Transition-metal-free C(sp3)-H/C(sp3)-H dehydrogenative coupling of saturated heterocycles with: N-benzyl imines

Article abstract of DOI:10.1039/d0sc00031k

A unique C(sp3)-H/C(sp3)-H dehydrocoupling of N-benzylimines with saturated heterocycles is described. Using super electron donor (SED) 2-azaallyl anions and aryl iodides as electron acceptors, single-electron-transfer (SET) generates an aryl radical. Hydrogen atom transfer (HAT) from saturated heterocycles or toluenes to the aryl radical generates alkyl radicals or benzylic radicals, respectively. The newly formed alkyl radicals and benzylic radicals couple with the 2-azaallyl radicals with formation of new C-C bonds. Experimental evidence supports the key hydrogen-abstraction by the aryl radical, which determines the chemoselectivity of the radical-radical coupling reaction. It is noteworthy that this procedure avoids the use of traditional strong oxidants and transition metals. This journal is

Full text of DOI:10.1039/d0sc00031k

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Transition-Metal-Free C(sp3)–H/C(sp3)–H Dehydrogenative
Coupling of Saturated Heterocycles with N-Benzyl Imines
Zhengfen Liu,†a Minyan Li,*†b Guogang Deng,a Wanshi Wei,a Ping Feng,a Quanxing Zi,a Tiantian Li,a,c
Received 00th January 20xx,
Accepted 00th January 20xx
Hongbin Zhang,*a Xiaodong Yang,*a & Patrick J. Walsh*b
DOI: 10.1039/x0xx00000x
A unique C(sp3)–H/C(sp3)–H dehydrocoupling of N-benzylimines with saturated heterocycles is described. Using super
electron donor (SED) 2-azaallyl anions and aryl iodides as electron acceptors, single-electron-transfer (SET) generates an aryl
radical. Hydrogen atom transfer (HAT) from saturated heterocycles or toluenes to the aryl radical generates alkyl radicals or
benzylic radicals, respectively. The newly formed alkyl radicals and benzylic radicals couple with the 2-azaallyl radicals with
formation of new C–C bonds. Experimental evidence supports the key hydrogen-abstraction by the aryl radical, which
determines the chemoselectivity of the radical-radical coupling reaction. It is noteworthy that this procedure avoids the use
of traditional strong oxidants and transition metals.
Pd catalysts, presumably through
a concerted metalation-
deprotonation (CMD) mechanism.6 These reactions are quite
challenging, and even with highly optimized directing groups, require
Introduction
Cyclic ethers and amines are fundamental structural motifs in nature
and are found in a vast number of bioactive compounds, small-
molecule drugs1 and functional materials. As such, tremendous
effort has been devoted to their synthesis.2 Despite significant
progress in the synthesis of saturated heterocycles, approaches to
their C–H activation and subsequent C–C bond formation remain in
great demand. The high C–H bond dissociation energies (~90−100
kcal/mol)3 and low acidity (pKa’s usually >45) of saturated
heterocycles have significantly hindered the development of
methods to functionalize these robust C(sp3)−H bonds.
o
very high reaction temperatures (150 C). Since 2011, visible-light-
induced C–H bond functionalization has emerged as a powerful
strategy for the activation of heterocycles,7 as shown in the
representative example8 in Scheme 1b. Mechanistically, photoredox-
driven single-electron transfer and α-C–H deprotonation enabled the
activation of C–H bonds adjacent to nitrogen. Other strategies to
activate the C(sp3)–H bonds of heterocycles include application of
hydrogen atom transfer (HAT).9 For example, Porta et. al developed
a radical coupling where HAT of aryl radical from THF was the key
step for radical generation
. More recently, Doyle and co-workers found that photolysis of a
Ni(III)–Cl intermediate generated chlorine radicals that underwent
HAT with THF10 to achieve a unique THF arylation (Scheme 1c). In the
same year, MacMillan and co-workers11 used photoredox catalysis to
oxidize 3-acetoxyquinuclidine to the radical cation, which promoted
HAT with cyclic amines (Scheme 1c). Wu’s team12 developed a Eosin
Y photocatalytic HAT activation of tetrahydrofurans.
