Chiral Arylated Amines via C?N Coupling of Chiral Amines with Aryl Bromides Promoted by Light

Article abstract of DOI:10.1002/anie.202108587

The Buchwald-Hartwig C-N coupling reaction has found widespread applications in organic synthesis. Over the past two decades or so, many improved catalysts have been introduced, allowing various amines and aryl electrophiles to be readily used nowadays. However, there lacks a protocol that could be used to couple a wide range of chiral amines and aryl halides, without erosion of the enantiomeric excess (ee). Reported in this article is a method based on molecular Ni catalysis driven by light, which enables stereoretentive C-N coupling of optically active amines, amino alcohols, and amino acid esters with aryl bromides, with no need for any external photosensitizer. The method is effective for a wide variety of coupling partners, including those bearing functional groups sensitive to bases and nucleophiles, thus providing a viable alternative to accessing synthetically important chiral N-aryl amines, amino alcohols, and amino acids esters. Its viability is demonstrated by 92 examples with up to 99 % ee.

Full text of DOI:10.1002/anie.202108587

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Chiral Arylated Amines via C-N Coupling of Chiral Amines with
Aryl Bromides Promoted by Light
Authors: Dong Xue, Geyang Song, Liu Yang, Jing-Sheng Li, Wei-Jun
Tang, Wei Zhang, Rui Cao, Chao Wang, and Jianliang Xiao
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.202108587
Link to VoR: https://doi.org/10.1002/anie.202108587

10.1002/anie.202108587
Angewandte Chemie International Edition
RESEARCH ARTICLE
Chiral Arylated Amines via C-N Coupling of Chiral Amines with
Aryl Bromides Promoted by Light
Geyang Song,[a] Liu Yang,[a] Jing-Sheng Li,[a] Wei-Jun Tang,[a] Wei Zhang,[a] Rui Cao,[a] Chao Wang,[a]
Jianliang Xiao,*[b] and Dong Xue*[a]
[a]
Key Laboratory of Applied Surface and Colloid Chemistry, Ministry of Education and School of Chemistry and Chemical Engineering, Shaanxi Normal
University, Xi’an, 710062 (China).
[b]
Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD (UK).
E-mail: j.xiao@liv.ac.uk; xuedong_welcome@snnu.edu.cn
Abstract: The Buchwald-Hartwig C-N coupling reaction has found
widespread applications in organic synthesis. Over the past two
decades or so, many improved catalysts have been introduced,
allowing various amines and aryl electrophiles to be readily used
nowadays. However, there lacks a protocol that could be used to
couple a wide range of chiral amines and aryl halides, without erosion
of the enantiomeric excess (ee). Reported in this article is a method
based on molecular Ni catalysis driven by light, which enables
stereoretentive C-N coupling of optically active amines, amino
alcohols, and amino acid esters with aryl bromides, with no need for
any external photosensitizer. The method is effective for a wide
variety of coupling partners, including those bearing functional groups
sensitive to bases and nucleophiles, thus providing
a viable
alternative to accessing synthetically important chiral N-aryl amines,
amino alcohols, and amino acids esters. Its viability is demonstrated
by 92 examples with up to 99% ee.
Introduction
The palladium-catalyzed Buchwald-Hartwig amination[1] is
ranked as one of the 20 most frequently used reactions in
medicinal chemistry.[2] Together with the copper-catalyzed
Ullmann type coupling,[3] it is also considered one of the most
commonly used C-N bond formation reactions in modern organic
chemistry (Scheme 1, A). Due to its much higher natural
abundance and lower cost than palladium,[4] nickel has also been
explored for catalyzing the C-N coupling of aryl halides with
amines in the past two decades or so.[5-6] The efficiency and
substrate scope of the nickel catalysis have been greatly
improved with the advent of novel strategies in recent years.[7-9]
Thanks to the Pd, Cu and Ni catalysis, diverse ranges of aryl
amines can now be readily accessed via the C-N coupling
reactions.
