Transition-metal-free chemo- and regioselective vinylation of azaallyls

Article abstract of DOI:10.1038/nchem.2760

Direct C(sp 3)-C(sp 2) bond formation under transition-metal-free conditions offers an atom-economical, inexpensive and environmentally benign alternative to traditional transition-metal-catalysed cross-coupling reactions. A new chemo- and regioselective coupling protocol between 3-aryl-substituted-1,1-diphenyl-2-azaallyl derivatives and vinyl bromides has been developed. This is the first transition-metal-free cross-coupling of azaallyls with vinyl bromide electrophiles and delivers allylic amines in excellent yields (up to 99%). This relatively simple and mild protocol offers a direct and practical strategy for the synthesis of high-value allylic amine building blocks that does not require the use of transition metals, special initiators or photoredox catalysts. Radical clock experiments, electron paramagnetic resonance studies and density functional theory calculations point to an unprecedented substrate-dependent coupling mechanism. Furthermore, an electron paramagnetic resonance signal was observed when the N-benzyl benzophenone ketimine was subjected to silylamide base, supporting the formation of radical species upon deprotonation. The unique mechanisms outlined herein could pave the way for new approaches to transition-metal-free C-C bond formations.

Full text of DOI:10.1038/nchem.2760

ARTICLES
PUBLISHED ONLINE: 17 APRIL 2017 | DOI: 10.1038/NCHEM.2760
Transition-metal-free chemo- and regioselective
vinylation of azaallyls
1
1
1
1
1
Minyan Li , Osvaldo Gutierrez , Simon Berritt , Ana Pascual-Escudero , Ahmet Yeşilçimen ,
1
1
1
2
1
Xiaodong Yang , Javier Adrio , Georgia Huang , Eiko Nakamaru-Ogiso , Marisa C. Kozlowski
*
and Patrick J. Walsh1,3
*
3
2
Direct C(sp )–C(sp ) bond formation under transition-metal-free conditions offers an atom-economical, inexpensive and
environmentally benign alternative to traditional transition-metal-catalysed cross-coupling reactions. A new chemo- and
regioselective coupling protocol between 3-aryl-substituted-1,1-diphenyl-2-azaallyl derivatives and vinyl bromides has been
developed. This is the first transition-metal-free cross-coupling of azaallyls with vinyl bromide electrophiles and delivers
allylic amines in excellent yields (up to 99%). This relatively simple and mild protocol offers a direct and practical
strategy for the synthesis of high-value allylic amine building blocks that does not require the use of transition metals,
special initiators or photoredox catalysts. Radical clock experiments, electron paramagnetic resonance studies and density
functional theory calculations point to an unprecedented substrate-dependent coupling mechanism. Furthermore, an
electron paramagnetic resonance signal was observed when the N-benzyl benzophenone ketimine was subjected to
silylamide base, supporting the formation of radical species upon deprotonation. The unique mechanisms outlined herein
could pave the way for new approaches to transition-metal-free C–C bond formations.
3
2
ransition-metal-catalysed coupling reactions are among the
Here, we report the first transition-metal-free C(sp )–C(sp )
most widely used, robust and efficient methods for carbon– coupling of vinyl bromide electrophiles with azaallyl anions and
carbon and carbon–heteroatom bond formations. The azaallyl radicals (Fig. 1c). Specifically, we describe coupling of
impact of these transformations has extended well beyond organic 1,1-diphenyl-3-aryl-2-azaallyl anions with vinyl bromides to
T
synthesis into biology, materials science and engineering, and was afford the E vinylation products in high yields with excellent
1,2
highlighted by the Nobel Prize in 2010. The development of chemo- and regioselectivity. Notably, the vinylation reaction
transition-metal-free protocols would offer an inexpensive and outperforms a rapid background reaction arising from the base-
environmentally benign alternative to accomplish C–C and promoted elimination of the vinyl bromide to form a terminal
3
C–heteroatom bond constructions . In this regard, we focused our alkyne. In addition, the base/solvent combination efficiently
attention on transition-metal-free assembly of allylic amines, promotes the metal-free vinylation but does not deprotonate the
which are key building blocks in the synthesis of complex natural product (Fig. 1d). Thus, neither product deprotonation/isomerization,
4
products and are prevalent in biologically active compounds . So which will form a more stable conjugated by-product, nor product
far, approaches to the synthesis of allylic amine derivatives generally deprotonation/cyclization, is observed. Additional experiments,
5
,6
rely on transition metals and include amination reactions , some electron paramagnetic resonance (EPR) studies and calculations
7
,8
nucleophilic additions of organometallic reagents to imines and provide a preliminary picture of the mechanistic landscape of the
catalysed Overman rearrangements , among others10,11.
9
observed vinylations.
Our team1
2–15
and others
16–21
have been interested in the synthesis
of amines via an umpolung approach involving the functionali- Results
zation of 2-azaallyl anions. Recently, we reported the synthesis of We reported previously the arylation of 1,1-diphenyl-3-arylallyl-2-
both allylic amines and enamines through the transition-metal- azaallyl anions via in situ deprotonation of ketimine substrates
catalysed arylation of 1,1-diphenyl-3-arylallyl-2-azaallyl anions (ArCH N=CPh ) followed by palladium-catalysed arylation with
2
2
1
3
(
shown retrosynthetically in Fig. 1a, Path a) . We envisioned an Ar′–X to give ArAr′CHN=CPh2 (refs 12–15). Under these
alternative route to the same allylic imines via vinylation of conditions, deprotonation of the product was not observed, as judged
1
9,29
1
,1-diphenyl-3-aryl-2-azaallyl anions (Fig. 1a, Path b). Transition- by the absence of isomerized product (ArAr′C=NCHPh2)
.
