Stereospecific Nucleophilic Substitution with Arylboronic Acids as Nucleophiles in the Presence of a CONH Group

Article abstract of DOI:10.1002/anie.201712829

Stereospecific nucleophilic substitution was achieved for the first time with arylboronic acids as nucleophiles. This transition-metal-free coupling between chiral α-aryl-α-mesylated acetamides and arylboronic acids provided access to a series of chiral α,α-diaryl acetamides with excellent enantioselectivity and moderate to good yields. The CONH functionality proved to be crucial for bridging the reactants and promoting the reaction. Efficient syntheses of a cannabinoid CB₁ receptor ligand, the antidepressant (S)-diclofensine, and a key chiral building block of the inhibitor implitapide were successfully accomplished by using this method.

Full text of DOI:10.1002/anie.201712829

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Accepted Article
Title: Stereospecific Nucleophilic Substitution with Arylboronic Acids as
Nucleophiles: A Crucial CONH Effect
Authors: Wenjun Tang, Duanshuai Tian, Chengxi Li, Guoxian Gu,
Xumu Zhang, and Henian Peng
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201712829
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10.1002/anie.201712829
Angewandte Chemie International Edition
DOI: 10.1002/anie.200((will be filled in by the editorial staff))
Nucleophilic Substitution
Stereospecific Nucleophilic Substitution with Arylboronic Acids as
Nucleophiles: A Crucial CONH Effect
Duanshuai Tian,§ Chengxi Li,§ Guoxian Gu, Henian Peng, Xumu Zhang,* and Wenjun Tang*
to a π system,[3] i.e. Petasis-borono Mannich reaction[4] (Figure 1,
Abstract: Stereospecific nucleophilic substitution is achieved for the
equation 1), while few reports were available of arylboronic acids
for nucleophilic substitution to a tetravalent (sp3) carbons.[5] No
example is available on SN2-type transformation with arylboronic
acids as nucleophiles. Our previous report on stereospecific
nucleophilic substitution of chiral functionalized benzylic mesylates
applied well for alkenylboronic acids, but not for arylboronic acids
(equation 2).[6] Taken inspiration from the α-hydroxyl group-
promoted Petasis-borono Mannich reaction,[4c,d] we envisioned that
the SN2-type process with an arylboronic acid as the nucleophile
could be accomplished by introducing a functionality capable of
bridging two reactants. In this sense, the installation of a CONH
moiety[7] in one reactant could be suitable for promoting such
transformation. Herein we report for the first time a stereospecific
nucleophilic substitution between chiral α-aryl-α-mesylated
acetamides and arylboronic acids that have led to the access of a
series of chiral α,α,-diaryl carboxyamides for the first time in
excellent enantioselectivities and moderate to good yields (equation
3). The transition metal-free cross-coupling features mild reaction
conditions and good functional group tolerance complementary to
the stereoselective transition metal-catalyzed aryl-alkyl cross-
couplings.[8-10]
first time with arylboronic acids as nucleophiles. The transition
metal-free coupling between chiral α-aryl-α-mesylated acetamides
and arylboronic acids have provided the syntheses of a series of
chiral α,α-diaryl acetamides in excellent enantioselectivities and
moderate to good yields. The CONH functionality proved to be
crucial in bridging reactants and promoting the reaction. Efficient
syntheses of a cannabinoid CB1-receptor, antidepressant (S)-
diclofensine, and a key chiral building block of implitapide are
successfully accomplished by using this method.
Arylboronic acids as stable, environmentally benign, and readily
available feedstock are widely applied in modern organic synthesis,
in particular used as coupling reagents in transition-metal catalyzed
Suzuki-Miyaura cross-couplings.[1] Their applications as
nucleophiles in transition metal-free cross-couplings have been
relatively overlooked.[2] Because of their low nucleophilicity,
arylboronic acids as nucleophiles are mostly reported for addition
Figure 2. Biologically important molecules or therapeutic agents
containing chiral β,β-diarylamines and related structures
α,α-Diaryl acetamides are important structural unit in medicinal
chemistry.[11] In particular, the structures of their reduced forms
chiral β,β-diarylamines exist in many therapeutic agents or alkaloids
such as diclofensine,[12a] nomifensine,[12b] and cherylline[12c] (Figure
2). Despite their biological relevance, an efficient preparation of
Figure 1. Stereospecific nucleophilic substitution with arylboronic
acids as nucleophiles
[]
Prof. Dr. W. Tang, D. Tian, Dr. C. Li, H. Peng, State Key
Laboratory of Bio-Organic and Natural Products Chemistry
Center for Excellence in Molecular Synthesis
chiral α,α-diaryl acetamides is not available. We believe
a
stereospecific nucleophilic substitution between chiral α-aryl-α-
mesylated acetamides and arylboronic acids would be an ideal
solution to these chiral molecules and derivatives. Herein we
detailed our results.