However, throughout the history of C-N coupling chemistry,
there have been only sporadic reports on either Pd, Cu or Ni
catalyzed coupling of chiral amines and amino acid esters to
access chiral N-aryl amines and amino acids(esters), compounds
of significant importance to the pharmaceutical industry.[10, 11] This
discrepancy may not be surprising, however, as chiral amino
compounds can be racemized by Pd,[10a] Ni[12] or a strong base
such as alkali-metal alkoxides,[13] which are commonly employed
in C-N coupling (Scheme 1, B, C). This is particularly acute for
amino acids(esters), due to the presence of an acidic proton at
their stereogenic centers.[10e, 10g] In the few successful examples
using Pd catalysts bearing bulky ligands, the aryl electrophiles are
limited to electron-deficient aryl bromides or more active aryl
Scheme 1. Metal catalyzed C-N coupling of aryl halides for the synthesis of
chiral N-aryl amines and amino acid esters.
triflates[10d] and, in the case of heteroaryl halides, to
chloropyridines.[10c,e-g] The Cu-catalyzed coupling of amino
acids(esters) has been shown to be setereoretentive, albeit being
limited to active aryl halides while requiring a relatively long
reaction time.[11] In the burgeoning area of Ni-catalyzed C-N
coupling, the only examples known thus far are seen in a recent
report, in which electrochemical C-N coupling by Ni catalysis
afforded chiral N-aryl amino acids esters with high yields but low
levels of enantioretention.[9b] Clearly, a more general protocol that
displays a wider substrate scope and retain the stereochemistry
of the amino substrates remains highly desirable for further
developing the widely used Buchwald-Hartwig C-N coupling
reaction. Herein, we report a photochemically driven, Ni-catalyzed
C-N coupling that enables a wide range of (hetero)aryl bromides
to couple, stereoretentively, with chiral amines, amino alcohols,
and amino acid esters (Scheme 1, D).
Results and Discussion
1
This article is protected by copyright. All rights reserved.

10.1002/anie.202108587
Angewandte Chemie International Edition
RESEARCH ARTICLE
To develop a stereoretentive protocol for Ni-catalyzed C-N
coupling, amine racemization must be avoided. We surmised that
this could be achieved by stabilizing the metal with a bidentate
ligand and by replacing the strong alkali-metal alkoxide base with
a milder base. Indeed, while palladium complexes catalyze the
racemization via
a dehydrogenation/hydrogenation process
triggered by hydrogen elimination, the racemization can be
effectively suppressed by coordinating Pd with bidentate
phosphine ligands.[10a] Bidentate pyridine ligands can be used to
stabilize nickel species from decomposing into Ni
nanoparticles,[14] which are known to catalyze amine
racemization.[12] In our study into light-driven, Ni-catalyzed C-X (X
= O, N) coupling, we have found that nickel complexes bearing
bipyridine ligands are efficient catalysts, allowing for the coupling
in the presence of a mild organic base, with no need for an
additional photosensitizer.[15] Building on this basis, we set out to
examine the possibility of Ni-catalyzed C-N coupling of chiral
amines with aryl halides, aiming to establish a protocol that
displays
a wider substrate scope and a high level of
enantioretention.
In our initial study, the coupling reaction of optically pure (R)-
1-phenylethan-1-amine (1) with bromobenzene (2) was selected
as a model system for reaction development. Delightedly, we
found that using a Ni(II) complex in combination with a bipyridine
ligand, the cross-coupling reaction readily took place under the
irradiation of long-wave UV light (390-395 nm) in the absence of
any external photosensitizer (Table 1). Among all the surveyed Ni
catalysts (Table S1-S2, SI), the in-situ generated Ni(OAc)2-d-
Mebpy complex (d-Mebpy: 4,4’-dimethybipyridine) exhibited the
best catalytic activity, affording the C-N coupling product (3) with
86% isolated yield (Table 1, entry 1).[16] Importantly, the
Table 1. Search for optimal reaction conditions for the target C-N coupling.[a]
Entry
Variation from standard conditions
Standard conditions
Yield (%)
1
2
3
4
5
6
7
8
9
86[b] (99%)[c]
Standard conditions, no ligand
10[d]
0[d]
Standard conditions, UV (360-365 nm)
Standard conditions, blue LEDs (460-465 nm)
Standard conditions, white LEDs
Scheme 2. Scope of chiral amines. Isolated yields are shown; configuration of
the products and those below were determined by X-ray diffraction anyalysis or
by analogy. [a] Gram scale reaction.