Recently, a variety of tactics have been introduced to tackle the
functionalization of saturated heterocycles. Directing group
facilitated C(sp3)−H activation has evolved into an enabling strategy
to functionalize heterocycles. Recently, Yu4 and Sanford5 developed
the arylation of nitrogen-containing heterocycles with the aid of
thioamide and perfluorinated amide directing groups (Scheme 1a).
In these examples, the C–H bonds of the substrates were cleaved by
a. Key Laboratory of Medicinal Chemistry for Natural Resources, Ministry of
Education and Yunnan Province, State Key Laboratory for Conservation and
Utilization of Bio-Resources in Yunnan, School of Chemical Science and Technology,
Yunnan University Kunming, 650091 (P. R. China).E-mail: xdyang@ynu.edu.cn,
zhanghb@ynu.edu.cn
b. Roy and Diana Vagelos Laboratories Penn/Merck Laboratory for High-Throughput
Experimentation Department of Chemistry, University of Pennsylvania 231 South
34th Street, Philadelphia, PA (USA) E-mail: pwalsh@sas.upenn.edu,
liminyan@sas.upenn.edu
c. Department of Soil and Water Science, University of Florida. 2181 McCarty Hall A,
Gainesville, FL 32611-0290
† These authors contributed equally to this work.
Electronic supplementary information (ESI) available. CCDC 1943984 and CCDC
1944046. For ESI and crystallographic data in CIF or other electronic format See
DOI: 10.1039/x0xx00000x
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possessing weaker C(sp3)–H bonds. Such a HAT would generate
new radicals that we envisioned would couple with the 2-
a. Directed C(sp3)–H activation.
Yu, 2015
View Article Online
DOI: 10.1039/D0SC00031K
azaallyl radical (Scheme 2c). The net result would be a cross-
dehydrogenative coupling reaction17 between two C(sp3)–H
bonds to form a C(sp3)–C(sp3) bond under mild and transition
metal-free conditions. Although much of this study is dedicated
to mapping the reactivity of the HAT and coupling steps, the
synthetic utility of this process is also explored. The products of
these reactions are heterocyclic methylamine derivatives,
which are of importance in the pharmaceutical industry,18 but
would be otherwise difficult to access under mild conditions.
Ar1
tBu
Ar2
1) Cat. Pd,Ar1B(OH)2
N
N
2) Cat. Pd, Ar2B(OH)2
S
tBu
S
Sanford, 2016
NHArF
Ar
NHArF
O
Cat. Pd
ArI
N
N
O
Me Me
Me Me
Herein, we report a unique activation strategy of relatively
inert heterocyclic C(sp3)–H bonds. The strategy is founded on
the reducing character of 2-azaallyl anions and the HAT
abstraction feature of aryl radicals (Scheme 2c). To inhibit the
aryl radical from coupling with the 2-azaallyl radical, as in
Scheme 2a, a sterically protected aryl radical precursor was
employed and found to undergo single-electron-transfer with
diverse 2-azaallyl anions. The resulting hindered aryl radical
effectively abstracts hydrogen from the heterocycles’ C(sp3)–H,
generating alkyl radicals in a reaction akin to an intermolecular
b. Visible-light-induced C(sp3)–H activation.
MacMillan, 2011
CN
O
via
O
O
Ir(ppy)3, hv
NaOAc
+
N
N
N
Ar
Ph
Ph
Ph
CN
Ar = 4-C6H4-CN
c. Photocatalytic HAT promoted C(sp3)–H activation.
via
Cl
Doyle, 2016
Ar–Cl
photocatalyst
Cat. Ni
a. Radical coupling strategies enabled by azaallyl anions.
hv
+
Ar
NH2
Aryl
or
Cl
Ph
(L)
Ni Ar
Ar
Ph
N
Ar
N
Ar
K3PO4, hv
O
O
Radical-radical
coupling
–
Ph
H
Ph SET
H
work-up
R–I
R = Aryl, Alkyl
R
MacMillan, 2016
[IrIII]
AcO
Ar
NH2
Alkyl
3-acetoxyquinuclidine
Ar
N
Ar–Br
N
as abstractor
+
NiBr2, ligand
hv
N
NH2
Ar
Boc
b. Tandem cyclization-coupling reactions.
