Radical 1,4-Aryl Migration Enabled Remote Cross-Electrophile Coupling of α-Amino-β-Bromo Acid Esters with Aryl Bromides

Article abstract of DOI:10.1002/anie.202106273

We report an unprecedented, efficient nickel-catalysed radical relay for the remote cross-electrophile coupling of β-bromo-α-benzylamino acid esters with aryl bromides via 1,4-aryl migration/arylation cascades. β-Bromo-α-benzylamino acid esters are consid

Full text of DOI:10.1002/anie.202106273

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Angewandte
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Accepted Article
Title: Radical 1,4-Aryl Migration Enabled Remote Cross-Electrophile
Coupling of a-Amino-β-Bromo Acid Esters with Aryl Bromides
Authors: Shi Tang, Zhen-Hua Xu, Ting Liu, Shuo-Wen Wang, Jian Yu,
Jian Liu, Hong Yu, Shi-Lu Chen, Jin He, and Jin-Heng Li
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10.1002/anie.202106273
Angewandte Chemie International Edition
RESEARCH ARTICLE
Radical 1,4-Aryl M igration Enabled Rem ote Cross-Electrophile
Coupling of -Am ino-β-Brom o Acid Esters w ith Aryl Brom ides
Shi Tang,*[a] Zhen-Hua Xu,[a] Ting Liu,[a] Shuo-Wen Wang,[a] Jian Yu,[a] Jian Liu,[a] Yu Hong,[a] Shi-Lu
Chen,[b] Jin He,[a] and Jin-Heng Li*[c]
Dedication ((optional))
[a]
Prof. Dr. S. Tang, Z.-H. Xu, T. Liu, S.-W. Wang, J. Liu, Y. Hong, J. He
College of Chemistry and Chemical Engineering
Jishou University
Jishou 416000, China.
E-mail: stang@jsu.edu.cn
[b]
[c]
Prof. Dr. S.-L. Chen
Key Laboratory of Cluster Science of Ministry of Education
Beijing Institute of Technology
Beijing 100081, China.
Prof. Dr. J.-H. Li
Key Laboratory of Jiangxi Province for Persistent Pollutants Control and Resources Recycle
Nanchang Hangkong University
Nanchang 330063, China
State Key Laboratory of Chemo/Biosensing and Chemometrics
Hunan University
Changsha 410082, China.
E-mail: jhli@hnu.edu.cn
Supporting information for this article is given via a link at the end of the document. (Please delete this text if not appropriate).
Abstract: Herein, we report an unprecedented, efficient nickel- important for synthetic chemists.[2] Consequently, the
catalysed radical relay for the remote cross-electrophile coupling of construction of C(sp2)–C(sp3) bonds via the cross-coupling of
β-bromo-α-benzylamino acid esters with aryl bromides via 1,4-aryl
migration/arylation cascades. β-Bromo-α-benzylamino acid esters
two (pseudo)halide partners has recently received considerable
research attention,[3] and progress in this research field has
are considered as unique molecular scaffolds allowing for the aryl been achieved through the use of the earth-abundant nickel
migration reactions, which are conceptually novel variants for the catalyst.[4]
radical Truce–Smiles rearrangement. This reaction enables the
formation of two new C(sp3)-C(sp2) bonds using a bench-stable
Ni/bipyridine/Zn system featuring
a broad substrate scope and
excellent diastereoselectivity, which provides an effective platform
for the remote aryl group migration and arylation of amino acid
esters
Mechanistically, this cascade reaction is accomplished by combining
two powerful catalytic cycles consisting of cross-electrophile
via
redox-neutral
C(sp3)-C(sp2)
bond
cleavage.
a
coupling and radical 1,4-aryl migration through the generation of
C(sp3)-centred radical intermediates from the homolysis of C(sp3)-Br
bonds and the switching of the transient alkyl radical into a robust α-
aminoalkyl radical.