10[d]
0[d]
enantiomeric excess of 3 was 99%, showing complete retention
of the amine stereochemistry in the C-N coupling. The bipyridine
ligand is critical to the success of the reaction, with the product
yield reduced considerably in its absence (entry 2). Further
optimization indicates that light played a crucial role as well, as
only the long-wave UV light afforded a high yield (Table 1, entries
3-6).[16] The choice of base also impacted on the reaction (entry
7), and pleasingly among the bases examined, the mild DBU
promoted the reaction significantly better than other bases (Table
S3-S4). Subsequent studies revealed a mixture of THF and DMF
to be the optimum solvent for the coupling reaction (Table S5).
Finally, control experiments showed that the reaction did not
proceed in the absence of nickel catalyst or light (entries 8-9,
Table S8).
Standard conditions, green LEDs (530-535 nm)
Standard conditions, no base
0[d]
17[d]
0[d]
Standard conditions, no nickel catalyst
Standard conditions, no light, heating to 120 °C
0[d]
[a] Standard conditions: 1 (0.4 mmol), 2 (0.2 mmol), Ni(OAc)2 (5.0 mol %), d-
Mebpy (5.0 mol %), DBU (0.3 mmol), DMF:THF (2 mL), purple LEDs (390-395
nm), 85 °C, Ar, 24 h. [b] isolated yield. [c] The ee value was determined by HPLC
with chiral stationary phases, and the absolute configuration of
3 was
determined to be R by comparison of the HPLC retention time with literature. for
details see SI. [d] Yields determined by 1H NMR, using 1,3-benzodioxole as
internal standard.
2
This article is protected by copyright. All rights reserved.

10.1002/anie.202108587
Angewandte Chemie International Edition
RESEARCH ARTICLE
With the optimized conditions in hand, we first explored the
scope of chiral amines of this light-promoted C-N coupling
reaction. As shown in Scheme 2, a wide range of diverse chiral
amines could be coupled with 4-bromobenzotrifluoride, affording
the desired products with high yields (4-25). Notably, the
enantiomeric excess of products was excellent, >98% in most
cases, showing a high level of enantioretention. Thus, when chiral
aliphatic amines, such as 2-aminobutylamine, 2-octylamine and
1-cyclohexylethylamine, were used, the chiral aryl amines were
obtained with high yields and ee’s (4-6). We next extended the
protocol to chiral amino alcohols, bearing in mind their importance
in medicinal chemistry. It is significant to note that the desired
products were obtained with good yields and high ee’s (7-15), with
no protection of the hydroxyl group required. In contrast,
protection was required in a Pd-catalyzed C-N coupling of amino
alcohols,[10a] demonstrating the advantage of the light-promoted
C-N coupling reaction via nickel catalysis. The chiral aliphatic
amines containing furan (16) and trifluoromethyl (18) and a
tertiary chiral amine, arylated α-methylpyrrolidine (17),[17] could
also be accessed.[18] It is noted that these chiral aliphatic amines,
particularly those having sterically less differentiating substitutes
at the stereogenic carbon, e.g. 4, 7 and 18, would be difficult to
obtain by common asymmetric hydrogenation reactions. Equally,
for chiral aryl amines with different substituents (19-22), phenyl
propamine (23) and naphthyl amines (24-25), the desired chiral
arylated amines were obtained with high ee’s. Using the
deuterated phenethylamine (26), the chiral amine product was
obtained with 99% ee and full deuterium retention (94 D%). In
contrast, H/D exchange may occur in the presence of a strong
base or with metal catalysts capable of hydrogen elimination in
traditional C-N coupling. Notable is also the formation of
medicinally important aryl amines containing pyridine (27-28),
thiophene (30), and tetralone (31) and indanone derivates (32),
all with excellent ee’s.
The scope of aryl halides was next examined. As summarized
in Scheme 3, aryl bromides with a variety of functional groups
reacted efficiently with optically pure (R)-1-phenylethan-1-amine
(1), delivering the desired chiral aryl amines with high yields and
excellent enantiomeric excess. Thus, the coupling of electron-
neutral and rich aryl bromides afforded the desired chiral aryl
amines in high yields with full retention of the amine
stereochemistry (3, 33-37). Such substates have been
challenging with the traditional C-N coupling protocols.[10] Similar
observations were made for aryl bromides bearing various
electron-withdrawing substituents (38-45). It is noted that
substrates with an ester group (39) or a cyano group (45,46) may
not be compatible with the conventional, strongly-basic conditions.
