Palladium-catalyzed construction of amidines from arylsilanes in the absence of a ligand under oxidative conditions

Article abstract of DOI:10.1039/c8nj01883a

An interesting palladium-catalyzed procedure for the synthesis of amidines from arylsilanes, isocyanides and amines has been developed. Moderate to good yields of the desired amidines were produced in the absence of a phosphine ligand under oxidative conditions.

Full text of DOI:10.1039/c8nj01883a

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Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
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Palladium-Catalyzed Construction of Amidines from Arylsilanes
in the absence of Ligand under Oxidative Conditions
Fengxiang Zhu[a] and Xiao-Feng Wu*[a]
Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Strasse 29a, 18059 Rostock (Germany), E-mail: Xiao-
Feng.Wu@catalysis.de
Abstract: An interesting palladium-catalyzed procedure on the
synthesis of amidines from arylsilanes, isocyanides and amines has
been developed. Moderate to good yields of the desired amidines
were produced in the absence of phosphine ligand under oxidative
conditions.
In order to further extend the toolbox for amidines
synthesis, we become interested to explore the possibility on
using arylsilanes as the substrates. In general, organosilicon
compounds have several unique advantages in the respect of
stability, solubility, nontoxicity, and easy-handling.[8] In this
communication, we wishes to report our new results on
palladium-catalyzed cross-coupling of arylsilanes, isocyanides
and amines for the synthesis of amidines. In this system, no
addition of phosphine ligand or inert gas protection is required.
Amidine is a class of important chemicals which have been
widely used as antibiotics, diuretics, antiphlogistic drugs,
anthelmintics and acaricides.[1] Amidines have also been applied
as valuable synthons for the preparation of azacyclic
compounds in organic synthesis as well.[2] Considering their
importance, various synthetic procedures have been established
for their preparation. Traditionally, amidines can be synthesized
by the addition of amines to nitriles or imido ester intermediates
or by the condensation of amides with amines.[3] However some
disadvantages such as limited substrates scope, relatively harsh
reaction conditions and etc. limited their applications in
nowadays.
Initially, we choose trimethoxyphenylsilane, tert-butyl
isocyanide and aniline as the model substrates to establish this
catalytic system. With Pd(OAc)2 and DPPF as the catalyst,
different fluoride sources were tested and the desired amidine
can be obtained with KF as the activator (Table 1, entries 1-3).
Then different phosphine ligands were tested in order to improve
the catalytic activity, however, no significant variation on the
yields can be detected (Table 1, entries 4-7). To our surprise, no
product could be detected by replacing Cu(OAc)2 with Cu(acac)2
or CuCl2 (Table 1, entries 8 and 9). And if increasing the loading
of DPPF from 5 mol% to 10 mol%, the reaction was totally
inhibited (Table 1, entry 10). This result implies that phosphine
ligand may have no effect or even negative effect on this
transformation. Hence, a reaction in the absence of phosphine
ligand was carried out and 41% of the desired amidine was
formed (Table 1, entry 11). Then different palladium precursors
were checked (Table 1, entries 12-16) and 69% of the
corresponding product can be produced with PdCl2 as the
catalyst (Table 1, entry 12). Concerning the amount of
isocyanide, one and two equivalents of it were tested
respectively; the yields were decreased in both cases.
On the other hand, palladium known as the metal of the
21st century, its catalysts have been widely applied in cross-
coupling chemistry and also many other topics.[4] In general,
there are three types of reaction pathways for the palladium-
catalyzed reactions. They are: 1) Pd(0)→Pd(II)→Pd(0); 2)
Pd(II)→Pd(0)→Pd(II); 3) Pd(II)→Pd(IV)→Pd(II). The first type of
Pd(0) initiated chemistry usually requires inert gas protection,
addition of expensive ligands and under basic reaction
conditions. These conditions which will surely increase the
manipulation complexity and prevent the usage of base sensitive
functional group substituted substrates. The third type of
transformation pathway requires strong oxidant to oxidize Pd(II)
to Pd(IV). This pathway is quite useful for certain type of reaction,
such as C-F bond formation, as the reductive elimination from
Pd(IV) is much easier. However, its limitations are obvious as
well. The second type of pathway is an interesting option, as the
oxidant needed is milder and no inert gas protection or ligand
addition is required.
Table 1. Optimization of the reaction conditions.a
Entry
[Pd]/Ligand
Additive
TBAF
AgF
KF
Yield (%)b
Not surprisingly, methodologies for amidines synthesis
using palladium-catalyzed isocyanides insertion were developed.
As early as in 1986, the cross-coupling of bromobenzene, tert-
butyl isocyanide and organotin reagents was reported and 22 %
of the desired amidine was formed.[5] In 2000, Whitby and co-
workers developed a procedure with aryl bromides, isocyanides
and amines as the starting materials.[6] Good yields of the
desired amidines can be obtained. Later on, they also succeed
to extend the substrates of their methodology to alkenyl
bromides to produce α,β-unsaturated amidines and cyclic
1
Pd(OAc)2/dppf
Pd(OAc)2/dppf
Pd(OAc)2/dppf
Pd(OAc)2/DPEPhos
Pd(OAc)2/XantPhos
Pd(OAc)2/PPh3
Pd(OAc)2/DPPE
Pd(OAc)2/dppf
-
2
-
3
38
37
35
35
26
-
4
KF
5
KF
6c
7
KF
amidines. In 2016, we developed
a palladium-catalyzed
procedure based on the cross-coupling of arylboronic acids,
isocyanides and anilines.[7] Under air and with copper salt as the
terminal oxidant, various amidines were isolated in good yields.
KF
8d
KF

