Visible-light-mediated external-reductant-free reductive cross coupling of benzylammonium salts with (hetero)aryl nitriles

Article abstract of DOI:10.1007/s11426-019-9597-8

Herein we report a novel visible-light-mediated external reductant-free reductive cross coupling for the construction of C sp²–C sp³ bonds. A variety of benzylammonium salts underwent selective coupling with (hetero)aryl nitriles to

Full text of DOI:10.1007/s11426-019-9597-8

SCIENCE CHINA
Chemistry
•
ARTICLES•
https://doi.org/10.1007/s11426-019-9597-8
SPECIAL ISSUE: Organic Free Radical Chemistry
Visible-light-mediated external-reductant-free reductive cross
coupling of benzylammonium salts with (hetero)aryl nitriles
1
1
1
2*
1*
Meng Miao , Li-Li Liao , Guang-Mei Cao , Wen-Jun Zhou & Da-Gang Yu
1
Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064,
China;
2
College of Chemistry and Chemical Engineering, Neijiang Normal University, Neijiang 641100, China
Received July 23, 2019; accepted August 23, 2019; published online October 8, 2019
2
Herein we report a novel visible-light-mediated external reductant-free reductive cross coupling for the construction of C sp –
3
C sp bonds. A variety of benzylammonium salts underwent selective coupling with (hetero)aryl nitriles to deliver important
diarylmethanes under mild reaction conditions. Importantly, photocatalysts can be omitted for many cases, which might involve
the electron donor acceptor (EDA) complex. Mechanistic studies indicated benzylic radicals might be involved as the key
intermediates. Moreover, the in situ generated NMe via cleavage of C–N bond in ammonium salts acts as the electron donor,
3
thus avoiding the use of external-reductant.
reductive cross coupling, visible light, external-reductant-free
Citation:
Miao M, Liao LL, Cao GM, Zhou WJ, Yu DG. Visible-light-mediated external-reductant-free reductive cross coupling of benzylammonium salts with
hetero)aryl nitriles. Sci China Chem, 2019, 62, https://doi.org/10.1007/s11426-019-9597-8
(
2
2
3
1
Introduction
C sp and C sp –C sp bonds via metal/visible-light photo-
redox dual catalysis [14–24]. Meanwhile, carbonyl-containing
Cross coupling has emerged to be an attractive strategy to
form C−C bond in synthetic chemistry [1]. Compared with
normal cross couplings between nucleophiles and electro-
philes, reductive cross-electrophile couplings avoid the pre-
preparation of organometallic compounds (Figure 1(a)), thus
being sustainable and step-economic [2–8]. Recently, visible-
light photoredox catalysis has been applied as a powerful
technique in organic synthesis [9–14]. Recent advancements
demonstrated that the visible-light-mediated reductive cross
couplings (Figure 1(b)) could be achieved in the presence of
organic amines and Hantzsch ester (HE) as reductants to re-
compounds (such as aldehydes, ketones and CO ) and imines
2
have also been explored in visible-light-promoted reductive
cross/homo-coupling reactions [13,14,25–40]. However, other
pseudohalides, which may also be readily available and
widely used in transition-metal-catalyzed coupling reactions,
are rarely investigated in this field.
Organoammonium salts are easily prepared, air and ther-
mal stable, and widely used as additives in organic synthesis.
They are also served as electrophiles in transition-metal-
catalyzed coupling reactions via C–N bond cleavage [41].
Recently, our group [42] realized the visible-light-driven
cross-electrophile couplings of tetraalkyl ammonium salts
place stoichiometric metallic (ZnEt , Mn, etc.) reductants,
2
which are often used in transition-metal-catalyzed cross-
electrophile couplings. In such transformations, organohalides
are widely investigated as electrophiles to construct C sp –
with aldehydes, ketone and CO (Figure 1(c)). In these re-
2
actions, we proposed that the ammonium salts underwent
single electron reduction (SER) to generate benzyl radical as
one of the key intermediates. Importantly, the byproduct
trimethylamine, catalytically generated in low concentration,
2
*Corresponding authors (email: wjzhou@njtc.edu.cn; dgyu@scu.edu.cn)
©
Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2019
chem.scichina.com link.springer.com

