Preparation of α-amino acids: via Ni-catalyzed reductive vinylation and arylation of α-pivaloyloxy glycine

Article abstract of DOI:10.1039/d0sc05452f

This work emphasizes easy access to α-vinyl and aryl amino acids via Ni-catalyzed cross-electrophile coupling of bench-stable N-carbonyl-protected α-pivaloyloxy glycine with vinyl/aryl halides and triflates. The protocol permits the synthesis of α-amino acids bearing hindered branched vinyl groups, which remains a challenge using the current methods. On the basis of experimental and DFT studies, simultaneous addition of glycine α-carbon (Gly) radicals to Ni(0) and Ar-Ni(ii) may occur, with the former being more favored where oxidative addition of a C(sp2) electrophile to the resultant Gly-Ni(i) intermediate gives a key Gly-Ni(iii)-Ar intermediate. The auxiliary chelation of the N-carbonyl oxygen to the Ni center appears to be crucial to stabilize the Gly-Ni(i) intermediate.

Full text of DOI:10.1039/d0sc05452f

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DOI: 10.1039/D0SC05452F
ARTICLE
Preparation of α-Amino Acids via Ni-Catalyzed Reductive
Vinylation and Arylation of α-Pivaloyloxy Glycine
Xianghua Tao,a Yanchi Chen,a Jiandong Guo,b Xiaotai Wang,*bc and Hegui Gong*a
Received 00th January 20xx,
Accepted 00th January 20xx
This work emphasizes easy access to α-vinyl and aryl amino acids via Ni-catalyzed cross-electrophile coupling of bench-stable
N-carbonyl-protected α-pivaloyloxy glycine with vinyl/aryl halides and triflates. The protocol permits the synthesis of α-
amino acids bearing hindered branched vinyl groups that remains a challenge using the concurrent methods. On the basis
of experimental and DFT studies, simultaneous addition of glycine α-carbon (Gly) radicals to Ni(0) and Ar-Ni(II) may operate,
with the former being more favored where oxidative addition of a C(sp2) electrophile to the resultant Gly–Ni(I) intermediate
gives a key Gly–Ni(III)–Ar intermediate. The auxiliary chelation of the N-carbonyl oxygen to the Ni center appears to be
crucial to stabilize the Gly–Ni(I) intermediate.
DOI: 10.1039/x0xx00000x
(a) examples of bioactive amnio acids
Introduction
NH2
CHO
H2N
O
N
Ni-catalyzed cross-electrophile coupling has emerged as a powerful
tool for expeditious creation of C(sp3)–C bonds,1 in which alkyl radical
intermediates are generally involved. However, to the best of our
knowledge, application of this strategy to the reductive coupling of
α-glycinyl electrophiles that enables direct decoration of the α-
carbon of glycine derivatives remains unexplored.2 A prominent
obstacle may owe to the rapid conversion of α-glycinyl electrophiles
to imino or iminium esters that are well-established for addition
reactions.3-4 Reduction of α-glycinyl electrophile to generate glycinyl
α-C(sp3)–radical is hither to unknown. Realization of such a radical
forming process may invoke a reductive coupling protocol for facile
structural enrichment of α-amino acids.2
Unusual and unnatural α-vinyl and -aryl amino acids have
seen a broad range of applications in drug discovery,
biomaterials, and protein engineering.5–7 Selected examples
include amoxicillin,8 Forphenicine,9 the trypsin inhibitor
radiosumin,10 the phytotoxin rhizobitoxine,11 butadienylglycine
(found in the defensive secretion of beetles),12 and 2-amino-3-
(3,4-dihydroxyphenyl)but-3-enoic acid as an antidepressant
(Scheme 1a).13 Numerous synthetic methods have been
developed to access α-aryl and -vinyl amino acids based on two-
electron addition (e.g., R-Li, -Zn and –B and electron-rich
arenes) to glycine cation equivalents such as iminoesters
(Scheme 1b).14-16 Nevertheless, decoration of glycine α-carbons
with branched vinyl groups bearing multiple substituents
remains a challenge.17
HO
H
H
O
S
Me
Me
H
N
H
Me
N
O
H
O
O
CO2H
H2N
CO2H
forphenicine
CO2H
N
Me
HO
HO
amoxicilin
(antibiotic)
radiosumin
H
(alkaline phosphatase inhibitor)
HO
HO
CO2H
CO2H
NH2
CO2H
NH2
O
NH2
NH2
2-amino-3-(3,4-dihydroxyphenyl)
but-3-enoic acid
doryphorina beatles
rhizobitoxine
(b) nucleophilic addition (2e process)
R2
N
R2
N
R2
N
CO2R'
C(sp2)
C(sp2)
M
R1
CO2R'
R1
CO2R'
R1
M = Li, Zn, B, etc.
