A recyclable Cu-catalyzed C-N coupling reaction in water and its application to synthesis of imidazo[1,2-a]quinoxaline

Article abstract of DOI:10.1016/j.tet.2013.07.036

Polystyrene-supported pyrrole-2-carbohydrazide (PSP) was synthesized and combined with CuI to make up a recyclable heterogeneous catalytic system for Ullmann-type C-N coupling reaction in water. In which, a variety of functionalized aryl halides animated efficiently with anilines, benzylamine, aliphatic amines, and imidazole. its preliminary application resulted in a more practical synthesis of imidazo[1,2-a]quinoxaline.

Full text of DOI:10.1016/j.tet.2013.07.036

Accepted Manuscript
A recyclable Cu-catalyzed C-N coupling reaction in water and its application to
synthesis of imidazo[1,2-a]quinoxaline
Liye Huang, Ruina Yu, Xinhai Zhu, Yiqian Wan
PII:
S0040-4020(13)01129-0
10.1016/j.tet.2013.07.036
TET 24617
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 1 May 2013
Revised Date: 22 June 2013
Accepted Date: 3 July 2013
Please cite this article as: Huang L, Yu R, Zhu X, Wan Y, A recyclable Cu-catalyzed C-N coupling
reaction in water and its application to synthesis of imidazo[1,2-a]quinoxaline, Tetrahedron (2013), doi:
10.1016/j.tet.2013.07.036.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
A Recyclable Cu-catalyzed C-N Coupling Reaction in Water and
Its Application to Synthesis of Imidazo[1,2-a]quinoxaline
Liye Huang, Ruina Yu, Xinhai Zhu* and Yiqian Wan*
School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, P. R.
China.
Tel: +86-2084113610.
Fax: +86-2084113610.
E-mail: ceswyq@mail.sysu.edu.cn
Abstract:
Polystyrene-supported pyrrole-2-carbohydrazide (PSP) was synthesized and combined with CuI to
make up a recyclable heterogeneous catalytic system for Ullmann-type C-N coupling reaction in
water. In which, a variety of functionalized aryl halides animated efficiently with anilines,
benzylamine, aliphatic amines and imidazole. its preliminary application resulted in a more
practical synthesis of imidazo[1,2-a]quinoxaline.
Keyword:
Green chemistry / Heterogenous catalysis / Copper / Ullmann-type C-N coupling reaction
1
. Introduction
Ullmann-type C-N coupling reaction is one of the most important and versatile tools for direct
preparation of nitrogen-containing arylamines, which have been widely used as agrochemicals,
1
-5
pharmaceutics, conducting polymers, dyes and many intermediates for organic synthesis .
Significant improvements have been recently achieved to reduce the required harsh conditions,
such as high reaction temperature, stoichiometric equivalent of copper reagents and long reaction
6
time, which usually occurs in the initially reported protocols . One of the most critical factors for
the renaissance of Ullmann-type C-N coupling is judicious developments of proper ligands (such
7
,8
9,10
11,12
13
14,15
16,17
18
as: diamines , amino acids , diols , triols , β-diketones , imines
, amino alcohols ,
1
9
diazaphospholane , etc.), because these ligands usually enhanced the solubility of copper salts in
20-22,1,23-26
reaction media and reduced aggregation of copper salts in reaction process
. However,
those protocols based on the ligand-enhancement strategies are usually carried out in the organic
solvents and require relatively complicatied work-up. Recently, several groups have successfully
1
/ 11

ACCEPTED MANUSCRIPT
27-29
performed the Ullmann-type C-N reactions in pure water or aqueous media
with using
water-soluble ligands instead of hydrophobic counterparts. For example, utilization of hydrophilic
27
28
pyridine N-oxides and thiazolyl phosphines
as ligands efficiently facilitaed Cu-catalyzed
amination of aryl bromides and iodides in aqueous media. On the other hand, heterogenous
copper-catalyzed C-N coupling protocols have recently been developed due to their intrinsic
3
0-32
characteristics in the following way: (1) using polymer-supported copper complexs
, (2) using
O in PEG with microwave irradiation
. It should be noted that heterogenization of an
homogeneous catalyst to make a heterogenous one recently has been paid more and more
3
3,34
suitable reaction media, such as CuI in ionic liquid , Cu
2
35
36-38
at 150 ℃ , (3) using nanocatalysts
3
9
attention , because it can often greatly facilitate the work-up of the reaction and the recycle of the
catalyst, as well as can reduce cost and metal contamination, ultimately can lead to greener and
4
0
more environmentally-sustainable chemical transformation processes . For example, Alper and
39
coworkers developed an heterogenous ligand with loading proline that is widely used for
homogenous copper catalyzed C-N couplings in organic solvents, on magnetic nanoparticles by a
simple click chemistry. the recyclable and recoverable ligand coupling with CuI effectively
catalyzed arylation of nitrogen nucleophiles, such as imidazole, pyrazole, indole and
benzimidazole with aryl bromides in DMF. However, developing a recyclable heterogeneous
copper-catalyzed Ullmann-type C-N coupling in water is still little reported and is desired and
challenging to our knowledge. During the investigation of Cu-catalyzed Ullmann-type crossing
41-44
coupling reactions in water
, we have found N'-phenyl-1H-pyrrole-2-carbohydrazide to be
promising to make the reaction with the advantage of broad substrate range, low catalyst loading,
4
2
and availability of various copper sources when relatively high loading of the ligand . Hence, it is
reasonable for us to immobilize the pyrrole-2-carbohydrazide to make up a recyclable
heterogeneous catalytic system to reduce its consumption.
2
. Experimental
All starting materials and reagents are commercially available and were used as received. All
reactions were carried out in 10 mL vials sealed with a septum. Flash column chromatography was
performed on silica gel (200-300 mesh). Thin-layer chromatography was carried out with Merck
1
13
silica gel GF254 plates. H NMR and C NMR spectra were recorded at r.t. on a Mercury-Plus 300
or a Bruker AVANCE 400 instrument with TMS as an internal reference. LC/MS was run on a
2
/ 11

ACCEPTED MANUSCRIPT
LCMS-2010A or a LCQ DECA XP instrument. GC/MS was run on a Finnigan Voyager with an
electron impact (70 eV) mass selective detector and an innowax 30 m × 0.25 mm × 0.25 µm
capillary apolar column. GC-MS method: Initial temperature: 50 ℃, initial time: 3 min; Ramp: 20
℃
/min; Final temperature: 250 ℃, Final time: 2 min. EI mass spectra were recorded on the
Thermo DSQ mass spectrometer. GPC was run on a Waters Breeze Gel Permeation
Chromatograph. IR spectra were recorded on an EQUINOX 55 Fourier transformation infrared
spectrometer coupled with an infrared microscope.
45
2
.1 Preparation of Polystyrene-supported pyrrole-2-carbohydrazide (PSP)
PS-NO : atactic polystyrene (PS, 10 g) in CH Cl (100 mL) was added dropwise to the nitrating
mixture (90 mL 70% HNO and 10 mL concentrated H SO ) with vigorous stirring at 0 ℃ over 1
2
2
2
3
2
4
hour. The mixture was then stirred at room temperature until the conversion of PS up to 40-50%
1
indicated by H NMR monitoring. The acid phase was removed and the organic phase was
dropped into 800 mL ethanol to precipitate the nitrated PS. The crude nitrated PS was re-dissolved
in CH
was dried in vacuo for 24 hours at 50 ℃ to afford yellow solids (12 g).
PS-NH : PS-NO (5 g) was dissolved in DMF (50 mL) and added dropwise to 100 mL of muriatic
2 2 2
Cl and precipited in ethanol for another three times for further purification. the PS-NO
2
2
acid (12 mol/L) with stirring at 60 ℃. The mixture was then heated to 100 ℃ and granulate tin
metal (10 g) was added, after 3 h stirring, another 20 g of tin metal was added in four portions
every 3 h. The reaction mixture was filtrated at that temperature until the tin metal disappeared
and the precipitates was washed with water to pH=7 and dried in vacuo at room temperature for
2
4 hours to afford yellowish solids (4 g).
PS-NHNH : PS-NH (1 g) was swollen in 15 mL CH
muriatic acid (12 mol/L) in ice bath with stirring. NaNO
to the reaction mixture in 6 portions within 18 h. The solution of SnCl
acid (12 mol/L) was then added dropwise over 30 min. The reaction was allowed to rise naturally
to r.t. and then stirred overnight. After removal of CH Cl in vacuo and filtration, the precipitates
O, dried in vacuo at room temperature for 24
2
2
2
Cl
2
and the mixture was added to 25 mL of
(1.2 g in 3 mL H O) was carefully added
(10 g) in 8 mL of muriatic
2
2
2
2
2
were washed with muriatic acid (12 mol/L) and H
2
hours to afford yellow solids (1 g).
PSP: PS-NHNH
2
(1 g), 1H-pyrrole-2-carboxylic acid (1 g), 4-Dimethylaminopyridine (DMAP, 2
g), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI, 3 g) and 100 mL of
3
/ 11

