Iridium-Catalyzed Regio- and Enantioselective Borylation of Unbiased Methylene C(sp3)?H Bonds at the Position β to a Nitrogen Center

Article abstract of DOI:10.1002/anie.202016009

Reported herein is the pyrazole-directed iridium-catalyzed enantioselective borylation of unbiased methylene C?H bonds at the position β to a nitrogen center. The combination of a chiral bidentate boryl ligand, iridium precursor, and pyrazole directing group was responsible for the high regio- and enantioselectivity observed. The method tolerated a vast array of functional groups to afford the corresponding C(sp³)?H functionalization products with good to excellent enantioselectivity.

Full text of DOI:10.1002/anie.202016009

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Iridium-Catalyzed Regio- and Enantioselective Borylation of
Unbiased Methylene C(sp3)-H Bonds at the Position Beta to a
Nitrogen Center
Authors: Rongrong Du, Luhua Liu, and Senmiao Xu
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202016009
Link to VoR: https://doi.org/10.1002/anie.202016009

10.1002/anie.202016009
Angewandte Chemie International Edition
COMMUNICATION
Iridium-Catalyzed Regio- and Enantioselective Borylation of
Unbiased Methylene C(sp3)-H Bonds at the Position Beta to a
Nitrogen Center
Rongrong Du,[a][b]‡ Luhua Liu,[a][b]‡ and Senmiao Xu*[a][c]
Dedication ((optional))
[a]
Ms. R. Du, Mr. L. Liu, and Dr. S. Xu
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Center for Excellence in Molecular Synthesis, Suzhou Research Institute
Lanzhou Institute of Chemical Physics
Chinese Academy of Sciences
Lanzhou 730000, China
E-mail: senmiaoxu@licp.cas.cn
[b]
[c]
Ms. R. Du, and Mr. L. Liu
University of Chinese Academy of Sciences
Beijing 100049, China
Dr. S. Xu
Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education
Hangzhou Normal University
Hangzhou 311121, China
‡
R. Du and L. Liu contributed equally to this work
Supporting information for this article is given via a link at the end of the document. ((Please delete this text if not appropriate))
18]
Abstract: Reported here is the first example of pyrazole-directed
iridium-catalyzed enantioselective borylation of unbiased methylene
C-H bonds at the position beta to a nitrogen center. The combination
of a chiral bidentate boryl ligand, iridium precursor, and pyrazole
directing group is responsible for achieving high regio- and
enantioselectivities. The current method can tolerate a vast array of
functional groups, affording corresponding C(sp3)-H functionalization
products in good to excellent enantioselectivities.
In stark contrast, there are only two efficient methods for
asymmetric α-C(sp3)-H borylation (Scheme 1a).[12b, 14d] And, while
achiral versions of β-selective reactions have been realized,[19] the
enantioselective discrimination of two enantiotopic methylene
C(sp3)-H necessary for asymmetric, β-selective C-H borylation is
highly challenging. Thus, it is still appealing to develop novel and
complementary methods in this area.
Optically active alkyl boronic acid and its derivatives have
received considerable interest owing to their diverse applications
in synthetic chemistry and drug discovery.[1] Among these, β-
aminoboronates are of significant importance as building blocks
for many biologically active compounds.[2] Apart from one-carbon
homologation of α-aminoboronates,[3] they could also be prepared
by means of transition-metal-catalyzed 1,2-aminoboration of
alkenes,[4] hydroboration of enamides,[5] conjugate borylation of α-
dehydroamino acid derivatives,[6] 1,2-addition of 1,1-diboron
compounds to aldimines,[7] and borylative ring opening of 2-
arylaziridines.[8] Nevertheless, reactive sites of substrates of the
above methods need to be preactivated, which will apparently
cost extra reagents and tedious steps.
Scheme 1. Regio- and Enantioselective C(sp3)-H Borylation of Acyclic Amine
Derivatives.
Recently, transition-metal-catalyzed enantioselective C-H
borylation has emerged as an attractive alternative to access
chiral organoboron compounds in an atom- and step-economical
way.[9] In this context, novel chiral ligands and new strategies
developed by Yu,[10] Hartwig,[11] Sawamura,[12] Phipps[13] and our
group[14] were capable of enantioselective discrimination of
enantiotopic C-H bonds enabled by Pd-, Ir-, and Rh-catalysis.
