Palladium-catalyzed denitrative Sonogashira-type cross-coupling of nitrobenzenes with terminal alkynes

Article abstract of DOI:10.1039/c9cc08663c

Described herein is a palladium-catalyzed cross-coupling reaction between nitroarenes and terminal alkynes, offering a facile method for C(sp²)-C(sp) bond formation. The utility of this protocol has been proven by the construction of polycyclic aromatic hydrocarbons (PAHs) and orthogonal cross-coupling.

Full text of DOI:10.1039/c9cc08663c

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Palladium-catalyzed denitrative Sonogashira-type
cross-coupling of nitrobenzenes with terminal
alkynes†
Cite this:DOI: 10.1039/c9cc08663c
Received 6th November 2019,
Accepted 9th December 2019
Boya Feng,
Yudong Yang * and Jingsong You
*
DOI: 10.1039/c9cc08663c
rsc.li/chemcomm
Described herein is a palladium-catalyzed cross-coupling reaction coupling reactions, has to be activated.11 In 2017, Nakao and
between nitroarenes and terminal alkynes, offering a facile method co-workers reported the first palladium-catalyzed Suzuki–Miyaura
for C(sp2)–C(sp) bond formation. The utility of this protocol has coupling of nitroarenes with aryl boronic acids, demonstrating
been proven by the construction of polycyclic aromatic hydro- the feasibility of oxidative addition of Ar–NO2 bonds onto a
carbons (PAHs) and orthogonal cross-coupling.
transition-metal center.12 Then the palladium-catalyzed denitrative
Buchwald–Hartwig amination,13a,d reductive denitration,13b and
The development of efficient and selective methods for the intramolecular C–H arylation,13c have been described.13 Herein,
construction of carbon–carbon bonds is always an attractive we disclose the palladium-catalyzed coupling reaction between
and challenging topic in organic synthesis.1 Transition metal- nitroarenes and terminal alkynes, which obviates the conventional
catalyzed cross-coupling between an aryl electrophile and a tedious synthetic procedures in transformation of nitroarenes to
terminal alkyne species (Sonogashira reaction) represents one arylalkynes (Scheme 1).
of the most powerful and reliable methods to forge C(sp2)–C(sp)
We started our investigation by using 4-nitro-1,10-biphenyl
bonds.2 Furthermore, the resulting aryl alkynes are versatile (1a) and triisopropylsilylacetylene (2a) as the model substrates.
building blocks widely used in the synthesis of carbo- and As shown in Table 1, the reaction conducted in the presence of
heterocycles.2d,3 However, the aryl electrophilic coupling part- Pd(OAc) (5 mol%), XPhos (15 mol%) and K3PO4 (2 equiv.) in
ners for this reaction have been limited to aryl halides and toluene at 130 1C for 24 h furnished the cross-coupling product
triflates for a long time. Recently, increasing efforts have been 3a in 12% yield (entry 1). The yield was improved to 45% when
devoted to finding alternative coupling partners in transition BrettPhos was used as the ligand (entry 2). Other ligands
metal-catalyzed coupling reactions,4 which involve the cleavage such as RuPhos, dppb and SIPr in tests proved to be totally
of less reactive chemical bonds such as C–S,5 C–O,6 C–P,7 C–C8 ineffective (entries 3–5). Interestingly, copper additives such as
and C–N9 bonds.
CuI and CuF2 were detrimental to this reaction probably owing
Nitroarenes are highly common and versatile building
blocks in organic synthesis.10 They are often used to prepare
the corresponding anilines by reduction and aryl halides via
a further Sandmeyer reaction. The development of transition
metal-catalyzed reactions using nitroarenes as electrophilic
coupling partners could not only provide novel carbon–carbon
bond formation methods but also shorten the synthetic routes.11
In order to develop transition metal-catalyzed denitrative
Sonogashira-type alkynylation reactions, two challenges need
to be addressed: (1) the alkyne homocoupling and formation of
enyne via addition have to be suppressed; (2) the Ar–NO2 bond,
which is typically inert in conventional transition metal-catalyzed
Key Laboratory of Green Chemistry and Technology of Ministry of Education,
College of Chemistry, Sichuan University, 29 Wangjiang Road, Chengdu 610064,
P. R. China. E-mail: jsyou@scu.edu.cn, yangyudong@scu.edu.cn
Scheme 1 Transition metal-catalyzed Sonogashira-type reaction.
