via a Rh(I)-catalyzed asymmetric addition reaction
of arylboronic acids to β-imido vinyl sulfones.
E
synthons in synthetic chemistry1,2 and display a wide
range of biological activities as compounds of medicinal
importance.3 For example, the oral drug apremilast (Otezla)
(Figure 1), which is an inhibitor of phosphodiesterase 4
Figure 1. Drug molecules containing β-amino sulfone moieties.
(PDE4), is currently being used to treat active psoriatic
arthritis and plaque psoriasis.3b ABT-518, a selective and
potent matrix metalloproteinase inhibitor, has shown inhib-
ition of cancer cell growth,3c while canfosfamide is a nitrogen
mustard prodrug with potential antineoplastic activity that has
been explored in phase 2 clinical trials for the treatment of
several cancer indications.3d
Chiral β-amino sulfones and their derivatives are generally
prepared from amino acids,2a−d by the diastereoselective
addition of lithiated sulfone carbanions to chiral N-
sulfinylimines,2e,f,4 or through enantioselective aza-Michael
additions to vinyl sulfones.5 However, these methods require
multistep manipulations and/or relatively expensive chiral
auxiliaries. Transition-metal-catalyzed syntheses of β-amino
sulfones are limited to Rh-catalyzed homogeneous enantiose-
lective hydrogenations of β-sulfonyl enamines6a and β-
acetylamino vinyl sulfones.6b
With a need to identify an efficient and enantioselective
synthetic method for producing the active pharmaceutical
ingredient apremilast, we set out to assess whether the Rh-
catalyzed addition reaction could be applied to β-phthalimido
Received: April 30, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01513
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Letter
Investigations commenced with a model addition reaction of
phenylboronic acid (2a) to β-phthalimido (E)-vinyl sulfone 1a
catalyzed by complexes formed from [RhCl(C2H4)2]2
(precatalyst) and chiral 2,5-diaryl-substituted bicyclo[2.2.1]-
heptadiene ligands L1a−e previously developed in our
laboratory13 (Table 1). Ligands L2, L3, and L4 have been
diphosphine ligand (S)-BINAP (L4) was employed (entries 8
and 9), the use of chiral bicyclo[2.2.2]octadiene ligand L2
provided a 91% yield of 3aa with −98% ee (entry 7), thereby
allowing access to the other enantiomer of the product. While
comparable enantioselectivities were observed when the
reactions were conducted in the presence of 3 and 1 mol %
Rh(I)/L1a, the chemical yield dropped to 89% and 50%,
respectively (entries 10 and 11).
a
Table 1. Optimization of the Reaction Conditions
Next, the scope of the addition reaction of β-phthalimido
α,β-unsaturated sulfone 1a was examined by substituting
variously adorned arylboronic acids for phenylboronic acid
(2a) from the model reaction using diene ligand L1a or L2
(Scheme 1). Electron-rich (2c and 2d), electron-neutral (2e−
entry
L
time
yield (%)
ee (%)
a
1
2
3
4
5
L1a
L1b
L1c
L1d
L1e
L1a
L2
L3
L4
L1a
L1a
2
3
4.5
3
5
3
99
90
83
92
58
80
91
N.R.
N.R.
89
99
97
98
97
99
94
−98
N.D.
N.D.
98
Scheme 1. Substrate Scope I
b
c
6
7
8
9
3
24
30
7
d
10
e
11
24
50
96
a
Reaction conditions: 1a (0.11 mmol), 2a (0.22 mmol), [RhCl-
(C2H4)2]2 (2.5 mol %), ligand L (6 mol %), and Et3N (0.11 mol).
Isolated yields are reported (N.R. = no reaction). The ee values were
determined by chiral HPLC analysis (N.D. = not determined). The
absolute configuration of 3aa was determined as (R) by single-crystal
b
c
X-ray crystallography. (Z)-1a was used. 12% (E)-1a was recovered.
d
e
3 mol % catalyst. 1 mol % catalyst.
reported elsewhere as being useful in Hayashi−Miyaura
reactions and were therefore examined also. Initial screening14
of the reaction conditions involved a large array of inorganic or
organic amine bases in dioxane, MeOH, EtOH, or i-PrOH as
the solvent in the presence of Rh(I)/L1a (5 mol %) at 60 °C.