22–28
metal-catalysed vinylation methods are less common
, especially Key to preventing product deprotonation was the use of hindered
in the absence of preformed organometallic reagents (Fig. 1b). We bases [MN(SiMe ) (M=Li, Na)] at room temperature. To explore
3
2
anticipated that the vinylation of azaallyl anions (Fig. 1a, Path b) the analogous vinylation reaction, we investigated the deprotonative
would occur in a similar manner to the transition-metal-catalysed cross-coupling of ketimine 1a and β-bromostyrene 2a using
arylation of the same azaallyl anions. To our surprise, however, microscale high-throughput screening (0.01 mmol) of 23 electroni-
we found that the Path b vinylation of 1,1-diphenyl-3-aryl-2-azaallyl cally diverse mono- and bidentate phosphine ligands in the
anions occurred rapidly when no palladium catalyst was added.
presence of Pd(OAc) , NaN(SiMe ) and THF at room temperature
2 3 2
1
Department of Chemistry, Roy and Diana Vagelos Laboratories, Penn/Merck Laboratory for High-Throughput Experimentation, University of Pennsylvania,
2
2
4
31 South 34th Street, Philadelphia, Pennsylvania 19104, USA. Department of Biochemistry and Biophysics, EPR Laboratory, University of Pennsylvania,
3
22 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA. Institute of Advanced Synthesis (IAS), School of Chemistry and Molecular Engineering
(
SCME), Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing Tech University (Nanjing Tech), 30 South Puzhu Road,
Nanjing 211816, China. *e-mail: pwalsh@sas.upenn.edu; marisa@sas.upenn.edu
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1
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2760
Table 1 | Optimization of the transition-metal-free vinylation.
ARTICLES
a
Ph
–
Ar
Br
R1
Path a
+
Ar R1
Ph Ar R1
Ph
N
Ar´
Br
Ph
N
Ph
Ph
Ph
N
Ph
a
(1 equiv.)
R2
R2
Base
H2N
Ph
N
Ph Ar
Ph
1a
b
R3
R3
R2
+
–
+
Path b Ph
N
Solvent, rt, Time, Conc.
R3
Ph
Br
b(
(2 equiv.)
Ph
3aa
i)
2a
R4
Pd cat. or Ni cat.
R4
Entry
Base
Solvent
Time
(min)
Conc.
Yield 3aa
(%)
O
O
R2
R3
R5
R5
+
R1
LiN(SiMe3)2
THF, 0–22 °C
R1
X
R6
R2 R3 R6
1
NaN(SiMe
(3 equiv.)
NaN(SiMe
(3 equiv.)
NaN(SiMe3)2
(3 equiv.)
NaN(SiMe3)2
)
THF
180
180
10
0.1 M
0.2 M
0.2 M
0.2 M
0.2 M
0.2 M
0.2 M
0.2 M
0.2 M
0.2 M
0.2 M
51
65
0
3
2
2
X = Cl, Br, I, OTf
(
ii)
2
3
4
5
6
7
8
9
10
3
)
THF
OR
R1
R2 R3
Pd(NIXANTPHOS)
OR
Br
R1
+
Py
LiN(SiMe3)2
o
CPME
THF
Py
CPME, 65 C
R2
R3
Py = 2-Py, 4-Py
10
32
0
(
3 equiv.)
NaN(SiMe
(3 equiv.)
(
iii)
R1
R1
R1
3
)
2
2
2-Me
THF
DME
10
Pd cat.
CH3NO2
Pd cat.
X
NO2
Ph
R2
R2
NaN(SiMe
(3 equiv.)
10
98
0
R2
NO2
3
)
CH3NO2
R3
X = OTf, Br
R3
R3
NaN(SiMe3)2
3 equiv.)
LiN(SiMe
(3 equiv.)
LiN(SiMe
2 equiv.)
Dioxane
DME
10
(
c
Ar
N
R2
MN(SiMe3)2
Transition-metal free
3
)
2
2
10
99
98*
54
21
Ph
N
Ar
+
R2
Ph
Br
R1
Ph
R1
3
)
DME
30
30
30
(
Ar
N
Ph
Ar
Ph
Ph
LiN(SiMe3)2
(1.5 equiv.)
DME
N
–
via
+
M
Ph
1
1
LiN(SiMe
1 equiv.)
3
)
2
DME
Azaallyl
anion
Azaallyl
radical
(
d
1
Reactions conducted on a 0.1 mmol scale. Assay yields determined by H NMR spectroscopy of the
reaction mixture on 0.1 mmol scale using an internal standard. *Isolated yield after
chromatographic purification.
Ar1 MN(SiMe3)2 Ph
X
Ar1 Ph
Ar1
Ar2
Ph
OR Ph
Ar2
Ph
N
N
N
N
Ar1
a
+
Ph
Ph
Ph
Ar2
Ar2
(1b) and 4-OMe (1c)) and electron-withdrawing (4-F (1d), 4-Cl
(
1e), 3,5-di-F (1f) and 3,5-di-CF (1g)) N-benzyl derived groups
3
Deprotonation and
isomerization
Deprotonation and
cyclization
with β-bromostyrene (2a) proceeded in excellent yields. The
sterically demanding 2-tolyl substituted ketimine (1h) underwent
coupling, albeit in lower yield (61%), even when performed with
Figure 1 | Overview of allylic amines synthesis and vinylation reactions.
a, Retrosynthesis of allylic amines. b, Prior metal-catalysed vinylation
reactions of carbanions generated in situ. c, Transition-metal-free vinylation
of azaallyl anions. d, Possible by products derived from product
deprotonation/isomerization and deprotonation/cyclization.
3
equiv. of LiN(SiMe ) and an extended reaction time (8 h). For
3 2
more acidic heterocyclic 2-pyridyl (1i, 77%), 3-pyridyl (1j, 71%)
and 2-thiophenyl (1k, 82%) ketimine substrates, 0.05 M
concentration was optimal with 1.5 equiv. of LiN(SiMe3)2 to
prevent deprotonation, isomerization and cyclization (Fig. 1d).
We next determined the scope in the vinyl bromide component
for 3 h. To our surprise, a considerable amount of the targeted
vinylated product (3aa) was found in the control vial, which and found it to be broad (Fig. 2b). We found that trans-β-aryl
t
contained no added transition metal or ligand (see Supplementary vinyl bromides bearing neutral (4-C H - Bu) and electron-donating
6
4
page 10 for high-throughput experimentation screenings). (4-C H -OMe) groups furnished coupling products 3ab and 3ac in
6
4
Validation on a larger scale (0.1 mmol) provided further support 92 and 98% yield, respectively. 4-Fluoro- (2d) and 4-trifluoro-
for a transition-metal-free process; specifically, reactions conducted methyl-substituted vinyl bromides (2e) afforded coupled products
without addition of catalyst led to the vinylation product 3aa in 51% 3ad and 3ae in 96 and 70% yields. The reactions also proceeded
1
assay yield (AY) in THF, as determined by H NMR spectroscopy well with substitution at the 3-position of the β-bromostyrene, such
(
(
(
(
Table 1, entry 1). Increasing the concentration from 0.1 to 0.2 M as 3-OMe (2f) and 3-CF (2g), giving the products in 98 and 75%
3
entry 2) led to an increase to 65% AY. We next tested five solvents yield, respectively. trans-β-2-Tolyl vinyl bromide (2h) was an
CPME (cyclopentyl methyl ether), THF, 2-Me-THF, DME excellent substrate, affording the product in 96% yield. Surprisingly,
dimethoxyethane) and 1,4-dioxane, entries 3–7). Surprisingly, the the aliphatic vinyl bromides 1-bromo-2-methylprop-1-ene (2i) and
reaction was complete in just 10 min in DME, giving 98% AY of (bromomethylene)cyclohexane (2j) were successfully coupled with
3
2
9
aa (entry 6). Further optimization of the base ratio revealed that 1a to afford 3ai and 3aj in 54–55% yield. Monitoring the reaction
equiv. of LiN(SiMe ) and a 30 min reaction time resulted in with 3aj revealed that the transformation was complete in 15 min
3
2
8% isolated yield (entry 9).