ACCEPTED MANUSCRIPT
CH Cl were charged to a 250 mL round flask. The mixture was stirred at r.t. for 48 h. after
2
2
filtration, the precipitates were washed with CH
temperature for 24 hours to afford PSP to afford brownish solids (1.4 g).
.2 Quantitative determination of ligand loading in PSP
Potassium sulfocyanate (KSCN) was chosen as an internal standard, because it has only one
2 2
Cl and MeOH, dried in vacuo at room
2
-1
strong absorption peak at 2050 cm and the peak was chosen as its quantitative peak. The peak at
-1
1
630 cm is the characteristic absorption of carbonyl and was chosen as the quantitative peak of
the ligand. The ratio of the two absorbencies is defined as I, and I = A /AKSCN. KSCN and the
Lig
ligand were mixed according to a certain mass ratio C = MLig/( MLig +MKSCN) to prepare standard
samples. The curve of C versus I was defined as the quantitative work curve. The results of the
expt. indicated that the work curve has good linearity when the ligand concentration was in the
range of 10% -60% of the mixture. Hence, the loading of the ligand was caculated according to
the formula (Y = 0.03 + 2.03X, Y: the absorbance ratio, X: the quantity of ligand).
Scheme 1. the preparation of PSP
2
.3. General protocol for C-N coupling reaction
A 10 mL of vial was charged with CuI (10 mg, 0.05 mmol), PSP (0.25 mmol, size less than 90
M ), TBAB (40 mg, 0.25 mmol), base (1.0 mmol), aryl halides ( 0.5 mmol), arylamine (2.0
mmol), H O (1.0 mL) and a magnetic stir bar. The vessel was sealed with a septum and placed
ꢀ
2
into an oil bath, which was preheated to 70 ℃ (90 ℃ for alkyl amine, 120 ℃ for imidazole).
The reaction mixture was stirred for another 16 hours (8 h for imidazole). After allowing the
mixture to cool to room temperature, the reaction mixture was filtrated, the precipitates were
washed with water and ethyl acetate thoroughly. The filtrate was extracted with ethyl acetate (3 ×
4
/ 11

ACCEPTED MANUSCRIPT
25 mL). The combined organic phases was washed with water and brine, dried over anhydrous
Na
silica gel to afford the desired products.
. Results and Discussion
The PS-supported pyrrole-2-carbohydrazide (PSP) was successfully prepared (scheme 1) referring
2 4
SO , and concentrated in vacuo. The residue was purified by flash column chromatograph on
3
4
2,45,46
to the reported methods
and confirmed to be thermal stable below 200 ℃ by thermal
gravitational analysis. Hence, we initially examined PSP as a ligand for promoting the
Cu-catalyzed amination of 4-bromoanisole with aniline (Scheme 2). As expected, addition of 57
mol % of PSP and CuI resulted in the desired product with 69% isolated yield after 1 hour at 130
°
C in water.
Scheme 2. the model reaction for optimization
The scope and generality of the C-N coupling reaction promoted by CuI/PSP was then
investigated after detailed exploration of the reaction parameters, including common
commercially available copper sources, bases, the reaction times, temperature, and the catalyst
loading under the optimized conditions [amine (400 mol %), CuI (10 mol %), PSP (50 mol %),
2
TBAB (50 mol %), KOH (200 mol %), H O (1 mL), 70 ℃, 16 h]. As expected, this
heterogeneous catalyst system promoted amination of a variety of functionalized aryl halides with
anilines, benzylamine and aliphatic amines and imidazole in water, although highly sterically
hindered amine did not arylated efficiently under the experimental conditions(Fig 1, 2, 3, 4),
5
/ 11

ACCEPTED MANUSCRIPT
[
a] Reaction condition: aryl bromide (0.5 mmol), aniline or bezylamine (2.0 mmol), CuI (10 mol
%
), PSP (50 mol %), TBAB (50 mol %), KOH (200 mol %), H
Aryl halide was 4-Iodoanisole. [c] Reaction time was 8 h. [d] The Aryl halide was
-Chloronitrobenzene.
Fig 1. the reaction of aryl halides with aniline and benzylamine
2
O (1 mL), 70 ℃, 16 h. [b] The
4
[
(
a] Reaction condition: aryl bromide (0.5 mmol), alkyl amine (2.0 mmol), CuI (10 mol %), PSP
50 mol %), TBAB (50 mol %), KOH (200 mol %), H O (1 mL), 90 ℃, 16 h. [b] Isolate yield for
2
1
-bromobutane reacting with aniline. [c] Normalized GC yield for 1-bromobutane reacting with
aniline. [d] Reaction temperature was 70 ℃. [e] Reaction temperature was 120 ℃. [f] The Aryl
halide was 4-Iodoanisole.
Fig 2. the reaction of aryl halides with alkyl amines.
[
a] Reaction condition: aryl Iodide (0.5 mmol), imidazole (2.0 mmol), CuI (10 mol %), PSP (50
mol %), TBAB (50 mol %), K PO (200 mol %), H O (1 mL), 120 ℃, 16 h. [b] Base was KOH.
c] The Aryl halide was 4-bromoanisole.
Fig 3. the reaction of aryl iodide with imidazole
3
4
2
[
6
/ 11

ACCEPTED MANUSCRIPT
[
a] Reaction condition: 3-bromopyridine (0.5 mmol), amine (2.0 mmol), CuI (10 mol %), PSP (50
mol %), TBAB (50 mol %), KOH (200 mol %), H O (1 mL), 16 h.
2
Fig 4. the reaction of 3-bromopyridine with different nitrogen sources.
To make it to advance, we explored its recyclability using arylation of imidazole with
1
-iodo-4-methoxybenzene as a model reaction. After filtration, washed with water and ethyl
acetate in succession, dried in vacuo, the recovered PSP was used again to run the model reaction
directly. As shown in Fig 5, after four times of recycling of PSP, the yields of reaction was
retained. Hence, the shortage of necessitating high loading of ligand and CuI could be partially
overcome by the reuse of the PSP.
1
00
9
8
7
6
5
0
0
0
0
0
Series1
1
2
3
4
5
Recycle time
Fig 5. The recyclability of PSP for the reaction of 1-iodo-4-methoxybenzene with 1H-imidazole
7
/ 11