Introduction
Over the past few decades, cross-coupling chemistry has
emerged as a powerful technology for the efficient construction
of carbon–carbon bonds.[1] As an alternative to classic cross-
coupling reactions, reductive cross-coupling represents
a
valuable strategy, wherein two bench-stable and easily
accessible electrophiles (often alkyl or aryl halides) can be
coupled in the presence of an external reductant (such as Zn
and Mn). This strategy circumvents the preparation and handling
of organometallic reagents that have limited stability and
commercial availability, thus making the strategy considerably
Figure 1. Radical 1,n-aryl migration from carbon atom to carbon atom via the
C(sp3)-centred radical intermediate.
1
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10.1002/anie.202106273
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RESEARCH ARTICLE
complexes to form a new C(sp2)–C(sp3) bond. Remarkably, this
process might represent a new mode of aryl radical Smiles-type
rearrangement, and N-benzyl amino acid esters were
unprecedentedly disclosed as a molecular skeleton for radical
rearrangement chemistry.[19] In addition, this cascade reaction
has the advantages of involving redox-neutral conditions, mild
reaction conditions (35  C) and having broad substrate scope
and good diastereoselectivity (dr > 20:1). Compared to the
typical stepwise synthesis of phenylalanine derivatives via N-
benzylation followed by Ni-catalysed direct arylation of the
C(sp3)–Br bond,[13-15] our method undoubtedly has numerous
positive characteristics such as the formation of two new C–C
bonds in one reaction step, mild reaction conditions, excellent
regioselectivity (dr) ， and rapid entry to interesting motifs with
asymmetric tertiary amine moieties.[20,21]
reactions commonly occurs at a specific reactive functional
group (such as Cl, Br, I and OTf) preinstalled on the two
coupling partners. Accordingly, a complementary technique that
facilitates the formation of a new C−C bond at a remote,
unfunctionalised site in the starting materials is still in high
demand in chemistry, which will allow straightforward access to
some novel motifs that would otherwise be difficult to prepare
(such as “chain-walking” cross-coupling).[5]
The radical Smiles-type rearrangement is an aryl migration
strategy that usually involves the homolysis of C-X (X = S, N, O,
etc.) bonds to form robust C- and X-centred radicals;[6] this is an
effective strategy for the synthesis of substituted aromatic
structural
motifs
with
difficult-to-construct
connectivity
otherwise.[7] This rearrangement is widely utilised for the
reorganisation of the carbon skeleton of various molecular
scaffolds such as allylic/benzyl alcohols[8], sulfonylamides[9],
vinylboronate complexes[10] as well as less common, but still
established, functionalised aliphatic/aryl amines[6b,11] and
others[12]. By analysing the mechanism of these reactions,[8-12] it
was found that the C(sp3)-centred radical intermediate is
frequently formed in an array of radical aryl migration reactions.
Inspired by the well-established cross-electrophile coupling
reactions,[2,3] we propose that the readily formed C(sp3)-centred
radical arising from the aryl migration process could be directly
funnelled into a subsequent catalytic cycle (i.e. nickel-catalysed
cross-coupling with aryl halides), thereby offering the possibility
of a remote cross-coupling leading to the formation of a new
C(sp3)–C(sp2) bond. However, a strategy that combines radical
aryl migration and cross-coupling reactions in a radical cascade
poses a significant challenge and remains unexplored to date. In
general, the as-formed C(sp3)-centred radical in these previously
reported 1,n-aryl migration reactions (e.g. from C to C atom) are
terminated by a common process, such as single-electron
transfer (SET) oxidation (Figure 1a),[8] SET oxidation followed by
nucleophilic substitution (Figure 1b),[8l,12c], and hydrogen atom
transfer (HAT) (Figure 1c).[11a] Herein, we disclose the first
cascade Smiles rearrangement and cross-electrophile coupling
using a Ni-catalysed radical relay strategy, which leads to the
distal trans-arylation of N-benzyl amino acid esters via redox-
neutral C-C bond cleavage at the 2-C atom site (Figure 1d).