2
Miao et al. Sci China Chem
tube (10 mL) containing a stirring bar was charged with (if
using Method B, Ir(ppy) (dtbbpy)∙PF (0.006 mmol) was
2
6
added) ammonium salt 1 (0.2 mmol), (hetero)aryl nitrile 2
0.4 mmol), then the Schlenk tube was transferred to glo-
vebox to add Cs CO (0.6 mmol). The tube was then evac-
(
2
3
uated and back-filled with nitrogen for three times, 1 mL
anhydrous N,N-dimethylformamide (DMF) was added via
syringe under nitrogen atmosphere. Afterwards, the tube was
placed at a distance of 2–3 cm from 30 W blue light emitting
diode (LED) (with cooling fan) and stirred for 24 h. After
finishing the reaction, the resulting mixture was diluted with
3
mL EtOAc and quenched by 2 mL H O, then extracted
2
with EtOAc (3 mL×4) and the combined organic phases
were concentrated in vacuo. The residue was purified by
silica gel flash column chromatography to give the pure
desired product 3.
Figure 1 Reductive cross-coupling reactions (color online).
3
Results and discussion
served as the efficient reductant with assistance of base, thus
avoiding the addition of external reductants. Encouraged by
the exciting results, we envisioned that whether this strategy
could be applied in cross-electrophile couplings with other
electrophiles to construct important products.
We initiated the project with screening the reaction condi-
tions for the external reductant-free reductive cross coupling
with 1-([1,1′-biphenyl]-4-yl)-N,N,N-trimethylethan-1-ami-
nium trifluoromethanesulfonate (1a) and 1,4-dicyano-
benzene (1,4-DCB, 2a) as model substrates. To our delight,
when we used Ir(ppy) (dtbbpy)∙PF as photocatalyst,
Cs CO as base and DMF as solvent, the desired product 3aa
could be obtained in 95% isolated yield under 30 W blue
LED irradiation at room temperature (entry 1, Table 1).
As we know, diarylmethanes are valuable structural mo-
tifs, which are widely found in natural compounds, phar-
maceuticals, functional materials, dyes and biologically
active molecules [43–45]. We designed to synthesize such
motifs through cross coupling of benzylammonium salts and
aryl nitriles, which have been demonstrated to undergo ra-
dical-radical cross coupling reactions via visible-light pho-
toredox catalysis [32,33,46–58]. We hypothesized that the
aryl nitrile radical anions, which are generated via SER of
corresponding aryl nitriles, might undergo selective cross
coupling with the in-situ generated benzylic radicals via
homolysis of the C–N bond in benzylammonium salts.
However, to our best knowledge, visible-light driven re-
ductive cross couplings of aryl nitriles via inert C–C bond
cleavage have been rarely studied [32,33]. Besides the
challenges arising from low reactivities, it is also difficult to
control the chemo- and regio-selectivities and minimize side
reactions, such as homo-coupling of above-mentioned radi-
cal species, and reductive protonation of both electrophiles.
Herein, we report a visible-light-mediated external re-
ductant-free system that enables the direct arylation of ben-
zyl ammonium salts with aryl nitriles to generate valuable
diarylmethanes under mild reaction conditions (Figure 1(d)).
Importantly, photocatalyst can be omitted for many cases,
indicating a novel pathway for this reaction.
2
6
2
3
Other bases, such as Li CO , Na CO , K CO , CsF and
KO Bu, were tested to give lower yields (entries 2–6).
Control experiments revealed that no product was observed
2
3
2
3
2
3
t
a)
Table 1 Optimization of the reductive cross-coupling reaction
b)
Entry
Alteration from standard conditions
No change
Yield
>99% (95%)
25%.
1
2
3
4
5
6
7
8
9
Li CO instead of Cs CO
3
2
3
2
Na CO instead of Cs CO
3
60%
2
3
2
K CO instead of Cs CO
3
99%
2
3
2
CsF instead of Cs CO
94%
2
3
t
c)
KO Bu instead of Cs
CO
3
n.d.
2
No light
n.d.
n.d.
No Cs CO
2
3
d)
No [Ir]
99% (90%)
a) Reaction condition: 1a (0.2 mmol), 2a (0.4 mmol), [Ir] (0.006 mmol),
Cs CO (0.6 mmol) in 1 mL DMF under N atmosphere, 30 W blue LED,
room temperature (rt), 24 h. b) Yields are determined by GC analysis with
2
3
2
2
Experimental
n-dodecane as the internal standard. Isolated yields are in parentheses. c)
n.d.=not detected. d) [Ir]=Ir(ppy) (dtbbpy)∙PF .
General experimental procedure: The oven-dried Schlenk
2
6

