Ligand free open air copper(II) mediated aryl formamidation and amination of aryl halides

Article abstract of DOI:10.1016/j.tetlet.2014.01.046

A simple synthetic procedure for direct formamidation and amination of aryl halides mediated by copper(II) salts was developed in open air, without an external ligand in formamide with potassium carbonate as a base. This approach is particularly efficient when electron active aryl halides are used as substrates. In these cases almost quantitative formamidation was observed.

Full text of DOI:10.1016/j.tetlet.2014.01.046

Accepted Manuscript
Ligand Free Open Air Copper (II) Mediated Aryl Formamidation and Amination
of Aryl Halides
Rajesh Komati, Branko S. Jursic
PII:
S0040-4039(14)00079-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.01.046
TETL 44078
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
24 October 2013
24 December 2013
14 January 2014
Please cite this article as: Komati, R., Jursic, B.S., Ligand Free Open Air Copper (II) Mediated Aryl Formamidation
and Amination of Aryl Halides, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.01.046
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Revised Ms. Ref. No. TETL-D-13-02657
Ligand Free Open Air Copper (II) Mediated Aryl Formamidation and
Amination of Aryl Halides
Rajesh Komati and Branko S. Jursic
Department of Chemistry, University of New Orleans, New Orleans, LA 70148 and
Stepharm LLC, P.O. Box 24220, New Orleans, LA 70119

Revised Ms. Ref. No. TETL-D-13-02657
Ligand Free Open Air Copper (II) Mediated Aryl Formamidation and
Amination of Aryl Halides
Rajesh Komati and Branko S. Jursic*
Department of Chemistry, University of New Orleans, New Orleans, LA 70148 and
Stepharm LLC, P.O. Box 24220, New Orleans, LA 70119.
Corresponding author: Tel: 504-858-0515, Tax: 504-280-7090, e-mail: bjursic1@uno.edu
Abstract
A simple synthetic procedure for direct formamidation and amination of aryl halides
mediated by copper (II) salts was developed in open air, without an external ligand in
formamide with potassium carbonate as a base. This approach is particularly efficient
when electron active aryl halides are used as substrates. In these cases almost
quantitative formamidation was observed.
Research highlights
Direct foramidation procedure of electron rich aromatic halides was developed.
Aryl amination was performed on open air without copper ligand.
Economical approach to aryl C-N bond formation.
Copper (II) sulfate mediated reactions.
Keywords
Copper coupling, anilines, aryl formamidation, aryl amination, aryl dimethylamination,
aryl halides, copper (II) mediated C-N bond formation, formyl anilines.

Introduction
Metal catalyzed coupling reactions between aryl halides and amides have been
recognized for years for their application in academia and pharmaceutical industries.
These reactions attract significant attention due to fact that many biologically active
1
compounds possess aryl-nitrogen bond. In fact over 90% of commercially available
2
drugs have at least one nitrogen in their structure. In the past, several research groups
reported the Pd catalyzed formation of C-N bond by coupling aromatic halides with
3
4,
5
amines, amides and imides . Recently the Zhang group reported Pd catalyzed
amidation of aryl halides using 2-dialkylphosphino-2’-alkoxy-1,1’-binaphthyl as ligand.
Besides of high cost of external ligands, it is also difficult to scale-up Pd catalyzed
amination reactions. It is important to mention that removing Pd residues from the
reaction media requires special methods, which increase its cost.
6
Copper catalyzed coupling has emerged as a very good alternate because it is easy to
handle, cost less, and most importantly it is safer. In recent years several research groups
7
reported their work on this area mostly by using external ligands such as α-amino acids,
8
9
10
bis- pyridylimines, 1,2-diamines, 1,10-phenanthroline, and 1,3- diketones.
11
However, because the use of Cu (I) and external ligands, these methods are also
expensive. There are also some reports regarding the copper catalyzed formamidation of
1
2
arylboronic acids. Therefore, it is of paramount interest for both the academic and
industrial community to develop simple, safe, and economical methods for preparation
aniline and aryl formamide derivatives from readily available and inexpensive aryl
halides. The most economical approach to aryl coupling reactions is to use extremely
1
3
inexpensive copper (II) sulfate as source of the coupling catalyst.
Results and Discussion
Here we report a simple, efficient, ligand free, and inexpensive method for direct aryl
formamidation and amination of readily available aryl halides. The reaction was
performed by heating a formamide suspension of corresponding aryl halide, copper (II)
sulfate pentahydrate and potassium carbonate at 150-160°C for few hours on open air
(
Figure 1). The product was isolated by extraction of water diluted reaction mixture with