Shanghai Institute of Organic Chemistry, University of Chinese
Academy of Sciences, 345 Ling Ling Rd, Shanghai 200032
E-mail: tangwenjun@sioc.ac.cn
Prof. Dr. X. Zhang, Dr. G. Gu, Department of Chemistry, South
University of Science and Technology of China, Shenzhen
518055 E-mail: zhangxm@sustc.edu.cn
The coupling between chiral α-phenyl-α-mesylated acetamide 1a
and 4-methoxy phenylboronic acid (2a) was chosen as the reaction
for study with K3PO4 as the base (Table 1). While no coupling
product 3a was formed in cyclohexane, DMF, or THF (entries 1-3),
[§]
D. Tian and C. Li contributed equally to this work.
[] We are grateful to the Strategic Priority Research Program of the
Chinese Academy of Sciences XDB20000000, CAS (QYZDY-
SSW-SLH029), NSFC (21725205, 21432007, 21572246)，and
K.C. Wong Education Foundation.
o
a decent yield (57%) of 3a was formed in dichloroethane at 50 C
for 48 h, albeit in a low ee (20%, entry 4). A better ee (52%) and a
similar yield were obtained in toluene (entry 5). An excellent ee
(95%) was observed when C6F6 was employed as the solvent, albeit
with a low yield (38%, entry 6). Increase of the reaction temperature
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
1
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10.1002/anie.201712829
Angewandte Chemie International Edition
to 80 oC did not improve the yield, but further compromise the ee
(entry 7). Switch of the base from K3PO4 to K2CO3 was beneficial to
the ee (entries 8 vs 5).When a mixture of C6F6/toluene (1:1 v/v) was
employed as the solvent, a decent yield (53%) and an excellent ee
(96%) were formed (entry 9). Further screening of bases did not
improve the yield (entries 10-15). Interestingly, the addition of
sodium bromide was slightly beneficial for the yield, providing 3a
in 60% isolated yield, whose inversed stereochemistry relative to 1a
was confirmed by its X-ray structure (entry 16).[13] Besides mesylate
1a, the corresponding tosylate 1a’ was also applicable with a
slightly low yield (entry 17).
w (entries 20-22) in good ee’s (86-93%) and moderate yields (30-
36%). Surprisingly, partial racemization of the coupling product (3x
or 3y) was observed when 4-MeSPhB(OH)2 (2j) or 4-
Me2NPhB(OH)2 (2k) was employed (entries 23-24). 2,4,6-
Me3PhB(OH)2 (2l) also led to partial racemization and a low yield
due to its steric hindrance (entry 25). 1-Naphthylboronic acid (2m)
led to a mixture of regio-isomers in high enantioselectivities (entry
26).