Boc
1) base
I
Scheme
heterocyclic alkanes.
1
General strategies in C(sp3)–H activation of
Ph
Ar
N
+
2) hydrolysis
O
O
Ph
R
R
These impressive and impactful advances inspired us to
ponder the prospect of exploiting so called super electron
donors (SED)13 to functionalize C(sp3)–H bonds in the absence
of transition metals or photoredox catalysts. Our team has been
pursuing the fascinating chemistry of 2-azaallyl anions,14 which
are easily generated by deprotonation of readily accessible N-
benzyl benzophenone imines.15 We identified the inherent
reducing nature of the highly colored 2-azaallyl anions, which
enabled the introduction of a series of transition metal free
coupling reactions (Scheme 2a). In its simplest form, the 2-
azaallyl anion reduces aryl iodides or tertiary alkyl iodides and
bromides to generate aryl or alkyl radicals and the 2-azaallyl
radical.14f These two radicals then undergo selective coupling
with each other to generate a new C–C bond, providing
diarylmethyl amines and benzylic amines after hydrolysis. More
sophisticated radical cyclization/coupling reactions to afford
benzofurylethylamines (Scheme 2b) and their isochromene
analogues have also been accomplished.14a, 14b Given the high
reactivity of aryl radicals, we hypothesized that if the aryl
radical16 coupling with the 2-azaallyl radical in Scheme 2a could
be sufficiently slowed, perhaps the aryl radical would
preferentially undergo HAT with other organic compounds
c. This work
Ph
X
H
R
–
Aryl
X = C, N, O
HAT
Ph
N
Ph
Base
SET
Aryl
H
Ph
R
Ph
R
+
Aryl–I
I
X
Ph
N
Ar
Ph
N
Ph
R = H, Ph
Radical-radical
coupling
Ar–I =
X
R
Ph
tBu
Ph
N
Ar
Scheme 2 Application of 2-azaallyl anions in radical coupling
reactions. a) Radical coupling strategies enabled by 2-azaallyl
anions as super-electron-donors. b) Tandem reactions for the
synthesis of heterocycles. c. Radical relay design for the
synthesis of heterocyclic amine derivatives.
2 | Chem. Sci., 2020, xx, xx-xx
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3a-3h
(3 equiv)
View Article Online
O
Ph
radical translocation process.19 The coupling of alkyl radicals
and 2-azaallyl radicals furnishes valuable heterocyclic benzylic
amines. This HAT protocol employs a sacrificial aryl radical to
overcome the limitation of redox potentials and acidities.
Finally, we disclose that toluene derivatives can also be
activated and coupled with 2-azaallyl intermediates in this
transformation.
DOI: 10.1039/D0SC00031K
LiN(SiMe3)2 (3 equiv)
24 h, 0.1 M, 80 oC
Ph
O
Ph
N
Ph
Ph
N
4aa
Ph
2a
, solvent
I
1a
I
I
I
tBu
OMe
Cl
3a
3b
3c
3d
4aa
, 35%
dr = 3.5:1
4aa
dr = 3.5:1
4aa
dr = 3.6:1
, 46%
, 35%
4aa
dr = 3.2:1
Results and Discussion
, 56%
With the mechanistic hypothesis in Scheme 2c in mind, we first
investigated the aryl iodides as precursors to hydrogen
abstractors. The benzophenone imine 1a and tetrahydrofuran
solvent (2a) were chosen as the model substrates for the
I
I
I
iPr
iPr
tBu
I
3h
o
tBu
3f
iPr
3g
coupling studies at 80 C (Table 1). When iodobenzene 3a was
4aa,
0%
3e
used, the target coupling product was obtained in an overall
35% assay yield (AY, determined by 1H NMR integration against
an internal standard). We next examined substituent effects on
the aryl motif. The electron donating alkyl of 1-(tert-butyl)-4-
iodobenzene (3b) resulted in an increase in the overall assay
yield to 56%. The more electron donating 4-OMe (3c) or
halogenated 4-Cl (3d) exhibited decreased AY of 46 and 35%,
respectively. Although it is known that the phenyl radical will
react with THF very quickly (k =4.8 X 106 M–1 sec–1),20 coupling
products derived from reaction of the aryl radical with the 2-
azaallyl radical were still observed (10–20% AY). To discourage
the direct coupling event, sterically hindered substrates
possessing two ortho-substituents were examined. While 2-
iodo-1,3-dimethyl benzene (3e) afforded little improvement
(combined AY of 43%), addition of a tert-Bu group, which
proved beneficial in the reaction of 3b vs. 3a, again resulted in
an increase in the AY. Thus, 5-(tert-butyl)-2-iodo-1,3-
dimethylbenzene (3f) reacted to generate the coupling
products with a combined AY of 59%. Further increasing the size
of the flanking substituents on the aryl radical to isopropyl (3g)
led to a combined AY of 48%. As might be expected, neopentyl
iodide (3h) as HAT precursor did not participate in the C–H
activation pathway, implying that sacrificial HAT abstractors
derived from C(sp3)–X bonds are not viable in our approach.
