Palladium-catalyzed alkynylation of aromatic amines via in situ formed trimethylammonium salts

Article abstract of DOI:10.1016/j.tetlet.2020.151647

A palladium-catalyzed alkynylation of aromatic amines with terminal alkynes via in situ formed trimethylammonium salts is developed. Compared with previous system using ammonium salts as starting materials and high loading of pre-prepared NHC-Pd catalyst (10 mol% Pd), this reaction directly employed amines as the coupling partners and the commercially available Pd₂(dba)₃/PPh₂Cy (1 mol% Pd) as the catalyst, greatly simplifying the manipulation and decreasing the cost.

Full text of DOI:10.1016/j.tetlet.2020.151647

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Tetrahedron Letters
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Palladium-catalyzed alkynylation of aromatic amines via in situ formed
trimethylammonium salts
⇑
Long Liu, Wen-Qing Yu, Tianzeng Huang, Tieqiao Chen
Key Laboratory of Ministry of Education for Advanced Materials in Tropical Island Resources, Hainan Provincial Key Lab of Fine Chem, Hainan University, Haikou 570228, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A palladium-catalyzed alkynylation of aromatic amines with terminal alkynes via in situ formed
trimethylammonium salts is developed. Compared with previous system using ammonium salts as start-
ing materials and high loading of pre-prepared NHC-Pd catalyst (10 mol% Pd), this reaction directly
employed amines as the coupling partners and the commercially available Pd2(dba)3/PPh2Cy (1 mol%
Pd) as the catalyst, greatly simplifying the manipulation and decreasing the cost.
Ó 2020 Published by Elsevier Ltd.
Received 22 November 2019
Revised 8 January 2020
Accepted 17 January 2020
Available online xxxx
Keywords:
Palladium catalysis
Internal alkynes
Sonogashira coupling
Trimethylammonium salts
Introduction
Internal alkynes are a class of important organic compounds
occurring in many natural products and functional materials [1].
They are also used as versatile synthons in organic synthesis due
to the diverse reactivity of the triple bonds [2]. Therefore, the direct
and efficient synthesis of such frameworks is meaningful and
highly demanded. Among the established methods, transition-
metal catalyzed Sonogashira coupling has proved to be one power-
ful tool for the construction of internal alkynes [3]. During the past
decades, in addition to aryl halides, many electrophiles such as
sodium sulfonates [4], arylhydrazines [5], arylsulfonyl hydrazides
[6], amides [7] and esters [8] etc. [9] have also been developed as
the coupling partners. Aromatic amines are widespread in both
nature and synthetic world. Because of the high dissociation
energy of aromatic CAN bonds, those compounds are usually
transformed into the corresponding salts and then used in coupling
chemistry [10–12]. Recently, Cao and co-workers developed a pal-
ladium-catalyzed Sonogashira coupling reaction of aryltrimethy-
lammonium salts with terminal alkynes (Scheme 1) [13]. Despite
the fact that the pre-prepared NHC-Pd catalyst with relatively high
loading was required, this reaction provided an efficient method
for converting tertiary aromatic amines into internal alkynes for
the first time.
Scheme 1. Pd-catalyzed alkynylation of aromatic amines.
Given that aryltrimethylammonium salts were prepared from
the reaction of aromatic amines and MeOTf, we envisioned that
the aromatic amines might be used directly as the starting materi-
als, if the quaternization process would take place readily in situ.
Herein, we report such an alkynylation reaction of aromatic amines
in one step (Scheme 1). Worth noting is that catalyst was also not
necessary to be pre-synthesized, the commercially available Pd2(-
dba)3/PPh2Cy with a low loading (1 mol% Pd) served well under
the reaction conditions. These measures simplified the experimen-
tal manipulation and decreased the cost of Cao’s system, making
the reaction more practical in organic synthesis.
Results and discussion
⇑
By heating a mixture of N,N-dimethylnaphthalen-2-amine (1a),
phenylacetylene (2a, 2.0 equiv.), MeOTf (2.5 equiv.), NaOtBu (2.0
Corresponding author.
E-mail address: chentieqiao@hnu.edu.cn (T. Chen).
https://doi.org/10.1016/j.tetlet.2020.151647
0040-4039/Ó 2020 Published by Elsevier Ltd.
Please cite this article as: L. Liu, W. Q. Yu, T. Huang et al., Palladium-catalyzed alkynylation of aromatic amines via in situ formed trimethylammonium
salts, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151647