Despite the fact, this area is still underdeveloped compared to
asymmetric C-C bond forming reactions. For example, a plethora
of α-, β- and γ-selective asymmetric C-H functionalization to form
C-C bonds has been accomplished for the amine derivatives.[15-
Pyrazoles not only possess a broad spectrum of biological
activities and pharmaceutical properties,[20] but also are often
used as the directing groups in C-H bond functionalization.[21] One
benefit of pyrazoles as directing groups is that they could enable
the formation of five-membered metallacyclic intermediate to
activate C(sp3)-H bond at the position beta to a nitrogen center.
Another distinct advantage is that they could be easily converted
to amides through ozonolysis,[22] which makes them synthetically
1
This article is protected by copyright. All rights reserved.

10.1002/anie.202016009
Angewandte Chemie International Edition
COMMUNICATION
more useful. Thus, the use of pyrazoles in asymmetric C(sp3)-H
functionalization could be poised to provide both optically active
pyrazoles and β-chiral amine derivatives. Here, we report our own
studies on the use of the chiral bidentate boryl ligand (CBL) to
enable the pyrazole-directed Ir-catalyzed enantioselective
borylation of unbiased methylene C(sp3)-H bonds at the position
beta to a nitrogen center (Scheme 1b).[12,14f,23]
NaBO3·4H2O to afford 3aa in 71% isolated yield with 63% ee.
Notably, no desired product was observed when the reaction was
carried out without CBL1 under otherwise identical reaction
conditions. These initial findings encouraged us to further
investigate the impact of CBL’s substituent on the reaction
performance. For example, switching methyl (Me) group to bulkier
groups ethyl (Et) (CBL2) and cyclohexyl (Cy) (CBL3) did not
further improve both reactivity and enantioselectivity (Table 1,
entries 2 and 3). CBL bearing N-aryl groups of 2,6-Et2-C6H3
(CBL4) resulted in low yield (23%) and moderate
enantioselectivities (Table 1, entry 4). To our great delight, when
CBL5 bearing a 2,4,6-Cy3-C6H2 group was used, 3aa could be
obtained in 87% isolated yield with 98% ee (Table 1, entry 5).
Further tuning the substituent at the pyridine ring resulted in
product with slightly lower ee value (Table 1, entry 6). With the
optimized ligand CBL5 in hand, we then further surveyed the
effect of iridium precursor, temperature, and solvent on the
catalytic performance (Table 1, entries 7-10, which indicates
[IrOMe(cod)]2, 60 °C and n-hexane were optimal in terms of both
reactivity and chiral induction.
Table 1. Optimization of reaction conditions
Table 2. Substrate scope generality
Entry[a]
CBL
Yield (%)[b]
ee (%)[c]
63
1
CBL1
CBL2
CBL3
CBL4
CBL5
CBL6
CBL5
CBL5
CBL5
CBL5
71
2
67
67
3
32
45
4
23
78
5
87
98
6
85
96
7[d]
8[e]
9[f]
10[g]
74
95
83
95
73
94
trace
n.d.
[a] Unless otherwise noted, all the borylation reactions were carried out with 1aa
(0.2 mmol), B2pin2 (0.3 mmol), CBL (0.01 mmol), and [Ir(OMe)(cod)]2 (0.005
mmol) at 60 °C in n-hexane (2.0 mL) for 12 h. [b] Yield refers to isolated product.
[c] Enantiomeric excess (ee) value was determined by HPLC on a chiral
stationary column OD-H. [d] [IrCl(cod)]2 was used instead of [Ir(OMe)(cod)]2.
[e]The reaction was carried out at 70 °C. [f] Cyclohexane was used. [g]
Tetrahydrofuran (THF) was used as the solvent.
Our research commenced with the optimization of the
reaction conditions using 3,5-dimethyl-1-propyl-1H-pyrazole 1aa
as the model substrate as shown in Table 1.[24] Preliminary
examination of borylation of 1aa (0.20 mmol) with B2pin2
(bis(pinacolato)diboron) (0.30 mmol, 1.5 equiv) in the presence of
2.5 mol% [Ir(OMe)(cod)]2 (cod: 1,5-cyclooctadiene) and 5.0 mol%
CBL1 in n-hexane (2.0 mL) at 60 °C for 12 h resulted in good
conversion (Table 1, entry 1). Due to the instability of the
borylated product 2aa during isolation by chromatography on
silica gel, the crude reaction mixture was treated with
2
This article is protected by copyright. All rights reserved.