dichloromethane followed by flash chromatography. Isolated yields are almost
quantitative (Table 1).
Figure 1. Reaction outcomes of copper (II) mediated aryl formamidation and amination
The coupling reaction proceeds easily with aryl chlorides, bromides, and iodides.
However the ideal substrates are aryl bromides because aryl chlorides are generally less
reactive resulting in longer reaction time and lower conversion, while aryl iodides are
more reactive resulting in formation of undesired byproducts. This makes the
purification process difficult and isolated yields lower. Regardless of the nature of the
aryl substituents, the first step of the reaction is always formamidation (path (a) products
2
a-2g, Figure 1). However with electron-withdrawing substituents formed aryl
formamides (2d, 2e, and 2f) are too reactive and they easily hydrolyzed under the same
reaction conditions. Consequently only products (3d, 3e, and 3f) of direct amination
were isolated (Table 1). On the other hand isolated formamidation products with aryl
electron-donating groups were easily hydrolyzed with sodium hydroxide in aqueous
ethanol to produce corresponding anilines. In this way, aryl amination product can be
prepared in the presence of either electron-donating or electron-withdrawing groups.

Table 1. Isolated yields of formamidation and/or amination of aryl halides
Entry Aryl Halide
Formamide
Yield 2(%) Aniline
Yield 3 (%)
Cl
97a
1
93
1
aCl
2
3
95
96
98a
4
93
96a
97a
5
6
90
96
56b
40b
8
9
trace
trace
40b
1
0
trace
a
b
Prepared in two steps: formamidation followed by NaOH hydrolysis. Isolated directly
from formamidation without NaOH hydrolysis.

Scheme 1. Proposed mechanism for copper (II) mediated N-formylation and amination
of aryl halides
1
In nature, the reaction is transition metal catalyzed aryl coupling between aryl halides
4
and nitrogen nucleophiles such as NHCHO anion. We propose that the active coupling
1
reagent is a short-live copper (III) complex with aryl and nuclephilic nitrogen moieties
5
(
Scheme 1). During the reaction, the color of the reaction changes from a clear green
solution, to dark blue and finally to dark red suspension. If the formamide suspension of
copper (II) sulfate and potassium carbonate is heated at 160°C for few hours, it forms a
1
6
red precipitate of Cu
left stirring overnight in open air, the colorless solution above the precipitate gradually
becomes green (soluble copper II) and eventually all the precipitate (Cu O) dissolves to
2
O that can be separated by filtration. If the dark red suspension is
2
form a solution with the original color of copper (II). On the basis of these observations
we are proposing copper catalytic cycle for formamidation of aryl halides as outlined in
Scheme 1.
Formamidation with N,N-dimethylformamide cannot be done because formamide
nucleophile cannot be formed during copper (II) mediated reaction. Therefore it does not
come as surprise that there was no reaction with aryl halides that possess electron
donating substituents. However in the reaction with aryl halides that possess electron
withdrawing substituents, corresponding dimethylamination products were isolated
(
Figure 2, Table 2).

Figure 2. Dimethylamination of electron deficient aryl halides
Table 2. Copper (II) mediated dimethylamination of electron-deficient aryl halides
Entry
Aryl Halide
Product
Yield (%)
Cl
NO2
1
95
1d
NO2
2
96
2
In the course of the reaction, red Cu O precipitate was formed as in the case of the
reaction with formamide (Scheme 1). Considering that reaction conditions for both
formamide and DMF are identical, we proposed a similar catalytic mechanism for copper
(
II) reduction to copper (I) to generate copper (I) dimethylamide (Scheme 2). In the case
of DMF it is not possible to form more stable copper (I) salt as it is the case with
formamide (Scheme 1, CuNHCHO). Therefore CuN(CH reacts as nucleophile in the
Ar), which is feasible for electron deficient
3 2
)
1
7
classic nuclephilic aromatic substitution (S
aryl halides in our case.
N