ACCEPTED MANUSCRIPT
Scheme 3. a practical route to imidazo[1,2-a]quinoxaline
As well known, many imidazo[1,2-a]quinoxaline derivatives have been confirmed to be diversely
47
48
bioactive (e.g. anticancer agents , A1-adenosine receptor antagonist , or 5-HT3 receptor
49
agonists ). EAPB2023, a lead compound with significant activity in vitro against the human
4
7
melanoma cell line A375, was recently reported . To construct the key tricyclic structure, the
intramolecular cyclization of N-(2-fluorophenyl)-1H-imidazole-2-carboxamide with NaH in DMA
is necessary. The shortages of requiring inert atomsphere, strong base and organic solvent
encouraged us to apply our system for the synthesis of EAPB2023. In which, the crucial step is
using N-(2-iodophenyl)-1H-imidazole-2-carboxamide C instead of N-(2-fluorophenyl)-1H-
imidazole-2-carboxamide to perform the intramolecular C-N coupling (scheme 3). As expected,
the tricyclic key intermediate D for the synthesis of imidazo[1,2-a]quinoxaline derivatives was
obtained with the following advantages: ⑴ K
water was used to replace organic solvent DMA.
. Conclusions
In conclusion, we have established a recyclable, environmentally benign heterogeneous
3 4
PO was used instead of the air-sensitive NaH, ⑵
4
CuI/PSP catalytic system for Ullmann-type C-N coupling reaction. This heterogenous catalyst
system has almost the same talent as that of our previously reported homogenous one. In which, a
variety of functionalized aryl halides can efficiently animate with anilines, benzylamine, aliphatic
amines and imidazole. its preliminary application gives birth to a alternative route to
imidazo[1,2-a]quinoxaline derivatives, in which, avoiding use of the air-sensitive NaH and the
organic solvent DMA made the operation much more practical.
Acknowledgments
8
/ 11

ACCEPTED MANUSCRIPT
This work was supported financially by grants from the National Natural Science Foundation
of China (21272287, 21272282) and the Fundamental Research Funds for the Central Universities.
1
2
.
.
Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428-2439.
Lawrence, S. A. Amines: Synthesis Properties and Applications; Cambridge University Press:
Cambridge, UK, 2004.
3
.
Weissermel, K.; Arpe, H.-J. Industrial Organic Chemistry 3rd ed.; Wiley-VCH: Weinheim,
1
997.
4
5
6
.
.
.
Corbet, J.-P.; Mignani, G. Chem. Rev. 2006, 106, 2651-2710.
Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054-3131.
C.Larock, R. Comprehensive Organic Transformations: a guide to functional group
preparation, 2nd ed.; Wiley-VCH: New York, 1999.
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
.
Klapars, A.; Huang, X.; Buchwald, S. L. J Am Chem Soc 2002, 124, 7421-7428.
Antilla, J. C.; Klapars, A.; Buchwald, S. L. J Am Chem Soc 2002, 124, 11684-11688.
Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450-1460.
.
.
0.
1.
2.
3.
4.
5.
6.
7.
8.
9.
0.
1.
Ma, D.; Xia, C. Org. Lett. 2001, 3, 2583-2586.
Jiang, D.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2007, 72, 672-674.
Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581-584.
Chen, Y.-J.; Chen, H.-H. Organic Letters 2006, 8, 5609-5612.
Xia, N.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 337-339.
Shafir, A.; Buchwald, S. L. Journal of the American Chemical Society 2006, 128, 8742-8743.
Liu, Y.-H.; Chen, C.; Yang, L.-M. Tetrahedron Letters 2006, 47, 9275-9278.
Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Chem.--Eur. J. 2004, 10, 5607-5622.
Lu, Z.; Twieg, R. J. Tetrahedron Letters 2005, 46, 2997-3001.
Yang, M.; Liu, F. J. Org. Chem. 2007, 72, 8969-8971.
Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004, 248, 2337-2364.
Cai, Q.; Zhang, H.; Zou, B.; Xie, X.; Zhu, W.; He, G.; Wang, J.; Pan, X.; Chen, Y.; Yuan, Q.;
Liu, F.; Lu, B.; Ma, D. Pure. Appl. Chem. 2009, 81, 227-234.
2
2
2
2
2
2
2
2.
3.
4.
5.
6.
7.
8.
Das, P.; Sharma, D.; Kumar, M.; Singh, B. Curr. Org. Chem. 2010, 14, 754-783.
Ley, S. V.; Thomas, A. W. Angewandte Chemie, International Edition 2003, 42, 5400-5449.
Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954-6971.
Surry, D. S.; Buchwald, S. L. Chem. Sci. 2010, 1, 13-31.
Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450-1460.
Liang, L.; Li, Z.; Zhou, X. Org. Lett. 2009, 11, 3294-3297.
Oshovsky, G. V.; Ouali, A.; Xia, N.; Zablocka, M.; Boere, R. T.; Duhayon, C.; Taillefer, M.;
Majoral, J. P. Organometallics 2008, 27, 5733-5736.
2
3
9.
0.
Carril, M.; SanMartin, R.; Dominguez, E. Chem. Soc. Rev. 2008, 37, 639-647.
Islam, S. M.; Mondal, S.; Mondal, P.; Roy, A. S.; Tuhina, K.; Salam, N.; Mobarak, M. J.
Organomet. Chem. 2012, 696, 4264-4274.
3
1.
Islam, S. M.; Mondal, S.; Mondal, P.; Roy, A. S.; Tuhina, K.; Mobarok, M. Inorganic
Chemistry Communications 2011, 14, 1352-1357.
9
/ 11

ACCEPTED MANUSCRIPT
3
2.
Kantam, M. L.; Roy, M.; Roy, S.; Sreedhar, B.; Lal De, R. Catalysis Communications 2008, 9,
2
226-2230.
3
3
3
3
3.
4.
5.
6.
Yan, J.-C.; Zhou, L.; Wang, L. Chin. J. Chem. 2008, 26, 165-169.
Lv, X.; Wang, Z.; Bao, W. Tetrahedron 2006, 62, 4756-4761.
Colacino, E.; Villebrun, L.; Martinez, J.; Lamaty, F. Tetrahedron 2010, 66, 3730-3735.
Harsha, K.; Reddy, V.; Satish, G.; Ramesh, K.; Karnakar, K.; Nageswar, Y. V. D.
Tetrahedron Lett. 2012, 53, 3061-65.
3
7.
Ganesh Babu, S.; Karvembu, R. Industrial & Engineering Chemistry Research 2011, 50,
9
594-9600.
3
3
8.
9.
Rout, L.; Jammi, S.; Punniyamurthy, T. Org. Lett. 2007, 9, 3397-3399.
Chouhan, G.; Wang, D.; Alper, H. Chemical Communications (Cambridge, United Kingdom)
2
007, 4809-4811.
Zeng, M.; Zhang, X.; Shao, L.; Qi, C.; Zhang, X.-M. Journal of Organometallic Chemistry
012, 704, 29-37.
4
0.
2
4
4
1.
2.
Meng, F.; Wang, C.; Xie, J.; Zhu, X.; Wan, Y. Appl. Organomet. Chem. 2011, 25, 341-347.
Xie, J.; Zhu, X.; Huang, M.; Meng, F.; Chen, W.; Wan, Y. Eur. J. Org. Chem. 2010,
3
219-3223.
Zhu, X.; Su, L.; Huang, L.; Chen, G.; Wang, J.; Song, H.; Wan, Y. Eur. J. Org. Chem. 2009,
35-642.
4
3.
6
4
4
4
4.
5.
6.
Zhu, X.; Ma, Y.; Su, L.; Song, H.; Chen, G.; Liang, D.; Wan, Y. Synthesis 2006, 3955-3962.
Chattopadhyay, P.; Sinha, C.; Pal, D. K. Fresenius' J. Anal. Chem. 1997, 357, 368-372.
Hunsberger, I. M.; Shaw, E. R.; Fugger, J.; Ketcham, R.; Lednicer, D. J. Org. Chem. 1956, 21,
3
94-9.
4
4
4
7.
8.
9.
Deleuze-Masquefa, C.; Moarbess, G.; Khier, S.; David, N.; Gayraud-Paniagua, S.; Bressolle,
F.; Pinguet, F.; Bonnet, P.-A. Eur. J. Med. Chem. 2009, 44, 3406-3411.
Ceccarelli, S.; D'Alessandro, A.; Prinzivalli, S.; Zanarella, S. Eur. J. Med. Chem. 1998, 33,
9
43-955.
Campiani, G.; Morelli, E.; Gemma, S.; Nacci, V.; Butini, S.; Hamon, M.; Novellino, E.; Greco,
G.; Cagnotto, A.; Goegan, M.; Cervo, L.; Dalla Valle, F.; Fracasso, C.; Caccia, S.; Mennini, T.
J. Med. Chem. 1999, 42, 4362-4379.
10 / 11