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9e
Pd(OAc)2/dppf
Pd(OAc)2/dppf
Pd(OAc)2
KF
KF
KF
KF
KF
KF
KF
KF
-
diphenylphosphinophenyl)ether. XantPhos: 4,5-bis(diphenylphosphino)-9,9-
dimethylxanthene. DPPE: 1,2-bis(diphenylphosphino)ethan.
10f
11
12
13
14
15
16g
-
41
69
-
With the best reaction conditions in hand, the testing of
substrates was performed (Table 2). The testing of amines was
carried out firstly. Basically, all the tested anilines can give the
desired amidines with various functional groups (Table 2, entries
1-10). In the case of aliphatic amines, no desired product could
be detested with cyclohexylamine. However, around 30% of the
desired product can be formed with piperidine as the reaction
partner (Table 2, entry 11). But the product is too sensitive to be
isolated. In addition to tert-butyl isocyanide, cyclohexyl
isocyanide can be used as well (Table 2, entries 6-10, 18). Then,
the testing of various arylsilanes was performed (Table 2, entries
12-18). Moderate to good yields can be achieved in all the
tested cases.
PdCl2
Pd(TFA)2
Pd(CH3CN)2Cl2
Pd(COD)Cl2
[(Cinnamyl)PdCl]2
42
48
56
[a] 1a (0.2 mmol), 2a (0.3 mmol), 2a (0.3 mmol), [Pd] (5 mol%), ligand (5
mol%), Cu(OAc)2 (0.4 mmol), DMF (2 mL), additive (0.4 mmol), 24 h. [b] GC
yields using hexadecane as internal standard. [c] PPh3 (10 mol%). [d]
Cu(acac)2 (0.4 mmol). [e] CuCl2 (0.4 mmol). [f] dppf (10 mol%). [g] [Pd] (2.5
mol%).
dppf:
1,1′-bis(diphenylphosphino)ferrocen.
DPEPhos:
bis(2-
Table 2. Pd-catalyzed amidines synthesis from arylsilanes.[a]
Entry
Arylsilanes
isocyanides
Amines
Products
Isolated yield
67%
1
tBuNC
PhNH2
2
3
tBuNC
tBuNC
61%
55%
4
5
tBuNC
tBuNC
68%
66%
Cy
CN
NH
N
6
7
CyNC
CyNC
61%
63%
4f