Amino acids are important building blocks for bioactive
molecules and are extensively employed in many fields, such as
medicinal chemistry, process chemistry, and materials
Results and Discussion
We investigated the optimal conditions for the cascade
Smiles rearrangement/cross-coupling reaction of ethyl 3-
bromo-2-(dibenzylamino)
hexanoate
1a
and
4-
bromobenzonitrile 2a as model substrates (Table 1). After
extensive investigation of the reaction parameters (see SI for
details), we found that the remote coupling product (3aa) was
obtained in 71% yield when NiBr2(dme) (10 mol%), 4,4’-
dimethoxy-2,2’-bipyridine L1 (12 mol%), and zinc powder (2
equiv.) were used as the catalyst, ligand, and reductant,
respectively, in the presence of MgCl2 (2 equiv.) and melamine
(0.5 equiv.). In contrast, almost no regioselective isomer (3aa’)
formed via the direct coupling of the two pre-halogenated sites
was detected through GC–MS. The exact configuration of the
as-obtained product (3aa) was unambiguously confirmed by X-
ray crystallography (see SI for details).[22] The addition of MgCl2
appears to be important for this cascade reaction, wherein the
yield decreased noticeably in the absence of this reagent (entry
2), which is consistent with the fact that MgCl2 accelerates the
reduction of NiII complexes by Zn.[23] When investigating the
efficiency of other N ligands, such as bidentate ligands L2–L8,
L12-15, tridentate ligands L9–L10, and carbene ligand L11, 4,4’-
dimethoxy-2,2’-bipyridine L1 exhibited the optimal performance
(entries 4-17; Table S1; Supporting Information). In addition,
other readily accessible nickel(II) sources, including NiCl2(dme),
NiI2, and Ni(acac)2, failed to afford better yields (entries 3–5).
Pyridine-derived additives seem to be important for the Smiles
rearrangement/cross-coupling sequence, and melamine 4a
bearing a 1,3,5-triamino-substituted motif showed the highest
efficiency compared to the additives studied, such as 3-
fluoropyridine and 3-aminopyridine (entries 6–8). In the control
experiments, the migratory coupling reactions were observed to
be significantly suppressed with the removal of L1 or 4a (entries
9 and 10), whereas 4a could prefer to function as a labile
ligand,[24] according to its catalytic efficiency.
science.[13] In this context, cross-coupling technology is
a
valuable approach to the site-selective functionalisation of
amino acid scaffolds, and substantial progress has been
achieved by employing conventional Negishi[14] and Suzuki–
Miyaura[15] coupling reactions, reductive cross-coupling
reactions[16]
,
and C-H functionalisation[17]
.
Despite the
aforementioned success, continued expansion of the cross-
coupling technology in this regard will provide a new platform for
the late-stage modification of amino acids and their derivatives.
Considering this background in mind, we sought to explore the
chemistry of radical aryl migration and cross-electrophile
coupling in a radical cascade using readily accessible β-bromo-
substituted amino acid esters as precursors. In the presence of
bench-stable NiCl2(dme)/4,4‘-dimethoxy-2,2‘-bipyridine/Zn, the
nascent α-aminoalkyl radical formed via C→C aryl migration with
concomitant C(sp2)–C(sp3) bond cleavage via intramolecular
radical ipso-substitution, which is a frequently encountered and
robust radical cross-coupling partner,[18] smoothly undergoes
further radical–metal crossover reactions with Ar-NiIIL-Br
With the optimized conditions in hand, the scope of the aryl
bromides used in this radical cascade reaction was examined
(Table 2). To our delight, the coupling reactions of 1a with an
array
of
activated
aryl
bromides,
including
4-
bromobenzonitrile,1-(4-bromophenyl)ethenone and ethyl 4-
bromobenzoate, proceeded smoothly, leading to the formation of
the corresponding remote coupling products in moderate to
good yields and at dr of >20:1. This set of reactions also
exhibited excellent regioselectivity toward the remote coupling
2
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10.1002/anie.202106273
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RESEARCH ARTICLE
derivative (3bd) via the tandem radical rearrangement/cross-
coupling reaction.[3c] Changing the ester moiety from ethyl to
methyl did not affect the reaction outcome (3be–3bg). The exact
configuration of 3bg was unambiguously confirmed through X-
Table 1. Screening of optimal reaction conditions[a]
Table 2. Variation of aryl bromides (2)[a]
Entry
1
Variation from the Standard Conditions
none
Yield [%][b]
76 (71; >20:1
dr)[c]
2
without MgCl2
32
62
47
33
52
57
25
<10
49
3
NiCl2(dme) instead of NiBr2(dme)
NiI2 instead of NiBr2(dme)
Ni(acac)2 instead of NiBr2(dme)
Py instead of 4a
4
5
6
7
4b instead of 4a
8
4e instead of 4a
9
without L1
10
without 4a
[a] Standard conditions: 4-Bromobenzonitrile 2a (0.2 mmol), 1a (1.5 equiv.),
NiBr2(dme) (10 mol%), L1 (12 mol%), Zn (2 equiv.), MgCl2 (2 equiv.),
melamine 4a (0.5 equiv.), K3PO4 (1 equiv.), and DMA (2 mL) at 35 C under N2
atmosphere for 24 h. [b] Yields were determined by GC using an internal
standard and the isolated yield reported in the parentheses. DMA = dimethyl
acetamide; Py = pyridine. [c] The diastereomeric ratio (dr) was determined by
1H NMR analysis.