ACCEPTED MANUSCRIPT
Graphic Abstract,
11 / 11

ACCEPTED MANUSCRIPT
Supporting information for:
A Recyclable Cu-catalyzed C-N coupling reaction in water and
its application to synthesis of imidazo[1,2-a]quinoxaline
Liye Huang, Ruina Yu, Xinhai Zhu* and Yiqian Wan*
School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, P. R.
China.
Tel: +86-2084113610.
Fax: +86-2084113610.
E-mail: ceswyq@mail.sysu.edu.cn
Table of contents
1
2
3
4
5
6
7
. General condition........................................................................................................................ s2
. General procedure....................................................................................................................... s2
. Characterization of PSP .............................................................................................................. s3
. Data of coupling reaction of aryl halides with amines................................................................ s6
. Analytical data ............................................................................................................................ s7
. IR and NMR spectra ................................................................................................................. s25
. References................................................................................................................................. s80
s1

ACCEPTED MANUSCRIPT
1
. General condition
All starting materials and reagents are commercially available and were used as received. All
reactions were carried out in 10 mL vials sealed with a septum. Flash column chromatography was
performed with silica gel (200-300 mesh). Thin-layer chromatography was carried out with Merck
1
13
silica gel GF254 plates. H NMR and C NMR spectra were recorded at r.t. on a Mercury-Plus 300
or a Bruker AVANCE 400 instrument with TMS as an internal reference. LC/MS was run on a
LCMS-2010A or a LCQ DECA XP instrument. GC/MS was run on a Finnigan Voyager with an
electron impact (70 eV) mass selective detector and an innowax 30 m × 0.25 mm × 0.25 um
capillary apolar column. GC-MS method: Initial temperature: 50 ℃, initial time: 3 min; Ramp:
2
0 ℃/min; Final temperature: 250 ℃, Final time: 2 min. EI mass spectra were recorded on the
Thermo DSQ mass spectrometer. GPC was run on a Waters Breeze Gel Permeation
Chromatograph. IR spectra were recorded on an EQUINOX 55 Fourier transformation infrared
spectrometer coupled with an infrared microscope.
2
. General procedure
A 10 mL of vial was charged with CuI (10 mg, 0.05 mmol), PSP (0.25 mmol, size less than 90
μM ), TBAB (40 mg, 0.25 mmol), base (1.0 mmol), aryl halides ( 0.5 mmol), arylamine (2.0
2
mmol), H O (1.0 mL) and a magnetic stir bar. The vessel was sealed with a septum and placed
into an oil bath, which was preheated to 70 ℃ (90 ℃ for alkyl amine, 120 ℃ for imidazole).
The reaction mixture was held at this temperature for 16 hours (8 h for imidazole). After allowing
the mixture to cool to room temperature, the reaction mixture was filtrated, the precipitates was
washed with water and ethyl acetate thoroughly. The filtrate was extracted with ethyl acetate (3 ×
2
5 mL). The combined organic phases was washed with water and brine, dried over anhydrous
Na SO , and concentrated in vacuo. The residue was purified by flash column chromatograph on
2
4
silica gel to afford the desired products.
After reaction, the PSP was obtained by filtration following washed with water and ethyl acetate.
After dried in vacuo, the PSP was used again to run the model reaction directly
s2

ACCEPTED MANUSCRIPT
3
. Characterization of PSP
Fig 1. The GPC of PS
C
mass loss/%
100
80
60
40
20
0
time /min
0
50
100
150
200
250
300
350
400
temp
Fig.2 Tg curve of PSP
s3

ACCEPTED MANUSCRIPT
Table 1. the XPS result of PSP
Start
BE
Peak
BE
End
BE
Height
CPS
FWHM Area (P) Area (N)
Name
At. %
eV
CPS.eV
43753.23
11905.44
4868.58
8689.61
683.05
KE^1.0
0.24
0.03
0.02
0.01
0
C1s 296.35 284.78 281.3 26674.18
O1s 538.55 533.14 527.1 4132.99
1.34
2.49
1.87
2.04
0.09
0.37
1.27
78.32
9.12
5.46
4.87
0.08
0.94
1.2
N1s
F1s
410.7 400.33 394.45 1683.19
696.4 690.33 685.65 3748.24
5
Sn3d 493.06 487.1
482.2
215.1
248.3
Si2p
Cl2p
111.1 103.93 99.45
210.6 200.59 195.65
610.17
0
884.74
2021.54
0
Table 2. Analytical data of IR spectra
entry
Lig % (w/w)
A
Lig
A
KSCN
Rate (ALig / AKSCN
)
1
2
3
4
5
6
10
20
30
40
50
60
19.65
19.65
27.63
46.13
45.21
47.00
83.25
40.38
47.32
53.47
45.95
36.08
0.236
0.487
0.5842
0.863
0.984
1.303
C=O
KSCN
Fig 3. Part of IR spectra for different rate of WLig /( WLig+WKSCN
)
s4

ACCEPTED MANUSCRIPT
Linear Regression for Data15_B:
Y = A + B * X
Parameter
Value
Error
------------------------------------------------------------
A
B
0.03226 0.05252
2.02965 0.13487
-
-----------------------------------------------------------
SD N
-----------------------------------------------------------
.99128 0.05642 6 1.13609E-4
R
P
-
0
Scheme 1. the formula of the absorbance ratio (ALig / AKSCN) with the quantity of ligand
When WPSP/ (WPSP+WKSCN) = 90%, measure APSP/AKSCN = 1.074,
So Wlig/ (WPSP+WKSCN) = 0.51
The quantitative determination of ligand loading in PSP is Wlig/ WPSP = 0.51/0.9 = 57%.
s5

ACCEPTED MANUSCRIPT
4
. Data of coupling reaction of aryl halides with amines
[
a]
Table 2. Optimization of coupling reaction of 4-bromoanisole with aniline .
Entry [Cu]
PSL
Base
PTC
Yield
[
b]
(
mol-%)
(mol-%) (mol-%)
(mol-%)
(%)
0
1
2
3
none
50
50
50
KOH (200)
TBAB (50)
TBAB (50)
TBAB (50)
CuI (5)
CuI (10)
KOH (200)
KOH (200)
60
[
d]
[c]
(95/92, 98/98 , ) ,
7
2
[
[
[
[
[
c]
c]
c]
c]
c]
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
Cu
CuSO
CuO (10)
Cu(NO
Cu(OAc)
CuCl (10)
2
O (10)
50
50
50
50
50
50
50
none
25
75
50
50
50
50
50
50
50
50
KOH (200)
KOH (200)
KOH (200)
KOH (200)
KOH (200)
KOH (200)
KOH (200)
KOH (200)
KOH (200)
KOH (200)
KOH (100)
KOH (300)
TBAB (50)
TBAB (50)
TBAB (50)
TBAB (50)
TBAB (50)
TBAB (50)
TBAB (50)
TBAB (50)
TBAB (50)
TBAB (50)
TBAB (50)
TBAB (50)
TBAB (50)
TBAB (50)
TBAB (50)
TBAB (50)
TBAB (50)
TBAB (25)
(84/82)
(90/88)
(85/83)
(57/56)
4
(10)
3
)
2
(10)
(10)
2
(94/92) , 66
[
c]
2
(77/76)
0
1
2
3
4
5
6
7
8
9
0
1
Cu (10)
50
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
0
30
29
35
35
K
3
2
PO
4
(200)
(200)
48
K
CO
3
16
Na
Cs
2
CO
3
(200)
(200)
17
2
CO
3
28
KF (200)
trace
21
KOH (200)
s6