G
M = H (Friedel-Crafts)
poor suitability for
G = OR', halides, etc.
multi-substituted vinyl
(c) this work: reductive coupling and a proposed mechanism
H
N
I
CO2Me
R3
R1
R3
P
H
Ni (cat.)
dttBpy
PHN
PHN
CO2Me
CO2Me
R2
N
CO2Me
OPiv
R1
or
P
X
Zn, MgCl2
TBAI
R2
aryl & multi-substituted
vinyl aryl glycines
X = Br, I, OTf P = Bz, Cbz, Boc in situ (low concentraion)
(unknown)
TBAI + Zn
.
tBu
tBu
tBu
tBu
BzHN
CO2Et
G
= -66.1
N
N
N
N
Ni0
NiI
CO2Et
O
tBu
NH
Br
Ph
Ph-Br
Zn
tBu
IM1
Ln-Ni(I)Br
N
N
O
NiIII
G = -7.3
= 16.9
G = -21.4
BzHN
CO2Me
Ph
G
OEt
G
= 17.3
a. College of Materials Science and Engineering, Center for Supramolecular
Materials and Catalysis, and Department of Chemistry Shanghai University 99
Shang-Da Road, Shanghai 200444, China Address here.
O
N
IM2
Ph
H
b. Hoffmann Institute of Advanced Materials, Shenzhen Polytechnic 7098 Liuxian
Boulevard, Nanshan District, Shenzhen 518055, P. R. China
Scheme 1. (a) Examples of the bioactive compounds consisting of
unusual amino acids. (b) C(sp2)–Functionalization of glycine cation
equivalents using 2e addition strategies. (c) Ni-catalyzed reductive
coupling strategy for the preparation of unusual α-amino acids.
c. Department of Chemistry University of Colorado Denver Campus Box 194, P. O.
Box 173364, Denver, Colorado 80217-3364, United States
hegui_gong@shu.edu.cn; xiaotai.wang@ucdenver.edu
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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NiBr2 (10%)
L1
(5%)
Zn (200%)
Herein, we describe the Ni-catalyzed reductive coupling of N-
Ph
View Article Online
DOI: 10.1039/D0SC05452F
Br
DtBBPy
O
OPiv
O
carbonyl-protected α-pivaloyloxy glycine derivatives with aryl and
vinyl halides/triflates to afford unusual α-aryl/vinyl amino acids. The
use of the α-pivaloyloxy glycine proved crucial for the coupling
reaction probably because it converts in situ into active α-
iodoglycine or iminium ester at low concentrations. Upon SET
reduction or halide abstraction, a glycinyl (Gly) radical intermediate
was produced. DFT studies suggests that the Gly radical may
simultaneously add to Ni(0) and Ar-Ni(II), but with former being more
favored to give a highly stable Gly–Ni(I) chelate wherein the auxiliary
chelation of the N-carbonyl oxygen to the Ni center appears to be
pivotal. Oxidative addition of aryl halide to the Ni(I) species forms a
key Gly–Ni(III)–Ar intermediate (Scheme 1c). The necessity of the N-
carbonyl protecting groups may provide useful information about
coupling reactions of functionalized alkyl precursors which are
currently essential for Ni-catalyzed stereoselective syntheses of C–C
bonds.18
+
OEt
Ph NH
MgCl2 (150%)
TBAI (200%)
OEt
Ph
(E/Z = 5:1)
(1.5 equiv)
BzHN
O
1a
2
3a
(E-product only)
(1 equiv)
dioxane, 60 o
C
R
t-Bu
R
t-Bu
t-Bu
N
N
N
N
L1
N
: R = tBu: dtBBPy
: R = H: Bpy
: R = OMe
N
N
L2
L3
L4
L5
entry
variation from the standard conditions
yield%a
1
2
no changes
w/o Ni
65 (75)b
trace
3
4
w/o Zn
w/o TBAI
w/o MgCl2
NiCl2
not detected
trace
5
trace
6
7
10
L2
L3
L4
L5
L1
L1
L1
L1
instead of
instead of
instead of
instead of
trace
8
9
62
18
10
11
not detected
63c
1a
(8 mmol)
Result and Discussion
Optimization of the reaction conditions
a NMR yield using 2,5-dimethylfuran as the internal standard. b
Isolated yield. c The reaction was run on a gram scale.
