Transition-Metal-Free Radical C(sp3)-C(sp2) and C(sp3)-C(sp3) Coupling Enabled by 2-Azaallyls as Super-Electron-Donors and Coupling-Partners

Article abstract of DOI:10.1021/jacs.7b09394

The past decade has witnessed the rapid development of radical generation strategies and their applications in C-C bond-forming reactions. Most of these processes require initiators, transition metal catalysts, or organometallic reagents. Herein, we report the discovery of a simple organic system (2-azaallyl anions) that enables radical coupling reactions under transition-metal-free conditions. Deprotonation of N-benzyl ketimines generates semistabilized 2-azaallyl anions that behave as super-electron-donors (SEDs) and reduce aryl iodides and alkyl halides to aryl and alkyl radicals. The SET process converts the 2-azaallyl anions into persistent 2-azaallyl radicals, which capture the aryl and alkyl radicals to form C-C bonds. The radical coupling of aryl and alkyl radicals with 2-azaallyl radicals makes possible the synthesis of functionalized amine derivatives without the use of exogenous radical initiators or transition metal catalysts. Radical clock studies and 2-azaallyl anion coupling studies provide mechanistic insight for this unique reactivity.

Full text of DOI:10.1021/jacs.7b09394

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Article
Transition-Metal-Free Radical C(sp3)–C(sp2) and C(sp3)–C(sp3) Coupling
Enabled by 2-Azaallyls as Super-Electron-Donors and Coupling-Partners
Minyan Li, Simon Berritt, Lucas Matuszewski, Guogang Deng, Ana Pascual-Escudero,
Grace B Panetti, Michal Poznik, Xiaodong Yang, Jason J. Chruma, and Patrick J Walsh
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b09394 • Publication Date (Web): 11 Oct 2017
Downloaded from http://pubs.acs.org on October 11, 2017
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Transition-Metal-Free Radical C(sp3)–C(sp2) and C(sp3)–C(sp3) Cou-
pling Enabled by 2-Azaallyls as Super-Electron-Donors and Coupling-
Partners
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Minyan Li,1 Simon Berritt,1 Lucas Matuszewski,1 Guogang Deng,2 Ana PascualꢀEscudero,3 Grace B.
Panetti,1 Michal Poznik,4 Xiaodong Yang,2 Jason J. Chruma4 and Patrick J. Walsh*,1
1Department of Chemistry, Roy and Diana Vagelos Laboratories, Penn/Merck Laboratory for HighꢀThroughput Experimenꢀ
tation, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104, USA.
2Key Laboratory of Medicinal Chemistry for Natural Resource, School of Chemical Science and Technology, Yunnan Uniꢀ
versity, Kunming, 650091, China.
3Dpto. Química Orgánica, Facultad de Ciencias, Universidad Autónoma de Madrid, Madrid, Spain.
4Key Laboratory of Green Chemistry & Technology (MOE), College of Chemistry and SinoꢀBritish Materials Research
Institute, College of Physical Science & Technology, Sichuan University, No. 29, Wangjiang Road, Chengdu, Sichuan,
610064, China.
ABSTRACT: The past decade has witnessed the rapid development of radical generation strategies and their applications in C–C
bondꢀforming reactions. Most of these processes require initiators, transition metal catalysts or organometallic reagents. Herein, we
report the discovery of a simple organic system (2ꢀazaallyl anions) that enables radical coupling reactions under transitionꢀmetalꢀ
free conditions. Deprotonation of Nꢀbenzyl ketimines generates semiꢀstabilized 2ꢀazaallyl anions that behave as “superꢀelectronꢀ
donors” (SEDs) and reduce aryl iodides and alkyl halides to aryl and alkyl radicals. The SET process converts the 2ꢀazaallyl anions
into persistent 2ꢀazaallyl radicals, which capture the aryl and alkyl radicals to form C–C bonds. The radical coupling of aryl and
alkyl radicals with 2ꢀazaallyl radicals makes possible the synthesis of functionalized amine derivatives without the use of exogeꢀ
nous radical initiators or transition metal catalysts. Radical clock studies and 2ꢀazaallyl anion coupling studies provide mechanistic
insight for this unique reactivity.