Table 2. Transition-metal-free cross-coupling between chiral α-aryl-
[a]
α-mesylated acetamide 1 and arylboronic acid 2
Table 1. Transition-metal-free cross-coupling between chiral α-
phenyl-α-mesylated acetamide 1a and 4-methoxy phenylboronic
acid (2a)[a]
Substrates
R
Ee
of 3
(%)
Entries
Ar’
Yield (%)[b]
Ee
1
2
Ph(1a)
Ph(1a)
99
99
99
99
99
99
99
99
99
99
99
91
97
97
97
94
98
99
4-MePh(2b)
4-iPrOPh(2c)
40(3b)
54(3c)
77(3d)
57(3e)
63(3f)
64(3g)
72(3h)
64(3i)
90
94
96
95
91
94
96
95
94
95
95
86
97
94
88
91
86
90
3
Ph(1a)
2-Me-4-MeOPh(2d)
2-Me-4-BnOPh(2e)
2,5-Me-4-MeOPh(2f)
4-MeOPh(2b)
4
Ph(1a)
Entries
Base
Solvent
Additive
Yield (%)[b]
Ee (%)[c]
5
Ph(1a)
1
2
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
K2CO3
TEA
cyclohexane
DMF
none
none
none
none
none
none
none
none
none
none
none
none
none
none
none
NaBr[g]
NaBr[g]
0
0
0
0
6
2-ClPh(1b)
2-ClPh(1b)
2-ClPh(1b)
2-ClPh(1b)
4-ClPh(1c)
4-ClPh(1c)
3-ClPh(1d)
2-FPh(1f)
2-FPh(1f)
2-BrPh(1g)
4-BrPh(1h)
4-FPh(1i)
Ph(1a)
7
4-MePh(2a)
3
THF
0
0
8
2-Me-4-MeOPh(2d)
Ph (2g)
4
DCE
57
56
38
30
50
53
0
20
52
95
72
88
96
0
9
35(3j)
5
toluene
10
11
12
13
14
15
16
17
18
2-Me-4-MeOPh(2d)
4-MeOPh(2a)
57(3k)
50(3l)
6
7[d]
C6F6
C6F6
2-Me-4-MeOPh(2d)
4-MeOPh(2a)
47(3m)
71(3n)
64(3o)
32(3p)
61(3q)
53(3r)
40(3s)
8
toluene
9
C6F6/Tol[e]
C6F6/Tol[e]
C6F6/Tol[e]
C6F6/Tol[e]
C6F6/Tol[e]
C6F6/Tol[e]
C6F6/Tol[e]
C6F6/Tol[e]
C6F6/Tol[e]
2-Me-4-OMePh(2d)
4-OMePh(2d)
10
11
12
13
14
15
16
17[h]
Na2CO3
NaOtBu
NaH
0
0
2-Me-4-OMePh(2d)
2-Me-4-OMePh(2d)
21
25
46
<5
60[f]
45
86
82
90
ND
96
96
1-cyclopentenyl(2h)
(E)-2-(p-
tolyl)ethenyl(2i)
NaOH
CsF
19
Ph(1a)
99
60(3t)
92
K2CO3
K2CO3
20[c]
21[c]
22[c]
23
iPr(1j)
iBu(1k)
BnCH2(1l)
Ph(1a)
99
98
99
99
99
99
4-MeOPh(2a)
30(3u)
35(3v)
36(3w)
54(3x)
66(3y)
93
86
90
25
28
4-MeOPh(2a)
4-MeOPh(2a)
o
[a] Unless otherwise specified, all reactions were performed at 50 C
for 48 h in the selected solvent (5 mL) with 1a (0.5 mmol), 2a (1
mmol), base (2 equiv), additive (2 equiv). The absolute configuration
of 3a was determined by its X-ray structure.[10] [b] 1HNMR yields using
dimethyl fumarate as internal standard. [c] Determined by Chiral
HPLC on a chiralcel OJ column. [d] T = 80 oC. [e] C6F6/toluene (1:1). [f]
Isolated yields. [g] NaBr (2 equiv) was added. [h] 1a’ (0.5 mmol) was
employed.
4-MeSPh(2j)
24
Ph(1a)
4-N(Me)2Ph(2k)
2,4,6-(Me)3Ph(2l)
25
Ph(1a)
15(3z)
15(3zb, C1)
15(3zc, C2)
51
90
90
26
Ph(1a)
99
1-Np(2m)
[a] Unless otherwise specified, all reactions were performed in
C6F6/toluene (1/1 v/v, 5 mL) at 50 C for 48 h with mesylate 1 (0.5
o
We then looked into the substrate scope of the cross-coupling
reaction. As depicted in Table 2, a series of chiral α,α-diaryl
acetamides were formed for the first time in excellent
enantioselectivities and moderate to good yields from chiral α-
substituted-phenyl-α-mesylated acetamides and arylboronic acids
with minimum loss of enantiomeric purity (entries 1-17). Halogen-
substituted benzylic mesylates (1a-i) at various positions were all
applicable (entries 6-17). Mesylates with electron-donating
substituents at aryl groups were generally too unstable to prepare.