Miao et al. Sci China Chem
3
in the absence of visible light or base, which indicated both
of these two components are vital to carry out this reaction
entries 7 and 8). Interestingly, the reaction also performed
(
efficiently in the absence of Ir-catalyst to give the 3aa in
comparable yield (entry 9).
With the optimal conditions in hand, we turned our at-
tention to the scope of benzyl ammonium salts (Scheme 1).
In addition to the Ir-catalyst-free system (Table 1, entry 9,
Method A), we also examined the cross-electrophile cou-
plings of some ammonium salts (1a–1k) in the presence of
Ir-catalyst (entry 1, Method B). The substrates bearing linear
and more sterically hindered cyclic alkyl groups at the
benzylic position (1a–1f) reacted well with 2a to give desired
products in good to excellent yields. Besides, the benzyl
ammonium salts with primary C–N bonds also underwent
the reaction smoothly, no matter bearing electron-rich or
electron-neutral substituents on arenes. However, those with
electron-deficient groups were not reactive under these
conditions. Steric hindrance has little effect on the reaction,
as ammonium salts 1u and 1w showed good reactivity.
Various functional groups, such as ethers (1h, 1k, 1m, 1n,
1
q), fluorides (1j, 1r) and heterocycles (1o, 1p and 1x),
could be well tolerated in the reaction.
To our delight, the highly challenging reductive cross
coupling of tertiary C–N bonds also worked in high effi-
ciency to give 3ya in a 93% isolated yield by using Method B
(Reaction (1) as following), which represented the a rare
example of functionalization of tertiary C–N bond via pho-
toredox catalysis.
Scheme 1 Substrate scope of ammonium salts. Method A: 1a (0.2 mmol),
1
b (0.4 mmol), Cs CO (0.6 mmol) in 1 mL DMF under N atomsphere,
2
3
2
30 W blue LED, rt, 24 h; Method B: Method A with [Ir] (0.006 mmol)
(color online).
To show the synthetic utility of this strategy, we performed
a gram scale reaction of 1a and 2a. To our delight, the re-
action underwent smoothly to give 3aa in 79% yield (Re-
action (2) as following).
To extend the scope of this reaction, we further evaluated
other (hetero)aryl nitriles as coupling partners (Scheme 2).
First, different aryl nitriles with multi-cyano groups were
tested. The substrate 2b containing methyl group worked
well in this transformation to afford the corresponding pro-
duct in excellent yields, albeit with a 1:2.9 regiomeric ratio.
1
,2-dicyanobenzene (1,2-DCB, 2c) and 1,2,4,5-tetra-
cyanobenzene (TCB, 2d) showed much lower reactivity,
both of which could be promoted in the presence of Ir-
photocatalyst. Moreover, a range of 4-cyanopyridine deri-
vatives were investigated in this reaction by using Method B
to generate corresponding products in moderate to good
yields. This reaction showed good functional group com-
patibility, as chloride (2f), fluoride (2g, 2k), ether (2h, 2l)
could be tolerated in the reaction, providing potential for
further functionalizations. Remarkably, isoquinoline (2m)
and 7-azaindole derivatives (2n) were also amenable in this
transformation.
To gain more insight about this reaction, we conducted
radical trapping experiments (Figure 2). The yield of desired
product 3aa was sharply decreased when adding radical
scavenger 2,6-di-tert-butyl-4-methylphenol (BHT), 2,2,6,6-
tetramethylpiperding-1-oxyl (TEMPO) and diphenyldisele-
nide (PhSeSePh) under the standard conditions. Moreover,
the adducts of BHTand benzylic radical could be detected by
HRMS (see the Supporting Information online for details),
indicating the benzylic radical might be involved in this re-
action.

4
Miao et al. Sci China Chem
Scheme 2 Substrate scope of (hetero)aryl nitriles. The reaction condi-
tions are as shown in Scheme 1 (color online).
Figure 2 Radical trapping experiments (color online).
Figure 4 Proposed mechanism (color online).
tested the single or the mixture of reaction components by
UV-Vis absorption spectroscopy. Although substrate 2a had
almost no absorption in the visible region, clear red-shift
absorption (up to 475 nm) was displayed by adding stoi-
chiometric Cs CO , stoichiometric 1a or 10 mmol% of NEt
2
3
3
(
similar to the in situ generated NMe ). We speculated that
3
some interaction between 2a and base was responsible for
the absorption of visible light and triggered the reaction.
Based on mechanistic studies and previous work [32,42],
we proposed the possible mechanism for these reactions as
shown in Figure 4. For photocatalyst-free system, the EDA
complex [59,60] between 1,4-DCB (2a) and electron donor
(
ED, the in situ generated NMe or α-amino radical) gave
3
radical anion A under blue LED irradiation. Then ammo-
nium salt 1a underwent single electron reduction (SER) by
radical anion A to generate benzyl radical B. Finally, an
intermolecular radical-radical coupling between inter-
mediate A and B would give C, which would further deliver
the target compound 3aa via elimination of a cyanide anion.
In the presence of Ir-catalyst, two redox cycles might be
involved in the catalytic process. Upon absorption of visible
Figure 3 UV-Vis absorption spectra of different components in DMF
(path length=1 cm) at the reaction concentrations for each species (color
online).
To shed light on the mechanism of the catalyst-free reac-
tion, we further conducted UV-Vis spectroscopic experiment
Figure 3), from which the catalyst-free reaction system was
found obvious absorption in visible light region. Then we
(
III
light, the excited photocatalyst Ir * was generated and fur-

Miao et al. Sci China Chem
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