1. Introduction
(SEDs).5 SEDs possess reduction potentials as high as –1.50 V
(versus SCE)6 and reduce a range of substrates to generate
radicals (Scheme 1c). The reducing features of SEDs have
been demonstrated in intramolecular radical cyclization experꢀ
iments.7 In contrast, kinetically slower intermolecular (bimoꢀ
lecular) C–C bond formations enabled by excess amounts of
SEDs are far less developed.8
Reactions that form C–C bonds have received tremendous
attention due to their value in synthetic organic chemistry and
drug discovery.1 Of these, the formation of C–C bonds via
radical intermediates has witnessed increasing popularity due
to the mild nature of many of these processes.1h, 2 Over the past
few decades, a series of groundbreaking radicalꢀbased couꢀ
pling strategies have been developed that enable a wide varieꢀ
ty of bonds to be formed. Among these, use of visibleꢀlight
activated transition metal and organoꢀphotocatalysts to generꢀ
ate organic radicals has found tremendous applications in
novel C–C bondꢀforming methods.3 A key feature of such
photocatalysts (PC*) is their ability to behave as both reductꢀ
ants and oxidants, as shown in Scheme 1a. Under photocataꢀ
lytic conditions, a wide variety of reagents undergo oxidative
or reductive fragmentation to organic radicals. Another beautiꢀ
ful strategy for radical generation is through redoxꢀactive
esters, which are converted efficiently to radicals by reductive
fragmentation using transitionꢀmetals as electron donors
(Scheme 1b).4 Finally, a metalꢀfree strategy to generate radiꢀ
cals involves the use of organic superꢀelectronꢀdonors
Along these lines, we recently became interested in radical
coupling reactions while investigating a unique transition
metalꢀfree reaction of 2ꢀazaallyl species with vinyl halide
electrophiles (Scheme 2a). We found that deprotonation of
triaryl ketimines to generate semiꢀstabilized 2ꢀazaallyl anions
also resulted in the formation of radical species that were
detected by EPR.9 This unexpected observation led us to specꢀ
ulate that the 2ꢀazaallyl anion and neutral ketimine are in
equilibrium with the 2ꢀazaallyl radical and ketimine radical
anion (Scheme 2b). This hypothesis was supported by DFT
computational studies, but experimental evidence for the inꢀ
termediacy of radicals in the coupling reactions was elusive.
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The proposed reducing nature of 2ꢀazaallyl anions inspired
Page 2 of 9
1
us to ponder their potential to behave as organic superꢀ
electronꢀdonors (SEDs) and their possible applications in C–C
bondꢀformation. We hypothesized that 2ꢀazaallyl anions might
reduce aryl halides and possibly alkyl halides to generate aryl
and alkyl radicals. If the 2ꢀazaallyl anion is indeed sufficiently
reducing in nature to undergo SET with aryl and alkyl halides,
the resulting 2ꢀazaallyl radical must be relatively stable (long
lived). Owing to the persistent radical effect,10 it might behave
as a persistent radical and capture the transient radicals which
are aryl and alkyl radicals, enabling formation of sp3–sp2 and
sp3–sp3 C–C bonds (Scheme 2c). Herein, we report the first
transition metalꢀfree arylation and alkylation of 2ꢀazaallyl
radicals enabled by the use of 2ꢀazaallyl anions as superꢀ
electron donors. A variety of unactivated aryl iodides and
alkyl halides were successfully coupled with 2ꢀazaallyl species
at room temperature without the use of special initiators, phoꢀ
tocatalysts or transition metal catalysts. Notably, the arylation
protocol enables the synthesis of diarylmethylamine derivaꢀ
tives, which are of great importance in medicinal and pharmaꢀ
ceutical chemistry.11 Arylation at the benzhydryl carbon (sideꢀ
reaction) was also observed which afforded pharmaceutically
valuable triarylmethylamine derivatives.10c The alkylation
protocol overcomes limitations of hindered alkyl halide elecꢀ
trophiles that show little or no reactivity in classic nucleophilic
substitution reactions12 and provides efficient synthesis of
challenging alkyl amine derivatives.13 In addition, mechanistic
studies provide insight into these C–C bondꢀforming reactions.