Scheme 2. Proposed copper (II) mediated dimethylamination of electron deficient aryl
halides
Up to now, the results with copper (II) sulfate pentahydrate as the coupling mediator
have been reported. However, reactions with copper(II) chloride dihydrate, copper(II)
acetate monohydrate as well as with copper(II) oxide were performed. There is no
noticeable difference in reaction time or isolated yield of the product. Since copper (II)
sulfate pentahydrate is broadly available and affordable, only the results with this salt
were reported here. It is therefore a reasonable assumption that any copper (II) salt with
reasonable formamide solubility will be a good mediator of formamidation for electron
rich aromatic halides.
Initially, spectroscopic analysis shows formamide products with two sets of signal in
1 13
both their H-NMR as well as C-NMRs in ratio of ~3:1 (Figure 3). Considering the
hydrogen coupling constant of the formamide group (HNCHO), the major isomer is cis (J
=
1.6 Hz) with trans (J = 10.8 Hz) only around 30%. To our surprise, the ratio of the
isomers did not change even when the DMSO-d solution was refluxed for five minutes.
Similar findings were reported in literature. It was estimated that the rotational energy
6
18
1
barrier around the C-N formamide bond is around 17 kcal/mol. In fact, it was reported
9
2
0
that N-phenylformamide forms co-crystal with its two isomers.

6
Figure 3. Part of hydrogen NMR spectra of 2b in DMSO-d at room temperature.
In conclusion, we have developed a simple and economical copper (II) mediated
2
1
22
method for formamidation and consequent amination of electron rich aryl halides.
For electron deficient aryl halides modest yield of direct amination were reported.
However electron deficient aryl halides are ideal substrates for copper (II) mediated aryl
dimethylamination.
REFERENCES
1
.
(a) Masse, C. E.; Yang, M.; Solomon, J.; Panek, J. S. “ Total Synthesis of (+)-
Mycotrienol and (+)-Mycotrienin I; Application of Asymmetric Crotylsilane Bond
Constructions” J. Am. Chem. Soc. 1998, 120, 4123-4134. (b) Evano, G.; Schaus, J.
V.; Panek, J. S. “A Convergent Synthesis of the Macrocyclic Core of Cytotrienins:
“Application of RCM for Macrocyclization” Org. Lett. 2004, 6, 525-528. (c) Evano,
G.; Blanchard, N.; Toumi, M. “Copper-Mediated Coupling Reactions and Their
Applications in Natural Products and Designed Biomolecules Synthesis” Chem.
Rev. 2008, 108, 3054-3131. (d) Satyanarayana, K.; Srinivivas, K.; Himabindu, V.;
Reddy, G. M. “A Scaleable Synthesis of Dutasteride: A Selective 5α-Reductase
Inhibitor” Org. Process Res. Dev. 2007, 11, 842-845. (e) Sadig, J. E. R.; Willis, M.
C. ‘‘Palladium-and Copper-Catalyzed Aryl Halide Amination, Etherification and
Thioetherification Reactions in the Synthesis of Aromatic Heterocycles’’Synthesis
2
011, 1-22. (f) Hickman, A. J.; Sanford, M. S. ‘‘High- Valent Organo Metallic

Copper and Palladium in Catalysis’’ Nature, 2012, 484, 177-185. (g) Aubin, Y.;
Fischmeister, C.; Thomas, C. M.; Renaud, J. L. “Direct amination of aryl halides
with ammonia” Chem. Soc. Rev, 2010, 39, 4130-4145.
2
.
(a) Dua, R.; Shrivastava, S.; Sonwane, S. K.; Srivastava, S. K. “Pharmacological
Significance of Synthetic Heterocycles Scaffold; A Review” Advan. Biol. Res.
2
011, 5, 120-144. (b) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T.
Analysis of the reactions used for the preparation of drug candidate molecules”
Org. Bio. Chem. 2006, 4, 2337-2347. (c) Cao, C.; Lu, Z.; Cai, Z.; Pang, G.; Shi, Y.
Cheap Cu(I)/Hexamethylenetetramine (HMTA) Catalytic System for C-N
“
“
Coupling Reactions” Synth. Comm. 2012, 42, 279-284. (d) Evano, G.; Blanchard,
N.; Toumi, M. “Copper-Mediated Coupling Reactions and Their Applications in
Natural Products and Designed Biomolecules Synthesis” Chem. Rev. 2008, 108,
3
054-3131.
(a) Maiti, D.; Fors, P. B.; Henderson, L. J.; Nakamura, Y.; Buchwald, S. L.
Palladium-catalyzed coupling of functionalized primary and secondary amines
with aryl and heteroaryl halides: two ligands suffice in most cases” Chem. Sci.
011, 2, 57-68, (b) Gooben, L. J.; Paetzold, J.; Briel, O.; Rivas-Nass, A.; Karch, R.;
3
.
“
2
Kayser, B. “Buchwald-Hartwig Aminations of Aryl Chlorides: A Practical Protocol
Based on Commercially Available Pd(0)-NHC Catalysts” Synlett. 2005, 275–278.
(a) Jiang, L.; Buchwald, S. L. In Metal-Catalyzed Cross-Coupling Reactions; De
Meijere, A., Diederich, F. Eds.; Wiley-VCH: Weinheim, 2004; Vol. 2, p 699. (b)
Hartwig, J. F. In Modern Amination Methods; Ricci, A., Ed.; Wiley-VCH:
Weinheim, Germany, 2000.
4
.
5
6
.
.
Tye,W.J.; Weng, Z.; Johns, M. A.; Incarvito, D. C.; Hartwig, F. J. “Copper
Complexes of Anionic Nitrogen Ligands in the Amidation and Imidation of Aryl
Halides” J. Am. Chem. Soc. 2008, 130, 9971-9983.
Ma, F.; Xie, X.; Zhang, L.; Peng, Z.; Ding, L.; Fu, L.; Zhang, Z.
“Palladium-Catalyzed Amidation of Aryl Halides Using 2-Dialkylphosphino-2′-
alkoxyl-1,1′-binaphthyl as Ligands” J. Org. Chem. 2012, 77, 5279-5285.
7
.
Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. “Accelerating Effect Induced by the
Structure of α-Amino Acid in the Copper-Catalyzed Coupling Reaction of Aryl
Halides with α-Amino Acids. Synthesis of Benzolactam-V8” J. Am. Chem. Soc.