Indeed, transesterification in copper catalysis[19] and formation of
impurities in palladium catalysis due to the cyano group[20] have
been reported. In contrast, aryl bromides containing an ester or a
cyano group are suitable with this protocol, demonstrating the
advantage of using organic amines as base. Note for aryl
bromides bearing a chloro or an additional bromo substituent, the
corresponding mono-substituted chiral aryl amines were obtained
with high yields (42-44), demonstrating not only a high degree of
enantioretention but also chemoselectivity. Multisubstituted aryl
bromides also worked successfully with this protocol (47-51), as
showcased by the trifluoro-substituted aniline derivative 51. In
particular, aryl bromides with substitutes at the ortho position are
viable substrates, causing no erosion of the amine
stereochemistry in the coupling (52-58), albeit affording a
3
This article is protected by copyright. All rights reserved.

10.1002/anie.202108587
Angewandte Chemie International Edition
RESEARCH ARTICLE
Scheme 3. Scope of aryl halides. Isolated yields are shown. [a] Gram scale
reaction. [b] Catalyst (15 mol %, 36 h). [c] Catalyst (10 mol %).
brominated Gemfibrozil methyl ester, amination of which afforded
the chiral N-arylation product with 62% yields and 98% ee (71).
These examples further demonstrate the power of the light-driven
Ni catalysis in stereoretentive C-N coupling reactions.
Bearing in mind the significant importance of N-arylated
amino acids esters in the synthesis of bio-medically active
molecules,[21] we next explored the more challenging N-arylation
of amino acid esters. However, when applied to valine methyl
ester, the desired product was obtained with a good yield (74%)
but a low ee (53%) under our standard condition (Table 1). We
quickly found that temperature is critical to maintaining the
stereochemistry for the C-N coupling with amino acids esters
prone to racemization. Together with the mild DBU base, a lower
temperature thus makes possible highly enantioretentive arylation
of this class of substrates with aryl bromides, a reaction that is
difficult with conventional methods where harsh conditions are
usually employed. As summarized in Scheme 4, a wide range of
amino acid esters, such as methyl, tert-butyl, or benzyl esters, are
suitable for this N-arylation reaction. For amino acid esters of
alanine (72), valine (75), cyclohexylglycine (76), leucine (78),
phenylalanine (79-80), tyrosine (81), threonine (82), glutamic acid
(83), lysine (84), the C-N coupling products were obtained with
excellent levels of enantioretention. For methionine methyl ester
(85) and serine tert-butyl ester (86), the N-arylated amino acid
ester were obtained with reduced enantioretention, probably due
to the proton being slightly more acidic. The previously reported
Ni catalysis is less likely to work on these amino acid esters (See
Section 2.2, Supporting Information).
We next evaluated the scope of aryl bromides. As can be
seen in Scheme 4, various aryl bromides can be brought into the
C-N coupling, regardless of being electron-neutral (87), rich (88-
89) or deficient (90-92) or being a heteroaryl (93), with little
erosion of enantiomeric excess observed. Moreover, the protocol
is suitable for intramolecular C-N coupling, as shown by the
formation of indoline (94) with good yield and excellent
enantiomeric excess. Note for amino acid esters bearing the tert-
butyl group, a lower temperature is not necessary (see 77, 87-91).
This is likely to stem from the steric encumbrance of the group
which hinders the deprotonation of the α-proton.
The mechanism of this light-promoted Ni-catalyzed C-N
coupling has not been thoroughly investigated. However, on the
basis of our recent studies of C-O and C-N coupling reactions
enabled by a similar Ni catalytic system[15] and closely related
studies by other groups,[22-25] the coupling reaction in question is
Scheme 4. Scope of amino acid esters. Isolated yields are shown.
moderate yield in the case of the sterically more demanding
isopropyl substituent (54).
Few examples have been reported of heteroaryl halides
coupling with chiral amines,[9b, 10b,e-g, 20] which could easily lead to
drug-like chiral amine molecules. As can be seen in Scheme 3,
heteroaryl bromides are compatible with this Ni catalysis,
affording the desired chiral aryl amines featuring a range of
diverse heterocycles, thiophene (58, 59), pyridine (60-62),
pyrimidine (63-65), benzothiophene (66), benzofuran (67), indole
(68), isoindole (69) and carbazole (70). These compounds would
be difficult to access via asymmetric hydrogenation or reductive
amination due to possible interference of the heteroatoms with
metal coordination and their electron withdrawing effect.