10.1002/anie.202016009
Angewandte Chemie International Edition
COMMUNICATION
With the optimized reaction conditions in hand, we then
determined the additional substrate scope of the current C(sp3)-H
borylation reactions as shown in Table 2. Firstly, we surveyed the
tolerance of substituent on the pyrazole ring. Groups such as Me,
NO2, Br, and CO2Et at C4 position of pyrazole are compatible with
the reaction conditions. Corresponding products 3ab-3ae were
obtained in 70-86% yields with constantly excellent ee values
ranging from 97% to 99%. We then focused on the performance
of substrates bearing the varying chain length of linear N-alkyl
group. All the reactions with chain length ranging from four to
eighteen carbon atoms proceeded smoothly under standard
reaction conditions. Accordingly, products 3ba-3ia were obtained
in 51-95% yields with excellent enantioselectivities (92-97%). We
then turned our attention to the substrates containing branched
N-alkyl chain. Pleasingly, products 3ja-3na were obtained in 57-
89% yields with excellent ee values (93-95%) although the
reaction sites are more congested. The current method could also
be compatible with substrate containing transformable group such
as amide, acetal, and TBS-protected hydroxyl. For example,
although there are two amide-directed competitive reaction sites
α-C(sp3)-H of piperidine motif[12b,14d] and β-C(sp3)-H bond of
amide[14f] in substrate 1oa, 3oa could be obtained as exclusive
product in 76% yield with 83% ee. Excellent enantioselectivity
(3pa: 94%) and good yield was observed when an acetal group
resides on the N-alkyl chain. Although TBS-protected alcohol
derivatives 1qa and 1ra gave respective products 3qa and 3ra
with 80% and 87% ees, excellent enantioselectivities (3qe: 97%;
3re: 96%) were observed when the substrate contains a CO2Et
group at its pyrazole’s C4 position.[25]
To further extend the generality of the current reaction, we
then moved to substrate bearing an aryl group at the terminal
position of linear N-alkyl group as shown in Table 3. When the
reaction occurred at the non-benzylic position using 3,5-
dimethylpyrazole as the directing group, high ee values ranging
from 89% to 94% were observed for the corresponding products
5aa-5ia. On the other hand, the benzylic functionalized product
5ja was obtained with low enantioselectivity (33%) probably due
to the significant background reaction.[25] Fortunately, the
background reaction could be significantly reduced when
pyrazole possesses an electron-withdrawing group at its C4
position (4jc-4je).[25] Particularly, product 5jc could be obtained in
69% yield with 83% ee when a nitro group resides at pyrazole’s
C4 position.
Next, we applied the current method for the C(sp3)-H
functionalization of cholic and deoxycholic acids derived
pyrazoles 1sa and 1ta as shown in Scheme 2. Moderate reactivity
and diastereomeric ratio (dr) were observed when CBL5 was
applied. As a comparison, the use of the enantiomer of CBL5
(ent-CBL5) resulted in diastereomers 3sa’ and 3ta’ in 71% and
81% yields with excellent dr values. These results not only
indicate the stereochemistry of the formation of C-B bonds is
predominantly controlled by the catalyst, but also provide a
promise of late-stage modification of pyrazole-tethered bioactive
compounds.
Table 3. Substrate scope generality
Scheme 2. Late-stage C(sp3)-H functionalization of bioactive cholic and
deoxycholic acids derived pyrazoles.
Scheme 3. Transformations of crude borylated product 2aa. NBS = N-
bromosuccinimide, Boc2O
diazabicyclo[2.2.2]octane.
= di-tert-butyl decarbonate, DABCO = 1,4-
3
This article is protected by copyright. All rights reserved.

10.1002/anie.202016009
Angewandte Chemie International Edition
COMMUNICATION
[1]
a) D. Leonori, V. K. Aggarwal, Reagent-Controlled Lithiation–Borylation.
In Synthesis and Application of Organoboron Compounds (Eds.: E.