While it was evident that some conditions provided poor
yields, the combination of Et3N13c and MeOH was found to
furnish both an excellent yield (96%) and enantioselectivity
(99% ee) of sulfone 3aa. Single-crystal X-ray crystallography
unequivocally determined that 3aa was R-configured. Further
screening under these conditions with diene ligands L1b−e
revealed that moderate to good yields and high enantiose-
lectivities of 97−99% ee were attainable (Table 1, entries 2−
5); among the five dienes L1a−e, however, phenyl-substituted
derivative L1a offered the best yield and enantioselectivity
(entry 1). Contrary to our expectation, addition of 2a to the Z
isomer of 1a gave rise to the same enantiomer of the addition
product, (R)-3aa, albeit with slightly reduced selectivity and
yield (entry 6). In situ isomerization of (Z)-1a to the
thermodynamically more stable E isomer accounted for the
production of (R)-3aa rather than the anticipated enantiomer
(S)-3aa; this was supported by the recovery of unreacted (E)-
1a from the reaction mixture. While the same reaction failed
when chiral bicyclo[3.3.0]octadiene ligand L3 or the chiral
a
Reaction conditions: 1a (0.11 mmol), 2 (0.22 mmol), [RhCl-
(C2H4)2]2 (2.5 mol %), ligand L (6 mol %), and Et3N (0.11 mol).
Isolated yields are reported. The ee values were determined by chiral
HPLC analysis.
g), and electron-deficient (2k−o) arylboronic acids all
performed well, offering the corresponding chiral addition
adducts in good yields (up to 99%) with excellent stereo-
selectivities (94−99% ee) of both enantiomers, except for 2-
methoxyphenylboronic acid (2b), which furnished only a
moderate yield of 3ab as a result of the ortho substituent.
Arylboronic acids harboring conjugated or extended π
substituents (2h−j) also underwent efficient additions, giving
B
DOI: 10.1021/acs.orglett.9b01513
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Letter
highly enantioenriched products in 70−95% yield with 95−
98% ee.
The scope of the reaction was examined further using several
S-substituted β-phthalimido vinyl sulfones as substrates
(Scheme 2). As for the S-tolyl substrates described above, S-
wherein the Rh atom of the complex coordinates to the Re face
of substrate 1a is energetically favored, explaining the observed
stereochemistry. The corresponding Si-face-coordinated com-
plex 4b, which would lead to the stereochemistry opposite to
that observed ((S)-3aa), was calculated to be 3.37 kcal·mol−1
higher in energy than 4a.
a
When the addition of 2a to 1a was conducted in CD3OD at
60 °C, deuterated product 3aa-d was isolated as a single
Scheme 2. Substrate Scope II
1
diastereomer (according to H NMR spectroscopy) in 93%
yield with 97% ee; >95% of the deuterium was incorporated at
the α-carbon with a syn relationship to the phenyl group.
These results demonstrate that alkylrhodium intermediate 3aa-
A (Scheme 3), formed by syn-phenylrhodation, underwent
deuteration (protonation) without β-hydrogen elimination9 or
isomerization.
Scheme 3. Deuterium Incorporation Experiment in the
Addition of 2a to 1a
To illustrate the usefulness of the imido sulfone products of
our method, phthalimido derivative 3aa was treated with
hydrazine and then acidified with HCl to liberate ammonium
salt 5 (Scheme 4). This was converted to the corresponding N-
a
Reaction conditions: 1 (0.11 mmol), 2 (0.22 mmol), [RhCl-
(C2H4)2]2 (2.5 mol %), ligand L1a (6 mol %), and Et3N (0.11 mol).
Isolated yields are reported. The ee values were determined by chiral
HPLC analysis.
Scheme 4. Synthesis of Boc-Protected β-Amino Sulfone 6
dodecyl (1b) and S-methyl (1c) derivatives were generally
well-tolerated, supplying the corresponding addition products
in 47−94% yield with 95−98% ee. Conversely, while the
enantioselectivities were moderately high (93−96% ee), the
yields of the β-succinimido-substituted derivatives 3da, 3dd,
and 3dg formed upon addition of boronic acids to 1d were less
pleasing (42−48%).15
With the aim of understanding the basis of the observed
stereoselectivity, DFT calculations were performed with the
putative phenylrhodium(I) complex using the B3LYP hybrid
functional16,17 in Gaussian 1618 on two putative transition
structures. The basis sets 6-31G (d,p)19 and LAN2LDZ20 were
employed for the main-group elements and the Rh atom,
respectively. As illustrated in Figure 2, transition structure 4a
Boc-protected chiral β-phenyl β-amino sulfone 6 without
erosion of stereointegrity in 75% overall yield over three steps.