ACCEPTED MANUSCRIPT
2
2
2
2
2
3
4
5
CuI (10)
CuI (10)
CuI (10)
CuI (10)
50
50
50
50
KOH (200)
KOH (200)
KOH (200)
KOH (200)
TBAB (100)
73
SDS-Na (50) 14
[
e]
[f]
TBAB (50)
TBAB (50)
55 , 73
[g]
[h]
[i]
54 , 71 , 49
[
a] Reaction condition: 4-bromoanisole (0.5 mmol), aniline (2.0 mmol), catalyst, PSL,
Phase-transfer (PTC), base, water (1 mL), 70 ℃, 14 h. [b] Isolate yield. [c] conversion / yield,
calculate by GC. [d] Reaction time was 16 h. [e] Aniline (1.5 mmol). [f] Aniline (2.5 mmol). [g]
Reaction temperature was 70 ℃. [h] Reaction temperature was 90 ℃. [i] Reaction time was 8 h.
5. Analytical data
IR of ligand with KSCN
-
1
IR (KBr cm ): 3434, 3283, 2050, 1630, 1596, 1564, 1534, 1488, 1437, 1357, 1134, 1114, 772,
39, 704.
IR of PSP with KSCN
7
-
1
IR (KBr cm ): 3426, 3025, 2916, 2050, 1600, 1505, 1484, 1448, 1488, 1244, 1032, 748, 696,.
1
PS: HNMR (300MHz, CDCl
3
): δ 7.20-6.81 (m, ArH, 3H), 6.76-6.28 (m, ArH, 2H), 1.97-1.12 (m,
CHCH
2
, 3H).
1
PS-NO
2
: HNMR (300MHz, CDCl
3
): δ 7.84 (s, ArH, 0.95H), 7.05 (m, ArH, 1.26H), 6.48 (s, ArH,
2
2
H), 1.85-1.19 (m, CHCH , 3H).
s7

ACCEPTED MANUSCRIPT
1
Diphenylamine (1a)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:80) as eluent to afford Diphenylamine (63 mg, 74%), colorless solid.
+
+
1
3
MS (EI ): m/z: 169 (M , 100). HNMR (300MHz, CDCl ): δ 7.35-7.27 (m, ArH, 4H), 7.15-7.08
1
3
(
3
m, ArH, 4H), 7.01-6.93 (m, ArH, 2H). CNMR (75 MHz, CDCl ): δ 143.1, 129.4, 121.1, 117.9.
1
4
-methoxy-N-phenylaniline (1b)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:40) as eluent to afford 4-methoxy-N- phenylaniline (72 mg, 72%),
white solid.
+
+
1
MS (EI ): m/z: 199 (M , 55), 184 (M-CH
3
, 100). HNMR (300MHz, CDCl
3
): δ 7.30-7.10 (m, ArH,
, 3H).
2
H), 7.10-6.94 (m, ArH, 2H), 6.92-6.52 (m, ArH, 5H), 5.44 (brs, 1H), 3.76 (s, OCH
3
1
3
CNMR (75 MHz, CDCl
3
): δ 155.3, 145.1, 135.7, 129.3, 122.3, 119.7, 115.8, 114.8, 55.7.
2
2
-methoxy-N-phenylaniline (1c)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:80) as eluent to afford 2-methoxy-N- phenylaniline (57 mg, 57%),
colorless oil .
+
+
+
1
MS (EI ): m/z: 199 (M , 100), 184 ([M-CH
ArH, 3H), 7.16-7.09 (m, ArH, 2H), 6.96-6.80 (m, ArH, 4H), 3.87 (s, OCH
MHz, CDCl ): δ 148.3, 142.7, 133.0, 129.3, 121.2, 120.9, 120.0, 118.6, 114.8, 110.6, 55.8.
3
] , 75). HNMR (300MHz, CDCl
3
): δ 7.31-7.20 (m,
1
3
3
, 3H). CNMR (75
3
3
3
-methoxy-N-phenylaniline (1d)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:40) as eluent to afford 3-methoxy-N- phenylaniline (78 mg, 78%),
s8

ACCEPTED MANUSCRIPT
white solid.
+
+
1
MS (EI ): m/z: 199 (M , 100). HNMR (300MHz, CDCl
3
): δ 7.36-7.28 (m, ArH, 2H), 7.25-7.18
(
m, ArH, 1H), 7.13 (m ArH , 2H), 7.04-6.96 (m, ArH, 1H), 6.70 (m, ArH, 2H), 6.58-6.51 (m, ArH,
1
3
1
1
3 3
H), 5.44 (brs, 1H), 3.82 (s, OCH , 3H). CNMR (75 MHz, CDCl ): δ 160.6, 144.6, 142.8, 130.1,
29.3, 121.3, 118.4, 110.2, 106.2, 103.3, 55.3.
1
4
-methyl-N-phenylaniline (1e)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:80) as eluent to afford 4-methyl-N- phenylaniline (66 mg, 72%),
colorless solid.
+
+
1
MS (EI ): m/z: 183 (M , 100). HNMR (300MHz, CDCl
3
): δ 7.25-7.15 (m, ArH, 2H), 7.10-7.01
(
m, ArH, 2H), 7.01-6.92 (m, ArH, 4H), 6.88-6.80 (m, ArH, 1H), 5.56 (brs, 1H), 2.28 (s, CH , 3H).
3
1
3
CNMR (75 MHz, CDCl
3
): δ 143.9, 140.3, 131.0, 129.9, 129.3, 120.4, 119.0, 116.9, 20.9.
1
4
-chloro-N-phenylaniline (1f)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:20) as eluent to afford 4-chloro-N-phenylaniline (83 mg, 82%),
colorless solid.
+
+
+
1
MS (EI ): m/z: 203 (M , 100), 167 ([M-Cl] , 70). HNMR (300MHz, CDCl
3
): δ 7.36-7.27 (m,
ArH, 2H), 7.27-7.21 (m, ArH, 2H), 7.12-7.04 (m, ArH, 2H), 7.04-6.96 (m, ArH, 3H), 5.30 (brs,
1
H).
1
3
CNMR (75 MHz, CDCl
3
): δ 142.6, 141.8, 129.4, 129.3, 125.5, 121.5, 118.8, 118.1.
1
1
-(4-(phenylamino)phenyl)ethanone (1g)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:5) as eluent to afford 1-(4-(phenylamino)phenyl)ethanone (86 mg,
8
2%), yellow solid.
+
+
+
1
MS (EI ): m/z: 211 (M , 40), 196 ([M-CH
3
] , 100), 167 (M-COCH3-2H, 70). HNMR (300MHz,
s9

