Palladium catalyzed Heck reaction of 2-iodoanilines under ligand-free conditions in air

Article abstract of DOI:10.1080/00397911.2017.1365905

Palladium catalyzed Heck reaction of 2-iodoanilines and acrylate has been developed. The palladium catalyzed Heck reaction of 2-iodoanilines can readily occur in CH₃CN using Pd(OAc)₂ (5.0 mol%) as catalyst, NEt₃ as base un

Full text of DOI:10.1080/00397911.2017.1365905

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Palladium catalyzed heck reaction of 2-
iodoanilines under ligand-free conditions in air
Xia Chen, Xiao-Yu Zhou & Liang-Guang Wang
To cite this article: Xia Chen, Xiao-Yu Zhou & Liang-Guang Wang (2017): Palladium catalyzed
heck reaction of 2-iodoanilines under ligand-free conditions in air, Synthetic Communications, DOI:
10.1080/00397911.2017.1365905
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1365905
View supplementary material
Accepted author version posted online: 21
Aug 2017.
Submit your article to this journal
Article views: 5
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=lsyc20
Download by: [Australian Catholic University]
Date: 26 August 2017, At: 10:30

Palladium catalyzed heck reaction of 2-iodoanilines under
ligand-free conditions in air
Xia Chen*
Department of Chemistry and Materials Engineering, Liupanshui Normal University,
Liupanshui, China
Xiao-Yu Zhou*
Department of Chemistry and Materials Engineering, Liupanshui Normal University,
Liupanshui, China
Liang-Guang Wang
College of Chemistry and Chemical Engineering, Anshun University, Anshun, China
Address correspondence to Xia Chen. E-mail: xia811@live.cn
Address correspondence to Xiao-Yu Zhou. E-mail: Zhouxiaoyu20062006@126.com
ABSTRACT
Palladium catalyzed Heck reaction of 2-iodoanilines and acrylate has been developed. The
palladium catalyzed Heck reaction of 2-iodoanilines can readily occur in CH3CN using Pd(OAc)2
(5.0 mol%) as catalyst, NEt3 as base under ligand-free conditions. And 2-alkenylanilines were
obtained as the cross-coupling products with medium to high yield.
GRAPHICAL ABSTRACT
1

KEYWORDS: 2-iodoaniline, catalysis, heck reaction, ligand-free, palladium
Transition metal catalyzed cross-coupling reactions have been the most effective method
for the construction of carbon-carbon (C-C), carbon-nitrogen (C-N) and carbon-oxygen (C-O)
bonds and lot of literatures data have been reported on palladium catalyzed C-C cross-coupling
reactions. Among the C-C cross-coupling reactions, palladium catalyzed Heck reactions, Suzuki
cross-coupling reactions and Negishi cross-coupling reactions are by far the most widely
exploited.[1] Heck reaction of aryl halides and olefins is one of the earliest and most powerful tools
to construct C-C bonds, which has a great value for the synthesis of natural products,
pharmaceuticals and other functionalized molecules.[2] Alkenyl substituted anilines are a key kind
of building blocks in organic synthesis, which are common and important precursors for the
synthesis of indoles and quinolines. The most simple and direct method to get these compounds is
transition metal catalyzed C-C coupling reaction of halides substituted anilines and alkenes, due
to the high efficiency and selectivity of catalytic systems for the Heck reactions.
Recently, a new generation of catalysts, such as heterogeneous palladium,[3]
palladacycles,[4] iridium,[5] rhodium,[6] nickel[7] and copper[8] catalyst, have extended the scope of
the Heck reaction to almost all aryl halides. Even the electrochemically assisted Heck reaction has
been developed to enhance the efficiency of catalyst.[9] Among these various metal catalyzed
coupling reactions, palladium is largely utilized for forming C-C bond in Heck reactions.[10]In
order to satisfy the needs of organic synthesis, palladium catalyzed Heck reaction in green
2