Substrate Scope
We began our studies by investigating the coupling of benzoyl
protected α-pivaloyloxy glycine ethyl ester 1a and (2-
The established vinylation conditions (Table 1, entry 1) proved to
be general for various vinyl halides (Figure 1). The substituents on
the phenyl rings of styrenyl bromides include both electron-donating
and -withdrawing groups as evidenced by 3b–3f. For 3d, 20% of the
enamine tautomer was also detected.19 The napthyl, anthranyl, furyl,
and thiyl-conjugated vinyl bromides all delivered the corresponding
vinyl glycines (4–7) in good to excellent yields. The dienyl glycine 8
was obtained in 75% yield, which can be used for further
transformations (e.g., Diels-Alder reactions). The alkyl-substituted 1-
vinyl bromides (E and Z mixtures) en route to 9 and 10 were also
viable, wherein conversion of the Z-vinyl bromides to the E-products
was much less effective than that observed for 2 (Table 1). The 2,2-
disubstituted vinyl bromides appeared to be slightly more effective
than the mono-substituted ones (e.g., 11–15). An outstanding
feature of this vinylation protocol was its competency in the cases of
α-vinyl bromide substrates, which produced the phenyl, alkyl, and
silyl-substituted vinyl glycines 16–20 in moderate to good yields. The
low yield for 18 was due to homocoupling of the α-vinyl bromide. The
1,2-disubstituted Z-alkenyl bromides were compatible with the
coupling conditions, affording 21–24 in moderate to good yields. To
our delight, the trimethyl substituted vinyl bromide delivered 25 in
44% yield, which is difficult to access with concurrent methods.
Vinyl triflates that could be readily obtained from ketones or
alkynes were viable (Figure 1). By replacing NiBr2 with NiCl2(Py)4,
coupling of 1a with cyclohexenyl triflate produced 26 in 80% yield.
The products 27 and 28 bearing cycloheptenyl and cyclooctenyl
groups were obtained in moderate yields, whereas the formation of
cyclododecenyl amino acid 29 was of lower yield. The conjugated
3,3,5-trimethyl-4-oxocyclohexa-1,5-dien-1-yl, sterically hindered
bromovinyl)benzene
2 (E/Z = 5:1). An extensive survey of
experimental parameters led us to identify the optimal reaction
conditions at 60 oC comprising NiBr2/dtBBpy in combination with the
reductant Zn, the additives MgCl2 and TBAI, and the solvent 1,4-
dioxane.19 The vinyl glycine product 3a was isolated in 75% yield
consisting only of the E-isomer (Table 1, entry 1).20 Control
experiments indicated that NiBr2, Zn, MgCl2, and TBAI all were
essential reagents (entries 2–5). Other nickel sources, ligands or
temperatures gave inferior results (entries 6–10 and Table 1). The
reaction could be performed on a gram scale with slightly diminished
efficiency (entry 11). The need of 5 mol% of ligand (L1) was
tentatively explained by inhibiting formation of hydro-reduction
product 1a-H. The remaining non-ligand chelated 5 mol% of Ni
maybe stabilized by weak coordination with 1a, which could ensure
the formation of decent amount of Ni-L1 complex for efficient
catalysis, provided formation of inactive Ni species is possible over
the course of the reaction.
Table 1. Optimization for the Reaction of 1a with 2.
2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoindenyl
and
phenyl-
conjugated vinyl triflates within a cycloheptene ring resulted in 30–
32 in moderate yields. While 2-hexenyl glycine 33 as obtained in 62%
yield, the more hindered heptenyl glycine 34 was produced in 20%
yield.