Electron-rich or -neutral arylboronic acids such as 2a-f were all
suitable, while electron-deficient ones containing halogen, nitro, or
cyano substituents provided no or little desired products due to their
weak nucleophilicities. It should be noted that ortho-alkyl
substituted arylboronic acids such as 2d-f and ortho-halo substituted
benzylic mesylates such as 1b,1f-g were all suitable for the
mmol), aryl/alkenylboronic acid 2 (1.0 mmol), K2CO3 (2 equiv) and
NaBr (2 equiv). [b] Isolated yields. [c] K3PO4 (2 equiv) as base and
DCE as solvent, T = 80 oC.
To shed light on the mechanism of this transformation, the
following experiments were implemented (Scheme 1). Under similar
reaction conditions, mesylate 4 bearing a carboxylic ester or 7
bearing a ketone moiety did not form the corresponding coupling
product 5 or 8, indicating the significance of the CONH moiety in
promoting the coupling reaction (equations 1 and 2). Additional
experiment with TEMPO as additive excluded the possibility of a
radical process (equation 3). A deuterium-labeling experiment
proved no deprotonation occurring at the benzylic position of both
mesylate 1a” and coupling product 3d” (equation 4). In order to
understand the low enantioselectivity of 3x when 4-MeSPhB(OH)2
(2j) was employed, chiral deuterated mesylate (R)-1a” was
subjected to the reaction with 2j (equation 5). The resulting product
3x was isolated in 20% yield and 29% ee with complete loss of
deuterium, while no loss of deuterium and only slight deterioration
of ee (96%) was observed with the recovered mesylate. The result
demonstrated the easy deprotonation and racemization of 3x under
basic reaction conditions, which was in sharp contrast to other
products listed in entries 1-22 (Table 2). The presence of the thio
group on the aromatic ring might have facilitated the deprotonation
transformation, providing
a diverse set of chiral α,α-diaryl
acetamides in excellent ee‘s. In addition, alkenylboronic acids such
as 2h and 2i were applicable, forming the corresponding coupling
products 3s-t in moderate to good yields (entries 18-19).
Encouragingly, α-alkyl-α-mesylated acetamides 1j-l were also good
substrates to react with 2a, forming the corresponding products 3u-
2
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10.1002/anie.201712829
Angewandte Chemie International Edition
process. The coupling product 3y containing a dimethylamino
functionality could have similar properties prone to deprotonation
and racemization.
Scheme 1. Mechanistic studies
Figure 3. Proposed mechanism
All above experiments suggested a SN2-type process between
chiral α-phenyl-α-mesylated acetamide (1a) and 4-methoxy
phenylboronic acid (2a) depicted in Figure 3. In the presence of a
base, the CONH group of the mesylate 1a can be deprotonated to
form anion A, which can then coordinate with arylboronic acid 2a to
form complex B. An intramolecular SN2-type attack of aryl group to
the mesylate forms 3a. Noteworthy is the CONH moiety that not
only helps the stabilization of the mesylate but also serve to bridge
the mesylate and arylboronic acid, promoting the intramolecular
stereospecific nucleophilic substitution. A similar model C can well
explain the formation of regio-isomers from 1-naphthylboronic acid.
It should be noted that this plausible mechanism is different from
those proposed for nonchiral and less challenging substrates.[5]
Scheme 2. Synthetic applications
In conclusion, we have developed a stereospecific nucleophilic
substitution for the first time with arylboronic acids as nucleophiles.
The SN2-type reaction between α-aryl-α-mesylate amide and
arylboronic acid have provided an expedite access to a series of
chiral α,α-diaryl acetamides in excellent ee’s and moderate to good
yields. The crucial CONH moiety has not only helped the
stabilization of the mesylate, but also served to bridge the mesylate
with arylboronic acid to promote the transformation. By employing
this method, efficient syntheses of a cannabinoid CB1-receptor 10,
antidepressant (S)-diclofensine (15), and a key chiral building block
of implitapide 16, are successfully demonstrated. The discovery of
the stereospecific nucleophilic substitution of arylboronic acids as
nucleophile have not only enriched the scope of nucleophilic
substitution, but also provide an alternative method for transition
metal-catalyzed stereoselective aryl-alkyl cross-coupling reactions.