solvents,[11] asymmetric Heck reactions[12] and oxidative Heck reactions[13] have been reported
respectively. But there are almost no reports focused on palladium catalyzed Heck reactions of
amino substituted starting materials. In view of the application of palladium catalyzed Heck
reactions, the development of catalysis systems to realise the coexisting of palladium catalyst and
amino substituted starting materials is necessary.
From the perspective of productive practice, the previous homogeneous palladium catalyst
suffers several drawbacks like incompatibility with the amino group due to the poisoning of active
palladium catalyst. Besides, the necessary ligands used to form the active catalyst may be
expensive and the removal of the catalyst from the product will be a challenge as the level of
residual palladium in the active pharmaceutical ingredient (API) has to be consistently under 10
ppm. Therefore, the development of palladium catalyzed Heck reaction of 2-iodoanilines under
ligand-free conditions is noteworthy and this simplified catalysis system will promote the
homogeneous palladium catalyzed Heck reaction towards industrialization. Herein, we report an
efficient process for the Pd-catalyzed Heck reaction of 2-iodoanilines and acrylate without the use
of ligand in air (Scheme 1).
In the course of our continuous research on palladium catalyzed reactions of aryl halides
and olefins, ethyl 3-(2-aminophenyl)acrylate 3a was found as the cross-coupling product in Heck
reaction. The study began with 2-iodoaniline and ethyl acrylate as the starting materials, Pd(OAc)2
(5.0 mol%) as catalyst and NEt3 (2.0 equiv) as base in acetonitrile (CH3CN) at 80 oC. The product
3a was isolated with 52% yield (Table 1, Entry 1). This result encouraged us to continue our
studies and confirmed that homogeneous Pd(OAc)2 can be used as the catalyst in Heck reaction of
aryl halides with amino group. And the other solvents, catalysts and bases were evaluated to
improve the efficiency of the reaction.
3

Firstly, ethanol (EtOH, 70%, Entry 2), tetrahydrofuran (THF, 48%, Entry 3) and toluene
(43%, Entry 4) were tested as solvent to improve the yield of 3a in Pd(OAc)2 catalyzed Heck
reaction of 2-iodoaniline at 80 oC. Unfortunately, the results were not satisfactory and only 70%
yield was obtained as the best result. The higher yield was desired and then the reaction was carried
out at 100 oC in solvent of EtOH, 1,4-dioxane and CH3CN respectively (Entries 5-7). The results
indicated that CH3CN (at 100 oC) was the best solvent for Pd(OAc)2 catalyzed Heck reaction of 2-
iodoanilines. Then, other catalysts were evaluated to improve yield of the product 3a. The
heterogeneous catalyst Pd/C and homogeneous catalyst PdCl2 were tested respectively in CH3CN
and no more positive results were obtained (56% and 65%, Enties 8 and 9).
In order to test the effect of base in the Heck reaction, other bases and their amounts were
investigated. The results showed that the yield was decreased to 57% and 53% in the presence of
K2CO3 (1.0 equiv) and Na2CO3 (1.0 equiv) respectively (Entries 10 and 11). These results could
be attributed to the fact that catalyst may be poisoned by the inorganic base and the catalytic
activity was weakened in the Heck reaction. When N-ethyl-N-isopropylpropan-2-amine (DIPEA,
2.0 equiv) was employed as the organic base, the better result was got with 85% yield (Entry 12).
To some extent, this speculation that the catalyst may be poisoned by the inorganic base was
confirmed. Subsequently, the amount of NEt3 was tested and the yield decreased dramatically
when NEt3 (1.0 equiv) was chosen as the base (45%, Entry 13). The Pd(OAc)2 catalyzed Heck
reaction can occur without base but only 19% of 3a was isolated (Entry 14). The above results
indicated that NEt3 (2.0 equiv) and CH3CN might be the choice of base and solvent in Pd(OAc)2
(5.0 mol%) catalyzed Heck reaction of 2-iodoanilines.
With the optimization of solvents, catalysts and bases, the best reaction conditions of
Pd(OAc)2 catalyzed Heck reaction of 2-iodoanilines were obtained, using Pd(OAc)2 (5.0 mol%)
4

