Palladium-catalyzed three-component reaction of N-tosyl hydrazones, isonitriles and amines leading to amidines

Article abstract of DOI:10.1039/c5cc06771e

A palladium-catalyzed three-component reaction between N-tosyl hydrazones, aryl isonitriles and amines was developed, leading to amidines in moderate to good yields. This procedure features the rapid construction of amidine frameworks with high diversity and complexity. Ketenimines serve as intermediates, which encounter nucleophilic attack by amines to produce amidines.

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DOI: 10.1039/C5CC06771E
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Palladium-catalyzed three-component reaction of N-tosyl hydrazones,
isonitriles and amines leading to amidines†
Qiang Dai, Yan Jiang, Jin-Tao Yu and Jiang Cheng*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
demonstrated the copperꢀcatalyzed MCRs of azide, alkyne and
amine towards amidine.13 Very recently, Xu developed the access
of amidine between terminal alkyne, acid chloride and
35 carbodiimides.14 Recently, Cai disclosed that isonitriles can react
with Pdꢀcarbenes to form ketenimines, which can be transformed
into amides in the presence of water.15 However, the ketenimine
intermediate failed to be trapped with amines in their procedure,
which would be a potencially facile pathway leading to amidines.
40 Occasionally, we observed the formation of the Nꢀnucleophilic
product when using phenyl isonitrile rather than tertꢀbutyl
isonitrile. This inspired us to further investigate the MCRs
between NꢀTs hydrazone, isonitrile and amine, allowing to rapid
access amidine with high diversity and complexity, which was
45 beneficial to combinatorial chemistry.
A palladium-catalyzed three-component reaction between N-
tosyl hydrazone, aryl isonitrile and amine was developed,
leading to amidines in moderate to good yields. This
procedure features with the rapid construction of amidine
10 framework with high diversity and complexity. Ketenimine
serves as intermediate, which encounters a nucleophilic
attack by amine to produce amidines.
Amidines are ubiquitous in bioactive natural products,1
pharmaceutical
compounds,2
synthetic
intermediates,3
15 neonicotinoid insecticides,4 and ligands in coordinate
chemistry.5 Moreover, they serve as super base6 and
nucleophilic catalysts7 in organic synthesis. However, except
some recent developed methods catalyzed by transition
metal,8 the traditional pathways towards amidines were
20 limited to the transformation of the simple precursors such as
amides, nitriles and oximes.9 The increasing demand on the
diversity and complexity spurred the chemist to develop the
MCRs leading to amidine (Scheme 1). Whitby reported the
combination of ArBr, isonitrile and amine were efficient to
25 construct amidine frameworks.10 Consequently, Zhu
developed the reaction between amine, cyclic ketone and
fluoroalkanesulfonyl azide leading to such a structure.11 The
MCRs between isonitrile, amine and aldehyde was well
developed towards αꢀamino amidines.12 Recently, Chang
Table 1 Screening the optimized reaction conditionsa,
a
Reaction conditions: under air, 1a (0.3 mmol), 2a (0.3 mmol), 3a (0.2
mmol), LiOtBu (0.4 mmol), indicated palladium (5 mol%), PPh3 (15
mol%), solvent (2 mL) at the indicated temperature for 5 h in sealed tube.
b
c
d
Isolated Yields. Indicated reaction conditions without Pd. Indicated
e
f
reaction conditions without PPh3. K2CO3 (0.4 mmol). Cs2CO3 (0.4
mmol). g 1a (0.2 mmol). h 1a (0.2 mmol), 2a (0.4 mmol).
30
Scheme 1 MCRs towards amidine
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DOI: 10.1039/C5CC06771E
We initially test the reaction between benzaldehyde NꢀTs
Next, the scope of isonitrile was studied, as shown in Figure 2.
As expected, all substrate ran smoothly under the procedure.
Notably, the crowded 2,6ꢀdisubstitued phenyl isonitrile provided
35 the MCRs product 23 and 24 in excellent yields (85% and 88%).
Disappointingly, alkyl isonitriles such as tertꢀbutyl isonitrile
didn’t work in our system.
hydrazone, phenyl isonitrile and morpholine in the presence of
o
PdCl2(dppf), PPh3, and LiOtBu in THF under air at 100 C
.