(Supplementary Fig. 1). Notably, product isomerization and/or
cyclization were not detected for any of the examples in Fig. 2a,b.
The vinylation is amenable to a telescoped imine synthesis/
Reaction scope. With the optimized reaction conditions (entry 9,
Table 1), the scope of the N-benzyl group on the ketimine was vinylation protocol on the gram scale (Fig. 2c). For example, the
examined (Fig. 2a). Overall, some tuning of the reaction sequential one-pot synthesis of 2-thiophenyl ketimine 1k, followed
parameters, such as the base, reagent ratios, concentration and by vinylation with 2a, successfully afforded product 3ka in 90%
reaction times, was necessary for certain substrates. Nonetheless, yield (1.02 g). Finally, hydrolysis of the vinylated product 3ka was
vinylation of ketimine substrates bearing electron-donating (4-Me performed to isolate the allylic amine 4ka in 99% yield (Fig. 2d).
2
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2760
ARTICLES
a
b
LiN(SiMe3)2
LiN(SiMe3)2
(
1.5 equiv.)
Ph
N
Ar
Ph
N
Ar
(3 equiv.)
Ph
N
Ar
Ph
(
N
Ar
Br
+
Vinyl–Br
+
Ph
DME, rt, 0.2 M
Ph
Ph
DME, rt, 3 h
0.2 M
Ph Vinyl
Ph
a–1k
1 equiv.)
1a
2a–2j
(2 equiv.)
1.5 h
1
2a
3ab–3aj
Ph
(1 equiv.)
(2 equiv.)
N
3aa–3ka
Ph
N
Ph
Ph
N
Ph
Ph
N
Ph
Me
OMe
Ph
F
Ph
Ph
Ph
Ph
N
Ph
N
N
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
tBu
3ab, 92%a
OMe
F
3ad, 96%a
Ph
3
aa, 98%a
3ba, 99%b
3ca, 99%b
3da, 99%c
3ac, 98%
Ph
Ph
N
Ph
F
CF3
Ph
N
Ph
N
Cl
Ph
Ph
Ph
Ph
N
Ph
N
Ph
N
Ph
N
F
CF3
Ph
Me
Ph
Ph
Ph
Ph
Ph
OMe
CF3
Ph
Ph
CF3
3fa, 99%d
3ga, 93%e
3ha, 61%f
3ae, 70%b
3af, 98%a
3ag, 75%b
3ea, 99%
Ph
N
Ph
Ph
N
Ph
N
N
Ph
N
Ph
N
Ph
N
S
Ph
N
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Ph
ia, 77%d
Ph
3ja, 71%d
Ph
3ka, 82%g
3
3ai, 54%c
3aj, 55%d
3ah, 96%
c
S
3
NH2
Br
Ph
Ph
N
d
S
mmol
NH
3 mmol
DCM, rt, 12 h
Remove solvent
Ph
N
1) 1M HCl, MeOH
2) NaOH
Ph
S
S
S
Ph
LiN(SiMe3)2
1.5 equiv.)
DME, rt, 0.05 M
Ph
Ph
(
Ph
N
Ph
H2N
Ph
3ka
.02 g
0% yield
Ph
3
Ph
mmol
4ka: 99% yield
1
9
Figure 2 | Overview of reaction scope. a, Scope of ketimines in the vinylation reaction. Unless otherwise noted, reactions were conducted on a 0.1 mmol
a
b
scale using 1 equiv. ketimine 1 and 2 equiv. 2a at 0.2 M. Isolated yields after chromatographic purification. 2 equiv. LiN(SiMe
3
)
2
, 30 min; 3 equiv.
, 8 h; 0.05 M, 3 h. b, Scope of vinyl
bromides in transition-metal-free vinylation. Unless otherwise noted, reactions were conducted on a 0.1 mmol scale using 1 equiv. 1a (0.2 M), 2 equiv.
c
d
e
f
g
3 2 3 2 3 2 3 2
LiN(SiMe ) , 3 h; 2 equiv. LiN(SiMe ) , 6 h; 0.05 M; 1.2 equiv. LiN(SiMe ) , 0.05 M, 15 min; 2 equiv. LiN(SiMe )
a
b
c
LiN(SiMe ; 0.1 M; 3 equiv. NaN(SiMe
3
)
2
d
and 2 equiv. vinyl bromides at 0.2 M. Isolated yields after chromatographic purification. 2 equiv. LiN(SiMe
)
3 2
3 2
) ,
1
3 2
2 h, 0.1 M; 3 equiv. NaN(SiMe ) , 15 min, 60 °C. c, Gram-scale sequential one-pot imine synthesis/vinylation protocol. d, Ketimine hydrolysis.
Mechanistic studies. Given the unexpected and unusual coupling of from this intermediate (Path ii, Fig. 3a), with the first leading
ketimines with vinyl bromides in the absence of added catalyst, a to the observed product after elimination of bromide. However,
synergistic computational and experimental study was undertaken significant steric interactions arise in this pathway between
to gain insight into the mechanistic possibilities. Several the vinyl aryl group and the diphenyl moiety of the azaallyl
reasonable mechanisms can be envisioned (Fig. 3a), including anion. The alternative cyclization pathway gives rise to the
those involving alkyne intermediates, cycloadditions, addition/ regioisomeric product, which was not observed. Computations
eliminations, substitutions and carbene insertions.
undertaken on the azaallyl anion found the concerted [3+2] cycli-
Of relevance to Path i in Fig. 3a, in the absence of ketimine, zation pathway to be higher in energy (Supplementary Fig. 6) than
the vinyl bromide undergoes rapid (1 h at room temperature) the stepwise substitution mechanism described in the following
NaN(SiMe ) -promoted background elimination to yield the (Path iv, Fig. 3a).