ACCEPTED MANUSCRIPT
CDCl
3
): δ 7.87 (d, J = 8.7 Hz, ArH, 2H), 7.40-7.30 (m, ArH, 2H), 7.24-7.16 (m, ArH, 2H),
7
3
.13-7.04 (m, ArH, 1H), 7.00 (d, J = 8.7 Hz, ArH, 2H), 6.18 (brs, 1H), 2.54 (s, COCH , 3H).
1
3
CNMR (75 MHz, CDCl
3
): δ 196.4, 148.5, 140.6, 130.6, 129.5, 128.8, 123.3, 120.6, 114.4, 26.3.
1
N-phenyl-4-(trifluoromethyl)aniline (1h)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:20) as eluent to afford N-phenyl-4-(trifluoromethyl)aniline (84 mg,
7
1%), white solid.
+
+
+
1
MS (EI ): m/z: 237 (M , 100), 167 ([M-CF
3
-H] , 50). HNMR (300MHz, CDCl
3
): δ 7.50 (d, J =
8
5
.3 Hz, ArH, 2H), 7.41-7.33 (m, ArH, 2H), 7.17 (d, J = 8.3 Hz, ArH, 2H), 7.13-7.03 (m, ArH, 3H),
.92 (brs, 1H).
1
3
CNMR (75 MHz, CDCl
3
): δ 146.9, 141.3, 129.7, 126.9, 126.9, 123.2, 121. 9 (q, J = 65.6 Hz),
1
20.3, 115.6.
3
4
-(phenylamino)benzonitrile (1i)
the crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:20) as eluent to afford 4-(phenylamino)benzonitrile (50 mg, 52%),
white solid.
+
+
1
MS (EI ): m/z: 194 (M , 100). HNMR (300MHz, CDCl
3
): δ 7.46 (d, J = 8.7 Hz, ArH, 2H),
7
.40-7.32 (m, ArH, 2H), 7.21-7.15 (m, ArH, 2H), 7.15-7.08 (m, ArH, 1H), 6.98 (d, J = 8.6 Hz,
1
3
3
ArH, 2H), 6.21 (brs, 1H). CNMR (75 MHz, CDCl ): δ 148.1, 140.0, 133.7, 129.6, 123.9, 121.2,
1
20.0, 114.9, 101.4.
1
4
-nitro-N-phenylaniline (1j)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:10) as eluent to afford 4-nitro-N-phenylaniline (60 mg, 56%), yellow
solid.
-
-
1
MS (ESI ): m/z: 213 ([M-H] ). HNMR (300MHz, CDCl
3
): δ 8.10 (d, J = 9.1 Hz, ArH, 2H),
7
.45-7.34 (m, ArH, 2H), 7.25-7.12 (m, ArH, 3H), 6.95 (d, J = 9.2 Hz, ArH, 2H), 6.49 (brs, 1H).
s10

ACCEPTED MANUSCRIPT
1
3
CNMR (75 MHz, CDCl
3
): δ 150.3, 139.6, 139.5, 129.7, 126.3, 124.6, 121.9, 113.7.
4
2
-methoxy-N-(4-methoxyphenyl)aniline (1k)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:20) as eluent to afford 2-methoxy-N-(4-methoxyphenyl)aniline (77 mg,
6
7%), colorless solid.
+
+
+
1
MS (EI ): m/z: 229 (M , 100), 214 ([M-CH
3
] , 75), 183 (M-CH
3
O-CH
3
, 50). HNMR (300MHz,
, 3H),
3 3
, 3H). CNMR (75 MHz, CDCl ): δ 155.4, 147.6, 135.2, 134.7, 122.9, 121.0, 119.1,
CDCl
.83 (s, OCH
14.6, 113.2, 110.4, 55.8, 55.7.
3 3
): δ 7.23-7.06 (m, ArH, 3H), 6.94-6.77 (m, ArH, 5H), 6.39 (brs, 1H), 3.92 (s, OCH
1
3
3
1
5
bis(4-methoxyphenyl)amine (1l)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:10) as eluent to afford bis(4-methoxyphenyl)amine (77 mg, 67%),
colorless solid.
+
+
+
1
MS (EI ): m/z: 229 (M , 55), 214 ([M-CH
3 3
] , 100). HNMR (300MHz, CDCl ): δ 6.97 (d, J = 8.5
1
3
Hz, ArH, 4H), 6.86 (d, J = 8.9 Hz, ArH, 4H), 5.17 (brs, 1H), 3.81 (s, OCH
3
, 6H). CNMR (75
MHz, CDCl
3
): δ 154.1, 137.8, 119.5, 114.7, 55.7.
1
N-benzylaniline (2a)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:40) as eluent to afford N-benzylaniline (70 mg, 76%), colorless oil.
+
+
+
+
1
MS (EI ): m/z: 183 (M , 90), 106 ([M-C
6 5 6 5 2
H ] , 20), 91 ([C H -CH ] , 100). HNMR (300MHz,
CDCl ): δ 7.47-7.28 (m, ArH, 5H), 7.27-7.18 (m, ArH, 2H), 6.82-6.73 (m, ArH, 1H), 6.73-6.65 (m,
3
13
ArH, 2H), 4.38 (s, CH
2
, 2H). CNMR (75 MHz, CDCl
3
): δ 148.1, 139.4, 129.3, 128.6, 127.5,
s11

ACCEPTED MANUSCRIPT
1
27.2, 117.7, 112.9, 48.5.
H
O
N
1
N-benzyl-4-methoxyaniline (2b)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:20) as eluent to afford N-benzyl-4-methoxyaniline (83 mg, 78%),
colorless solid.
+
+
+
1
MS (ESI ): m/z: 214 ([M+H] ), 246 ([M+H+MeOH] ). HNMR (300MHz, CDCl
3
): δ 7.47-7.28
m, ArH, 5H), 6.84 (d, J = 8.9 Hz, ArH, 2H), 6.66 (d, J = 8.9 Hz, ArH, 2H), 4.33 (s, CH , 2H),
): δ 152.1, 142.4, 139.7, 128.5,
(
2
13
3
3 3
.80 (s, OCH , 3H), 3.57 (brs, 1H). CNMR (75 MHz, CDCl
1
27.5, 127.1, 114.9, 114.1, 55.9, 49.3.
6
N-benzyl-2-methoxyaniline (2c)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:20) as eluent to afford N-benzyl-2-methoxyaniline (63 mg, 59%),
colorless oil.
+
+
+
+
1
MS (EI ): m/z: 213 (M , 100), 136 ([M-C
6 5 6 5 2
H ] , 35), 91 ([C H -CH ] , 100). HNMR (300MHz,
CDCl ): δ 7.45-7.28 (m, ArH, 5H), 7.17-7.09 (m, ArH, 1H), 6.37-6.28 (m, ArH, 2H), 6.27-6.23 (m,
3
13
ArH, 1H), 4.36 (s, CH
2 3 3
, 2H), 3.80 (s, OCH , 3H). CNMR (75 MHz, CDCl ): δ 160.8, 149.4,
1
39.3, 130.0, 128.6, 127.5, 127.2, 106.0, 102.8, 99.0, 55.2, 48.5.
H
N
O
5
N-benzyl-3-methoxyaniline (2d)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:20) as eluent to afford N-benzyl-3-methoxyaniline (81 mg, 76%),
colorless solid.
+
+
+
+
1
MS (EI ): m/z: 213(M , 100), 198 ([M-CH
3
] , 40), 91 ([C
6
H
5
-CH
2
] , 100). HNMR (300MHz,
s12