2 | J. Name., 2012, 00, 1-3
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ARTICLE
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DOI: 10.1039/D0SC05452F
"standard method"
Br
NiCl2 (Py)4 (10%)
L1
L1
NiBr2 (10%),
(5%)
O
OPiv
O
O
OPiv
O
OTf
(5%), Zn (200%)
Zn (200%)
OEt
OEt
+
Ph NH
+
OEt
Ph NH
OEt
MgCl2 (200%)
TBAI (200%)
dioxane, 60 o
C
MgCl2 (150%)
TBAI (200%)
BzHN
26-34
BzHN
O
O
dioxane, 60 o
C
1a
1a
(1 equiv)
(1.5 equiv)
(1 equiv)
1.5 equiv
3-25, 35-40
scope of vinyl-Br
R
O
O
O
OMe
3b
, R = OMe: 70%
3f
: 65%
3c
3d
3e
, R = t-Bu: 80%
3h
6
: 68%
: 65%
3g
: 70%
4
: 81%
a
, R = CF3: 60% (20%)
, R = NMe2: 40%
5
: 70%
R
S
Ph
Ph
Ph
Ph
MeO
10
: 61%
b
9
: 65% (E/Z >2.2:1)
8
: 75%
11
12
: R = Me: 70%
: R = Ph: 65%
7
(E/Z >10:1)c
: 75%
13
14
15
: 70%
: 70%
: 68%
Me
R
Me
R
Me
TMS
PhO
Me
Ph
18
Ph
16
17
: R = Me: 72%
: R = Et: 50%
23
24
: R= Ph: 70%
: R = Me: 50%
[d]
: 25%
19
20
: 65%
: 55%
scope of vinyl-OTf
21
22
25
: 44%
: 70%
: 70%
O
H
Me
Me
Me
H
31
32
33
34
: 60%
: 65%
: 62%
: 20%
OMe
26
27
28
29
30
: 50%
: 80%
: 57%
: 50%
: 20%
R
scope of aryl halides
Br
Br
Br
Br
R
Br
, R = H: 85%
, R = CO2Et: 78%
, R = CHO: 70%
, R = Bpin: 80%
, R = TMS: 75%
Bz
MeO
OMe
I
N
35a
35b
35c
35d
35e
R
X
, X = S: 40%
Br
36
35h
, R = Ac: 75%
, R = Me2N: 68%
35f
: R = H ,72%
35g
e
I
35j
38
39
: 75%
: R = CO2Me, 70% 35i
40
: 82%
: 75%
, X = O: 32%
37
: 83%
Figure 1. Coupling of 1a with vinyl bromides and triflates, and aryl halides using the conditions in Table 1, entry 1 with isolated yields. a
Yield of isomerization to α-enamine determined by 1H NMR analysis after purification. b A mixture of E/Z vinyl–Br in a ratio of 1.8:1 was
used. c A mixture of E/Z vinyl–Br in a ratio of 10:1 was used. d NiCl2(DME). e NiCl2(DME).
The vinylation method was also extended to the generation of
Ph
Ph
Ph
arylated glycines 35–40 (Figure 1). The reactions exhibited excellent
functional group compatibility, retaining such functionalities as
aldehyde in 35c and vinyl in 35f and 35g. The naphthyl and anthrenyl
bromides afforded 36 and 37 in high yields. Electron-rich
heteroaromatics such as 3-bormofuran and thiophene gave 38 and
39 in low yields. This problem could be solved using the iodo analogs,
as exemplified by 40 and 35j.
The N-carbonyl protecting groups ranging from benzoyl groups
decorated with electron-donating and –withdrawing substituents,
thiophenyl to Cbz, and Boc were suitable as evidenced in 41–45
(Figure 2). In the case of arylation, Fmoc was more effective than Boc
and Cbz groups (see 46–48). By contrast, N-tert-butylsulfinyl was
ineffective. Moreover, hydrolysis of 26 and 35k with hydrochloric
acid afforded the amino acid salts 50 and 51 in good yields (eqn (1)).