products (3aa–3ai). Sterically hindered 2-bromobenzonitrile was
also shown to be a viable coupling partner in this cascade
reaction, albeit with a slightly lower yield (3ad). Moreover, the
configuration of 3ae was unambiguously confirmed through X-
ray crystallography.[22] In addition, unactivated aryl bromides
such as phenolic ester and aniline derivatives were well
tolerated in this cascade reaction (3ak–3an), while halogen
functional groups (e.g., Cl, F, and CF3) remained intact during
the cascade reaction (3am , 3ao, and 3ap). The synthetically
interesting Bpin substituent was also compatible with the optimal
reaction conditions, thereby allowing the introduction of some
functional groups via a further cross-coupling reaction (3aq).
The cascade process also provides successful results for N-
heterocyclic motifs, such as quinoline and pyridine, which are in
high demand in medicinal chemistry (3ar and 3as). Additionally,
this migratory coupling reactions were observed to be less
efficient for some electron-rich aryl bromides such as p-
BrC6H4OMe and m -BrC6H4Me, possibly owing to the drawback
that it is sluggish for Ni complex to add onto the inert C(sp2)-Br
bond (3at and 3au). Overall, 1a was found to be a robust
starting material for the sequential Smiles rearrangement and
cross-electrophile coupling reaction, affording good yields with
excellent diastereoselectivity (usually dr > 20:1).
[a] Reaction conditions: 1a (1.5 equiv.), 2a (0.3 mmol), NiBr2(dme) (10 mol%),
L1 (12 mol%), Zn (2 equiv.), MgCl2 (2 equiv.), 4a (0.5 equiv.), K3PO4 (1 equiv.),
and DMA (2 mL) at 30 C under N2 atmosphere for 24 h; isolated yield. The
19
diastereomeric ratio (dr) was determined by 1H NMR and/or F NMR analysis.
ray crystallography.[22] Subsequently, we examined the
compatibility of other N-benzyl groups in this remote cross-
coupling reaction and a variety of amino acid esters bearing
symmetric benzyl groups on the N-atom, including p-(t-
Bu)C6H4CH2, p-CH3C6H4CH2, and p/m -ClC6H4CH2, were
observed to undergo the migration process, thereby leading to
the formation of 3bh–3bo in good yield. Subsequently, we
investigated the aryl migratory ability of different benzyl groups
tethered to the N atom (Scheme 2). Minimally differentiated
benzyl and 4-methylbenzyl groups on the N atom were initially
examined, and both phenyl and 4-methylphenyl served as
migrating groups, but the relatively more electron-rich 4-
methylphenyl group was preferred, resulting in a regioselective
Subsequently, we investigated the compatibility of structurally
diverse N-benzyl amino acid esters under the optimal reaction
conditions (Table 3). A series of R1 substituents on this coupling
partner (1), such as n-Pr, Et, i-Pr, PhCH2CH2, cyclohexyl, and H,
were well tolerated under the optimal reaction conditions and
afforded their corresponding remote coupling products (3av–3bc)
with excellent diastereoselectivity (dr > 20:1). Notably, serine
primary bromides (R1 = H) also appeared to be compatible with
the optimal reaction conditions leading to the phenylalanine
3
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10.1002/anie.202106273
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ratio (rr) of 2:1 (3bp). Another pair comprising 4-tert-butylbenzyl
with benzyl groups showed similar selectivity to yield the
diarylation product (3bq) with 66% yield and rr = 4:1. Moreover,
electronically biased arenes, such as pairs of Ph/p-FC6H5 or t-
BuC6H4/p-FC6H5, demonstrate specific migratory abilities to
afford the trans-arylation of the electron-rich aromatic ring (3br–
3bu). Notably, the amino acid ester bromides with an alkyl or
hydrogen on the N atom seem to be unstable and difficult to
prepare efficiently; therefore, we used the corresponding
mesylate instead of bromide to investigate the effect of the N
substituent on the amino acid ester in the radical rearrangement.