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c9cc08663c
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Table 1 Optimization of the reaction conditionsa
Table 2 Investigation of the substrate scopea
Entry
[Pd]
Ligand
XPhos
Base
Solvent
Yieldb (%)
1
2
3
4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(en)(NO3)2
Pd(acac)2
Pd(COD)Cl2
Pd(en)(NO3)2
Pd(en)(NO3)2
Pd(en)(NO3)2
Pd(en)(NO3)2
Pd(en)(NO3)2
Pd(en)(NO3)2
Pd(en)(NO3)2
Pd(en)(NO3)2
Pd(en)(NO3)2
Pd(en)(NO3)2
Pd(en)(NO3)2
Pd(en)(NO3)2
—
K3PO4
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Dioxane
THF
12
45
Trace
n.d.
n.d.
n.d.
25
52
50
36
58
Trace
o10
Trace
n.d.
Trace
8
46
80
42
68
BrettPhos K3PO4
RuPhos
dppb
SIPr
BrettPhos K3PO4
BrettPhos K3PO4
BrettPhos K3PO4
BrettPhos K3PO4
BrettPhos K3PO4
BrettPhos Cs2CO3
BrettPhos CsF
K3PO4
K3PO4
K3PO4
5
6c
7d
8
9
10
11
12
13
14
15
16
17
18
19e
20f
21e,g
22e,h
23
BrettPhos Na2CO3
BrettPhos Et3N
BrettPhos iPr2NH
BrettPhos Cs2CO3
BrettPhos Cs2CO3
BrettPhos Cs2CO3
BrettPhos Cs2CO3
BrettPhos Cs2CO3
BrettPhos Cs2CO3
BrettPhos Cs2CO3
BrettPhos Cs2CO3
PhCF3
Toluene
Toluene
Toluene
Toluene
Toluene
46
n.d.
a
Reaction conditions: 1a (0.2 mmol, 1 equiv.), 2a (0.4 mmol, 2 equiv.),
Pd catalyst (5 mol%), ligand (15 mol%) and base (2 equiv.), solvent
b
c
(0.6 mL), 130 1C, and 24 h. Isolated yield. CuI (10 mol%) was added.
d
e
f
g
CuF2 (10 mol%) was added. 150 1C. 110 1C. Ligand (10 mol%)
h
was used. Ligand (5 mol%) was used. TIPS = triisopropylsilyl; Xphos =
2-(dicyclohexylphosphino)-20,40,60-triisopropylbiphenyl; BrettPhos
=
2-(dicyclohexylphosphino)-3,6-dimethoxy-20-40-60-triisopropyl-1,10-biphenyl;
RuPhos = 2-dicyclohexylphosphino-20,60-diisopropoxy-1,10-biphenyl;
SIPr
= 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidine;
dppb = 1,4-diphenyl phosphinobutane; en = ethylenediamine; COD =
1,5-cyclooctadiene; n.d. = not detected.
a
Reaction conditions: nitrobenzene 1 (0.2 mmol, 1 equiv.), alkyne 2
(0.4 mmol, 2 equiv.), Pd(en)(NO3)2 (5 mol%), BrettPhos (15 mol%) and
Cs2CO3 (2 equiv.), toluene (0.6 mL), 150 1C, and 24 h. Isolated yield.
to its effect on promoting the alkyne homocoupling and
inhibiting Pd catalyst activation (entries 6 and 7).14 Screening
of the palladium sources indicated that Pd(en)(NO3)2 was the
most efficient and Pd(acac)2 could give a comparable yield
(entries 8–10). The base was also optimized. The reaction with
Cs2CO3 as the base was slightly improved to 58% yield (entry 11).
b
e
c
d
Pd(acac)2 (5 mol%) and K3PO4 (2 equiv.). 36 h. 1.2 equiv. of alkyne.
3 equiv. of alkyne and Cs2CO3.
However, no beneficial effect was observed when other common ortho-/meta-/para-positions all worked well with triisopropyl-
bases such as CsF and Na2CO3 were added (entries 12 and 13). silylacetylene under the standard conditions (3a, 3f, 3g and 3h).