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DOI: 10.1039/C8NJ01883A
8
9
CyNC
CyNC
CyNC
64%
47%
57%
10
11
tBuNC
<30%b
12
13
tBuNC
tBuNC
PhNH2
67%
64%
PhNH2
14
15
tBuNC
tBuNC
PhNH2
58%
53%
PhNH2
16
tBuNC
PhNH2
58%
17
18
tBuNC
58%
57%
CyNC
PhNH2
[a] 1 (0.2 mmol), 2 (0.3 mmol), 2 (0.3 mmol), PdCl2 (5 mol%), Cu(OAc)2 (0.4 mmol), DMF (2 mL), KF (0.4 mmol), 24 h, isolated yield. [b] NMR yield using
mesitylene as internal standard.
Concerning the reaction pathway, a possible reaction
mechanism is proposed in Scheme 1.9 The reaction starts with
Pd(II), then transmetalation with fluoride activated arylsilane to

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DOI: 10.1039/C8NJ01883A
give the corresponding aryl-palladium intermediate. After the
insertion of isocyanide, nucleophilic attract of anilines take place
which will provide the terminal product after rearrangement. The
Pd(0) will be oxidized back to Pd(II) for the next catalyst cycle.
ethyl acetate three times. The combined organic phases were
washed with saturated NaCl solution and dried over Na2SO4.
The crude product was purified by column chromatography
(ethyl acetate/pentante = 1:10) to give the pure product.
Keywords: Palladium catalyst • Domino reaction • Amidines
synthesis • Isocyanide • CO surrogate
[1]
[2]
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J. S. Fairlamb, Chem. Rev., 2010, 110, 824-889.
[4]
Scheme 1. Proposed reaction mechanism.
In conclusion, an interesting palladium-catalyzed
procedure for the synthesis of amidines from arylsilanes,
isocyanides and amines has been developed. Moderate to good
yields of the desired amidines were produced in the absence of
phosphine ligand under oxidative conditions.
[5]
[6]
M. Kosugi, T. Ogata, H. Tamura, H. Sano, T. Migita, Chem. Lett. 1986,
15, 1197-1200.
a) C. G. Saluste, R. J. Whitby, M. Furber, Angew. Chem. Int. Ed. 2000,
39, 4156-4158; b) K. K. R. Tetala, R. J. Whitby, M. E. Light, M. B.
Hurtshouse, Tetrahedron Lett. 2004, 45, 6991-6994; c) C. G. Saluste,
S. Crumpler, M. Furber, R. J. Whitby, Tetrahedron Lett. 2004, 45,
6995-6996.
Acknowledgements
[7]
[8]
[9]
F. Zhu, Y. Li, Z. Wang, R. V. A. Orru, B. U. W. Maes, X.-F. Wu, Chem.
Eur. J. 2016, 22, 7743-7746.
The authors thank the Chinese Scholarship Council for financial
Support. We also appreciate the general supports from
Professor Matthias Beller in LIKAT. The analytic supports of Dr.
W. Baumann, Dr. C. Fisher, S. Buchholz, and S. Schareina are
gratefully acknowledged.
a) T. Komiyama, Y. Minami, T. Hiyama, ACS Catal. 2017, 7, 631-651;
b) Y. Nakao, T. Hiyama, Chem. Soc. Rev., 2011, 40, 4893-4901.
H. Kuniyasu, K. Sugoh, M. S. Su, H. Kurosawa, J. Am. Chem. Soc.,
1997, 119, 4669-4677.
General procedure: In a 5 mL pressure tube equipped with a
stirring bar, trimethoxyphenylsilane (0.2 mmol), Cu(OAc)2 (0.4
mmol), PdCl2 (5 mol%), KF (0.4 mmol), isocyanide (0.3 mmol),
aniline (0.3 mmol) and DMF (2 mL) were added. Then close the
tube and heat it up to 120 ℃ for 1 day. Cool the reaction mixture
to room temperature when the reaction completed. The reaction
solution was quenched with distilled water and extracted with
Graphic Abstract
An interesting palladium-catalyzed procedure for the synthesis of amidines
from arylsilanes, isocyanides and amines has been developed.

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