4aa
4aa
, 43%
dr = 3.6:1
4aa
, 48%
dr = 3.6:1
, 59%
dr = 3.4:1
a Reactions conducted on a 0.1 mmol scale. Assay yield determined by
1H NMR spectroscopy of the crude reaction mixtures using C2H2Cl4 as an
internal standard.
Based on these initial studies, we continued the optimization
with aryl iodide 3f as the hydrogen abstractor precursor. We
next set out to determine the optimal reaction time and found
that decreasing from 24 h to 1 h led to an increase in the AY
from 49 to 73% (Table 2, entry 1–5). Replacing LiN(SiMe3)2 with
NaN(SiMe3)2 led to an overall 81% AY (entry 6). For reasons that
are not clear, using KN(SiMe3)2 resulted in formation of a
complex mixture with no expected product detected (entry 7).
Under the same conditions with NaN(SiMe3)2 but increasing
or decreasing the temperature resulted in diminished AY
(entries 8–9). Finally, tuning the concentration to 0.2 M and
decreasing the aryl iodide 3f to 2 equiv afforded product 4aa in
overall 84% assay yield and 80% isolated yield (dr = 1.7:1, entry
11).
Table 2 Optimization studies of the coupling of ketimine 1a and
tetrahydrofuran 2a.a,b
Ph
O
MN(SiMe3)2 (3 equiv)
Time, 0.1 M, T.
Ph
O
Table 1 Effect of aryl iodide electron-acceptors and hydrogen
Ph
N
Ph
abstractor precursors.a
Ph
N
4aa
Ph
1a
Entry M =
3f
2a
(3 equiv)
T / oC
, solvent
Time / h
Yield of 4aa / %
1
2
Li
Li
24
12
6
80
80
80
80
80
80
80
100
60
80
80
49 (dr = 3.4:1)
58 (dr = 2.8:1)
64 (dr = 2.7:1)
68 (dr = 2.8:1)
73 (dr = 2.8:1)
81 (dr = 1.6:1)
Complex mixtue
52 (dr = 1.5:1)
69 (dr = 1.7:1)
81 (dr = 1.7:1)
3
Li
4
Li
3
5
Li
1
6
Na
K
1
7
1
8
Na
Na
Na
Na
1
9
1
10c
11c,d
1
1
84 (80)e (dr = 1.7:1)
a Reactions conducted on a 0.1 mmol scale. Assay yields determined by
1H NMR spectroscopy of the crude reaction mixture using C2H2Cl4 as an
b
internal standard. Diastereomeric ratio (dr) of alfa coupling
product between 1a and 2a determined by HPLC. The beta
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Chem. Sci., 2020, xx, xx-xx | 3
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coupling product was observed in trace amounts by HPLC but
the dr could not be determined. 0.2 M. 3f (2 equiv). Isolated
yield and diastereomeric ratio after chromatographic purification.