Fernandez, A. Whiting), Springer International Publishing: Cham, 2015,
pp. 271-295; b) H.-Y. Sun, D. G. Hall, At the Forefront of the
Suzuki−Miyaura Reaction: Advances in Stereoselective Cross-
Couplings. In Synthesis and Application of Organoboron Compounds
(Eds.: E. Fernandez, A. Whiting), Springer International: Cham,
Switzerland, 2015, pp. 221−242.
In order to demonstrate the synthetic utility of the current
methods, several stereospecific transformations of C-B bond are
conducted as shown in Scheme 3. Although borylated product
2aa is difficult to isolate, the C-B bond of crude 2aa could undergo
a series of stereospecific C-C and C-heteroatom bonds forming
reactions under various reaction conditions,[26] providing
corresponding β-functionalized pyrazoles 6-9 in overall 72-87%
yields with 98-99% ee. Interestingly, ozonolysis of aminated
pyrazole 7 could afford chiral vicinal diamine derivative 10 in 57%
yield and 98% ee (eq 2).[21f]
[2]
a) A. S. Gorovoy, O. V. Gozhina, J. S. Svendsen, A. A. Domorad, G. V.
Tetz, V. V. Tetz, T. Lejon, Chem. Bio. Drug Des. 2013, 81, 408-413; b)
A. S. Gorovoy, O. Gozhina, J.-S. Svendsen, G. V. Tetz, A. Domorad, V.
V. Tetz, T. Lejon, J. Pept. Sci. 2013, 19, 613-618.
By prolonging the reaction time, current method is also
amendable to gram-scale borylation of 1aa (1.38 g, 10 mmol) in
the presence of reduced catalyst loading (1.0 mol%) with 96% ee
(eq 1) which is comparable to that obtained from standard
reaction conditions (98% ee). The subsequent one-pot treatment
of crude 2aa with KHF2 afforded potassium trifluoroborate 11
(1.47 g) in 60% yield (eq 1).[27] Finally, the absolute configuration
of 3aa was unambiguously confirmed to be R by X-ray single-
crystal diffraction analysis of its acyl protected derivative 12 (eq
2).[28]
[3]
[4]
C. Solé, H. Gulyás, E. Fernández, Chem. Commun. 2012, 48, 3769-3771.
a) N. Matsuda, K. Hirano, T. Satoh, M. Miura, J. Am. Chem. Soc. 2013,
135, 4934-4937; b) H.-C. Jiang, X.-Y. Tang, M. Shi, Chem. Commun.
2016, 52, 5273-5276; c) A. Parra, L. Amenós, M. Guisán-Ceinos, A.
López, J. L. García Ruano, M. Tortosa, J. Am. Chem. Soc. 2014, 136,
15833-15836; d) R. Sakae, K. Hirano, M. Miura, J. Am. Chem. Soc. 2015,
137, 6460-6463; e) R. Sakae, K. Hirano, T. Satoh, M. Miura, Angew.
Chem. Int. Ed. 2015, 54, 613-617; f) R. Sakae, N. Matsuda, K. Hirano, T.
Satoh, M. Miura, Org. Lett. 2014, 16, 1228-1231; g) C.-H. Yang, Y.-S.
Zhang, W.-W. Fan, G.-Q. Liu, Y.-M. Li, Angew. Chem. Int. Ed. 2015, 54,
12636-12639.
[5]
[6]
[7]
X.-Y. Bai, W. Zhao, X. Sun, B.-J. Li, J. Am. Chem. Soc. 2019, 141,
19870-19878.
Z.-T. He, Y.-S. Zhao, P. Tian, C.-C. Wang, H.-Q. Dong, G.-Q. Lin, Organ.
Lett. 2014, 16, 1426-1429.
a) J. Park, Y. Lee, J. Kim, S. H. Cho, Org. Lett. 2016, 18, 1210-1213; b)
J. Kim, K. Ko, S. H. Cho, Angew. Chem. Int. Ed. 2017, 56, 11584-11588;
c) J. Kim, C. Hwang, Y. Kim, S. H. Cho, Org. Process Res. Dev. 2019,
23, 1663-1668.