3
2
corresponding alkyne. Mixing the terminal alkyne and imine 1a
under the same conditions as those used in the vinylation did not presence of MN(SiMe ) (M=Na, K) to form vinylidenes . A
Another possibility is the α-elimination of vinyl halides in the
3
4,35
3
2
result in formation of the vinylated product 3aa (Path ii, Fig. 3b). highly reactive vinylidene could then insert into the benzylic C–H
These results indicate that the alkyne is not an intermediate en bond of the ketimine. If this mechanism is operative in our
route to the vinylation product, discounting Path i in Fig. 3a.
system, the hydrogen of the vinyl motif would originate from a
Addition of the silylamide base is expected to cause rapid benzylic hydrogen of ketimine 1a. With this in mind, the deuterated
deprotonation of the N-benzyl ketimine, giving rise to an azaallyl ketimine 1a′ was prepared and investigated in the coupling with
anion (Fig. 3a)3 . It is known that azaallyl anions undergo vinyl bromides 2i and 2a. The results (Fig. 3c) indicate that vinyl
cycloadditions with styrene, so this pathway was explored with hydrogens of the products are not deuterated, which excludes the
β-bromostyrene3 . Two isomeric [3+2] reactions are possible α-elimination mechanism in Path iii, Fig. 3a.
0,31
2,33
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2760
ARTICLES
a (i) Elimination pathway
(iii) Carbene insertion
Ph
Ph
N
Ar
Ph
Ph
N
Ar
H
–
H
H
–
Ph
N
H
Ar
H
R1
Base
C
R1
H
Ph
Ph
N
Ar
Ph
Ph
N
Ar
Br
Br
Ph
R1
Elimination
α-elimination
R2
Insertion
R2
–
R2
Base
–
) R1 = Ph, R = H
2
1
Ar´
Vinyl carbene
Ar´
Ar´
1
2
Ar´
2) R = R = Me
(
ii) [3+2]/Ring opening
(iv) Addition/elimination or substitution
Ph
Ph
–
Ph
N
Ar
N
Ph
Ph
Ar´
Ar
–
N
–
Ar
Br
Br
1) Stepwise
Ar´
Ph
Br
Nu
Nu
Ar´
[3+2]
–
Ph
Ph
N
Ar
Ar´
Br
Nu
Ar´
–
‡
Ph
Ph
Br
–
Ph
N
–
Ar
Ph
Ph
H
Br
Ar
2) Concerted (SNV)
N
N
Ar
Ar´
Ph
Ar´
Ar´
Ar´
H
Br
Ar´
b
c
MN(SiMe3)2
(3 equiv.)
(
i)
(ii)
Ph
Ph
1 equiv.)
N
Ph
Ph
N
Ph
Ph
Br
NaN(SiMe3)2 (3 equiv.)
DME, rt, 1 h, 0.2 M
Ph
+
+
Ph
Ph
X
DME, rt, 1 h, 0.2 M
M = Li, Na
92% AY
(
Ph
Not observed
NaN(SiMe3)2
(3 equiv.)
NaN(SiMe3)2
(3 equiv.)
Br
Ph
N
(
i)
Br
Ph
D
(ii) Ph
Ph
Ph
Ph
N
N
Ph
Hb
Ph
N
+
Ha
D
+
Ha
Ph D
D
Hb
D
DME, 4 h
Ph
DME, 1 h
23 °C, 0.2 M
Ph
Ha
Ph D
Ha
Ph
2a
60 °C, 0.1 M
1a´
2i
1a´
Ph
Ha retained
a
b
H , H retained
Figure 3 | Overview of mechanistic study. a, Possible mechanisms for vinylation of benzyl ketimines: (i) elimination-addition pathway; (ii) [3+2]
cycloaddition between azaallyl anion and vinyl bromide, followed by ring opening; (iii) carbene insertion; (iv) addition/elimination or substitution.
b, Probing the intermediacy of an alkyne. c, Probing the vinylidine insertion mechanism.
4
3
playing a role . All attempts to calculate intermediates for the
corresponding stepwise process (Path iv, Fig. 3a) using functionals
1.31 Å
‡
1.36 Å
Ph Ph
Ph
+ Br–
previously used to study S V reactions (B3LYP and OPBE) led
N
N
directly to dissociation back to the starting materials or the
formation of vinylated product and bromide. Density functional
theory (DFT) calculations did, however, reveal a concerted displace-
1.32 Å
2
.08 Å
1.34 Å
Ph
1.98 Å
5
–
N
2
4
1
3
–1
A1-B1-TS
B1
ment with a low energetic barrier (11.7 kcal mol ) to deliver the
A1
11.7
–46.8
vinylated product B1 with concomitant release of bromide
‡
–1
0.0
(Fig. 4). A strong kinetic preference (ΔΔG > 7 kcal mol ) for
nucleophilic attack perpendicular to the carbon–carbon double
1.39 Å
‡
+
1.29 Å
3
9–42
Br
bond (S V)
at the less sterically encumbered β-position
N
Ph
Ph Ph
(A1-B1-TS versus A1-C1-TS) was found. Notably, both product
regioisomers (B1 and C1) are nearly isoenergetic.
2
.18 Å
.06 Å
A1-C1-TS
Ph
N
Ph
2a
2
+ Br–
These computational results are in accord with both the experi-
mentally observed reactivity (20 min to 3 h at room temperature)
and regioselectivity (>20:1 d.r.) using bromostyrene. However,
experiments with the Z-bromostyrene 2a′ at room temperature
yield a near 2:1 ratio of E and Z products, albeit in low yield
(14%) due to rapid competing elimination of Z-bromostyrene 2a′
C1
–46.9
19.1
Figure 4 | Computed free-energy profile for nucleophilic vinyl substitution
of azaallyl anion A1 and vinyl bromide 2a. Nucleophilic attack by C1 carbon
of azaallyl anion A1 via A1-B1-TS is kinetically favoured, leading to B1. M06-
to form alkyne (Supplementary Fig. 5). The anionic-pathway S V
N
−1
36–38
2
X/6-31G(d)-CH
Cl
2 2
(CPCM) Gibbs free energies (blue) are in kcal mol
shown in Fig. 4 is a concerted and stereospecific process
,
relative to isolated reactants A1 and 2a. Selected distances (red) shown
are in Å.
which is inconsistent with the stereochemical scrambling observed.