Unfortunately, the results demonstrate that amino acid esters
with H or Me on the N atom are inefficient substrates in this
radical cascade reaction. Thus, substrates bearing a dibenzyl-
substituted N-atom moiety are critical for sequential migration
and cross-coupling processes.
Table 3. Scope of the α-amino-β-bromo acid esters.[a,b] [a] Reaction conditions: 2a (0.3 mmol), 1a (1.5 equiv.), NiBr2(dme) (10 mol%), L1 (12 mol%), Zn (2 equiv.),
MgCl2 (2 equiv.), 4a (0.5 equiv.), K3PO4 (1 equiv.), and DMA (2 mL) at 35 C under N2 atmosphere for 24 h; isolated yield. [b] The diastereoselective ratio (dr) and
regioselective ratio (rr) were determined by 1H NMR and/or 19 F NMR analysis. [c] In these reactions, 2.0 equiv. of LiBr was added.
Considering their ready availability from inexpensive serine
derivatives, we next investigated the compatibility of serine
mesylates instead of serine bromides under the reaction
conditions. After brief screening, we found that serine mesylate
with 4-bromobenzonitrile in the presence of LiBr (2 equiv.)
underwent sequential radical rearrangement and cross-coupling
to yield the desired products in moderate yields [Eq. (1),
Scheme 1]. In addition, aryl trifluoromethanesulfonate (p-
EtO2CC6H4OTf) was also a viable coupling partner, albeit with a
lower product yield [Eq. (2)]. Based on our investigation about
the cascade migration/cross-coupling of amino acid esters, we
found that 1,4-FGM (FGM = functional group migration) was
beneficial in the kinetically favoured five-membered cyclic
transition state, whereas 1,5-FGM using a γ-bromo amino acid
ester via a six-membered cyclic transition state appeared to be
less effective [Eq. (3)]. In addition, a β-bromo alkyl amine upon
the removal of the α-ester group, independent of the amino acid
ester bromide, underwent a radical cascade reaction with low
efficiency, which can be attributed to the increasing torsional
strain triggered by the adjacent ester substituent in the five-
membered cyclic transition state and was beneficial for breaking
the cyclic transition state to initiate migration [Eq. (4)]. We
investigated the use of a radical scavenger, 2,2,6,6-tetramethyl-
1-piperidinyloxyl (TEMPO). As expected, the migratory coupling
process was significantly suppressed, suggesting the
involvement of a radical-mediated process in the reaction [Eq.
(5)]. In addition, a standard radical clock cyclopropane substrate
was subjected to the optimal reaction conditions, and no
expected β-arylation amino acid ester (3bv) was observed.
However, the formation of 5 was observed through 1H NMR
analysis via a radical cyclopropane ring-opening reaction [Eq.
(6)], which clearly indicates that the alkyl radical formed via
dehalogenation by Ni likely triggered the sequential
migration/cross-coupling reaction.[25]
Based on the aforementioned experimental results and
previously reported mechanisms[2-17], a possible mechanism for
the cascade reaction was proposed, as shown in Scheme 2.