2
L. Liu et al. / Tetrahedron Letters xxx (xxxx) xxx
Table 1
obtained (Table 1, entries 20–23). Further studies revealed that
Optimization of the reaction conditions.a
the reaction could also take place smoothly with almost an equiv-
alent amount of starting terminal alkynes at a lower reaction tem-
perature (Table 1, entries 24–26).
With the optimized conditions at hand, the substrate scope was
subsequently investigated. As shown in Table 2, both aromatic and
aliphatic terminal alkynes were applicable to this reaction. Thus,
derivatives bearing groups such as -tBu (3b), -Me (3c-e), -OMe
(3f), or -Ph (3g) served well, producing the corresponding internal
alkynes in 76–85% yields. When 4-ethynyl-N,N-dimethylaniline
was used as the coupling partner, only 32% yield was given under
similar reaction conditions (3 h). The result was probably ascribed
to the in-situ formation of ammonium salt from the starting alkyne
with MeOTf, which was a strong electron-deficient substrate with
low reactivity (described below). Indeed, when 4-ethynyl-N,N-
dimethylaniline was allowed to react with 2-naphthyl trimethy-
lammonium triflates in the absence of MeOTf, 3 h was generated
in 91% yield. Worth noting is that halo groups (F and Cl) survived
well (3i-3l) under the reaction conditions, facilitating further
derivatization of the products via cross coupling. The substrate
with a CF3 group on the benzene ring also coupled readily with
1a to give 3 m in 80% yield; however, more electron-deficient ter-
minal alkyne, i.e. having a CN group showed low reactivity in the
current catalytic system (3n). By elevating the loading of palladium
catalyst and allowing it to couple with 2-naphthyl trimethylam-
monium triflates, 68% yield of 3n was obtained. To our delight,
the heteroaromatic terminal alkynes were also applicable to this
reaction (3o and 3p).
Entry
Cat. Pd
Ligand
Base
Yield (%)b
1
Pd2(dba)3
Pd(OAc)2
PdCl2
Pd(acac)2
Pd(OTFA)2
Pd2(dba)3
none
PPh2Cy
PPh2Cy
PPh2Cy
PPh2Cy
PPh2Cy
PPh2Cy
PPh2Cy
none
PPh3
TFP
PPh2Py
DPPM
DPPP
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
KOtBu
NaOMe
Cs2CO3
Na2CO3
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
77
72
45
71
66
71
n.d.
n.d.
65
31
55
12
34
40
n.d.
20
2c
3c
4c
5c
6d
7
8
9
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
10
11
12
13
14
15
16
17
18
19
20e
21f
22g
23h
24h,i
25h,i,j
26h,i,k
DPPF
1,10-phen
PPh2Cy
PPh2Cy
PPh2Cy
PPh2Cy
PPh2Cy
PPh2Cy
PPh2Cy
PPh2Cy
PPh2Cy
PPh2Cy
PPh2Cy
16
trace
n.d.
66
51
trace
86
85
85
83
In addition to the aromatic terminal alkynes, aliphatic ones
were also workable under the reaction conditions (3q-3s). Spe-
cially, by using the strategy, silylated alkyne 3s was successfully
produced in 84% yield, which could be easily converted into other
various alkynes through transformation of silyl group.
a
Reaction conditions: 1a (0.2 mmol), 2a (2.0 equiv), catalyst (0.5 mol%), ligand
(2.0 mol%), base (2.0 equiv), THF (2.0 mL), N2, 130 °C, 2 h.
b
GC yield using tridecane as an internal standard.
Catalyst (1 mol%).
Pd2(dba)3 (0.25 mol%), PPh2Cy (1.0 mol%).
dioxane as solvent.
DME as solvent.
toluene or DMF as solvent.
The ratio of THF/dioxane is 2:1 (v:v, 3 mL).
2a (1.2 equiv.)
c
Other aromatic amines were also investigated. When N,N-
dimethylnaphthalen-1-amine was used, a low yield was given
probably due to the high steric hindrance hampering the formation
of target aryl ammonium salt. By employing the aryl ammonium
salt as the coupling partner to coupling with phenylacetylene, a
high yield of 3t was obtained. Meanwhile, N,N-dimethylanthra-
cen-2-amine could be directly transformed into 3u in 72% yield.
Heterocyclic skeletons such as dibenzofuran and benzothiophene
were compatible in this reaction, and the corresponding products
were obtained in 67% and 51% yields, respectively (3v and 3w).
Phenyl N,N-dimethylamines were also successfully alkynlated,
despite the fact that relatively low yields were afforded (3x-3za).
The results were possibly attributed to the inherent inertia of phe-
d
e
f
g
h
i
j
120 °C.
100 °C.
k
equiv.), Pd2(dba)3 (0.5 mol%) and PPh2Cy (2.0 mol%) in THF at
130 °C for 2 h, the corresponding alkynylated product (3a) was
produced in 77% GC yield (Table 1, entry 1). Other palladium cata-
lysts such as Pd(OAc)2, PdCl2, Pd(acac)2 and Pd(OTFA)2 could also
mediate this reaction, furnishing 3a in 45–72% yields (Table 1,
entries 2–5). Lowering the loading of Pd2(dba)3 to 0.25 mol%
slightly decreased the yield of 3a (Table 1, entry 6). When the reac-
tion was carried out in the absence of any catalyst, no desired pro-
duct was detected (Table 1, entry 7), indicating that this
transformation proceeded via a transition metal catalytic process
rather than a nucleophilic substitution [14]. The phosphine ligand
was also crucial to this reaction since no 3a was detected in its
absence (Table 1, entry 8). A variety of monodentate (PPh3, TFP,
PPh2Py) and bisdentate (DPPM, DPPP,DPPF) phosphine ligands as
well as nitrogen ligand (1,10-phen) were subsequently screened
with PPh2Cy being the best choice (Table 1, entries 9–15). Plausibly
due to the suitable alkalinity and weak nucleophilicity of anion,
NaOtBu served as the right base for this reaction. When other bases
such as
nyl ammonium salts compared with
p-extended ones under this
reaction conditions [11c]. Both N,N-dimethyl benzyl amine and
its ammonium salt showed low reactivity and only a trace amount
of 3zb was yielded. It should be noted that a similar alkynylation
reaction using ammonium salts has been realized under other pal-
ladium-catalyzed conditions [15].
On the basis of previous literature reports [11,13,16], a plausi-
ble reaction mechanism was proposed and illustrated in Scheme 2.
Pd(0) complex firstly added to aryltrimethylammonium salts gen-
erated in-situ to give speceis I with the release of NMe3. Speceis I
subsequently underwent ligand exchange with a terminal alkyne
in the presence of a base, generating the intermediate II. Reductive
elimination of II produced the target internal alkynes and regener-
ated the Pd(0) complex to complete the catalytic cycle.
KOtBu, NaOMe, Cs2CO3 or Na2CO3 were used, the yield of 3a
decreased dramatically (Table 1, entries 16–19). It seems that this
reaction preferred to occur in ether solvents and when it proceeded
in a mixed solvent of THF/dioxane, a higher yield of 3a was
Conclusions
In conclusion, we have improved Cao’s alkynylation system
with use of aromatic amines as the coupling partners, avoiding
Please cite this article as: L. Liu, W. Q. Yu, T. Huang et al., Palladium-catalyzed alkynylation of aromatic amines via in situ formed trimethylammonium
salts, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151647