O
O
O
MeO
MeO
N
CO2Et
N
CO2Et
S
H
H
N
H
CO2Et
MeO2C
42
43
41
: 75%
: 80%
: 65%
OMe
Ph
Ph
Cbz
Boc
46
47
48
49
: P = Cbz: 40%
: P = Boc: 30%
: P = Fmoc: 60%
P
N
H
CO2Et
N
H
CO2Et
N
H
CO2Et
a
44
45
: 61%
: 50%
: P = N-tert-butanesulfinyl: trace
Figure 2. Variation of amine-protecting groups. a NiCl2 was used in
place of NiBr2.
O
OH
OH
O
OMe
OBoc
or
aqueous HCl
26
(1)
or
Cl
H3N
Cl
H3N
CO2H
CO2H
(90%)
BzHN
CO2Et
35k
50
51
(75%)
Mechanistic and Computational Studies
(1) Possible in situ formation of α-haloglycine or iminium salt
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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The use of pivaloyloxy glycine is crucial for this coupling event.21 (3) Addition of α-glycinyl carbon radical to ArNi(0) vs ArNi(II)
View Article Online
DOI: 10.1039/D0SC05452F
Reaction of bromobenzene with unstable iminoester 52 (with or According to a well-established radical-chain mechanism, the
without 1 equiv of PivOH) or unstable α-bromo glycine 53 only putative Gly radical could be trapped by a Ar–Ni(II) species (eqn (6)
resulted in a trace amount of 35a (eqn (3)). The formation of and Scheme S4).24 Thus, we performed stoichiometric reactions of
hydrodeoxygentive glycine 1a-H as the major products (eqn (2)) the Ar1–NiII complex 56 with 1a with and without Zn (eqn (7)).19,25
implied that reduction of iminoester and α-halo glycine at high The reactions resulted in 35l in 30% and 60% yields, respectively,
concentrations is kinetically much faster than the cross-coupling suggesting that C(sp2)–NiII complexes might engage in the coupling
process.19
event.24 However, in a deliberately designed competition reaction of
1a with an equimolar mixture of 55 and ethyl bromobenzoate (Ar2Br),
35b was formed in preference to 35l (2.3:1) (eqn (8)). Without Ni/L1,
35b remained to be the dominant product when Zn was used. The
preferential formation of 35b should not be directed by addition of
Gly radical to in situ formed Ar2-Ni(II), which would instead give 35a
as the major product. Thus, a competing process that bypass aryl–NiII
species may operate and more favored. This idea was further
confirmed by the reaction profiles shown in Figure 3. The formation
of 35b becomes much faster than that of 35l after an induction
period, during which Ni(0) species is presumably generated.26
Likewise, the reaction cannot be dictated by Ar–Ni(I) that is most
likely generated from single electron reduction of Ar–Ni(II). 27-28 This
would again warrant 35a as the major product, which opposes the
Ph Br
CO2Et
Ph
Br
H
1.5 equiv
Bz
Bz
Bz
OEt
N
CO2Et
or
(2)
N
N
BzHN
CO2Et
: major
standard
method
with or without
H
H
O
35a
1a-H
: trace
53
52
pivOH (1 equiv)
Exposure of 1a to TABI and/or MgCl2 resulted in nearly full
recovery of 1a even after 48 h, indicating that halide substitution was
unable to effectively cleave the C–O bond in 1a (eqn (3)). However,
in the presence of Zn and TBAI, 1a was consumed and majorly
reduced to 1a-H within ~1 hour, whereas use of Zn and MgCl2 was
ineffective. It was noted that in the standard catalytic coupling
reaction, 1a went completion within ~1 h (Figure S1). 19 We reason
that TBAI triggers the conversion of 1a to imino/iminium ester or α-
iodoglycine which acts as the actual coupling partner. This process
could be equilibrated or slow so that low concentrations of the active
species were maintained. When Zn was present, fast reduction of the
in situ generated active species facilitates the consumption of 1a and
ensures a matched coupling reactivity with the C(sp2)-partners (eqn
(4)). No deuterium incorporation to 1a-H was detected when D2O
was added to eqn (3), implying that a radical process may take place
in the reduction.
observation in eqn (8).
I
X
NiII
OEt
OEt
BzHN
or
.