as catalyst and NEt3 (2.0 equiv) as base in CH3CN at 100 oC. Based on the optimized conditions,
the substrate scope of Pd(OAc)2 catalyzed Heck reaction of 2-iodoanilines with olefins was tested.
Under the optimal conditions, a variety of 2-iodoanilines 1a–o and derivatives were
subjected to the Pd(OAc)2 catalyzed Heck reaction, as shown in Table 2. For the 2-iodoanilines
1a–j (Table 2, entries 1–10) with different substituents, such as–CH3, -CF3, -Cl, -Br, -F, -NO2 and
–CN, on the 4- or 5- of 2-iodoanilnes, reacted with ethyl acrylate under the optimal reaction
conditions, moderate to high isolated yields (60–93% yield) of 3a-j were achieved. The relatively
higher yields were obtained while the substrates 2-iodoanilines with stronger electron-withdrawing
substituents, such as -NO2 and -CN. And the reaction system also can be applied for the Heck
reaction of 2-iodophenol 1k with 56% yield (Entry 11). The starting material iodobenzene 1l also
been tested in the system and ethyl cinnamate 3l was prepared with 85% yield (Entry 12). It’s
worthy to note that the above optimal conditions are not appropriate for the Heck reaction of
bromobenzene 1m, 2-bromoaniline 1n, 3-iodopyridin-4-amine 1o (Entries 13-15) and almost all
of the starting material were recycled. The reason was speculated that these substrates had the
lower reactivity. The oxidative addition of active palladium species with aryl bromides can’t
proceed smoothly because the C-Br bond was more stable than C-I bond when bromobenzene 1m
and 2-bromoaniline 1n was used as the substrates. And C-I bond in 3-iodopyridin-4-amine 1o also
showed lower activity due to the electron effect of pyridine. When the other olefins were tested in
the Heck reaction, such as ethyl but-2-enoate and ethyl methacrylate, no target products were
detected under the optimal conditions. It may be because the insertion reaction of palladium
complex with olefins is hindered by the substituents of ethyl but-2-enoate and ethyl methacrylate.
In summary, the Pd(OAc)2 catalyzed Heck reaction of 2-iodoanilines and acrylate without
ligands was successfully developed and afforded 2-alkenylanilines with up to 93% yield.[14] And
5

the catalysis system of these reactions will provide a powerful means to develop new applications
for palladium catalyzed C-C, C-N and C-O cross-coupling reactions.
Experimental Section
General Methods: All commercially available reagents were used without further
purification. Column chromatography was performed on silica gel (200–400 mesh). The chemical
shifts (δ) of the 1H NMR (400 MHz) signals are reported in ppm relative to tetramethylsilane (TMS)
and by employing the residual solvent resonance as the internal standard. Data are reported in the
following order: chemical shift, multiplicity [s (singlet), d (doublet), dd (doubletof doublets), t
(triplet), q (quartet), and m (multiplet)], couplingconstants (Hz), and integration. The chemical
shifts (δ) of the 13CNMR (100 MHz) signals are reported in ppm relative tetramethylsilane (TMS)
and by employing the solvent resonance as the internal standard.
A mixture of 2-iodoaniline 1 (0.5mmol) and Pd(OAc)2 (5.6 mg, 0.025 mmol, 5.0 mol%) in
CH3CN (3 mL) was added into a Schlenk flask (25 mL) and stirred at room temperature. Followed
by addition of ethyl acrylate 2a (100 mg, 1,0mmol, 2,0equiv) and triethylamine (101 mg, 1.0
mmol, 2,0 equiv), the mixture was stirred at 100 °C until the reaction was finished. Then the
mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was
purified by column chromatographyon silica gel (petroleum ether/ethyl acetate, 5:1 to 2:1)
afforded the corresponding alkenylanilines 3.
Ethyl 3-(2-aminophenyl)acrylate (3a): Yield: 86%, 82.2 mg, light yellow solid, m.p. 75-
76 oC. 1H NMR (400 MHz, CDCl3): δ 1.33 (t, J = 7.2 Hz,3H), 4.26 (q, J = 7.2 Hz,2H), 6.35 (d, J
= 15.8 Hz,1H), 6.70-6.79 (m, 2H), 7.15-7.19 (m, 1H), 7.37-7.39 (m, 1H), 7.80-7.85 (m, 1H); 13C
6