The chiral α,α-diaryl acetamides are important building blocks
in medicinal chemistry. Thus, chiral mesylate 9 was coupled with 2a
to form 10, a cannabinoid CB1-receptor,[14] in 91% ee and 50%
yield. (S)-diclofensine (15) is an effective antidepressant,[12b] which
was efficiently synthesized using this method. By employing Ir-
(S,S,R)-f-amPhox as the catalyst,[15] asymmetric hydrogenation of α-
keto amide 11 followed by mesylation formed the α-mesylated
amide 12 in 94% ee and 96% yield. Stereospecific coupling of 12
and 2a provided the α,α-diaryl acetamide 13 in 92% ee and 75%
yield at a gram scale. DIBAL-H reduction of the amide followed by
formylation, ring closure, and reduction yielded (S)-diclofensine (15)
in 53% overall yield from 11. Finally, coupling of chiral mesylate 1c
with cyclopentenylboronic acid (2h) followed by hydrogenation
furnished chiral amide 16, a key building block for microsomal
triglyceride transfer protein inhibitor implitapide, in 88% ee and
38% yield.
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Published online on ((will be filled in by the editorial staff))
Keywords: nucleophilic substitution ·arylboronic acids ·α,α-diaryl
acetamides·stereospecific·enantioselectivity
3
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10.1002/anie.201712829
Angewandte Chemie International Edition
[1] Selected reviews of Suzuki-Miyaura couplings: a) N. Miyaura,
A. Suzuki, Chem. Rev. 1995, 95, 2457. b) A. F. Littke, G. C.
Fu, Angew. Chem., Int. Ed. 2002, 41, 4176; Angew. Chem.
2002, 114, 4350. c) R. J. Lundgren, M. Stradiotto, Chem. Eur.
J. 2012, 18, 9758. d) C. Li, D. Chen, W. Tang, Synlett 2016,
27, 2183. e) H. Yang, X. Yang, W. Tang, Tetrahedron 2016,
72, 6143.
[2] For recent reviews of transition-metal-free coupling, see: a) C.-
L. Sun, Z.-J. Shi, Chem. Rev. 2014, 114, 9219. b) S. Roscales,
A. G. Csákÿ, Chem. Soc. Rev. 2014, 43, 8215. c) C. Zhu, J. R.
Falck, Adv. Synth. Cat. 2014, 356, 2395. d) S. M. Roopan, J.
Palaniraja, Res. Chem. Intermed. 2015, 41, 8111. For other type
of stereospecific transition metal-free coupling, see: e) A.
Bonet, M. Odachowski, D. Leonori, S. Essafi, V. K. Aggarwal,
Nat. Chem. 2014, 6, 584. f) J. Llaveria, D. Leonori, V. K.
Aggarwal, J. Am. Chem. Soc. 2015, 137, 10958. g) D. Leonori,
V. K. Aggarwal, Angew. Chem., Int. Ed. 2015, 54, 1082;
Angew. Chem. 2015, 127, 1096. h) R. J. Armstrong, C. Garcíz-
Ruiz, E. L. Myers, V. K. Aggarwal, Angew. Chem., Int. Ed.
2017, 56, 786; Angew. Chem. 2017, 129, 804. i) V. Ortega, E.
del Castillo, A. G. Csákÿ, Org. Lett. 2017, 19, 6236.
[3] For recent examples, see: (a) J. Barluenga, M. Tomás-Gamasa,
F. Aznar, C. Valdés, Nat. Chem. 2009, 1, 494. (b) M. C. Pérez-
Aguilar, C. Valdés, Angew. Chem., Int. Ed. 2012, 51, 5953.
Angew. Chem. 2012, 124, 6055. (c) C. Peng, W. Zhang, G. Yan,
J. Wang, Org. Lett. 2009, 11, 1667. (d) O. A. Argintaru, D.
Ryu, I. Aron, G. A. Molander, Angew. Chem., Int. Ed. 2013, 52,
13656. Angew. Chem. 2013, 125, 13901. (e) K. Ito. H.
Tamashima, N. Iwasawa, H. Kusama, J. Am. Chem. Soc. 2011,
133, 3716. (f) T. R. Wu, J. M. Chong, J. Am. Chem. Soc. 2007,
129, 4908. (g) Y. Luan, S. E. Schaus, J. Am. Chem. Soc. 2012,
134, 19965. (h) S. Lee, D. W. C. MacMillan, J. Am. Chem. Soc.