Such compounds may serve as chiral building blocks or amino
acid analogues.
Having demonstrated the scope of the addition reaction, we
returned to the original inspiration for developing the method:
the asymmetric synthesis of apremilast. To date, several
synthetic approaches to apremilast have been published. In
2009, Man et al.3b constructed the racemic chiral β-amino β-
aryl sulfone backbone required for this molecule and
completed the synthesis by its resolution using N-acetyl-L-
leucine and coupling with 3-N-acetylaminophthalic anhydride.
Man’s method, while able to provide apremilast with high ee,
suffered from a <20% yield for the first two steps combined.
This approach was later improved by Ruchelman and
Connolly,6a who implemented the asymmetric hydrogenation
of an enamine derivative of the β-amino β-aryl sulfone moiety
using a Rh(I)−t-Bu-Josiphos complex followed by upgrading
of the ee, again using N-acetyl-L-leucine. Overall, the yield was
almost quadrupled. More recently, it was reported6c that
asymmetric hydrogenation of a β-acetylamino vinyl sulfide
using a Rh(I)−DuanPhos catalyst could be used to generate an
apremilast precursor, thereby representing a formal synthesis of
Figure 2. Calculated transition structures for the phenylation step
with 1a. L1a is shown in space-filling mode, and rhodium and
reactants are presented in ball-and-stick mode. Interatomic distances
are shown in Å.
C
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Letter
apremilast. None of these methods utilized a conjugate
addition as described herein.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hlw@ntnu.edu.tw.
ORCID
To our delight, vinyl methyl sulfone 1e harboring a free
amino group on the phthalimido group reacted smoothly with
arylboronic acid 2o under the reaction conditions described
above using ligand L1a or L2, affording (R)- or (S)-3eo
(prepared on a gram scale) in 95% or 85% yield, respectively
(Scheme 5). Subsequent acetylation of (S)-3eo provided
Ming-Kang Tsai: 0000-0001-9189-5572
Hsyueh-Liang Wu: 0000-0001-7462-8536
Notes
The authors declare no competing financial interest.
Scheme 5. Synthesis of Apremilast and Its Enantiomer
ACKNOWLEDGMENTS
■
Financial support from the Ministry of Science and
Technology of the Republic of China (104-2628-M-003-001-
MY3 and 107-2113-M-003-014-MY3) is gratefully acknowl-
edged.
REFERENCES
■
́
̈
(1) For reviews, see: (a) Backvall, J. E.; Chinchilla, R.; Najera, C.;
Yus, M. Chem. Rev. 1998, 98, 2291−2312. (b) Najera, C.; Yus, M.
́
Tetrahedron 1999, 55, 10547−10658. (c) Prilezhaeva, E. N. Russ.
Chem. Rev. 2000, 69, 367−408. (d) Meadows, D. C.; Gervay-Hague,
J. Med. Res. Rev. 2006, 26, 793−814. (e) Back, T. G. Can. J. Chem.
2009, 87, 1657−1674.
apremilast in 94% yield with 97% ee. The enantiomer of
apremilast was readily prepared in the same way from (R)-3eo
in 98% yield with 96% ee.
(2) For selected examples using chiral β-amino sulfones in the
synthesis, see: (a) Lehman de Gaeta, L. S.; Czarniecki, M.;
Spaltenstein, A. J. Org. Chem. 1989, 54, 4004−4005. (b) Rama Rao,
A. V.; Gurjar, M. K.; Pal, S.; Pariza, R. J.; Chorghade, M. S.
Tetrahedron Lett. 1995, 36, 2505−2508. (c) Ermolenko, L.; Sasaki, N.
A.; Potier, P. J. Chem. Soc., Perkin Trans. 2000, 1, 2465−2473.
(d) Mirilashvili, S.; Chasid-Rubinstein, N.; Albeck, A. Eur. J. Org.
Chem. 2010, 2010, 4671. (e) Kumareswaran, R.; Balasubramanian, T.;
Hassner, A. Tetrahedron Lett. 2000, 41, 8157−8162. (f) Kumareswar-
an, R.; Hassner, A. Tetrahedron: Asymmetry 2001, 12, 2269−2276.
(3) (a) Zajac, M.; Peters, R. Chem. - Eur. J. 2009, 15, 8204−8222.