ACCEPTED MANUSCRIPT
CDCl
3
): δ 7.45-7.28 (m, ArH, 5H), 6.93-6.81 (m, ArH, 2H), 6.77-6.69 (m, ArH, 1H), 6.68-6.62 (m,
13
ArH, 1H), 4.41 (s, CH
2 3 3
, 2H), 3.90 (s, OCH , 3H). CNMR (75 MHz, CDCl ): δ 146.8, 139.6,
1
38.1, 128.6, 127.5, 127.1, 121.3, 116.7, 110.2, 109.5, 55.6, 48.2.
H
N
1
N-benzyl-4-methylaniline (2e)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:40) as eluent to afford N-benzyl-4-methylaniline (81 mg, 82%), white
solid.
+
+
+
1
MS (ESI ): m/z: 198 ([M+H] ), 230 ([M+H+MeOH] ). HNMR (300MHz, CDCl
3
): δ 7.45-7.27
m, ArH, 5H), 7.02 (d, J = 8.3 Hz, ArH, 2H), 6.59 (d, J = 8.2 Hz, ArH, 2H), 4.35 (s, CH , 2H),
): δ 145.9, 139.7, 129.7, 128.6, 127.5, 127.2, 126.8,
(
2
1
3
2
3 3
.29 (s, CH , 3H). CNMR (75 MHz, CDCl
113.1, 48.9, 20.6.
H
Cl
N
1
N-benzyl-4-chloroaniline (2f)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:20) as eluent to afford N-benzyl-4-chloroaniline (80 mg, 74%),
colorless solid.
+
+
+
1
MS (EI ): m/z: 217(M , 55), 91 ([C
6
H
5
-CH
2
] , 100). HNMR (300MHz, CDCl
3
): δ 7.39-7.27 (m,
, 2H), 4.20
ArH, 5H), 7.13 (d, J = 8.5 Hz, ArH, 2H), 6.57 (d, J = 8.7 Hz, ArH, 2H), 4.33 (s, CH
2
13
(
brs, 1H). CNMR (75 MHz, CDCl
3
): δ 146.5, 138.9, 129.1, 128.7, 127.5, 122.2, 114.0, 48.6
1
1
-(4-(benzylamino)phenyl)ethanone (2g)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:10) as eluent to afford 1-(4-(benzylamino)phenyl)ethanone (85 mg,
7
6%), yellow solid.
s13

ACCEPTED MANUSCRIPT
+
+
+
+
1
MS (EI ): m/z: 225(M , 45), 210 ([M-CH
3
] , 65), 91 ([C
6
H
5
-CH
2
] , 100). HNMR (300MHz,
CDCl ): δ 7.82 (d, J = 8.6 Hz, ArH, 2H), 7.41-7.27 (m, ArH, 5H), 6.60 (d, J = 8.6 Hz, ArH, 2H),
3
1
3
4
1
2 3 3
.75 ((brs, 1H), 4.41 (s, CH , 2H), 2.50 (s, CH , 3H). CNMR (75 MHz, CDCl ): δ 196.2, 151.9,
38.2, 130.8, 128.8, 127.5, 127.3, 126.9, 111.6, 47.7, 26.2.
H
NC
N
6
4
-(benzylamino)benzonitrile (2h)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:20) as eluent to afford 4-(benzylamino)benzonitrile (46 mg, 44%),
white solid.
+
+
+
1
MS (EI ): m/z: 213(M , 55), 91 ([C
6 5 2 3
H -CH ] , 100). HNMR (300MHz, CDCl ): δ 7.41 (d, J = 8.6
Hz, ArH, 2H), 7.39-7.27 (m, ArH, 5H), 6.60 (d, J = 8.6 Hz, ArH, 2H), 4.77 (brs, 1H), 4.39 (s, CH
2
,
13
2
4
H). CNMR (75 MHz, CDCl
3
): δ 151.1, 137.8, 133.7, 128.8, 127.6, 127.3, 120.4, 112.4, 98.9,
7.6.
.
1
N-benzyl-4-nitroaniline (2i)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:20) as eluent to afford N-benzyl-4-nitroaniline (53 mg, 46%), yellow
solid.
-
-
-
1
MS (ESI ): m/z: 227 ([M-H] ), 263 ([M+Cl] ). HNMR (300MHz, CDCl
3
): δ 8.21-7.98 (m, ArH,
1
3
2
H), 7.54-7.28 (m, ArH, 5H), 6.70-6.49 (m, ArH, 2H), 4.98 (brs, 1H), 4.44 (s, CH , 2H). CNMR
2
(
75 MHz, CDCl
3
): δ 153.1, 138.3, 137.4, 129.0, 127.9, 127.4, 126.4, 111.3, 47.8.
7
N-butylaniline (3a)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:40) as eluent to afford 4-methoxy-N- phenylaniline (45 mg, 60%,
s14

ACCEPTED MANUSCRIPT
prepared by bromobenzene and butan-1-amine; 60 mg, 80%, prepared by 1-bromobutane and
aniline.), colorless oil.
+
+
+
1
MS (EI ): m/z: 149 (M , 15), 106 ([M-C
ArH, 2H), 6.74-6.66 (m, ArH, 1H), 6.65-6.56 (m, ArH, 2H), 3.13 (t, J = 7.0 Hz, CH
H), 1.69-1.57 (m, CH CH CH CH , 2H), 1.52-1.39 (m, CH CH CH CH , 2H), 0.98 (t, J = 7.3
): δ 148.5, 129.3, 117.2, 112.8, 43.9, 31.9,
H
3 7
] , 100). HNMR (300MHz, CDCl
3
): δ 7.23-7.12 (m,
2
CH CH CH
2
2
3
,
2
2
2
2
3
2
2
2
3
1
3
Hz, CH
2
CH
2
CH
2
CH
3
, 3H). CNMR (75 MHz, CDCl
3
2
0.6, 14.2.
1
N-butyl-4-methoxyaniline (3b)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:20) as eluent to afford 4-methoxy-N- phenylaniline (64 mg, 72%),
colorless solid.
+
+
+
1
MS (EI ): m/z: 179 (M , 45), 136 ([M-C
Hz, ArH, 2H), 6.60 (d, J = 8.9 Hz, ArH, 2H), 3.76 (s, OCH
Hz, CH CH CH CH , 2H), 1.67-1.56 (m, CH CH CH CH , 2H), 1.52-1.38 (m, CH
H), 0.98 (t, J = 7.2 Hz, CH CH CH CH , 3H). CNMR (75 MHz, CDCl ): δ 152.0, 142.8, 115.0,
14.2, 56.0, 45.0, 32.0, 20.6, 14.2.
3
H
7
] , 100). HNMR (300MHz, CDCl
, 3H), 3.22 (brs, 1H), 3.09 (t, J = 7.2
3
CH CH CH ,
3
): δ 6.79 (d, J = 8.9
3
2
2
2
3
2
2
2
3
2
2
2
13
2
2
2
2
3
3
1
NH
O
7
N-butyl-2-methoxyaniline (3c)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:40) as eluent to afford N-butyl-2-methoxyaniline (55 mg, 61%),
colorless oil.
+
+
+
1
MS (EI ): m/z: 179 (M , 45), 136 ([M-C
H
3 7
] , 100). HNMR (300MHz, CDCl
3
): δ 6.97-6.88 (m,
, 3H),
2 3
CH CH , 2H), 1.59-1.44 (m,
ArH, 1H), 6.84-6.78 (m, ArH, 1H), 6.74-6.61 (m, ArH, 2H), 4.21 (brs, 1H), 3.89 (s, OCH
3
3
.18 (t, J = 7.0 Hz, CH
2
CH
2
CH
2
CH
3
, 2H), 1.79-1.64 (m, CH
2
CH
2
13
CH CH CH CH , 2H), 1.03 (t, J = 7.3 Hz, CH
2
2
2
3
2
CH CH CH
2
2
3
, 3H). CNMR (75 MHz, CDCl
3
): δ
s15