1
998, 120, 12459-12467.
8
9
.
.
Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. “Highly Efficient and
Mild Copper-Catalyzed N- and C-Arylations with Aryl Bromides and Iodides”
Chem.- Eur. J. 2004, 10, 5607-5622.
(a) Klapars, A.; Huang, X.; Buchwald, S. L. “A General and Efficient Copper
Catalyst for the Amidation of Aryl Halides” J. Am. Chem. Soc. 2002, 124, 7421-
7
428. (b) Antilla, J. C.; Klapars, A.; Buchwald, S. L. “The Copper-Catalyzed N-
Arylation of Indoles” J. Am. Chem. Soc. 2002, 124, 11684-11688.
1
0. (a) Gujadhur, R.; Venkataraman, D.; Kintigh, J. T. “Formation of aryl nitrogen
bonds using a soluble copper(I) catalyst” Tetrahedron Lett. 2001, 42, 4791-4793.
(
b) Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. “Formation of Aryl−Nitrogen,
Aryl−Oxygen, and Aryl−Carbon Bonds Using Well-Defined Copper(I)-Based
Catalysts” Org. Lett. 2001, 3, 4315-4317 (c) Goodbrand, H. B.; Hu, N. X. “Ligand-
Accelerated Catalysis of the Ullmann Condensation: Application to Hole
Conducting Triarylamines” J. Org. Chem. 1999, 64, 670-674.
1
1. (a) Shafir, A.; Buchwald, S. L. “Highly Selective Room-Temperature Copper-
Catalyzed C−N Coupling Reactions” J. Am. Chem. Soc. 2006, 128, 8742-8743. (b)
de Lange, B.; Lambers-Verstappen, M. H.; Schmieder-van de Vondervoort, L.;
Sereinig, N.; De Rijk, R.; De Vries, A. H. M.; De Vries, J. G. “Aromatic Amination
of Aryl Bromides Catalysed by Copper/β-Diketone Catalysts: The Effect of
Concentration” Synlett 2006, 3105-3109.
1
1
2. Sribastava, V. P.; Yadav, D. K.; Yadav, A. K.; Watal, G.; Yadav, L. D. S. “Copper-
Catalyzed Formamidation of Arylboronic Acids: Direct Access to Formanilides”
Synlett 2013, 24, 1423-1427.
3. Results that are obtained with 98% copper (II) sulfate pentahydrate purchased from
Aldrich are also reproduced with 99% copper (II) sulfate pentahydrate from Alpha
4 2
Chemicals. Current Aldrich price for 100g of SuSO x5H O is $30.00 whereas 10
pounds 99% CuSO x5H O from Alpha Chemicals is only $24.
4
2
1
1
4. de Meijere, A.; Bräse, S. Oestreich, M. (Eds) “Metal Catalyzed Cross-Coupling
Reactions and More” three volume sets, Wiley-VCH, New York, 2014.
5. Hickman, A. J.; Sanford, M. S. “High-Valent Organometallic Copper and
Palladium in Catalysis” Nature 2012, 484, 177-185.