2007, 129, 15438. (i) T. A. Mitchell, J. W. Bode, J. Am. Chem.
Soc. 2009, 131, 18057. (j) V. T. Vo, A. Mitchell, J. W. Bode, J.
Am. Chem. Soc. 2011, 133, 14082.
[4] (a) N. A. Petasis, I. Akritopoulou, Tetrahedron Lett. 1993, 34,
583. (b) N. A. Petasis, I. A. Zavialov, J. Am. Chem. Soc. 1997,
119, 445. (c) N. A. Petasis, I. A. Zavialov, J. Am. Chem. Soc.
1998, 120, 11798. (d) N. R. Candeias, F. Montalbano, P. M. S.
D. Cal, P. M. P. Gois, Chem. Rev. 2010, 110, 6169. (e) T. R.
Ramadhar, R. A. Batey, In D. G. Hall, Ed. Boronic Acids, 2nd
edn., Wiley-VCH, Weinheim, 2011; pp427-477.
N. D. Schley, G. C. Fu, J. Am. Chem. Soc. 2014, 136, 16588. d)
J. Schmidt, J. Choi, A. T. Liu, M. Slusarczyk, G. C. Fu, Science
2016, 354, 1265. e) A. H. Cherney, S. E. Reisman, J. Am.
Chem. Soc. 2014, 136, 14365. f) N. T. Kadunce, S. E. Reisman,
J. Am. Chem. Soc. 2015, 137, 10480. g) C. Sun, B. Potter, J. P.
Morken, J. Am. Chem. Soc. 2014, 136, 6534. h) K.-J. Xiao, D.
W. Lin, M. Miura, R.-Y. Zhu, W. Gong, M. Wasa, J.-Q. Yu, J.
Am. Chem. Soc. 2014, 136, 8138. i) R. Oost, A. Misale, N.
Maulide, Angew. Chem., In. Ed. 2016, 55, 4587; Angew. Chem.
2016, 128, 4663. j) Z. Zuo, H. Cong, W. Li, J. Choi, G. C. Fu,
D. W. C. MacMillan, J. Am. Chem. Soc. 2016, 138, 1832. k) L.
Li, C.-Y. Wang, R. Huang, M. R. Biscoe, Nat. Chem. 2013, 5,
607. l) S. C. Matthew, B. W. Glasspoole, P. Eisenberger, C. M.
Crudden, J. Am. Chem. Soc. 2014, 136, 5828. m) L. Li, S.
Zhao, A. Joshi-Pangu, M. Diane, M. R. Biscoe, J. Am. Chem.
Soc. 2014, 136, 14027. n) M. R. Harris, L. E. Hanna, M. A.
Greene, C. E. Moore, E. R. Jarvo, J. Am. Chem. Soc. 2013,
135, 3303. o) Q. Zhou, H. D. Srinivas, S. Dasgupta, M. P. A.
Watson, J. Am. Chem. Soc. 2013, 135, 3307. p) P. Maity, D. M.
Shacklady-McAtee, G. P. A. Yap, E. R. Sirianni, M. P.
Watson, J. Am. Chem. Soc. 2013, 135, 280. q) D. K. Nielsen,
C.-Y. Huang, A. G. Doyle, J. Am. Chem. Soc. 2013, 135,
13605. r) Y. Takeda, Y. Ikeda, A. Kuroda, S. Tanaka, S.
Minakata, J. Am. Chem. Soc. 2014, 136, 8544. s) P. Schäfer, T.
Palacin, M. Siera, S. P. Fletcher, Nat. Commun. 2017, 8,
15762. t) W. Huang, X. Wan, Q. Shen, Angew. Chem., Int. Ed.
2017, 56, 11986; Angew. Chem. 2017, 129, 12148. u) M. S.
Eno, A. Lu, J. Morken, J. Am. Chem. Soc. 2016, 138, 7824.
[11] a) D. Ameen, T. J. Snape, Med. Chem. Commun. 2014, 4, 893.
b) B. Zheng, T. Jia, P. J. Walsh, Adv. Synth. Catal. 2014, 356,
165.
[12] a) S. Gasić, A. Korn, H. G. Eichler, Clin. Pharmacol. Ther.
1986, 39, 582. b) S. L. Corman, B. A. Fedutes, C. M. Culley,
Am. J. Health Syst. Pharm. 2004, 61, 2391. c) S. Lebrun, A.