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Scheme 2. 2ꢀAzaallyl anions as superꢀelectron donor and
radical coupling partners in transitionꢀmetalꢀfree C–C bond
formation.
2. Result and Discussion
2.1 Transition Metal-free C(sp3)–C(sp2) Coupling to 2-
Azaallyl Species. Among organic electron acceptors with C–
X bonds, we decided to first examine aryl iodides because
their reduction potentials are lower than other aryl halides
(Scheme 3a).14 A focused microscale (10 ꢁmol) highꢀ
throughputꢀscreen (HTS) was performed for the study of aryꢀ
lation of ketimine 1a with 4ꢀtertꢀbutyliodobenzene (2a) at
room temperature for 6 h. Other parameters included six solꢀ
vents (THF, CPME, DME, MTBE, toluene, and cyclohexane),
two bases [LiN(SiMe3)2 and NaN(SiMe3)2] and two concentraꢀ
tions (0.1 M and 0.2 M). The best conditions in this screen
involved DME, NaN(SiMe3)2 at 0.2 M concentration. We next
monitored the reaction of 4ꢀtertꢀbutyl iodobenzene (2a, 10
ꢁmol) with ketimine 1a and NaN(SiMe3)2 and found that the
reaction reached completion in 4 h. (see Figure S1 of Supportꢀ
ing Information for details). A laboratory scale (0.4 mmol)
repeat (Scheme 3b) of these optimal conditions gave the C3ꢀ
arylation product 4aa in 55% isolated yield. To our surprise,
the product from arylation at the benzhydryl carbon (C3ꢀ
arylation, 4aa’) was isolated in 16% yield. We propose that
the C3ꢀarylation is derived from the coupling of azaallyl radiꢀ
cal with phenyl radical at the more substituted C3 carbon.
Steric influences also affect the ratio of C1 vs. C3 arylation,
leading to greater arylation at the less substituted carbon in the
2ꢀazaallyl system.
(a) Radical generation enabled by photoredox process
*
PC
A
D
oxidative fragmentation
D+
–
*
+
PC
PC
Radical
precursor
(A or D)
PC–
Via
PC+
hv
A–
+PC+
*
PC
reductive fragmentation
PC
photocatalyst
Substrate suitable for oxidative fragmentation (D):
O
–
R-H, R-CO2H, R-BF3K, R-DHP, R Si
Substrate suitable for reductive fragmentation (A):
R-I, R-CF3, R-N2BF4
2
O
Conversion of alkenes to radical cations
*
PC
+
R
R
PC–
(b) Radical generation enabled by redoxactive esters
O
O
reductive fragmentation
[M]
A
A
R
R
O
R
O
CO2
A:
O
N
N
N
N
etc.
N
S
N
O
(c) Radical generation enabled by organic-super-electron-doners
Ar-X
N
N
Ar
Ar
(X= I, Br, Cl)
N
ONa
N
N
+
Ar-N2
SED
Me
Me
R1
R1
X
N
super-electron-donor
(SED)
N
R2
R2
(X = Ts, Benzyl, CH2CO2Et)
Scheme 1. Representative strategies for radical generation.
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coupling product 4ai. Notably, arylation at the more hindered
(a) Initial microscale (10 mol) screening
I
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C3 position was not observed. These results indicate that benꢀ
zyne intermediates are not necessary in these coupling reacꢀ
tions. Coupling of 2ꢀiodonaphthalene (2j) with ketamine 1a
afforded product 4aj in 35% yield and product 4aj’ in 11%
yield. From this reaction mixture, we were also able to isolate
naphthalene in 20% yield. We hypothesize that naphthalene is
derived from hydrogen atom transfer (HAT) to a 2ꢀnaphthyl
radical intermediate from the DME solvent. This result is
significant, because it provides support for the existence of
isolated aryl radical intermediates in these transformations.
Ph
Ph
Ph
N
Ph
Ph
N
Base (3 equiv)
+
4aa
Solvent, rt, 6 h
Conc.