ACCEPTED MANUSCRIPT
1
46.7, 138.5, 121.3, 116.1, 109.8, 109.4, 55.5, 43.6, 31.9, 20.6, 14.2.
NH
O
7
N-butyl-3-methoxyaniline (3d)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:40) as eluent to afford N-butyl-3-methoxyaniline (56 mg, 63%),
colorless oil.
+
+
+
1
MS (EI ): m/z: 179 (M , 45), 136 ([M-C
H
3 7
] , 100). HNMR (300MHz, CDCl
, 3H), 3.57 (brs, 1H),
, 2H), 1.54-1.40 (m,
): δ
3
): δ 7.15-7.06 (m,
ArH, 1H), 6.32-6.23 (m, ArH, 2H), 6.23-6.18 (m, ArH, 1H), 3.81 (s, OCH
3
3
.13 (t, J = 7.2 Hz, CH
2
CH
2
CH
2
CH
3
, 2H), 1.70-1.58 (m, CH
2
CH
2
2 3
CH CH
1
3
CH CH CH CH , 2H), 1.00 (t, J = 7.3 Hz, CH
2
2
2
3
2
CH CH CH
2
2
3
, 3H). CNMR (75 MHz, CDCl
3
1
60.8, 149.9, 129.9, 106.0, 102.2, 98.7, 55.2, 43.8, 31.8, 20.5, 14.1.
8
1
-(4-(butylamino)phenyl)ethanone (3e)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:20) as eluent to afford 4-methoxy-N- phenylaniline (69 mg, 72%),
colorless solid.
+
+
+
1
MS (EI ): m/z: 191 (M , 30), 148 ([M-C
3 7 3
H ] , 100). HNMR (300MHz, CDCl ): δ 7.81 (d, J = 8.9
Hz, ArH, 2H), 6.55 (d, J = 8.8 Hz, ArH, 2H), 4.38 (brs, 1H), 3.18 (t, J = 7.1 Hz, CH
2
CH
2
CH
2
CH
3
,
,
2
2
1
H), 2.49 (s, COCH
3
, 3H), 1.70-1.56 (m, CH
2
CH
2
CH
2
CH
3
, 2H), 1.52-1.36 (m, CH
2
CH
2
CH
2
CH
3
13
H), 0.97 (t, J = 7.3 Hz, CH
2
CH CH CH , 3H). CNMR (75 MHz, CDCl
2
2
3
3
): δ 196.2, 152.2, 130.8,
26.6, 111.4, 43.3, 31.5, 26.2, 20.4, 14.1.
7
N-butyl-4-nitroaniline (3f)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:20) as eluent to afford N-butyl-4-nitroaniline (50 mg, 51%), yellow
s16

ACCEPTED MANUSCRIPT
solid.
MS (EI ): m/z: 194 (M , 25), 151 ([M-C
CDCl
.1 Hz, CH
CH CH CH CH
+
+
+
1
H
3 7
] , 100), 105 (M-C
3
H
7
-NO
2
, 30). HNMR (300MHz,
3
): δ 8.07 (d, J = 9.1 Hz, ArH, 2H), 6.51 (d, J = 9.1 Hz, ArH, 2H), 4.57 (brs, 1H), 3.22 (t, J =
7
2
CH
2
2
CH CH
3
, 2H), 1.73-1.58 (m, CH
2
CH
2
CH
2
CH
3
, 2H), 1.53-1.36 (m,
): δ
13
2
2
2
3
, 2H), 0.99 (t, J = 7.3 Hz, CH
2
CH CH CH
2
2
3
, 3H). CNMR (75 MHz, CDCl
3
1
53.5, 137.7, 126.5, 111.0, 43.3, 31.3, 20.4, 14.0.
9
N-cyclohexylaniline (3g)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:40) as eluent to afford N-cyclohexylaniline (64 mg, 73%), colorless oil.
+
+
1
MS (ESI ): m/z: 176 ([M+H] ). HNMR (300MHz, CDCl
3
): δ 7.24-7.11 (m, ArH, 2H), 6.74-6.66
m, ArH, 1H), 6.65-6.57 (m, ArH, 2H), 3.54 (brs, 1H), 3.35-3.24 (m, CH(CH 1H), 2.16-2.12 (m,
): δ 147.4, 129.3, 116.9, 113.2, 51.9, 33.7, 26.2, 25.2.
(
2 5
)
1
3
CH(CH
2
)
5
, 10H). CNMR (75 MHz, CDCl
3
1
N-cyclohexyl-4-methoxyaniline (3h)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:40) as eluent to afford N-cyclohexyl-4-methoxyaniline (78 mg, 76%),
white solid.
+
+
1
MS (ESI ): m/z: 206 ([M+H] ). HNMR (300MHz, CDCl
3
): δ 6.78 (d, J = 8.7 Hz, ArH, 2H), 6.59
, 3H), 3.26-3.06 (m, CH(CH and brs, 2H), 2.14-1.07 (m,
): δ 151.9, 141.5, 114.9, 56.0, 53.0, 33.8, 26.2, 25.3.
(
d, J = 8.6 Hz, ArH, 2H), 3.76 (s, OCH
3
2 5
)
1
3
CH(CH
2
)
5
, 10H). CNMR (75 MHz, CDCl
3
9
N-cyclohexyl-2-methoxyaniline (3i)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:40) as eluent to afford N-cyclohexyl-2-methoxyaniline (65 mg, 63%),
colorless oil.
+
+
1
MS (ESI ): m/z: 206 ([M+H] ). HNMR (300MHz, CDCl
3
): δ 6.92-6.84 (m, ArH, 1H), 6.82-6.77
s17

ACCEPTED MANUSCRIPT
(
m, ArH, 1H), 6.70-6.63 (m, ArH, 2H), 4.22 (brs, 1H), 3.87 (s, OCH
3
, 3H), 3.36-3.24 (m,
13
CH(CH
2
)
5
, 1H), 2.16-1.22 (m, CH(CH
2
)
5
, 10H). CNMR (75 MHz, CDCl
3
): δ 146.7, 137.2, 121.3,
115.9, 110.4, 109.6, 55.5, 51.6, 33.6, 26.2, 25.3.
9
N-cyclohexyl-3-methoxyaniline (3j)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:40) as eluent to afford N-cyclohexyl-3-methoxyaniline (145 mg, 73%),
colorless solid.
+
+
1
MS (ESI ): m/z: 206 ([M+H] ). HNMR (300MHz, CDCl
3
): δ 7.15-6.99 (m, ArH, 1H), 6.29-6.20
, 3H), 3.55 (brs, 1H), 3.33-3.21 (m,
, 10H). CNMR (75 MHz, CDCl ): δ 160.8, 148.7, 129.9,
(
m, ArH, 2H), 6.19-6.16 (m, ArH, 1H), 3.79 (s, OCH
3
13
CH(CH
2
)
5
, 1H), 2.17-1.10 (m, CH(CH
2
)
5
3
1
1
06.4, 101.8, 99.2, 55.2, 51.9, 33.7, 26.1, 25.2.
9
-(4-(cyclohexylamino)phenyl)ethanone (3k)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:40) as eluent to afford 1-(4-(cyclohexylamino)phenyl)ethanone (79 mg,
7
3%), white solid.
+
+
+
1
MS (EI ): m/z: 217 (M , 35), 174 ([M-C
H
3 7
] , 100). HNMR (300MHz, CDCl
3
): δ 7.79 (d, J = 8.8
1H), 2.49 (s,
): δ 196.2, 151.4, 131.1,
2 5
Hz, ArH, 2H), 6.52 (d, J = 8.8 Hz, ArH, 2H), 4.23 (brs, 1H), 3.41-3.26 (m, CH(CH )
1
3
COCH
3
, 3H), 2.12-1.14 (m, CH(CH
2
)
5
, 10H). CNMR (75 MHz, CDCl
3
1
26.4, 111.8, 51.6, 33.5, 26.3, 26.1, 25.2.
10
N-cyclohexyl-4-nitroaniline (3l)
The crude product was purified by column chromatography on silica gel using ethyl
acetate/petroleum ether (1:10) as eluent to afford N-cyclohexyl-4-nitroaniline (61 mg, 55%),
yellow solid.
+
+
+
1
MS (EI ): m/z: 220 (M , 15), 177 ([M-C
H
3 7
] , 100). HNMR (300MHz, CDCl
3
): δ 8.06 (d, J = 9.2
s18