These results motivated us to examine alternative pathways.
4
4–46
We speculated that an azaallyl radical A0 (Fig. 5a)
could
Our attention next turned to possible substitution pathways36–38. participate in the process. This azaallyl radical could form by
39–42
Both stepwise and concerted (S V)
substitutions have been electron transfer from the azaallyl anion (A1) to a molecule of
N
4
7
reported for vinyl halides, but not with carbon-derived anions. ketimine 1a (Fig. 5a) . DFT calculations for azaallyl radical
4
5,48
Mechanisms are case-dependent, with the nature of the nucleophile, recombination with a putative vinyl radical
showed very small
–
1
the leaving group and the electrophile substitution pattern all energetic barriers (∼11 kcal mol ), indicating that such a process
4
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a
N
Base
–
–
+
N
C1 C3
A0 (Azaallyl radical)
Spin density
N
C1 C3
N
N
Single electron transfer
(
SET)
A2 Ketimine radical anion
A1
1a
Azaallyl anion
Spin density
Ketimine
1
1
C = 0.45
C = 0.05
2
2
N = –0.19
N = 0.37
3
3
C = 0.50
C = 0.18
–
b
Br
‡
N
N
N
Br
Br
SET/
elimination
Br
P-1a
TS-1a
8.0
Int-1a
.1
+
–46.8
1
1
–
N
N
1a + A1
N
1a
A2
A0
0.0
SET/
elimination
‡
N
N
N
–
Br
TS-2a
Br
Br
Int-2a
P-2a
23.2
4.2
–46.9
c
e
Ph
N
Ph
(
i)
Me
Me
LiN(SiMe3)2
Ph
Br
Ph
Br
Cl
Br
Cl
Br
Ph
N
Ph
Ph
Radical: 18.0
Ph
Me
Me
(3 equiv.)
Ar
+
Ar
o
Ar
Ph
DME, 23 C
19.3
15.1
20.7
15.5
21.5
28.0
25.5
33.2
Ar
2k
0.2 M, 12 h
1:1 Z and E isomers
Overall 60% yield
1a
Anionic:
11.7
(
2 equiv.)
(1 equiv.)
+
Ar = 4-C6H4-OMe
d
Ar
NaN(SiMe3)2 (3 equiv.) Ph
DME, –40 °C, 0.2 M, 3 h
N
Ph
Proposed intermediate:
(
i) Ph
N
Ph
Br
Ar
+
+
Ph
Ph
Ph
N
Ph
Ar
Ph
Ph
1 equiv.)
96%
28% yield
–
(
(2 equiv.)
Ph
Ph
Br
LiN(SiMe3)2 (3 equiv.) Ph
DME, –40 °C, 0.2 M, 3 h
N
(
ii)
Ph
N
Ph
Ar
Ph
Ph
(ii)
Ph
Ph
1 equiv.)
Br
6
%
Ph
Ph
Ph
LiN(SiMe3)2 (3 equiv.)
Full
N
Ph
(
(2 equiv.)
(
Also 67% alkyne and
Br
+
decomposition
8
7% recovered ketimine)
LiN(SiMe3)2 (3 equiv.) Ph
DME, rt, 0.2 M, 1 h
DME, 60 °C, 0.2 M, 12 h
Ph
(
iii)
N
Ph
N
Ph
Cl
1a
2l
(1 equiv.)
+
+
Ph
Ph
(2 equiv.)
Ph
1 equiv.)
9
8%
(
(2 equiv.)
Proposed intermediate:
(
iv) Ph
N
Ph
NaN(SiMe3)2 (3 equiv.)
DME, 60 °C, 0.2 M, 3 h
Br
NR
Ph
Ph
N
Ph
Ph
Ph
N
Ph
Ph
1 equiv.)
Br
Br
(
(2 equiv.)
Figure 5 | Overview of possible radical mechanism. a, Proposed formation of azaallyl radical A0 and azaallyl radical anion A2 via a single electron transfer
−
1
(
SET) process. b, Gibbs free energy (M06-2X/6-31G(d)-CH
isolated reactants. Substituent effects of electrophile on the radical and anionic addition barriers (free energies in kcal mol at 298 K) were calculated using
M06-2X/6-31G(d)-CH Cl (CPCM). Selected Mulliken spin densities with hydrogens summed into heavy atoms are listed in blue. Selected distances
are in Å. c, Substituent effects of electrophile on the radical A0 and anionic A1 addition barriers (free energies in kcal mol at 298 K) were calculated using
M06-2X/6-31G(d)-CH Cl (CPCM). d, Substrate study of vinylation. e, Radical clock study.
2 2
Cl (CPCM)) profile for the azaallyl radical additions. Energies (kcal mol ) are relative to
−1
2
2
−1
2
2
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is facile. The energy difference between the competing transition errors associated with determining accurate quantitative barriers
states, however, indicates negligible levels of E/Z product regioselec- with charged species, computations employing the commonly used
tivity, which is inconsistent with experiments (see Supplementary B3LYP functional, which has been used by others to study S V
N
–
1
Fig. 7 for structures).
reactions, predicted prohibitively high barriers (>36 kcal mol )
Transition states could also be located for the addition of azaallyl for the azaallyl anion A1 and 1-bromo-2-methylprop-1-ene in
radical A0 to trans-bromostyrene (Fig. 5b), which proceeds in a both the gas phase and in implicit solvent. Moreover, the greater
–1
stepwise manner with an overall barrier of 18.0 kcal mol (via reactivity of 1-bromo-2-methylprop-1-ene (Fig. 2b, 2i) versus E-1-
TS-1a) to yield radical intermediate Int-1a, and eventually to the bromo-prop-1-ene (Path iv, Fig. 5d) also seemingly runs counter
observed regioisomer (Fig. 5b). The transition state TS-2a, which to the azaallyl anion mechanism; a build-up of negative charge
leads to the unobserved regioisomer, is much higher in energy would be less favourable with two methyl substituents, as is the
–
1
(
23.2 kcal mol ) due to increased steric interactions between the case for the former.