Ph
1a
tBu
2a
tBu
Solvent: THF, CPME, DME, MTBE, toluene, cyclohexane
Base: LiN(SiMe3)2 and NaN(SiMe3)2
Concentration: 0.1 M and 0.2 M
Ph
Ph
C1
N
9
(b) Lab-scale (0.4 mmol) optimization
I
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Ph
+
4aa
C1-arylation
Table 1. Scope of arylation.a,b
55% yield
Ph
Ph
NaN(SiMe3)2 (3 equiv)
DME, rt, 4 h, 0.2 M
N
C3
+
C1
tBu
Ph
1a
tBu
tBu
2a
4aa'
C3-arylation
16% yield
Ph
H
C3
N
Ph
Ph
Scheme 3. Reaction optimization of arylation. (a) Initial miꢀ
croscaleꢀscreening, (b) Labꢀscale (0.4 mmol) optimization.
We then turned to the scope of the transition metalꢀfree aryꢀ
lation with different aryl iodides (Table 1). Iodobenzene (2b)
furnished C1ꢀarylation product 4ab in 58% yield and C3ꢀ
arylated 4ab’ in 14% yield. Electronꢀrich 4ꢀiodoanisole (2c)
coupled with 1a in 50% yield at the C1 position (4ac) and
13% yield at the C3 position (4ac’). Using MTBE as solvent,
electronꢀwithdrawing 1ꢀbromoꢀ4ꢀiodobenzene (2d) coupled
with 1a affording product 4ad (C1) in 43% yield and 4ad’
(C3) in 14% yield. Under the same conditions, coupling beꢀ
tween 1ꢀchloroꢀ4ꢀiodobenzene (2e) and 1a led to C1ꢀarylated
product 4ae and C3ꢀarylated product 4ae’ in 44% and 15%
yield, respectively. We observed that these aryl iodides unꢀ
derwent reaction with high chemoselectivity at the C–I sites,
indicating that 2ꢀazaallyl anions preferentially reduce aryl
iodides over aryl chlorides or aryl bromides under these reacꢀ
tion conditions. It is noteworthy that aryl iodides 2d and 2e are
Bunnett and Crearys’ dihalide mechanistic probes (see the
mechanistic study section).15 The fluoro analogue, 4ꢀ
fluoroiodobenzene (2f), coupled with 1a to give 4af and 4af’
in 48% and 13% yield, respectively. The arylation also preꢀ
ceded with metaꢀsubstituted aryl iodides (3ꢀOMe, 2g) to give
C1ꢀarylated product 4ag in 47% yield and its C3ꢀarylated
counterpart 4ag’ in 17% yield.
We next wanted to address the possibility of benzyne forꢀ
mation under the basic conditions for the arylation reaction.
We therefore examined 2ꢀiodotoluene and 2ꢀiodoꢀ1,3ꢀ
dimethylbenzene. If benzyne intermediates were involved in
the reactions in Table 1, the benzyne generated from 2ꢀ
iodotoluene would likely undergo reaction at the less hindered
position of the benzyne and generate product with a 3ꢀtolyl
group. Furthermore, 2ꢀiodoꢀ1,3ꢀdimethylbenzene would be
expected to be unreactive if benzyne intermediates are reꢀ
quired for the reactions in Table 1. In the event, 2ꢀiodotoluene
participated in the arylation to afford the 2ꢀtolyl product, albeit
in 21% yield after 4 h. When the reaction time was extended
to 9 h, product 4ah was formed in 46% yield. Interestingly, C3
arylated 4ah’ was isolated in 15% yield. More hindered 2ꢀ
iodoꢀ1,3ꢀdimethylbenzene (2i) furnished 44% yield of the
aReactions were conducted on a 0.4 mmol scale using 2 equiv.
ketimine, 1 equiv. aryl iodide and 3 equiv. NaN(SiMe3)2 at 0.2
M. Isolated yields after chromatographic purification. bMTBE.
cReaction time 9 h.