Furthermore, this methodology can be applied to the late-stage
modification of drug molecules. An example is seen in the
Figure 1. UV-Vis absorption spectra of dtbbpy, (R)-1-phenylethan-1-amine and
Ni(II) species in THF (5.0×10–4 M, 1 mm pathlength quartz cuvette). For details,
see Supporting Information (Section 4.1).
4
This article is protected by copyright. All rights reserved.

10.1002/anie.202108587
Angewandte Chemie International Edition
RESEARCH ARTICLE
likely to proceed via a Ni(I)/Ni(III) cycle. The few probing
experiments we have conducted appear to support this view.
First, the measurements of UV-Vis absorption support the
formation of Ni(II)-dtbbpy species duing the catalysis, with or
without the amine substrate. As showed in Figure 1, the species
generated by in-situ mixing Ni(OAc)2 and the chiral amine (R)-1-
phenylethanamine in THF shows absorption bands similar to
those of an octahedral Ni(II)-amine complex reported by the
groups of Miyake[8c] and MacMillan[8e]. In contrast, the in situ-
made Ni(OAc)2-dtbbpy complex shows features distinctively
different in the region of 350-800 nm, and more significantly, the
presence of a large amount of (R)-1-phenylethanamine has little
effect on its absorption, suggesting that Ni(II) is ligated by the
bidentate dtbbpy ligand in the reaction mixture and the resulting
Ni(II)-dtbbpy complex, which does not appear to interact with the
chiral amine, is likely to be the light-absorbing species. This
conjecture also explains why, without the ligand, the C-N coupling
cannot take place under the irradiation of purple light.
We also measured the mass spectra of possible Ni species
formed upon mixing the starting Ni(II) complex with an amine and
ligand. As shown in Scheme 5, when Ni(OAc)2 was mixed with an
excess amount of the chiral amine for 30 min in THF, the HRMS
revealed a m/z peak at 359.1267, which is consistent with the
formation of Ni(OAc)2[(R)-1-phenylethanamine] or {Ni(OAc)[(R)-
1-phenylethanamine]}+. However, after the addition of the dtbbpy
ligand (1 equivalnet to Ni), the peak of the chiral amine-nickel
complex disappeared and a new peak at m/z 385.1423 was
detected, which was also detected by mixing Ni(OAc)2 and dtbbpy
in the absence of the amine and is consistent with the formation
Scheme 5. Mass spectrometry study of possible Ni species.
of Ni(OAc)2(dtbbpy) or [Ni(OAc)(dtbbpy)]+. Similarly, when
Ni(OAc)2 was mixed with both the bipyridine and excess chiral
amine, the peak at m/z 385.1422, but not that at 359.1267, was
detected. These results lend further support to the notion that
theactive catalytic species in the reaction is likely to be a Ni(II)-
bipyridine complex.
5
This article is protected by copyright. All rights reserved.

10.1002/anie.202108587
Angewandte Chemie International Edition
RESEARCH ARTICLE
Furthermore, when the in situ-made Ni(OAc)2-dMebpy complex
was irradiated by purple light for 1 h, the formation of OAc radical
was observed by electron paramagnetic resonance (EPR)
spectroscopy (Figure S15) with N-tert-butyl-α-phenylnitrone
(PBN) as a radical trap (Scheme 6, 1). The spin adduct of the OAc
radical is characterized by hyperfine coupling constants that
agree with the literature data.[26] The formation of the OAc radical
indicates homolysis of the Ni-O bond and hence the formation of
Ni(I) species under the irradiation of light. We next probed the
possibility of oxidative addition at the Ni(I) species with an aryl
halide and the following C-N coupling reaction. In the absence of
substrates, the Ni(OAc)2-dMebpy complex was irradiated under
the purple light for 4 h, which was expected to generate a Ni(I)
complex. Then in the dark, the substrates were introduced and
reacted for 24 h, affording the corresponding arylamine with 16%
yield (Scheme 6, 2). Still further, when the Ni(I) complex,
generated in situ from the comproportionation of Ni(II)(OAc)2-
dMebpy and Ni(0)(dMebpy)(cod) complexes, was used as
catalyst, the desired product was obtained in 93% yield under the
irradiation of light and 25% yield under thermal conditions
(Scheme 6, 3). In addition, as shown in Table 1, Ni(II) species are
inactive without light irradiation. These observations support the
view that this C-N coupling proceeds via a dMebpy-ligated
Ni(I)/N(III) cycle, involving oxidative addition of ArBr at a Ni(I)-
dMebpy species and reductive elimination of an aryl and amide
group at Ni(III)-dMebpy to form the C-N bond, with light required
to generate the Ni(I) species from off-cycle Ni(II)-dMebpy species
and sustain the catalytic turnover.[8e] However, the possibility of a
Ni(II)-amine species being the active catalyst and/or amine
participation in the Ni(II)-dMebpy catalysed C-N coupling, as put
forward by Miyake and coworkers, cannot be ruled out.[8c]
Acknowledgements
This research is supported by the National Natural Science
Foundation of China (21871171), and the 111 project (B14041).