diaryl moiety of the azaallyl radical and β-bromostyrene. The EPR results support the presence of radicals, but do not
•
From Int-1a, a scan for dissociation of Br and formation of indicate if they are involved in the vinylation reactions. To probe
observed product P-1a was computed to be prohibitively high in for the direct participation of radicals in the vinylations, we next
–1
energy (>35 kcal mol ; see Supplementary Fig. 8 for scan). examined the reactions of radical clock-containing styryl and
Alternatively, radical intermediate Int-1a can undergo single- non-styryl substrates. We prepared the radical clock 2k (Fig. 5e)
electron reduction to generate a negatively charged species, which– to test for the intermediacy of radical intermediates in the reaction
facilitates the heterolytic cleavage of the C–Br bond to generate Br
with β-bromostyrene derivatives. As outlined in Fig. 5b, Int-1a
and the observed product P-1a. In support of this hypothesis, all possesses a stabilized benzylic radical. Thus, a second aryl group
optimizations of– anionic version of Int-1a led directly to was built into the substrate such that, in the event the benzylic
dissociation of Br and formation of P-1a. This result implies that radical analogous to Int-1a is formed, ring opening would also
once radical Int-1a undergoes single-electron reduction, it quickly dis- give a stabilized benzylic radical. The reaction of the E-styryl
sociates bromide, leading to the observed product, consistent with the radical clock 2k with ketimine 1a in the presence of LiN(SiMe3)2
–1
highly exergonic (–47 kcal mol ) nature of the net process. This furnished a mixture of Z and E vinylated products in a 1:1 ratio
process also converts radical anion A2 back to ketimine 1a. Product (Path i, Fig. 5e, overall 60% yield). An alkyne side product was
regioisomers P-1a and P-2a are nearly isoenergetic, so the regioselec- observed in 28% isolated yield, which we propose is derived from
tivity derives from the kinetic preference of TS-1a over TS-2a. In con- the α-elimination–migration mechanism. Thus, no cyclopropane
trast to the azaallyl anion nucleophilic vinyl substitution pathway ring-opened products were detected, suggesting that the reaction
(
Fig. 4), the pathway involving the radical intermediates Int-1a of styryl substrates does not proceed through radical intermediates.
accounts for the stereochemical scrambling from Z-bromostyrene 2a Furthermore, the scrambling of the double-bond geometry is
(bond rotation more rapid than reduction/elimination). inconsistent with an anionic concerted S V substitution mechanism.
The mechanism in Fig. 5 proposes radical intermediates (A0 and Based on these results, the pathway favoured is the addition/elimi-
′
N
A2). To probe for the presence of radicals, an electron paramagnetic nation, where the azaallyl anion adds to the styrene to generate a
resonance (EPR) study was undertaken. In these experiments, DME benzylic carbanion that can rotate about the single bond before
solutions of NaN(SiMe ) were added to DME solutions of ketimine elimination, giving rise to the observed products (see structure of
3
2
1a and the samples were allowed to react for ∼5 min at room the proposed intermediate in Path i, Fig. 5e). Unfortunately, we
temperature (rt) before freezing in liquid nitrogen. The EPR were unable to locate such an intermediate computationally
spectra were acquired in DME glass at 190 K and microwave without an additional anion-stabilizing group.
power of 1 mW. No signal was detected in samples with only base
To probe the participation of radicals with aliphatic vinyl
in DME or DME alone. In contrast, for the deprotonations of 1a, bromides, radical clock 2l was prepared and isolated as the pure E
EPR spectra showed clear signals for the presence of radical isomer (see Supplementary page 19, ‘Synthesis of radical clock 2l’,
species (Supplementary Fig. 2). The observation of an EPR signal for details). Reaction of E-2l (Path ii, Fig. 5e) with ketimine 1a in
is supportive of one or more radicals, but definitive conclusions the presence of LiN(SiMe ) led to a complex mixture, as determined
3
2
1
concerning the nature of the radical species must await future by H NMR. Furthermore, no clean products could be isolated from
investigations. Despite numerous studies of azaallyl anions in the this mixture. We propose that ring opening occurs to give a reactive
literature, to the best of our knowledge this is the only evidence of radical. These results suggest the presence of a radical addition
radical formation upon deprotonation of ketimines.
mechanism for aliphatic vinyl bromides.
Given the evidence for the presence of radicals, which we
Based on the computational, spectroscopic (EPR) and experimental
propose to be the azaallyl radical (A0) and the ketimine radical results, both the azaallyl anion and azaallyl radical exist under the
anion (A2), an effort was made to distinguish the azaallyl anion reaction conditions. To rationalize these observations, we propose
SNV and azaallyl radical additions by calculating the reaction substrate-dependent reactions with different electrophiles. Thus,
barriers (Fig. 5c). Based on the computations, similar trends were with aliphatic vinyl bromides the azaallyl radical addition
observed for both mechanisms, as listed in Fig. 5c. Thus, E-β- mechanism best fits with the experimental and computational
bromostyrene was predicted to react more readily than the Z results. In contrast, for the styryl vinyl bromides, the data are
isomer or E-β-chlorostyrene. Experimentally, E-β-bromostyrene most consistent with the anionic pathway.
reacted at –40 °C to afford the vinylation product in 96% AY
(Path i, Fig. 5d), while Z-β-bromostyrene generated the E product Conclusion
in 6% yield (no cis-product observed and elimination dominating In summary, we report a unique transition-metal-free coupling of
the reaction, Path ii, Fig. 5d). At room temperature, coupling of 1,1-diphenyl-3-aryl-2-azaallyl anions with vinyl bromides to
E-β-chlorostyrene afforded product in 98% AY. For substrates afford allylic amine derivatives, which are of great importance in
lacking a β-aryl group, reaction is expected to slow according to the pharmaceutical industry. High regioselectivities and yields of
both mechanisms, but to a far larger degree for the azaallyl anion E-vinylation products were observed. The vinylation reaction out-
mechanism3 . As illustrated in Fig. 2b, 1-bromo-2-methylprop- competes a rapid background reaction arising from the elimination
9–42
1-ene (2i) and (bromomethylene)cyclohexane (2j) underwent of the styryl bromides to form alkynes. Several mechanistic possibi-
reaction, albeit more slowly (12 h) and with reduced yields (54 lities were explored both experimentally and with DFT calculations.
and 55%, respectively). Although there are well-documented EPR studies indicate the presence of radicals, which we have
6
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2760
ARTICLES
tentatively assigned to be the azaallyl radical and imino-ketyl radical 22. Ankner, T., Cosner, C. C. & Helquist, P. Palladium- and nickel-catalyzed
alkenylation of enolates. Chem. Eur. J. 19, 1858–1871 (2013).
anion species. The detection of radicals is consistent with the
unusual azaallyl radical addition mechanism with aliphatic vinyl
bromides. For styryl bromides, a radical clock-bearing substrate
2
3. Grigalunas, M., Ankner, T., Norrby, P. O., Wiest, O. & Helquist, P.
Palladium-catalyzed alkenylation of ketone enolates under mild conditions.