To
our delight, the amidines was isolated in 49% yield (Table 1,
entry 1). Replacing PdCl2(dppf) with PdCl2 slightly increased the
yield to 68% (Table 1, entry 2). Among the palladium tested,
Pd(OAc)2 was the best (74%, Table 1, entry 3); while Pd(PPh3)4
worked to some extent (61%, Table 1, entry 4). Palladium was
essential for this transformation indicated by the blank
5
Figure 2 Substrate scope of isonitriles
10 experiments (Table 1, entry 3). The reaction efficiency decreased
at 80 and 120 C (Table 1, entries 5 and 6). Some solvents, such
Ph
Pd(OAc)2 (5 mol%)
PPh3 (15 mol%)
NNHTs
H
NC
o
HN
R
+
+
R
Ph
O
N
N
tBuOLi (2 equiv.)
THF (2 mL), 100 oC, 5 h
as dioxane, acetonitrile, acetone, ethyl acetate were tested but
they were all inferior to THF (Table 1, entries 7ꢀ10). Switching
the base to K2CO3 and Cs2CO3 slightly decreased the reaction
15 efficiency (63% and 48%, Table 1, entry 11). The ratio of the
three components had some effect on this transformation (Table 1,
entry 12). The configuration of C=N in 5 was confirmed to be E
by single crystal test (for details, see Supporting Information).16
O
1a
3a
2
17-25
Ph
N
MeO
Ph
N
NC
Ph
N
N
N
N
O
O
O
17, 71%
Ph
18, 53%
Ph
19, 72%
Ph
Cl
20 Figure 1 Substrate scope of aldehydic hydrazone
N
N
N
N
N
N
O
O
OMe
O
20, 70%
21, 70%
22, 62%
R
NNHTs
H
Pd(OAc)2 (5 mol%)
PPh3 (15 mol%)
Ph
iPr
Ph
N
Ph
HN
Ph NC
+
+
Ph
tBuOLi (2 equiv.)
THF (2 mL), 100 oC, 5 h
R
N
N
O
N
N
N
N
N
O
O
iPr
O
O
5-16
3a
2a
1
24, 88%
25, 77%
23, 85%
40
OMe
Reaction conditions: under air, 1a (0.2 mmol), 2 (0.4 mmol), 3a (0.2
mmol), LiOtBu (0.4 mmol), Pd(OAc)2 (5 mol%), PPh3 (15 mol%), THF
(2 mL), 100 oC in sealed tube, 5 h.
Ph
Ph
Ph
N
N
N
N
N
N
O
O
O
Figure 3 Substrate scope of amine
6, 66%
5, 70%
7, 55%
Ph
Cl
CN
Br
Pd(OAc)2 (5 mol%)
R1
R2
NNHTs
H
PPh3 (15 mol%)
Ph
R1
+
Ph NC
+
N
N
N
R2
tBuOLi (2 equiv.)
THF (2 mL), 100 oC, 5 h
H
Ph
Ph
Ph
Ph
N
N
N
N
N
N
1a
2a
3
26-37
O
O
O
9, 67%
8, 57%
10, 62%
Ph
N
Ph
N
Ph
N
Ph
Ph
Ph
nPr
N
N
N
N
nPr
Ph
Ph
Ph
N
N
26, 77%
Ph
27, 75%
Ph
28, 90%
N
N
N
N
O
Ph
O
O
13, 71%
12, 61%
Ph
Cy
Ph
Ph
Ph
Ph
11, 76%
N
N
N
N
Ph
N
N
Ph
Cy
Ph
Br
Cl
29, 36%
30, 81%
31, 47%
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
nBu
N
N
N
N
N
N
N
N
Ph
N
N
N
N
O
O
O
H
SiMe3
16, 68%
15, 59%
14, 65%
32, 67%
33, 68%
34, 76%
Ph
Ph
Ph
Reaction conditions: under air, 1 (0.2 mmol), 2a (0.4 mmol), 3a (0.2
mmol), LiOtBu (0.4 mmol), Pd(OAc)2 (5 mol%), PPh3 (15 mol%), THF
(2 mL), 100 oC in sealed tube, 5 h.