Keywords: C-N coupling • chiral N-aryl amines • chiral N-aryl
amino acids • chiral N-aryl amino alcohols • nickel catalysis
[1] a) J. Bariwal, E. V. Van der Eycken, Chem. Soc. Rev. 2013, 42, 9283-
9303; b) P. Ruiz-Castillo, S. L. Buchwald, Chem. Rev. 2016, 116,
12564-12649; c) P. A. Forero-Cortés, A. M. Haydl, Org. Process Res.
Dev. 2019, 23, 1478-1483; d) R. Dorel, C. P. Grugel, A. M. Haydl,
Angew. Chem. Int. Ed. 2019, 58, 17118-17129; Angew. Chem. 2019,
131, 17276-17287.
[2] D. G. Brown, J. Bostrꢀm, J. Med. Chem. 2016, 59, 4443-4458.
[3] S. Bhunia, G. Goroba Pawar,S.VijayKumar,Y. Jiang, D. Ma, Angew.
Chem. Int. Ed. 2017, 56, 16136-16179; Angew. Chem. 2017, 129,
16352-16397.
[4] S. Z. Tasker, E. A. Standley, T. F. Jamison, Nature 2014, 509, 299-309.
[5] M. Marín, R. J. Rama, M. C. Nicasio, Chem. Rec. 2016, 16, 1819-1832.
[6] a) J. P. Wolfe, S. L. Buchwald, J. Am. Chem. Soc. 1997, 119, 6054-
6058; b) G. Manolikakes, A. Gavryushin, P. Knochel, J. Org. Chem.
2008, 73, 1429-1434.
7] a) S. D. Ramgren, A. L. Silberstein, Y. Yang, N. K. Garg, Angew. Chem.
Int. Ed. 2011, 50, 2171-2173; Angew. Chem. 2011, 123, 2219-2221; b)
N. H. Park, G. Teverovskiy, S. L. Buchwald, Org. Lett. 2014, 16, 220-
223; c) S. Ge, R. A. Green, J. F. Hartwig, J. Am. Chem. Soc. 2014, 136,
1617-1627; d) C. M. Lavoie, P. M. MacQueen, N. L. Rotta-Loria, R. S.
Sawatzky, A. Borzenko, A. J. Chisholm, B. K. V. Hargreaves, R.
McDonald, M. J. Ferguson, M. Stradiotto, Nat. Commun. 2016, 7,
11073; e) J. P. Tassone, E. V. England, P. M. MacQueen, M. J.
Ferguson, M. Stradiotto, Angew. Chem. Int. Ed. 2019, 58, 2485-2489;
Angew. Chem. 2019, 131, 2507-2511;f) J. S. K. Clark, M. J. Ferguson,
R. McDonald, M. Stradiotto, Angew. Chem. Int. Ed. 2019, 58, 6391-
6395; Angew. Chem. 2019, 131, 6457-6461; g) R. Y. Liu, J. M. Dennis,
S. L. Buchwald, J. Am. Chem. Soc. 2020, 142, 4500-4507.
[8] a) E. B. Corcoran, M. T. Pirnot, S. Lin, S. D. Dreher, D. A. DiRocco, I.
W. Davies, S. L. Buchwald, D. W. C. MacMillan, Science 2016, 353,
279-283; b) M. S. Oderinde, N. H. Jones, A. Juneau, M. Frenette, B.
Aquila, S. Tentarelli, D. W. Robbins, J. W. Johannes, Angew. Chem.
Int. Ed. 2016, 55, 13219-13233; Angew. Chem. 2016, 128, 13413-
13417; c) C.-H. Lim, M. Kudisch, B. Liu, G. M. Miyake, J. Am. Chem.