Chemical Science
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NaN(SiMe3)D2OI: 10.1039/D0SC00031K
c
d
e
Ph
X
(3 equiv)
X
Ph
Ph
N
Ph
1 h, 0.2 M, 80 oC
Ph
N
Ph
H
In an effort to explore the scope of this transformation, we
first examined saturated heterocycles. In general, we found that
a wide variety of substrates with ring sizes ranging from 4 to 6
underwent the C–H functionalization/coupling process (54–
87% isolated yields). The scope of the reaction is outlined in
Table 3. With more expensive substrates, we explored the
coupling reactions in benzene solvent. Thus, 5 equiv of 3,3-
dimethyloxetane (2b) coupled with ketimine 1a in 56% yield
(2.8:1 dr). As for the dioxolanes, 1,4-dioxane (2c) furnished 54%
yield (1.4:1 dr) of the product isomers. The acyclic analogue 1,2-
dimethoxyethane (DME, 2d) was found to couple with ketimine
1a in 73% yield exclusively at the methylene. The symmetrical
1,3,5-trioxane 2e participated in the coupling reaction to furnish
the protected α-amino aldehyde 4ae in 58% yield. We were also
interested in exploring selectivity between C–H’s positioned α
to oxygen vs. α to nitrogen. We were pleased to find that
coupling of N-methylmorpholine 2f provided the coupling
product 4af in 55% yield, with coupling observed only adjacent
to the amino group (3.2:1 dr). Likewise, N-methyl pyrrolidine 2g,
N-phenyl pyrrolidine 2h and N-phenyl piperidine 2i coupled in
56, 81 and 87% yields (1:1, 4.1:1 and 1.9:1 dr), respectively.
Moreover, N-methyl pyrrole 2j afforded product 4aj in 77%
yield. Finally, 5 equiv of N,N-dimethylaniline (2k) in benzene
coupled with ketimine 1a in 58% yield. These latter two
examples highlight the potential utility of this chemistry for the
synthesis of diamines. Coupling products with the following H-
atom donor either failed or gave trace products: DMF, DMA,
N,N-dimethylbenzamide and 1,3-dimethylimidazolidin-2-one
afforded only tract product. Sulfur-containing substrates, such
as tetrahydrothiophene and DMSO did not lead to coupling
products under the standard conditions.
2a-2k
1a
4aa-4ak
3f
(2 equiv)
X = O, N
O
O
O
O
Ph
Ph
Ph
Ph
N
4aa
Ph
80%
dr = 1.7:1
Ph
N
Ph
56%
Ph
N
Ph
4abb
4ac
54%
dr = 1.4:1
dr = 2.8:1
O
O
O
Ph
N
O
N
N
O
O
Ph
Ph
Ph
Ph
Ph
73%
dr = 1.5:1
Ph
Ph
Ph
Ph
Ph
N
Ph
4ad
4ae
4af
55%
dr = 3.2:1
58%
N
N
N
Ph
Ph
Ph
Ph
Ph
N
Ph
N
Ph
56%
dr = 1:1
N
Ph
87%
dr = 1.9:1
4aib
4ag
4ah
81%
dr = 4.1:1
Ph
N
N
Ph
Ph
Ph
N
Ph
Ph
N
4aj
Ph
4akb
58%
77%
a
Reactions conducted on 0.6 mmol scale using 1 equiv of 1a. Isolated
yields and diastereomeric ratios after chromatographic purification.
Benzene was used as the solvent with 5 equiv substrate.
b
Table 3 Scope of saturated heterocycles.a
Encouraged by the results with saturated heterocycles, we
selected tetrahydrofuran 2a as coupling partner and
investigated the imine scope. As shown in Table 4, the reaction
proceeded with good overall yields (up to 88%). N-Benzyl imines
bearing substituents on the arene, such as 4-tBu (1b), generated
the product 4ba in 81% yield. For electron donating substituents
(1c, 4-OMe and 1d, dioxol), good yields of the coupled products
were obtained (4ca, 84% yield and 4da, 75% yield). The halide
substituted ketimines (1e, 4-F, 1f, 4-Cl and 1g, 4-Br) underwent
coupling with 2a in lower yield (26–58%). Although the reason
for this is not obvious, it could be attributed to the weaker
reducing power of azaallyl anions or destabilization of the 2-
azaallyl radical by the halide. Reaction with biphenyl substrate
(1h) proceeded in 67% yield. Unfortunately, ketimines derived
from heterocyclic benzylic amines (2-, 3-, 4-pyridyl, 2-furanyl
and 2-thiophene) did not afford coupling products under our
standard conditions.