L. Liu et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Table 2
Substrate scope.a
aReaction conditions: 1 (0.2 mmol), 2 (1.2 equiv), Pd2(dba)3 (0.5 mol%), PPh2Cy (Pd/P = 1:2), MeOTf (2.5 equiv.), NaOtBu (2.0
b
equiv), THF (2.0 mL) and dioxane (1.0 mL), N2, 120 °C, 2 h. Isolated yield. Aryltrimethylammonium triflates 10 instead of 1
was used in the absence of MeOTf. cPd(acac)2 (5 mol%), THF (2.0 mL), 100 °C, 1 h. d2 (2.0 equiv). ePd(OTFA)2 (5 mol%), THF
(2.0 mL), 130 °C, 1 h.
the synthesis and isolation of ammonium salts. In addition, com-
mercially available Pd2(dba)3/Ph2PCy was used as the catalyst
instead of pre-prepared NHC-Pd complex, making the manipula-
tion more simple. This reaction not only provides an alternative
method for directly converting aromatic amines into the value-
added internal alkynes, but also enriches the toolbox of amines
in organic chemistry.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgements
This work is supported by the National NSF of China (Grant Nos.
21871070) and the NSF of Hainan Province (Grant No. 219MS005).
Hainan University start-up funds (KYQD(ZR)1854 and KYQD(ZR)
1857) are also appreciated.
Scheme 2. Possible reaction mechanism.
Please cite this article as: L. Liu, W. Q. Yu, T. Huang et al., Palladium-catalyzed alkynylation of aromatic amines via in situ formed trimethylammonium
salts, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151647

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Please cite this article as: L. Liu, W. Q. Yu, T. Huang et al., Palladium-catalyzed alkynylation of aromatic amines via in situ formed trimethylammonium
salts, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151647