Soc. 2018, 140, 7667-7673; d) M. Kudisch, C.-H. Lim, P. Thordarson,
G. M. Miyake, J. Am. Chem. Soc. 2019, 141, 19479-19486; e) N. A.
Till, L. Tian, Z. Dong, G. D. Scholes, D. W. C. MacMillan, J. Am. Chem.
Soc. 2020, 142, 15830-15841.
[9] a) C. Li, Y. Kawamata, H. Nakamura, J. C. Vantourout, Z. Liu, Q. Hou,
D. Bao, J. T. Starr, J. Chen, M. Yan, P. S. Baran, Angew. Chem. Int.
Ed. 2017, 56, 13088-13093; Angew.Chem. 2017, 129,13268-13273; b)
Y. Kawamata, J. C. Vantourout, D. P. Hickey, P. Bai, L. Chen, Q. Hou,
W. Qiao, K. Barman, M. A. Edwards,A. F. Garrido-Castro, J. N. Gruyter,
H. Nakamura, K. Knouse, C. Qin, K. J. Clay, D. Bao, C. Li, J. T. Starr,
C. Garcia-Irizarry, N. Sach, H.S. White, M. Neurock, S. D. Minteer, P.S.
Baran, J. Am. Chem. Soc. 2019, 141, 6392-6402.
[10] For the synthesis of chiral N-aryl amines and amino acid esters by Pd
catalysis, see: a) S. Wagaw, R. A. Rennels, S. L. Buchwald, J. Am.
Chem. Soc. 1997, 119, 8451-8458; b) Q. Shen, S. Shekhar, J. P.
Stambuli, J. F. Hartwig, Angew. Chem. Int. Ed. 2005, 44, 1371-1375;
Angew. Chem. 2005, 117, 1395-1399; c) R. Surasani, D. Kalita, A. V.
Dhanunjaya Rao, K. B. Chandrasekhar, Beilstein J. Org. Chem. 2012,
8, 2004-2018; d) S. M. King, S. L. Buchwald, Org. Lett. 2016, 18, 4128-
4131; e) B. T. Ingoglia, S. L. Buchwald, Org. Lett. 2017, 19, 2853-5856;
f) S. Sharif, D. Mitchell, M. J. Rodriguez, J. L. Farmer, M. G. Organ,
Chem. Eur. J. 2016, 22, 14860-14863; g) H. Hammoud, M. Schmitt, E.
Blaise, F. Bihel, J. Bourguignon, J. Org. Chem. 2013, 78, 7930-7937.
[11] For the synthesis of chiral N-aryl amino acids by Cu catalysis, see: a)
D. Ma, Y. Zhang, J. Yao, S. Wu, F. Tao, J. Am. Chem. Soc. 1998, 120,
12459-12467; b) D. Ma, C. Xia, Org. Lett. 2001, 3, 2583-2586.
Scheme 6. Reactions aimed to probe the C-N coupling mechanism. Yields
determined by 1H NMR. For details, see SI.
Conclusion
In summary, we have developed a highly enantioretentive
photochemical C-N coupling of commercially available chiral
amines, amino alcohols, and amino acid esters with various aryl
bromides. The reaction is catalyzed by an easily-available Ni(II)-
dMebpy complex, with no need for an external photosensitizer. It
exhibits a very wide substrate scope, good functional group
compatibility and excellent levels of enantioretention, providing a
practical, viable alternative pathway for the synthesis of chiral N-
aryl amines, amino alcohols, and amino acid esters, some of the
most important building blocks in pharmaceutical and
agrochemical synthesis. The stabilizing bidentate ligand and mild
organic base alongside the mild reaction conditions enabled by
light are likely to be the key for the observed enantioretention.
6
This article is protected by copyright. All rights reserved.

10.1002/anie.202108587
Angewandte Chemie International Edition
RESEARCH ARTICLE
[12] I. Geukens, E. Plessers, J. W. Seo, D. E. De Vos, Eur. J. Inorg. Chem.
2013, 14, 2623-2628.
[13] a) E. J. Ebbers, G. J. A. Ariaans, J. P. M. Houbiers, A. Bruggink, B.
Zwanenburg, Tetrahedron 1997, 53, 9417-9476; b) For examples, see
US 5,183,939.