[8]
[9]
Y. Takeda, A. Kuroda, W. M. C. Sameera, K. Morokuma, S. Minakata,
Chem. Sci. 2016, 7, 6141-6152.
a) Ł. Woźniak, J.-F. Tan, Q.-H. Nguyen, A. Madron du Vigné, V. Smal,
Y.-X. Cao, N. Cramer, Chem. Rev. 2020, 120, 10516-10543; b) M. Zhan,
P. Song, J. Jiao, P. Li, Chin. J. Chem. 2020, 38, 665-667; c) Y.-X. Wang,
P.-F. Zhang, M. Ye, Chin. J. Chem. 2020, 38, 1762-1766.
[10] J. He, Q. Shao, Q. Wu, J.-Q. Yu, J. Am. Chem. Soc. 2017, 139, 3344-
3347.
[11] B. Su, T.-G. Zhou, P.-L. Xu, Z.-J. Shi, J. F. Hartwig, Angew. Chem. Int.
Ed. 2017, 56, 7205-7208.
In summary, we have developed the CBL/Ir-catalyzed
enantioselective borylation of unbiased methylene C(sp3)-H
bonds at the position beta to a nitrogen center using pyrazole as
the directing group. A broad spectrum of functional groups could
be well tolerated, affording a variety of β-functionalized chiral
pyrazoles with good to excellent enantioselectivities under mild
reaction conditions. Both the C-B bond and the pyrazole group of
the borylated product could undergo downstream transformations,
which shows the potential synthetic utility of the current C(sp3)-H
borylation. Further applications of CBLs in other contexts of
asymmetric catalysis are currently underway in our laboratory.
[12] a) R. L. Reyes, T. Iwai, S. Maeda, M. Sawamura, J. Am. Chem. Soc.
2019, 141, 6817-6821; b) R. L. Reyes, M. Sato, T. Iwai, M. Sawamura,
J. Am. Chem. Soc. 2020, 142, 589-597; c) R. L. Reyes, M. Sato, T. Iwai,
K. Suzuki, S. Maeda, M. Sawamura, Science 2020, 369, 970-974.
[13] G. R. Genov, J. L. Douthwaite, A. S. K. Lahdenperä, D. C. Gibson, R. J.
Phipps, Science 2020, 367, 1246-1251.
[14] a) X. Zou, H. Zhao, Y. Li, Q. Gao, Z. Ke, S. Xu, J. Am. Chem. Soc. 2019,
141, 5334-5342; b) Y. Shi, Q. Gao, S. Xu, J. Am. Chem. Soc. 2019, 141,
10599-10604; c) Y. Shi, Q. Gao, S. Xu, Synlett 2019, 30, 2107-2112; d)
L. Chen, Y. Yang, L. Liu, Q. Gao, S. Xu, J. Am. Chem. Soc. 2020, 142,
12062-12068; e) X. Chen, L. Chen, H. Zhao, Q. Gao, Z. Shen, S. Xu,
Chin. J. Chem. 2020, 38, 1533-1537; (f) Y, Yang, L. Chen, S. Xu, Angew.
Chem. Int. Ed. doi.org/10.1002/anie.202013568.
[15] a) P. Jain, P. Verma, G. Xia, J.-Q. Yu, Nat. Chem. 2016, 9, 140; b) S.
Greßies, F. J. R. Klauck, J. H. Kim, C. G. Daniliuc, F. Glorius, Angew.
Chem. Int .Ed. 2018, 57, 9950-9954; c) Y. Wang, X. Wen, X. Cui, X. P.
Zhang, J. Am. Chem. Soc. 2018, 140, 4792-4796.
Acknowledgements
[16] a) S. Anas, A. Cordi, H. B. Kagan, Chem. Commun. 2011, 47, 11483-
11485; b) M. Nakanishi, D. Katayev, C. Besnard, E. P. Kündig, Angew.
Chem. Int. Ed. 2011, 50, 7438-7441; c) T. Saget, S. J. Lemouzy, N.
Cramer, Angew. Chem. Int. Ed. 2012, 51, 2238-2242; d) A. P. Smalley,
J. D. Cuthbertson, M. J. Gaunt, J. Am. Chem. Soc. 2017, 139, 1412-
1415; e) B. Su, T. Lee, J. F. Hartwig, J. Am. Chem. Soc. 2018, 140,
18032-18038.