Ph
Ph
Ph
N
N
N
N
N
N
H
N
N
35, 73%
36, 64%
37, 76%
45
25
After the establishment of the reaction conditions, the scope of
NꢀTs hydrazone was tested, as shown in Figure 1. To our delight,
the procedure tolerated some functional group, such as bromo,
chloro, cyano and N,Nꢀdimethylamino, which provided handles
for further functionalization. We also tested a variety of Nꢀ
Reaction conditions: under air, 1a (0.2 mmol), 2a (0.4 mmol), 3 (0.2
mmol), LiOtBu (0.4 mmol), Pd(OAc)2 (5 mol%), PPh3 (15 mol%), THF
(2 mL), 100 oC in sealed tube, 5 h.
50
Besides the cyclic amines, this procedure was applicable for
acyclic aliphatic analogues and hetero aromatic amines. For
example, 28, 30 and 35 were isolated in 90%, 81% and 73%
yields, respectively. Notably, hetero aromatic amine produced the
30 tosylhydrazones, such as alkyl aldehyde, alkenyl aldehyde and
ketone analogues, but they didn’t work in our system.
2
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We thank the National Natural Science Foundation of China
40 (nos. 21272028, 21572025 and 21202013), “Innovation &
Entrepreneurship Talents” Introduction Plan of Jiangsu
Province, Qing Lan Project of Jiangsu University, Key Fund
Project of Jiangsu Provincial Department of Education
(15KJA150001), Jiangsu Key Laboratory of Advanced
45 Catalytic Materials&Technology (nos. BM2012110), and the
Priority Academic Program Development of Jiangsu Higher
Education Institutions (PARD) for financial support.
MCRs products 36 and 37 in 64% and 76% yields respectively.
However, aniline failed to work under the standard procedure.
Particularly, diallyl amine worked well under the procedure,
providing 33 in 68% yield. Importantly, the procedure was
applicable for primary amine, as butyl amine delivered 34 in 76%
yield.
Some experiments were conducted to some insights into the
mechanism. Replacing amine with water, product 38 was isolated
in 60% yield, which derived from the nucleophilic attack of
5
10 intermediate by H2O (Scheme 2, eq 1). This result was consistent
with Cai’s report.15 Moreover, the intermediate was captured by
EtOH and BnOH, as confirmed by the formation of products 39
and 40 detected by GCꢀMS (Scheme 2, eq 2). Notably, during the
reaction between isonitrile and NꢀTs hydrazone, a species with
15 molecular weight 193, probably assigned to ketenimine, was
detected by GCꢀMS (For details, see Supporting Information).
Notes and references
School of Petrochemical Engineering, Jiangsu Key Laboratory of
50 Advanced Catalytic Materials & Technology, Jiangsu Province Key
Laboratory of Fine Petrochemical Engineering, Changzhou University,
Changzhou, 213164, P. R. China. E-mail: jiangcheng@cczu.edu.cn
†
Electronic supplementary information (ESI) available: Detailed
synthetic procedures and characterization of new compounds. See DOI:
55 10.1039/ b000000x
1
2
(a) J. V. Greenhill and P. Lue, Prog. Med. Chem., 1993, 30, 203; (b)
Y. Ma, S. De and C. Chen, Tetrahedron, 2015, 71, 1145.
(a) A. Stamford and C. Strickland, Current Opinion in Chemical
Biology in Next generation Therapeutics; P. J. Carter, D. Hazuda,
and J. A. Wells, Eds. 2013, 17, pp 320ꢀ328; (b) S. D. Guile, L.
Alcaraz, T. N. Birkinshaw, K. Bowers, M. R. Ebden, M. Furber, and
M. J. Stocks, J. Med. Chem., 2009, 52, 3123; (c) D. Oehlrich, H.
Prokopcova and H. J. M. Gijsen, Bioorg. Med. Chem. Lett., 2014,
24, 2033; (d) R. D. do Espirito Santo, M. G. M. Machado, J. L. dos
Santos, E. R. P. Gonzalez and C. M. Chin, Curr. Org. Chem., 2014,
18, 2572; (e) J. Oleksyszyn, B. Boduszek, C.ꢀM. Kam and J. C.
Powers, J. Med. Chem., 1994, 37, 226.