(b) Man, H.-W.; Schafer, P.; Wong, L. M.; Patterson, R. T.; Corral, L.
G.; Raymon, H.; Blease, K.; Leisten, J.; Shirley, M. A.; Tang, Y.;
Babusis, D. M.; Chen, R.; Stirling, D.; Muller, G. W. J. Med. Chem.
2009, 52, 1522−1524. (c) Wada, C. K.; Holms, J. H.; Curtin, M. L.;
Dai, Y.; Florjancic, A. S.; Garland, R. B.; Guo, Y.; Heyman, H. R.;
Stacey, J. R.; Steinman, D. H.; Albert, D. H.; Bouska, J. S.; Elmore, I.
N.; Goodfellow, C. L.; Marcotte, P. A.; Tapang, P.; Morgan, D. W.;
Michaelides, M. R.; Davidsen, S. K. J. Med. Chem. 2002, 45, 219−232.
(d) McIntyre, J. A.; Castaner, J. Drugs Future 2004, 29, 985−991.
In conclusion, with the original motivation being a need for
an efficient and enantioselective method to access to the
marketed drug apremilast, a general asymmetric Rh(I)-
catalyzed arylation reaction of β-imido vinyl sulfones with
arylboronic acids has been realized.21 The reaction is mild and
affords highly enantioenriched β-phthalimido and β-succini-
mido β-aryl sulfones in high yields. Electron-rich, -neutral, or
-poor boronic acids are tolerated, as are modifications to the
imido moiety and the sulfur substituent of the Michael
acceptor. While a number of diene ligands (L1a−e and L2)
were found to be useful in the transformation when it was
conducted in the presence of 5 mol % Rh(I) precatalyst, chiral
ligands L1a and L2 permitted access to both enantiomers of
the chiral β-aryl β-imido sulfone products, which themselves
are prevalent motifs in biologically active molecules. Finally,
conversion of 3aa into N-Boc-protected β-aryl β-amino sulfone
6 and the conversion of (S)-3eo or (R)-3eo into apremilast or
its enantiomer, respectively, demonstrate the utility of the
method.
́
́
(4) (a) Fustero, S.; Soler, J. G.; Bartolome, A.; Rosello, M. S. Org.
́
Lett. 2003, 5, 2707−2710. (b) Velazquez, F.; Arasappan, A.; Chen, K.;
Sannigrahi, M.; Venkatraman, S.; McPhail, A. T.; Chan, T.-M.; Shih,
N.-Y.; Njoroge, F. G. Org. Lett. 2006, 8, 789−792. (c) Zhang, H.; Li,
Y.; Xu, W.; Zheng, W.; Zhou, P.; Sun, Z. Org. Biomol. Chem. 2011, 9,
6502−6505.
ASSOCIATED CONTENT
* Supporting Information
■
(5) (a) Enders, D.; Mu
1999, 38, 195−197. (b) Enders, D.; Mu
̈
ller, S. F.; Raabe, G. Angew. Chem., Int. Ed.
S
̈
ller, S. F.; Raabe, G.; Runsink,
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01513.
J. Eur. J. Org. Chem. 2000, 2000, 879−892.
(6) (a) Ruchelman, A. L.; Connolly, T. J. Tetrahedron: Asymmetry
2015, 26, 553−559. (b) Jiang, J.; Wang, Y.; Zhang, X. ACS Catal.
2014, 4, 1570−1573. For related work on asymmetric hydrogenation
of β-acetylamino vinyl sulfides, see: (c) Gao, W.; Lv, H.; Zhang, Z.
Org. Lett. 2017, 19, 2877−2880.
Experimental procedures, additional condition screening
table, complete characterization data, HPLC chromato-
grams and NMR spectra (PDF)
(7) For seminal reviews, see: (a) Hayashi, T. Synlett 2001, 2001,
879−887. (b) Fagnou, K.; Lautens, M. Chem. Rev. 2003, 103, 169−
196. (c) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829−2844.
(d) Edwards, H. J.; Hargrave, J. D.; Penrose, S. D.; Frost, C. G. Chem.
Soc. Rev. 2010, 39, 2093−2105. (e) Glorius, F. Angew. Chem., Int. Ed.
2004, 43, 3364−3366. (f) Johnson, J. B.; Rovis, T. Angew. Chem., Int.