NiIIX2(dme) is reduced to a NiI-Ln species via a single-electron
4
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10.1002/anie.202106273
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RESEARCH ARTICLE
reduction process with Zn powder in the presence of the N
ligand, which is then oxidatively treated with amino acid ester
bromide (1a) to yield the alkyl radical (Int-I) and a NiII-Ln
complex via a single-electron transfer process. A C→C atom
aryl migration with concomitant C(sp2)-C(sp3) bond homolytic
cleavage (with a bond dissociation energy of 72.9 kcal/mol) via a
complex, which is then directly involved in the next catalytic
cycle or reduced to Ni0-Ln species by Zn powder.
Schem e 2. Possible mechanism for the Smiles rearrangement and cross-
coupling reaction.
The exposure of the Ar-NiII(Ln)Br complex to 1a gave the
corresponding coupling product (3ab) in 31% yield (Eq. 7). This
result provides evidence for the oxidative capture of the α-
aminoalkyl radical (Int-III) by a Ni complex, Ar-NiII-X.[26] In
addition, the formation of the alkyl-alkyl dimerisation products,
as an isomeric mixture of the homo/cross-dimerisation of
radicals Int-III and Int-1 possibly, was observed to form by
HRMS, which gives substantial proof for the proposed
mechanism wherein the radical 1,4-aryl migration process was
possibly involved.
Next, unrestricted density functional theory (DFT) calculations
with the hybrid functional B3LYP implemented in the Gaussian
09 package were conducted to further understand the key 1,4-
aryl migration process from Int-I to Int-III (Figure 2; see SI for
details).[27] Our computational studies revealed that the radical
moiety in the Int-I intermediate was localised on the alkyl C atom.
From Int-I,
a transition state (TS1, Figure 2a) for its
Schem e 1. Application investigation and control experiments used to
intramolecular ipso attack on the distal phenyl ring to form the
key intermediate σ-complex (Int-II) via dearomatisation was
found and confirmed through frequency analysis to be a first-
order saddle point with an imaginary frequency of 458.4 cm–1. In
TS1, the key Ca-Cb distance was 2.11 Å. This step leads to the
formation of a spiro five-membered N-heterocycle connected to
a benzene radical (Int-II). The free energy barrier was calculated
to be 14.7 kcal/mol with a low endothermicity of 4.2 kcal/mol.
The spiro N-heterocycle complex (Int-II) readily breaks via a
transition state involving sequential C–C bond homolytic
dissociation and rearomatisation (TS2, Figure 2b), yielding the
α-aminoalkyl radical (Int-III). The barrier of this step is 17.1
kcal/mol relative to Int-I. The free energy of resultant Int-III lies
3.5 kcal/mol higher than that of Int- I, and Int-III is proposed to
react with the ArNiIIBr complex to generate the final cross-
coupling product. These results indicate that the mechanism
shown in Scheme 2 is reasonable.
determine the reaction mechanism.
spiro radical σ-complex (Int-II) then occurs,[11] generating an α-
aminoalkyl radical (Int-III), which is stabilised by the p-p
conjugation effect with its adjacent electron-rich
N atom.
Because of the binding effect of the inflexible five-membered
ring, the syn-configuration of the α-aminoalkyl radical is favoured,
which is consistent with the fact that this coupling reaction
typically exhibits high diastereoselectivity (syn/trans > 20:1). In
the cross-coupling catalytic cycle, NiIIBr2(dme) is first reduced to
a Ni0 species via a two-electron reduction with Zn, which then
undergoes oxidative addition to the aryl bromide to produce an
ArNiIIBr complex. Subsequently, the α-aminoalkyl radical (Int-III)
generated via 1,4-aryl migration adds to ArNiIIBr to form a NiIII
complex (Int-IV). Finally, the NiIII complex undergoes reductive
elimination to give the desired product (3aa) and the NiI-Ln
5
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RESEARCH ARTICLE
Figure 2. (a) Free energy profile for the mechanism from Int-1 to Int-III; (b) Transition states optimised using density functional calculations. The distances are
reported in angstrom (Å). The unpaired spin populations are also shown, indicated by “S”.
[2]
For selected reviews on cross-electrophile coupling, see: a) D. J. Weix,
Acc. Chem. Res. 2015, 48, 1767-1775; b) D. A. Everson, D. J. Weix, J.
Org. Chem. 2014, 79, 4793-4798; c) J.-D. Liu, Y. Ye, L. S. Jonathan,
H.-G. Gong, Acc. Chem. Res. 2020, 53, 9, 1833-1845; d) C. E. I.