CO2Et
Y
Zn or NiI
Ln
Ar
O
BzHN
Ar
BzHN
CO2Et
NiIII
or ArNiIIX
(6)
(7)
Ln
BzHN
O
CO2Me
tBu
tBu
1a
(1 equiv)
H
OPiv
N
N
I
TBAI, MgCl2
Zn, TBAI, MgCl2
1,4-dioxane, 60 o
OEt
Ni
OEt
1a
recovered
BzHN
Bz
OEt
35l
(3)
BzHN
1,4-dioxane
60 oC, 1 h
N
C
O
H
O
O
1a-H
1a-H
1a
MeO2C
56
w/o Zn: 30% yield
w/ Zn: 60% yield
MgCl2
Zn
time
48 h
48 h
1 h
recovered 1a
major
TBAI
100%
100%
0%
0%
150%
150%
0%
0%
not applicable
not applicable
trace
CO2Et
CO2Me
1a
, 1 equiv
0%
major
NiBr2 (10%)
L1
200%
200%
major
Br
DtBBPy
Zn (200%)
(5%)
100%
1 h
trace
major
56
+
I
(8)
OEt
OEt
MgCl2 (150%)
TBAI (200%)
BzHN
BzHN
OEt
0.5 equiv
BzHN
CO2Et
0.5 equiv
O
O
dioxane, 60 oC, 12 h
OPiv
O
O
TBAI
1,4-dioxane
Zn
35l
35b
, ~45%
, ~20%
OEt
yield based on 1a
TBAI
OEt
BzHN
(4)
1a-H
dioxane
L1
35l/35b
35l/35b
w/o NiBr2,
& Zn:
L1
= 9:1 (16% overall yield)
=1:1.5 (54% overall yield)
w/o w/o NiBr2, &
:
BzHN
PivO
O
(2) Formation of α-glycinyl carbon radical intermediate
More importantly, α-cylcopropyl imine 54 resulted in the radical
ring-opening product 55 under Zn/MgCl2/TBAI conditions (eqn (5)).
The catalytic reaction as in Table 1, entry 1 was completely inhibited
upon introduction of 2 equiv of TEMPO.19 These results suggest that
the catalytic reaction involves generation of a glycine α-carbon
radical via single-electron reduction/halide abstraction of the in situ-
formed iminium intermediate or α-iodoglycine by MgCl2-activated
Zn, or Ln–NiI (eqn 6).22-24 The Ln–NiI species can be generated from
reduction of Ln–NiII by Zn or from the reductive elimination of a Gly–
(Ln)NiIII–Ar intermediate (Scheme 1c).
Me
Zn (200%)
MgCl2 (150%)
(5)
TBAI (200%)
BocN
CO2Me
Figure 3. The reaction profile for the formation of 35l and 35b in eqn
8 in the presence of Zn. Yield based on 1 equiv of 1a.
1,4-dioxane, 60 o
C
BocHN
CO2Me
: ~15%
55
54
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tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
N
N
Ni0
N
N
Ni0
N
N
N
N
Ni0
Ni
sol
sol
sol
1cat
Br Ph
tBu
Ph
3cat
-6.2
0.0
Br
tBu
Ph
2cat
-9.9
Ph
sol
TS3
-10.7
Br
tBu
PhBr
tBu
N
IM5
-17.8
N
tBu
N
O
tBu
tBu
tBu
Ni
N
NiIII
OEt
Br
OEt
H
O
N
N
N
N
NiII
O
NH
2TS1
tBu
N
OEt
O
Ni0
Ph
N
NH
Ph
O
H
O
2TS2
-49.2
Ph
tBu
radical
PhBr
sol
Br
Ph
2IM1
-56.1
N
NiI
sol = dioxane
IM6
-71.1
2IM7
radical
Br
-66.1
tBu
O
-71.3
Ph
17.3
2IM2
OEt
tBu
tBu
tBu
N
Br
Ph
N
H
O
N
O
Gsol (kcal/mol)
Ni
Ph
OEt
2IM3
-73.4
N
O
N
tBu
Ph
OEt
NiI
-94.8
NH
Br
N
tBu
O
Ph
2IM4
O
N
NiIII
product
NH
-97.5
Ph
tBu
tBu
OEt
O
NH
O
N
N
Ph
Zn(s)
NiI
Br
1cat
Figure 4. Free energy profile comparing the favored Ni0NiINiIIINiI pathway (black) and the Ni0NiIINiIIINiI pathway (red).