2.2 Transition Metal-free C(sp3)–C(sp3) Coupling to 2-
Azaallyl Species. Given that the 2ꢀazaallyl anion is capable of
reacting with aryl iodides, presumably by initial SET, we
wanted to probe its reactivity with alkyl halides, which are
generally more difficult to reduce.14 We selected neopentyl
iodide (3a) as the model alkylation electrophile because its
steric hindrance precludes an SN2 coupling pathway.10 The
same parameters employed in Scheme 3a were applied to the
10 ꢁmol scale screening of ketimine 1a with neopentyl iodide
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(3a; rt for 6 h, Scheme 4a). We were pleased and surprised to tion and/or isomerization to the other ketimine tautomer was
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5
6
7
8
find that the alkylation reaction proceded. The leading result
from the HTS for alkylation was with MTBE and
NaN(SiMe3)2 at 0.1 M concentration. In a similar fashion, we
next monitored reaction profiles of alkylation at 10 ꢁmol scale
and results revealed that coupling of neopentyl iodide 3a with
ketimine 1a was completed in 2 h (see Figure S2 of Supportꢀ
ing Information for details). To our delight, lab scale reaction
(0.1 mmol) under the optimal conditions gave alkylation prodꢀ
uct 5aa in 95% isolated yield (Scheme 4b). Notably, C3ꢀ
alkylation was not observed under these reaction conditions.
detected in the substrates listed in Table 1 and 2.
Table 2. Scope of alkylation.a,b
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Scheme 4. Reaction optimization of arylation. (a) Initial miꢀ
croscaleꢀscreening, (b) Labꢀscale (0.1 mmol) optimization.
aReactions were conducted on a 0.1 mmol scale using 2 equiv.
ketimine, 1 equiv. alkyl iodide and 3 equiv. NaN(SiMe3)2 at
0.1 M. Isolated yields after chromatographic purification.
bToluene.
With the optimal conditions, we investigated the scope of
the alkylation reaction with respect to unactivated and hinꢀ
dered alkyl halide electrophiles (Table 2). We were concerned
that tertꢀbutyl iodide would undergo rapid E2 elimination
under the basic reaction conditions. Nevertheless, tertꢀbutyl
iodide reacted to afford the alkylation product 5ab in 53%
yield. Furthermore, both 1ꢀiodoꢀ1ꢀmethylcyclohexane 3c and
1ꢀbromoꢀ1ꢀmethylcyclohexane 3d successfully coupled with
ketimine 1a, leading to products 5ac in 41% and 37% yield,
respectively. Aminoadamantane derivatives are widely present
in medications to fight Parkinson’s disease,16 antiviral
agents,17 and NꢀmethylꢀDꢀaspartate (NMDA) receptor antagꢀ
onists.18 To our delight, 1ꢀadamantyl iodide 3e underwent
coupling with ketimine 1a in excellent yield (93%). The same
product could also be synthesized from 1ꢀadamantyl bromide
(3f) in 61% yield with toluene as solvent. Considering the
value of aminoadamantane derivatives, we continued surveyꢀ
ing the coupling of 1ꢀadamantyl iodide 3e with a few
ketimines. tertꢀButyl substituted triaryl ketimine 1b underwent
coupling with 1ꢀadamantyl iodide 3e in 58% yield. The relaꢀ
tively electronꢀrich (4ꢀC6H4ꢀOMe) ketimine 1c provided prodꢀ
uct 5ce in 68% yield. Coupling electronꢀwithdrawing (3ꢀC6H4ꢀ
CF3) ketimine 1d with 3e proceeded in 80% yield. Heterocyꢀ
clic 2ꢀfuryl (1e) and 2ꢀthiophenyl (1f) ketimines were also
examined and afforded products 5ee and 5fe in 60 and 85%
yield, respectively. No C3ꢀalkylated products were observed
in the coupling of ketimines with 1ꢀadamantyl halides, preꢀ
sumably due to steric effects. Notably, no product deprotonaꢀ
To test the scalability of our method, we conducted the
gramꢀscale synthesis of heterocyclic product 5fe. Thus,
ketimine 1f was synthesized from amine and benzophenone
imine precursors and dried under vacuum.19 Using the unpuriꢀ
fied imine, the alkylation reaction was performed with 1ꢀ
adamantyl iodide 3e as described above leading to product 5fe
in 82% yield (1.69 g, Scheme 5a). Hydrolysis of ketimine 5fe
was also performed to afford 1ꢀadamantyl(thiophenꢀ2ꢀ
yl)methanamine (6fe) in 99% isolated yield (Scheme 5b).