NMR (100 MHz, CDCl3): δ 14.3, 29.7, 60.4, 116.8, 118.2, 119.0, 120.0, 128.1, 140.0, 145.3, 167.5;
HRMS (EI) Calcd for C11H13NO2: 191.0946 [M]+; found: 191.0942.
Acknowledgment
The work was supported by the Youth Science and Technology Talent Development
Project in Education Department of Guizhou Province (Grant No. qianjiaohe KY zi [2016] number
263) and Innovation Team of Liupanshui Normal University (Grant No. LPSSYKJTD201601).
Supporting Information
1
13
Full experimental detail, H and C NMR spectra. This material can be found via the
“Supplementary Content” section of this article’s webpage.
References
<Number>[1]</Number> Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. Chem. Rev. 2015, 115,
9587.
<Number>[2]</Number> For the application of Heck reaction see: (a) Tietze, L. F.; Nobel, T.;
Spescha, M. J. Am. Chem. Soc.1998, 120, 8971. (b) Dounay, A. B.; Overman, L. E. Chem.
Rev. 2003, 103, 2945. (c) Kwok, T. J.; Virgilio, J. A. Org. Process Res. Dev. 2005, 9, 694.
(d) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4442. (e)
Martins, A.; Marquardt, U.; Kasravi, N.; Alberico, D.; Lautens, M. J. Org. Chem. 2006,
71, 4937. (f) Cvetovich, R. J.; Reamer, R. A.; DiMichele, L.; Chung, J. Y. L.; Chilenski, J.
R. J. Org. Chem. 2006, 71, 8610. (g) Brovetto, M.; Gamenara, D.; Mendez, P. S.; Seoane,
G. A. Chem. Rev. 2011, 111, 4346. (h) Ires, M. J. D.; Poeira, P D. L.; Purificaꢀꢁo, S. I.;
Marques, M. M. B. Org. Lett. 2016, 18, 3250. (i) Azcargorta, A. R.; Coya, E.; Barbolla, I.;
Lete, E.; Sotomayor, N. Eur. J. Org. Chem. 2016, 2054. (j) Donatoni, M. C.; Vieira, Y.
W.; Brocksom, T. J.; Rabelo, A. C.; Leite, E. R.; de Oliveira, K. T. Tetrahedron Lett. 2016,
57, 3016. (k) Debnath, S.; Malakar, S.; Mondal, S. Synthesis 2016, 48, 3544.
<Number>[3]</Number> For Heck reaction under heterogeneous catalysis see: (a) Beletskaya, I.
P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009. (b) Hamza, K.; Abu-Reziq, R.; Avnir,
D.; Blum, J. Org. Lett. 2004, 6, 925. (c) Dahan, A.; Portnoy, M. Org. Lett. 2005, 5, 1197.
(d) Yin, L.; Liebscher, J. Chem. Rev. 2007, 107, 133. (e) Jiang, X.; Sclafani, J.; Prasad, K.;
Repic, O.; Blacklock, T. J. Org. Process Res. Dev. 2007, 11, 769. (f) Lipshutz, B. H.; Taft,
B. R. Org. Lett. 2008, 10, 1329. (g) Schils, D.; Stappers, F.; Solberghe, G.; van Heck, O.
R.; Coppens, M.; den Heuvel, D. V.; der Donck, P. V.; Callewaert, T.; Meeussen, F. Org.
7