1
6. Red precipitate was separated by filtration, washed with water and dried on air. It
dissolves in concentrated hydrochloric acid and brown color of the solution quickly
changes into green (copper II).
1
1
7. Terrier, F. “Modern Nucleophilic Aromatic Substitution” Wiley-VCH Verlag,
Weinheim, Germany, 2013.
8. (a) Quintanilla-Licea, R.; Colunga-Valladares, J. F.; Caballero-Quintero, A.;
Rodriguez-Padilla, C.; Tamez-Guerra, R.; Gomez-Flores, R.; Waksman, N. “NMR
detection of isomers arising from restricted rotation of the C-N amide bond of N-
formyl-o-toluidine and N,N’-bisformyl-o-tolidine” Molecules 2002, 7, 662-673. (b)
Rao, S. N.; Mohan, D. C.; Adimurthy, S. “L-Priline: an efficient catalyst for
transformation of carboxamides with amines” Org. Lett. 2013, 15, 1496-1499.
1
9. Taha, A. T.; True, N. S. “Experimental H NMR and computational atudies of
1
2
2
internal rotation od solvated formamide” J. Phys. Chem. A 2000, 104, 2985-2993.
0. Omondi, B.; Fernandes, M. A.; Layh, M.; Levendis. D. C. Acta Cryst. 2008, C64,
o137-o138.
1
General Procedure for formamidation of electron-rich aryl halides and
dimethylamination of electron-deficient aryl halides. Preparation of N-p-
tolylformamide (2d). Formamide (10 ml) suspension of 4-bromotoluene (1d) (342
mg, 2 mmol), potassium carbonate ( 690 mg, 5mmol), and copper (II) sulfate
pentahydrate (600 mg; 2.4 mmol) was heated with magnetic stirring at 160°C for
2
.5 hours. After cooling reaction mixture was mixed with ice cold water (50 ml)
and extracted with dichloromethane (3x20 ml). Combined organic layers were
dried over anhydrous sodium sulfate and evaporated to give crude product. This
product was further purified by silica gel column chromatography with hexane-
1
ethyl acetate (4:1) as an eluent. Isolated 360 mg (96%) of pure product. H-NMR
(
DMSO-d
CHO), 7.45 (2H, d, J = 8.0 Hz, o-H), 7.09 (2H, d, J =8.0 Hz, m-H), and 2.22 (3H, s,
CH ). (trans isomer) 10.03 (1H, d, J = 10.8 Hz, NH), 8.69 (1H, d, J = 10. 8 Hz,
CHO), 7.09 (2H, d, o-H), 7.05 (2H, d, J =8.4 Hz), and, 2.22 (3H, s, CH
NMR (DMSO-d ) δ (cis isomer) 160.0, 136.5. 133.2, 129.9, 119.8, and 21.1. (trans
isomer) 163.2, 136.5, 133.4, 130.5, 118.4, and 21.0 ppm.
6
) δ (cis isomer) 10.97 (1H, broad singlet NH), 8. (1H, d, J = 1.6 Hz),
3
1
3
3
) ppm. C-
6

2
2. General procedure for hydrolysis of aryl formamides. Preparation of aniline (3a).
Into ethanol (10 ml) solution of N-phenylformamide (2b) (120 mg; 1 mmol)
aqueous (2 ml) sodium hydroxide (40 mg; 1 mmol) was added. Resulting
solution was refluxed for one hour. Volume of the solvent was reduced (2 ml)
and extracted with dichloromethane (3x5 ml). Combined organic extracts
were dried over anhydrous sodium sulfate and evaporate to give pure aniline
(90mg; 97%).

Table 1. Isolated yields of formamidation and/or amination of aryl halides
Entry Aryl Halide
1
Formamide
Yield 2(%) Aniline
Yield 3 (%)
97a
93
2
95
96
Br
98a
3
1bBr
4
93
NH2
96a
97a
5
6
90
O
3c
96
56b
40b
40b
8
9
trace
NH2
NO2
3d
NO2
trace
NHCHO
1
0
trace
2f
CN

Table 2. Copper (II) mediated dimethylamination of electron-deficient aryl halides
Entry
Aryl Halide
Product
Yield (%)
Cl
NO2
1
95
1d
NO2
2
96

Revised Ms. Ref. No. TETL-D-13-02657
Ligand Free Open Air Copper (II) Mediated Aryl Formamidation and
Amination of Aryl Halides
Rajesh Komati and Branko S. Jursic
Department of Chemistry, University of New Orleans, New Orleans, LA 70148 and
Stepharm LLC, P.O. Box 24220, New Orleans, LA 70119