Scheme 5. (a) Gramꢀscale oneꢀpot synthesis of 5fe through a
telescoped imine synthesis/alkylation process. (b) Ketimine
hydrolysis.
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formation supports the existence of 2ꢀazaallyl radicals under
3. Mechanistic Studies
1
the reaction conditions.
In our initial study of the transition metalꢀfree vinylation of
2ꢀazaallyl species (Scheme 2a),9 our computational work
pointed to substrate dependent mechanisms. Reactions were
proposed to proceed through either an anionic vinyl substituꢀ
tion pathway with 2ꢀazaallyl anions and βꢀbromostyrenes or
by the addition of 2ꢀazaallyl radicals to the C=C bonds of
vinyl halides.20 The reactions presented herein with aryl ioꢀ
dides and alkyl halides, however, must proceed by different
pathways and are most easily rationalized by SET from the 2ꢀ
azaallyl anion (A1, Scheme 6) to either the aryl iodide or alkyl
halide to generate radical intermediates. The transient arꢀ
yl/alkyl radicals can react with the 2ꢀazaallyl radical (A0,
proposed to be a persistent radical) to afford the coupled prodꢀ
uct (Path a, Scheme 6). Or, they might instead react with
azaallyl anion (A1) to give a ketiminyl radical anion (A2),
which then reduces Ar–I or Alkyl–X to give product and Ar•
/Alkyl• in an SRN1 process (Path b, Scheme 6).21
(a)
2
3
4
5
6
7
8
9
Ph
Ph
N
I
Ph
Ph
N
NaN(SiMe3)2 (3 equiv)
Tol, rt, 6 h, 0.2 M
Ph
+
Ph
1a
(2 equiv)
2k
(1 equiv)
4ak, 96% yield
dr = 1:1
Proposed intermediates:
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(b)
Ph
Ph
Ph
N
I
Ph
N
NaN(SiMe3)2 (3 equiv)
DME, rt, 6 h, 0.2 M
Ph
+
Ph
N
N
Me
1a
(2 equiv)
Me
2l
(1 equiv)
4al, 88% yield
dr = 1:1
Proposed intermediates:
N
Ph
Ar
N
N
–
2-azaallyl
Me
Me
anion (A1)
A1
Ph
H
Scheme 7. Radical clock study in the arylation.
path b
–
Ph
Ar
H
N
Ar–I
Ar
SET
Alkyl–X
I
Alkyl
Ph
Ar/Alkyl
Ph
NaN(SiMe3)2 (3 equiv)
DME, rt, 6 h, 0.2 M
Ph
N
+
radical anion
A2
Ph
N
Ph
Ar
N
SET
azaallyl
Me
2l
(0.1 mmol)
anion (A0)
1a
(0.2 mmol)
Ph
H
Ar–I
Alkyl–X
path b
path a
Ph
N
Ph
Ph
N
Ph
N
Ph
N
Ph
N
Ph
Ph
Ph
+
+
Ph
Ph
Ph
Ar
H
Ph
Ph
Ph
Ph
N
N
Me
4al
rac-dimer (7a)
meso-dimer (7a')
Ph
Ar/Alkyl
0.088 mmol
0.0075 mmol
0.015 mmol
Scheme 6. Possible reaction mechanisms. Path a: radicalꢀ
radical coupling. Path b: SRN1 mechanism.
via:
Ph
Ph
N
dimerization
To investigate the SET process, we undertook a series of
experiments with radical clock substrates that undergo rapid
cyclization in the presence of radicals. In order to probe for
aryl radicals in the coupling of ketimine 1a with aryl iodides,
radical clock 2k was employed.22 In the presence of ketimine
1a, 2k was treated with 3 equiv of NaN(SiMe3)2 at rt (Scheme
7). The cyclized product 4ak was obtained in 96% yield as a
1:1 mixture of diastereomers. A second radical trap based on
Nꢀallylꢀ2ꢀiodoꢀNꢀmethylaniline was subjected to similar conꢀ
ditions and again gave rise to cyclized product in 88% yield.