The attempts with organic bases led to no or trace amount of In general, electron-deficient nitrobenzenes exhibited higher
the desired product (entries 14 and 15). Other solvents such as reactivity than their electron-rich analogues. Various functional
1,4-dioxane, THF and trifluorotoluene gave trace or diminished groups including fluoro, aldehyde, ketone, methyl, methoxy,
yields (entries 16–18). Finally, elevation of the temperature to phenoxy and tertiary amine could be tolerated (3i–3n). When
150 1C provided the desired product 3a in 80% yield (entry 19). 4-bromo- and 4-chloro-1-nitrobezenes were used, mixtures of
A decrease of the temperature or ligand loading showed a negative mono- and di-alkynylation products (3s and 3s0) were afforded
effect on the product yield (entries 20–22). No reaction was with the preferential cleavage of Ar–Br and Ar–Cl bonds. In the
detected in the absence of a metal catalyst (entry 23).
case of p-nitrobenzene tosylate, decomposition of the substrate
With the optimized reaction conditions in hand, the sub- was detected and no alkynylation was observed. Notably,
strate scope of the denitrative alkynylation reaction was inves- alkynylation took place regioselectively at the C2-site of
tigated. As shown in Table 2, a variety of condensed aromatic 2,4-dinitrobenzaldehyde, probably owing to the directing effect
nitro compounds could easily undergo the alkynylation to give of –CHO. Heteroaromatics such as pyridine and quinoline were
the desired products in good to high yields (3b–3e). Simple compatible in this Sonogashira-type reaction (3o and 3p).
nitrobenzene and nitroarenes with phenyl substituents at the Although the attempt with phenylacetylene failed, aliphatic
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acetylenes were demonstrated to be suitable substrates under
the standard conditions (3q and 3r).
To demonstrate the synthetic utility of the denitrative alky-
nylation reaction, several transformations were conducted. It is
known that the –NO2 group could serve as an activation group
to facilitate the ortho-C–H arylation of nitroaromatics with aryl
bromide.15 We envisioned that the combination of ortho-
selective C–H arylation and denitrative alkynylation reaction
would provide a new and concise synthetic route to polycyclic
aromatic hydrocarbons, which are widely applied in the area of
organic electronics and optoelectronics.16 As illustrated in
Scheme 2, the phenanthrene ring was easily constructed via
an ortho-C–H arylation/ipso-denitrative alkynylation/deprotection/
cyclization sequence starting from nitrobenzene. In addition,
9,90-bifluorenylidene (9,90BF) and dispiro-[fluorene-9,50-indeno-
[2,1-a]indene-100,900-fluorene] (DSFIIF), which are respectively
promising scaffolds applied in photovoltaic and electrolumines-
cent materials, could be prepared based on this protocol.17,18
Furthermore, considering the inertness of the Ar–NO2 bond in
conventional transition metal-catalyzed coupling reactions, the
denitrative alkynylation reaction would offer a valuable opportu-
nity for orthogonal cross-coupling.19 As shown in Scheme 3,
functional arylalkyne 7 was successfully prepared by orthogonal
cross-coupling reactions of Ar–Br and Ar–NO2 in a completely
predictable manner.
Scheme 3 Orthogonal cross-couplings.
Based on the above results and previous reports,13 a plau-
sible mechanism for the denitrative alkynylation is proposed in
Scheme 4. Firstly, the oxidative addition of an Ar–NO2 bond onto a
Pd(0) species affords an Ar-Pd(II)-NO2 complex A. Subsequently,
transmetalation with cesium acetylide B, which is formed from the
reaction of alkyne 2 and Cs2CO3, delivers an Ar-Pd(II)-alkynyl
intermediate C. Following reductive elimination delivers aryl alkyne
3 and extrudes the Pd(0) species to complete the catalytic cycle.
Scheme 4 A plausible mechanism for the denitrative alkynylation.
In conclusion, we have developed a novel cross-coupling
reaction between nitrobenzenes and terminal alkynes. A set of
terminal silyl/aliphatic alkynes and nitroaromatics bearing
various substituents could be tolerated in this reaction. This
method provides straightforward access to aryl alkynes from
nitroarenes. The orthogonal cross-coupling and successful
synthesis of phenanthrene, 9,90-bifluorenylidene and spirobi-
fluorene derivatives showcases the utility of the denitrative
alkynylation in organic synthesis. Further investigations on
the substrate scope extension and applications in the prepara-
tion of organic optoelectronic materials are currently ongoing
in our laboratories.
We gratefully acknowledge the financial support from the
National NSF of China (No. 21432005 and 21502123).
Conflicts of interest
There are no conflicts to declare.
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Scheme 2 Synthesis of polycyclic aromatic hydrocarbons based on
denitrative alkynylation reaction.
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