We thank National Natural Science Foundation of China
(21873261 and 91956116), Natural Science Foundation of
Jiangsu Province (BK20170422), Hangzhou Normal University
(KFJJ2021001), and Lanzhou Institute of Chemical Physics for
generous financial support.
[17] a) K. S. L. Chan, H.-Y. Fu, J.-Q. Yu, J. Am. Chem. Soc. 2015, 137, 2042-
2046; b) H. Wang, H.-R. Tong, G. He, G. Chen, Angew. Chem., Int. Ed.
2016, 55, 15387-15391; c) Q. Shao, Q.-F. Wu, J. He, J.-Q. Yu, J. Am.
Chem. Soc. 2018, 140, 5322-5325; d) C. Li, K. Lang, H. Lu, Y. Hu, X.
Keywords: C-H borylation • asymmetric catalysis • pyrazoles •
organoboron • chiral amines
4
This article is protected by copyright. All rights reserved.

10.1002/anie.202016009
Angewandte Chemie International Edition
COMMUNICATION
Cui, L. Wojtas, X. P. Zhang, Angew. Chem. Int. Ed. 2018, 57, 16837-
16841; e) Z. Zhuang, J.-Q. Yu, J. Am. Chem. Soc. 2020, 142, 12015-
12019.
[18] a) R. Giri, B.-F. Shi, K. M. Engle, N. Maugel, J.-Q. Yu, Chem. Soc. Rev.
2009, 38, 3242-3272; b) T. G. Saint-Denis, R.-Y. Zhu, G. Chen, Q.-F. Wu,
J.-Q. Yu, Science 2018, 359; c) C. He, W. G. Whitehurst, M. J. Gaunt,
Chem 2019, 5, 1031-1058; d) H. Hayashi, T. Uchida, Eur. J. Org. Chem.
2020, 2020, 909-916; e) Q. Shao, K. Wu, Z. Zhuang, S. Qian, J.-Q. Yu,
Acc. Chem. Res. 2020, 53, 833-851; f) A. Trowbridge, S. M. Walton, M.
J. Gaunt, Chem. Rev. 2020, 120, 2613-2692.
[19] a) C. W. Liskey, J. F. Hartwig, J. Am. Chem. Soc. 2012, 134, 12422-
12425; b) R. Oeschger, B. Su, I. Yu, C. Ehinger, E. Romero, S. He, J.
Hartwig, Science 2020, 368, 736-741.
[20] a) R. A. Mesa, U. Yasothan, P. Kirkpatrick, Nat. Rev. Drug Discov. 2012,
11, 103-104; b) P. Koppikar, N. Bhagwat, O. Kilpivaara, T. Manshouri, M.
Adli, T. Hricik, F. Liu, L. M. Saunders, A. Mullally, O. Abdel-Wahab, L.
Leung, A. Weinstein, S. Marubayashi, A. Goel, M. Gönen, Z. Estrov, B.
L. Ebert, G. Chiosis, S. D. Nimer, B. E. Bernstein, S. Verstovsek, R. L.
Levine, Nature 2012, 489, 155-159; c) L. Da Costa, E. Scheers, A.
Coluccia, A. Casulli, M. Roche, C. Di Giorgio, J. Neyts, T. Terme, R. Cirilli,
G. La Regina, R. Silvestri, C. Mirabelli, P. Vanelle, J. Med. Chem. 2018,
61, 8402-8416; d) M. Naim, O. Alam, F. Nawaz, M. Alam, P. Alam, J.
Pharm. Bioall. Sci. 2016, 8, 2-17.
[21] a) S. Kawamorita, T. Miyazaki, H. Ohmiya, T. Iwai, M. Sawamura, J. Am.
Chem. Soc. 2011, 133, 19310-19313; b) P. Gao, W. Guo, J. Xue, Y. Zhao,
Y. Yuan, Y. Xia, Z. Shi, J. Am. Chem. Soc. 2015, 137, 12231-12240; c)
W.-C. C. Lee, Y. Shen, D. A. Gutierrez, J. J. Li, Org. Lett. 2016, 18, 2660-
2663; d) Y. Shen, W.-C. Cindy Lee, D. A. Gutierrez, J. J. Li, J. Org. Chem.