[14] S. Gisbertz, S. Reischauer, B. Pieber, Nat. Catal. 2020, 3, 611-620.
[15] a) L. Yang, H.-H. Lu, C.-H. Lai, G. Li, W. Zhang, R. Cao, F. Liu, C.
Wang, J. Xiao, D. Xue, Angew. Chem. Int. Ed. 2020, 59, 12714-12719;
Angew. Chem. 2020, 132, 12814-12819; b) G. Li, L. Yang, J.-J. Liu,
W. Zhang, R. Cao, C. Wang, Z. Zhang, J. Xiao, D. Xue, Angew. Chem.
Int. Ed. 2021, 60, 5230–5234; Angew. Chem. 2021, 133, 5290-5294.
[16] For details, please see SI.
[17] Arylation of α-branched amines by Pd catalysis, see: N. H. Park, E. V.
Vinogradova, D. S. Surry, S. L. Buchwald, Angew. Chem. Int. Ed. 2015,
54, 8259-8262; Angew. Chem. 2015, 127, 8377-8380.
[18] Arylation of fluoroalkylamines by Pd catalysis, see: A. T. Brusoe, J. F.
Hartwig, J. Am. Chem. Soc. 2015, 137, 8460-8468.
[19] Z. Chen, Y. Jiang, L. Zhang, Y. Guo, D. Ma, J. Am. Chem. Soc.
2019,141, 3541-3549.
[20] J. B. Sperry, K. E. P. Wiglesworth, I. Edmonds, P. Fiore, D. C. Boyles,
D. B. Damon, R. L. Dorow, E. L. P. Chekler, J. Langille, J. W. Coe,
Org. Process Res. Dev. 2014, 18, 1752-1758.
[21] a) D. Ma, Y. Zhang, J. Yao, S. Wu, F. Tao, J. Am. Chem. Soc. 1998,
120, 12459-12467; b) J. Haynes-Smith, I. Diaz, K. L. Billingsley, Org.
Lett. 2016, 18, 2008-2011; c) C. Han, S. M. Kelly, T. Cravillion, S. J.
Savage, T. Nguyen, F. Gosselin, Tetrahedron 2019, 75, 4351-4357;
d) C. Zhang, E. V. Vinogradova, A. M. Spokoyny, S. L. Buchwald, B.
L. Pentelute, Angew. Chem. Int. Ed. 2019, 58, 4810-4839; Angew.
Chem. 2019, 131,4860-4892; e) H. A. Young, Q. A. E. Guthrie, C.
Proulx, J. Org. Chem. 2020, 85, 1748-1755.
[22] R. Sun, Y. Qin, S. Ruccolo, C. Schnedermann, C. Costentin, D. G.
Nocera, J. Am. Chem. Soc. 2019,141, 89-93.
[23] a) B. J. Shields, A. G. Doyle, J. Am. Chem. Soc. 2016, 138, 12719-
12722; b) B. J. Shields, B. Kudisch, G. D. Scholes, A. G. Doyle, J. Am.
Chem. Soc. 2018, 140, 3035-3039; c) S. K. Kariofillis, A. G. Doyle,
Acc. Chem. Res. 2021, 54, 988-1000.
[24] a) L. Tian, N. A. Till, B. Kudisch, D. W. C. MacMillan, G. D. Scholes,
J. Am. Chem. Soc. 2020,142, 4555-4559; b) S. I. Ting, S.
Garakyaraghi, C. M. Taliaferro, B. J. Shields, G. D. Scholes, F. N.
Castellano, A. G. Doyle, J. Am. Chem. Soc. 2020, 142, 5800-5810.
[25] N. A. Till, L. Tian, Z. Dong, G. D. Scholes, D. W. C. MacMillan, J. Am.
Chem. Soc. 2020, 142, 15830-15841.
[26] C. A. Jenkins, D. M. Murphy, C. C. Rowlands, T. A. Egerton, J. Chem.
Soc. Perkin Trans. 1997, 2, 2479-2485.
7
This article is protected by copyright. All rights reserved.

10.1002/anie.202108587
Angewandte Chemie International Edition
RESEARCH ARTICLE
A stereoretentive C-N coupling of optically active amines and amino acid esters with aryl bromides is achieved by nickel catalysis
under light irradiation, without the use of any external photosensitizers.
8
This article is protected by copyright. All rights reserved.