̈
Ed. 2008, 47, 840−871. (g) Defieber, C.; Grutzmacher, H.; Carreira,
E. M. Angew. Chem., Int. Ed. 2008, 47, 4482−4502. (h) Shintani, R.;
Hayashi, T. Aldrichimica Acta 2009, 42, 31−38. (i) Tian, P.; Dong,
Accession Codes
CCDC 1907355 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 e-mailing
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.
D
DOI: 10.1021/acs.orglett.9b01513
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
H.-Q.; Lin, G.-Q. ACS Catal. 2012, 2, 95−119. For some early
representative studies on chiral dienes, see: (j) Paquin, J.-F.; Defieber,
C.; Stephenson, C. R. J.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127,
10850−10851. (k) Wang, Z.-Q.; Feng, C.-G.; Xu, M.-H.; Lin, G.-Q. J.
Am. Chem. Soc. 2007, 129, 5336−5337. (l) Luo, Y.; Carnell, A. J.;
Lam, H. W. Angew. Chem., Int. Ed. 2012, 51, 6762−6766.
́
(8) (a) Mauleon, P.; Carretero, J. C. Org. Lett. 2004, 6, 3195−3198.
́
(b) Mauleon, P.; Carretero, J. C. Chem. Commun. 2005, 4961−4963.
́
(c) Mauleon, P.; Alonso, I.; Rivero, M. R.; Carretero, J. C. J. Org.
Chem. 2007, 72, 9924−9935.
(9) (a) Yoshida, K.; Hayashi, T. J. Am. Chem. Soc. 2003, 125, 2872−
2873. (b) So, C. M.; Kume, S.; Hayashi, T. J. Am. Chem. Soc. 2013,
135, 10990−10993. (c) Yang, Q.; Wang, Y.; Luo, S.; Wang, J. Angew.
Chem., Int. Ed. 2019, 58, 5343−5347.
(10) (a) Nishimura, T.; Takiguchi, Y.; Hayashi, T. J. Am. Chem. Soc.
2012, 134, 9086−9089. (b) Lim, K. M.-H.; Hayashi, T. J. Am. Chem.
Soc. 2015, 137, 3201−3204.
(11) For a related arylation of β-phthalimido acrylates, see:
Nishimura, T.; Wang, J.; Nagaosa, M.; Okamoto, K.; Shintani, R.;
Kwong, F.-Y.; Yu, W.-Y.; Chan, A. S. C.; Hayashi, T. J. Am. Chem. Soc.
2010, 132, 464−465.
(12) Truce, W. E.; Brady, D. G. J. Org. Chem. 1966, 31, 3543−3550.
(13) (a) Wei, W.-T.; Yeh, J.-Y.; Kuo, T.-S.; Wu, H.-L. Chem. - Eur. J.
2011, 17, 11405−11409. (b) Huang, K.-C.; Gopula, B.; Kuo, T.-S.;
Chiang, C.-W.; Wu, P.-Y.; Henschke, J. P.; Wu, H.-L. Org. Lett. 2013,
15, 5730−5733. (c) Gopula, B.; Tsai, Y.-F.; Kuo, T.-S.; Wu, P.-Y.;
Henschke, J. P.; Wu, H.-L. Org. Lett. 2015, 17, 1142−1145.
(d) Gopula, B.; Yang, S.-H.; Kuo, T.-S.; Hsieh, J.-C.; Wu, P.-Y.;
Henschke, J. P.; Wu, H.-L. Chem. - Eur. J. 2015, 21, 11050−11055.
(e) Fang, J.-H.; Jian, J.-H.; Chang, H.-C.; Kuo, T.-S.; Lee, W.-Z.; Wu,
P.-Y.; Wu, H.-L. Chem. - Eur. J. 2017, 23, 1830−1838.
(14) See the Supporting Information for additional results on
screening and optimization.
(15) Decompositions of substrate 1d were observed during the
reaction course.
(16) Becke, A. D. Phys. Rev. A: At., Mol., Opt. Phys. 1988, 38, 3098−
3100.
(17) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B: Condens. Matter
Mater. Phys. 1988, 37, 785−789.
(18) Frisch, M. J.; et al. Gaussian 16, revision A.03; Gaussian, Inc.:
Wallingford, CT, 2016.
̈
(19) Andrae, D.; Haussermann, U.; Dolg, M.; Stoll, H.; Preuss, H.
Theor. Chim. Acta 1990, 77, 123−141.
(20) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 299−310.
(21) No desired product was observed in the reaction of 1e and
trans-2-phenylvinylboronic acid under the optimized reaction
conditions.
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