The seemingly unusual observation in eqn (8) led us to consider the carbonyl to the Ni center appears to play a profound role in
viability of addition of a Gly radical to Ni(0) that would generate a stabilizing the Ni intermediate, which may become crucial in
Gly–Ni(I) species.29 Subsequent oxidative addition of aryl halide to developing an asymmetric version of this amino-acid forming event
Gly–Ni(I) would give the key Gly–Ni(III)–Ar intermediate (Scheme 1). that is ongoing in our laboratory and will be reported in due course.
DFT computations provide support for this mechanistic proposal
(Scheme 1 and Figure S6).19 There is a large decrease of free energy
of 66 kcal/mol as the Ni(0) catalyst binds the Gly radical carbon,
forming the highly stable Gly–Ni(I)–Ln intermediate IM1 wherein the
Conflicts of interest
chelation of benzoyl oxygen to the Ni(I) center is prominent.
Oxidative addition of bromobenzene to IM1 requires overcoming an
energy barrier of 16.9 kcal/mol to give the Ni(III) intermediate IM2.
The subsequent reductive elimination proved to be rate-determining
with an activation energy of 17.3 kcal/mol. By comparison, DFT
studies indicate that the radical-chain mechanism as in Scheme S4
was disfavored, because the precursor complex to the oxidative
addition of bromobenzene to Ln–Ni(0) would be much less stable
than complex IM1 (Figure 4).19 The Ni(0) catalyst would proceed to
IM1, which is completely irreversible.
There are no conflicts to declare.
Acknowledgements
Financial support was provided by the Chinese NSF (No.
21871173). We are grateful to Dr. Deli Sun for preparation of
compound 54.
Notes and references
‡ Footnotes relating to the main text should appear here. These
might include comments relevant to but not central to the matter
under discussion, limited experimental and spectral data, and
crystallographic data.
Conclusions
In summary, we have demonstrated that by section of α-pivaloyloxy
glycine as the electrophile, Ni-catalyzed reductive vinylation and
arylation of vinyl/aryl halides and vinyl triflates enable the formation
of C(sp2)–functionalized α-amino acids. This method displays unique
competency for incorporating hindered α- and tri-substituted vinyl
moieties into the α-position of glycine, which is unattainable by
previous methods. Mechanistically, a glycine α-carbon radical is
thought to arise from the reduction of an in situ generated iminium
or α-iodoglycine by Zn or a Ni(I) species, which then participates in
the coupling process by addition to Ni(0) and Ar-Ni(II). DFT
calculations showed that addition of the glycinyl carbon radical to Ln–
Ni0 to give Ln–NiI–Gly followed by oxidative addition with ArX is
possibly a more favored process. The auxiliary chelation of N-
1
For reviews on cross-electrophile couplings, see: (a) C. E. I.
Knappke, S. Grupe, D. Gärtner, M. Corpet, C. Gosmini and A. J.
Wangelin, Chem. Eur. J. 2014, 20, 6828–6842; (b) T. Moragas, A.
Correa, R. Martin, Chem. Eur. J. 2014, 20, 8242–8252; (c) D. J.
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2
The generation and utility of glycine α-carbon radicals have also
been proaposed in the recent photo-induced or oxidative
dehydride of the C-H bonds of glycine derivatives, wherein
electron-rich substituents on amine are curial, see: (a) C. Wang,
M. Guo, R. Qi, Q. Shang, Q. Liu, S. Wang, L. Zhao, R. Wang and Z.
Xu, Angew. Chem. Int. Ed. 2018, 57, 15841–15846; (b) Y.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Chemical Science
Page 6 of 6
ARTICLE
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6
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25 For details of the reaction profile including formation of Ar1I in
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19 See the Supporting Information for details.
20 The coupling of pure (Z)-2a with 1a under the standard reaction
conditions led to trace amount of 3a along with dimerization and
substantial amount of unknown products that may arise from
oligomerization of styrene via hydrodebromination of (Z)-2a,
suggesting that (Z)-vinyl bromides are not suitable for the
coupling event.
21 For examples of coupling of activated benzyl C–OPiv via oxidative
addition to Ni(0), see: (a) Q. Zhou, H. D. Srinivas, S. Dasgupta and
6 | J. Name., 2012, 00, 1-3
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