2017, 82, 11620-11625; e) C. Yuan, G. Tu, Y. Zhao, Organ. Lett. 2017,
19, 356-359; f) N. Gulia, O. Daugulis, Angew. Chem. Int. Ed. 2017, 56,
3630-3634; g) V. Botla, A. Akudari, C. Malapaka, Tetrahedron Lett.2019,
60, 115-119; h) Y. Wang, H. Liu, B. Li, B. Wang, Adv. Synth. Catal. 2019,
361, 1564-1569; i) H. Cai, R. S. Thombal, X. Li, Y. R. Lee, Adv. Synth.
Catal. 2019, 361, 4022-4032; j) H. Kim, R. S. Thombal, H. D. Khanal, Y.
R. Lee, Chem. Commun. 2019, 55, 13402-13405; k) E. Kang, H. T. Kim,
J. M. Joo, Org. Biomol. Chem. 2020, 18, 6192-6210; l) T. Saitou, Y. Jin,
K. Isobe, T. Suga, J. Takaya, N. Iwasawa, Chem. Asian J. 2020, 15,
1941-1944.
[22] C. Kashima, S. Hibi, T. Maruyama, K. Harada, Y. Omote, J. Heterocycl.
Chem. 1987, 24, 637-639.
[23] a) S.-B. Yan, S. Zhang, W.-L. Duan, Org. Lett. 2015, 17, 2458-2461; b)
G. Chen, W. Gong, Z. Zhuang, M. S. Andrä, Y.-Q. Chen, X. Hong, Y.-F.
Yang, T. Liu, K. N. Houk, J.-Q. Yu, Science 2016, 353, 1023-1027; c) S.-
Y. Yan, Y.-Q. Han, Q.-J. Yao, X.-L. Nie, L. Liu, B.-F. Shi, Angew. Chem.
Int. Ed. 2018, 57, 9093-9097; d) Y.-Q. Han, Y. Ding, T. Zhou, S.-Y. Yan,
H. Song, B.-F. Shi, J. Am. Chem. Soc. 2019, 141, 4558-4563; e) Y. Ding,
Y.-Q. Han, L.-S. Wu, T. Zhou, Q.-J. Yao, Y.-L. Feng, Y. Li, K.-X. Kong,
B.-F. Shi, Angew. Chem. Int. Ed. 2020, 59, 14060-14064.
[24] The use of non-substituted 1-propylpyrazole results in a mixture of
multiple mono- and di-borylated products.
[25] Racemic-3qa, racemic-3ra, and racemic-5ja were observed in 8%, 3%
and 91% 1H NMR yields without CBL5 under otherwise identical reaction
conditions. While reduced background reactions were observed for
substrates 1qe, 1re, and 4jc-4je (See supporting information Table S1
for more details). The electron-withdrawing feature of C4 substituent
could probably reduce the coordination ability of the C2 nitrogen atom of
the pyrazole moiety, which may be the reason for the deceleration of the
background reaction.
[26] a) R. P. Sonawane, V. Jheengut, C. Rabalakos, R. Larouche-Gauthier,
H. K. Scott, V. K. Aggarwal, Angew. Chem. Int. Ed. 2011, 50, 3760-3763;
b) A. Bonet, M. Odachowski, D. Leonori, S. Essafi, V. K. Aggarwal, Nat.
Chem. 2014, 6, 584-589; c) X. Liu, Q. Zhu, D. Chen, L. Wang, L. Jin, C.
Liu, Angew. Chem. Int. Ed. 2020, 59, 2745-2749.
[27] G. A. Molander, I. Shin, Org. Lett. 2012, 14, 4458-4461.
[28] Crystallographic data for 12 could be found in the Supporting Information.
CCDC 2042469 contains the supplementary crystallographic data for this
paper. The data can be obtained free of charge from The Cambridge
Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif.
5
This article is protected by copyright. All rights reserved.

10.1002/anie.202016009
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
Beta to Nitrogen: Unbiased methylene C(sp3)-H bonds at the position beta to a nitrogen center could be borylated in an
enantioselective manner in the presence of a catalytic amount of the chiral bidentate boryl ligand (CBL) and iridium precursor. The
method could tolerate a broad spectrum of functional groups, furnishing a variety of C(sp3)-H functionalized products in good yields
with excellent enantioselectivities.
6
This article is protected by copyright. All rights reserved.