Org. Lett. 16, 3970–3973 (2014).
reacted without ring opening, but with loss of the double-bond 24. Hardegger, L. A., Habegger, J. & Donohoe, T. J. Modular synthesis of
highly substituted pyridines via enolate alpha-alkenylation. Org. Lett. 17,
stereochemistry. This observation disfavours the radical mechanism
3222–3225 (2015).
and is better explained by an anionic addition/elimination mechan-
ism. Further studies are under way to broaden this class of reactions
using ketimine derivatives in the absence of added transition-metal
catalyst and to definitively assign the structures of the radical species
observed by EPR.
2
2
5. Padilla-Salinas, R., Walvoord, R. R., Tcyrulnikov, S. & Kozlowski, M. C.
Nitroethylation of vinyl triflates and bromides. Org. Lett. 15, 3966–3969 (2013).
6. Piers, E. & Marais, P. C. A new five-membered ring annulation method based on
palladium(0)-catalyzed intramolecular coupling of vinyl iodide and enolate
anion functions. J. Org. Chem. 55, 3454–3455 (1990).
7. Solé, D., Peidró, E. & Bonjoch, J. Palladium-catalyzed intramolecular coupling of
vinyl halides and ketone enolates. synthesis of bridged azabicyclic compounds.
Org. Lett. 2, 2225–2228 (2000).
2
Data availability. All relevant data are included with the
manuscript, in the Supplementary Information, and are available 28. Yang, X., Kim, B. S., Li, M. & Walsh, P. J. Palladium-catalyzed selective
from the corresponding authors on reasonable request.
alpha-alkenylation of pyridylmethyl ethers with vinyl bromides. Org. Lett. 18,
371–2374 (2016).
2
2
3
3
9. Niwa, T., Suehiro, T., Yorimitsu, H. & Oshima, K. Carbon–carbon bond
formations at the benzylic positions of N-benzylxanthone imines and
N-benzyldi-1-naphthyl ketone imine. Tetrahedron 65, 5125–5131 (2009).
0. Tang, S., Park, J. Y., Yeagley, A. A., Sabat, M. & Chruma, J. J. Decarboxylative
generation of 2-azaallyl anions: 2-iminoalcohols via a decarboxylative
Erlenmeyer reaction. Org. Lett. 17, 2042–2045 (2015).
1. Yeagley, A. A., Lowder, M. A. & Chruma, J. J. Tandem C–C bond-forming
processes: interception of the Pd-catalyzed decarboxylative allylation of
allyl diphenylglycinate imines with activated olefins. Org. Lett. 11,
Received 22 April 2016; accepted 1 March 2017;
published online 17 April 2017
References
1.
2.
3.
4.
Negishi, E. Magical power of transition metals: past, present, and future (Nobel
Lecture). Angew. Chem. Int. Ed. 50, 6738–6764 (2011).
Suzuki, A. Cross-coupling reactions of organoboranes: an easy way to construct
C–C bonds (Nobel Lecture). Angew. Chem. Int. Ed. 50, 6722–6737 (2011).
Sun, C. L. & Shi, Z. J. Transition-metal-free coupling reactions. Chem. Rev. 114,
4022–4025 (2009).
9
219–9280 (2014).
3
3
3
2. Kauffmann, T., Berger, D., Scheerer, B. & Woltermann, A. Anionic 3+2
cycloaddition of a 1,2-diazaallyllithium compound. Angew. Chem. Int. Ed. 9,
Petranyi, G., Ryder, N. & Stutz, A. Allylamine derivatives: new class of
synthetic antifungal agents inhibiting fungal squalene epoxidase. Science 224,
961–962 (1970).
1
239–1241 (1984).
3. Pandiancherri, S. & Lupton, D. W. Preparation of 2-azaallyl anions and imines
5.
6.
7.
Roggen, M. & Carreira, E. M. Stereospecific substitution of allylic alcohols to give
optically active primary allylic amines: unique reactivity of a (P,alkene)Ir
complex modulated by iodide. J. Am. Chem. Soc. 132, 11917–11919 (2010).
Yamashita, Y., Gopalarathnam, A. & Hartwig, J. F. Iridium-catalyzed,
asymmetric amination of allylic alcohols activated by Lewis acids. J. Am. Chem.
Soc. 129, 7508–7509 (2007).
Patel, S. J. & Jamison, T. F. Asymmetric catalytic coupling of organoboranes,
alkynes, and imines with a removable (trialkylsilyloxy)ethyl group—direct access
to enantiomerically pure primary allylic amines. Angew. Chem. Int. Ed. 43,
from N-chloroamines and their cycloaddition and allylation. Tetrahedron Lett.
52, 671–674 (2011).
4. Taber, D. F., Sahli, A., Yu, H. & Meagley, R. P. Efficient intramolecular C–H
insertion by an alkylidene carbene generated from a vinyl chloride. J. Org. Chem.
6
0, 6571–6573 (1995).
5. Taber, D. F., Sikkander, M. I. & Storck, P. H. Enantioselective synthesis of
+)-majusculone. J. Org. Chem. 72, 4098–4101 (2007).
6. Bernasconi, C. F. & Rappoport, Z. Recent advances in our mechanistic
understanding of S V reactions. Acc. Chem. Res. 42, 993–1003 (2009).
3
3
3
3
3
(
N
3
941–3944 (2004).
7. Rappoport, Z. Nucleophilic vinylic substitution. A single- or a multi-step
process? Acc. Chem. Res. 14, 7–15 (1981).
8
.
.
Shi, X., Kiesman, W. F., Levina, A. & Xin, Z. Catalytic asymmetric petasis
reactions of vinylboronates. J. Org. Chem. 78, 9415–9423 (2013).
Overman, L. E. A general method for the synthesis of amines by the
rearrangement of allylic trichloroacetimidates. 1,3 Transposition of alcohol and
amine functions. J. Am. Chem. Soc. 98, 2901–2910 (1976).
8. Rappoport, Z. The rapid steps in nucleophilic vinylic addition–elimination
substitution. Recent developments. Acc. Chem. Res. 25, 474–479 (1992).
9. Bach, R. D., Baboul, A. G. & Schlegel, H. B. Inversion versus retention of
configuration for nucleophilic substitution at vinylic carbon. J. Am. Chem. Soc.