Knappke, S. Grupe, D. Gartner, M. Corpet, C. Gosmini, A. Jacobi von
Wangelin, Chem. Eur. J. 2014, 20, 6828-6842; e) D. A. Everson, D. J.
Weix, J. Org. Chem. 2014, 79, 4793-4798; f) T. Moragas, A. Correa, R.
Martin, Chem. Eur. J. 2014, 20, 8242-8258; g) X. Wang, Y. Dai, H.
Gong, Top. Curr. Chem. 2016, 374, 43.
For selected examples on the construction of C(sp3)-C(sp2) bond via
cross-electrophile coupling, see: a) D. A. Everson, R. Shrestha, D. J.
Weix, J. Am. Chem. Soc. 2010, 132, 920-921; b) E. C. Hansen, C. Li, S.
Yang, D. Pedro, D. J. Weix, J. Org. Chem. 2017, 82, 7085-7089; c) S.
Kim, M. J. Goldfogel, M. M. Gilbert, D. J. Weix, J. Am. Chem. Soc. 2020,
142, 9902-9907; d) P. Zhang, C. Le, D. W. C. MacMillan, J. Am. Chem.
Soc. 2016, 138, 8084-8087; e) Z.-L. Duan, W. Li, A.-W. Lei, Org. Lett.
2016, 18, 4012-4015; f) X. Wang, G.-B. Ma, Y. Peng, C. E. Pitsch, B. J.
Moll, T. D. Ly, X.-T. Wang, J. Am. Chem. Soc. 2018, 140, 14490-14497;
g) R. T. Smith, X.-H. Zhang, J. A. Rincon, J. Agejas, C. Mateos, M.
Barberis, S. García-Cerrada, O. D. Frutos, J. Am. Chem. Soc. 2018,
140, 17433-17438; h) J.-C. Duan, Y.-F. Du, X.-B. Pang, X.-Z. Shu,
Chem. Sci. 2019, 10, 8706-8712; i) J.-W. Wang, J.-H. Zhao, H.-G.
Gong, Chem. Commun. 2017, 53, 10180—10183.
Conclusions
In summary, we have discovered a new molecular scaffold (i.e.,
N-benzyl amino acid ester) that enables sequential aryl
migration and cross-coupling reactions through a Ni-catalysed
radical relay for the first time. Mechanistically, the radical
cascade reaction was achieved by combining two powerful
catalytic cycles consisting of an aryl radical rearrangement and
cross-electrophile coupling reaction via a C(sp3)-centred radical
intermediate, wherein an umpolung strategy for switching the
transient alkyl radical into a robust α-aminoalkyl radical via 1,4-
aryl migration from C to C atom was demonstrated, which
serves as a mild, efficient strategy for the synthesis of unnatural
or natural phenylalanine and their derivatives as well as versatile
tertiary aliphatic amines. Likewise, this synthetic strategy affords
an elusive entry to the late-stage functionalisation of amino acid
esters via redox-neutral C(sp3)–C(sp2) bond cleavage through Ni
catalysis, representing an interesting complement to both the
radical rearrangement and cross-electrophile coupling reactions
in the synthetic community.
[3]
[4]
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Acknow ledgem ents
We wish to thank the National Natural Science Foundation of
China (NFSC) (Grant No. 20196011, 21462017, 21673019, and
21625203) and the Hunan Provincial Natural Science
Foundation of China (Grant No. 2018JJ1020).
Conflict of Interest
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Keyw ords: radical aryl migration, cross-electrophile coupling,
nickel radical relay, amino acid esters
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Entry for the Table of Contents
A nickel-catalysed radical relay strategy has been developed to combine radical rearrangement and cross-coupling reaction via a
C(sp3)-centred radical, wherein an N-benzyl amino acid ester was also discovered as a new molecular scaffold for the aryl migration
reaction. This synthetic method is advantageous because of mild reaction conditions, high diastereoselectivity, and broad substrate
scope; therefore, it represents a rapid approach to valuable phenylalanine derivatives that would otherwise be difficult to prepare.
8
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