The impact of more sterically hindered N-benzylimines was
next probed. Interestingly, 1-naphthyl (1i) and 2-Me (1j)
ketimines coupled with tetrahydrofuran in high yields (64% and
88%, respectively). Interestingly, tetraphenyl ketimine 1k,
4 | Chem. Sci., 2020, xx, xx-xx
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which has proven unreactive in our previous radical coupling derivatives with 4-Me (1l), 4-OMe (1c) and 2-Me (1j) groups
View Article Online
DOI: 10.1039/D0SC00031K
studies, successfully coupled with 2a in 71% yield. This result were tested and gave yields of 70–74%.
demonstrates that the tetraphenyl 2-azaallyl anion is also
Table 5 Scope of toluene derivatives.a
strongly reducing. We also tested the coupling of tetraphenyl
imine 1k with 1,4-dioxane (2c) and isolated 48% yield of the
coupled product. The final two entries in Table 4 would be
challenging to efficiently prepare by other methods.
NaN(SiMe3)2
R
(3 equiv)
Ph
Ph
R
1 h, 0.2 M
110 °C
Ph
N
Ar
Ph
N
Ar
3f
(2 equiv)
5a-5f
solvent
Table 4 Scope of ketimines.a
1a-1l
6aa-6ld
Ph
R
O
O
Ph
NaN(SiMe3)2 (3 equiv)
1 h, 0.2 M, 80 oC
Ph
N
Ar
Ph
Ph
N
Ar
Ph
N
Ph
R
1b-1k
R = H, Ph
3f
(2 equiv)
2a
, solvent
Ph
N
Ph
Ph
4ba-4kc
Ph
Ph
Ph
N
Ph
6aa
60%
6ab
71%
6ac
70%
O
O
O
Ph
Ph
Ph
Ph
O
O
Ph
N
N
Ph
N
Ph
Ph
Ph
tBu
OMe
Ph
N
Ph
Ph
Ph
N
4ca
dr = 1.4:1
4da
75%
dr = 1.7:1
84%
Ph
N
6afb
Ph
45%
4ba
dr = 1.3:1
81%
6ad
6ae
73%
75%
O
O
O
Ph
Ph
Ph
Ph
Ph
Ph
Ph
N
Ph
X
N
Ph
Ph
N
N
Ph
N
Ph
N
4ea
, X = F, 58% (dr = 1.3:1) 4ha
4ia
67%
64%
dr = 1.7:1
OMe
6cdc
6jd
70%
6ld
74%
73%
4fa
4ga
, X = Cl, 47% (dr = 1:1)
, X = Br, 26% (dr = 1:1)
dr = 1.3:1
a Reactions conducted on 0.3 mmol scale using 1 equiv of 1a–1l. Isolated
yield after chromatographic purification. b 12 h, 150 oC. c 12 h.
O
O
O
O
Ph
N
Ph
Ph
Scalability test and product hydrolysis were next conducted.
We first formed the ketimine 1a in gram scale (Scheme 3a).
Next, treatment of unpurified 1a with tetrahydrofuran 2a and 3
equiv. NaN(SiMe3)2 following the standard procedure afforded
1.17 g of 4aa (86% over 2 steps). It's worth noting that the β-
coupling product was isolated together with α-coupling product
at gram scale (8:1 regioselectivity). Using a single diastereomer
of α-4aa as example, hydrolysis of the product afforded α-7aa
in 96% yield (Scheme 3b).
Ph
Ph
Ph
Ph
Ph
Ph
N
Ph
N
4kcb
4kab
48%
71%
4ja
88%
dr = 1:1
a
Reactions conducted on 0.6 mmol scale using 1 equiv of 1b–1k.
Isolated yields and diastereomeric ratios after chromatographic
purification. b 24 h.