9
1
0. Ngai, M.-Y., Barchuk, A. & Krische, M. J. Enantioselective iridium-catalyzed
imine vinylation: optically enriched allylic amines via alkyne–imine reductive
coupling mediated by hydrogen. J. Am. Chem. Soc. 129, 12644–12645 (2007).
1. Skucas, E., Kong, J. R. & Krische, M. J. Enantioselective reductive coupling of
acetylene to N-arylsulfonyl imines via rhodium catalyzed C–C bond-forming
hydrogenation: (Z)-dienyl allylic amines. J. Am. Chem. Soc. 129,
123, 5787–5793 (2001).
40. Castro, E. A., Gazitua, M. & Santos, J. G. Kinetics and mechanism of the
anilinolysis of aryl 4-nitrophenyl carbonates in aqueous ethanol. J. Org. Chem.
1
70, 8088–8092 (2005).
4
4
4
1. Castro, E. A., Ramos, M. & Santos, J. G. Concerted pyridinolysis of
aryl 2,4,6-trinitrophenyl carbonates. J. Org. Chem. 74, 6374–6377 (2009).
2. Williams, A. Concerted mechanisms of acyl group transfer reactions in solution.
Acc. Chem. Res. 22, 387–392 (1989).
7
242–7243 (2007).
1
1
1
2. Li, M., Berritt, S. & Walsh, P. J. Palladium-catalyzed regioselective arylation
of 1,1,3-triaryl-2-azaallyl anions with aryl chlorides. Org. Lett. 16,
3. Fernandez, I., Bickelhaupt, F. M. & Uggerud, E. Reactivity in nucleophilic vinylic
4
312–4315 (2014).
substitution (S
N N π N σ
V): S V versus S V mechanistic dichotomy. J. Org. Chem. 78,
3. Li, M. et al. Palladium-catalyzed C–H arylation of α,β-unsaturated imines:
catalyst-controlled synthesis of enamine and allylic amine derivatives.
Angew. Chem. Int. Ed. 128, 2875–2879 (2016).
4. Li, M., Yucel, B., Adrio, J., Bellomo, A. & Walsh, P. J. Synthesis of
diarylmethylamines via palladium-catalyzed regioselective arylation of
8574–8584 (2013).
44. Baum, A. A. & Karnischky, L. A. Photochemical formation of oxazolidines from
aryl ketones and aliphatic imines. J. Am. Chem. Soc. 95, 3072–3074 (1973).
45. Dannenberg, J. J. & Tanaka, K. Theoretical studies of radical recombination
reactions. 1. Allyl and azaallyl radicals. J. Am. Chem. Soc. 107, 671–674 (1985).
46. Malassa, A., Agthe, C., Görls, H., Friedrich, M. & Westerhausen, M.
Deprotonation and dehydrogenation of di(2-pyridylmethyl)amine with
1
,1,3-triaryl-2-azaallyl anions. Chem. Sci. 5, 2383–2391 (2014).
1
1
1
5. Li, M. et al. Umpolung synthesis of diarylmethylamines via palladium-catalyzed
arylation of N-benzyl aldimines. Adv. Synth. Catal. 358, 1910–1915 (2016).
6. Wu, Y., Hu, L., Li, Z. & Deng, L. Catalytic asymmetric Umpolung reactions of
imines. Nature 523, 445–450 (2015).
7. Burger, E. C. & Tunge, J. A. Synthesis of homoallylic amines via the palladium-
catalyzed decarboxylative coupling of amino acid derivatives. J. Am. Chem. Soc.
M[N(SiMe
3 2 2 6 2 3 2
) ] (M=Mn, Fe, Co, Zn) and Fe(C H -2,4,6-Me ) . J. Organomet.
Chem. 695, 1641–1650 (2010).
4
7. Pallagi, I., Toró, A. & Horváth, G. Mechanism of the Gibbs reaction. Part 4.1
Indophenol formation via N-chlorobenzoquinone imine radical anions. The
Aza-SRN2 chain reaction mechanism. Chain initiation with 1,4-benzoquinones
and cyanide ion. J. Org. Chem. 64, 6530–6540 (1999).
1
28, 10002–10003 (2006).
1
1
2
2
8. Fields, W. H. & Chruma, J. J. Palladium-catalyzed decarboxylative benzylation of
diphenylglycinate imines. Org. Lett. 12, 316–319 (2009).
9. Niwa, T., Yorimitsu, H. & Oshima, K. Palladium-catalyzed benzylic arylation of
N-benzylxanthone imine. Org. Lett. 10, 4689–4691 (2008).
0. Zhu, Y. & Buchwald, S. L. Ligand-controlled asymmetric arylation of aliphatic
α-amino anion equivalents. J. Am. Chem. Soc. 136, 4500–4503 (2014).
1. Liu, Y. E. et al. Enzyme-inspired axially chiral pyridoxamines armed with a
cooperative lateral amine chain for enantioselective biomimetic transamination.
J. Am. Chem. Soc. 138, 10730–10733 (2016).
4
8. Giese, B. The stereoselectivity of intermolecular free radical reactions
[
New Synthetic Methods (78)]. Angew. Chem. Int. Ed. 28, 969–980 (1989).
Acknowledgements
The authors acknowledge the National Science Foundation (CHE-1464744 to P.J.W. and
CHE-1464778 to M.C.K.) and the National Institutes of Health (GM-104349 to P.J.W. and
GM-087605 to M.C.K.) for financial support. J.A. acknowledges support from Ministerio
de Educación, Cultura y Deporte, Subprograma Estatal de Movilidad, Salvador de
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2760
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Madariaga. Computational support was provided by XSEDE on SDSC Gordon (TG-
CHEM120052). This work was also financially supported by a SICAM Fellowship by
Jiangsu National Synergetic Innovation Center for Advanced Materials. The authors thank
S. Montel of UPenn and K. Scheidt of Northwestern University for discussions.
Additional information
Supplementary information and chemical compound information are available in the
online version of the paper. Reprints and permissions information is available online at
www.nature.com/reprints. Publisher’s note: Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations. Correspondence and
requests for materials should be addressed to M.C.K. and P.J.W.
Author contributions
M.L. and P.J.W. conceived and designed the experiments. M.L., S.B., A.P.-E., A.Y., X.Y., J.A.
and G.H. performed the research. O.G. and M.C.K. designed and performed the DFT
computational study. M.L. and E.N.-O. performed the EPR study. M.L., O.G., M.C.K. and Competing financial interests
P.J.W. wrote the paper.
The authors declare no competing financial interests.
8
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