These results confirm the intermediacy of radicals in these
reactions.
7a + 7a'
Ph
H
Scheme 8. Dimerization of 2ꢀazaallyl radicals.
We next performed parallel mechanistic studies using an alꢀ
kyl radical clock 3g.22 As outlined in Scheme 9, treatment of
ketimine 1a with NaN(SiMe3)2 in the presence of alkyl iodide
3g with a pendent alkene resulted in formation of 5ag in 95%
yield as a 1:1 mixture of diastereomers. The formation of the
cyclized product confirms that the alkylation reaction, as with
the arylation process, proceeds via a radical mechanism.
In the coupling of 1a with Nꢀallylaniline 2l, we observed the
formation of racꢀ and mesoꢀdiꢀketimines (See Figure S7 of
Supporting Information), which we proposed to be derived
from dimerization of 2ꢀazaallyl radicals (Scheme 8). NMR
spectra of the isolated diꢀketimine byproducts matched with
the racꢀ and mesoꢀdiꢀketimines independently prepared by
condensation of the racꢀ and mesoꢀdiamines with benzopheꢀ
none imine (See Figure S3ꢀS6 of Supporting Information).
Such dimers could be observed throughout all of the arylations
and alkylations of 2ꢀazaallyl species described above and their
Scheme 9. Radical clock study in the alkylation with unactiꢀ
vated alkyl iodides 3g.
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In order to further study the role of the 2ꢀazaallyl anion in
which are widely used in probing SRN1 mechanisms.15, 23 In
analogy to Kwong and Lei’s work,23a if the reaction follows
the SRN1 mechanism, aryl radical trapping by the 2ꢀazaallyl
anion would give radical anion Int 1 or Int 1’ (Scheme 11a).
The bromo or chloro group of Int 1 should then dissociate to
radical intermediate Int 2, which could undergo HAT to give
product 4ab or couple with another equivalent to 2ꢀazaallyl
anion to afford bisꢀcoupled products 9 (Scheme 11a). As we
reported in Table 1, coupling of 1ꢀbromoꢀ4ꢀiodobenzene (2d)
and 1ꢀchloroꢀ4ꢀiodobenzene (2e) with ketimine 1a afforded
4ad and 4ae in 43% and 44% yields with Br and Cl retained in
the products. Neither the dehalogenation product nor the bisꢀ
ketimine adduct were observed in the reaction. We interpret
this observation as evidence against an SRN1 mechanism.
Moreover, naphthalene isolated from coupling between 2ꢀ
iodonaphthalene 2j and ketimine 1a support the existence of
radical intermediate Int 4, which favors the radicalꢀradical
coupling pathway (Scheme 11b). Overall, the data points to an
SET process followed by a radicalꢀradical coupling mechaꢀ
nism as accounting for the unique reactivity of arylation and
alkylation of 2ꢀazaallyl species.
1
2
3
4
5
6
7
8
the SET process, and to shed light on the origin of diꢀ
ketimines 7a and 7a’, 2ꢀazaallyl anion stabilized by [K(18ꢀ
crownꢀ6)]+ cation (8) was synthesized and isolated through
recrystallization (Scheme 10a). Mixing salt 8 and aryl iodide
2f under the same conditions used in Table 1 led to product
4af in 12% assay yield (AY, Scheme 10b, i). Moreover, the
formation of diꢀketimines 7a and 7a’ were observed in 6 and
15% AY, respectively. As there is no neutral ketimine 1a
present at the start of the reaction, we propose that diꢀ
ketimines are derived from the homoꢀcoupling of 2ꢀazaallyl
radicals. To understand the low yields, control experiments
using ketimine 1a, KN(SiMe3)2 as base and 18ꢀcrwonꢀ6 as
additive were conducted. Assay yields of 20% 4af, 4% 7a and
15% 7a’ were observed with KN(SiMe3)2 in the absence of
crown ether (Scheme 10b, ii). Addition of 18ꢀcrownꢀ6 to the
solution of KN(SiMe3)2 and ketimine caused the yield of 4af
to drop to 10% with 8% 7a and 22% 7a’ observed (Scheme
10b, iii). These results support our hypothesis that the 2ꢀ
azaallyl anion behaves as an electron donor in the SET. The