Toluene derivatives are abundant and inexpensive
components of petroleum distillates, and we have been
interested in their functionalization via deprotonation under
relatively mild conditions.21 Here, however, we hypothesized
that the aryl radical intermediate would selectively abstract a
benzylic hydrogen to generate a benzylic radical. Subsequent
radical-radical coupling between the benzyl radical and 2-
azaallyl radical would give rise to benzylated imines. As shown
in Table 5, under slightly modified conditions (110 oC), net
dehydrocoupling of ketimine 1a and toluene 5a gave 60% yield
of the tetrasubstituted imine. Ortho-xylene 5b reacted with 1a
to form the desired product 6ab in 71% yield. Similarly, meta-
xylene 5c and para-xylene 5d afforded products 6ac and 6ad in
70 and 75% yields, respectively. Mesitylene 5e formed the
coupling product 6ae in 73% yield. Sterically hindered 1-
methylnaphthalene 5f underwent coupling with 1a to give 6af
in 45% yield. To demonstrate the versatility, ketimine
a.
Ph
NH2
O
2a
, solvent
THF, 50 oC
Ph
NaN(SiMe3)2
(3 equiv)


Ph
4 mmol
NH
12 h
Remove
solvent
Ph
N
Ph
4aa 86%
1.17 g
 = 8:1
 (dr = 1.7:1)
 (dr = 1.5:1)
Ph
N
Ph
1 h, 0.2 M
80 oC
3f
Ph
Ph
(2 equiv)
4 mmol
b.
1) 3 equiv NH2OH•HCl
O
O
THF:H2O = 1:1, rt, 12 h
Ph
2) 2 N HCl
3) 10% NaOH
H2N
7aa
Ph
Ph
N
Ph
4aa
-
-
96%
Scheme 3 a. Gram scale telescoped imine formation and
coupling. b. Product hydrolysis.
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Finally, we turned our attention to mechanistic studies to 21572197 and U1702286), Program for Changjiang Scholars and
confirm the role of aryl iodide as a hydrogen abstractor. A Innovative Research Teams in Universities (IRT17R94) and
control experiment was conducted in the absence of aryl iodide IRTSTYN, the NSF of Yunnan Province (2019FY003010), the
3f that led to no coupled product, confirming the essential role DongLu Scholar & Excellent Young Talents of Yunnan University,
of aryl iodide (Scheme 4a). Next, subjecting THF-d8 (D-2a) and and the YunLing Scholar of Yunnan Province. P. J. W. thanks the
ketimine 1a to the optimized conditions afforded deuterated US National Science Foundation (CHE-1902509) for financial
arene 8 in 68% yield (Scheme 4b). Thus, we favor the support.
mechanism outlined in Scheme 2c with key steps being SET from
the 2-azaallyl anion to the aryl iodide leading to generation of
the sterically protected aryl radical and the persistent 2-azaallyl
radical.22 The aryl radical then reacts with the ether, amine, or
Notes and references
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NaN(SiMe3)2
(3 equiv)
Ph
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no reaction
1 h, 0.2 M
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D7
D
3.
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NaN(SiMe3)2
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THF-d8
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64% dr = 1.5:1
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Conclusions
In summary, a new cross-dehydrogenative coupling reaction
between C(sp3)–H bonds of saturated heterocycles and the
benzylic C–H of benzophenone imines has been described.
Unlike many past successful advances, which are based on
photoredox catalysts and their specialized reactors or on use of
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reactivity from a readily accessible organic super electron
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a sterically protected sacrificial hydrogen atom
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TOC graphic
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DOI: 10.1039/D0SC00031K
Ar'
Ph
Ar'
Ph
N
R
Ph
N
N
Radical-radical
coupling
Ar'
X
R
Ph
Ar
Ph
R
Ph
SET
R = H, Ph
31 examples
up to 88% yield
TM-free
X
Ar–I
HAT
X = O, N, Ph
X
broad scope
H
Ar H
A
unique
transition-metal-free
C(sp3)–H/C(sp3)–H
dehydrocoupling of N-benzylimines with saturated heterocycles
is presented using 2-azaallyl anions as super electron donors to
initiate the generation of hydrogen atom abstracting aryl
radicals.
8 | Chem. Sci., 2020, xx, xx-xx
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