Process Res. Dev. 2008, 12, 530. (h) Niembro, S.; Shafir, A.; Vallribera, A.; Alibes, R.
Org. Lett. 2008, 10, 3215. (i) Borja, G.; Monge-Marcet, A.; Pleixats, R.; Parella, T.;
Cattoën, X.; Man, M. W. C. Eur. J. Org. Chem. 2012, 3625. (j) Liu, W.; Wang, D.; Duan,
Y.; Zhang, Y.; Bian, F. Tetrahedron Lett. 2015, 56, 1784.
<Number>[4]</Number> Herrmann, W. A.; Brossmer, C.; Ofele, K.; Reisinger, C.-P.; Priermeier,
T.; Beller, M.; Fischer, H. Angew. Chem. Int. Ed. Engl. 1995, 34, 1844.
<Number>[5]</Number> Satyanarayana, G.; Helmchen, G. Eur. J. Org. Chem. 2014, 2242.
<Number>[6]</Number> Martinez, R.; Voica, F.; Genet, J.-P.; Darses, S. Org. Lett. 2007, 9, 3213.
<Number>[7]</Number> Liu, C.; Tang, S.; Liu, D.; Yuan, J.; Zheng, L.; Meng, L.; Lei, A. Angew.
Chem. Int. Ed. 2012, 51, 3638.
<Number>[8]</Number> Nacci, V. C. A.; Monopoli, A.; Ieva, E.; Cioffi, N. Org. Lett. 2005, 7,
617.
<Number>[9]</Number> Tian, J.; Moeller, K. D. Org. Lett. 2005, 7, 5381.
<Number>[10]</Number> For the palladium catalysis system applied in Heck reactions see: (a)
Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989. (b) Mino, T.; Shirae, Y.; Sasai,
Y.; Sakamoto, M.; Fujita, T. J. Org. Chem. 2006, 71, 6834. (c) Muthumari, S.; Mohan, N.;
Ramesh, R. Tetrahedron Lett. 2015, 56, 4170. (d) Sperger, T.; Stirner, C. K.; Schoenebeck,
F. Synthesis 2017, 49, 115.
<Number>[11]</Number> For Heck reaction in green solvents see: (a) Carmichael, A. J.; Earle,
M. J.; Holbrey, J. D.; McCormac, P. B.; Seddon, K. R. Org. Lett. 1999, 1, 997. (b) Vallin,
K. S. A.; Emilsson, P.; Larhed, M.; Hallberg, A. J. Org. Chem. 2002, 67, 6243. (c)
Selvakumar, K.; Zapf, A.; Beller, M. Org. Lett. 2002, 4, 3031. (d) Chandrasekhar, S.;
Narsihmulu, C.; Sultana, S. S.; Reddy, N. R. Org. Lett. 2002, 4, 4399. (e) Mo, J.; Xu, L.;
Xiao, J. J. Am. Chem. Soc. 2005, 127, 751. (f) Li, S.; Lin, Y.; Xie, H.; Zhang, S.; Xu, J.
Org. Lett. 2006, 8, 391. (g) Xu, H.-J.; Zhao, Y.-Q.; Zhou, X.-F. J. Org. Chem. 2011, 76,
8036.
<Number>[12]</Number> For asymmetric Heck reactions see: (a) Lapierre, A. J. B.; Geib, S. J.;
Curran, D. P. J. Am. Chem. Soc. 2007, 129, 494. (b) Oestreich, M. Angew. Chem. Int. Ed.
2014, 53, 2282. c) Yue, G.; Lei, K.; Hirao, H.; Zhou, J. (S.) Angew. Chem. Int. Ed. 2015,
54, 6531.
<Number>[13]</Number> For oxidative Heck reactions see: (a) Beccalli, E. M.; Broggini, G.;
Martinelli, M.; Sottocornola, S. Chem. Rev. 2007, 107, 5318. (b) Lipshutz, B. H.; Taft, B.
R. Org. Lett. 2008, 10, 1329. (c) Bras, J. L.; Muzart, J. Chem. Rev. 2011, 111, 1170. (d)
He, Z.; Kirchberg, S.; Frçhlich, R.; Studer, A. Angew. Chem. Int. Ed. 2012, 51, 3699. (e)
Izawa, Y.; Zheng, C.; Stahl, S. S. Angew. Chem. Int. Ed. 2013, 52, 3672.
8

Table 1. Conditions optimization for the systhesis of 3a.a
Entry
1
Catalyst
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd/C
base
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
K2CO3
Solvent
CH3CNc
EtOHc
Yield (%)b
52
70
48
43
70
52
86
56
65
57
53
85
45
2
3
THFc
4
Toluenec
EtOH
5
6
1,4-dioxane
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
7
8
9
PdCl2
d
10
11
12
13
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
d
Na2CO3
DIPEA
d
NEt3
9

14
Pd(OAc)2
/
CH3CN
19
aUnless other stated, all reactions are carried out with 1a (0.5 mmol), 2a (1.0 mmol), palladium catalyst (5.0 mol%), base (2.0
equiv.), and solvent (3.0 mL) under air at 100C. bIsolated yields are provided. cCarried out at 80C. d1.0 equiv base was used.
10

Table 2. Investigation of the scope of the starting material 1a and 2a.
Entry
1
Substrate
Product
Yield (%)b
86
2
3
4
5
6
66
75
61
62
66
11

7
85
8
9
93
73
60
10
11
56
12
13
14
85
N/A
N/A
12

15
16
N/A
N/A
17
N/A
1a
aUnless other stated, all reactions are carried out with 1 (0.5 mmol), 2 (1.0 mmol), Pd(OAc)2 (5.0 mol%), NEt3 (2.0 equiv.), and
CH3CN (3.0 mL) under air at 100C. bIsolated yields are provided.
13

Scheme 1. Pd(OAc)2 catalyzed Heck reaction of 2-iodoanilines.
14