synthesis of the sodium salt of 2ꢀazaallyl anion following the
procedure employed with the potassium salt in Scheme 10a,
but without addition of crown ether to facilitate the recrystalliꢀ
zation, was not successful. We are currently probing the origin
of the impact of the crown ether on the reactivity of the 2ꢀ
azaallyl anions, which will be the focus of a subsequent study.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
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39
40
41
42
43
44
45
46
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49
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60
–
(a)
I
Ph
Ph
Ph
Ph
Ph
Ph
N
N
2-azaallyl
anion
2-azaallyl
anion
–
SRN1
X
X
X
Int 1'
X
Int 1
(X = Br, Cl)
2-azaallyl
radical
–
-X
Ph
Ph
N
Ph
Ph
Ph
N
Ph
N
Ph
HAT
Ph
Ph
Int 2
X
3ab
Not observed
Obseved:
4ad, X = Br, 43% yield
4ae, X = Cl, 44% yield
2-azaallyl
anion
Ph
Ph
N
–
Ph
Ph
N
Ph
Ph
Ph
Ph
Ph
N
Ph
Ph
N
Ph
9
Int 3
Not observed
(b)
I
2-azaallyl
anion
HAT
Int 4
20% yield
2j
2-azaallyl
radical
Ph
Ph
Ph
N
Scheme 10. (a) Synthesis of 2ꢀazaallyl anion 8. (b) Study of
coupling of 2ꢀazaallyl anion salt 8 with aryl iodide 2f.
4aj
35% yield
The radical clock studies and 2ꢀazaallyl anion coupling
studies support the SET process. We next focused on two
possible C–C bond forming pathways (radicalꢀradical coupling
vs. SRN1, paths a and b in Scheme 6). The goal of this study
was to probe the radical anion intermediate (A2, Scheme 6) to
determine if the reaction follows the SRN1 mechanism. Hence,
we employed Bunnett and Crearys’ dihalides [1ꢀbromoꢀ4ꢀ
iodobenzene (2d) and 1ꢀchloroꢀ4ꢀiodobenzene (2e) of Table 1],
Scheme 11. (a) Probe of SRN1 mechanism using Bunnett and
Crearys’ 1,4ꢀdihalobenzenes. (b) Reaction of 2ꢀ
iodonaphthalene.
4. Conclusion
In summary, we report a unique radical generation strategy
enabled by simple organic reagents, 2ꢀazaallyl anions, which
are a new class of superꢀelectron donors (SEDs). The SED
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Molander, G. A., Nat. Protoc. 2017, 12, 472; (h) Romero, N. A.;
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iodides and tertiary alkyl halides to aryl and alkyl radicals.
After SET from the 2ꢀazaallyl anion, the resulting 2ꢀazaallyl
radical behaves as a persistent radical that then traps both aryl
and alkyl radicals forming C–C bonds. Such radical coupling
processes occur under mild conditions and do not require
special initiators, light or photocatalysts. This radical coupling
method enables facile access to diarylmethyl and benzylalkyl
amines that are of great importance in medicinal and pharmaꢀ
ceutical chemistry. Diketimine dimer products isolated from
the reaction are proposed to arise via homoꢀcoupling of 2ꢀ
azaallyl radicals. Three radical clock studies, 2ꢀazaallyl anion
coupling studies, and Bunnett and Crearys’ dihalide probes
confirm the intermediacy of radical intermediates and lend
further support to a radical coupling mechanism. Further exꢀ
tension of this unique radical coupling mechanism to suitable
reaction partners is underway.
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures and characterization data for all comꢀ
pounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
pwalsh@sas.upenn.edu
ACKNOWLEDGMENT
P. J. W. thanks the National Science Foundation (CHEꢀ1464744)
and National Institutes of Health (NIGMS 104349) for financial
support. J. J. C. thanks the National Natural Science Foundation
of China (NSFCꢀ21372159) for financial support. A. P.ꢀE. thanks
MINECO, Spain, for predoctoral and mobility fellowships. G.D.
and X. Y. thank the Excellent Young Talents program of Yunnan
University.
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