60
65
70
75
80
85
Scheme 2 Preliminary mechanism study
20
Base on the property of isonitrile15 and reported literatures,17
similar with Cai’s report, a tentative mechanism was outlined in
Scheme 3. Firstly, the complex A of palladium coordinated with
isonitrile was formed. Then, under basic conditions, detosylation
took place to form a diazo compound, which reacted with
25 palladium to produce a palladium carbene B. After that, the
reaction between palladium carbene and isonitrile provided
ketenimine intermediate C via migratory insertion. Finally, amine
attacked ketenimine to produce the final MCRs product amidines.
3
(a) T. R. M. Rauws and B. U. W. Maes, Chem. Soc. Rev., 2012, 41,
2463; (b) L. Xu, H. Li, Z. Liao, K. Lou, H. Xie, H. Li and W. Wang,
Org. Lett., 2015, 17, 3434.
4
5
S. Kagabu, J. Agric. Food Chem., 2011, 59, 2887.
(a) M. P. Coles, Dalton Trans., 2006, 985; (b) P. S. Lobanov and D.
V. Dar’in, Chem. Heterocycl. Compd., 2013, 49, 507; (c) R. A.
Michelin, P. Sgarbossa, S. M. Sbovata, V. Gandin, C. Marzano and
R. Bertani, ChemMedChem, 2011, 6, 1172; (d) F. T. Edelmann,
Chem. Soc. Rev., 2009, 38, 2253; (e) M. N. Kopylovich and A. J. L.
Pombeiro, Coordin. Chem. Rev., 2011, 255, 339.
J. Y. Quek, T. P. Davis and A. B. Lowe, Chem. Soc. Rev., 2013, 42,
2109.
J. E. Taylor, S. D. Bull and J. M. J. Williams, Chem. Soc. Rev., 2012,
41, 2109.
6
7
8
9
For reviews, see: W.ꢀX. Zhang, L. Xu and Z. Xi, Chem. Commun.,
2015, 51, 254.
(a) P. Oxley and W. F. Short, J. Chem. Soc., 1948, 1514; (b) F.C.
Schaefer and A. P. Krapcho, J. Org. Chem., 1962, 27, 1255; (c) V.
K. Das and A. J. Thakur, Tetrahedron Lett., 2013, 54, 4164; (d) N.
Kumagai, S. Matsunaga and M. Shibasaki, Angew. Chem., Int. Ed.,
2004, 43, 478.
90 10 C. G. Saluste, R. J. Whitby and M. Furber, Angew. Chem., Int. Ed.,
2000, 39, 4156.
11 S. Zhu, Y. Xu and G. Jin, Can. J. Chem., 2003, 81, 265.
12 (a) W. Keung, F. Bakir, A. P. Patron, D. Rogers, C. D. Priest and V.
Darmohusodo, Tetrahedron Lett., 2004, 45, 733; (b) J. W.
30
95
McFarland, J. Org. Chem., 1963, 28, 2179.
Scheme 3 Tentative mechanism.
13 I. Bae, H. Han and S. Chang, J. Am. Chem. Soc., 2005, 127, 2038.
14 X. Xu, J. Gao, D. Cheng, J. Li, G. Qiang and H. Guo, Adv. Synth.
Catal., 2008, 350, 61.
In conclusion, we have developed a palladiumꢀcatalyzed
MCRs between Nꢀtosyl hydrazone, aryl isonitrile and amine,
35 leading to diverse amidines in moderate to excellent yields. The
procedure proceeded with ketenimine intermediate derived from
the reaction between palladium carbene and isonitrile via
migratory insertion.
15 F. Zhou, K. Ding and Q. Cai, Chem.-Eur. J., 2011, 17, 12268.
100 16 The molecular structure of 5 was determined by Xꢀray crystalloꢀ
graphic analysis. CCDC 1422945 (5) contains the supplementary
crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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17 (a) Z. Zhang, Y. Liu, L. Ling, Y. Li, Y. Dong, M. Gong, X. Zhao, Y.
Zhang and J. Wang, J. Am. Chem. Soc., 2011, 133, 4330; (b) L.
Zhou, F. Ye, Y. Zhang and J. Wang, J. Am. Chem. Soc., 2010, 132,
13590; (c) Z. Zhang, Y. Liu, M. Gong, X. Zhao, Y. Zhang and J.
Wang, Angew. Chem. Int. Ed., 2010, 49, 1139.
5
4
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