Couture, E. Deniau, P. Grandclaudon, Org. Biomol. Chem.
2013, 1, 1701.
[13] CD1587562 contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB21EZ, UK; fax: (+44)1223-336-033; or
deposit@ccdc.cam.ac.uk).
[5] For
non-stereospecific
transition-metal-free
aryl-alkyl
[14] P. Urbani, G. Cascio, A. Ramunno, T. Bisogno, C. Saturninno,
V. Di Marzo, Bioorg. Med. Chem. 2008, 16, 7510.
[15] G. Gu, T. Yang, O. Yu, H. Qian, J. Wang, J. Wen, L. Dang, X.
Zhang, Org. Lett. 2017, 19, 5920.
coupling, see: a) A. Scrivanti, V. Geghetto, M. Bertoldini, U.
Matteoli, Eur. J. Org. Chem. 2012, 2012, 264. b) M. Ueda, K.
Nishimura, R. Kasima, I. Ryu, Synlett 2012, 23, 1085. c) M.
Ueeda, K. Nishimura, I. Ryu, Synlett 2013, 24, 1683. d) G. Wu,
S. Xu, Y. Deng, C. Wu, X. Zhao, W. Ji, Y. Zhang, J. Wang,
Tetrahedron 2016, 72, 8022. e) Z. He, F. Song, H. Sun, Y.
Huang. J. Am. Chem. Soc. 2018, 140, 2693.
[6] C. Li, Y. Zhang, Q. Sun, T. Gu, H. Peng, W. Tang, J. Am.
Chem. Soc. 2016, 138, 10774.
[7] For an example of Petasis-borono Mannich reaction containing
a CONH moiety: L. Zhao, X. Liao, C.-J. Li Synlett 2009, 2953.
[8] Reviews of aryl-alkyl couplings: a) R. Jana, T. P. Pathak, M. S.
Sigman, Chem. Rev. 2011, 111, 1417. b) E. C. Swift, E. R.
Jarvo, Tetrahedron 2013, 69, 5799. c) E. L. Lucas, E. Jarvo,
Nat. Rev. Chem. 2017, 1, 65; d) G. C. Fu, ACS. Cent. Sci. 2017,
3, 692. Our previous work: e) C. Li, T. Chen, B. Li, G. Xiao,
W. Tang, Angew. Chem., Int. Ed. 2015, 54, 3792; Angew.
Chem. 2015, 127, 3863. f) C. Li, G. Xiao, Q. Zhao, H. Liu, T.
Wang, W. Tang, Org. Chem. Front. 2014, 1, 225.
[9] For reviews on enantioselective and enantiospecific aryl-alkyl
couplings: a) A. H. Cherney, N. T. Kadunce, S. E. Reisman,
Chem. Rev. 2015, 115, 9587. b) S. Z. Tasker, E. A. Standley, T.
F. Jamison, Nature 2014, 509, 299
[10] For recent reports, see: a) H.-Q. Do, E. R. R. Chandrashekar,
G. C. Fu, J. Am. Chem. Soc. 2013, 135, 16288. b) J. Choi, P.
Martín-Gago, G. C. Fu, J. Am. Chem. Soc. 2014, 136, 12161. c)
4
This article is protected by copyright. All rights reserved.

10.1002/anie.201712829
Angewandte Chemie International Edition
Nucleophilic Substitution
Duanshuai Tian,§ Chengxi Li,§ Guoxian
Gu, Henian Peng, Xumu Zhang,* and
Wenjun Tang* __________ Page –
Page
Stereospecific Nucleophilic Substitution
with Arylboronic Acids as Nucleophiles:
A Crucial CONH Effect
Stereospecific nucleophilic substitution is achieved for the first time with arylboronic
acids as nuclephiles. The transition metal-free coupling between chiral α-aryl-α-
mesylated acetamides and arylboronic acids have provided the syntheses of a
series of chiral α,α-diaryl acetamides in excellent ee’s and moderate to good yields.
The CONH functionality proved to be crucial in bridging both reactants and
promoting the reaction. Efficient syntheses of a cannabinoid CB1-receptor,
antidepressant (S)-diclofensine, and a key chiral building block of implitapide are
successfully accomplished by using this method.
5
This article is protected by copyright. All rights reserved.